Clinical trial NCT06181227
Conditions: Diabetic Macular Edema Diabetic Retinopathy
Sponsor: Aviceda Therapeutics, Inc.
Start date: 2023-11-30; Completion date: 2024-04-05
Enrollment: 21 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 2 study to determine the safety and preliminary efficacy of intravitreal injections of AVD-104, a novel glyco-mimetic nanoparticle, in reducing macular edema associated with diabetic retinopathy.

Detailed description:
The primary objective is to evaluate the tolerability and treatment effect of intravitreal injections (IVT) of AVD-104 in participants with diabetic macular edema (DME). Participants will receive either three intravitreal injections of low-dose AVD-104 (1.0 mg) each 28 days apart or two intravitreal injections of AVD-104 at a high-dose (2.0 mg) 56 days apart. Serial optical coherence tomography (OCT), ultra wide-field fluorescein angiography, and OCT-angiography (OCT-A) will be performed to evaluate the treatment effect on central subfield thickness (CST) and areas of non-perfusion. All participants will be followed-up for safety until day 84.

There will be a planned enrollment up to 30 participants.

Arms: arm 1: Three intravitreal injections at 1.0 milligram per eye each 28 days apart will be administered to the study eye. Participants will be followed for 84 days total. arm 2: Two intravitreal injections at 2.0 milligrams per eye 56 days apart will be administered to the study eye. Participants will be followed for 84 days total.
Interventions: intervention 1: AVD-104
Intervention descriptions: intervention 1: An intravitreal injection of 50 microliters at the doses described will be given. Visual acuity, optical coherence tomography thickness and vascular perfusion will be evaluated for an effect of the drug.

Protocol documents:
Prot_000.pdf: 
AVD-104-C301 
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Protocol Title: A Phase 2 Study to Evaluate the Safety and Treatment Effect of Intravitreal 
AVD-104 in Participants with Diabetic Macular Edema 
Protocol Number: AVD-104-C301 
Version 
Compound Number: AVD-104 
Sponsor Name and Legal Registered Address: Aviceda Therapeutics, Inc. 
One Broadway, Cambridge, MA. 02142, USA 
Approval Date: 
Sponsor Signatory: 
Date 
NCT number:  NCT06181227
Date:  25 SEP 2023


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PROTOCOL APPROVAL – PRINCIPAL INVESTIGATOR SIGNATURE 
 
 
Protocol Title: A Phase 2 Study to Evaluate the Safety, and Treatment Effect of Intravitreal 
AVD-104 in Participants with Diabetic Macular Edema 
Protocol Number: AVD-104-C301 
 
Version 
 
 
 
Version Date: __
 
 
 
 
I have read the protocol described above. I agree to conduct the study as described in the 
protocol. I also agree to conduct this study in compliance with Good Clinical Practice (GCP) and 
all applicable national and local laws and regulations, as well as with the requirements of the 
appropriate Institutional Review Board or Independent Ethics Committee (IRB/IEC) and any 
other institutional requirements. These are stated in “Guidance for Good Clinical Practice” 
International Council for Harmonisation (ICH) guideline E6(R1) of Technical Requirements for 
Registration of Pharmaceuticals for Human Use, the Declaration of Helsinki, and any other 
applicable regulatory requirements. No changes will be made to the study protocol without prior 
written approval of the Sponsor and the IRB/IEC. 
 
 
 
Principal Investigator: ________________________ 
 
 
Print Name of Investigator: ________________________ 
 
 
 
 
 
Date: ______________________ 
 
 
 


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TABLE OF CONTENTS 
1. 
SYNOPSIS ..................................................................................................... 6 
2. 
SCHEDULE OF ACTIVITIES (SOA) .............................................................. 8 
3. 
INTRODUCTION .......................................................................................... 10 
3.1. 
Study rationale ............................................................................................. 11 
3.2. 
Background .................................................................................................. 11 
3.3. 
Benefit/risk assessment ............................................................................... 12 
4. 
OBJECTIVES AND ENDPOINTS ................................................................ 13 
4.1. 
Study design ................................................................................................ 13 
4.1.1. 
Overall design .............................................................................................. 13 
4.1.2. 
End of study definition .................................................................................. 13 
4.2. 
Scientific rationale for study design .............................................................. 14 
4.3. 
Justification for dose .................................................................................... 14 
5. 
STUDY POPULATION ................................................................................. 15 
5.1. 
Inclusion criteria ........................................................................................... 15 
5.2. 
Exclusion criteria .......................................................................................... 15 
5.2.1. 
Medical condition exclusions ........................................................................ 17 
5.2.2. 
Lifestyle restrictions ...................................................................................... 17 
5.3. 
Screen failures ............................................................................................. 17 
6. 
TREATMENTS ............................................................................................. 19 
6.1. 
Treatments administered.............................................................................. 19 
6.2. 
Method of treatment assignment .................................................................. 19 
6.3. 
Masking ........................................................................................................ 19 
6.4. 
Dose discontinuation .................................................................................... 19 
6.5. 
Dose modification/interruption ...................................................................... 19 
6.6. 
Rescue criteria ............................................................................................. 19 
6.7. 
Preparation/handling/storage/accountability................................................. 20 
6.8. 
Concomitant therapy .................................................................................... 20 
6.9. 
Treatment after the end of the study ............................................................ 20 
6.10. 
Discontinuation from the study ..................................................................... 20 


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6.11. 
Lost to follow-Up .......................................................................................... 21 
7. 
STUDY PROCEDURES ............................................................................... 22 
7.1. 
Informed consent and patient privacy .......................................................... 22 
7.2. 
Visits and associated procedures ................................................................. 22 
8. 
ADVERSE EVENTS ..................................................................................... 24 
8.1. 
Time period and frequency for collecting AE and SAE information .............. 24 
8.2. 
Method of detecting AE and SAE ................................................................. 24 
8.3. 
Follow-up of AE and SAE ............................................................................. 24 
8.3.1. 
Regulatory reporting requirements for SAE.................................................. 25 
8.3.2. 
Pregnancy .................................................................................................... 25 
8.4. 
Treatment of overdose ................................................................................. 25 
8.5. 
Safety ........................................................................................................... 25 
8.5.1. 
General ........................................................................................................ 25 
8.5.2. 
Visual safety ................................................................................................. 25 
8.5.3. 
Physical examinations .................................................................................. 26 
8.5.4. 
Vital signs ..................................................................................................... 26 
8.5.5. 
Clinical safety laboratory assessments ........................................................ 26 
8.6. 
Health economics or medical resource utilization and health economics ..... 27 
9. 
STATISTICAL CONSIDERATIONS ............................................................. 28 
9.1. 
Sample size determination ........................................................................... 28 
9.2. 
Populations for analyses .............................................................................. 28 
9.3. 
Statistical analyses ....................................................................................... 28 
9.3.1. 
Efficacy analyses ......................................................................................... 28 
9.3.2. 
Safety analyses ............................................................................................ 28 
10. 
REFERENCES ............................................................................................. 29 
11. 
APPENDICES .............................................................................................. 31 
APPENDIX 1. ABBREVIATIONS AND TRADEMARKS .............................................. 32 
APPENDIX 2. CLINICAL LABORATORY TESTS ....................................................... 34 
APPENDIX 3. STUDY GOVERNANCE CONSIDERATIONS ..................................... 35 


