A First-in-Human, Phase 1/2, Dose-ascending, Multicenter, Masked, Randomized, Vehicle-controlled Study Evaluating the Safety, Tolerability, and Pharmacokinetics of AGN-241622 in Healthy Participants and Participants With Presbyopia (Stage 1 and Stage 2) and Efficacy in Participants With Presbyopia (Stage 2)
Phase: PHASE1
Conditions: Presbyopia
Sponsor: AbbVie

 
   
 
 
 
         NCT04403763 
 
Study ID: 2011-101-013  
 
 
Title: A First-in-Human, Phase 1/2, Dose-ascending, Multicenter, Masked, 
Randomized, Vehicle-controlled Study Evaluating the Safety, Tolerability, 
and Pharmacokinetics of AGN-241622 in Healthy Participants and 
Participants with Presbyopia (Stage 1 and Stage 2) and Efficacy in 
Participants with Presbyopia (Stage 2) 
 
                                         Protocol Date: March 25, 2020 

CONFIDENTIAL  
Protocol 2011-101-013 Amendment 1 
AGN-241622 
GRD-CLN-T-01-01 v5.0 
1 
Title Page 
Protocol Title: A First-in-Human, Phase 1/2, Dose-ascending, Multicenter, Masked, 
Randomized, Vehicle-controlled Study Evaluating the Safety, Tolerability, and 
Pharmacokinetics of AGN-241622 in Healthy Participants and Participants with Presbyopia 
(Stage 1 and Stage 2) and Efficacy in Participants with Presbyopia (Stage 2) 
Protocol Number: 2011-101-013 
Compound: AGN-241622 
Study Phase: Phase 1/2 
Short Title: Phase 1/2 study of AGN-241622 in healthy participants and participants with 
presbyopia 
Sponsor Name and Legal Registered Address: 
Allergan Sales, LLC 
5 Giralda Farms 
Madison, NJ 07940 
USA 
Regulatory Agency Identifier Number(s): IND 139578    
Emergency Telephone Number: Refer to the study contacts page 
SAE Reporting Fax Number/Email: 
Business Unit 
Email 
Phone 
Fax 
Allergan 
IR-Clinical-SAE@allergan.com 
 
Not applicable 
+1-714-796-9504 
Backup:  
+1-714-246-5295 
Sponsor Signatory: 
 
Vice President, Clinical Development - Ophthalmology 
 
Vice President, Clinical Pharmacology 
Refer to the final page of this protocol for electronic signature and date of approval. 
 
 

CONFIDENTIAL  
Protocol 2011-101-013 Amendment 1 
AGN-241622 
GRD-CLN-T-01-01 v5.0 
2 
Protocol Amendment Summary of Changes Table 
DOCUMENT HISTORY 
Document 
Date 
Original Protocol 
28 October 2019 
Amendment 1  
Overall Rationale for the Amendment: 
The overall rationale for Amendment 1 is to include modifications based on FDA feedback and 
minor clarifications. Minor editorial and document formatting revisions have not been 
summarized. The following is a summary of the changes that were made to each section of the 
protocol, and a brief rationale for these changes.   
Section # and Name 
Description of Change 
Brief Rationale 
Global 
Pupil diameter assessment wording edited 
to state that pupil diameter will be 
assessed in mesopic conditions during 
Stage 1. 
Light condition was added for clarification. 
Global 
 
Synopsis, Overall Design 
Figure 1-1, Study Schema 
Section 2.1, Study 
Rationale 
Section 2.3, Benefit/Risk 
Assessment 
Section 4.1, Overall Design 
Section 4.2, Scientific 
Rationale for Study Design 
Section 6.3, Measures to 
Minimize Bias: 
Randomization and 
Masking 
Section 7.1, 
Discontinuation of Study 
Intervention 
Section 7.1.1, Study 
Termination 
Section 9.6, Data 
Monitoring Committee 
(DMC) 
Wording edited to clarify that after each 
cohort is complete, an independent DMC 
will review unmasked safety and plasma 
PK data, along with target engagement and 
efficacy data if necessary (and applicable), 
to recommend if it is acceptable to proceed 
to the next planned cohort. Globally, 
description of DMC review data changed 
from masked to unmasked for the study. 
 
Wording added to state that the FDA will 
review study data after the completion of 
each cohort and the sponsor will wait until 
a positive response is received from the 
FDA to proceed to the next cohort. 
 
Wording modified to state that nonclinical 
studies have been completed and support 
the safe use of AGN-241622 ophthalmic 
solution in human eyes. AGN-241622 
ophthalmic solution is expected to be safe 
in healthy participants as well as 
participants with presbyopia. 
 
Wording edited to state: In addition, each 
cohort will not proceed until the preceding 
cohort(s) has been: 1) reviewed and 
deemed safe by a DMC, and 2) a positive 
response is received from the FDA. 
Wording modified to state: The DMC and 
FDA may recommend modifications to the 
protocol including discontinuation of study 
intervention and study upon review of 
safety data. 
Per FDA feedback and for clarification. 

CONFIDENTIAL  
Protocol 2011-101-013 Amendment 1 
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Section # and Name 
Description of Change 
Brief Rationale 
Section 1.3.1, Schedule of 
Activities (SoA) – Stage 1 
Section 1.3.2, Schedule of 
Activities (SoA) – Stage 2a 
Section 1.3.3.1, Schedule 
of Activities (SoA) – Stage 
2b (Cohort 7) 
Section 1.3.3.2, Schedule 
of Activities (SoA) – Stage 
2b (Cohort 8) 
Global 
Wording added that study assessments 
should be conducted in the sequence as 
listed in the SoA. Hour 0 definitions listed 
for the different stages, as applicable. 
Wording added to clarify that Pre-Hour 0 
assessments are assessments listed prior to 
study intervention dosing (e.g., laboratory 
assessments, PK, IWRS) and should be 
conducted before Hour 0. 
For Stage 1, wording added that all 
ophthalmic assessments are to be done in 
both eyes. More details can be found in the 
notes section.   
For Stages 2a and 2b, wording added that 
all ophthalmic assessments are to be done 
in both eyes except for the shaded 
timepoints. More details can be found in 
the notes section.   
For Stage 2, physical examination 
assessment added to Day 30/EOS Visits 
and weight assessment added to Day 14 
Visit at Hr 0. Wording changed to clarify 
that height and weight are a part of 
physical examination during all stages, and 
that height will only be assessed at 
screening. 
For clarification. 
Section 5.2.1, Stage 1 
(Exclusion Criteria) 
 
Section 5.2.2, Stages 2a 
and 2b (Exclusion Criteria) 
 
Section 6.5.1, Prohibited 
Interventions 
 
Section 6.5.2, Permitted 
Interventions 
For Stage 1, Exclusion Criterion 2.01 
deleted and Exclusion Criterion 2.02 
modified. 
 
For Stages 2a and 2b, combined and 
modified Exclusion Criteria 2.01 and 2.02. 
 
Section 6.5.1 modified for consistency 
against above updates and clarification. 
 
Section 6.5.2 modified for consistency 
against above updates and clarification. 
Wording modified for more conservative 
approach. Safety and PK data would be 
reviewed from Stages 1 and 2a to look at 
potential interactions. 
Section 8.5.1, Blood PK 
Sampling Procedure  
Wording modified to state: Study center 
staff will send plasma samples to the 
bioanalytical laboratory or the central 
laboratory for storage after the last 
collection on Day 1 (for Stage 1) and after 
the last collection on Days 1 and 14 (for 
Stage 2). On the day of shipment, the 
sponsor and the specified laboratory will 
be notified by email as to the time and 
method of shipment. 
 
For clarity. 

CONFIDENTIAL  
Protocol 2011-101-013 Amendment 1 
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GRD-CLN-T-01-01 v5.0 
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Table of Contents 
Title Page ........................................................................................................................................1 
Protocol Amendment Summary of Changes Table .........................................................................2 
Table of Contents .............................................................................................................................4 
List of Tables ...................................................................................................................................8 
List of Figures ..................................................................................................................................9 
1. 
Protocol Summary ........................................................................................................10 
1.1. 
Synopsis ..........................................................................................................................10 
1.2. 
Schema ............................................................................................................................16 
1.3. 
Schedule of Activities (SoA) ..........................................................................................17 
1.3.1. 
Schedule of Activities (SoA) – Stage 1 ..........................................................................17 
1.3.2. 
Schedule of Activities (SoA) – Stage 2a.........................................................................21 
1.3.3. 
Schedule of Activities (SoA) – Stage 2b ........................................................................31 
2. 
Introduction ...................................................................................................................53 
2.1. 
Study Rationale ...............................................................................................................53 
2.2. 
Background .....................................................................................................................53 
2.2.1. 
AGN-241622...................................................................................................................54 
2.2.2. 
Pilocarpine HCl (
) .....................................................................................56 
2.3. 
Benefit/Risk Assessment ................................................................................................57 
3. 
Objectives and Measures..............................................................................................59 
4. 
Study Design ..................................................................................................................62 
4.1. 
Overall Design ................................................................................................................62 
4.1.1. 
Clinical Hypotheses ........................................................................................................64 
4.2. 
Scientific Rationale for Study Design ............................................................................64 
4.3. 
Justification for Dose ......................................................................................................65 
4.4. 
End of Study Definition ..................................................................................................65 
5. 
Study Population ...........................................................................................................66 
5.1. 
Inclusion Criteria ............................................................................................................66 
5.1.1. 
Stage 1 .............................................................................................................................66 
5.1.2. 
Stages 2a and 2b..............................................................................................................67 
5.2. 
Exclusion Criteria ...........................................................................................................69 
5.2.1. 
Stage 1 .............................................................................................................................69 
5.2.2. 
Stages 2a and 2b..............................................................................................................70 
5.3. 
Lifestyle Considerations .................................................................................................72 
5.3.1. 
Habitual Distance Corrections (Stages 2a and 2b only) .................................................72 
5.3.2. 
Meals and Dietary Restrictions .......................................................................................72 
5.3.3. 
Caffeine, Alcohol, and Tobacco .....................................................................................73 
5.3.4. 
Activity ...........................................................................................................................73 
5.4. 
Screen Failures ................................................................................................................73 
6. 
Study Intervention ........................................................................................................74 
6.1. 
Study Intervention(s) Administered................................................................................74 
6.1.1. 
Instructions for Use and Administration .........................................................................75 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................75 

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6.3. 
Measures to Minimize Bias: Randomization and Masking ............................................75 
6.4. 
Study Intervention Compliance ......................................................................................76 
6.5. 
Concomitant Therapy .....................................................................................................77 
6.5.1. 
Prohibited Interventions ..................................................................................................77 
6.5.2. 
Permitted Interventions ...................................................................................................78 
6.6. 
Dose Modification ..........................................................................................................78 
6.7. 
Intervention after the End of the Study ...........................................................................78 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................79 
7.1. 
Discontinuation of Study Intervention ............................................................................79 
7.1.1. 
Study Termination ..........................................................................................................79 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................80 
7.3. 
Lost to Follow up ............................................................................................................80 
8. 
Study Assessments and Procedures.............................................................................81 
8.1. 
Efficacy Assessments .....................................................................................................81 
8.2. 
Safety Assessments .........................................................................................................82 
8.2.1. 
Physical Examinations ....................................................................................................83 
8.2.2. 
Vital Signs .......................................................................................................................83 
8.2.3. 
Electrocardiograms .........................................................................................................83 
8.2.4. 
Clinical Safety Laboratory Assessments ........................................................................83 
8.2.5. 
Study Intervention Tolerability and Drop Comfort Assessments ...................................84 
8.2.6. 
IOP ..................................................................................................................................84 
8.2.7. 
Slit lamp Biomicroscopy.................................................................................................84 
8.2.8. 
Sodium Fluorescein Corneal Staining ............................................................................85 
8.2.9. 
Dilated Fundoscopic Examination ..................................................................................85 
8.2.10. Contrast Sensitivity (Stages 2a and 2b only) ..................................................................85 
8.2.11. Photopic and Mesopic High-contrast CDVA (Stages 2a and 2b 
only) ................................................................................................................................85 
8.2.12. Manifest Refraction (Stages 2a and 2b only) ..................................................................85 
8.3. 
Adverse Events and Serious Adverse Events .................................................................85 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information .....................................................................................................................86 
8.3.2. 
Method of Detecting AEs and SAEs ..............................................................................86 
8.3.3. 
Follow-up of AEs and SAEs ...........................................................................................86 
8.3.4. 
Regulatory Reporting Requirements for SAEs ...............................................................87 
8.3.5. 
Pregnancy ........................................................................................................................87 
8.4. 
Treatment of Overdose ...................................................................................................87 
8.5. 
Pharmacokinetics ............................................................................................................87 
8.5.1. 
Blood PK Sampling Procedure .......................................................................................87 
8.5.2. 
Tear PK Sampling Procedure..........................................................................................88 
8.5.3. 
PK Sample Bioanalysis ...................................................................................................89 
8.6. 
Pharmacodynamics .........................................................................................................89 
8.7. 
Genetics ..........................................................................................................................89 
8.8. 
Biomarkers and Other Assessments ...............................................................................89 
8.8.1. 
Determination of Iris Color .............................................................................................89 

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8.8.2. 
Determination of Dominant Eye (Stages 2a and 2b only) ..............................................89 
8.8.3. 
OSDI ...............................................................................................................................89 
8.8.4. 
Pupillary Reaction to Light .............................................................................................89 
8.8.5. 
Cycloplegic Refraction (Stages 2a and 2b only).............................................................90 
8.8.6. 
Gonioscopy/Angle Assessment ......................................................................................90 
8.8.7. 
Dark Adaptation (Stages 2a and 2b only) .......................................................................90 
8.9. 
Immunogenicity Assessments.........................................................................................90 
8.10. 
Health Economics ...........................................................................................................90 
9. 
Statistical Considerations .............................................................................................92 
9.1. 
Statistical Hypotheses .....................................................................................................92 
9.2. 
Sample Size Determination ............................................................................................92 
9.3. 
Populations for Analyses ................................................................................................92 
9.4. 
Statistical Analyses .........................................................................................................92 
9.4.1. 
Efficacy Analyses ...........................................................................................................92 
9.4.2. 
Safety Analyses ...............................................................................................................93 
9.4.3. 
PK Analyses ....................................................................................................................95 
9.4.4. 
Other Analyses ................................................................................................................95 
9.5. 
Interim Analyses .............................................................................................................96 
9.6. 
Data Monitoring Committee (DMC) ..............................................................................96 
10. 
Supporting Documentation and Operational Considerations ..................................97 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................98 
10.1.1. Regulatory and Ethical Considerations ...........................................................................98 
10.1.2. Financial Disclosure........................................................................................................98 
10.1.3. Informed Consent Process ..............................................................................................98 
10.1.4. Data Protection................................................................................................................99 
10.1.5. Dissemination of Clinical Study Data.............................................................................99 
10.1.6. Data Quality Assurance ..................................................................................................99 
10.1.7. Source Documents ........................................................................................................100 
10.1.8. Study and Site Start and Closure ..................................................................................100 
10.1.9. Publication Policy .........................................................................................................101 
10.1.10. Compliance with Protocol.............................................................................................101 
10.2. 
Appendix 2: Clinical Laboratory Tests .........................................................................102 
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures 
for Recording, Evaluating, Follow-up, and Reporting .................................................104 
10.3.1. Definition of AE ...........................................................................................................104 
10.3.2. Definition of SAE .........................................................................................................105 
10.3.3. Recording and Follow-Up of AE and/or SAE ..............................................................107 
10.3.4. Reporting of SAEs ........................................................................................................109 
10.4. 
Appendix 4: Abbreviations ...........................................................................................110 
10.5. 
Appendix 5: Standard Discontinuation Criteria............................................................113 
10.6. 
Appendix 6: Study Tabular Summary ..........................................................................114 
10.7. 
Appendix 7: Contraceptive Guidance and Collection of 
Pregnancy Information .................................................................................................116 
Definitions: ..................................................................................................................................116 

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Contraception Guidance: .............................................................................................................116 
Pregnancy Testing:.......................................................................................................................118 
10.8. 
Appendix 8: Biomicroscopic Examination ...................................................................119 
10.9. 
Appendix 9: Study Intervention Tolerability/Drop Comfort 
Assessment....................................................................................................................123 
10.10. 
Appendix 10: Fundus (Indirect) Ophthalmoscope Examination ..................................124 
10.11. 
Appendix 11: IOP .........................................................................................................125 
10.12. 
Appendix 12: Gonioscopy/Angle Assessment .............................................................126 
11. 
References ....................................................................................................................127 
 

