Clinical trial NCT05325853
Conditions: Anesthesia, Local
Keywords: AG-920 Articaine Septocaine Intravitreal Injection Proparacaine
Sponsor: American Genomics, LLC
Start date: 2022-04-06; Completion date: 2022-05-27
Enrollment: 61 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
A Phase 3, randomized, active-controlled, study in pediatric subjects. It is designed to evaluate the safety and anesthetic efficacy of one dose of AG-920 ophthalmic solution compared to Proparacaine Hydrochloride Ophthalmic Solution.

Detailed description:
A Phase 3, randomized, active-controlled, single-masked, parallel-group design study in pediatric subjects performed in the US. It is designed to evaluate the safety and anesthetic efficacy of one dose of AG-920 compared to Proparacaine. In this study, parent/legal guardians will provide informed consent (and where applicable, subjects will provide assent). Subjects who fulfill all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio to receive a single dose of AG 920 or Proparacaine into one (study) eye.

Each dose of AG-920 or Proparacaine HCl will consist of two drops in the study eye. After the completion of dosing, subjects will undergo an eye exam, and the ability to conduct that eye exam will be documented. Investigational medicinal product (IMP) dosing will be performed by the study staff.

Arms: arm 1: Articaine Sterile Topical Ophthalmic Solution (AG-920) is a sterile, isotonic, non-preserved aqueous solution containing the active ingredient Articaine HCl 8%. arm 2: 0.5% Proparacaine Hydrochloride
Interventions: intervention 1: AG-920 intervention 2: Proparacaine Ophthalmic
Intervention descriptions: intervention 1: AG-920 Sterile Topical Ophthalmic Solution intervention 2: 0.5% Proparacaine Hydrochloride

Protocol documents:
Prot_000.pdf: 


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Contact Information and Protocol Authorization 
 
Clinical Study Protocol 
AG-920-CS304  
Phase 3 
 
 
Protocol Title: 
A Randomized, Single-Masked, Active-Controlled, Parallel-
Group Evaluation of Safety and the Local Anesthetic Effect of 
Articaine Sterile Topical Ophthalmic Solution (AG-920) in a 
Pediatric Population 
Protocol Number: 
AG-920-CS304 
This study will be conducted in compliance with the clinical study protocol (and 
amendments), International Conference on Harmonisation (ICH) guidelines for current 
Good Clinical Practice (GCP) and applicable regulatory requirements. 
Sponsor Signatory: 
Martin Uram, M.D. 
Chairman 
American Genomics LLC 
Signature: 
Date: 
 
 
 
02/09/22


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Abbreviations and Terms 
 
Abbreviation 
Full text 
AE 
Adverse event 
AG-920 
Articaine sterile topical ophthalmic solution 
BCVA 
Best corrected visual acuity 
BOCF 
Baseline observation carried forward 
CFR 
Code of Federal Regulations 
COVID-19 
Coronavirus Disease 2019 
CRO 
Contract Research Organization 
EDC 
Electronic Data Capture 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
HCl 
Hydrochloride 
ICH 
International Conference on Harmonisation 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee  
IMP 
Investigational Medical Product 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
logMAR 
Logarithmic Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
NSAID 
Non-steroidal anti-inflammatory drug 
OD 
Oculus dexter (Right eye) 
OTC 
Over the Counter 
OS 
Oculus sinister (Left eye) 
PP 
Per protocol 
PPE 
Personal protective equipment 
PT 
Preferred Term 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
System/Order/Class 
SOP 
Standard Operating Procedures 
TEAE 
Treatment emergent adverse event 
US 
United States 
VA 
Visual acuity 
 
 
 


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Summary 
Study Number 
AG-920-CS304 
 
Clinical Phase: 
Phase 3 
 
Type of study 
Efficacy and Safety 
 
Name of Investigational product: 
Articaine Sterile Topical Ophthalmic Solution (AG-920) 
 
Name of Comparator product 
0.5% Proparacaine Hydrochloride 
 
 
Duration of treatment per subject 1 day 
 
Objectives and Endpoints: 
Primary Objective 
Primary Endpoints 
 
To evaluate anesthetic 
efficacy of AG-920  
The proportion of subjects 
in which an eye exam was 
able to be performed  
 
 
Secondary Objective 
Secondary Endpoints 
 
To evaluate the safety and 
tolerability of AG-920 
Incidence of AEs, TEAEs, 
SAEs, withdrawals due to 
TEAEs 
 
Subject Population:  
Healthy pediatric volunteers 
Exclusion criteria may be found in Section 4.2. 
  
Design: 
Randomized, active-controlled, single-masked, parallel-
group. 
 
Visit Schedule: 
Study visits will consist of a Screening Visit, a dosing and 
eye exam visit, and a follow-up phone call 
 
Number of Investigational Sites: 
1-3 US sites 
 
Estimated Total Sample Size: 
Enroll up to 70 subjects to result in 60 evaluable subjects; 
~30 per treatment group 
 
Plan for Data Analysis:  
The sample size is as directed by the U.S. FDA for a 
Pediatric Study Plan. 
 
Investigational/Comparator 
Product(s), Dose and Mode of 
Administration 
Subjects will receive a single dose (two drops) of IMP in 
one (study) eye.  The IMP will be randomized as either 
AG-920 or Proparacaine HCl Ophthalmic Solution.  The 
study eye will be randomized as either right eye (OD) or 
left eye (OS).  The single dose will be administered by 
the clinic staff.  
 


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TABLE OF CONTENTS 
CONTACT INFORMATION AND PROTOCOL AUTHORIZATION.......................................................... 2 
ABBREVIATIONS AND TERMS ....................................................................................................................... 3 
SUMMARY ............................................................................................................................................................ 4 
1 
INTRODUCTION........................................................................................................................................ 8 
1.1 
Findings from nonclinical and clinical studies ...................................................................................... 8 
1.2 
Potential Risks and benefits to human subjects .................................................................................... 9 
1.3 
Design justification .................................................................................................................................. 9 
2 
OBJECTIVES AND ENDPOINTS ............................................................................................................ 9 
3 
STUDY DESIGN ........................................................................................................................................ 10 
3.1 
Description and schedule of visits and procedures ............................................................................. 10 
3.2 
Measures taken to minimize/avoid bias ............................................................................................... 12 
3.3 
Study medications ................................................................................................................................. 12 
 
IMP Packaging and labeling .......................................................................................................... 12 
 
Storage of study medication .......................................................................................................... 13 
 
Study medication accountability .................................................................................................... 13 
3.4 
Expected duration of subject participation ......................................................................................... 13 
3.5 
Randomization and procedure for breaking the code ....................................................................... 13 
3.6 
Participant and Study completion ....................................................................................................... 14 
 
Completed subject ......................................................................................................................... 14 
 
Non-completing subject/Subject Withdrawal ................................................................................ 14 
 
Discontinuation of the Study ......................................................................................................... 14 
 
Discontinuation of a Clinical Site .................................................................................................. 14 
 
Actions after discontinuation ......................................................................................................... 15 
 
Completed study ............................................................................................................................ 15 
 