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APPENDIX 4. ADVERSE EVENTS: DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ............... 38 
APPENDIX 5. CONTRACEPTIVE GUIDANCE AND COLLECTION OF PREGNANCY 
INFORMATION ............................................................................................ 43 
 
LIST OF TABLES 
Table 1: ... Analysis Populations .................................................................................... 28 
Table 2: ... Statistical Analysis Methods ........................................................................ 28 
Table 3: ... Protocol-Required Safety Laboratory Assessments ..................................... 34 
 




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Treatment Groups and Duration: 
One group will receive three injections of low-dose AVD-104
 each 28 
days apart. The second group will receive two injections of high dose AVD-104 
 
56 days apart.  Both groups will be followed for 84 days after injection. 


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2. 
SCHEDULE OF ACTIVITIES (SOA) 
 
Activity 
Screen 
Baseline 
Predose 
Dose 
Post 
Dose 
Day/month 
Day -28 to -1 
Day 0 
Day 28 
Day 56 Day 84 
Window (±days) 
±7 
±7 
±7 
Informed Consent/HIPAA 
X 
Eligibility Criteria 
X 
X 
Medical History 
X 
Ocular History1 
X 
Demographics2 
X 
Review adverse events/ocular 
symptoms3 
X 
X 
X 
X 
X 
Record TEAEs 
X 
X 
X 
X 
Vital signs4 
X 
X 
 
X 
X 
X 
Brief Physical examination5 
 
X 
X 
Urine/Serum Pregnancy Test6 
X 
X 
X 
X 
X 
Prior/Con Medications 
X 
X 
X 
X 
X 
Central Labs7 
X 
X 
 
 
 
 
 
BCVA by ETDRS8 
OU 
OU 
SE 
SE 
OU 
Slit Lamp Biomicroscopy 
OU 
OU 
SE 
SE 
OU 
IOP 
OU 
OU 
SE 
SE 
SE 
OU 
Indirect Ophthalmoscopy 
OU 
OU 
SE 
SE 
OU 
SD-OCT 
OU 
OU 
SE 
SE 
OU 
OCT-A 
 
OU 
SE 
SE 
OU 
Color fundus photographs  
OU 
 
 
 
OU 
Fluorescein angiogram 
 
OU 
SE 
 
OU 
Select/Confirm Study Eye 
X 
 
 
 
 
 
IVT injection high-dose group (n=15) 
SE 
 
SE 


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Activity 
Screen 
Baseline 
Predose 
Dose 
Post 
Dose 
Day/month 
Day -28 to -1 
Day 0 
Day 28 
Day 56 Day 84 
Window (±days) 
±7 
±7 
±7 
IVT injection low-dose group (n=15) 
 
 
SE 
 
SE 
SE 
 
 
Abbreviations AST = BCVA = best-corrected visual acuity; Con = concomitant; ETDRS = early-treatment diabetic retinopathy study; HIPPA = Health Insurance Portability and 
Accountability Act; IOP = intraocular pressure; IVT = intravitreal injection; OCT-A = Optical coherence tomographic angiography ; SD-OCT = spectral-domain optical coherence 
tomography; TEAE = treatment emergent adverse event; OU = Both eyes; SE = Study eye 
1. 
Ocular history shall include but is not limited to diabetic retinopathy-related events (hemorrhage, previous laser, etc.), eye involvement, and localization (central versus non-central). 
2. 
Demographics include age, gender, race, ethnicity, height, and weight. 
3. 
The severity of ocular symptoms (burning/stinging, itching, foreign body, discomfort, dryness, photophobia, and pain) shall be evaluated on a visual analogue scale of 0 to10. 
4. 
Vital signs include temperature (oral, tympanic, or temporal), resting heart rate, and blood pressure. 
5. 
Brief physical examination includes appearance, mood, and affect only. Physical examination for symptom driven findings may be conducted at any time during the study. 
6. 
Urine pregnancy tests shall be performed in females of childbearing potential only.  The high and low dose groups will be tested at screening, baseline, day 56, and day 84 or termination.  
The low dose group will be retested again at day 28 before their second injection.   If the test is positive at any of these timepoints, then a confirmatory serum pregnancy test must be 
conducted. 
7. 
Central labs consist of complete blood count and metabolic profile as outlined in Appendix 2. 
8. 
Best-corrected visual acuity measured using Early Treatment of Diabetic Retinopathy Study protocol. 


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3. 
INTRODUCTION 
Diabetic retinopathy is the leading cause of vision loss in working individuals and diabetic 
macular edema and macular ischemia are two of the major contributors to this morbidity. 
(Ixcamey 2021; Ting 2016).  Despite the widespread use of intravitreal anti-VEGF agents and 
steroids, there is still a large unmet medical need in this population (Haritoglou 2020; Sadiq 
2020). A significant percentage of patients with DME do not respond completely to anti-VEGF 
therapy (Bressler 2016; Felfeli 2019). Approximately 30% of patients treated with the most 
effective agent, faricimab, still have edema present at 24 weeks (Sahni 2019).  The use of anti-
VEGF and anti-Ang 2 agents targets specific pathways associated with increased vascular 
permeability and neovascularization but does not target up-stream causes of progressive 
diabetic retinopathy.  Although VEGF has been identified as one of the key factors, other 
inflammatory mediators such as MCP-1, TNF-𝛂𝛂, and IL-6 are upregulated in patients with 
chronic DME (Kwon 2018).  In addition, adhesion molecules including VCAM-1, ICAM-1, and E 
selectin are correlated with the progression of diabetic complications (Derosa 2016, Rajab 2015, 
Xu 2023).     
An understanding of the role of other inflammatory factors in DME will help elucidate why anti-
VEGF alone fails to resolve DME in many patients and why diabetic retinal ischemia persists. 
The activation and retinal leukostasis of neutrophils in the development of macular ischemia and 
retinal endothelial damage has been scientifically characterized for decades.(McLeod, Lefer et 
al. 1995)  VEGF alone has been shown to cause neutrophil chemoattraction, leukocyte 
plugging, retinal edema and ischemia in a non-human primate model. (Tolentino, Miller 1996, 
Hofman, Blaauwgeers 2000)  However, when VEGF was withdrawn in this model, leukocyte 
plugging, and edema did not resolve (Tolentino unpublished observation). This observation 
predicted the current situation of refractory macular edema and ischemia that is seen today with 
anti-VEGF agents. The persistence of macular edema and ischemia was due to neutrophil 
activation and ICAM-1 and CD18 mediated leukostasis. (Joussen, Murata et al. 2001). An 
optimal therapy for these refractory complications of diabetic retinopathy would be the 
deactivation or the elimination of these neutrophils in the retina and retinal vasculature coupled 
with elimination of the complement induced tight junction disruption and Selectin upregulation 
that captures and holds the leukocytes in retinal vascular stasis and maintains non-VEGF 
mediated vascular leakage.  
The knowledge of how to modulate immune cells, like monocytes and neutrophils, has 
progressed to the point that therapeutic interventions can be evaluated. All immune cells have 
glycoproteins that reside on their cell surfaces called sialic acid binding immunoglobulin-type 
lectins, or Siglecs. Each cell type tends to have more of one or a few particular Siglecs that 
control its activity. (Gonzalez-Gil, 2021) Neutrophils, in general, have Siglec 9 present on their 
surfaces. These Siglec receptors activate an inhibitory pathway within the cell called 
immunoreceptor tyrosine-based inhibitory motif (ITIM).  This is done through recruitment of the 
tyrosine phosphatase Src homology region 2 domain- containing phosphatase-1 (SHP-1). By 
activating these Siglec glycoproteins with an agonist, the neutrophils can be downregulated. 
AVD-104 is a novel glycan coated nanoparticle that is being developed as an intravitreal 
injection to treat diabetic retinopathy and its components. Its interaction with the Siglec 9 
receptors present on neutrophils activates this inhibitory pathway, which leads not only to a 