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List of Tables 
Table 1-1 
Schedule of Visits and Procedures: Screening to Day 2 (Stage 1) ....................... 17 
Table 1-2 
Schedule of Visits and Procedures: Screening to Day 7 (Stage 2a) ..................... 22 
Table 1-3 
Schedule of Visits and Procedures: Day 14 to Day 30/End-of-Study (Stage 2a) . 28 
Table 1-4 
Schedule of Visits and Procedures: Screening to Day 7 (Stage 2b; Cohort 7) ..... 31 
Table 1-5 
Schedule of Visits and Procedures: Day 14 to Day 30/End-of-Study (Stage 2b; 
Cohort 7) ............................................................................................................... 38 
Table 1-6 
Schedule of Visits and Procedures: Screening to Day 7 (Stage 2b; Cohort 8) ..... 42 
Table 1-7 
Schedule of Visits and Procedures: Day 14 to Day 30/End-of-Study (Stage 2b; 
Cohort 8) ............................................................................................................... 49 
Table 4-1 
Study Interventions by Study Stage and Cohort ................................................... 63 
Table 4-2 
Safety Margins of Starting Clinical Dose to Nonclinical NOAELs ..................... 65 
Table 6-1 
Study Interventions ............................................................................................... 74 
Table 10-1 
Protocol-Required Safety Laboratory Assessments ............................................ 103 
Table 10-2 
Highly Effective Contraceptive Methods ........................................................... 117 
 

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Protocol 2011-101-013 Amendment 1 
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List of Figures 
Figure 1-1 
Study Schema........................................................................................................ 16 
Figure 10-1 
Oxford Scale for Grading Corneal and Conjunctival Staining ........................... 122 
Figure 10-2 
Anterior Chamber Angle Grading ...................................................................... 126 
 

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1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A First-in-Human, Phase 1/2, Dose-ascending, Multicenter, Masked, 
Randomized, Vehicle-controlled Study Evaluating the Safety, Tolerability, and 
Pharmacokinetics of AGN-241622 in Healthy Participants and Participants with Presbyopia 
(Stage 1 and Stage 2) and Efficacy in Participants with Presbyopia (Stage 2) 
Short Title: Phase 1/2 study of AGN-241622 in healthy participants and participants with 
presbyopia 
Rationale: 
The objective of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy 
of AGN-241622 ophthalmic solution for the first time in human participants. Nonclinical studies 
have been completed and support the safe use of AGN-241622 ophthalmic solution in human 
eyes at the dose strengths of 
 selected for this study. These dose strengths of 
AGN-241622 ophthalmic solution are expected to be safe in healthy participants as well as 
participants with presbyopia. Stage 1 of this study will evaluate safety, tolerability, 
pharmacokinetics, and the target receptor engagement of AGN-241622 after a single unilateral 
dose in healthy participants (Cohorts 1 to 3). Stage 2a will evaluate safety, tolerability, 
pharmacokinetics, and efficacy of AGN-241622 ophthalmic solution after repeat bilateral 
administration in participants with presbyopia (Cohorts 4 to 6). Stage 2b will evaluate safety, 
tolerability, and efficacy of AGN-241622 ophthalmic solution compared with an active 
comparator (pilocarpine HCl 
 1.25% ophthalmic solution) after repeat bilateral 
administration in participants with presbyopia in Cohort 7; and safety, tolerability, tear 
pharmacokinetics, and efficacy of AGN-241622 ophthalmic solution after repeat bilateral 
administration in participants with presbyopia who wear contact lenses in Cohort 8. Together, 
the results from Stages 1 and 2 of this study will help characterize the safety, tolerability, 
pharmacokinetics, and efficacy profile of AGN-241622 and support the further development of 
AGN-241622 as a noninvasive, reversible, pharmacologic treatment for presbyopia.  

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Objectives and Measures 
 
 
Objectives 
Measures 
Stage 1 
Primary 
• 
To evaluate the safety and 
tolerability of AGN-241622 
administered once, unilaterally in 
healthy participants 
 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments 
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
Secondary  
• 
To evaluate the systemic and 
local pharmacokinetics of 
AGN-241622 administered once 
unilaterally in healthy 
participants 
• 
To evaluate the target receptor 
engagement of AGN-241622 as 
compared with vehicle 
administered once, unilaterally in 
healthy participants 
 
• 
Plasma and tear concentrations and PK parameters of 
AGN-241622, including but not limited to: AUC0-inf, 
AUC0-t, Cmax, Tmax, t1/2, CL/F (plasma only), and Vz/F 
(plasma only) 
 
• 
Pupil diameter measurement (mesopic) 
 
 
Stage 2a 
Primary 
• 
To evaluate the safety and 
tolerability of AGN-241622 after 
repeat bilateral administration in 
participants with presbyopia  
 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments  
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Contrast sensitivity  
• 
Photopic and mesopic high contrast CDVA binocularly  
• 
Manifest refraction (mesopic and photopic)  
• 
Dilated funduscopic examination 
Secondary 
• 
To evaluate the systemic and 
local pharmacokinetics of 
AGN-241622 after repeat 
bilateral administration in 
participants with presbyopia 
 
• 
Plasma and tear concentrations and PK parameters of 
AGN-241622, including but not limited to: AUC0-tau, 
AUC0-t, Cmax, Tmax, t1/2, CL/F (plasma only), and 
Vz/F (plasma only) 

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Objectives 
Measures 
Stage 2a (Continued) 
• 
To evaluate efficacy of 
AGN-241622 compared with 
vehicle after repeat bilateral 
administration in participants 
with presbyopia  
• 
Mesopic and photopic high contrast, binocular and 
monocular DCNVA  
• 
Mesopic and photopic pupil diameter (distance and near)  
• 
Depth of focus 
• 
PRO Questionnaires (NVPTQ, PICQ, Single-item PGIC, 
Single-item PGIS) 
• 
Bulbar conjunctival hyperemia  
Stage 2b 
• 
To evaluate safety, tolerability, 
and efficacy of AGN-241622 
compared with pilocarpine HCl 
 1.25% after 
repeat bilateral administration in 
participants with presbyopia in 
Cohort 7 
 
Safety and Tolerability: 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments 
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Contrast sensitivity  
• 
Photopic and mesopic high contrast CDVA binocularly  
• 
Manifest refraction (mesopic and photopic)  
• 
Dilated funduscopic examination 
Efficacy: 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCNVA 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCIVA 
• 
Mesopic and photopic pupil diameter (distance and near) 
• 
Depth of focus 
• 
PRO Questionnaires (NVPTQ, e-NVPTQ [iPhone/iPod], 
PICQ, Single-item PGIC, Single-item PGIS) 
• 
Bulbar conjunctival hyperemia 

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Objectives 
Measures 
• 
To evaluate safety, tolerability, 
tear pharmacokinetics, and 
efficacy of AGN-241622 after 
repeat bilateral administration in 
participants with presbyopia who 
wear contact lenses in Cohort 8  
Safety and Tolerability: 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments 
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Contrast sensitivity  
• 
Photopic and mesopic high contrast CDVA binocularly  
• 
Manifest refraction (mesopic and photopic)  
• 
Dilated funduscopic examination 
 
 
Tear Pharmacokinetics: 
• 
Tear concentrations and PK parameters of AGN-241622, 
including but not limited to: AUC0-tau, AUC0-t, Cmax, Tmax, 
t1/2 
Efficacy: 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCNVA 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCIVA 
• 
Mesopic and photopic pupil diameter (distance and near) 
• 
Depth of focus 
• 
PRO Questionnaires (NVPTQ, e-NVPTQ [iPhone/iPod], 
PICQ, Single-item PGIC, Single-item PGIS) 
• 
Bulbar conjunctival hyperemia  
 
Overall Design 
This is a multicenter, randomized, double-masked (except Cohort 7), Phase 1/2 study in healthy 
participants and participants with presbyopia. This study will be conducted in 3 stages (Stage 1, 
Stage 2a, and Stage 2b). In Stage 1, healthy participants will be randomized to participate in 
single-ascending dose cohorts (Cohorts 1 to 3) to evaluate safety, tolerability, pharmacokinetics, 
and target engagement of AGN-241622. In each cohort in Stage 1, approximately 12 participants 
will be randomized in a 3:1 ratio to receive AGN-241622 ophthalmic solution or vehicle. 
Participants randomized to receive active intervention will be administered a single drop of 
AGN-241622 at dose strengths ranging from 
 in the left eye. Each participant will 
be admitted to the study center on the evening before dosing (Day -1). Participants will receive 
their single dose in the morning of Day 1 and, after a full day of assessments, stay overnight and 
continue further safety and PK assessments on the next day (EOS Visit). After each cohort is 
complete, an independent DMC will review unmasked safety and plasma PK data, along with 
target engagement and efficacy data if necessary (and applicable), to recommend if it is 

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acceptable to proceed to the next planned cohort. The DMC may also recommend modifying the 
proposed dose strength (e.g., de-escalate to a lower dose strength), repeat the current dose 
strength, modify the cohort size, or stop the study. In addition, the FDA will review study data 
after the completion of each cohort and the sponsor will wait until a positive response is received 
from the FDA to proceed to the next cohort. Once Cohort 2 of Stage 1 is complete, in addition to 
making a recommendation on whether to initiate the final cohort of Stage 1 (Cohort 3), the DMC 
will also make a recommendation on whether to start Stage 2 (Cohort 4) in parallel.  
In Stage 2, participants with presbyopia will be selected to participate in the study. Stage 2 will 
be further divided into Stages 2a (Cohorts 4 to 6) and 2b (Cohorts 7 and 8). Cohorts 4 to 6 
(Stage 2a) will be multiple ascending dose cohorts in which participants will be randomized to 
receive either AGN-241622 at dose strengths ranging from 
 or vehicle once daily 
in both eyes for 14 days. In each cohort in Stage 2a, approximately 12 participants will be 
randomized in a 3:1 ratio to receive AGN-241622 ophthalmic solution or vehicle in order to 
evaluate safety, tolerability, pharmacokinetics, and efficacy of AGN-241622 (see Figure 1-1 of 
Section 1.2). As in Stage 1, the DMC may recommend modifying the proposed dose strength 
(e.g., de-escalate to a lower dose strength), repeat the current dose strength, modify the cohort 
size, or stop the study. After Cohort 6 has completed, the DMC will also recommend the dose 
strength to be tested in Stage 2b. 
Cohort 7 is a single-masked, active comparator cohort in which approximately 60 participants 
with presbyopia will be randomized in a 1:1 ratio to receive either pilocarpine HCl 
 1.25% ophthalmic solution or AGN-241622 ophthalmic solution administered at 
the dose strength recommended by the DMC once daily in both eyes for 14 days. Safety, 
tolerability, and efficacy of AGN-241622 compared with pilocarpine HCl (
) 1.25% 
will be assessed after repeat bilateral topical ocular administration. Cohort 8 is an exploratory 
cohort in which approximately 12 participants with presbyopia who wear contact lenses will be 
randomized in a 3:1 ratio to receive either AGN-241622 administered at the dose strength 
recommended by the DMC or vehicle once daily in both eyes for 14 days. Safety, tolerability, 
tear pharmacokinetics, and efficacy of AGN-241622 administered at the dose strength 
recommended by the DMC compared with vehicle will be assessed after repeat bilateral 
administration. 
In all cohorts of Stage 2, participants will receive their first dose in the clinic on Day 1, and stay 
in the clinic for safety, PK (except Cohort 7), and efficacy evaluations for approximately 10 
hours postdose. For Stage 2a, participants will then return for dosing once daily and assessments 
from Day 2 to Day 7. For Stage 2b, on Days 3 and 7, participants will return to the clinic for 
dosing and assessments; on Days 1 and 3, participants will also receive multidose bottles for 
single unit of use for at-home dosing on Days 2, 4, 5, and 6. For participants in both Stages 2a 
and 2b, they will then receive multidose bottles on Day 7 for single unit of use for at-home 
dosing from Days 8 to 13 and will return to the clinic on Day 14 for dosing as well as safety, 
tolerability, PK (except Cohort 7), and efficacy evaluations for approximately 10 hours postdose. 
On Day 30, participants will return for a safety follow-up and EOS Visit.  
The study will be conducted in the United States. 
Disclosure Statement: This is a parallel group treatment study (Stage 1 [Cohorts 1 to 3]: 
single ascending dose; Stage 2a [Cohorts 4 to 6]: multiple ascending dose; and Stage 2b 

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[Cohorts 7 and 8]: multiple dose) with 2 arms per cohort that is double-masked (participant, 
investigator, and study site staff), except Cohort 7 which is single-masked (participant).  
Number of Participants: 
In each cohort in Stage 1(Cohorts 1, 2, and 3), approximately 12 healthy participants will be 
randomized in a 3:1 ratio to receive AGN-241622 ophthalmic solution or vehicle. 
In each cohort in Stage 2a (Cohorts 4, 5, and 6), approximately 12 participants with 
presbyopia will be randomized in a 3:1 ratio to receive AGN-241622 ophthalmic solution or 
vehicle. 
In Cohort 7 of Stage 2b, approximately 60 participants with presbyopia will be randomized in a 
1:1 ratio to receive either AGN-241622 ophthalmic solution or pilocarpine HCl 
) 
1.25% ophthalmic solution. 
In Cohort 8 of Stage 2b, approximately 12 participants with presbyopia who wear contact lenses 
will be randomized in a 3:1 ratio to receive either AGN-241622 ophthalmic solution or vehicle.  
Participants who prematurely discontinue from the study may be replaced at the discretion of the 
sponsor. 
Intervention Groups and Duration: The study duration is approximately 20 days for Stage 1 
(including 18 days for screening, 1 day for study intervention, and the EOS Visit on Day 2); and 
approximately 60 days each for Stages 2a and 2b (including 30 days for screening, 14 days for 
study intervention, and the EOS Visit on Day 30).  
Study Interventions by Study Stage and Cohort 
Stage 1 
Single Ascending Dose in Healthy Participants  
Cohort 1 
AGN-241622
single dose 
left eye 
9 Active; 3 Vehicle  
Cohort 2 
AGN-241622
 single dose 
left eye 
9 Active; 3 Vehicle 
Cohort 3 
AGN-241622
 single dose 
left eye 
9 Active; 3 Vehicle 
Stage 2a 
Multiple Ascending Dose in Participants with Presbyopia  
Cohort 4 
AGN-241622 
  
QD × 14 days both eyes 
9 Active; 3 Vehicle 
Cohort 5 
AGN-241622
  
QD × 14 days both eyes 
9 Active; 3 Vehicle 
Cohort 6 
AGN-241622 
  
QD × 14 days both eyes 
9 Active; 3 Vehicle 
Stage 2b 
Multiple-Dose Exploratory Cohorts in Participants with Presbyopia 
Cohort 7  
AGN-241622 (dose strength TBD) versus 
pilocarpine HCl 
) 1.25%  
QD × 14 days both eyes 
60 (30 per treatment arm) 
Cohort 8 
AGN-241622 (dose strength TBD)  
(in participants who wear contact lenses) 
QD × 14 days both eyes 
9 Active; 3 Vehicle 
Data Monitoring Committee: Yes 
 

 
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1.3. 
Schedule of Activities (SoA) 
1.3.1. 
Schedule of Activities (SoA) – Stage 1 

 
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Table 1-2 
Schedule of Visits and Procedures: Screening to Day 7 (Stage 2a) 

 
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Table 1-3 
Schedule of Visits and Procedures: Day 14 to Day 30/End-of-Study (Stage 2a) 

 
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1.3.3. 
Schedule of Activities (SoA) – Stage 2b  

 
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1.3.3.2. 
Stage 2b (Cohort 8) 

 
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Table 1-7 
Schedule of Visits and Procedures: Day 14 to Day 30/End-of-Study (Stage 2b; Cohort 8) 