Procedure after the completion of the study .................................................................................. 15 
4 
SUBJECT INCLUSION AND EXCLUSION CRITERIA ..................................................................... 15 
4.1 
Subject inclusion criteria ...................................................................................................................... 15 
4.2 
Subject exclusion criteria...................................................................................................................... 15 
4.3 
Subject replacement .............................................................................................................................. 16 
5 
TREATMENT OF SUBJECTS ................................................................................................................ 16 
5.1 
Concomitant medications ..................................................................................................................... 16 
 
Prohibited medications .................................................................................................................. 16 
 
Allowed medications ..................................................................................................................... 17 
5.2 
Female Subjects ..................................................................................................................................... 17 
6 
STUDY PROCEDURES ........................................................................................................................... 17 
6.1 
General Procedures: ............................................................................................................................. 17 
6.2 
Re-screening Procedures: ..................................................................................................................... 17 
6.3 
Visit 1 (Screening) – Day -2 to 0/1 ........................................................................................................ 17 
6.4 
Visit 2 (Randomization/Treatment) – Day 1 ....................................................................................... 18 
 
Pre-dose ......................................................................................................................................... 18 
 
IMP Treatment ............................................................................................................................... 18 
 
Post Treatment and Eye Exam ....................................................................................................... 19 
 
Follow-Up Phone Call (Day 2-5)................................................................................................... 19 
6.5 
Unscheduled visits ................................................................................................................................. 19 
6.6 
COVID-19 Pandemic Accommodations .............................................................................................. 20 
7 
ASSESSMENT OF EFFICACY ............................................................................................................... 20 
8 
ASSESSMENT OF SAFETY .................................................................................................................... 20 
8.1 
Specification of safety parameters ....................................................................................................... 20 
8.2 
The methods and timing for assessing, recording, and analyzing safety parameters ..................... 20 


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8.3 
Adverse events ....................................................................................................................................... 21 
 
Adverse Event (AE) definitions ..................................................................................................... 21 
 
Serious Adverse Event (SAE) definitions ...................................................................................... 22 
 
Expedited reporting of Serious and Unexpected Adverse Events.................................................. 25 
 
Follow-up of subjects after adverse events .................................................................................... 26 
9 
STATISTICS .............................................................................................................................................. 26 
9.1 
Primary Hypotheses .............................................................................................................................. 26 
9.2 
Sample Size Considerations .................................................................................................................. 26 
9.3 
Analysis populations ............................................................................................................................. 27 
9.4 
Statistical methods to be employed ...................................................................................................... 27 
 
General Considerations .................................................................................................................. 27 
 
Interim analyses ............................................................................................................................. 27 
 
Analysis of Baseline Data .............................................................................................................. 28 
 
Subject Disposition ........................................................................................................................ 28 
 
Protocol Deviations ....................................................................................................................... 28 
 
Analysis of Efficacy ...................................................................................................................... 28 
 
Analysis of Safety .......................................................................................................................... 28 
 
Adverse Events .............................................................................................................................. 28 
9.5 
Procedure for accounting for missing, unused, or spurious data ...................................................... 29 
9.6 
Procedure for reporting deviations from the statistical plan ............................................................ 29 
9.7 
Data listings ........................................................................................................................................... 29 
10 
QUALITY CONTROL AND QUALITY ASSURANCE ....................................................................... 29 
10.1 
Audit and Inspection ........................................................................................................................ 29 
10.2 
Direct Access to Source Data Documents ....................................................................................... 29 
10.3 
Clinical Monitoring .......................................................................................................................... 29 
10.4 
Data Management and Coding ........................................................................................................ 30 
11 
ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD CLINICAL PRACTICE .... 30 
11.1 
Independent Ethics Committee or Institutional Review Board ................................................... 30 
11.2 
Regulatory Authorities ..................................................................................................................... 30 
11.3 
Ethical Conduct of the Study ........................................................................................................... 31 
11.4 
Written Informed Consent .............................................................................................................. 31 
11.5 
Subject Confidentiality .................................................................................................................... 31 
12 
DATA HANDLING AND RECORD KEEPING .................................................................................... 31 
12.1 
Data quality control and reporting ................................................................................................. 32 
12.2 
Inspection of Records ....................................................................................................................... 32 
12.3 
Records retention ............................................................................................................................. 32 
12.4 
Amendments to the protocol ............................................................................................................ 32 
13 
PUBLICATION ......................................................................................................................................... 32 
14 
REFERENCES ........................................................................................................................................... 33 
14.1 
Published references ......................................................................................................................... 33 
14.2 
Internal references ........................................................................................................................... 33 
 
APPENDIX 1: PROCEDURES............................................................................................................. 34 
APPENDIX 2: INVESTIGATOR SIGNATURE PAGE ............................................................................. 36 
 
List of tables 
TABLE 1: SCHEDULE OF VISITS AND PROCEDURES......................................................................... 11 
TABLE 2: AE ASSESSMENT OF CAUSALITY .................................................................................... 23 
TABLE 3: ASSESSMENT OF SEVERITY (INTENSITY) ......................................................................... 25 
 


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1 INTRODUCTION 
American Genomics is evaluating the formulation of articaine, an approved local anesthetic, for 
topical ocular use to provide local anesthesia. The Sponsor intends to develop Articaine Sterile 
Topical Ophthalmic Solution (AG-920) for topical ocular use to induce local anesthesia.  The 
systemic exposure to articaine after topical ocular instillation is not expected to be greater than 
that with oral (dental) use of the marketed product, Septocaine® (Package Insert).   
 
Injections of pharmacologic agents into the vitreous cavity for the purpose of treating various 
disorders of the retina as well as intraocular inflammatory disease have become the mainstream.  
In almost all cases, these injections are made through the pars plana.  An injection into the eye in 
this location, with the needle oriented properly, will be posterior to the human lens or an intraocular 
implant, but anterior to the retina, thereby avoiding damage to these important structures.  The pars 
plana is a zone that rings the eye extending from 3.0 mm to 5.5 mm from the edge of the cornea 
(Figure 1).   
 
Figure 1: Human Ocular Structure (coronal view) 
 
 
 
While topical agents such as Proparacaine achieve excellent anesthesia on the external surface of 
the eye, they do not numb the internal aspect of the pars plana, which is extremely sensitive.  
Currently, physicians fall into one of two methodologies: either injecting lidocaine under the 
conjunctiva first and then executing a second injection through the pars plana, or by using topical 
lidocaine gel and then performing the intravitreal injection.  Patients often report moderate to 
severe discomfort with each of these approaches. The purpose of the AG-920 topical drop would 
be to allow a technician to apply the topical solution to the eye, allow the articaine to penetrate the 
pars plana sufficiently to permit the intravitreal injection without undue discomfort.  Articaine was 
selected for this procedure based upon its clinical use in dental procedures, which suggest it 
penetrates soft tissue and bone.   
1.1 
Findings from nonclinical and clinical studies 
Detailed information on nonclinical and clinical studies with articaine including AG-920 is 
provided in the Investigator’s Brochure (2022).   


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1.2 
Potential Risks and benefits to human subjects 
Minimal risks are expected with AG-920.  Based upon clinical trials conducted to date, expected 
risks for subjects may include temporary, mild conjunctival/ocular hyperemia, eye pain, 
instillation site reaction (stinging/burning), and conjunctival hemorrhage upon instillation of the 
investigational medicinal product (IMP).  For any additional information on AG-920 use, please 
refer to the Investigator’s Brochure. 
 
