Clinical trial NCT04837482
Conditions: Presbyopia
Keywords: Presbyopia AGN-190584
Sponsor: AbbVie
Start date: 2021-05-14; Completion date: 2021-12-07
Enrollment: 43 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
The purpose of this study is to evaluate night-driving performance in real-world driving conditions in participants with presbyopia treated with AGN-190584 versus vehicle. Adverse events and change in disease symptoms will be assessed.

AGN-190584 is an investigational formulation of pilocarpine for treating symptoms associated with presbyopia as a topical, once-daily eyedrop delivered by a proprietary vehicle.

This crossover study consists of two parts. Part 1 consists of Visit 2 and Visit 3, and Part 2 consists of Visit 4 and Visit 5. Approximately half of the participants will receive AGN-190584 at Visit 2 through Visit 3 (Sequence 1 participants) and the remaining participants (Sequence 2 participants) will receive AGN-190584 at Visit 4 through Visit 5. All participants will receive AGN-190584 at home as instructed. Approximately 54 adult participants with presbyopia will be enrolled at 1 site in Australia.

Treatment duration is expected to be no more than 71 days. In Part 1, at Visit 2 (Day 1) and at home as instructed for 7 to 14 days, Sequence 1 participants will receive 1 eyedrop of AGN-190584 in each eye and Sequence 2 participants will receive 1 eyedrop of vehicle in each eye. All participants will have a driving assessment at Visit 3 (Day 8 to 15). In Part 2, at Visit 4 (Day 15 to 57) and at home as instructed for 7 to 14 days, Sequence 2 participants will receive 1 eyedrop of AGN-190584 in each eye and Sequence 1 participants will receive 1 eyedrop of vehicle in each eye. All participants will have a driving assessment at Visit 5 (Day 22 to 71).

There may be higher treatment burden for participants in this trial compared to their standard of care. Participants will attend regular visits during the course of the study at a hospital or clinic. The effects of the treatment will be checked by medical assessments, asking about side effects, and completing questionnaires.

Detailed description:

Arms: arm 1: AGN-190584 Sequence 1 (Participants will receive AGN-190584 from Visit 2 through Visit 3 followed by Vehicle from Visit 4 through Visit 5). arm 2: AGN-190584 Sequence 2 (Participants will receive Vehicle from Visit 2 through Visit 3 followed by AGN-190584 from Visit 4 through Visit 5).
Interventions: intervention 1: AGN-190584 intervention 2: Vehicle
Intervention descriptions: intervention 1: Topical eyedrop intervention 2: Topical eyedrop

Protocol documents:
Prot_000.pdf: 


CONFIDENTIAL
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SAE Reporting Fax Number/Email (only to be used as back-up for electronic data 
capture):
Business Unit
Email
Phone
Fax
Allergan
IR-Clinical-SAE@abbvie.com
Not applicable
+1-714-796-9504
Backup:
+1-714-246-5295
Sponsor Signatory:
 MD
Vice President, Global Therapeutic Area Head
Ophthalmology
Allergan, Inc.
Refer to the final page of this protocol for electronic signature and date of approval.
 
 
 
 
 
 
 
 




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Section No. and Name
Description of Change
Brief Rationale
Section 4.3, Justification for 
Dose
The analyses and CSRs preparation
for these studies are in progress
have been completed.
At the time of the original protocol 
completion, the 1883-301-013 and 
1883-302-013 CSRs were in progress. 
These CSRs have been completed.
Section 6.4, Study 
Intervention Compliance
Detail added to clarify that study 
drug will be delivered to the subject 
if they are unable to attend due to 
COVID-19, and a statement added 
that for Visit 2 and Visit 4, if a 
subject is unable to come to site the 
visit will be rescheduled.
Added per sponsor procedure during the 
COVID-19 pandemic
Section 6.5.2, Permitted 
Interventions
The concurrent use of nonocular 
medications that do not have a 
substantial effect on the pupil, 
accommodative properties, or 
retinal function of the eye will be 
permitted during the study if it is 
necessary for the participant’s 
welfare and/or if a stable dosing 
regimen is established.
Updated for clarification
Detail added on COVID-19 
pandemic-related vaccination 
guidance
Added per sponsor procedure during the 
COVID-19 pandemic
Section 7, Discontinuation 
of Study Intervention and 
Participant 
Discontinuation/Withdrawal
Reasons for discontinuation from 
the study intervention and/or the 
study EOS or EOT may include the 
following commonly used or other 
acceptable terms:
•
Withdrawal from treatment by 
subject (EOS)
•
Withdrawal from treatment by 
subject (EOT)
The reasons for discontinuation from the 
study intervention and/or the study were 
updated to include COVID-specific reasons 
and match the updated case report form.
Section 7.2, Participant 
Discontinuation/Withdrawal 
from the Study
Detail added on COVID-19 
pandemic-related acceptable 
protocol modification
Added per sponsor procedure during the 
COVID-19 pandemic
Section 8.1, Efficacy 
Assessments – Driving 
Performance 
Approximately After 1 hour ± 
15 minutes following study 
intervention instillation and 
following the visual function 
assessments, each participant will 
be driven to the start participants 
will start the driving test at the 
beginning of the closed road driving 
circuit.
Updated for clarity
Section 8.1.1, Sign 
Recognition
The percentage of signs sign items
correctly reported is will be 
calculated from the reported total 
number of signs and the number of 
signs correctly identified.
Updated for clarification
 
 
 


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Section No. and Name
Description of Change
Brief Rationale
Section 8.1.2, Hazard 
Avoidance
The percentage of hazards hit will 
be recorded calculated from the 
reported total number of hazards 
and the number of hazards hit.
Updated section for clarification after 
discussions with site
Section 8.1.3, Driving Time
Time to complete the road course 
will be recorded for each run (in 
minutes and seconds).
Clarified driving time recording after 
discussions with the site
Section 8.1.4, 
Lane-Keeping
Lane-keeping will be recorded by 
2 video cameras mounted on the 
vehicle roof and scored post testing 
as the percentage of time out of the 
lane calculated post-testing from the 
reported total driving time and 
reported time outside of lane.
Clarified lane-keeping assessment after 
discussion with the site
Section 8.1.7, Pupil 
Diameter
Pupil diameter will be measured 
during distance fixation 
(3 measures) using a NeurOptics 
Pupillometer for mesopic/photopic 
lights levels specified in the SoA 
(Section 1.3).
Removed the details of performing 
3 measures for the pupil diameter for 
accuracy, as different visits require 
different numbers of measurements.
Section 8.2.4, Mesopic and 
Photopic BDCVA and 
DCNVA
Binocular BCDVA and DCNVA 
will be tested using logMAR charts 
at 4 m and 40 cm under 2 lighting 
conditions: mesopic luminance (3.2 
to 3.5 cd/m2; 10 to 11 lux) and 
photopic luminance (≥80 cd/m2; 
≥251 lux) under normal room 
lighting.
Changed from cd/m2 to lux units to 
measure binocular BCDVA and DCNVA 
testing
Section 8.2.5, Mesopic and 
Photopic HDVA
Binocular HDVA will be tested 
using logMAR charts at 4 m and 
40 cm under 2 lighting conditions: 
mesopic luminance (3.2 to 3.5 
cd/m2; 10 to 11 lux) and photopic 
luminance (≥80 cd/m2; ≥251 lux) 
under normal room lighting.
Changed from cd/m2 to lux units to 
measure HDVA. Also corrected to remove 
40 cm.
Section 10.1.7, Source 
Documents
Additional bullet point added:
•
During the COVID-19 
pandemic, remote data 
review/verification may be 
employed if allowed by the local 
regulatory authority, IRB/IEC, 
and the study site.
Added per sponsor procedure during the 
COVID-19 pandemic
Section 10.1.10, 
Compliance with Protocol
Protocol deviations (including those 
that may be due to the COVID-19 
pandemic) will be discussed with 
the investigator upon identification.
Added per sponsor procedure during the 
COVID-19 pandemic
Section 10.2.4, Reporting of 
SAEs
Updated reporting process for SAEs 
with use of electronic data capture
Updated in line with sponsor process for 
reporting
 