 
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2. 
Introduction 
Allergan is investigating AGN-241622 ophthalmic solution as a noninvasive, reversible, 
pharmacologic treatment for presbyopia, a condition in which the eye exhibits a diminished 
ability to focus on near objects with increasing age. 
2.1. 
Study Rationale 
The objective of this study is to evaluate the safety, tolerability, pharmacokinetics, and efficacy 
of AGN-241622 ophthalmic solution for the first time in human participants. Nonclinical studies 
have been completed and support the safe use of AGN-241622 ophthalmic solution in human 
eyes. AGN-241622 ophthalmic solution is expected to be safe in healthy participants as well as 
participants with presbyopia. Stage 1 of this study will evaluate safety, tolerability, 
pharmacokinetics, and the target receptor engagement of AGN-241622 after a single unilateral 
dose in healthy participants (Cohorts 1 to 3). Stage 2a will evaluate safety, tolerability, 
pharmacokinetics, and efficacy of AGN-241622 ophthalmic solution after 14 days of dosing in 
participants with presbyopia (Cohorts 4 to 6). Stage 2b will evaluate safety, tolerability, and 
efficacy of AGN-241622 ophthalmic solution compared with an active comparator 
(pilocarpine HCl 
] 1.25% ophthalmic solution) after 14 days of dosing in 
participants with presbyopia in Cohort 7; and safety, tolerability, tear pharmacokinetics, and 
efficacy of AGN-241622 ophthalmic solution after 14 days of dosing in participants with 
presbyopia who wear contact lenses in Cohort 8. Together, the results from Stages 1 and 2 of this 
study will help characterize the safety, tolerability, pharmacokinetics, and efficacy profile of 
AGN-241622 and support the further development of AGN-241622 as a noninvasive, reversible, 
pharmacologic treatment for presbyopia. 
2.2. 
Background 
The impairment of near vision is common among older adults. In 2005, 1.044 billion people 
globally were estimated to have presbyopia, and prevalence is expected to increase to 
1.782 billion by 2050 (Holden 2008). Both nonsurgical and surgical methods for the correction 
of presbyopia are available. Traditional nonsurgical methods of refractive correction for 
presbyopia include the use of dedicated reading spectacles, bifocal or varifocal spectacles, and 
monovision or multifocal contact lenses. A number of surgical techniques are also used for the 
treatment of presbyopia, which include monovision PRK or LASIK, conductive keratoplasty, 
intraocular lenses, and corneal inlays. However, for each of the existing technologies 
mentioned above, visual quality is reduced at 1 or more viewing distances, and each comes with 
its own unique safety risks and associated complications. For example, bifocals and progressive 
lenses (e.g., reading glasses, contacts) produce optical aberrations and can increase the risk of 
falls (Johnson 2007; Lord 2002). Multifocal optics reduce image quality uniformly at all viewing 
distances. For surgical technologies, surgical risks, the need for repositioning and explantation, 
or regression of effect have limited their widespread adoption (Moshirfar 2017; Ruiz 2009; 
Tomita 2015). Thus, there remains a need for a noninvasive, reversible, pharmacologic treatment 
for presbyopia.  

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weight during the dosing phase, the dose of 
/kg/day was considered minimally tolerated. 
Effects noted in clinical observations, functional observational battery, and clinical and 
anatomical pathology were related to expected pharmacology of an α2-adrenergic receptor 
agonist, were reversible, and were considered nonadverse. For these reasons, the NOAEL for this 
study was
/kg/day and this dose has a 
 margin of safety over the predicted 
human exposure at the proposed starting clinical dose. 
Respiratory function was assessed in male Sprague Dawley rats administered a single 
subcutaneous dose of 
 mg/kg AGN-241622. All dose levels of AGN-241622 
lowered respiration rate (as much as -17%) and minute volume (as much as -26%), consistent 
with the expected pharmacologic activity of an α2-adrenergic receptor agonist, with the primary 
effects occurring between approximately 1 and 3.5 hours postdose. The changes were not 
considered adverse and did not display strict dose dependency. However, because the effects 
observed in this study were present at all doses, they will still be monitored closely in this 
clinical study. The NOAEL for this study was the top dose of 
 mg/kg, providing a 
 
margin of safety over the predicted human exposure at the proposed starting clinical dose. 
In the GLP-compliant dog toxicology study, male and female beagles were administered
 
 AGN-241622 once daily to the left eye via topical instillation for 28 days, 
followed by a 2-week recovery phase. AGN-241622 was tolerated up to 
 mg/left 
eye/day). AGN-241622-related findings at this dose level were generally limited to vomitus, thin 
appearance (1 animal), pupil constriction or dilation, red palpebral conjunctiva, and ocular 
discharge. AGN-241622-related clinical observations for animals administered 
 included 
adverse body weight loss, thin appearance, and inappetence, which ultimately required sacrifice 
for 2 females. Due to the mild severity of findings and the lack of impact on the health and 
well-being of animals administered
 AGN-241622, effects at this dose were considered 
nonadverse. Therefore, the NOAEL for this study was
 AGN-241622 (
 mg/left 
eye/day), and this dose has a 34-fold margin of safety over the predicted human exposure at the 
proposed starting clinical dose. 
In the GLP-compliant safety pharmacology study in dogs, 4 male beagles were topically 
administered 
of AGN-241622 as a single drop (approximate dose volume 
of 35 µL/drop) to the left eye in a Latin-square dosing design on Days 1, 5, 9, and 13, with 
cardiovascular telemetry data recorded. AGN-241622 had no effect on mortality, clinical 
observations, body weight, body temperature, or activity at any dose level. No qualitative ECG 
abnormalities were noted. A dose of
 increased PR interval (up to 13 msec; +12%), 
but this finding was likely secondary to lower heart rate values observed with a similar time 
course, consistent with the expected pharmacology of an α2-adrenergic receptor agonist. QT 
interval also lengthened as a result of lower heart rate, but no test article related effect on heart 
rate corrected QTc interval was noted. QRS duration was unaffected by AGN-241622. A dose of 
 caused increased diastolic arterial pressure by up to 10 mm Hg (+13%), and 
decreased arterial pulse pressure, by as much as -14 mm Hg (-21%), was noted at all dose levels. 
Cardiac contractility, as assessed by left ventricular dP/dtmax values, was decreased by as much 
as 
 Hg/sec (-25%) following administration of 
 No changes in systolic, 
mean arterial, or left ventricular end diastolic pressures were attributed to AGN-241622. 
Furthermore, no effects were observed at the lowest dose of 
 except for a minimal and 
transient decrease (up to 6%) in arterial pulse pressure. The NOAEL for this study was the top 

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were generally low and safety parameters were not clinically significant between participants 
who received 
 compared with participants who received vehicle or a combination 
therapy. The majority of AEs reported in any treatment group were mild to moderate in intensity. 
Efficacy measures for the Phase 2 clinical studies included mesopic uncorrected near visual 
acuity line and letter improvement. Of the various concentrations of 
 evaluated, 
near vision was most improved compared with vehicle under mesopic and photopic conditions at 
the 1.0% and 1.5% pilocarpine HCl concentrations, respectively. Pilocarpine HCl 
) 1.25% has been selected for further development for presbyopia in Phase 3 and 
is also the dose selected as an active comparator in this study.  
More detailed information regarding clinical safety findings, clinical efficacy findings, 
chemistry, and pharmacology is provided in the pilocarpine HCl investigator’s brochure. 
2.3. 
Benefit/Risk Assessment 
Based on the pharmacology of the 2 interventions (AGN-241622 and pilocarpine HCl 
[
 1.25%) and the nonclinical data, it is reasonable to expect that either or both may 
reduce pupil diameter after topical ocular administration in both healthy participants and 
participants with presbyopia, and potentially improve near vision in participants with presbyopia. 
Clinical data generated for pilocarpine HCl (
) 1.25% in participants with 
presbyopia supports this hypothesis. While there are no clinical data on AGN-241622 
ophthalmic solution to date, topical ocular administration of similar compounds in the same class 
have resulted in reduced pupil size and improved near vision in humans with presbyopia. 
Based on existing toxicology data, no risks of particular severity or seriousness are anticipated 
with topical ophthalmic administration of AGN-241622 or pilocarpine HCl 
 
1.25%. 
In the most recent clinical experience with pilocarpine HCl ophthalmic solution, pilocarpine HCl 
was dosed topically with oxymetazoline (Oxy) in different dose combinations and TEAEs were 
reported by 28.6% (8/28) of participants in the vehicle group, 40.0% (12/30) of participants in 
the Oxy 0.0125%/pilocarpine (Pilo) 0.5% OU group, 50.0% (15/30) of participants in the 
Oxy 0.05%/Pilo 1.0% OU group, 46.9% (15/32) of participants in the Oxy 0.125%/Pilo 1.5% 
OU group, and 32.3% (10/31) of participants in the Oxy 0.125%/Pilo 1.5% nondominant (ND) 
group. The majority of AEs were ocular, mild in intensity, and related to treatment. The most 
frequently reported TEAEs were headache, instillation site pain, and vision blurred. All TEAEs 
were deemed by the investigator to be mild or moderate in intensity; none were reported as 
severe. No participant died or experienced a serious TEAE. Discontinuations due to AEs were 
reported by 1 participant (moderate headache) in the Oxy 0.125%/Pilo 1.5% OU group and 
1 participant (mild heart rate increased and insomnia) in the Oxy 0.125%/Pilo 1.5% ND group. 
No clinically meaningful findings emerged from assessments of mesopic, high contrast 
uncorrected distance visual acuity, vital signs, macroscopic hyperemia assessment, temporal and 
supraorbital headaches, or IOP. One participant in the Oxy 0.125%/Pilo 1.5% OU group and 
1 participant in the Oxy 0.125%/Pilo 1.5% ND group had clinically significant slit lamp 
biomicroscopy findings (conjunctival hemorrhage, eyelid edema, and conjunctival hyperemia). 
No other slit lamp biomicroscopy findings occurred. Finally, the study intervention tolerability 

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and drop comfort assessments indicated that the majority of participants in all treatment groups 
found the study intervention to be tolerable. 
There is no clinical experience with AGN-241622. The dose escalation design, coupled with 
DMC review of safety data in between cohorts, is expected to minimize risk to participants in the 
study. In addition, the FDA will review study data after the completion of each cohort and the 
sponsor will wait until a positive response is received from the FDA to proceed to the next 
cohort.  
More detailed information about the known and expected benefits and risks and 
reasonably expected AEs of AGN-241622 and pilocarpine HCl (
) 1.25% may be 
found in the respective investigator’s brochures. 

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3. 
Objectives and Measures  
 
 
Objectives 
Measures 
Stage 1 
Primary 
• 
To evaluate the safety and 
tolerability of AGN-241622 
administered once, unilaterally in 
healthy participants 
 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments 
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
Secondary  
• 
To evaluate the systemic and 
local pharmacokinetics of 
AGN-241622 administered once 
unilaterally in healthy 
participants 
• 
To evaluate the target receptor 
engagement of AGN-241622 as 
compared with vehicle 
administered once, unilaterally in 
healthy participants 
 
• 
Plasma and tear concentrations and PK parameters of 
AGN-241622, including but not limited to: AUC0-inf, 
AUC0-t, Cmax, Tmax, t1/2, CL/F (plasma only), and Vz/F 
(plasma only)  
 
• 
Pupil diameter measurement (mesopic) 
Stage 2a 
Primary 
• 
To evaluate the safety and 
tolerability of AGN-241622 after 
repeat bilateral administration in 
participants with presbyopia  
 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments 
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Contrast sensitivity  
• 
Photopic and mesopic high contrast CDVA binocularly  
• 
Manifest refraction (mesopic and photopic)  
• 
Dilated funduscopic examination 
Secondary 
• 
To evaluate the systemic and 
local pharmacokinetics of 
AGN-241622 after repeat 
bilateral administration in 
participants with presbyopia 
 
• 
Plasma and tear concentrations and PK parameters of 
AGN-241622, including but not limited to: AUC0-tau, 
AUC0-t, Cmax, Tmax, t1/2, CL/F (plasma only), and 
Vz/F (plasma only) 

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Objectives 
Measures 
Stage 2a (Continued) 
• 
To evaluate efficacy of 
AGN-241622 compared with 
vehicle after repeat bilateral 
administration in participants 
with presbyopia  
• 
Mesopic and photopic high contrast, binocular and 
monocular DCNVA  
• 
Mesopic and photopic pupil diameter (distance and near)  
• 
Depth of focus 
• 
PRO Questionnaires (NVPTQ, PICQ, Single-item PGIC, 
Single-item PGIS) 
• 
Bulbar conjunctival hyperemia  
Stage 2b 
• 
To evaluate safety, tolerability, 
and efficacy of AGN-241622 
compared with pilocarpine HCl 
 1.25% after 
repeat bilateral administration in 
participants with presbyopia in 
Cohort 7 
 
Safety and Tolerability: 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments 
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Contrast sensitivity  
• 
Photopic and mesopic high contrast CDVA binocularly  
• 
Manifest refraction (mesopic and photopic)  
• 
Dilated funduscopic examination 
Efficacy: 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCNVA 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCIVA 
• 
Mesopic and photopic pupil diameter (distance and near) 
• 
Depth of focus 
• 
PRO Questionnaires (NVPTQ, e-NVPTQ [iPhone/iPod], 
PICQ, Single-item PGIC, Single-item PGIS) 
• 
Bulbar conjunctival hyperemia 

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Objectives 
Measures 
• 
To evaluate safety, tolerability, 
tear pharmacokinetics, and 
efficacy of AGN-241622 after 
repeat bilateral administration in 
participants with presbyopia who 
wear contact lenses in Cohort 8  
Safety and Tolerability: 
• 
AEs 
• 
Vital signs  
• 
12-lead ECG 
• 
Clinical laboratory assessments 
• 
Study intervention tolerability and drop comfort 
assessments 
• 
IOP 
• 
Slit lamp biomicroscopy 
• 
Contrast sensitivity  
• 
Photopic and mesopic high contrast CDVA binocularly  
• 
Manifest refraction (mesopic and photopic)   
• 
Dilated funduscopic examination 
 
Tear Pharmacokinetics: 
• 
Tear concentrations and PK parameters of AGN-241622, 
including but not limited to: AUC0-tau, AUC0-t, Cmax, Tmax, 
t1/2 
Efficacy: 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCNVA 
• 
Mesopic and photopic high contrast, binocular and 
monocular DCIVA 
• 
Mesopic and photopic pupil diameter (distance and near) 
• 
Depth of focus 
• 
PRO Questionnaires (NVPTQ, e-NVPTQ [iPhone/iPod], 
PICQ, Single-item PGIC, Single-item PGIS) 
• 
Bulbar conjunctival hyperemia  
 