Minimal risks are expected with the comparator, Proparacaine HCl ophthalmic solution.  
Occasional temporary stinging, burning and conjunctival redness may occur with the use of 
Proparacaine. A rare, severe, immediate-type, apparently hyperallergic corneal reaction 
(characterized by acute, intense and diffuse epithelial keratitis, a gray, ground glass appearance, 
sloughing of large areas of necrotic epithelium, corneal filaments and, sometimes, iritis with 
descemetitis) has been reported. Allergic contact dermatitis from Proparacaine with drying and 
fissuring of the fingertips has also been reported. For any additional information on Proparacaine 
use, please refer to the Package Insert. 
 
As this study is to be conducted in healthy pediatric subjects, there is no anticipated benefit other 
than the possibility that a subject’s participation in the present study may help others in the future 
to have more options for local anesthesia before ophthalmic procedures.  
 
Any new, unexpected adverse events (AEs) present among subjects in this clinical trial will be 
communicated to Investigators and to ethics committees or Institutional Review Board (IRBs) in 
accordance with local regulations.   
1.3 
Design justification  
Route of administration, dosage, dosage regimen, and treatment period(s) 
The dose selected for this study is based on clinical experience with this molecule by another route 
(dental) or from outside the United States, and preclinical safety studies.  The positive-control 
design is as discussed with the U.S. FDA for ethically and scientifically appropriate investigation 
in the pediatric population.  For more details, please refer to the Investigator’s Brochure. 
 
The selected dose of the investigational medicinal product AG-920 is 8% Articaine Sterile Topical 
Ophthalmic Solution which contains 80 mg/mL of Articaine Hydrochloride (HCl).  
 
The intended route of administration for AG-920 (testing treatment) and Proparacaine HCl 
Ophthalmic Solution (active-control or reference treatment) is topical ocular in this study.  Each 
dose of AG-920 or Proparacaine HCl will consist of two drops 30 seconds apart in the study eye.   
 
This study consists of a single treatment and subjects will be randomized 1:1 to AG-920 or 
Proparacaine HCl Ophthalmic Solution.   
2 OBJECTIVES AND ENDPOINTS 
 
Primary Objective 
Primary Endpoints 
To evaluate anesthetic efficacy of AG-920  
The proportion of subjects in which an eye 
exam was able to be performed 
 


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Secondary Objectives 
Secondary Endpoints 
To evaluate the safety and tolerability of 
AG-920 
Incidence of AEs, TEAEs, SAEs, withdrawals 
due to TEAEs 
 
 
3 STUDY DESIGN 
Randomized, Active-Controlled, single-masked, parallel. 
3.1 
Description and schedule of visits and procedures 
This is a Phase 3, randomized, active-controlled, single-masked, parallel-group design study in 
healthy pediatric subjects performed in the US.  It is designed to evaluate the safety and anesthetic 
efficacy of one dose of Articaine Sterile Topical Ophthalmic Solution (AG-920) compared to 
Proparacaine HCl Ophthalmic Solution (Proparacaine).  In this study, parent/legal guardians will 
provide informed consent (and where applicable, subjects will provide assent).  Subjects who 
fulfill all the inclusion criteria and none of the exclusion criteria will be randomized in a 1:1 ratio 
to receive a single dose of AG-920 or Proparacaine into one (study) eye.  
 
Each dose of AG-920 or Proparacaine HCl will consist of two drops 30 seconds apart in the study 
eye.  Two to 4 minutes after the completion of dosing, subjects will undergo an eye exam, and the 
ability to conduct that eye exam will be documented.  IMP dosing will be performed by the study 
staff. 
A schedule of assessments, including allowable visit windows, is displayed in Table 1.   
 
 


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Table 1: Schedule of Visits and Procedures 
 
 
Visit 1 
Visit 2 
Follow-Up 
 
Screening 
Screening & Baseline 
Phone call 
 
Day -2 -
0/1  
Pre-dose 
Day 11 
Day 2-5 
Procedures 
 
Dose 
2 -4 min 
post last 
drop 
15-60 min 
post eye 
exam 
 
 
 
0 sec 
30 sec 
 
 
 
Written Assent/Informed Consent 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria2 
X 
X2 
 
 
 
 
Demographics, Systemic and Ocular 
Medical History 
X 
 
 
 
 
 
Concomitant Medication Query 
X 
---------------------X-------------------------- 
X 
Visual Acuity3 
X3 
 
 
 
X3 
 
External Eye Exam 
X 
 
 
 
X 
 
Biomicroscopy 4 
 
 
 
 
X4 
 
Randomization 
 
X1 
 
 
 
 
IMP Administration5 
 
X 
X1 
 
 
 
Eye Exam Procedure 
 
 
 
X 
 
 
Adverse Event Assessment 
-----------------------------------X------------------------------- 
X 
IMP = investigational medicinal product 
                                                 
1 Screening may occur on the same day as Visit 2 or up to 3 days previously. If on separate days, inclusion/exclusion criteria should be re-evaluated prior to dosing 
subject to ensure subject still qualifies. 
2 If Visit 1 and 2 are not performed on the same day, these assessments must be performed prior to dosing at 0 seconds. 
3 Age appropriate optotype (if capable) with clinically appropriate test (either Teller acuity charts, Allen pictures, HOTV letters, or Snellen acuity, per standard of 
care), or reaction to light (if not).   
4 Biomicroscopy only performed if necessary for a suspected AE 
5 One dose is 2 drops.  First drop administered at 0 seconds and the second drop administered at 30 seconds (2 drops 30 seconds apart).  






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will be randomized in a 1:1 ratio to receive AG-920 or Proparacaine HCl Ophthalmic Solution. 
The site will have a randomization list that will assign each subject to treatment and study eye. 
 
The study is single masked. Treatment assignments will be masked to the subjects and their 
parent/legal guardian only so there is no reason to break the code.   
3.6 
Participant and Study completion 
 Completed subject 
A completed subject is defined as one who completes all Visits (1 and 2) and the Follow Up Phone 
call.  
 Non-completing subject/Subject Withdrawal 
A non-completing subject is defined as one who exits the study by their own volition, by decision 
of their parent/legal guardian, or at the discretion of the Investigator and/or the Medical Monitor.  
Any subject may decide to voluntarily withdraw from the study at any time without prejudice and 
the reason will be documented.  In the event that discontinuation of treatment is necessary, the 
Investigator will make every attempt to complete all subsequent safety assessments.  Every attempt 
should be made to keep subjects in the study and to perform the required study procedures, but if 
this is not possible, the subject may be withdrawn.   
 
All reasonable efforts should be made to contact the subject who is lost to follow-up.  These efforts 
must be documented in the subject’s records.  
 