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decrease in inflammatory mediators but the potential to induce programmed cell death in these 
hyperactivated neutrophils. (Chen, Bai et al. 2018) 
Another inflammatory factor that causes a non-VEGF dependent disruption of retinal vascular 
endothelium is anaphylatoxin C3a. C3a is a complement factor that binds to vascular 
endothelium causing an intracellular mediated disruption of the blood retinal barrier and a 
weakening of vascular cadherin mediated vascular tight junctions. (Wu, Zou et al. 2016). C3a 
also stimulates the expression of E-selectin a major adhesion receptor that binds activated sialyl 
Lewis a and x bearing leukocytes. (Smith and Bertozzi 2021) Inhibition of complement pathway 
production of C3a would also be effective in restoring the non-VEGF disrupted tight junctions of 
the blood retinal barrier and a significant reduction of E-selectin. The constitutive inhibitor of the 
alternative complement cascade is complement factor H (CFH).  Sialic acid molecules bind to 
CFH to activate the molecule and thereby inhibit the inflammatory complement cascade (Fearon 
1978). AVD-104 binds sialic acid binding domains on CFH to similarly downregulate the 
complement pathway as reported in the Investigator’s Brochure (IB). 
The emergence of glycobiology and the ability to directly modulate both the activity of immune 
cells and the complement pathway has opened the opportunity to treat this recalcitrant form of 
diabetic retinopathy with a dual mechanism Siglec-9 agonist and complement inhibitor. In 
pulmonary literature, agonizing Siglec-9 with a rudimentary glyco-mimetic induced selective 
apoptosis in activated neutrophils (Chen 2018). AVD-104 while designed to target complement 
and Siglec 11, does bind and agonize Siglec-9 which is the main Siglec found on neutrophils 
and T Cells. The mechanism of resolving neutrophil and complement activation locally in the 
eye with AVD-104 has the potential to treat patients that failed anti-VEGF therapy and to treat 
macular ischemia; as of now, an untreatable and visually compromising complication of 
diabetes. This dual mechanism of action of AVD-104 – inhibition of activated neutrophils and 
down- regulation of the alternative complement system -- shows great promise in slowing the 
visual loss in diabetic retinopathy due to chronic inflammation. 
3.1. 
Study rationale 
Numerous studies now support the concept that abnormalities in the innate cellular immune 
system are causative agents in the pathophysiology of diabetic retinopathy (Xu 2017).   Sialic 
acid binding immunoglobulin like receptors (Siglecs) are a target to affect an inhibitory 
mechanism to thereby downregulate immune cells, including neutrophils (Varki, 2022). AVD-104 
binds to Siglec receptors to inhibit neutrophils and lower inflammatory cytokine production. It 
also enhances the action of complement factor H (CFH) to dampen the complement system. 
This dual mechanism of action of AVD-104 should be effective in treating the chronic 
inflammation present in diabetic retinopathy (DR). This study is designed to assess the 
treatment effect of this novel compound, which for the first time addresses the cellular 
component of diabetic retinopathy. 
3.2. 
Background 
Scott and team first reported the increased anti-inflammatory effect of sialic acid molecules 
when placed on nanoparticles and then presented to inflammatory cells with appropriate Siglec 
receptors (Spence, 2015). His experiments in a mouse sepsis model showed a remarkable 
down-regulation of inflammation using sialic acid coated nanoparticles compared to sialic acid 


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alone. 
 
 
 
 
 
 
 It has previously been shown that sialic acid 
molecules also have a direct effect on the complement cascade (Fearon, 1978). Sialic acid 
polymers also bind properdin and subsequently reduce the complement amplification pathways 
(Shahraz, 2022). These studies strongly support the potential role of a sialic acid mimetic in 
downregulating the innate immune system involved in inflammatory conditions like DR.  In vitro 
studies using FACS analysis have demonstrated that 98% of blood derived neutrophils express 
Siglec 9. 
 
 
 
 
 
  
The unique dual mechanism of action of AVD-104 will be highlighted in the pre-clinical data 
presented in the IB.
 
3.3. 
Benefit/risk assessment 
The need for a therapy to significantly reduce the visual morbidity in DR is clear and, if 
accomplished, would provide great benefit to patients with progressive vision loss. The risk of 
intravitreal injections is relatively small and well characterized. More detailed information about 
the known and expected benefits and risks and reasonably expected adverse events of AVD-
104 may be found in the Investigator’s Brochure. 




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4.2. 
Scientific rationale for study design 
The trial is designed to provide initial efficacy data for AVD-104 in participants with DR.  The 
parameters evaluated will include change in vision, change in CST on OCT, or changes in 
perfusion of the macula or peripheral retina to see if AVD-104 has any effect on them.  
4.3. 
Justification for dose 
 
 
 
 
 
 
 
 
 
 
 
 
 