 
 
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Section No. and Name
Description of Change
Brief Rationale
Section 10.5, Appendix 5: 
Study Tabular Summary
Value column: 22 to 64 71 days, 
with a 30-day screening period
Corrected the number of days in trial length 
row
Parameter column: Planned 
Number of Enrolled Participants
Value column: Approximately 40
54
Corrected the number of enrolled 
participants
Section 10.6, Appendix 6: 
Contraceptive Guidance and 
Collection of Pregnancy 
Information
Updated reporting process for 
pregnancy with use of electronic 
data capture
Updated in line with sponsor process for
reporting
 
 
 


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Table of Contents
Title Page ........................................................................................................................................1
Protocol Amendment Summary of Changes...............................................................................3
Table of Contents...........................................................................................................................7
List of Tables ..................................................................................................................................9
List of Figures...............................................................................................................................10
1.
Protocol Summary ........................................................................................................11
1.1.
Synopsis...........................................................................................................11
1.2.
Schema.............................................................................................................13
1.3.
Schedule of Activities (SoA) ...........................................................................14
2.
Introduction...................................................................................................................20
2.1.
Study Rationale................................................................................................20
2.2.
Background......................................................................................................20
2.3.
Benefit/Risk Assessment .................................................................................21
3.
Objectives and Measures..............................................................................................22
4.
Study Design..................................................................................................................23
4.1.
Overall Design .................................................................................................23
4.2.
Scientific Rationale for Study Design..............................................................23
4.3.
Justification for Dose.......................................................................................23
4.4.
End of Study Definition...................................................................................24
5.
Study Population...........................................................................................................25
5.1.
Inclusion Criteria .............................................................................................25
5.2.
Exclusion Criteria ............................................................................................26
5.3.
Lifestyle Considerations ..................................................................................28
5.4.
Screen Failures.................................................................................................28
6.
Study Intervention........................................................................................................29
6.1.
Study Interventions Administered ...................................................................29
6.2.
Preparation/Handling/Storage/Accountability.................................................30
6.3.
Measures to Minimize Bias: Randomization and 
Masking............................................................................................................30
6.4.
Study Intervention Compliance .......................................................................31
6.5.
Concomitant Therapy.......................................................................................31
6.5.1.
Prohibited Interventions and Washout Before 
the Study ...........................................................................................32
6.5.2.
Permitted Interventions.....................................................................32
6.5.3.
Rescue Medicine...............................................................................33
6.5.4.
Prohibited Interventions During the Study .......................................33
6.6.
Dose Modification ...........................................................................................33
6.7.
Intervention after the End of the Study............................................................33
 
 
 


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7.
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................34
7.1.
Discontinuation of Study Intervention.............................................................34
7.2.
Participant Discontinuation/Withdrawal from the Study.................................35
7.3.
Lost to Follow-up.............................................................................................35
8.
Study Assessments and Procedures.............................................................................37
8.1.
Efficacy Assessments – Driving Performance.................................................37
8.1.1.
Sign Recognition...............................................................................38
8.1.2.
Hazard Avoidance.............................................................................38
8.1.3.
Driving Time.....................................................................................38
8.1.4.
Lane-Keeping....................................................................................38
8.1.5.
Pedestrian Recognition Distance ......................................................39
8.1.6.
Composite Driving Z Score ..............................................................39
8.1.7.
Pupil Diameter ..................................................................................40
8.1.8.
Halometer..........................................................................................40
8.1.9.
Night-driving Experience Questionnaire ..........................................40
8.2.
Safety Assessments..........................................................................................40
8.2.1.
Ophthalmic Examinations.................................................................40
8.2.1.1. Slit-lamp Biomicroscopy ...................................................40
8.2.1.2. Manifest Refraction ...........................................................43
8.2.1.3. Dilated Fundoscopic Examination.....................................43
8.2.2.
Vital Signs.........................................................................................44
8.2.3.
Pregnancy Testing.............................................................................44
8.2.4.
Mesopic and Photopic BCDVA and DCNVA..................................44
8.2.5.
Mesopic and Photopic HDVA ..........................................................45
8.2.6.
Clinical Safety Laboratory Assessments ..........................................45
8.2.7.
Suicidal Ideation and Behavior Risk 
Monitoring ........................................................................................45
8.3.
Adverse Events and Serious Adverse Events ..................................................45
8.3.1.
Time Period and Frequency for Collecting AE 
and SAE Information........................................................................45
8.3.2.
Method of Detecting AEs and SAEs ................................................46
8.3.3.
Follow-up of AEs and SAEs.............................................................46
8.3.4.
Regulatory Reporting Requirements for SAEs.................................46
8.3.5.
Pregnancy..........................................................................................47
8.4.
Treatment of Overdose ....................................................................................47
8.5.
Pharmacokinetics.............................................................................................47
8.6.
Pharmacodynamics ..........................................................................................47
8.7.
Genetics............................................................................................................47
8.8.
Biomarkers.......................................................................................................47
8.9.
Immunogenicity Assessments..........................................................................47
8.10.
Health Economics............................................................................................47
9.
Statistical Considerations.............................................................................................48
9.1.
Statistical Hypotheses ......................................................................................48
 
 
 