Subjects may be withdrawn from the study for any reason at any time, including but not limited to 
the following reasons: 
• Subject or parent/legal guardian request 
• Use of prohibited concomitant medication/therapy 
• Lost to follow-up 
• Occurrence of AEs that are not compatible with the continuation of the subject in the study, 
in the Investigator’s opinion, or that make it unacceptable to the subject to continue 
• Investigator judgment 
• Sponsor request 
 
The reason for early discontinuation will be collected. 
 Discontinuation of the Study 
If the clinical study is prematurely terminated or suspended, the Sponsor or designee will inform 
the Investigators and the regulatory authorities of the termination/suspension and the reason(s) for 
the termination/suspension.  The Investigators should promptly notify their Independent Ethics 
Committee (IEC) or Institutional Review Board (IRB) of the termination or suspension and of the 
reasons. 
 Discontinuation of a Clinical Site 
The Sponsor reserves the right to close an investigational site or terminate the study in its entirety 
at any time, for reasonable cause.  Reasons for the closure of any investigational site or termination 
of the study may include: 


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• Failure to accrue subjects into the study at an acceptable rate. 
• Failure of the Investigator to comply with applicable regulations and Good Clinical 
Practice (GCP) guidelines. 
• Submission of knowingly false information from the research facility to the Sponsor, Food 
and Drug Administration (FDA), or other regulatory authorities. 
• Insufficient adherence to protocol requirements and procedures. 
If the study is prematurely discontinued, all study data must be returned to the Sponsor or designee.  
Additionally, the site must conduct final disposition of all unused IMP in accordance with CRO 
procedures.  Study termination and follow-up will be performed in compliance with the conditions 
set forth in regulatory guidelines. 
 Actions after discontinuation 
All subjects who discontinue IMP due to a report of an AE must be followed-up and provided 
appropriate medical care until their signs and symptoms have remitted, stabilized, determined to 
be chronic, or until abnormal laboratory findings have returned to acceptable or pre-study limits if 
performed as part of the AE assessment.  
 
For the subject who chooses to withdraw consent or who is non-compliant, every possible effort 
should be made by the Investigator to perform all examinations listed for Visit 2.  
 Completed study 
The end of the study is defined as the date the last subject completes the Follow-up Phone Call.   
 Procedure after the completion of the study 
When the study is completed and the site has been closed out, the Investigator will be asked to 
notify the governing IRB of study closure.  
4 SUBJECT INCLUSION AND EXCLUSION CRITERIA 
Subjects must meet all of the following inclusion criteria to be eligible for participation in this 
study.  On criteria that involve the eyes, both eyes must qualify.   
4.1 
Subject inclusion criteria 
1. Male or female aged 10 years or less (pre-pubescent with no childbearing potential)  
2. Capable of undergoing an eye exam per investigator judgement 
3. Subject’s legally appointed and authorized representative willing to sign and date an 
informed consent form (ICF) and, where appropriate, the subject willing to sign an assent 
form prior to any study-related procedures being performed. 
4. Parent/legal guardian and subject are willing and able to follow instructions and can be 
present for the required study visits and Follow-up Phone Call for the duration of the study. 
5. Have a healthy, normal cornea. 
6. Have a planned ophthalmic examination. 
4.2 
Subject exclusion criteria 
Subjects who meet any of the following exclusion criteria are ineligible for this study: 
 
1. Have participated in an investigational study (drug or device) within the past 30 days. 












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8.3 
Adverse events1 
All AEs occurring after the first dose of IMP and throughout the remainder of the study period 
(Follow-up Phone Call) will be considered TEAEs and must be documented on the relevant 
Electronic Data Capture (EDC) pages and in the source documents.  Whenever possible, the 
diagnosis, if available, and not the symptoms should be reported as the AE.  AEs and Serious 
Adverse Events (SAEs) will be coded according to the Medical Dictionary for Regulatory 
Activities (MedDRA).  
 
Documentation of adverse events/adverse reactions includes start date and stop date, severity, 
action(s) taken, seriousness and outcome.   
 Adverse Event (AE) definitions 
An AE is any untoward medical occurrence in a subject or clinical investigation subject, temporally 
associated with the use of a medicinal product, whether or not considered related to the medicinal 
product. 
 
Note: An AE can therefore be any untoward or unfavorable medical occurrence in a human subject, 
including any abnormal sign (for example, abnormal physical exam or laboratory finding), 
symptom, or disease, temporally associated with the subject’s participation in the research, 
whether or not considered related to the subject’s participation in the research. 
 
Any untoward or unfavorable medical occurrence in a human subject, including any abnormal sign 
(for example, abnormal physical exam or laboratory finding), symptom, or disease, temporally 
associated with the subject’s participation in the research, whether or not considered related to the 
subject’s participation in the research will be documented.  
 
Events meeting the definition of an AE include: 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase 
in frequency and/or intensity of the condition 
• New conditions detected or diagnosed after study drug administration even though it may 
have been present prior to the start of the study 
• Signs, symptoms, or clinical sequelae of a suspected interaction 
• Signs, symptoms, or clinical sequelae of a suspected overdose of either study drug or a 
concomitant medication (overdose per se will not be reported as an AE/SAE). 
 
Events that do not meet the definition of an AE include: 
• Medical or surgical procedure (e.g., endoscopy, appendectomy); the condition that leads to 
the procedure is an AE 
• Situations where an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital) 
• 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 significantly worsen 
                                                 
1 Note: This section is referenced to 21 CFR 312.32 (IND safety reports), updated as per “Investigational New Drug 
Safety Reporting Requirements for Human Drug and Biological Products and Safety Reporting Requirements for 
Bioavailability and Bioequivalence Studies in Humans (Fed Reg 2010: 75 (188): 59935-59963). 


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• The disease/disorder being studied, or expected progression, signs, or symptoms of the 
disease/disorder being studied, unless rescue medication or other medical treatment is 
required. 
8.3.1.1 Life-threatening adverse event or life-threatening suspected adverse reaction.   
An adverse event or suspected adverse reaction is considered “life-threatening” if, in the view of 
either the Investigator or Sponsor, its occurrence places the subject at immediate risk of death.  It 
does not include an adverse event or suspected adverse reaction that, had it occurred in a more 
severe form, might have caused death.   
8.3.1.2 Suspected adverse reaction 
Suspected adverse reaction means any adverse event for which there is a reasonable possibility 
that the drug caused the adverse event.  For the purposes of IND safety reporting, ‘‘reasonable 
possibility’’ means there is evidence to suggest a causal relationship between the drug and the 
adverse event.  Suspected adverse reaction implies a lesser degree of certainty about causality than 
adverse reaction, which means any adverse event caused by a drug.   
8.3.1.3 Unexpected adverse event or unexpected suspected adverse reaction.   
An adverse event or suspected adverse reaction is considered ‘‘unexpected’’ if it is not listed in 
the Investigator brochure or is not listed at the specificity or severity that has been observed; or, if 
an investigator brochure is not required or available, is not consistent with the risk information 
described in the general investigational plan or elsewhere in the current application, as amended.  
For example, under this definition, hepatic necrosis would be unexpected (by virtue of greater 
severity) if the investigator brochure referred only to elevated hepatic enzymes or hepatitis.  
Similarly, cerebral thromboembolism and cerebral vasculitis would be unexpected (by virtue of 
greater specificity) if the Investigator brochure listed only cerebral vascular accidents.  
“Unexpected,” as used in this definition, also refers to adverse events or suspected adverse 
reactions that are mentioned in the Investigator brochure as occurring with a class of drugs or as 
anticipated from the pharmacological properties of the drug, but are not specifically mentioned as 
occurring with the particular drug under investigation. 
 