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5. 
STUDY POPULATION 
Participants will be 18 years or older with evidence of DME secondary to DR and no history of 
neovascularization in the study eye. There will be no racial or sex limitations. 
5.1. 
Inclusion criteria 
Participants are eligible to be included in the study only if all the following criteria apply: 
1. Willingness and the ability to provide signed informed consent as to the full nature and 
purpose of the study (includes compliance with the requirements and restrictions listed in the 
informed consent form (ICF) and in this protocol), acknowledging the possible risks of study 
procedures. Additionally, participants must provide Health Insurance Portability and 
Accountability Act (HIPAA) authorization. 
2. ≥18 years old at the time of signed informed consent 
3. Sufficiently clear ocular media, adequate pupillary dilation, and fixation to permit quality 
fundus imaging, and able to cooperate sufficiently for adequate ophthalmic visual function 
testing and anatomic assessment as determined by the Investigator 
4. Male participants: 
• 
Males with female partners of childbearing potential must agree to use protocol-
defined methods of contraception and agree to refrain from donating sperm for up to 
 after the last dose of study drug. 
5. Female participants: 
• 
A female participant is eligible to participate if she is not pregnant (see Appendix 5), 
or breastfeeding, and at least one of the following conditions applies: 
• 
Not a woman of childbearing potential (WOCBP) as defined in Appendix 5 OR 
• 
A WOCBP who agrees to follow the contraceptive guidance in Appendix 5 during the 
treatment period and for at least [
 after the last dose of study 
treatment]. 
6. Diagnosis of diabetes mellitus (type 1 or 2), as defined by the World Health Organization 
and/or American Diabetes Association  
7. Decreased visual acuity (VA) due to DME, with BCVA letter score of 75−20 letters on 
ETDRS-like charts (20/32−20/320 Snellen equivalent)  
8. DME represented by macular thickening on SD-OCT involving the center of the macula: 
CST ≥325 μm with Spectralis (Heidelberg Engineering Inc., Heidelberg, Germany) at 
screening or CST ≥315 μm for Cirrus (Carl Zeiss Meditec, Dublin, CA), CST ≥315 μm for 
Topcon (Tokyo, Japan), or CST ≥295 μm for Optovue (Fremont, CA) where Spectralis is 
unavailable. 
5.2. 
Exclusion criteria 
Participants are excluded from the study if any of the following criteria apply: 
A. Presence of the following ocular conditions – in the Study Eye: 
1. Any IVT anti-VEGF treatment within 3 months before randomization 






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7. 
STUDY PROCEDURES 
Only prospective participants as defined by the criteria in Sections 5.1 and Section 5.2 
(inclusion/exclusion criteria) will be considered for entry into this study. 
For all potential participants, eligibility based on severity of diabetic retinopathy must be 
confirmed by the central reading center prior to participant enrollment. In addition, all screening 
laboratory tests must be performed, and the results must be evaluated and determined to be 
acceptable by the investigator prior to participant enrollment into the study. Screening laboratory 
tests may be repeated once at the discretion of the investigator or Aviceda. 
A urine or serum pregnancy test administered to WOCBP at the baseline (day 1) visit must be 
negative prior to randomization. 
A participant is considered to have entered the study at the time of enrollment to baseline (day 
0). 
7.1. 
Informed consent and patient privacy 
The study will be fully discussed with the patient. Any patient wishing to participate must give 
informed consent prior to any study-related procedures are performed or there is a change in 
treatment. The patient must also give authorization (US only), data protection consent (Europe 
only), and other written documentation in accordance with the relevant country and local privacy 
requirements (where applicable) prior to any study-related procedures are performed or there is 
a change in treatment. 
Each patient who provides informed consent will be assigned a patient number that will be used 
on patient documentation throughout the study. 
7.2. 
Visits and associated procedures 
Evaluations should be performed by the same evaluator throughout the study whenever 
possible.  
Unless otherwise specified, procedures are recommended to be done in the order listed. 
Screening 
• 
Obtain informed consent and authorization 
• 
Review eligibility criteria 
• 
Collect demographic information and medical and ophthalmic history 
• 
Vital signs (blood pressure and pulse rate) 
• 
Urine pregnancy test for women of childbearing potential (confirmed with serum if positive) 
• 
Collect information about concomitant medications and procedures 
• 
Collect blood for central labs 
• 
Perform the following procedures in both eyes: 
o BCVA using ETDRS method following refraction 
o Full ophthalmic examination: slit lamp biomicroscopy, IOP assessment, and dilated 
indirect ophthalmoscopy examination 
o SD-OCT imaging 
 


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o Dilated ultra-wide field (UWF) color fundus photography  
o  
Baseline (Day 0) 
• 
Review eligibility criteria and reading center confirmation of eligibility 
• 
Query for ocular symptoms  
• 
Vital signs (blood pressure and pulse rate) 
• 
Brief physical exam 
• 
Urine pregnancy test for women of childbearing potential (confirmed with serum if positive) 
• 
Collect information about concomitant medications and procedures 
• 
Perform the following procedures in both eyes: 
o BCVA using ETDRS method following refraction 
o Full ophthalmic examination: slit lamp biomicroscopy, IOP assessment, and dilated 
indirect ophthalmoscopy examination 
o SD-OCT imaging 
o OCT-A 
o Ultra wide-field fluorescein angiography 
After completion of these procedures, and the participant still meets entry criteria, and the 
central reading center (CRC) has confirmed participant eligibility based on ocular 
inclusion/exclusion criteria from the screening visit, and the investigator has confirmed patient 
eligibility based on the results from the blood chemistry, hematology, and urine or serum 
pregnancy test from the screening visit; the participant will be enrolled 
• 
Perform the following procedures in the study eye: 
o Administer assigned study medication 
o Conduct post-injection assessments at 30 minutes 
Days 28, 56, and 84 
• 
Query for adverse events and ocular symptoms 
• 
Vital signs (blood pressure and pulse rate) 
• 
Brief physical exam (month 3 only) 
• 
Urine pregnancy test where indicated and positive results confirmed with serum test (low 
dose group at day 28 prior to second injection; both groups at month 3 only) 
• 
Review concomitant medications and procedures 
• 
Collect blood samples for central lab (month 3 only) 
• 
Perform the following procedures in the study eye (both eyes at month 3) 
o BCVA using ETDRS method following refraction 
o full ophthalmic examination: slit lamp biomicroscopy, IOP assessment, and dilated 
indirect ophthalmoscopy examination 
o SD-OCT imaging 
o OCT-A 
o Dilated ultra-wide field (UWF) color fundus photography (both eyes at month 3 only) 
o UWF Fluorescein angiogram (month 1 and 3) 
o Administer assigned study medication at day 28 and 56 in low-dose group; day 56 in 
high dose group 
o Conduct post-injection assessment at 30 minutes  


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8. 
ADVERSE EVENTS 
The definitions of an AE and SAE can be found in Appendix 4. 
AE will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The investigator and any designees are responsible for detecting, documenting, and reporting 
events that meet the definition of an AE or SAE and remain responsible for following up AEs 
that are serious, considered related to the study treatment or other aspects of the study, or that 
caused the participant to discontinue the study treatment or other aspects of the study (see 
Section 9). 
8.1. 
Time period and frequency for collecting AE and SAE 
information 
All AEs and SAEs will be collected from the start of treatment until the final follow-up visit at the 
time points specified in the SoA (Section 2). 
Medical occurrences that begin before the start of study treatment but after obtaining informed 
consent will be recorded on the Medical History/Current Medical Conditions section of the case 
report form (CRF). 
All SAEs will be recorded and reported to the sponsor or designee within 
 as indicated 
in Appendix 4. The investigator will submit any updated SAE data to the sponsor within 
 
of it being available. 
Investigators are not obligated to actively seek AE or SAE in former study participants. 
However, if the investigator learns of any SAE, including a death, at any time after a participant 
has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must promptly 
notify the sponsor. 
The method of recording, evaluating, and assessing causality of AE and SAE and the 
procedures for completing and transmitting SAE reports are provided in Appendix 4 
8.2. 
Method of detecting AE and SAE 
Care will be taken not to introduce bias when detecting AE and/or SAE. Open-ended and non-
leading verbal questioning of the participant is the preferred method to inquire about AE 
occurrence. 
8.3. 
Follow-up of AE and SAE 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs and AEs (as defined in Appendix 4), will be followed 
until resolution, stabilization, until the event is otherwise explained, or the participant is lost to 
follow-up (as defined in Section 6.11). Further information on follow-up procedures is given in 
Appendix 4. 