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9.2.
Sample Size Determination..............................................................................48
9.3.
Populations for Analyses .................................................................................48
9.4.
Statistical Analyses ..........................................................................................48
9.4.1.
Efficacy Analyses .............................................................................48
9.4.1.1. Analysis Endpoints ............................................................49
9.4.1.2. Primary Analyses...............................................................49
9.4.1.3. Other Efficacy Analyses ....................................................49
9.4.2.
Safety Analyses.................................................................................49
9.4.2.1. Adverse Events ..................................................................49
9.4.2.2. Other Safety Analyses........................................................50
9.5.
Interim Analyses ..............................................................................................50
9.6.
Data Monitoring Committee............................................................................50
10.
Supporting Documentation and Operational Considerations..................................51
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations..................................................................................................51
10.1.1.
Regulatory and Ethical Considerations.............................................51
10.1.2.
Financial Disclosure..........................................................................51
10.1.3.
Informed Consent Process ................................................................52
10.1.4.
Data Protection..................................................................................52
10.1.5.
Dissemination of Clinical Study Data...............................................52
10.1.6.
Data Quality Assurance ....................................................................53
10.1.7.
Source Documents ............................................................................54
10.1.8.
Study and Site Start and Closure ......................................................54
10.1.9.
Publication Policy.............................................................................55
10.1.10. Compliance with Protocol.................................................................55
10.2.
Appendix 2: Adverse Events: Definitions and 
Procedures for Recording, Evaluating, Follow-up, and 
Reporting..........................................................................................................56
10.2.1.
Definition of AE ...............................................................................56
10.2.2.
Definition of SAE .............................................................................57
10.2.3.
Recording and Follow-up of AE and/or SAE...................................58
10.2.4.
Reporting of SAEs............................................................................60
10.3.
Appendix 3: Abbreviations..............................................................................61
10.4.
Appendix 4: Standard Discontinuation Criteria...............................................63
10.5.
Appendix 5: Study Tabular Summary .............................................................65
10.6.
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information.....................................................................................66
10.7.
Appendix 7: Night-driving Experience Questionnaire ....................................69
11.
References......................................................................................................................70
List of Tables
Table 1-1
Schedule of Visits and Procedures............................................................................ 14
 
 
 


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Table 10–1
Highly Effective and Acceptable Contraceptive Methods.................................... 67
List of Figures
Figure 1-1
Study Schema........................................................................................................ 13
Figure 8-1
Night-time View of Road Hazards and Signs....................................................... 38
Figure 8-2
Experimental Pedestrian in Reflective Gear......................................................... 39
 
 
 


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1.
Protocol Summary
1.1.
Synopsis
Protocol Title:
Evaluating the Impact of AGN-190584 on Night-driving Performance
Study Number:
1883-306-013
Study Rationale:
In previous studies, the sponsor established the safety and efficacy of various concentrations of 
AGN-190584 dosed once daily, bilaterally or in the nondominant eye, over a period of up to 
30 days in participants with presbyopia. As with all miotics, participants were advised to exercise 
caution in night driving and other hazardous occupations under poor illumination. 
Study 1883-306-013 is evaluating the effect of AGN-190584 compared with vehicle when dosed 
in both eyes on driving performance under real-world, night-lighting conditions in participants 
with presbyopia.
Objectives and Measures:
Objectives
Measures
To evaluate night-driving performance in 
real-world driving conditions in participants 
with presbyopia treated with AGN-190584 
versus vehicle 

Overall driving performance

Hazard avoidance

Road sign recognition

Road sign recognition distance

Pedestrian recognition distance

Lane-keeping

Driving time

Pupil diameter

Halometer

Night-driving experience questionnaire
To evaluate safety in participants with 
presbyopia treated with AGN-190584 
versus vehicle 

Mesopic/photopic HDVA

AEs

Pregnancy tests for WOCBP

Slit-lamp biomicroscopy
 
 
 


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Overall Design:
This is a single center, randomized, double-masked, crossover, Phase 3b study evaluating the 
effect of AGN-190584 compared with vehicle when dosed in both eyes on driving performance 
under real-world, night-lighting conditions in participants with objective and subjective evidence 
of presbyopia. Approximately 54 participants will be enrolled at one study site (Queensland 
University of Technology, Australia). At the randomization/first dosing visit (Visit 2), 
participants will be randomized in a 1:1 ratio to one of the 2 study intervention sequences, either 
AGN-190584 followed by vehicle after a minimum 1-week washout period (study intervention 
sequence 1), or vehicle followed by AGN-190584 after a minimum 1-week washout period
(study intervention sequence 2). All participants will receive the first dose at Visit 2 and continue 
daily dosing through the end of the first driving visit (Visit 3). After the first driving visit 
(Visit 3) and a minimum 1-week washout period, participants will complete a second dosing visit 
(Visit 4) and continue daily dosing following the assigned study intervention sequence through 
the end of the study (Visit 5, second driving visit). There will be a 7- to 14-day study 
intervention adaptation period before each driving visit (Visits 3 and 5) and a 7- to 42-day 
washout period between Visits 3 and 4.
Disclosure Statement:
This is a crossover treatment study with 2 arms that is participant and investigator masked.
Number of Participants:
The sample size calculation is based on the primary efficacy endpoint (overall composite driving 
Z score of AGN-190584 versus vehicle [Visit 3 versus Visit 5] approximately 1 hour after study 
intervention instillation). Assuming no difference between treatment groups and variance of 
0.11, approximately 40 participants will be required to obtain 90% power for a 1-sided 
noninferiority test with type 1 error of 0.025 and noninferiority margin of -0.25 units in mean 
overall composite driving Z score. Therefore, approximately 54 participants will be enrolled to 
achieve 40 participants completing the study assuming an anticipated dropout rate of 25% or 
less.
Intervention Groups and Duration:

Each participant will receive 2 ophthalmic solutions (AGN-190584 [pilocarpine
HCl 1.25% ophthalmic solution] and its vehicle) in a crossover design as described above.

Study intervention will be administered by the investigator or designated site personnel at
Visits 2, 3, 4, and 5, consisting of 1 drop in each eye.

Participants will be supplied with randomized study intervention at Visit 2
(randomization/first dosing visit) and instructed to dose at home 1 drop in each eye, once
daily in the morning between 08:00 and 10:00 for 7 to 14 days (adaptation period). On the
scheduled day of Visit 3 (first driving visit), the participant will not instill study
intervention at home (study intervention will be instilled by site personnel during the
visit). Study intervention supplied at Visit 2 will be collected from the participant at
Visit 3.
 
 
 


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
At least a 7-day and up to a 42-day washout period will be observed between Visits 3 and
4.

Participants will be supplied with new study intervention (following the study intervention
sequence assigned at Visit 2) at Visit 4 and instructed to dose at home one drop in each
eye, once daily in the morning between 08:00 and 10:00 for 7 to 14 days (adaptation
period). On the scheduled day of Visit 5 (second driving visit), the participant will not
instill study intervention at home (study intervention will be instilled by site personnel
during the visit). Study intervention supplied at Visit 4 will be collected from the
participant at Visit 5 (study exit).
Visit 2 through Visit 3
Washout Period
Visit 4 through Visit 5
Study intervention sequence 1
AGN-190584
Vehicle
Study intervention sequence 2
Vehicle
AGN-190584
Data Monitoring Committee:
No
1.2.
Schema
The study schema is provided in Figure 1-1.
Figure 1-1
Study Schema
 
  
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
  
 
 
 
  
   
 
 
 
 
  
 
 
 
 