Note: Any medical condition present prior to administration of the masked study medication which 
remains unchanged or improved should not be recorded as an adverse event at subsequent visits. 
 Serious Adverse Event (SAE) definitions 
An SAE is an AE that:  
• Results in death. 
• Is life-threatening (an AE is life-threatening if the subject was at immediate risk of death 
from the event as it occurred, i.e., it does not include a reaction that might have caused 
death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization.  Complications occurring during 
hospitalization are AEs or SAEs if they cause prolongation of the current hospitalization.  
Hospitalization or prolonged hospitalization for elective treatment of a pre-existing non 
worsening condition is not, however, considered an AE.   
• Results in persistent or significant disability/incapacity.  (An AE is incapacitating or 
disabling if it results in a substantial and/or permanent disruption of the subject’s ability to 
carry out normal life functions). 


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• Is a congenital anomaly/birth defect. 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above. 
 
Medical and scientific judgment is required to decide if prompt notification is required in situations 
other than those defined for SAEs above.  This can include an AE that suggests any significant 
hazard, contraindication, adverse event, or precaution that may be associated with the use of the 
IMP. 
8.3.2.1 Recording an AE and/or SAE including Onset Date, End Date  
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 CRF. 
If an AE starts but does not end before the final visit, the Investigator must make a reasonable 
effort to establish the outcome and the end date of the AE.  If this is not possible (e.g., because the 
AE is still ongoing) or the subject is lost to follow-up, there will be no end date for the AE and the 
status will be recorded as “ongoing.”  For all AEs that resolve, resolve with sequelae, or have a 
fatal outcome, an end date must be provided. 
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. 
8.3.2.2 Assessment of Causality 
Every effort will be made by the Investigator to assess the relationship of the AE, if any, to the 
IMP.  Causality should be assessed as unrelated or related using the categories defined in Table 2.   
 
 
Table 2: AE Assessment of Causality 
Unrelated: 
• Clinical event with an incompatible time relationship to IMP 
administration, and that could be explained by underlying disease or 
other drugs or chemicals or is incontrovertibly not related to the IMP, 
or 
• Clinical event whose time relationship to IMP makes a causal 
connection improbable, but that could plausibly be explained by 
underlying disease or other drugs or chemicals. 
Related: 
• Clinical event with a reasonable time relationship to IMP, but that 
could also be explained by concurrent disease or other drugs or 
chemicals, or 
• Clinical event with a reasonable time relationship to IMP and is 
unlikely to be attributed to concurrent disease or other drugs or 
chemicals, or 
• Clinical event with plausible time relationship to IMP, and that 
cannot be explained by concurrent disease or other drugs or 
chemicals. 
Abbreviations:  AE=Adverse Event; IMP=investigational medicinal product 


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8.3.2.3 Assessment of Severity (Intensity) 
The severity of an adverse event is defined as a qualitative assessment of the level of discomfort 
of an adverse event as is determined by the Investigator or reported to him/her by the subject.  The 
assessment of intensity is made irrespective of study medication relationship or seriousness of the 
event.  The investigator will make an assessment of intensity for each AE and SAE reported during 
the study and assign it to 1 of the following categories: and should be evaluated according to the 
scale in Table 3. 
 
 


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Table 3: Assessment of Severity (Intensity) 
Mild 
An event that is easily tolerated by the participant, causing minimal 
discomfort and not interfering with everyday activities. 
Moderate 
An event that causes sufficiently discomfort and interferes with normal 
everyday activities. 
Severe 
An event that prevents normal everyday activities. An AE that is assessed as 
severe should not be confused with a SAE. Severe is a category utilized for 
rating the intensity of an event; and both AEs and SAEs can be assessed as 
severe. 
 
Please note: the term “severe” is used to describe the intensity (severity, see above) of an 
event/reaction; the event/reaction itself may be of relatively minor medical significance (such as 
severe headache).  This is not the same as a “Serious” Adverse Event, which is based on 
subject/event outcome or action criteria usually associated with events that pose a threat to the 
subject’s life or vital functions.  “Serious” (NOT severity) serves as a guide for defining regulatory 
reporting obligations.  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. 
 Expedited reporting of Serious and Unexpected Adverse Events 
Safety reports   
An investigator must immediately report to the Sponsor or Sponsor representative any serious 
adverse event, whether or not considered drug-related, including those listed in the protocol or 
investigator brochure and must include an assessment of whether there is a reasonable possibility 
that the drug caused the event.  Study endpoints that are serious adverse events (e.g., all-cause 
mortality) must be reported in accordance with the protocol unless there is evidence suggesting a 
causal relationship between the drug and the event (e.g., death from anaphylaxis).  In that case, the 
Investigator must immediately report the event to the Sponsor.  The investigator must record non-
serious adverse events and report them to the Sponsor according to the timetable for reporting 
specified in the protocol.  In case of incomplete information, the Investigator must provide follow-
up information as soon as possible, again using the SAE report form.   
 
This requirement applies to occurrences observed during the course of the study and within four 
(4) weeks of last administration of the study medication.   
 
In addition, in the case of immediately life-threatening AEs or AEs with fatal outcome, or adverse 
events that are serious, unexpected (i.e., not in the Clinical Investigator’s Brochure) and judged 
related to the investigational product, the Investigator must inform the Sponsor or Sponsor 
representative by phone within 24 hours of observation or occurrence of the SAE. 
 
SAEs must be reported to the IRB/EC according to the IRB/EC requirements. 
 
The Investigator/designee will forward all source documents (redacted, if necessary, to maintain 
the blind) related to the SAE to the Medical Monitor.  For each SAE and follow-up to an SAE, the 
site should ensure that an SAE Narrative and critical baseline CRFs are completed as of the onset 
date for the SAE (e.g., demographics, concomitant medications, and medical history) and emailed 




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9.3 
Analysis populations 
Randomized Population: The randomized population will include all subjects who were 
randomized to treatment.  Baseline (screening) variables and demographic characteristics will be 
summarized for this population. 
 
Intent-to-Treat Population (ITT): The ITT population will include all randomized subjects who 
have received at least one dose (two drops) of study medication.  This population will be the 
primary population for the efficacy analyses and all efficacy variables will be summarized using 
this set of subjects.  The ITT population will include subjects as randomized. 
 
Per-protocol population (PP): The PP population is a subset of the ITT population, which will 
include those subjects (and their visits) who do not have major protocol violations likely to 
seriously affect the primary outcome of the study as judged by a masked evaluation prior to the 
unmasking of the study treatment.  This population will be the secondary population for efficacy 
analyses and all efficacy variables will be summarized using this set of subjects.  If the PP and ITT 
populations are exactly the same and there are no missing data, then additional efficacy analyses 
on the PP population will not be performed.  The PP population will include subjects as treated. 
 
Safety Population: The safety population will include all randomized subjects who have received 
at least one drop of study medication.  This population will be used to summarize the safety 
variables and will summarize subjects as treated.   
9.4 
Statistical methods to be employed 
 General Considerations 
All continuous study assessments will be summarized by treatment and time point (as applicable) 
using descriptive statistics (n, mean, median, standard deviation, minimum, and maximum).  All 
categorical study assessments will be summarized by treatment and time point (as applicable) 
using frequency counts and percentages.   
 