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8.3.1. 
Regulatory reporting requirements for SAE 
• 
Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants 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 (IRB)/IEC, and investigators. 
• 
Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions (SUSAR) according to local regulatory requirements and sponsor policy and 
forwarded to investigators, as necessary. 
• 
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will file it along 
with the Investigator’s Brochure and will notify the IRB/IEC, if appropriate according to local 
requirements. 
8.3.2. 
Pregnancy 
• 
Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study treatment and until 
 after the last 
dose. 
• 
If a pregnancy is reported, the investigator should inform 
Medical Monitor and 
Aviceda within 
 of learning of the pregnancy and should follow the procedures 
outlined in Appendix 5. 
• 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, ectopic pregnancy) are considered SAE. 
8.4. 
Treatment of overdose 
N/A 
8.5. 
Safety 
8.5.1. 
General 
Participants will be monitored for any safety and tolerability issues affecting any system. 
Any significant abnormality in the opinion of the investigator noted on systemic values obtained 
from the clinical laboratory testing should be reported as possible adverse events. If there is any 
question that these represent serious abnormalities, both the medical monitor and sponsor 
should be notified. 
8.5.2. 
Visual safety 
For issues affecting vision. The following are guidelines for reporting the possible adverse 
events: 
• 
 
 
 


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8.5.3. 
Physical examinations 
• 
A physical examination will include, at a minimum, assessments of appearance, mood, and 
affect. Height and weight will also be measured and recorded at screening. 
• 
A brief physical examination will include, at a minimum, assessments of appearance, mood, 
and affect and symptoms. 
• 
Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
8.5.4. 
Vital signs 
• 
Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
• 
Blood pressure and pulse measurements should be taken before blood collection for 
laboratory tests and after the participant has been sitting for 5 minutes. Repeat testing can 
be done if needed by the Investigator. 
8.5.5. 
Clinical safety laboratory assessments 
Any significant abnormality noted in systemic values obtained from the clinical laboratory testing 
(central laboratory) should be reported as possible adverse events. If there is any question that 
these represent serious abnormalities, both the medical monitor and sponsor should be notified. 
• 
Refer to Appendix 2 for the list of clinical laboratory tests to be performed and to the SoA for 
the timing and frequency. 
• 
The investigator must review the laboratory report, document this review, and record any 
clinically relevant changes occurring during the study in the AE section of the CRF. The 
laboratory reports must be filed with the source documents. Clinically significant abnormal 
laboratory findings are those which are not associated with the underlying disease, unless 
judged by the investigator to be more severe than expected for the participant’s condition. 
• 
All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 
 after the last dose of study treatment should be 
repeated until the values return to normal or baseline. If such values do not return to 
• 
normal/baseline within a period judged reasonable by the investigator, the etiology should 
be identified, and the sponsor notified. 
• 
All protocol-required laboratory assessments, as defined in Appendix 2, must be conducted 
in accordance with the laboratory manual and the SoA. 
• 
If there is an urgent need and laboratory values from a non-protocol specified laboratory 
assessments performed at the institution’s local laboratory require a change in participant 
management or are considered clinically significant by the investigator (eg, SAE or AE or 
dose modification), then the results must be recorded in the eCRF. 


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8.6. 
Health economics or medical resource utilization and health 
economics 
 
 
 




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10. 
REFERENCES 
Bressler SB, Ayala AR, Bressler NM, Melia M, Qin H, Ferris FL, et al. Persistent macular 
thickening after ranibizumab treatment for diabetic macular edema with vision impairment. 
JAMA Ophthalmol. 2016; 134(3): 278–85. 
Chen Z, Bai FF, Han L, et al. Targeting Neutrophils in Severe Asthma via Siglec-9. Int Arch 
Allergy Immunol. 2018;175(1-2):5-15. doi:10.1159/000484873 
Derosa G, Maffioli P. A review about biomarkers for the investigation of vascular function and 
impairment in diabetes mellitus. Vasc Health Risk Manag. 2016;12:415-419. Published 2016 
Nov 9. doi:10.2147/VHRM.S64460 
Emami A, Tepper J, Short B, et al. Toxicology Evaluation of Drugs Administered via Uncommon 
Routes: Intranasal, Intraocular, Intrathecal/Intraspinal, and Intra-Articular. Int J Toxicol. 
2018;37(1):4-27. doi:10.1177/1091581817741840 
Fearon DT. Regulation by membrane sialic acid of beta1H-dependent decay-dissociation of 
amplification C3 convertase of the alternative complement pathway. Proc Natl Acad Sci U S A. 
1978;75(4):1971-1975. 
Felfeli T, Juncal VR, Hillier RJ, Mak MYK, Wong DT, Berger AR, et al. Aqueous humor 
cytokines and long-term response to anti-vascular endothelial growth factor therapy in 
diabeticmacular edema. Am J Ophthalmol.  2019; 206: 176–83. 
Gonzalez-Gil A, Schnaar RL. Siglec ligands. Cells. 2021;10(5):1260. 
Haritoglou, C.; Maier, M.; Neubauer, A.S.; Augustin, A.J. Current concepts of pharmacotherapy 
of diabetic macular edema.  Expert Opin. Pharmacother. 2020, 21, 467–475. 
Hofman P, Blaauwgeers HG, Tolentino MJ, et al. VEGF-A induced hyperpermeability of blood-
retinal barrier endothelium in vivo is predominantly associated with pinocytotic vesicular 
transport and not with formation of fenestrations. Vascular endothelial growth factor-A. Curr Eye 
Res. 2000;21(2):637-645. 
Ixcamey, M.; Palma, C. Diabetic macular edema. Dis. Mon. 2021, 67, 101138. 
Joussen AM, Poulaki V, Mitsiades N, et al. Suppression of Fas-FasL-induced endothelial cell 
apoptosis prevents diabetic blood-retinal barrier breakdown in a model of streptozotocin-
induced diabetes. FASEB J. 2003;17(1):76-78. doi:10.1096/fj.02-0157fje 
Kwon JW, Jee D. Aqueous humor cytokine levels in patients with diabetic macular edema 
refractory to anti-VEGF treatment. PLoS One. 2018; 13(9): e0203408–9. 
McLeod DS, Lefer DJ, Merges C, Lutty GA. Enhanced expression of intracellular adhesion 
molecule-1 and P-selectin in the diabetic human retina and choroid. Am J Pathol. 
1995;147(3):642-653. 
Rajab HA, Baker NL, Hunt KJ, et al. The predictive role of markers of Inflammation and 
endothelial dysfunction on the course of diabetic retinopathy in type 1 diabetes. J Diabetes 
Complications. 2015;29(1):108-114. doi:10.1016/j.jdiacomp.2014.08.004 