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2.
Introduction
The sponsor is investigating pilocarpine HCl 1.25% ophthalmic solution (AGN-190584) as a 
noninvasive, reversible, pharmacological 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
In previous studies, the sponsor established the safety and efficacy of various concentrations of 
AGN-190584 dosed once daily, bilaterally or in the nondominant eye, over a period of up to 
30 days in participants with presbyopia. As with all miotics, participants were advised to exercise 
caution in night driving and other hazardous occupations under poor illumination.
Study 1883-306-013 is a single-center, randomized, double-masked, crossover, Phase 3b study 
evaluating the effect of AGN-190584 compared with vehicle when dosed in both eyes on driving 
performance under real-world, night-lighting conditions in participants with 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 one or more viewing distances, and each comes with its own 
unique safety risks and associated complications. For example, bifocals and progressive lenses 
(eg, 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, pharmacological 
treatment for presbyopia.
Pilocarpine is a muscarinic receptor agonist that mimics the actions of the parasympathetic 
neurotransmitter, acetylcholine, on smooth muscle. This causes 2 effects that enhance near 
vision: 1) constriction of the iris sphincter muscle, resulting in pupil constriction (miosis), and 
2) contraction of the ciliary muscle, resulting in central lens steepening and lens accommodation 
(focusing from distance to near) (García-Lázaro 2012). Reducing the pupil size has long been 
recognized as an effective way to increase the useful depth of focus, in part by reducing 
peripheral aberrations (Tucker 1975).
Pilocarpine ophthalmic solutions are currently used for the reduction of elevated IOP in patients 
with open-angle glaucoma or ocular hypertension, management of acute-angle closure glaucoma, 
 
 
 


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prevention of postoperative elevated IOP associated with laser surgery, and induction of miosis 
(Pilocarpine HCl ophthalmic solution package insert 2011). Currently, the use of pilocarpine 
ophthalmic solution is limited by the commonly experienced AE of temporal and periorbital 
headache (ie, brow ache), which is believed to be due to the rapidity of the ciliary muscle 
contraction (Tsai 2009). However, the sponsor has established an acceptable safety profile of 
AGN-190584 in 3 Phase 2 clinical studies (Studies 199201-007, 199201-009, and 199201-010). 
This is likely because the posology of pilocarpine evaluated for the treatment of presbyopia to 
date is of lower concentration (0.5% to 1.5%) and less frequently administered (once to 
twice daily) than for the treatment of glaucoma (1.0% to 4.0% administered up to 4 times daily). 
As a result, discontinuation rates for all Phase 2 clinical studies were generally low and safety 
parameters were not clinically significant between participants who received AGN-190584 
compared to 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 Phase 2 clinical studies included mesopic uncorrected near visual acuity 
line and letter improvement. Of the various concentrations of AGN-190584 evaluated, near 
vision was most improved compared with vehicle under mesopic and photopic conditions at the 
1.0% and 1.5% pilocarpine concentrations, respectively. Efficacy and safety of AGN-190584 
(1.25%) were also evaluated in 2 Phase 3 studies (1883-301-013 and 1883-302-013), for which 
the analyses and CSRs are, at the time this protocol was finalized, still in progress.
More detailed information regarding clinical safety findings, clinical efficacy findings, 
chemistry, and pharmacology is provided in the IB.
2.3.
Benefit/Risk Assessment
Currently available approaches to presbyopia correction include nonsurgical options (spectacles 
or contact lenses) and surgical options (PRK or LASIK, conductive keratoplasty, intraocular 
lenses, or corneal inlays). Each approach has its own risk-benefit ratio. Because the risk-benefit 
ratio with nonsurgical options is generally lower than that of surgical procedures, both historical 
and contemporary practice has been to attempt nonsurgical or pharmacological treatment before 
resorting to more invasive alternatives.
Although the use of spectacles and contact lenses to correct presbyopia is widespread, this 
approach has limitations. Multifocal spectacles impair depth perception and edge-contrast 
sensitivity at critical distances for detecting obstacles in the environment (Lord 2002), and 
varifocal lenses have a corridor of nondistorted vision. For these reasons, older people are more 
than twice as likely to fall when wearing multifocal spectacles, and many participants have 
difficulty adjusting to using them (Johnson 2007, Lord 2002). As a result, the sponsor is 
developing a noninvasive, reversible, pharmacological treatment for presbyopia.
Considering the COVID-19 pandemic, the benefit and risk to participants in this study have been 
re-evaluated. Based on the limited information to date, no additional risk to study participants is 
anticipated with the use of AGN-190584 and no potential interactions are anticipated between 
the COVID-19 vaccine and the study drug.
More detailed information about the known and expected benefits and risks and reasonably 
expected AEs of AGN-190584 may be found in the IB.
 
 
 


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3.
Objectives and Measures
Objectives
Measures
To evaluate night-driving performance in 
real-world driving conditions in participants 
with presbyopia treated with AGN-190584 
versus vehicle 

Overall driving performance

Hazard avoidance

Road sign recognition

Road sign recognition distance

Pedestrian recognition distance

Lane-keeping

Driving time

Pupil diameter

Halometer

Night driving experience questionnaire
To evaluate safety in participants with 
presbyopia treated with AGN-190584 
versus vehicle

Mesopic/photopic HDVA

AEs

Pregnancy tests for WOCBP

Slit-lamp biomicroscopy
 
 
 


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4.
Study Design
4.1.
Overall Design
This is a single-center, randomized, double-masked, crossover, Phase 3b study evaluating the 
effect of AGN-190584 compared with vehicle when dosed in both eyes on driving performance 
under real-world, night-lighting conditions in participants with objective and subjective evidence 
of presbyopia. 
The study consists of 5 visits (screening [Visit 1], randomization/first dosing [Visit 2], first 
driving [Visit 3], second dosing [Visit 4], and second driving [Visit 5] visits) with a crossover of 
AGN-190584 and vehicle. There will be a 7- to 14-day study intervention adaptation period 
before each driving visit (Visits 3 and 5) and a 7- to 42-day washout period between Visits 3 and 
4. Participants will require transport to and from both of the driving visits.
Approximately 54 participants will be enrolled at one study site (Queensland University of 
Technology, Australia) and approximately 40 participants are expected to complete the study 
based on an anticipated dropout rate of 25% or less. Participants who prematurely discontinue 
from the study will not be replaced.
4.2.
Scientific Rationale for Study Design
The current Phase 3b clinical study is designed to evaluate the effect of AGN-190584 compared 
with vehicle when dosed in both eyes on driving performance under real-world, night-lighting
conditions in participants with presbyopia.
Phase 2 Studies 199201-009 and 199201-010 supported the administration of AGN-190584 
monotherapy as an effective and safe treatment for presbyopia at doses up to 1.5%. The nearly
completed Phase 3 Studies 1883-301-013 and 1883-302-013 evaluated AGN-190584 1.25% in 
an expanded participant population to establish efficacy and safety (data analysis and CSRs in 
progress). 
As with all miotics, participants should be advised to exercise caution in night driving and other 
hazardous occupations in poor illumination. Participants should be advised not to drive or use 
machinery until vision is cleared. This study is being conducted to better understand and quantify 
the effect of AGN-190584 on night driving under real-world conditions.
4.3.
Justification for Dose
Through modeling and evaluation of the Phase 2 results (Studies 199201-007, 199201-009, and 
199201-010), the sponsor has determined the optimal dose of AGN-190584 to be 1.25% for the 
treatment of presbyopia. AGN-190584 1.25% was evaluated in 2 nearly completed Phase 3 
studies (1883-301-013 and 1883-302-013). The analyses and CSRs for these studies have been 
completed.
 