Hypothesis testing, unless otherwise indicated, will be performed at a two-sided 0.05 significance 
level.  Where applicable, two-sided 95% confidence intervals will be reported.  All p-values will 
be displayed to four decimal places, with p-values less than 0.0001 presented as '<0.0001' and p-
values greater than 0.9999 presented as ‘>0.9999’.  Difference between Articaine Sterile Topical 
Ophthalmic Solution (AG-920) and Proparacaine will be calculated as Articaine Sterile Topical 
Ophthalmic Solution – Proparacaine, with the 95% CI of the difference being reported for the 
reference of the treatment therapeutical equivalence.  
 
All study data will be listed by treatment, subject, time point, and eye (as applicable).   
 
Statistical methods will be more fully described in a separate document (Statistical Analysis Plan).   
 Interim analyses 
There is no planned interim analysis.   


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 Analysis of Baseline Data 
Demographic and baseline characteristics such as age, sex, ethnicity, race, and iris color will be 
summarized and listed.  Depending upon the extent of medical and ocular history and concomitant 
medications in these healthy subjects, coding systems such as MedDRA and WHODrug will be 
used, and these data will be summarized and listed.   
 Subject Disposition 
Subject enrollment and exit status (completed or discontinued) will be summarized and listed. 
 Protocol Deviations 
Important protocol deviations are deviations from the protocol that potentially could have a 
meaningful impact on study conduct, or on the primary efficacy or key safety outcomes for an 
individual subject.  The criteria for identifying important protocol deviations will be defined within 
the appropriate protocol-specific document.  Important protocol deviations will be reviewed as 
part of the ongoing data cleaning process and all important deviations will be identified and 
documented prior to unmasking to confirm exclusion from analysis sets.  Further details will be 
provided in the SAP. 
 Analysis of Efficacy 
Analyses will be performed primarily on the ITT population and will be repeated on the PP 
population to determine robustness of results.  For the primary efficacy endpoint of the proportion 
of subjects in whom there was adequate local anesthetic effect to perform an eye exam for which 
the subject is seeing the ophthalmologist, a Pearson chi-square test will be used for the comparison 
of the two proportions from the two treatment groups.  In addition, a two-sided 95% confidence 
interval for the difference in response rates between the two treatment groups will be calculated.  
If the difference in response rates is around zero and the P value is NOT statistically significant 
(i.e., P>0.05), then the therapeutical equivalence of AG-920 to the Proparacaine will be claimed, 
without reference to a pre-defined non-inferiority margin.  The 95% CI of the difference in 
response rates will be reported to measure the extend or margin of the efficacy equivalence of 
AG920 to Proparacaine.  
 
Sub-group analyses based upon pre-study characteristics such as sex, iris color, age, and race may 
be completed to further investigate the efficacy and safety measures.   
 Analysis of Safety 
External eye exam measures and slit lamp biomicroscopy (if applicable) will be summarized at 
each measured time point using discrete summary statistics. 
 
Visual Acuity data will be summarized at each time point organized by the age and clinically 
appropriate test, which may be continuous, categorical or both. 
 Adverse Events 
Verbatim descriptions of AEs will be mapped to MedDRA thesaurus terms and presented in a data 
listing.  Treatment emergent AEs, those that occur after the first dose of study medication, will be 
summarized by treatment group using frequency counts and percentages for each System Organ 
Class (SOC) and Preferred Term (PT) within each SOC.  Summaries will be presented separately 
for ocular and non-ocular AEs.  These summaries will also be presented by the relationship to the 


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Investigational Medicinal Product (related, unrelated) and by severity of the AE (mild, moderate, 
severe).  Fisher’s exact test will be used to test the difference in proportions of subjects with each 
AE between treatment groups (SOC and PT).   
9.5 
Procedure for accounting for missing, unused, or spurious data 
A minimal amount of missing data is expected in this study because of the short duration and the 
subjects being in the clinic on Day 1.  For the ITT population, any missing data on Day 1 will be 
imputed using the method of last observation carried forward (LOCF), where the closest non-
missing value prior to the missing value will be carried forward and imputed for the missing value.  
The PP and Safety populations will be based on observed data only (without imputation).  Any 
missing, unused, or spurious data will be noted and explained in the final statistical report. 
9.6 
Procedure for reporting deviations from the statistical plan 
Any deviations from the statistical plan will be described and a justification given in the final 
statistical report. 
9.7 
Data listings 
Data listings will be prepared for all data on the database. 
10 QUALITY CONTROL AND QUALITY ASSURANCE 
10.1 Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audits during the 
study by the Sponsor or its designee.  In addition, inspections may be conducted by regulatory 
authorities at their discretion. 
10.2 Direct Access to Source Data Documents 
Authorized representatives of the Sponsor, a regulatory authority, an IEC or IRB may visit the site 
to perform audits or inspections, including source data verification.  The purpose of a Sponsor 
audit or inspection is to systematically and independently examine all study-related activities and 
documents to determine whether these activities were conducted, and data were recorded, 
analyzed, and accurately reported according to the protocol, GCP guidelines, and any applicable 
regulatory requirements.  The Investigator should contact the Sponsor immediately if contacted by 
a regulatory agency about an inspection. 
10.3 Clinical Monitoring 
Data for each subject will be recorded in a source document and in EDC for each subject who has 
had a parent/legal guardian sign an informed consent form (ICF)/assent. 
 
In accordance with current GCP and International Conference of Harmonisation (ICH) guidelines, 
the study monitor will carry out source document verification at regular intervals to ensure that the 
data collected in EDC are accurate and reliable.  
 
The Investigator must permit the monitor, the IEC/IRB, the Sponsor’s internal auditors, and 
representatives from regulatory authorities’ direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within EDC.   
 


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Due to the COVID-19 Pandemic, remote monitoring visits may replace some of the onsite 
monitoring visits.  It will still be the responsibility of the monitor to discuss the study and any 
issues with the Principal Investigator via telephone or videoconference.  
10.4 Data Management and Coding 
The CRO will be responsible for data management per their SOPs.  This will include setting up a 
relevant database and data transfer mechanisms, along with appropriate validation of data and 
resolution of queries.  Data generated within this clinical study will be handled according to the 
relevant standard operating procedures of the data management and biostatistics departments of 
the CRO. 
 
All data for subjects who sign an ICF/assent and receive a dose of IMP will be recorded via EDC.  
Subjects who are screened but found ineligible for the study and who do not receive IMP will be 
considered screen failures.  The reason for exclusion from the study will be recorded.   
 
Data entered into EDC must be verifiable against source documents at the study center.  Any 
changes to the data entered into the EDC system will be recorded in the audit trail and will be FDA 
Code of Federal Regulations (CFR) 21 Part 11 compliant. 
 