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4. 
Study Design 
4.1. 
Overall Design 
This is a multicenter, randomized, double-masked (except Cohort 7), Phase 1/2 study in healthy 
participants and participants with presbyopia. This study will be conducted in 3 stages (Stage 1, 
Stage 2a, and Stage 2b). In Stage 1, healthy participants will be randomized to participate in 
single-ascending dose cohorts (Cohorts 1 to 3) to evaluate safety, tolerability, pharmacokinetics, 
and target engagement of AGN-241622. In each cohort in Stage 1, approximately 12 participants 
will be randomized in a 3:1 ratio to receive AGN-241622 ophthalmic solution or vehicle. 
Participants randomized to receive active intervention will be administered a single drop of 
AGN-241622 at dose strengths ranging from 
 in the left eye. Each participant will 
be admitted to the study center on the evening before dosing (Day -1). Participants will receive 
their single dose in the morning of Day 1 and, after a full day of assessments, stay overnight and 
continue further safety and PK assessments on the next day (EOS Visit). After each cohort is 
complete, an independent DMC will review unmasked safety and plasma PK data, along with 
target engagement and efficacy data if necessary (and applicable), to recommend if it is 
acceptable to proceed to the next planned cohort. The DMC may also recommend modifying the 
proposed dose strength (e.g., de-escalate to a lower dose strength), repeat the current dose 
strength, modify the cohort size, or stop the study. In addition, the FDA will review study data 
after the completion of each cohort and the sponsor will wait until a positive response is received 
from the FDA to proceed to the next cohort. Once Cohort 2 of Stage 1 is complete, in addition to 
making a recommendation on whether to initiate the final cohort of Stage 1 (Cohort 3), the DMC 
will also make a recommendation on whether to start Stage 2 (Cohort 4) in parallel.  
In Stage 2, participants with presbyopia will be selected to participate in the study. Stage 2 will 
be further divided into Stages 2a (Cohorts 4 to 6) and 2b (Cohorts 7 and 8). Cohorts 4 to 6 
(Stage 2a) will be multiple ascending dose cohorts in which participants will be randomized to 
receive either AGN-241622 at dose strengths ranging from 
 or vehicle once daily 
in both eyes for 14 days. In each cohort in Stage 2a, approximately 12 participants will be 
randomized in a 3:1 ratio to receive AGN-241622 ophthalmic solution or vehicle in order to 
evaluate safety, tolerability, pharmacokinetics, and efficacy of AGN-241622 (Figure 1-1). As in 
Stage 1, the DMC may recommend modifying the proposed dose strength (e.g., de-escalate to a 
lower dose strength), repeat the current dose strength, modify the cohort size, or stop the study. 
After Cohort 6 has completed, the DMC will also recommend the dose strength to be tested in 
Stage 2b. 
Cohort 7 is a single-masked, active comparator cohort in which approximately 60 participants 
with presbyopia will be randomized in a 1:1 ratio to receive either pilocarpine HCl 
 1.25% ophthalmic solution or AGN-241622 ophthalmic solution administered at 
the dose strength recommended by the DMC once daily in both eyes for 14 days. Safety, 
tolerability, and efficacy of AGN-241622 compared with pilocarpine HCl (
) 1.25% 
will be assessed after repeat bilateral topical ocular administration. Cohort 8 is an exploratory 
cohort in which approximately 12 participants with presbyopia who wear contact lenses will be 
randomized in a 3:1 ratio to receive either AGN-241622 administered at the dose strength 
recommended by the DMC or vehicle once daily in both eyes for 14 days. Safety, tolerability, 
tear pharmacokinetics, and efficacy of AGN-241622 administered at the dose strength 

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recommended by the DMC compared with vehicle will be assessed after repeat bilateral 
administration.  
In all cohorts of Stage 2, participants will receive their first dose in the clinic on Day 1, and stay 
in the clinic for safety, PK (except Cohort 7), and efficacy evaluations for approximately 10 
hours postdose. For Stage 2a, participants will then return for dosing once daily and assessments 
from Day 2 to Day 7. For Stage 2b, on Days 3 and 7, participants will return to the clinic for 
dosing and assessments; on Days 1 and 3, participants will also receive multidose bottles for 
single unit of use for at-home dosing on Days 2, 4, 5, and 6. For participants in both Stages 2a 
and 2b, they will then receive multidose bottles on Day 7 for single unit of use for at-home 
dosing from Days 8 to 13 and will return to the clinic on Day 14 for dosing as well as safety, 
tolerability, PK (except Cohort 7), and efficacy evaluations for approximately 10 hours postdose. 
On Day 30, participants will return for a safety follow-up and EOS Visit.   
The study will be conducted in the United States. 
Participants who prematurely discontinue from the study may be replaced at the discretion of the 
sponsor. 
Study interventions by study stage and cohort are summarized in Table 4-1. 
Table 4-1 
Study Interventions by Study Stage and Cohort 
Study Interventions by Study Stage and Cohort 
Stage 1 
Single Ascending Doses in Healthy Participants  
Cohort 1 
AGN-241622
 single dose 
left eye 
9 Active; 3 Vehicle 
Cohort 2 
AGN-241622
 single dose 
left eye 
9 Active; 3 Vehicle 
Cohort 3 
AGN-241622 
 single dose 
left eye 
9 Active; 3 Vehicle 
Stage 2a 
Multiple Ascending Dose in Participants with Presbyopia  
Cohort 4 
AGN-241622 
  
QD × 14 days both eyes 
9 Active; 3 Vehicle 
Cohort 5 
AGN-241622 
  
QD × 14 days both eyes 
9 Active; 3 Vehicle 
Cohort 6 
AGN-241622 
  
QD × 14 days both eyes 
9 Active; 3 Vehicle 
Stage 2b 
Multiple-Dose Exploratory Cohorts in Participants with Presbyopia 
Cohort 7  
AGN-241622 (dose strength TBD) versus 
pilocarpine HCl 
 1.25%  
QD × 14 days both eyes 
60 (30 per treatment arm)  
Cohort 8 
AGN-241622 (dose strength TBD)  
(in participants who wear contact lenses) 
QD × 14 days both eyes 
9 Active; 3 Vehicle 
 

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4.1.1. 
Clinical Hypotheses 
Stage 1 
• A single dose of AGN-241622 ophthalmic solution dosed unilaterally will demonstrate an 
acceptable safety and tolerability profile in healthy participants. 
• A single dose of AGN-241622 ophthalmic solution dosed unilaterally will result in 
systemic exposure in healthy participants with sufficient safety margins to nonclinical 
safety studies. 
• A single dose of AGN-241622 ophthalmic solution dosed unilaterally will demonstrate a 
decrease in pupil diameter in healthy participants as compared with vehicle. 
Stage 2a 
• Repeat doses of AGN-241622 ophthalmic solution dosed bilaterally for 14 days will 
demonstrate an acceptable safety and tolerability profile in participants with presbyopia. 
• Repeat doses of AGN-241622 ophthalmic solution dosed bilaterally for 14 days will 
result in systemic exposure in participants with presbyopia with sufficient safety margins 
(see Table 4-2). 
• Repeat doses of AGN-241622 ophthalmic solution dosed bilaterally for 14 days will 
demonstrate a numeric improvement in DCNVA compared with vehicle in participants 
with presbyopia. 
Stage 2b 
• Repeat doses of AGN-241622 ophthalmic solution dosed bilaterally for 14 days will 
demonstrate an acceptable safety and tolerability profile in participants with presbyopia 
(Cohort 7) and participants with presbyopia wearing contact lenses (Cohort 8).   
• Repeat doses of AGN-241622 ophthalmic solution dosed bilaterally for 14 days will 
demonstrate similar improvement in DCNVA compared with pilocarpine HCl 
1.25% in participants with presbyopia (Cohort 7).  
4.2. 
Scientific Rationale for Study Design 
This study is designed as 3 distinct stages to ensure that the safety and tolerability of 
AGN-241622 are achieved in healthy participants in Stage 1 before participants with presbyopia 
are exposed and assessed for safety, tolerability, and efficacy in Stages 2a and 2b. Although 
α2-adrenergic receptor agonists are a class of compounds with extensive clinical experience, 
AGN-241622 is a new chemical entity, and the study design of this Phase 1/2 study will assess 
its ocular and systemic safety in an adaptive fashion. Healthy participants and participants with 
presbyopia will be subject to various ocular assessments such as IOP measurements, 
biomicroscopy, and fundus examination, while systemically they will be assessed with 12-lead 
ECG, vital signs measurements, and clinical laboratory assessments to ensure participant safety. 
In addition, each cohort will not proceed until the preceding cohort(s) has been: 1) reviewed and 
deemed safe by a DMC, and 2) a positive response is received from the FDA. Vehicle has been 
selected as a comparator for Stages 1 and 2a and 2b (Cohort 8 only) of this study as there are 

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5.02 
Female participants must be willing to minimize the risk of inducing pregnancy 
throughout the study, up through 30 days after the last dose of study intervention 
(refer to Appendix 7, Section 10.7)  
 
A female participant is eligible if at least 1 of the following conditions 
applies: 
a. She is not a female of childbearing potential as defined in 
Appendix 7, Section 10.7 
OR 
b. She is a female of childbearing potential who agrees to follow the 
contraceptive guidance in Appendix 7, Section 10.7 throughout the study  
 
In addition, all female participants of childbearing potential must 
test negative for pregnancy at Screening (serum test) and on Day 1 (urine test).  
6. 
Other 
6.01 
Able, as assessed by the investigator, and willing to follow study instructions and 
likely to complete all required study visits 
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
5.2.1. 
Stage 1  
1.04 
History of alcohol or other substance abuse within the previous 5 years 
3. 
Prior/Concurrent Clinical Study Experience 
3.01 
Current enrollment in an investigational drug or device study or participation in 
such a study within 30 days of entry into this study 

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3.01 
Current enrollment in an investigational drug or device study or participation in 
such a study within 30 days of entry into this study 

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5.01 
Females who are pregnant, nursing, or planning a pregnancy during the study. 
Female or males who are of childbearing potential and do not agree to use highly 
effective contraception during the study (refer to Appendix 7, Section 10.7)  
5.3. 
Lifestyle Considerations 
5.3.1. 
Habitual Distance Corrections (Stages 2a and 2b only) 
Participants who wear bifocal or multifocal spectacles or contact lenses will be provided with a 
pair of monofocal spectacles or contact lenses (only for Cohort 8) with the same or improved 
distance correction (20/32 or better) as their new habitual correction. Participants whose distance 
habitual corrections are worse than 20/32 will also be provided with a pair of new spectacles or 
contact lenses (only Cohort 8) with improved distance correction (20/32 or better). Participants 
are required to wear the newly provided spectacles or contact lenses for at least 7 days before 
Day 1 and during the study, and no bifocal or multifocal or old habitual correction lenses should 
be used. Only monofocal spectacles or contact lenses (only for Cohort 8) can be worn between 
study visits and on the study visit days. Reading glasses are allowed between study visits when 
needed. 
5.3.2. 
Meals and Dietary Restrictions 
Participants must not take dietary supplements or other foods or beverages that may affect 
various drug-metabolizing enzymes and transporters (e.g., grapefruit, grapefruit juice, 
grapefruit-containing beverages) during the study. 

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5.3.3. 
Caffeine, Alcohol, and Tobacco 
1. Participants must refrain from ingesting caffeine during the 30 minutes preceding vital 
signs measurements.  
2. Participants must abstain from drinking alcohol from 72 hours before administration of 
study intervention and during the study treatment period (defined as Day 1 postdosing 
through Day 2 during Stage 1; defined as Day 1 postdosing through Day 14 during 
Stage 2). 
3. Participants are nonsmoking and nonusers of nicotine-containing products (never smoked 
or used nicotine-containing products or have not smoked or used nicotine-containing 
products within the previous 1 year) at screening. Use of tobacco/nicotine products is also 
not allowed from the Screening Visit until after the final follow-up visit. 
5.3.4. 
Activity 
Participants must not engage in strenuous activity at any time during the study intervention 
period. Participants may participate in light recreational activities during the study 
(e.g., watching television, reading, jogging).  
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently randomly assigned to study intervention/entered in the study. 
A minimal set of screen failure information is required to ensure transparent reporting of screen 
failure participants to meet the CONSORT publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes indicating screen failure as reason 
for ending the study, demography, screen failure details, eligibility criteria, and any SAE. 
Individuals who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened. 

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6. 
Study Intervention 
Study intervention is defined as any investigational intervention(s), marketed product(s), 
placebo, or medical device(s) intended to be administered to a study participant according to the 
study protocol. 
6.1. 
Study Intervention(s) Administered 
Table 6-1 
Study Interventions  
Study Intervention Name 
AGN-241622 
 
Vehicle 
Type 
Drug 
Drug 
Drug 
Drug Substance 
AGN-241622-2A  
Pilocarpine HCl 
 1.25% 
Not applicable 
Dosage Formulation 
Topical eye drop 
Topical eye drop 
Topical eye drop 
Identity of Formulation 
and Unit Dose Strengths 
AGN-241622 ophthalmic 
solutions  
Pilocarpine HCl 
) 1.25% 
ophthalmic solution 
 
AGN-241622 ophthalmic 
solution (placebo) 
) 
Dosage Levels 
1 drop in left eye once 
(Stage 1)  
1 drop in each eye once 
daily for 14 days 
(Stage 2a/Stage 2b) 
1 drop in each eye once 
daily for 14 days 
(Cohort 7) (Stage 2b) 
1 drop in left eye once  
(Stage 1)  
1 drop in each eye once daily 
for 14 days  
(Stage 2a/Stage2b 
[Cohort 8]) 
Route of Administration  
Topical eye drop 
Topical eye drop 
Topical eye drop 
Use 
Experimental 
Active-comparator 
Placebo-comparator 
IMP  
IMP 
IMP  
IMP 
Sourcing 
Provided centrally by the 
sponsor 
Provided centrally by the 
sponsor  
Provided centrally by the 
sponsor  
Packaging and Labeling 
Study intervention will be 
provided in sterile, 10-mL 
bottles. Each bottle will be 
labeled as required per 
country requirement. 
An investigational caution 
label will appear on the 
individual bottle and the 
outer carton: 
Use as directed 
Keep Out of Reach of 
Children 
Caution: New Drug--
Limited by Federal Law to 
Study intervention will be 
provided in sterile, 5-mL 
bottles. Each bottle will be 
labeled as required per 
country requirement. 
An investigational caution 
label will appear on the 
individual bottle and the 
outer carton: 
Use as directed 
Keep Out of Reach of 
Children 
Caution: New Drug--
Limited by Federal Law to 
Study intervention will be 
provided in sterile, 10-mL 
bottles. Each bottle will be 
labeled as required per 
country requirement. 
An investigational caution 
label will appear on the 
individual bottle and the 
outer carton: 
Use as directed  
Keep Out of Reach of 
Children 
Caution: New Drug--
Limited by Federal Law to 
 

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The study intervention will be supplied in LDPE eye dropper bottles each containing 5 or 3.5 mL 
of study intervention and labeled with the protocol number, kit number, volume, storage 
information, warning language (Caution: New Drug—Limited by Federal Law to Investigational 
Use. Keep Out of Reach of Children), and instructions to use as directed. 
6.1.1. 
Instructions for Use and Administration 
6.2. 
Preparation/Handling/Storage/Accountability 
1. The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are 
reported and resolved before use of the study intervention. 
2. Only participants enrolled in the study may receive study intervention and only authorized 
site staff may supply or administer study intervention in the clinic (participants will 
administer study intervention themselves on days of at-home dosing). All study 
intervention must be stored in a secure, environmentally controlled, and monitored 
(manual or automated) area in accordance with the labeled storage conditions with access 
limited to the investigator and authorized site staff. 
3. The investigator, institution, or the head of the medical institution (where applicable) is 
responsible for study intervention accountability, reconciliation, and record maintenance 
(i.e., receipt, reconciliation, and final disposition records). 
4. Further guidance and information for the final disposition of unused study interventions 
are provided in the study reference manual or other specified location. 
5. Participants will be instructed on the proper storage of study intervention and to keep it 
out of the reach of children at all times.  
6.3. 
Measures to Minimize Bias: Randomization and Masking 
All participants will be centrally assigned to study intervention using an IWRS. The cap of the 
number of participants can be recommended by the DMC for Cohort 7. Randomization and kit 
assignment will be conducted on Day 1. In Cohorts 1 to 6 and 8, participants will be randomized 
in a 3:1 ratio to receive AGN-241622 ophthalmic solution or vehicle. In Cohort 7, participants 
will be assigned in a 1:1 ratio to receive pilocarpine HCl 
 1.25% ophthalmic 
solution or AGN-241622 ophthalmic solution. Cohort 7 will be single masked, in which 

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participants will be masked for the study intervention assignment and site staff and the 
investigator will not discuss the study intervention assignment with the participants. 
Before the study is initiated, login information and directions for the IWRS will be provided to 
each study center. Study intervention and vehicle will be dispensed at the study visits 
summarized in the SoA for Stages 1, 2a, and 2b (Sections 1.3.1, 1.3.2, and 1.3.3, respectively). 
The identity of study intervention will be masked to the participants and study centers for 
Cohorts 1 to 6 and 8. The identity of study intervention will be masked to the participants only 
for Cohort 7. The IWRS will be programmed with mask-breaking instructions. In case of an 
emergency, the investigator has the sole responsibility for determining if unmasking of a 
participant’s study intervention assignment is warranted. Participant safety must always be the 
first consideration in making such a determination. If the investigator decides that unmasking is 
warranted, the investigator should make every effort to contact the sponsor prior to unmasking a 
participant’s study intervention assignment unless this could delay emergency treatment of the 
participant. If a participant’s study intervention assignment is unmasked, the sponsor must be 
notified within 24 hours after breaking the mask. The date and reason that the mask was broken 
must be recorded in the source documentation. 
At the end of each cohort or at ad hoc meetings, the DMC will review unmasked safety and 
plasma PK data, along with target engagement and efficacy data if necessary (and applicable), 
from each cohort and provide a recommendation on whether the study can proceed to the next 
cohort. In addition, the FDA will review study data after the completion of each cohort and the 
sponsor will wait until a positive response is received from the FDA to proceed to the next 
cohort.  
An internal independent review team (comprised of but not limited to, a medical safety 
physician, statistician, clinical pharmacologist, and a clinical representative) will make up the 
DMC for the study. The composition of the independent team will be documented in the DMC 
Charter, TMF, and clinical study report. The members of the independent team will be different 
from the study team members who manage and maintain the study conduct activities, including 
data collection, data clarification, analysis development, safety monitoring, study center 
monitoring and management.  
6.4. 
Study Intervention Compliance 
For the inpatient dosing during Stages 1 (Day 1), 2a (Days 1 to 7, and Day 14), and 2b (Days 1, 
3, 7, and 14), participants will receive all doses under the direct supervision of study center 
personnel. Study intervention compliance will be assumed to be 100% when dosing has been 
recorded in the eCRF. 
For home dosing during Stages 2a and 2b (Days 8 to 13), study intervention compliance will be 
monitored by counting the number of bottles dispensed and returned. Before dispensing new 
study intervention at each visit, study center personnel will make every effort to collect all 
unused study intervention and empty bottles.  
The study center will keep an accurate drug disposition record that specifies the amount of study 
intervention administered to each participant and the date of administration for inpatient dosing. 