 
 


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4.4.
End of Study Definition
The EOS is defined as the date of the last driving visit of the last participant in the study.
A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last driving visit.
 
 
 


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5.
Study Population
The study population will consist of adult male and female participants with objective and 
subjective evidence of presbyopia.
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted.
5.1.
Inclusion Criteria
Participants are eligible to be included in the study only if all of the following criteria apply:
1.
Age
1.01
Participant must be 40 to 55 years of age inclusive, at the time of the screening visit.
2.
Type of Participant and Presbyopia Characteristics
2.01
In good general health at the screening visit, as determined by the investigator from 
medical history
2.02
Subjective complaints of poor near vision that impacts activities of daily living, as 
defined by at least a moderate impact (score ≥ 3) on at least 1 question on 
NEI VFQ-25 Questions 5 to 7 in the main questionnaire or near vision subscale, 
Questions A3 to A5 in the Appendix of Optional Additional Questions, at the 
screening visit
Note: Please advise the participant that for this questionnaire they are to interpret the 
instructions as referring to glasses or contacts they need for seeing objects at a 
distance (if required), not their reading glasses or bifocals.
2.03
Photopic, high-contrast, best distance correction in the range of spherical -4.00 D to 
+1.00 D inclusively and cylinder ≤ ±2.00 D with photopic at the screening visit and
photopic, high-contrast BCDVA of 20/25 or better OD and OS at the screening visit
2.04
Photopic, high-contrast HDVA of 20/32 or better OU at screening as well as before 
and 1 hour after dosing at both driving tests. Only monofocal correction (either 
spectacles or contact lenses) is allowed for the driving tests. If the participant does 
not have monofocal correction of 20/32 or better OU, the study site will provide 
monofocal spectacles.
2.05
Mesopic, high-contrast DCNVA of 20/40 to 20/100 OD and OS at screening
2.06
Photopic, high-contrast near visual acuity correctable to 20/40 or better in each eye 
at the screening visit
2.07
Mesopic pupil diameter < 8.0 mm in both eyes at the screening visit
 
 
 


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3.
Sex
3.01
Male or female
4.
Informed Consent
4.01
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol
4.02
Written informed consent from the participant or a legally authorized representative 
has been obtained prior to any study-related procedures.
4.03
Written documentation has been obtained in accordance with the relevant country 
and local privacy requirements, where applicable.
5.
Other
5.01
Participant must hold a valid driver’s license as governed by local regulations.
5.02
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:
1.
Medical Conditions
1.01
Uncontrolled systemic disease
1.02
Clinically significant disease state, in the opinion of the examining investigator or 
designee, in any body system
1.03
Any clinical condition or previous surgery that might affect the absorption, 
distribution, biotransformation, or excretion of AGN-190584. History of cataract 
surgery, phakic intraocular lens surgery, corneal inlay surgery, radial keratotomy, or 
any intraocular surgery. However, participants with a history of PRK or LASIK with 
CDVA meeting inclusion criteria will be allowed to enroll.
1.04
Known allergy or sensitivity to the study intervention or its components or other 
cholinergic agonist medications
 
 
 


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2.
Prior/Concomitant Therapy
2.01
Concurrent use of any topical ophthalmic medications, including artificial tears, 
other than the study intervention during the course of the study
2.02
Concurrent use of temporary or permanent punctal plugs or history of punctal 
cautery in one or both eyes
2.03
Prior/concomitant use of any interventions outlined in Section 6.5.1 (prohibited 
interventions and washout before the study).
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
4.
Diagnostic Assessments
4.01
Presence of any ocular condition that, in the opinion of the investigator, could affect 
the safety of the participant or interpretation of efficacy parameters (eg, uveitis, 
retinal detachment)
4.02
Severe dry eye disease (defined as total corneal staining ≥ Grade 3 on the 5-point 
Oxford scale and an OSDI score of > 33) at the screening visit
4.03
Corneal abnormalities (including keratoconus, corneal scar, Fuchs’ endothelial 
dystrophy, guttata, or edema) in either eye that are likely to interfere with visual 
acuity
4.04
Narrow iridocorneal angles (Shaffer Grade ≤ 2 or lower on gonioscopy 
examination), history of angle-closure glaucoma, or previous iridotomy
4.05
History of iris trauma, Adie’s tonic pupil, abnormal pupil shape in either eye, or 
anisocoria > 1 mm between pupils under mesopic conditions at the screening visit
4.06
Lens opacity in either eye that is determined to cause significant disturbance of the 
central visual axis on screening biomicroscopy
4.07
Diagnosis of any type of glaucoma or ocular hypertension
4.08
Bifocal or multifocal spectacles or contact lenses for habitual correction are 
permissible, although they cannot be used at the driving visits.
4.09
Abnormal and clinically significant results according to the investigator or designee, 
on physical/ophthalmic examination or medical history
 
 
 


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5.
Other
5.01
Females who are pregnant, nursing, or planning a pregnancy during the study;
WOCBP or males with partners of childbearing potential who do not agree to use 
reliable contraception during the study
5.02
The participant has a condition or is in a situation which, in the investigator’s 
opinion, may put the participant at significant risk, may confound the study results, 
or may interfere significantly with the participant’s participation in the study.
5.3.
Lifestyle Considerations
Participants who wear bifocal or multifocal spectacles or contact lenses will be provided a pair of 
monofocal spectacles with the same or improved distance correction (20/32 or better) as their 
new habitual correction for use at the driving visits. Bifocal or multifocal spectacles or contact 
lenses for habitual correction are permissible throughout the study, although they cannot be used 
at the driving visits. 
5.4.
Screen Failures
Screen failures are defined as participants who consent to participate in the clinical study and 
sign the ICF but are not subsequently entered in the study. A minimal set of screen failure 
information is required to ensure transparent reporting of screen failure participants to meet the 
Consolidated Standards of Reporting Trials publishing requirements and to respond to queries 
from regulatory authorities. Minimal information includes demography, screen failure details (ie, 
reason for failure), eligibility criteria, and any SAEs.
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 interventions intended to be administered to 
a study participant according to the study protocol.
6.1.
Study Interventions Administered
Study Intervention Name
AGN-190584
Vehicle
Dosage Formulation
Topical ophthalmic solution
Topical ophthalmic solution
Identity of Formulation
Pilocarpine HCl 1.25% Ophthalmic 
Solution
Manufactured at Allergan Waco
Oxymetazoline HCl and Pilocarpine 
HCl Placebo Ophthalmic Solution
Manufactured at Allergan Waco
Drug Substance
Pilocarpine HCl 1.25%
Not applicable
Route of Administration 
Topical eyedrop
Topical eyedrop
Dosing Instructions
1 drop in each eye at Visits 2 through 
5 and at home as instructed
1 drop in each eye at Visits 2 through 
5 and at home as instructed
Packaging and Labeling
Study intervention will be provided in 
sterile, 5 mL bottles. Each bottle will 
be labeled in compliance with local 
labeling regulations.
Study intervention will be provided in 
sterile, 5 mL bottles. Each bottle will 
be labeled in compliance with local 
labeling regulations.
Manufacturer
Allergan Sales, LLC.
Allergan Sales, LLC.
Number and Timing of 
Interventions
1 drop bilaterally, once at Visits 2
through 5 and at home as instructed
1 drop bilaterally, once at Visits 2 
through 5 and at home as instructed
Volume Per Intervention
3.5 mL per bottle
3.5 mL per bottle
As this is a double-masked study, AGN-190584 and vehicle will be supplied to the study center 
in identically appearing bottles and cartons.
Please refer to the SoA (Table 1-1) for the timing of study visits referenced below. As described 
in the SoA (Table 1-1) and Section 6.3, the study site will contact the IxRS for study intervention 
kit assignment.
Study intervention will be administered by the investigator or designated site personnel at 
Visits 2, 3, 4, and 5. 
Participants will be supplied with study intervention at Visit 2 (randomization/first dosing visit) 
and instructed to dose at home 1 drop in each eye, once daily in the morning between 08:00 and 
10:00 for 7 to 14 days (adaptation period). On the scheduled day of Visit 3 (first driving visit), 
the participant will not instill study intervention at home. Participants will be reminded by the 
study site before driving visits to not instill study intervention on the day of the visit. If the 
participant arrives for a driving visit having instilled study intervention at home that same day, 
the driving visit must be rescheduled for another day. Study intervention dispensed to the 
participant at Visit 2 will be collected by the study site at Visit 3.
After the washout period (crossover), participants will be supplied with study intervention at 
Visit 4 (second dosing visit) and again instructed to dose at home 1 drop in each eye, once daily 
 