MedDRA will be used to code AEs.  Medications will be coded by WHODrug.  Missing or 
inconsistent data will be noted within the EDC system and queried with the Investigator for 
clarification.  Subsequent modifications to the database will be documented. 
11 ETHICAL CONSIDERATIONS AND COMPLIANCE WITH GOOD 
CLINICAL PRACTICE 
11.1 Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the subject, and any other relevant study documentation will be submitted to the 
appropriate IEC/IRB.  Written approval of the study and all relevant study information must be 
obtained before the study center can be initiated or the IMP released to the Investigator.  Any 
necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the study 
such as amendments to the protocol, the ICF or other study documentation. The written approval 
of the IEC/IRB together with the approved ICF must be filed in the study files. 
The Investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the study.  The Investigator will submit written 
summaries of the study status to the IEC/IRB as required.  On completion of the study, the IEC/IRB 
will be notified that the study has ended. 
11.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the beginning 
of the study.  On completion of the study, the regulatory authorities will be notified that the study 
has ended. 


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11.3 Ethical Conduct of the Study 
The Investigator(s) and all parties involved in this study should conduct the study in adherence to 
the ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines, and the 
applicable national and local laws and regulatory requirements. 
11.4 Written Informed Consent 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to GCP. 
 
The Investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before the parent(s)/legal guardian(s) have given written informed consent 
for their child to participate in the study. 
 
The Investigator or designated personnel will inform the parent(s)/legal guardian(s) of the 
objectives, methods, anticipated benefits and potential risks and inconveniences of the study. The 
parent(s)/legal guardian(s) should be given every opportunity to ask for clarification of any points 
s/he does not understand and, if necessary, ask for more information. At the end of the interview, 
the parent(s)/legal guardian(s) will be given ample time to consider the study. The parent(s)/legal 
guardian(s) will be required to sign and date the ICF. After signatures are obtained, the ICF will 
be kept and archived by the Investigator in the Investigator’s study file. A signed and dated copy 
of the subject ICF will be provided to the subject’s authorized representative. 
 
It should be emphasized that the parent(s)/legal guardian(s) may refuse permission for their child 
to enter the study or may withdraw their child from the study at any time, without consequences 
for their further care or penalty or loss of benefits to which the subject is otherwise entitled. 
Children of parents(s)/legal guardian(s) who refuse to give or who withdraw written informed 
consent should not be included or continue in the study. 
 
If new information becomes available that may be relevant to the willingness of the subject’s 
parent(s)/legal guardian(s) to allow continuation of their child’s participation in the study, a new 
ICF will be approved by the IEC(s)/IRB(s) (and regulatory authorities, if required). The 
parent(s)/legal guardian(s) of the study subjects will be informed about this new information and 
reconsent will be obtained. 
11.5 Subject Confidentiality 
Monitors, auditors, and other authorized agents of the Sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, as well as that of any other applicable agency, will be 
granted direct access to the study subjects’ original medical records for verification of clinical 
study procedures and/or data, without violating the confidentiality of the subjects to the extent 
permitted by the law and regulations.  In any presentations of the results of this study or in 
publications, the subjects’ identity will remain confidential. 
12 DATA HANDLING AND RECORD KEEPING 
All procedures for the handling and analysis of data will be conducted using good computing 
practices meeting ICH and U.S. Food and Drug Administration (FDA) guidelines for the handling 
and analysis of data for clinical trials. 


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12.1 Data quality control and reporting 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database.  Queries are entered directly into the 
eCRF page and are answered by the sites. They are then reviewed by the data manager and/or 
monitor. All database changes (and the query history) is documented automatically in the audit 
trail of the eCRF system.    
12.2 Inspection of Records 
American Genomics or designee will be allowed to conduct site visits to the investigation facilities 
for the purpose of monitoring any aspect of the study.  The Investigator agrees to allow the monitor 
to inspect the drug storage area, IMP stocks, drug accountability records, subject charts and study 
source documents, and other records pertaining to study conduct. 
12.3 Records retention 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced.  After completion of the study, all documents and data 
relating to the study will be kept in an orderly manner by the Investigator in a secure study file.  
This file will be available for inspection by the Sponsor or its representatives.  Essential documents 
should be retained for 2 years after the final marketing approval in an ICH region or for at least 2 
years from the discontinuation of clinical development of the investigational product.  It is the 
responsibility of the Sponsor or its representatives to inform the study center when these 
documents no longer need to be retained.  The Investigator must contact the Sponsor before 
destroying any study related documentation.  In addition, all subject medical records and other 
source documentation will be kept for the maximum time permitted by the hospital, institution, or 
medical practice. 
12.4 Amendments to the protocol 
Modifications of the signed protocol are only possible by approved protocol amendments and with 
the agreement of all responsible persons.  The procedure for approval of a protocol amendment is 
identical to that for approval of the protocol.  The ethics committee must be informed of all 
protocol amendments and should be asked for its opinion as to whether a full re-evaluation of the 
ethical aspects of the study is necessary by the committee.  This should be fully documented.   
 
The investigator must not implement any deviation from or change to the protocol, without 
discussion with, and agreement by American Genomics, LLC and prior review and documented 
approval/favorable opinion of the amendment from the relevant ethics committee, except where it 
is necessary to eliminate an immediate hazard to study subjects, or where the change(s) involves 
only logistical or administrative aspects of the study (e.g., change in monitor(s), change of 
telephone number(s)).   
 
Protocol amendments will be submitted to the appropriate authority(ies) as required by the 
applicable regulatory requirement(s).   
13 PUBLICATION 
The Sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the Investigator(s).  Published data must not compromise the objectives of 


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the study. Data from individual study centers in multicenter studies must not be published 
separately. 
14 REFERENCES 
14.1 Published references 
• Septocaine® package insert, 2018. 
• Proparacaine Hydrochloride package insert, 2020 
• FDA Guidance on Conduct of Clinical Trials of Medicinal Products during COVID-19 
Public Health Emergency, March 2020; https://www.fda.gov/media/136238/download. 
14.2 Internal references 
• American Genomics, LLC, Articaine Sterile Topical Ophthalmic Solution Investigator’s 
Brochure, 2021.  
 




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CONJUNCTIVA  
Hyperemia 
None (0)=  
Normal. Appears white with a small number of conjunctival blood vessels easily 
observed.  
Mild (+1)= 
Prominent, pinkish-red color of both the bulbar and palpebral conjunctiva; 
Moderate (+2)= 
Bright, scarlet red color of the bulbar and palpebral conjunctiva 
Severe (+3)= 
“Beefy Red” with petechiae --- Dark red bulbar and palpebral conjunctiva with 
evidence of subconjunctival hemorrhage   
 
Edema 
None (0)= 
Normal, no swelling of the conjunctiva or less than mild 
Mild (+1)= 
Slight diffuse or regional swelling of the conjunctiva 
Moderate (+2)= 
General swelling of the conjunctiva 
Severe (+3)= 
Extensive swelling of the conjunctiva 
 
CORNEA 
Edema 
None (0)= 
Transparent and clear or less than mild 
Mild (+1) = 
Dull glassy appearance 
Moderate (+2)= 
Dull glassy appearance of epithelium with large number of vacuoles 
Severe (+3) = 
Stromal edema, localized or diffuse, with stromal striae 
 