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6.5. 
Concomitant Therapy 
The use of any concomitant medication, prescription or over-the-counter, is to be recorded on 
the participant’s eCRF at each study visit along with the reason the medication is taken. 
From the Screening Visit to the EOS Visit, site staff will question each participant specifically on 
the use of concomitant medications.  
6.5.1. 
Prohibited Interventions  
The decision to administer a prohibited medication/treatment will be made with the safety of the 
study participant as the primary consideration. If the permissibility of a specific 
medication/treatment is in question, please contact the sponsor. 
For Stages 1 and 2a, use of any medication, other than the study intervention or medications 
administered to conduct study procedures is prohibited from the Screening Visit through study 
exit, except for those contraceptives listed in Table 10-2. 
For Stage 2b, use of any ophthalmic medications, other than the study intervention or 
medications administered to conduct study procedures is prohibited from the Screening Visit 
through study exit.  
 

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6.5.2. 
Permitted Interventions 
Use of the following systemic medications are permitted in Stage 2b, provided that the treatment 
regimen has remained stable for at least 1 month prior to Screening and is not anticipated to 
change during the duration of the study: 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of screening or receives 
during the study must be recorded along with: 
• Indication 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor. 
The sponsor or designee should be contacted if there are any questions regarding concomitant or 
prior therapy. 
Any medication taken during the study between the date of the first dose of study intervention 
and the date of the EOS Visit will be recorded in the eCRF as a concomitant medication; any 
medication started after the EOS Visit will not be considered a concomitant medication and 
should not be captured in the eCRF. 
6.6. 
Dose Modification 
Dose modification is not applicable. 
6.7. 
Intervention after the End of the Study 
No intervention is planned following the end of the study.  

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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
A premature discontinuation will occur if a participant who signs the ICF and is dosed ceases 
participation in the study, regardless of circumstances, before the completion of the 
protocol-defined study procedures. 
Notification of early participant discontinuation from the study and the reason for 
discontinuation will be made to the sponsor and will be clearly documented on the appropriate 
eCRF. 
Reasons for discontinuation from the study intervention and/or the study may include the 
following: 
• AE 
• Lost to follow-up 
• Noncompliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Site terminated by sponsor 
• Study terminated by sponsor 
• Withdrawal by subject 
• Death  
• Other 
7.1. 
Discontinuation of Study Intervention 
See the SoA (Sections 1.3.1, 1.3.2, and 1.3.3) for data to be collected at the time of early 
termination. 
The DMC and FDA may recommend modifications to the protocol including discontinuation of 
study intervention upon review of safety data. 
Study intervention may also be paused due to safety concerns at any time by the site investigator. 
The sponsor and DMC should be notified immediately if study intervention was paused.  
7.1.1. 
Study Termination 
The sponsor may stop the study (and/or the study center) for any reason with appropriate 
notification. The DMC and FDA may recommend study termination upon review of safety data. 

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7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. This is expected to be uncommon. 
• The participant will be permanently discontinued both from the study intervention and 
from the study at that time. 
• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
• At the time of discontinuing from the study, if possible, an EOS Visit should be 
conducted, as shown in the SoA (Sections 1.3.1, 1.3.2, and 1.3.3).  
7.3. 
Lost to Follow up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in 
the study. 
• Before a participant is deemed lost to follow up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, 
if necessary, a certified letter to the participant’s last known mailing address or local 
equivalent methods). These contact attempts should be documented in the participant’s 
medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study.  
Discontinuation of specific sites or of the study as a whole are handled as part of 
Appendix 1, Section 10.1. 

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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (Sections 1.3.1, 1.3.2, and 
1.3.3). Protocol waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor immediately upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1. 
Efficacy Assessments 
Stage 1 
No efficacy measures will be assessed in Stage 1. Pupil diameter (mesopic) will be assessed as a 
measure of target engagement.  
Stages 2a and 2b 
Efficacy assessments in Stages 2a and 2b are:  
• Mesopic and photopic high contrast, binocular and monocular DCNVA (refer to 
Sections 1.3.2 and 1.3.3 for assessment timepoints) 
• Mesopic and photopic high contrast, binocular and monocular DCIVA (only in Stage 2b; 
(refer to Section 1.3.3 for assessment timepoints)  
Measurement: Visual acuity for near (40-cm), intermediate (66-cm) and distance (4-meter) 
targets will be measured in mesopic and photopic conditions. Mesopic condition is defined as 
lighting 3.2 to 3.5 candelas per square meter (cd/m2; 10 to 11 lux) measured at the target. 
Photopic condition is defined as lighting ≥ 80 cd/m2 (251 lux) measured at the target.  
• Mesopic and photopic pupil diameter (distance and near) (refer to Sections 1.3.2 and 
1.3.3 for assessment timepoints) 
• Depth of focus (refer to Sections 1.3.2 and 1.3.3 for assessment timepoints)  
Measurement: Depth of focus will be measured on each eye. 
• Bulbar conjunctival hyperemia (refer to Sections 1.3.2 and 1.3.3 for assessment 
timepoints)  
Measurements: Bulbar conjunctival hyperemia in each eye will be graded separately by the 
investigator using sponsor-provided reference photographs.    

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Assessment should be performed by the same evaluator whenever possible in the same 
facility. Illumination should be consistent throughout the study. Note: The bulbar 
conjunctival hyperemia assessment is a different assessment than the hyperemia scales 
described as part of the biomicroscopic examination (Appendix 8, Section 10.8). 
• PRO Questionnaires (only in Stages 2a and 2b) (refer to Sections 1.3.2 and 1.3.3 for 
assessment timepoints) 
Near Vision Presbyopia Task-based Questionnaire (NVPTQ): Comprised of 12 questions 
on 4 reading tasks (i.e., reading a paragraph from a book, reading excerpts from an article in 
a newspaper, reading a portion of a nutrition label, and reading a section from a restaurant 
menu). 
 
Electronic Near Vision Presbyopia Task-based Questionnaire (e-NVPTQ) (iPhone/iPod 
version) (only in Stage 2b; refer to Section 1.3.3): Comprised of 5 questions on an electronic 
reading task (i.e., reading a text on iPhone or iPod) 
 
Measurements (NVPTQ and e-NVPTQ):  
o Participants will complete specific reading tasks under mesopic (for NVPTQ) and 
photopic (for e-NVPTQ) conditions without any near-vision correction. 
o Participants will then answer 3 questions for each task (5 questions for 
e-NVPTQ), rating their vision-related reading ability and satisfaction with their 
vision-related reading ability. 
o There is no explicit recall period used for the NVPTQ and e-NVPTQ; the 
intention is for participants to complete the questionnaire immediately after 
completing each task. 
Presbyopia Impact and Coping Questionnaire (PICQ): Participants will answer 
20 questions about the degree to which they were impacted by their difficulty seeing up close 
(e.g., found daily near vision tasks difficult, or experienced self-consciousness); or engaged 
in coping behaviors (e.g., changed the font size on electronic screens) during the previous 
7 days.  
Single-Item Patient Global Impression of Status (PGIS): Participants will answer a single 
question about their global impression of the status of their near-vision acuity in the past 
7 days. 
Single-Item Patient Global Impression of Change (PGIC): Participants will answer a single 
question about their global impression of change in their near-vision acuity. 
Details are provided in the study procedure manual. 
8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Sections 1.3.1, 1.3.2, and 
1.3.3). 

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8.2.1. 
Physical Examinations 
• A complete physical examination will include, at a minimum, assessments of the 
cardiovascular, respiratory, gastrointestinal and neurological systems. Height (only at 
screening) and weight will also be measured and recorded. 
• Investigators should pay special attention to clinical signs related to previous serious 
illnesses. 
• Physical examinations should be completed by a professionally trained physician or 
health professional listed on Form FDA 1572 and licensed to perform physical 
examinations. 
8.2.2. 
Vital Signs 
Vital signs will be assessed as follows: 
• Oral/axillary temperature, heart rate, respiration rate, and blood pressure will be assessed.  
• Systolic and diastolic blood pressure and heart rate will be measured after participants 
have been at rest (seated) for at least 5 minutes in a quiet setting without distractions 
(e.g., television, cell phones). 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 will be recorded in mm Hg and heart 
rate will be recorded in bpm. 
8.2.3. 
Electrocardiograms 
• Sites shall transmit all study-required ECGs obtained to the ECG vendor, unless 
otherwise specified in the study procedure manual.  
• A standard 12-lead ECG that measures PR, QRS, QT, QTc, QTcB, and QTcF intervals 
will be performed in the supine position at the nominal times (relative to the dosing 
times) as outlined in the SoA (Sections 1.3.1, 1.3.2, and 1.3.3). 
8.2.4. 
Clinical Safety Laboratory Assessments 
• See Appendix 2, Section 10.2 for the list of clinical laboratory tests to be performed and 
to the SoA (Sections 1.3.1, 1.3.2, and 1.3.3) for the timing and frequency.  
• At screening, the investigator or sub-investigator will assess the clinical significance of 
any values outside the reference ranges provided by the laboratory, and participants with 
abnormalities judged to be clinically significant will be excluded from the study. 
• 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 eCRF. 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 
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• All laboratory tests with values considered clinically significantly abnormal during 
participation in the study or within 30 days after the last dose of study intervention should 
be repeated until the values return to normal or baseline or are no longer considered 
clinically significant by the investigator or medical safety physician. 
o If such values do not return to normal/baseline within a period of time judged 
reasonable by the investigator, the etiology should be identified and the sponsor 
notified. 
o All protocol-required laboratory assessments, as defined in Appendix 2, Section 10.2 
must be conducted in accordance with the laboratory manual and the SoA. 
o If laboratory values from 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 (e.g., SAE or AE or dose 
modification), then the results must be recorded as an SAE or AE in the eCRF. 
o Urine dipstick kits may be used to conduct drugs-of-abuse screens and pregnancy 
tests and alcohol screen at the study center post-screening. Alternatively, a 
breathalyzer may be used for an alcohol screen.  
8.2.5. 
Study Intervention Tolerability and Drop Comfort Assessments 
The presence and severity of ocular symptoms will be elicited from the participant separately for 
their treated eye(s), as applicable. Symptoms including blurred vision, foreign body sensation, 
pain, burning/stinging, tearing, and itching will be classified using a 5-point grading scale with 
duration of symptoms immediately after the drop instillation of each dose of study intervention. 
If any other ocular symptoms are present, these will be captured. 
Participants will be asked to rate the overall comfort of the eye drops using a 6-point scale 
(i.e., soothing, very comfortable, comfortable, uncomfortable, very uncomfortable, or 
intolerable) immediately after the drop instillation for the right and left eyes separately, as 
applicable. Refer to Sections 1.3.1, 1.3.2, and 1.3.3 for assessment timepoints. Details are 
outlined in Appendix 9, Section 10.9. 
8.2.6. 
IOP 
IOP should be measured only after the biomicroscopic exam is completed and must be measured 
prior to pupil dilation. Measurements will be taken using a Goldmann applanation tonometer 
affixed to a slit lamp with the participant seated. Both eyes will be tested, with the right eye 
preceding the left eye. Refer to Sections 1.3.1, 1.3.2, and 1.3.3 for assessment timepoints. Details 
are outlined in Appendix 11, Section 10.11. 
8.2.7. 
Slit lamp Biomicroscopy 
Biomicroscopic examinations will be performed using a slit lamp. The examinations will include 
evaluation of the condition of the eyelids, conjunctiva, cornea, anterior chamber, iris/pupil, and 
sodium fluorescein corneal staining. Refer to Sections 1.3.1, 1.3.2, and 1.3.3 for assessment 
timepoints. Details are outlined in Appendix 8, Section 10.8.   

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8.2.8. 
Sodium Fluorescein Corneal Staining 
Sodium fluorescein corneal staining assessments will be assessed and graded according to the 
Oxford Scale per Appendix 8, Section 10.8. Refer to Sections 1.3.1, 1.3.2, and 1.3.3 for 
assessment timepoints. Details are outlined in Appendix 8, Section 10.8.  
8.2.9. 
Dilated Fundoscopic Examination 
The fundus (indirect) ophthalmoscope examination assessments should be conducted through a 
dilated pupil. The examinations will include evaluation of the lens, vitreous, fundus, and 
optic nerve. The cup to disc ratio will be assessed. The investigator should note if the pupil 
dilated normally. Refer to Sections 1.3.1, 1.3.2, and 1.3.3 for assessment timepoints. Details are 
outlined in Appendix 10, Section 10.10.   
8.2.10. 
Contrast Sensitivity (Stages 2a and 2b only)  
Contrast sensitivity assessments will be conducted with participant’s best distance correction, 
except for participants in Cohort 8, for which contrast sensitivity will be conducted with habitual 
distance correction. Refer to Sections 1.3.2 and 1.3.3 for assessment timepoints. Details will be 
outlined in the study procedures manual. 
8.2.11. 
Photopic and Mesopic High-contrast CDVA (Stages 2a and 2b 
only)   
Photopic and mesopic high-contrast CDVA will be conducted with the participant’s best distance 
correction, except for participants in Cohort 8, for which photopic and mesopic high-contrast 
CDVA will be conducted with the participant’s habitual distance correction. The assessment is to 
be measured binocularly. Pupil diameter must be measured in each individual eye. Refer to 
Sections 1.3.2 and 1.3.3 for assessment timepoints. 
For all lighting conditions, different charts must be used for the repeated visual acuity measures 
within the same day. 
Details will be outlined in the study procedures manual.  
8.2.12. 
Manifest Refraction (Stages 2a and 2b only) 
Manifest refraction (distance and near, mesopic and photopic) will be performed according to 
standard clinical practice in both mesopic and photopic conditions. If a participant loses ≥ 1 line 
of CDVA or DCNVA compared with Hour 0 of the same study visit at Hour 1 after dosing, a 
manifest refraction should be repeated under the same lighting conditions. 
Refer to Sections 1.3.2 and 1.3.3 for assessment timepoints. Details will be outlined in the study 
procedures manual.  
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 3, Section 10.3. 
AEs will be reported by the participant. 

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The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and any other study-specific terms as 
relevant and remain responsible for following up AEs that are serious, considered related to the 
study intervention or study procedures, or that caused the participant to discontinue the study 
intervention/study (see Section 7). 
8.3.1. 
Time Period and Frequency for Collecting AE and SAE 
Information 
All AEs from the signing of the ICF until EOS Visit will be collected at the timepoints specified 
in the SoA (Sections 1.3.1, 1.3.2, and 1.3.3), and as observed or reported spontaneously by study 
participants. 
All SAEs from the signing of the ICF until up to 30 days after last dosing will be collected at the 
timepoints specified in the SoA (Sections 1.3.1, 1.3.2, and 1.3.3), and as observed or reported 
spontaneously by study participants. 
Medical occurrences that begin before the start of study intervention but after obtaining informed 
consent will be recorded in the AE section of the eCRF and will be considered pretreatment AEs. 
All SAEs will be recorded and reported to the sponsor or designee immediately and under no 
circumstance should this exceed 24 hours, as indicated in Appendix 3, Section 10.3. The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. 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 intervention or study participation, the investigator must promptly 
notify the sponsor. 
8.3.2. 
Method of Detecting AEs and SAEs 
The method of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in 
Appendix 3, Section 10.3.  
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences.  
8.3.3. 
Follow-up of AEs and SAEs 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). Further 
information on follow-up procedures is provided in Appendix 3, Section 10.3.   