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Sadiq MA, Halim MS, Hassan M, Onghanseng N, Karaca I, Agarwal A, et al. Pharmacological 
agents in development for diabetic macular edema. Int J Retina Vitreous. 2020;6(1): 29–11. 
Sahni J, Patel SS, Dugel PU, Khanani AM, Jhaveri CD, Wykoff CC, et al. Simultaneous 
inhibition of angiopoietin-2 and vascular endothelial growth factor-A with faricimab in diabetic 
macular edema: BOULEVARD phase 2 randomized trial. Ophthalmology.  2019; 126(8): 1155–
70.  
Shahraz A, Lin Y, Mbroh J, et al. Low molecular weight polysialic acid binds to properdin and 
reduces the activity of the alternative complement pathway. Sci Rep. 2022;12(1):5818. 
Published 2022 Apr 6. doi:10.1038/s41598-022-09407-2 
Short B. Selected Aspects of Ocular Toxicity Studies With a Focus on High-Quality Pathology 
Reports: A Pathology/Toxicology Consultant's Perspective. Toxicol Pathol. 2021;49(3):673-699. 
doi:10.1177/0192623320946712 
Smith BAH, Bertozzi CR. The clinical impact of glycobiology: targeting selectins, Siglecs and 
mammalian glycans [published correction appears in Nat Rev Drug Discov. 2021 Feb 8;:]. Nat 
Rev Drug Discov. 2021;20(3):217-243. doi:10.1038/s41573-020-00093-1 
Spence S, Greene MK, Fay F, et al. Targeting siglecs with a sialic acid-decorated nanoparticle 
abrogates inflammation. Sci Transl Med. 2015;7(303):303ra140. 
Ting DS, Cheung GC, Wong TY. Diabetic retinopathy: global prevalence, major risk factors, 
screening practices and public health challenges: a review. Clin Exp Ophthalmol. 
2016;44:260e277. 
Tolentino MJ, Miller JW, Gragoudas ES, et al. Intravitreous injections of vascular endothelial 
growth factor produce retinal ischemia and microangiopathy in an adult primate. Ophthalmology. 
1996;103(11):1820-1828. doi:10.1016/s0161-6420(96)30420-x 
Varki A, Cummings RD, Esko JD, et al., editors. Essentials of Glycobiology. 4th edition. Cold 
Spring Harbor (NY): Cold Spring Harbor Laboratory Press; 2022. 
https://www.ncbi.nlm.nih.gov/books/NBK579918/doi: 10.1101/9781621824213. 
Vezina, M. (2013). Comparative Ocular Anatomy in Commonly Used Laboratory Animals. In A. 
B. Weir, Assessing Ocular Toxicology in Laboratory Animals (S. 1-21). Totowa, NJ: Humana 
Press. doi:10.1007/978-1-62703-164-6_1 
Wu F, Zou Q, Ding X, et al. Complement component C3a plays a critical role in endothelial 
activation and leukocyte recruitment into the brain. J Neuroinflammation. 2016;13:23. Published 
2016 Jan 28. doi:10.1186/s12974-016-0485-y 
Xu H, Chen M. Diabetic retinopathy and dysregulated innate immunity. Vision Res. 
2017;139:39-46. doi:10.1016/j.visres.2017.04.013 
Xu Y, Hou H, Zhao L. The role of VCAM-1 in diabetic retinopathy: A systematic review and 
meta-analysis. J Diabetes Complications. 2023;37(1):108380. 
doi:10.1016/j.jdiacomp.2022.108380 
 
 


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11. 
APPENDICES 


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Appendix 1. 
Abbreviations and trademarks 
 
Term 
Definition 
ADL 
Activities of daily living 
AE 
Adverse event 
ALT 
Alanine Aminotransferase 
ANOVA 
Analysis of variance 
AMD 
Age-related macular degeneration 
AST 
Aspartate Aminotransferase 
AVD-104 
PSA-PLGA-nanoparticle construct 
BCVA 
Best-Corrected Visual Acuity 
BLD 
Bright-light damage 
C3 
Complement 3 
CATT 
Comparison of Age-Related Macular Degeneration Treatments Trial 
CFH 
Complement factor H 
CFI 
Complement factor I 
CFR 
Code of Federal Regulations 
CIOMS 
Council for International Organizations of Medical Sciences 
CNV 
Choroidal neovascularization 
CRC 
Central reading center 
CRF 
Case report form 
CSR 
Clinical study report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DA 
Disk area 
DLT 
Dose-Limiting Toxicity 
DMC 
Data Monitoring Committee 
DR 
Diabetic retinopathy 
DSMC 
Data and Safety Monitoring Committee 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EIOP 
Elevated intraocular pressure 
EOM 
Every other month 
ERG 
Electroretinogram 
ETDRS 
Early-Treatment Diabetic Retinopathy Study 
EZ 
Ellipsoid zone 
FA 
Fluorescein angiography 
FAF 
Fundus Autofluorescence 
FSH 
Follicle-stimulating hormone 
F/U 
Follow-up 
GA 
Geographic Atrophy 
GCP 
Good clinical practice 
HBsAg 
Hepatitis B surface antigen 
hCG 
Human chorionic gonadotropin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human immunodeficiency virus 
HRT 
Hormonal replacement therapy 
IB 
Investigator’s Brochure 
ICF 
Informed consent form 


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Term 
Definition 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committees 
INR 
International normalized ratio 
IOP 
Intraocular pressure 
IRB 
Institutional review board 
ITIM 
Immunoreceptor tyrosine-based inhibitory motif 
IUD 
Intrauterine device 
IUS 
Intrauterine hormone-releasing system 
IVRS 
Interactive Voice Response System 
IVT 
Intravitreal Injection 
IWRS 
Interactive Web Response System 
MCH 
Macrocytic anemia 
MCV 
Mean corpuscular volume 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIP-1 
Macrophage inflammatory protein 1 A and B 
MPO 
Myeloperoxidase 
MTD 
Maximum Tolerated Dose 
NCI 
National Cancer Institute 
NET 
Neutrophil extracellular trap 
NHP 
Non-human primate 
OCT 
Optical Coherence Tomography 
PEG 
Polyethylene glycol 
PD 
Pharmacodynamics 
 