 
 


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in the morning between 08:00 and 10:00 for 7 to 14 days (adaptation period). On the scheduled 
day of Visit 5 (second driving visit), the participant will not instill study intervention at home.
Participants will be reminded by the study site before driving visits to not instill study 
intervention on the day of the visit. If the participant arrives for a driving visit having instilled 
study intervention at home that same day, the driving visit must be rescheduled for another day.
Study intervention dispensed to the participant at Visit 4 will be collected by the study site at 
Visit 5.
6.2.
Preparation/Handling/Storage/Accountability
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.
Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply or administer study intervention. 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. All study intervention must be stored upright, in a refrigerator, and protected from freezing.
The investigator is responsible for study intervention accountability, reconciliation, and record 
maintenance (ie, receipt, reconciliation, and final disposition records). Include participant ID 
number and bottle/carton serial or lot number, as applicable.
Participants will be instructed on the proper storage of study intervention and to keep it out of the 
reach of children at all times.
All unused study intervention and empty bottles/cartons must be returned to the sponsor at the 
conclusion of the study. All study intervention must be accounted for. Unused drug supplies and 
empty drug bottles/cartons will be returned to the sponsor.
6.3.
Measures to Minimize Bias: Randomization and Masking
All participants will be centrally assigned to randomized study intervention using the IxRS. 
Participant IDs will be assigned at the screening visit. Randomization and kit assignment will be 
conducted at the randomization/first dosing visit (Visit 2). At the randomization/first dosing visit
(Visit 2), participants will be randomized in a 1:1 ratio to one of the 2 study intervention 
sequences, either AGN-190584 followed by vehicle after a minimum 1-week washout period 
(study intervention sequence 1), or vehicle followed by AGN-190584 after a minimum 1-week 
washout period (study intervention sequence 2). All participants will receive the first dose at 
Visit 2 and continue daily dosing through the end of the first driving visit (Visit 3). After the first 
driving visit (Visit 3) and a minimum 1-week washout period, participants will complete a
second dosing visit (Visit 4) and continue daily dosing following the assigned study intervention 
sequence through the end of the study (Visit 5, second driving visit). The IxRS will be contacted 
again at the second dosing visit (Visit 4) for kit dispensing before study intervention instillation. 
 
 
 


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Before the study is initiated, login information and directions for the IxRS will be provided to the 
site. Study intervention and vehicle will be dispensed at the study visits summarized in the SoA 
(Section 1.3).
The identity of study intervention will be masked to the participants and the study center. The 
IxRS 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.
As described in Section 6.1, study intervention will be administered by the investigator or 
designated site personnel at Visits 2, 3, 4, and 5, and at home by the participant between 
Visits 2/3 and 4/5 to allow for study intervention adaptation before each driving test (Visits 3 
and 5).
6.4.
Study Intervention Compliance
Study intervention will be administered by designated site personnel on visit days and at home 
by the participant during the adaptation periods (in the morning between 08:00 and 10:00). On 
the days of the driving tests (Visits 3 and 5), the participant will not instill study intervention at 
home (as it will be instilled by site staff during the visit). Participants will be instructed to return 
study intervention dispensed at Visits 2 and 4 at Visits 3 and 5, respectively.
On visit days, study intervention compliance will be assumed to be 100% when dosing has been 
recorded in the eCRF.
Participants will be encouraged to consistently instill study intervention during the adaptation 
periods as instructed at home in between Visits 2/3 and 4/5.
If a subject is unable to come to the study site to pick up their study drug due to COVID-19, a 
direct-to-patient study drug shipment can be made from the study site to the subject if allowed by 
local regulations. The sponsor will submit any required notifications to the regulatory authority 
as applicable. For Visit 2 and Visit 4, if a subject is unable to come to site the visit will be 
rescheduled.
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 visit along with the reason the medication is taken.
From screening to the second driving visit, site staff will question each participant specifically on 
the use of concomitant medications. Site staff must notify the sponsor immediately if a 
participant consumes any concomitant medications not permitted by the protocol. Participants 
 
 
 


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who used prohibited concomitant medications may be discontinued from the study at the 
discretion of the investigator or the sponsor.
6.5.1.
Prohibited Interventions and Washout Before the Study
Use of medications that may have a substantial effect on visual function or the optical properties 
of the eye, or may have interaction with the study intervention is prohibited during the study:

Ophthalmic, systemic, or intranasal cholinergic receptor agonist/antagonist and 
α-adrenergic receptor agonist/antagonist with potential pupillary or accommodative 
effects, including oxymetazoline, commercially available pilocarpine, tetrahydrozoline, 
phenylephrine, naphazoline, cyclopentolate, atropine, or antihistamines 
o
Note: Over-the-counter antihistamines used PRN between study visits are allowed but 
must not be used within 24 hours of any study visit.