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8.3.4. 
Regulatory Reporting Requirements for SAEs 
• Prompt notification by the investigator to the sponsor of a SAE is essential so that Legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention 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 intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRB/IEC, and investigators.  
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (e.g., summary or listing of SAEs) from the sponsor will 
review and then file it along with the investigator’s brochure and will notify the IRB/IEC, 
if appropriate, according to local requirements. 
• Investigator safety reports must be prepared for SUSARs according to local regulatory 
requirements and sponsor policy and forwarded to investigators as necessary. 
8.3.5. 
Pregnancy 
• Details of all pregnancies in female participants, and if indicated, female partners of male 
participants, will be collected from signing of the ICF and until the EOS. 
• If a pregnancy is reported, the investigator should inform the sponsor or designee within 
24 hours of learning of the pregnancy and should follow the procedures outlined in 
Appendix 7, Section 10.7. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an 
elective abortion or not) are considered SAEs. 
8.4. 
Treatment of Overdose 
Treatment of overdose is not applicable. 
8.5. 
Pharmacokinetics 
Blood and tear samples for quantification of AGN-241622 in participant’s plasma and tears will 
be collected from all enrolled participants in Cohorts 1 to 6, PK tear samples will be collected 
from enrolled participants in Cohort 8, and neither PK blood nor tear samples will be collected 
from enrolled participants in Cohort 7. 
Refer to Sections 1.3.1, 1.3.2, and 1.3.3 for assessment timepoints. 
8.5.1. 
Blood PK Sampling Procedure 
• For Cohorts 1 to 6, a qualified phlebotomist will collect 5 mL of each participant’s blood 
via an indwelling catheter or venipuncture from either arm into one 6 mL vacutainer tube 
containing K2EDTA as an anticoagulant.  

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• Plasma samples of approximately 2.5 mL will be collected for measurement of plasma 
concentrations of AGN-241622 at each of the timepoints specified in the SoA from 
enrolled participants in Cohorts 1 to 6 (Sections 1.3.1 and 1.3.2).  
• Instructions for the collection and handling of biological samples will be provided by the 
sponsor. The actual date and time (24-hour clock time) of each sample will be recorded. 
PK blood samples to determine AGN-241622 concentrations should be drawn at the 
nominal times, relative to the dosing time, and the actual time of the blood draw must be 
recorded in the source documents and eCRFs. Samples must be taken within 5 minutes of 
the nominal times. Predose samples must be drawn within 15 minutes of the dosing time.  
• Study center staff will record the atomic clock times of all blood draws for each 
participant and will label vacutainer and polypropylene tubes with a coded label that 
corresponds to the participant number and blood draw time. The central laboratory will 
supply the coded labels, vacutainers, and polypropylene tubes.  
• Samples will be used to evaluate the pharmacokinetics of AGN-241622. Each plasma 
sample will be divided into 2 aliquots (1 each for primary and backup PK samples). 
Samples collected for analyses of AGN-241622 plasma concentration may also be used to 
evaluate safety or efficacy aspects related to concerns arising during or after the study. 
Drug concentration information that would unmask the study will not be reported to study 
centers or masked personnel until the study has been unmasked. 
Bioanalytical representatives will be unmasked for PK sample bioanalysis during the conduct of 
the study. The unmasking of bioanalytical representatives is to be carried out in a secure manner 
following the sponsor’s standard operating procedures. Extreme care and diligence will be taken 
to ensure no other individuals outside the bioanalytical team will be unblinded. 
Blood Volume Collection   
Within 30 minutes from the time of the blood draw, blood samples must be centrifuged at no less 
than 2000 g for 15 minutes at approximately 4°C. After centrifugation, the plasma samples will 
be harvested and aliquoted into 2 cryovials (1 primary and 1 backup). The samples should be 
placed on wet ice immediately after aliquoting and transferred to a –20°C freezer within 1 hour 
of processing to plasma. 
Study center staff will send plasma samples to the bioanalytical laboratory or the central 
laboratory for storage after the last collection on Day 1 (for Stage 1) and after the last collection 
on Days 1 and 14 (for Stage 2). On the day of shipment, the sponsor and the specified laboratory 
will be notified by email as to the time and method of shipment. 
8.5.2. 
Tear PK Sampling Procedure  
Tear collections for ocular pharmacokinetics will be conducted at all sites in all participants 
(except for Cohort 7). Tear samples will be collected from left eye only. The same eye must be 
sampled throughout the study. Information regarding tear collection procedures will be provided 
in the study procedure manual.  

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8.5.3. 
PK Sample Bioanalysis 
Concentrations of AGN-241622 in plasma and tear will be determined using validated or 
qualified liquid chromatography-tandem mass spectrometry methods. 
8.6. 
Pharmacodynamics 
In Stages 1, 2a, and 2b, pupil diameter will be assessed as a measure of pharmacodynamic 
activity in participants. Pupil diameter for near (40-cm) and distance (4-meter) targets will be 
measured with the pupillometer in mesopic conditions during Stage 1 and mesopic and photopic 
conditions in Stage 2. 
Refer to Sections 1.3.1, 1.3.2, and 1.3.3 for assessment timepoints. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers and Other Assessments 
Biomarkers are not evaluated in this study. Refer to Sections 1.3.1, 1.3.2, and 1.3.3 
for assessment timepoints. 
8.8.1. 
Determination of Iris Color  
The investigator will assess iris color on a gross, macroscopic level using the following 
classification: brown, blue, grey, green, or hazel.  
8.8.2. 
Determination of Dominant Eye (Stages 2a and 2b only)  
Participants will be asked to extend their arms out in front of them at eye level, with their palms 
facing away, fingers together and facing upward. Participants will bring their hands together, 
forming a small window by overlapping their thumbs and overlapping their fingers. Participants 
will select a small object at least 10 feet in front of them and look at it with both eyes through the 
view window in their hands. While remaining focused on the object, participants will close the 
right eye and take note of whether the image remains visible. If the image remains visible, the 
left eye is the dominant eye. If the image is no longer visible, the right eye is the dominant eye. 
This will be confirmed by closing the left eye and taking note of whether the image remains 
visible. Refer to Sections 1.3.2 and 1.3.3 for assessment timepoints. 
8.8.3. 
OSDI 
Severe dry eye disease (defined as an OSDI score of > 33) will be assessed. Details will be 
outlined in the study procedures manual.  
8.8.4. 
Pupillary Reaction to Light 
The swinging light test is used to detect pupillary reaction to light. The test will be performed for 
Stage 1 and in either mesopic conditions (preferred) or photopic conditions for Stages 2a and 2b. 
In this test, a steady light is used. The light is shone into one eye, and then quickly switched to 

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the other. This is repeated back and forth, with an assessment of constriction when light is shone 
on the pupil. Details will be outlined in the study procedures manual.  
8.8.5. 
Cycloplegic Refraction (Stages 2a and 2b only) 
Cycloplegic refraction (photopic) will be performed at distance at least 30 minutes after 
instillation of the dilating eye drops. Refer to Sections 1.3.2 and 1.3.3 for assessment timepoints. 
Details will be outlined in the study procedures manual.  
8.8.6. 
Gonioscopy/Angle Assessment 
Gonioscopy will be performed to assess the iridocorneal (anterior chamber) angle. For slit lamp 
gonioscopy, the assessor’s preferred gonioscopy lens may be used. Details are outlined in 
Appendix 12, Section 10.12.  
8.8.7. 
Dark Adaptation (Stages 2a and 2b only) 
Dark adaptation assessments will be assessed at 5 to 10 minutes in mesopic conditions. Refer to 
Sections 1.3.2 and 1.3.3 for assessment timepoints.  
8.9. 
Immunogenicity Assessments 
Immunogenicity is not evaluated in this study. 
8.10. 
Health Economics  
Six PRO questionnaires are administered in this study; 2 of which consist of a single question. 
At the Screening Visit, participants (Stages 2a and 2b) will answer questions on vision 
functioning and health-related quality of life using the NEI VFQ-25, including the Near Vision 
Subscale items (Questions A3 to A5) from the Appendix of Optional Additional Questions. Refer 
to Sections 1.3.2 and 1.3.3 for assessment timepoints. Details are outlined in the study 
procedures manual. 
In Stages 2a and 2b only, each participant will perform 4 different near vision paper-based 
reading tasks under mesopic conditions. Participants will subsequently rate their vision-related 
reading ability, and satisfaction with their vision-related reading ability on the NVPTQ. Refer to 
Sections 1.3.2 and 1.3.3 for assessment timepoints. Details are outlined in the study procedures 
manual.  
In Stage 2b only, each participant will also perform 1 near vision electronic-based reading task 
(on iPhone/iPod) under photopic conditions. Participants will subsequently rate their 
vision-related reading ability, and satisfaction with their vision-related reading ability on the 
e-NVPTQ. Refer to Section 1.3.3 for assessment timepoints. Details are outlined in the study 
procedures manual. 
In Stages 2a and 2b only, participants will also answer questions assessing the impact of 
presbyopia on their life – and need for compensatory coping mechanisms – using the PICQ. Refer 
to Sections 1.3.2 and 1.3.3 for assessment timepoints. Details are outlined in the study 
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In Stages 2a and 2b only, participants will also answer single questions on their overall patient 
global impression of status (PGIS), and their overall patient global impression of change (PGIC). 
Refer to Sections 1.3.2 and 1.3.3 for assessment timepoints. Details are outlined in the study 
procedures manual. 
Health care resource utilization outcomes are not evaluated in this study. 

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9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
No statistical hypotheses will be tested in this study. 
9.2. 
Sample Size Determination 
The sample sizes for each study stage were not determined based on statistical consideration.  
The sample sizes for each cohort are expected to provide sufficient data to assess safety, 
PK parameters (as applicable), and efficacy (as applicable) of each dose of AGN-241622. 
9.3. 
Populations for Analyses 
For each stage, analysis populations will consist of participants as defined below:  
Population 
Description 
ITT 
The ITT population includes all randomized participants. 
Participants will be summarized according to the randomized 
study intervention. 
Safety 
The safety population includes all dosed participants who 
receive/take ≥ 1 administration of study intervention. 
Participants will be summarized according to the study 
intervention they actually received. 
PK 
The PK population includes all participants who have 
evaluable PK parameters. 
 
9.4. 
Statistical Analyses 
The SAP will be developed and finalized before database lock and will describe the analysis 
populations to be included in the analyses, and procedures to account for missing, unused, and 
spurious data. Detailed analysis plans of Stages 1, 2a, and 2b will be provided separately in the 
SAP. Baseline is defined as last nonmissing assessment before the first dose of study 
intervention. Section 9.4.1 is a summary of the main statistical analyses of the efficacy 
endpoints in Stages 2a and 2b. 
9.4.1. 
Efficacy Analyses 
In Stage 2, the efficacy analyses will be conducted based on the ITT population. When needed, 
exploratory statistical tests will be 2-sided hypothesis tests performed at the 5% level of 
significance and 95% CIs will also be estimated.  
Further details are provided in the SAP. 

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9.4.1.1. 
Analysis Endpoints 
The efficacy endpoints are as follows:  
Primary Efficacy Endpoint 
• Proportion of participants gaining 3 lines or more in mesopic, high contrast, binocular 
DCNVA at Day 14, Hour 3  
Other Efficacy Endpoints 
• Proportion of participants gaining 2 lines or more in mesopic, high contrast, binocular, 
DCNVA  
• Change from baseline in mesopic, high-contrast, binocular DCNVA letters  
• Change from baseline in mesopic pupil diameter (mm)  
• Change from baseline in photopic pupil diameter (mm) 
• Change from baseline in photopic, high-contrast, binocular DCIVA letters  
• Change from baseline in NVPTQ (paper based) Performance score  
• Change from baseline in NVPTQ (paper based) Satisfaction score  
• Change from baseline in PICQ Coping score  
• Change from baseline in PICQ Impact score  
9.4.1.2. 
Primary Analyses 
The proportion of participants gaining 3 lines or more in mesopic, high contrast, binocular 
DCNVA at Day 14, Hour 3 will be summarized for each AGN-241622 dose by treatment 
intervention using frequency tables. Missing data will be regarded as 3-line gain failure 
(nonresponder).   
9.4.1.3. 
Other Analyses 
All endpoints related to proportion of participants gaining 2 or 3 lines or more will be analyzed 
by timepoint using frequency tables. All endpoints related to change from baseline will be 
analyzed using summary tables. No data imputation will be used for the other efficacy endpoint 
analyses. 
The analyses for additional efficacy endpoints will be described in the SAP. 
9.4.2. 
Safety Analyses 
The safety analyses will be performed using the safety population and will be fully defined in 
the SAP. The safety parameters will include AEs, vital signs, 12-lead ECG, and clinical 
laboratory assessments. Other safety parameters will be defined in the SAP.  

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9.4.2.1. 
Adverse Events 
An AE will be considered a TEAE if the AE began or worsened (increased in severity or became 
serious) on or after the date of the first dose of study intervention. However, an AE that occurs 
more than 30 days after the last dose of study intervention will not be counted as a TEAE. 
An AE will be considered a TESAE if it is a TEAE that additionally meets any SAE criterion. 
For each study cohort, the number and percentage of participants reporting TEAEs during the 
study will be tabulated by system organ class and preferred term and by system organ class, 
preferred term, and severity. AE assessments will be presented by cohort and study intervention. 
If more than one AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention. 
Summary tables will be provided for participants with SAEs and participants with AEs leading to 
discontinuation if 5 or more participants reported such events. Listings of all AEs, SAEs, and 
AEs leading to discontinuation by participant will be presented. 
The definitions of an AE and SAE can be found in Appendix 3, Section 10.3.  
9.4.2.2. 
Clinical Laboratory Assessments 
Descriptive statistics for clinical laboratory values (in SI units) at baseline and changes from 
baseline at each assessment will be presented by study stage, cohort, and study intervention, and 
by pooled vehicle in each stage, for each clinical laboratory assessment. 
The criteria and analysis for PCS laboratory values will be detailed in the SAP.   
9.4.2.3. 
Vital Signs 
For each stage, descriptive statistics for vital signs (systolic and diastolic blood pressure, heart 
rate, weight, respiration rate, and temperature) at baseline and changes from baseline at each 
postdose timepoint will be presented by study stage, cohort, and study intervention and by 
pooled vehicle in each stage. 
Vital sign values will be considered to be PCS if they meet both the observed-value criteria and 
the change-from-baseline-value criteria that will be detailed in the SAP. Analysis will be detailed 
in the SAP. 
9.4.2.4. 
Electrocardiograms 
For each stage, descriptive statistics for ECG parameters (heart rate, PR interval, QRS duration, 
QT interval, and QTc) at baseline, each postdose timepoint, and EOS; and changes from baseline 
at each postdose timepoint and at EOS will be presented by stage, cohort, and study intervention, 
and by pooled vehicle in each stage.  
The criteria for PCS ECG values and analysis will be detailed in the SAP.   