 
PLGA 
Poly (D, L-lactic-co-glycolic acid) 
PMA 
Phorbol myristate acetate 
PSA 
Polysialic acid 
q 
Quisque (every) 
ROS 
Reactive oxygen species 
RP2D 
Recommended Phase 2 dosing 
RPE 
Retinal pigment epithelium 
SAE 
Serious adverse event 
SD-OCT 
Spectral-Domain Optical Coherence Tomography 
SGOT 
Serum Glutamic-Oxaloacetic Transaminase 
SGPT 
Serum Glutamic-Pyruvic Transaminase 
SHP-1 
Src homology region 2 domain-containing phosphatase-1 
SoA 
Schedule of Activities 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment emergent adverse event 
ULN 
Upper limit of normal 
VA 
Visual Acuity 
VAS 
Visual Acuity Scale 
VEGF 
Vascular endothelial growth factor 
WBC 
White blood cell 
WOCBP 
Women of childbearing potential 
YAG 
Yttrium aluminum garnet 


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Appendix 2. 
Clinical laboratory tests 
• 
The tests detailed in Table 3 will be performed by the central laboratory, except as noted 
below. 
• 
Local laboratory results are only required in the event that the central laboratory results are 
not available in time for either study treatment administration and/or response evaluation. If 
a local sample is required, it is important that the sample for central analysis is obtained at 
the same time. Additionally, if the local laboratory results are used to make either a study 
treatment decision or response evaluation, the results must be entered into the CRF. 
• 
Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5  of the protocol. 
• 
Additional tests may be performed at any time during the study as determined necessary by 
the investigator or required by local regulations. 
 
Table 3: 
Protocol-Required Safety Laboratory Assessments 


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Appendix 3. 
Study governance considerations 
Regulatory and ethical considerations 
• 
This study will be conducted in accordance with the protocol and with: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
(CIOMS) International Ethical Guidelines 
o Applicable ICH Good Clinical Practice (GCP) Guidelines 
o Applicable laws and regulations 
• 
The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• 
Any amendments to the protocol will require IEC/IRB approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants. 
• 
The investigator will be responsible for the following: 
o 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/EC 
o Notifying the IRB/IEC of SAE or other significant safety findings as required by IRB/IEC 
procedures 
o Overall conduct of the study at the site and adherence to requirements of 21 CFR, ICH 
guidelines, the IRB/IEC, European regulation 536/2014 for clinical studies (if 
applicable), and all other applicable local regulations 
Financial disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information in accordance with local regulations to allow the sponsor to submit complete and 
accurate financial certification or disclosure statements to the appropriate regulatory authorities. 
Investigators are responsible for providing information on financial interests during the course of 
the study and for 1 year after completion of the study. 
Informed consent process 
• 
The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 
• 
Participants must be informed that their participation is voluntary. Participants or their legally 
authorized representative, defined as an individual or judicial or other body authorized under 
applicable law to consent on behalf of a prospective subject to the subject's participation in 
the clinical research, will be required to sign a statement of informed consent that meets the 
requirements of 21 CFR 50, local regulations, ICH guidelines, Health Insurance Portability 
and Accountability Act (HIPAA) requirements, where applicable, and the IRB/IEC or study 
center. 
• 
The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF. 
• 
Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study. 


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• 
A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
Participants who are rescreened are required to sign a new ICF. 
Both blood and aqueous humor samples will be kept in storage for a potential exploratory 
analysis regarding the pathogenesis of macular degeneration and response to study treatment. 
Participants will be told that they are free to refuse to participate and may withdraw their 
specimens at any time and for any reason during the storage period. 
Data protection 
• 
Participants will be assigned a unique identifier by the sponsor. Any participant records or 
datasets that are transferred to the sponsor will contain the identifier only; participant names 
or any information, which would make the participant identifiable will not be transferred. 
• 
The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection law. The level of disclosure must also be 
explained to the participant. 
• 
The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
Publication policy 
• 
The results of this study may be published or presented at scientific meetings. If this is 
foreseen, the investigator agrees to submit all manuscripts or abstracts to the sponsor 
before submission. This allows the sponsor to protect proprietary information and to provide 
comments. 
• 
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 
multicenter 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. 
Dissemination of clinical study data  
Data quality assurance 
• 
All participant data relating to the study will be recorded on printed or electronic CRF unless 
transmitted to the sponsor or designee electronically (eg, laboratory data). The investigator 
is responsible for verifying that data entries are accurate and correct by physically or 
electronically signing the CRF. 
• 
The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF. 
• 
The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents. 
• 
The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• 
Study monitors will perform ongoing source data verification to confirm that data entered into 
the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study 


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is being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements. 
• 
Records and documents, including signed ICF, pertaining to the conduct of this study must 
be retained by the investigator for 10 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. 
Source documents 
• 
Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• 
Data reported on the CRF or entered 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. Definition 
of what constitutes source data can be found in 21 CFR 312.62(b). 
Study and site closure 
The sponsor or its designee may stop the study or study site participation in the study for 
medical, safety, regulatory, administrative, or other reasons consistent with applicable laws, 
regulations, and GCP. 












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Appendix 5. 
Contraceptive guidance and collection of pregnancy 
information 
Definitions 
Woman of Childbearing Potential (WOCBP) 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile. Permanent sterilization methods include hysterectomy, bilateral 
salpingectomy, and bilateral oophorectomy. 
Women in the following categories are not considered WOCBP 
1. 
Premenopausal female with 1 of the following: 
o Documented hysterectomy 
o Documented bilateral salpingectomy 
o Documented bilateral oophorectomy 
 
Note: Documentation can come from the site personnel’s: review of participant’s 
medical records, medical examination, or medical history interview. 
2. 
Premenarchal 
3. 
Postmenopausal female 
o 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 (HRT). However, in the absence of 12 
months of amenorrhea, a single FSH measurement is insufficient. 
o Females on HRT and whose menopausal status is in doubt will be required to use one 
of the non-hormonals highly effective contraception methods if they wish to continue 
their HRT during the study. Otherwise, they must discontinue HRT to allow confirmation 
of postmenopausal status before study enrollment. 
Contraception guidance  
Male participants 
• 
Male participants with female partners of childbearing potential are eligible to participate if 
they agree to the following during the protocol-defined time frame: 
o Are abstinent from penile-vaginal intercourse as their usual and preferred lifestyle 
(abstinent on a long-term and persistent basis) and agree to remain abstinent for 
duration of study and for 3 months after study completion or from last dose 
o Female partner is using a highly effective contraceptive method 
• 
Agree to use a male condom plus an additional method with a failure rate of <1% per year 
as described in the table below when having penile-vaginal intercourse with a woman of 
childbearing potential. 
• 
Men with a pregnant or breastfeeding partner must agree to remain abstinent from penile-
vaginal intercourse or use a male condom during each episode of penile penetration during 
the protocol-defined time frame. 
• 
Refrain from donating sperm for duration of study and for 3 months from last dose of study 
drug. 
 