Systemic medications with potential for acute ocular side effects (eg, tricyclic 
antidepressants with anticholinergic effects), or with chronic ocular side effects that have 
been reported (eg, hydroxychloroquine related retinopathy) 
6.5.2.
Permitted Interventions
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 enrollment 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.
The concurrent use of nonocular medications that do not have a substantial effect on the pupil, 
accommodative properties, or retinal function of the eye will be permitted during the study if it is 
necessary for the participant’s welfare and/or if a stable dosing regimen is established. The 
dosing regimen is not considered to be stable if a participant starts, stops, or changes the 
dose/drug during the study.
Any medication taken during the study between the date of the first dose of study intervention 
and the date of the second driving visit will be recorded in the eCRF as a concomitant 
 
 
 


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medication; any medication started after the second driving visit will not be considered a 
concomitant medication and should not be captured in the eCRF.
COVID-19 Pandemic-related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected vaccines (eg, mRNA, nonreplicating viral 
vector, protein subunit, etc.) to prevent SARS-CoV-2 infection may be administered during 
screening or the treatment period, as long as components of the vaccine are not contraindicated.
The decision to receive a locally available vaccine should be based on local guidance and an 
individual discussion between the treating physician and the participant.
The potential impact of AGN-190584 on SARS-CoV-2 vaccination is unknown. Therefore, 
study drug should be administered as follows:

The first dose of study drug(s) AGN-190584 is preferred to be given at least ± 7 days from 
the SARS-CoV-2 vaccine administration, when possible.
Note: The above guidance applies to all SARS-CoV-2 vaccine doses given as part of the 
complete vaccination course.
These recommendations may be subject to change based on the evolving knowledge around the 
use of SARS-CoV-2 vaccines in patients with presbyopia and as more data are collected in 
real-world scenarios and clinical trials.
Any SARS-CoV-2 vaccine information must be documented on the COVID-19 vaccine eCRF. 
6.5.3.
Rescue Medicine
Rescue medicine is not applicable.
6.5.4.
Prohibited Interventions During the Study
All interventions listed in Section 6.5.1 are also prohibited during the study.
Use of ocular medications other than the study intervention or medications administered to 
conduct study procedures are prohibited from the screening visit until study exit.
The decision to administer a prohibited medication/treatment will be made with the safety of the 
study participant as the primary consideration. When possible, the sponsor should be notified 
before the prohibited medication/treatment is administered.
6.6.
Dose Modification
Dose modification is not applicable.
6.7.
Intervention after the End of the Study
No interventions after the end of the study are planned.
 
 
 


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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 receives study 
intervention 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 EOS or EOT may include the following:

Completed study (EOS)

Completed treatment (EOT)

Adverse event (EOT)

Death (EOS)

Lost to follow-up

Withdrawal by subject (EOS)

Withdrawal from treatment by subject (EOT)

Non-compliance with study drug (EOT)

Study terminated by sponsor

Pregnancy

Protocol deviation

Site terminated by sponsor

Progressive disease (EOS)

COVID-19 infection

COVID-19 logistical restrictions

Other (specify)
7.1.
Discontinuation of Study Intervention
See the SoA (Section 1.3) for data to be collected at the time of early exit.
Participants who discontinue the study intervention early will be encouraged to stay in the study 
for the safety assessments at the second driving visit.
 
 
 


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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.

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.
See the SoA (Section 1.3) for data to be collected at the time of early exit.
COVID-19 Pandemic-related Acceptable Protocol Modification
During the COVID-19 pandemic, it has been necessary to employ mitigation strategies to enable 
the investigator to ensure participant safety and continuity of care.
The investigator should contact the sponsor medical contact before discontinuing a participant
from the study for a reason other than described in the protocol to ensure all acceptable 
mitigation steps have been explored.
During the study drug dosing period, a participant with confirmed (viral test positive) or 
suspected COVID-19 infection can only be dosed with study drug if the following COVID-19 
viral clearance criteria are met:

At least 14 days since first PCR test result have passed in asymptomatic patients or 
14 days since recovery, defined as resolution of fever without use of antipyretics and 
improvement in symptoms.
Delays in study drug dosing due to the above COVID-19 testing guidance for participants must 
be discussed with the sponsor medical contact, along with the possibility of premature 
discontinuation from the study drug dosing period. 
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, counsel the participant on the importance of maintaining the assigned visit 
schedule, and ascertain whether the participant wishes to and/or should continue in the 
study.
 
 
 


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
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 will 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.
 
 
 


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8.
Study Assessments and Procedures

Study procedures and their timing are summarized in the SoA (Section 1.3). 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.

Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for the screening or either
driving visit purposes provided the procedures met the protocol-specified criteria and were 
performed within the timeframe defined in the SoA.
8.1.
Efficacy Assessments – Driving Performance
Efficacy assessments for night-driving performance metrics include: sign recognition
(Section 8.1.1), hazard avoidance (Section 8.1.2), driving time (Section 8.1.3), lane-keeping
(Section 8.1.4), pedestrian recognition distance (Section 8.1.5), overall composite driving 
Z-score (Section 8.1.6), pupil diameter (Section 8.1.7), halometer (Section 8.1.8), and a
night-driving experience questionnaire (Section 8.1.9).
The night-driving evaluation will be performed at both driving visits. Please see the SoA in 
Section 1.3 for the timing of events at each visit. 
Pupil diameter and halometer measurements will be performed separately from the driving test. 
Please see the SoA in Section 1.3 for the timing of events at each visit.
After 1 hour ± 15 minutes following study intervention instillation and visual function 
assessments, participants will start the driving test at the beginning of the closed road driving 
circuit. The circuit is representative of a rural road, and includes hills, bends, curves, 
intersections, lengthy straight sections, and standard road signs and lane markings. The circuit
does not include artificial ambient lighting. All experimental sessions will be conducted during 
times when the road surface is dry and there is no rain. Driving performance will be assessed 
after nautical twilight (evening nautical twilight is defined to begin at sunset and end when the 
center of the sun is 12 degrees below the horizon).
Participants will undergo a 5-minute familiarization period with the instrumented vehicle and 
provided with standard instructions regarding the driving circuit and the tasks.
 
 
 






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8.1.7.
Pupil Diameter
Pupil diameter will be measured during distance fixation using a NeurOptics Pupillometer for 
mesopic/photopic lights levels specified in the SoA (Section 1.3).
8.1.8.
Halometer
The halo produced by glare from a bright white LED attached to the center of an iPad screen 
(iPad 4, Apple Inc., Cupertino, California, USA) will be determined as the position closest to the 
LED where 2 out of 3 presentations of a randomly presented, high-contrast 20/50 letter 
(0.4 logMAR) are correctly identified (Buckhurst 2015, Kimlin 2017). A seen-to-not-seen 
approach will be used with a 0.1˚ step size along 8 meridians. The halo area (cm2) will be 
determined by calculating the area of the halo surrounding the LED glare source.
8.1.9.
Night-driving Experience Questionnaire
A night-driving experience questionnaire consisting of 12 questions will be administered to 
participants to evaluate their night driving experience after the driving tests and is provided in 
Appendix 7 (Section 10.7).
8.2.
Safety Assessments
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3).
8.2.1.
Ophthalmic Examinations
8.2.1.1.
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, and iris/pupil.
 