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9.4.2.5. 
Other Safety Analyses 
All other safety endpoints will be analyzed with descriptive statistics. Detailed methods for the 
other safety endpoints will be described in the SAP. 
9.4.3. 
PK Analyses 
Detailed PK analyses will be described in the PK analysis plan.  
The principal parameters describing the PK of AGN-241622 will be derived from plasma and 
tear concentrations using noncompartmental analysis with the software program Phoenix 
WinNonlin (Version 8.0 or newer). Plasma and tear concentrations BLQ will be treated as zero 
for all PK calculations. The actual sampling times will be used in the calculation of PK 
parameters. 
9.4.3.1. 
PK Parameters 
Stage 1 
The following PK parameters in plasma will be calculated based on standard Phoenix WinNonlin 
equations: AUC0-t, AUC0-inf, Cmax, Tmax, λz, t1/2, CL/F, and Vz/F. In tears, the PK parameters to be 
calculated include AUC0-t, AUC0-inf, Cmax, Tmax, λz, and t1/2.    
Stage 2 
The following PK parameters in plasma following dosing on Day 1 and Day 14 will be 
calculated based on standard Phoenix WinNonlin equations: AUC0-t, AUC0-tau, Cmax, Cmin, Tmax, 
λz, t1/2, CL/F, Vz/F, and accumulation ratio. In tears, the PK parameters to be calculated includes 
AUC0-t, AUC0-tau, Cmax, Tmax, λz, and t1/2. 
The AUC parameters will be calculated by using the linear-log trapezoidal rule.  
Estimates of t1/2 will be calculated based on λz. The λz will be determined by performing a 
regression analysis on the terminal linear phase of semilogarithmic plots of individual 
AGN-241622 concentration-time data using a minimum of 3 concentration-timepoints in the 
elimination phase excluding Cmax. λz will be considered to be valid if r2 > 0.8.  
9.4.3.2. 
Statistical Analyses of PK Data  
No formal statistical analyses will be performed on the PK data. Descriptive statistics will be 
provided for the plasma and tear concentrations of AGN-241622 at each nominal timepoint by 
study cohort for participants in the PK population. Descriptive statistics will be provided for all 
PK parameters of AGN-241622 by study cohort for all participants in the PK population. Details 
of the analyses of PK concentrations and parameters will be described in the PK analysis plan 
finalized before database lock.  
9.4.4. 
Other Analyses 
Additional details on exploratory analyses will be described in the SAP finalized before database 
lock. 

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9.5. 
Interim Analyses 
No formal interim analysis is planned for this study. 
9.6. 
Data Monitoring Committee (DMC) 
An internal independent review team (comprised of but not limited to, a medical safety 
physician, statistician, clinical pharmacologist, and a clinical representative) will make up the 
DMC for the study. The composition of the independent team will be documented in the DMC 
Charter, TMF, and clinical study report. The members of the independent team will be different 
from the study team members who manage and maintain the study conduct activities, including 
data collection, data clarification, analysis development, safety monitoring, study center 
monitoring and management. The DMC will convene after the conclusion of each cohort in 
Stages 1 and 2a and conduct a comprehensive review of unmasked study data to recommend to 
either proceed to the next cohort(s), stop the next cohort(s), or modify the dose level or sample 
size of the next cohort(s). In addition, the FDA will review study data after the completion of 
each cohort and the sponsor will wait until a positive response is received from the FDA to 
proceed to the next cohort. Following the completion of Cohort 6 (Stage 2a), the DMC will 
review unmasked safety, exposure, and exploratory efficacy data to recommend dose selection 
for Stage 2b or additional dose strength to investigate.  
All details of the committee membership, procedures for safety review, frequency of review and 
communication between the safety review committee and other information will be detailed in 
the DMC charter.  

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10. 
Supporting Documentation and Operational Considerations 

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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
CIOMS International Ethical Guidelines 
o Applicable ICH/ISO GCP Guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, Investigator Brochure, and other relevant 
documents (e.g., 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 IRB/IEC 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/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the conduct of the study at the site and adherence to 
requirements of 21 CFR, ICH guidelines, the IRB/IEC, European regulation 536/2014 
for clinical studies (if applicable), European Medical Device Regulation 2017/745 for 
clinical device research (if applicable), and all other applicable local regulations 
10.1.2. 
Financial Disclosure 
Investigators and sub-investigators will provide the sponsor with sufficient, accurate financial 
information as requested to allow the sponsor to submit complete and accurate financial 
certification or disclosure statements to the appropriate regulatory authorities. Investigators are 
responsible for providing information on financial interests during the course of the study and for 
1 year after completion of the study. 
10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant and answer all questions regarding the study. 

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• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, privacy and data protection requirements, 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. 
• A copy of the ICF(s) must be provided to the participant. 
10.1.4. 
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; any 
identifiable participant information will only be transferred in accordance with the signed 
Informed Consent provisions. 
• The participant must be informed that his/her personal study-related data will be used by 
the sponsor in accordance with local privacy and data protection laws. The level of 
disclosure must also be explained to the participant who will be required to give consent 
for their personal data to be used as described in the informed consent. 
• 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. 
• 
Management of privacy incidents relating to clinical trial participant personal data, as 
well as handling of data participant rights requests (if applicable), should be handled in 
accordance with the agreed upon CTA provisions. 
10.1.5. 
Dissemination of Clinical Study Data 
Study information and tabular study results will be posted to the US National Institutes of Health 
website www.clinicaltrials.gov. 
Study data and information may be published in non-promotional, peer-reviewed publications 
either by or on behalf of the sponsor. 
Clinical study reports, safety updates, and annual reports will be provided to the regulatory 
authorities as required. 
10.1.6. 
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 (e.g., laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF. 

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• 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. 
• Monitoring details describing strategy (e.g., risk-based initiatives in operations and 
quality such as Risk Management and Mitigation Strategies and Analytical Risk-Based 
Monitoring), methods, responsibilities and requirements, including handling of 
noncompliance issues and monitoring techniques (central, remote, or on-site monitoring) 
are provided in the monitoring plans. 
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data. 
• The sponsor assumes accountability for actions delegated to other individuals 
(e.g., Contract Research Organizations). 
• 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 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 ICFs, pertaining to the conduct of this study 
must be retained by the investigator as stated in the clinical trial agreement. 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. 
10.1.7. 
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 the study procedures manual. 
10.1.8. 
Study and Site Start and Closure 
The sponsor or designee reserves the right to close the study site or terminate the study at any 
time for any reason at the sole discretion of the sponsor. Study sites will be closed upon study 
completion. A study site is considered closed when all required documents and study supplies 
have been collected and a study-site closure visit has been performed. 
The investigator may initiate study-site closure at any time, provided there is reasonable cause 
and sufficient notice is given in advance of the intended termination. 

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Reasons for the early closure of a study site by the sponsor or investigator may include but are 
not limited to: 
• Failure of the investigator to comply with the protocol, the requirements of the IRB/IEC 
or local health authorities, the sponsor's procedures, or GCP guidelines 
• Inadequate recruitment of participants by the investigator 
• Discontinuation of further study intervention development 
If the study is prematurely terminated or suspended, the sponsor shall promptly inform the 
Investigators, the IECs/IRBs, the regulatory authorities, and any contract research 
organization(s) used in the study of the reason for termination or suspension, as specified by the 
applicable regulatory requirements. The investigator shall promptly inform the participant and 
should assure appropriate participant therapy and/or follow-up. If a premature termination or 
suspension occurs, the sponsor shall remain responsible for providing resources to fulfill the 
protocol obligations and existing agreements for follow-up of participants enrolled in the study, 
and each investigator or authorized designee shall promptly inform enrolled participants, if 
applicable. 
10.1.9. 
Publication Policy 
• Allergan as the sponsor has proprietary interest as the sponsor in this study. Authorship 
and manuscript composition will reflect joint cooperation between multiple investigators 
and sites and Allergan personnel. Authorship will be established prior to the writing of 
the manuscript. As this study involves multiple centers, no individual publications will be 
allowed prior to completion of the final report of the multicenter study except as agreed 
with Allergan. 
• 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. 
10.1.10. 
Compliance with Protocol 
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. Significant protocol deviations will be 
reported to the IRB/IEC according to the IRB/IEC’s reporting requirements. 

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10.2. 
Appendix 2: Clinical Laboratory Tests 
• The tests detailed in Table 10-1 will be performed by the central laboratory.     
• Protocol-specific requirements for inclusion or exclusion of participants are detailed in 
Section 5 of the protocol. Refer to the Central Laboratory Manual for further details 
regarding central laboratory collection and shipment procedures.  
• Additional tests may be performed at any time during the study as determined necessary 
by the investigator or required by local regulations. The investigator or qualified site 
personnel must review all laboratory results for any AEs. Laboratory test results that 
represent AEs should be reflected on an AE eCRF page. Investigators must document 
their review of each laboratory safety report.   
• Evaluation and management of abnormal laboratory results should be conducted 
according to local site practice. 

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c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
• In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for 
observation and/or treatment that would not have been appropriate in the physician’s 
office or outpatient setting. Complications that occur during hospitalization are AEs. 
If a complication prolongs hospitalization or fulfills any other serious criteria, the 
event is serious. When in doubt as to whether hospitalization occurred or was 
necessary, the AE should be considered serious. 
• Hospitalization for elective treatment of a pre-existing condition that did not worsen 
from baseline is not considered an AE. 
d. Results in persistent disability/incapacity 
• The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Is a suspected transmission of any infectious agent via a medicinal product 
g. Other situations: 
• Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life-threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
• 
Examples of such events include invasive or malignant cancers, intensive treatment 
in an emergency room or at home for allergic bronchospasm, blood dyscrasias or 
convulsions that do not result in hospitalization, or development of drug dependency 
or drug abuse. 
 

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10.4. 
Appendix 4: Abbreviations  
Abbreviation/Term 
Definition 
λz 
terminal elimination rate constant 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST  
aspartate aminotransferase 
AUC 
area under the concentration-time curve  
AUC0-inf 
area under the concentration-time curve from time 0 to infinity  
AUC0-t 
area under the concentration-time curve from time 0 to time t  
AUC0-tau 
area under the plasma/tear concentration versus time curve from time 0 to the end of 
the dosing period  
BLQ 
below the limit of quantitation   
BMI 
body mass index  
BUN 
blood urea nitrogen 
CDISC 
Clinical Data Interchange Standards Consortium 
CDVA 
corrected distance visual acuity  
CFR 
Code of Federal Regulations 
CIOMS 
Declaration of Helsinki and Council for International Organizations of Medical 
Sciences 
CL/F 
apparent clearance  
Cmax 
maximum concentration  
Cmin 
minimum concentration 
CONSORT 
Consolidated Standards of Reporting Trials  
CRF 
case report form 
CTA 
Clinical Trial Agreement 
DCIVA 
distance-corrected intermediate visual acuity  
DCNVA 
distance-corrected near visual acuity 
DMC 
data monitoring committee  
EC50 
50% effective concentration 
ECG 
electrocardiogram 
eCRF 
electronic case report form  
e-NVPTQ 
electronic Near Vision Presbyopia Task-based Questionnaire  
EOS 
end-of-study 
FDA 
Food and Drug Administration  
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice  
HCl 
hydrochloride  
HIV 
human immunodeficiency virus 
ICF 
informed consent form 
ICH 
International Council on Harmonisation 
IEC 
independent ethics committee 
IMP 
investigational medicinal product 
IND 
investigational new drug 

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Abbreviation/Term 
Definition 
IOP 
intraocular pressure 
IRB 
institutional review board 
ISO 
International Organization for Standardization 
ITT 
intent-to-treat  
IUD 
intrauterine device 
IUS 
intrauterine system 
IWRS 
interactive web response system 
K2EDTA 
dipotassium ethylenediaminetetraacetic acid 
LASIK 
laser-assisted in situ keratomileusis  
LDPE 
low-density polyethylene  
MAOI 
monoamine oxidase inhibitor  
MCH 
mean corpuscular hemoglobin 
MCHC 
mean corpuscular hemoglobin concentration 
MCV 
mean corpuscular volume 
N/A 
not applicable  
NCI 
National Cancer Institute  
ND 
nondominant  
NEI VFQ-25 
National Eye Institute Visual Function Questionnaire 25  
NOAEL 
no observed adverse effect level  
NVPTQ 
Near Vision Presbyopia Task-based Questionnaire  
OSDI 
Ocular Surface Disease Index  
Oxy 
oxymetazoline  
PCS 
potentially clinically significant  
PDE5 
phosphodiesterase type 5 
PGIC 
Patient Global Impression of Change  
PGIS 
Patient Global Impression of Status   
PICQ 
Presbyopia Impact and Coping Questionnaire  
Pilo 
pilocarpine  
PK 
pharmacokinetic  
PRK 
photorefractive keratectomy  
PRO 
patient-reported outcome  
QD 
once daily  
QT 
electrocardiographic time from the beginning of the QRS complex to the end of the 
T wave on ECG (a measure of ventricular depolarization and repolarization) 
QTc 
corrected QT interval 
QTcB 
QT interval corrected for heart rate using the Bazett formula (QTcB = QT/(RR)1/2) 
QTcF 
QT interval corrected for heart rate using the Fridericia formula 
(QTcF = QT/(RR)1/3) 
r2 
coefficient of determination 
RBC 
red blood cell 
SAE 
serious adverse event  
SAP 
statistical analysis plan 

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Abbreviation/Term 
Definition 
SNRI 
serotonin norepinephrine reuptake inhibitor 
SoA 
schedule of activities  
SSRI 
selective serotonin reuptake inhibitor 
SUSAR 
suspected unexpected serious adverse reaction 
t1/2 
half-life  
TBD 
to be determined  
TEAE 
treatment-emergent adverse event   
TESAE 
treatment-emergent serious adverse event 
Tmax 
time to maximum concentration  
TMF 
trial master file  
Vz/F 
apparent volume of distribution during terminal elimination  
WBC 
white blood cell  
WOCBP 
women of childbearing potential 
 

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10.5. 
Appendix 5: Standard Discontinuation Criteria 
This table provides participant discontinuation criteria for this protocol. CDISC terminology is 
used, and thus subject or patient is used instead of participant (as used elsewhere in this 
protocol). These terms are interchangeable. 
CDISC Submission Value 
CDISC Definition 
Adverse event 
Any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product and 
which does not necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended sign (including 
an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, 
whether or not related to the medicinal (investigational) product. 
For further information, see the ICH Guideline for Clinical Safety 
Data Management: Definitions and Standards for Expedited 
Reporting (modified from ICH E2A) Synonyms: side effect, 
adverse experience. See also serious adverse event, serious adverse 
experience. (CDISC glossary) 
Death 
The absence of life or state of being dead (NCI) 
Lost to follow-up 
The loss or lack of continuation of a subject to follow-up 
Non-compliance with study drug 
An indication that a subject has not agreed with or followed the 
instructions related to the study medication (NCI) 
Other 
Different than the one(s) previously specified or mentioned (NCI) 
Physician decision 
A position, opinion, or judgment reached after consideration by a 
physician with reference to subject (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a developing embryo 
or fetus in the body (uterus), after union of an ovum and 
spermatozoon, during the period from conception to birth. (NCI) 
Protocol deviation 
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI) 
Site terminated by sponsor 
An indication that a clinical study was stopped at a particular site 
by its sponsor (NCI) 
Study terminated by sponsor 
An indication that a clinical study was stopped by its sponsor (NCI) 
Withdrawal by subject 
An indication that a study participant has removed itself from the 
study (NCI) 
 

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10.6. 
Appendix 6: Study Tabular Summary 
This table is intended for use in posting study information to registries (e.g., ClinicalTrials.gov). 
Parameter 
Group 
Parameter 
Value 
Trial information 
Trial Title 
A First-in-Human, Phase 1/2, 
Dose-ascending, Multicenter, Masked, 
Randomized, Vehicle-controlled Study 
Evaluating the Safety, Tolerability, and 
Pharmacokinetics of AGN-241622 in 
Healthy Participants and Participants 
with Presbyopia (Stage 1 and Stage 2) 
and Efficacy in Participants 
with Presbyopia (Stage 2) 
 
Clinical Study Sponsor 
Allergan Sales, LLC 
 
Trial Phase Classification 
Phase 1/2 
 
Trial Indication 
Presbyopia 
 
Trial Indication Type 
Treatment 
 
Trial Type 
Stage 1: Safety, Tolerability, 
Pharmacokinetics 
Stages 2a and 2b: Safety, Tolerability, 
Pharmacokinetics, Efficacy 
 
Trial Length 
Stage 1: Approximately 20 days 
Stages 2a and 2b: Approximately 
60 days each 
 
Planned Country of Investigational Sites 
United States 
 
Planned Number of Subjects 
Stage 1: 36 participants 
Stage 2a: 36 participants 
Stage 2b: approximately 60 participants 
(Cohort 7) and 12 participants 
(Cohort 8) 
 
FDA-regulated Device Study 
No 
 
FDA-regulated Drug Study 
Yes 
 
Pediatric Study 
No 
Subject 
information 
Healthy Subject Indicator 
Stage 1: Yes 
Stage 2: No 
 