 


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Highly Effective Contraceptive Methods That Are User Dependent 
Failure rate of <1% per year when used consistently and correctly. 
Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulationb 
• Oral 
• Intravaginal 
• Transdermal 
Progestogen-only hormonal contraception associated with inhibition of ovulation 
• Oral 
• Injectable 
Highly Effective Methods That Are User Independent 
• Implantable progestogen-only hormonal contraception associated with inhibition of 
ovulationb 
• Intrauterine device (IUD) 
• Intrauterine hormone-releasing system (IUS) 
• Bilateral tubal occlusion 
Vasectomized partner 
(A vasectomized partner is a highly effective contraception method provided that the partner 
is the sole male 
sexual partner of the WOCBP and the absence of sperm has been confirmed. If not, an 
additional highly effective method of contraception should be used.) 
Sexual abstinence 
(Sexual abstinence is considered a highly effective method only if defined as refraining from 
heterosexual intercourse during the entire period of risk associated with the study drug. The 
reliability of sexual abstinence 
needs to be evaluated in relation to the duration of the study and the preferred and usual 
lifestyle of the participant.) 
NOTES: 
a) Typical use failure rates may differ from those when used consistently and correctly. Use 
should be consistent with local regulations regarding the use of contraceptive methods for 
participants participating in clinical studies. 
 
Female participants 
Female participants of reproductive potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in the table 
above. 
Pregnancy testing 
• 
WOCBP should only be included after a confirmed menstrual period and a negative highly 
sensitive urine (dipstick or microscopy) pregnancy test 
• 
Pregnancy testing urine testing will be performed at screening, M12, and M24. If the urine 
test is positive, it should be confirmed by serum testing. 
• 
Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected 
Collection of pregnancy information 
Male participants with partners of reproductive potential who become pregnant 



SAP_001.pdf: 
Aviceda Therapeutics, Inc. 
AVD-104-C301 
Statistical Analysis Plan 
Page 1 of 10 
Statistical Analysis Plan 
A Phase 2 Study to Evaluate the Safety and Treatment Effect of Intravitreal AVD-104 in Participants with 
Diabetic Macular Edema 
Prepared for:  Aviceda Therapeutics, Inc. 
One Broadway, 14th Floor, Cambridge, MA 02142 
Protocol Details: 
Name:   
AVD-104-C301 
Version: 
SAP Details: 
Version: 
NCT number:  NCT06181227
Date:  10 JUL 2024




Aviceda Therapeutics, Inc. 
AVD-104-C301 
 
 
Statistical Analysis Plan 
Version 1.0 – 10-JUL-2024 
 
 
 
 
Page 3 of 10 
 
 
 
1 
INTRODUCTION ................................................................................................................................ 4 
1.1 
Trial Objectives ............................................................................................................................ 4 
2 
STUDY DESIGN ................................................................................................................................. 4 
2.1 
Trial rationale and Description of the Design ............................................................................... 4 
2.2 
Subject Randomization ................................................................................................................. 5 
2.3 
Sample Size Estimation ................................................................................................................ 5 
2.4 
Objectives and Endpoints ............................................................................................................. 5 
2.5 
Handling of Missing, Incomplete, and Repeat Data ..................................................................... 5 
2.6 
Statistical Methodology ................................................................................................................ 5 
3 
STUDY POPULATION ....................................................................................................................... 6 
3.1 
Definitions of Subject Populations ............................................................................................... 6 
3.2 
Screening and Enrollment ............................................................................................................ 6 
3.3 
Population Demography ............................................................................................................... 6 
3.4 
Disease Diagnosis and Prior Treatment ........................................................................................ 6 
3.5 
Disposition of Study Participants ................................................................................................. 6 
3.6 
Protocol Deviations ...................................................................................................................... 7 
4 
EFFICACY ANALYSES ..................................................................................................................... 7 
5 
SAFETY ANALYSES ......................................................................................................................... 7 
5.1 
Adverse Events ............................................................................................................................. 7 
6 
TABLE SHELLS ................................................................................................................................. 9 
7 
LIST OF KEY LISTING SHELLS .................................................................................................... 10 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Aviceda Therapeutics, Inc. 
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Statistical Analysis Plan 
 
 
 
 
 
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1 
INTRODUCTION 
 
Protocol Number:  
AVD-104-C301 
 
Protocol Title:  
A Phase 2 Study to Evaluate the Safety, and Treatment Effect of Intravitreal 
AVD-104 in Participants with Diabetic Macular Edema (DME). 
 
Rationale:  
To determine the safety and preliminary efficacy of intravitreal injections of 
AVD-104, a novel glyco-mimetic nanoparticle, in reducing macular edema 
associated with diabetic retinopathy. 
 
1.1 
Trial Objectives 
Primary Objective: 
• 
Evaluate the safety and tolerability of AVD-104 in participants with DME. 
Secondary Objectives: 
• 
Evaluate the treatment effect of AVD-104 at multiple doses on central subfield thickness 
(CST) as measured by Spectral-domain optical coherence tomography (SD-OCT). 
• 
Evaluate the treatment effect of AVD-104 at multiple doses on Best-corrected visual acuity 
(BCVA) using ETDRS (Early-Treatment Diabetic Retinopathy Study) visual acuity charts. 
Exploratory Objective: 
• 
 
 
2 
STUDY DESIGN 
2.1 
Trial rationale and Description of the Design 
The trial will be a multi-center, randomized evaluation of the effect of AV-104 in participants with 
diabetic macular edema. Participants will undergo baseline examinations to include BCVA, slit lamp and 
indirect ophthalmoscopy, both spectral domain OCT and OCT angiography, and ultrawide-field 
fluorescein angiography analysis. 
For all potential participants, eligibility based on severity of diabetic retinopathy must be confirmed by the 
central reading center prior to participant enrollment. In addition, all screening laboratory tests must be 
performed, and the results must be evaluated and determined to be acceptable by the investigator prior to 
participant enrollment into the study. 
Participants will then be randomized to one of two different groups: 
- 
Group 1: Two (2) injections of high-dose AVD-104 
  
- 
Group 2: Three (3) injections of low-dose AVD-104 
.    
Participants will be carefully monitored over the next 
 days with repeat evaluations to ascertain any 
effect from AVD-104.  Specific rescue criteria will allow the participants to be treated with the current 
standard-of-care agents should there be any significant decline in their vision. 
The end of the study is defined as the date of the last visit of the last participant in the study. 








Aviceda Therapeutics, Inc. 
AVD-104-C301 
 
 
Statistical Analysis Plan 
Version 1.0 – 10-JUL-2024 
 
 
 
 
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outcomes (e.g., spontaneous abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are 
considered SAEs and will be tabulated accordingly. 
 
 
 


Aviceda Therapeutics, Inc. 
AVD-104-C301 
 
 
Statistical Analysis Plan 
Version 1.0 – 10-JUL-2024 
 
 
 
 
Page 9 of 10 
 
 
 
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Aviceda Therapeutics, Inc. 
AVD-104-C301 
 
 
Statistical Analysis Plan 
Version 1.0 – 10-JUL-2024 
 
 
 
 
Page 10 of 10 
 
 
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