 
ANTERIOR CHAMBER 
Cells 
None (0)= 
No cells seen or less than mild 
Mild (+ 1) = 
+ cells 
Moderate (+2) = 
++ cells 
Severe (+3) = 
+++ cells 
Hypopyon (+4)= 
++++ cells, Hypopyon Formation (indicate size of hypopyon) 
 
 
Flare 
None (0)= 
No Tyndall effect or less than mild 
Mild (+1) = 
Tyndall beam in the anterior chamber has a mild intensity 
Moderate (+2) = 
Tyndall beam in the anterior chamber is of strong intensity 
Severe (+3) = 
Tyndall beam is very intense.  The aqueous has a white, milky appearance 
 
 
 
 


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Appendix 2: Investigator Signature Page 
 
Protocol Title: 
A Randomized, Single-Masked, Active-Controlled, Parallel-
Group Evaluation of Safety and the Local Anesthetic Effect of 
Articaine Sterile Topical Ophthalmic Solution (AG-920) in a 
Pediatric Population 
Protocol Number: 
AG-920-CS304 
Confidentiality and Current Good Clinical Practice Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including appendices, and I 
will conduct the study as described in compliance with this protocol (and amendments), GCP, and 
relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without 
obtaining prior approval of American Genomics, LLC and of the IEC/IRB.  I will submit the 
protocol amendments and/or any ICF modifications to American Genomics, LLC and IEC/IRB, 
and approval will be obtained before any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential.  No subjects’ name will be disclosed.  All 
subjects will be identified by assigned numbers on all EDC, laboratory samples, or source 
documents forwarded to American Genomics, LLC.  Clinical information may be reviewed by 
American Genomics, LLC or its agents or regulatory agencies.  Agreement must be obtained from 
the subject before disclosure of subject information to a third party. 
Information developed in this clinical study may be disclosed by American Genomics, LLC, to 
other clinical Investigators, regulatory agencies, or other health authority or government agencies 
as required. 
Investigator Signature 
Date 
Printed Name 
 
Institution 
 

SAP_001.pdf: 


S T A TI S TI C A L A N A L Y SI S P L A N 
A B B R E VI A TI O N S A N D D E FI NI TI O N S .................................................................................. 4  
1  
I N T R O D U C TI O N ............................................................................................................ 5  
2  
S T U D Y D E SI G N ............................................................................................................. 6  
3 
S T U D Y P O P U L A TI O N ................................................................................................. 1 2 
4  
E F FI C A C Y E V A L U A TI O N ............................................................................................ 1 3 
5 
S A F E T Y E V A L U A TI O N ............................................................................................... 1 4 


5. 6  
C o n c o mit a nt M e di c ati o n .......................................................................................... 1 6  
6 
R E F E R E N C E S ............................................................................................................. 1 6  
7  
LI S T O F S T A TI S TI C A L T A B L E S H E L L S .................................................................... 1 7  
8 
LI S T O F K E Y LI S TI N G S H E L L S ................................................................................. 2 0  
9 
LI S T O F FI G U R E S ....................................................................................................... 2 1  
1 0 
LI S T O F O T H E R C R F D A T A T A B U L A TI O N S (I C H E 3 TI T L E F O R S E C TI O N 1 6) .... 2 1  


A B B R E VI A TI O N S A N D D E FI NI TI O N S 


1 
I N T R O D U C TI O N 
1. 1  
Tri al O bj e cti v e s 
1. 2  
B a c k gr o u n d I nf or m ati o n 


2  
S T U D Y D E SI G N 
2.1  
R ati o n al e 
2. 2  
D e s cri pti o n of Tri al D e si g n 


2. 3  
S c h e d ul e of A s s e s s m e nt s 
2. 4  
R a n d o mi z ati o n 
2. 5  
S a m pl e Si z e E sti m ati o n 


2. 6  
E ffi c a c y a n d S af et y M e a s ur e m e nt s 
2. 6.1  
Pri m ar y e ffi c a c y m e a s ur e 
2. 6. 2 
S e c o n d ar y e ffi c a c y m e a s ur e 
2. 6. 3  
S af et y m e a s ur e s 
2. 6. 4  
Ot h er m e a s ur e s 
2. 7  
Dr u g C o n c e ntr ati o n a n d P K M e a s ur e m e nt s 
2. 8  
H a n dli n g of Mi s si n g, I n c o m pl et e, a n d R e p e at D at a 


2. 9  
St ati sti c al M et h o d s 
2. 9.1  
Pri m ar y e ffi c a c y a n al y si s 


2. 9. 2 
S e c o n d a ff e ffi c a c y a n al y si s 
2. 9. 3  
S af et y a n al y si s 


2. 9. 4 
Ot h er a n al y si s 


3  
S T U D Y P O P U L A TI O N 
3.1  
D efi niti o n of S u bj e ct P o p ul ati o n s 
3. 2  
S cr e e ni n g a n d E nr oll m e nt 


3. 3  
P o p ul ati o n D e m o gr a p h y 
3. 4 
Di s e a s e C h ar a ct eri sti c s a n d Pri or Tr e at m e nt 
3. 5  
M e di c al Hi st or y 
3. 6  
Di s p o siti o n of St u d y P a ffi ci p a nt s 
3. 7  
Pr ot o c ol D e vi ati o n s a n d Vi ol ati o n s
4  
E F FI C A C Y E V A L U A TI O N 
4.1  
D at a s et s A n al y z e d 


4. 2  
Tr e at m e nt C o m pli a n c e 
4. 3  
D at a Mi s si n g a n d I m p ut ati o n 
4. 4  
B a s eli n e M e a s ur e s 
4. 5 
E ffi c a c y R e s ult s a n d T a b ul ati o n s 
4. 5.1  
R e s ult s of pri m ar y e ffi c a c y a n al y si s 
4. 5. 2  
R e s ult s of s e c o n d ar y e ffi c a c y a n al y s e s 
5  
S A F E T Y E V A L U A TI O N 
5.1  
E xt e nt of Dr u g E x p o s ur e 


5. 2  
E arl y T er mi n ati o n 
5. 3  
A d v er s e E v e nt s 
5. 4  
Vi s u al A c uit y a n d E xt er n al E y e E x a m 


5. 5  
Bi o- mi cr o s c o p y 
5. 6  
C o n c o mit a nt M e di c ati o n 


7 
Li st of St ati sti c al T a bl e S h ell s 




  
  
 
 
 
  
  
 
 
  
 
  
 
 


8 
Li st of K e y Li sti n g S h ell s 
( S A P) 
I C H E 3 Titl e f or 
S e cti o n 1 4 ( T F L) 
Li sti n g 1 4. 1. 2. 1 
Li sti n g 1 4. 1. 3. 1 
Li sti n g 1 4. 1. 3. 2 
Li sti n g 1 4. 1. 1. 2 
Li sti n g 1 4. 1. 1. 1 
ff i sti n g 1 4. 2. 1. 1 
Li sti n g 1 4. 3. 1. 1 
Li sti n g 1 4. 3. 2. 3 
_i sti n g 1 4. 3. 2. 2 
Li sti n g 1 4. 1. 4. 1 


9  
Li st of Fi g ur e s 
1 0 
Li st of Ot h er C R F D at a T a b ul ati o n s (I C H E 3 Titl e f or S e cti o n 1 6)