Planned Minimum Age of Subjects 
40 years 
 
Planned Maximum Age of Subjects 
65 years 
 
Sex of Participants 
Male or female 
 
Stable Disease Minimum Duration 
Not applicable 
Treatments 
Investigational Therapy or Treatment 
AGN-241622 ophthalmic solutions 
 
Intervention Type 
Drug 

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Dose per Administration 
Stage 1: AGN-241622 
 single 
dose left eye (Cohort 1), AGN-241622 
 single dose left eye (Cohort 2), 
and AGN-241622 
 single dose left 
eye (Cohort 3) 
Stage 2a: AGN-241622
 once 
daily x 14 days in both eyes (Cohort 4), 
AGN-241622 
 once daily x 
14 days in both eyes (Cohort 5), and 
AGN-241622 
 once daily x 
14 days in both eyes (Cohort 6) 
Stage 2b: AGN-241622 (dose TBD) 
once daily x 14 days in both eyes 
 
Dose Units 
Stage 1: 1 drop in left eye once  
Stages 2a and 2b: 1 drop in each eye 
once daily x 14 days 
 
Dosing Frequency 
Stage 1: 1 drop in left eye once  
Stages 2a and 2b: 1 drop in each eye 
once daily x 14 days 
 
Route of Administration 
Topical eye drop 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
 
Planned Number of Arms 
2 arms per cohort 
 
Trial Is Randomized 
Yes 
 
Trial Blinding Schema 
Double-masked (except Cohort 7, 
which is single-masked) 
 
Adaptive Design 
Yes 
 

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10.7. 
Appendix 7: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
Woman of Childbearing Potential 
A woman is considered fertile following menarche and until becoming post-menopausal unless 
permanently sterile (see below). 
If fertility is unclear (e.g., amenorrhea in adolescents or athletes) and a menstrual cycle cannot be 
confirmed before first dose of study intervention, additional evaluation should be considered. 
Women in the following categories are not considered WOCBP 
1. Premenarchal 
2. Premenopausal female with one of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
For individuals with permanent infertility due to an alternate medical cause other than the above, 
(e.g., mullerian agenesis, androgen insensitivity), investigator discretion should be applied to 
determining study entry. 
Note: Documentation can come from the site personnel’s: review of the participant’s medical 
records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. 
Contraception Guidance: 
Male Participants 
Nonvasectomized male participants with female partners of childbearing potential are eligible to 
participate if they agree to ONE of the following during the protocol-defined timeframe in 
Section 5.1:  
• 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 
• Agree to use a male condom with spermicide plus partner use of a contraceptive method 
with a failure rate of < 1% per year as described in Table 10-2 when having 
penile-vaginal intercourse with a woman of childbearing potential who is not currently 
pregnant 
In addition, nonvasectomized male participants must refrain from donating sperm throughout the 
study, up through 30 days after the last dose of study intervention. 

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Nonvasectomized male participants 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 timeframe.   
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10-2. 
Table 10-2 
Highly Effective Contraceptive Methods 
Highly Effective Contraceptive Methods That Are User Dependenta 
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 Independenta 
• 
Implantable progestogen-only hormonal contraception associated with inhibition of ovulationb 
• 
IUD 
• 
IUS 
• 
Etonogestrel implant (i.e., Nexplanon®) 
• 
Bilateral tubal occlusion (e.g., Essure®, bilateral tubal ligation) 
• 
Intrauterine copper contraceptive (i.e., ParaGard®) 
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 intervention. 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. 
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. 
b Hormonal contraception may be susceptible to interaction with the study intervention, which may reduce the 
efficacy of the contraceptive method. In this case, 2 highly effective methods of contraception should be used 
during the study intervention period. 
 

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Pregnancy Testing: 
• WOCBP should only be included after a confirmed menstrual period and a negative 
highly sensitive serum pregnancy test at the Screening Visit and also a negative urine test 
on Day -1 (Stage 1) and Day 1 (Stages 2a and 2b). 
Collection of Pregnancy Information 
Male participants with partners who become pregnant 
• The investigator will attempt to collect pregnancy information on any male participant’s 
female partner who becomes pregnant while the male participant is in this study. This 
applies only to male participants who receive study intervention. 
• After obtaining the necessary signed informed consent from the pregnant female partner 
directly, the investigator will record pregnancy information on the appropriate form and 
submit it to the sponsor within 24 hours of learning of the partner’s pregnancy. The 
female partner will also be followed to determine the outcome of the pregnancy. 
Information on the status of the mother and child will be forwarded to the sponsor. 
Generally, the follow-up will be no longer than 6 to 8 weeks following the estimated 
delivery date. Any termination of the pregnancy will be reported regardless of fetal status 
(presence or absence of anomalies) or indication for the procedure. 
Female Participants who become pregnant 
• The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. The initial information will be 
recorded on the appropriate form and submitted to the sponsor within 24 hours of 
learning of a participant's pregnancy.  
• The participant will be followed to determine the outcome of the pregnancy. The 
investigator will collect follow-up information on the participant and the neonate and the 
information will be forwarded to the sponsor. Generally, follow-up will not be required 
for longer than 6 to 8 weeks beyond the estimated delivery date. Any termination of 
pregnancy will be reported, regardless of fetal status (presence or absence of anomalies) 
or indication for the procedure. 
• While pregnancy itself is not considered to be an AE or SAE, any pregnancy 
complication will be reported as an AE or SAE. 
• Abnormal pregnancy outcomes (e.g., spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an 
elective abortion or not) are always considered to be SAEs and will be reported as such. 
• Any post-study pregnancy related SAE considered reasonably related to the study 
intervention by the investigator will be reported to the sponsor as described in 
Section 8.3.4. While the investigator is not obligated to actively seek this information in 
former study participants, he or she may learn of an SAE through spontaneous reporting. 
• Any female participant who becomes pregnant while participating in the study will 
discontinue study intervention and be withdrawn from the study. 

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10.8. 
Appendix 8: Biomicroscopic Examination 
Biomicroscopic examinations will be performed using a slit lamp.  The examinations will 
include evaluation of the condition of the eyelids, conjunctiva, cornea, anterior chamber, 
iris/pupil.   
Eyelid/Eyelid Margins/Lashes  
Edema 
 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) 
= 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 
 
Erythema 
 
 
  0 
(None) 
= 
No erythema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) flush reddish color  
+1 
(Mild) 
= 
Localized, mild, flush reddish color 
+2 
(Moderate) 
= 
Diffuse reddish color encompassing the entire lid margin 
+3 
(Severe) 
= 
Deep diffuse reddish color of lid margins and superior 
and/or inferior eyelid 
Conjunctiva (Bulbar) 
Hyperemia  
  0 
(None) 
= 
No hyperemia 
+0.5 
(Trace) 
= 
Minimal (trace) flush, reddish color 
+1 
(Mild) 
= 
Mild flush, reddish color 
+2 
(Moderate) 
= 
Bright red color 
+3 
(Severe) 
= 
Deep, bright diffuse redness 

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Edema 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) = 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 
Conjunctiva (Palpebral)  
Hyperemia  
  0 
(None) 
= 
No hyperemia 
+0.5 
(Trace) 
= 
Minimal (trace) flush, reddish color 
+1 
(Mild) 
= 
Mild flush, reddish color 
+2 
(Moderate) 
= 
Bright red color 
+3 
(Severe) 
= 
Deep, bright diffuse redness 
 
Edema 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) = 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 
Cornea 
Edema 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) epithelial haze 
+1 
(Mild) 
= 
Dull glass appearance of epithelium that may include fine 
localized microcystic changes 
+2 
(Moderate) = 
Dull glass appearance of the epithelium with large 
number of cystic changes with or without stromal edema 
 +3 
(Severe) 
= 
Epithelial bullae and/or stromal edema, localized or 
diffuse, with or without stromal striae 

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Superficial Punctate Keratopathy 
 0 
= 
No superficial punctate keratopathy 
+0.5 
= 
Trace 
+1 
= 
Mild 
+2 
= 
Moderate 
+3 
= 
Severe 
Anterior Chamber 
The anterior chamber will be evaluated for pathology. If pathology is present, it will be 
described. 
Iris/Pupil 
The iris/pupil will be evaluated for pathology. If pathology is present, it will be described. 
Sodium Fluorescein Corneal Staining 
The examination will be performed with the slit lamp at 10x magnification. The dry eye test 
sodium fluorescein strip will be moistened with 0.9% saline and gently touched on the superior 
bulbar conjunctiva. A stopwatch will be started immediately after application. The corneal 
staining will be graded approximately 2 minutes after instillation of the sodium fluorescein. The 
entire cornea will be evaluated for staining using the supplied yellow barrier filter placed directly 
in front of the objective lens of the slit lamp. The slit lamp’s cobalt blue filter must be used to 
illuminate the cornea. Corneal sodium fluorescein staining should be evaluated as close to the 
2-minute timepoint as possible. Refer to the table outlined in the laminated chart provided to 
grade the staining (Figure 10-1).  
Only the cornea will be graded. Once grading of the right eye is complete, the entire procedure 
will be repeated for the left eye.  
For grades 0 to 2, the dot count will be collected and recorded.  Dot counts need not be collected 
or recorded for grades 3 and higher.  

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Figure 10-1 
Oxford Scale for Grading Corneal and Conjunctival Staining  
Note: For this study, only the cornea will be graded. 
 
 
 
 
 

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10.9. 
Appendix 9: Study Intervention Tolerability/Drop Comfort 
Assessment  
The presence and severity of ocular symptoms will be elicited from the participant for their 
treated eye(s), as applicable. Symptoms including blurred vision, foreign body sensation, pain, 
burning/stinging, tearing, and itching will be classified using a 5-point grading scale with 
0 = none, +0.5 = trace, +1 = mild, +2 = moderate, and +3 = severe. The duration of symptoms 
(< 1 minute, 1 to 5 minutes, > 5 minutes) will be captured once immediately after the drop of 
each dose of study intervention. If any other ocular symptoms are present, these will also be 
captured. 
Participants will be asked to rate the overall comfort of the eye drops using a 6-point scale 
(i.e., soothing, very comfortable, comfortable, uncomfortable, very uncomfortable, or 
intolerable) immediately after the drop instillation for the right and left eyes separately, as 
applicable. 

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10.10. 
Appendix 10: Fundus (Indirect) Ophthalmoscope Examination 
The fundus assessments should be conducted through a dilated pupil. The examinations will 
include evaluation of the lens, vitreous, fundus, and optic nerve. The cup to disc ratio will be 
assessed. 
Lens 
Lens Assessment: Use biomicroscopic examination, indirect lenses, direct/indirect 
ophthalmoscopy, etc., as appropriate, to visualize.   
Lens Status: The lens will be evaluated for pathology. If pathology is present, it will be 
described. 
Cataract Assessment: Under dilated opthalmoscope examination, the presence and severity of 
nuclear, cortical and posterior subcapsular cataract lens opacities will be evaluated. At the 
first dilated opthalmoscope examination, each type of cataract, if present, will be graded using 
the scale below. At the last follow-up dilated opthalmoscope examination, each type of cataract 
will be assessed for change from baseline and if changed, the current severity will be graded 
using the scale below: 
0 
= 
None 
+1 
= 
Mild 
+2 
= 
Moderate 
+3 
= 
Severe 
Vitreous 
The vitreous will be evaluated for pathology. If pathology is present, it will be described. It will 
be noted if the condition is not evaluable. 
Fundus 
The fundus (posterior pole; periphery, when dilated) will be evaluated for pathology. If 
pathology is present, it will be described. It will be noted if the condition is not evaluable.  
Optic Nerve 
The optic nerve will be evaluated for pathology. If pathology is present, it will be described. It 
will be noted if the condition is not evaluable.  
Cup/disc ratio will be reported using a 0.0 to 1.0 scale. It will be noted if the condition is not 
evaluable. 

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10.11. 
Appendix 11: IOP 
IOP should be measured only after the biomicroscopic exam is completed and must be measured 
prior to pupil dilation. Measurements will be taken using a Goldmann applanation tonometer 
affixed to a slit lamp with the participant seated. The participant and slit lamp should be adjusted 
so that the participant’s head is firmly positioned on the chin rest and against the forehead rest 
without leaning forward or straining. Tight fitting neckwear should be loosened. Both eyes will 
be tested, with the right eye preceding the left eye. The examiner looks through the binocular 
viewer of the slit lamp at low power. The tension knob is preset at a low pressure value 
(4 to 6 mm Hg). The examiner follows the image of the sodium fluorescein-stained semicircles 
while slowly rotating the tension knob until the inner borders of the sodium fluorescein rings 
touch each other at the midpoint of their pulsation in response to the cardiac cycle. When this 
image is reached, the examiner will take his/her fingers off the tension knob and record the IOP 
reading along with the date and time of day.  

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10.12. 
Appendix 12: Gonioscopy/Angle Assessment 
Gonioscopy will be performed to assess the iridocorneal (anterior chamber) angle. For slit lamp 
gonioscopy, the assessor’s preferred gonioscopy lens may be used. The room lights should be 
turned off during the examination and all participants should be examined in the same room with 
the same slit lamp and with consistent lighting conditions. 
The assessor will begin by applying adequate topical anesthesia (topical proparacaine 0.5%) to 
the participant’s eye. With the participant sitting comfortably at the slit lamp, the corneal surface 
of the lens will be wetted with an artificial tear or lubricating solution and the gonioscopy lens 
will be placed on the participant’s eye. A bright, narrow light beam will be directed away from 
the pupil to avoid inducing miosis and the angle assessment will be performed under high 
magnification. With the participant maintaining their gaze in the primary position, the assessor 
will examine/grade the 6 o’clock (inferior angle) position using the Shaffer anterior chamber 
angle grading system depicted in Figure 10-2. Lens tilting should be minimized; only minor 
movement of the lens is permissible, otherwise, the angle findings may be distorted and a closed, 
or a narrow angle may appear open. Excess pressure should not be used as this may cause 
indentation; the presence of corneal striations is an indication that the cornea is being indented. 
Figure 10-2 
Anterior Chamber Angle Grading 
 
Source: Becker and Shaffer. Clinical interpretation of gonioscopic findings. 8th ed. In: Stamper RL, Lieberman MF,  
Drake MV, editors. Becker-Shaffer's Diagnosis and Therapy of the Glaucomas. Amsterdam: Mosby Elsevier, 2009:78-90. 
 

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11. 
References 
García-Lázaro S, Ferrer-Blasco T, Radhakrishnan H, Cervino A, Charman WN, Montés-Micó R. 
Visual function through 4 contact lens-based pinhole systems for presbyopia. J Cataract Refract 
Surg. 2012;38(5):858-865. 
Holden BA, Fricke TR, Ho SM, Wong R, Schlenther G, Cronjé S, et al. Global vision 
impairment due to uncorrected presbyopia. Arch Ophthalmol. 2008;126:1731-1739. 
Johnson L, Buckley JG, Scally AJ, Elliott DB. Multifocal spectacles increase variability in toe 
clearance and risk of tripping in the elderly. Invest Ophthalmol Vis Sci. 2007;48:1466-1471. 
Lord SR, Dayhew J, Howland A. Multifocal glasses impair edge-contrast sensitivity and depth 
perception and increase the risk of falls in older people. J Am Geriatr Soc. 2002;50:1760-1766. 
Moshirfar M, Desautels JD, Wallace RT, Koen N, Hoopes PC. Comparison of FDA safety and 
efficacy data for KAMRA and Raindrop corneal inlays. Int J Ophthalmol. 
2017;10(9):1446-1451. 
Pilocarpine hydrochloride ophthalmic solution 1%, 2%, and 4%. Package Insert. Fort Worth, 
TX: Alcon Laboratories, Inc. 2011. 
Ruiz LA, Cepeda LM, Fuentes VC. Intrastromal correction of presbyopia using a femtosecond 
laser system. J Refract Surg. 2009;25(10):847-854. 
Tomita M. Advances in Implantation Over the Years. Changes in technique have a direct 
correlation with decreases in a corneal inlay’s removal rate. Cataract Refract Surg Today. 2015; 
June: 67-68. 
Tsai JC, Forbes M. Medical Management of Glaucoma. 3rd ed. West Islip, New York: 
Professional Communications, Inc.;2009. 
Tucker J, Charman WN. The depth-of-focus of the human eye for Snellen letters. Am J Optom 
and Physiol Opt. 1975;52(1):3–21.