 
 


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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
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
 
 
 


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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
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 
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Iris/Pupil:
The iris/pupil will be evaluated for pathology. If pathology is present, it will be described.
8.2.1.2.
Manifest Refraction
Manifest refraction (distance and near) will be performed according to standard clinical practice
in photopic conditions.
8.2.1.3.
Dilated Fundoscopic Examination
The fundus assessments should be conducted through a dilated pupil (using 1% tropicamide). 
The examinations will include evaluation of the lens, vitreous, fundus, and optic nerve. The C/D 
ratio will be assessed. The investigator should note if the pupil dilated normally.
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 examination, the presence and severity of nuclear, cortical, and posterior 
subcapsular cataract lens opacities will be evaluated. At the first dilated examination, each type 
of cataract, if present, will be graded using the scale below. At the last follow-up dilated 
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.
 
 
 


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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.
C/D Ratio:
C/D ratio will be reported using a 0.0 to 1.0 scale. It will be noted if the condition is not 
evaluable.
8.2.2.
Vital Signs
Vital signs will be assessed as follows:

Blood pressure and pulse rate will be assessed.

Systolic and diastolic blood pressure will be measured using an appropriate 
sphygmomanometer after participants have been at rest (seated) for at least 5 minutes. 
Blood pressure will be recorded in mm Hg.

Heart rate will be measured in bpm after the participant has been in a resting state (seated) 
for at least 5 minutes. Pulse will be recorded in bpm.

Participants should refrain from smoking or ingesting caffeine during the 30 minutes 
preceding the measurement.
8.2.3.
Pregnancy Testing
Pregnancy test kits will be provided by the investigator and will be administered according to the 
instructions provided with the tests. WOCBP must have a negative test result before receiving 
study intervention. Pregnancy tests will be performed at all study visits, and may be performed at 
any other visit (as applicable), at the investigator’s discretion. At each visit, the investigator 
should discuss contraceptive use compliance with WOCBP (see Appendix 6, Section 10.6).
8.2.4.
Mesopic and Photopic BCDVA and DCNVA
Binocular BCDVA and DCNVA will be tested using logMAR charts at 4 m and 40 cm under 
2 lighting conditions: mesopic luminance (10 to 11 lux) and photopic luminance (≥251 lux)
under normal room lighting. Testing will be conducted with the optimal distance refractive 
correction. Forced choice letter-by-letter scoring will be used for each test and the total number 
of correct letters or the highest value (number) of the grid identified (as applicable) will be 
recorded, in logMAR. Different logMAR charts will be used for each lighting condition and 
distance measured. 
 
 
 


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8.2.5.
Mesopic and Photopic HDVA
Binocular HDVA will be tested using logMAR charts at 4 m under 2 lighting conditions: 
mesopic luminance (10 to 11 lux) and photopic luminance (≥251 lux) under normal room 
lighting. Testing will be conducted with the participant’s habitual monovision distance refractive 
correction. Forced choice letter-by-letter scoring will be used for each test and the total number 
of correct letters or the highest value (number) of the grid identified (as applicable) will be 
recorded, in logMAR. Different logMAR charts will be used for each lighting condition and 
distance measured.
8.2.6.
Clinical Safety Laboratory Assessments
Clinical safety laboratory assessments are not applicable to this study.
8.2.7.
Suicidal Ideation and Behavior Risk Monitoring
Suicidal risk monitoring and behavior risk monitoring are not applicable to this ophthalmology 
study.
8.3.
Adverse Events and Serious Adverse Events
The definitions of an AE or SAE can be found in Appendix 2 (Section 10.2).
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative).
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (ie, repeat treatment) or study (see 
Section 7).
8.3.1.
Time Period and Frequency for Collecting AE and SAE Information
All AEs and SAEs from the signing of the ICF until 30 days after the last dose of study 
intervention will be collected at the timepoints specified in the SoA (Section 1.3), 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.
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 2 (Section 10.2). The investigator will submit any updated SAE data to the sponsor 
within 24 hours of it being available.
The investigator is 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.
 
 
 


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The methods of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2 
(Section 10.2).
8.3.2.
Method of Detecting AEs and SAEs
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
nonleading 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 AEs/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).
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by the sponsor to 
elucidate the nature and/or causality of the AE or SAE as fully as possible. This may include 
additional laboratory tests or investigations, histopathological examinations, or consultation with 
other health care professionals.
If a participant dies during participation in the study, the investigator will provide the sponsor
with a copy of any postmortem findings including histopathology.
If a participant is hospitalized and discharged, follow-up attempts must be made to obtain the 
discharge summary from the hospital and, if obtained, it should be sent to the sponsor.
New or updated information will be recorded in the originally completed eCRF.
The investigator will submit any updated SAE data to the sponsor within 24 hours of receipt of 
the information.
8.3.4.
Regulatory Reporting Requirements for SAEs

Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study 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, IRBs/IECs, and investigators. 

Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary.
 
 
 


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
An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements.
8.3.5.
Pregnancy

If a pregnancy is confirmed after the participant has received the study intervention, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in 
the study for all safety and efficacy follow-up assessments through the EOS visit.

Details of all pregnancies in female participants will be collected after the start of study 
intervention and through the duration of the pregnancy.

If a pregnancy is reported, the investigator should inform the sponsor within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6 
(Section 10.6).

Abnormal pregnancy outcomes (eg, 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 to this ophthalmology study.
8.5.
Pharmacokinetics
Pharmacokinetics are not evaluated in this study.
8.6.
Pharmacodynamics
Pharmacodynamic parameters are not evaluated in this study.
8.7.
Genetics
Genetics are not evaluated in this study.
8.8.
Biomarkers
Biomarkers are not evaluated in this study.
8.9.
Immunogenicity Assessments
Immunogenicity is not evaluated in this study.
8.10.
Health Economics
Health economics are not evaluated in this study.
 
 
 


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9.
Statistical Considerations
The SAP will be developed and finalized before database lock and unmasking and will describe 
the participant populations to be included in the analyses, procedures for accounting for missing, 
unused, and spurious data, and detailed statistical analysis methods. This section is a summary of 
the planned statistical analyses.
9.1.
Statistical Hypotheses
The null and alternative hypotheses for the primary efficacy endpoint are:

H0: The difference in mean overall composite driving Z score between AGN-190584 and 
vehicle (AGN-190584 minus vehicle) is < -0.25.

HA: The difference in mean overall composite Z score between AGN-190584 and vehicle 
(AGN-190584 minus vehicle) is ≥ -0.25. 
9.2.
Sample Size Determination
The sample size calculation is based on the primary efficacy endpoint. Assuming no difference 
between treatment groups and variance of 0.11, approximately 40 participants will be required to 
obtain 90% power for a 1-sided noninferiority test with type 1 error of 0.025 and noninferiority 
margin of -0.25 units in mean overall composite driving Z score. Therefore, approximately 
54 participants will be enrolled to achieve 40 participants completing the study assuming an 
anticipated dropout rate of 25% or less.
9.3.
Populations for Analyses
The following populations are defined:
Population
Description
ITT
The ITT population includes all randomized participants. 
Safety
The safety population includes all treated participants who 
receive ≥ 1 administration of study intervention.
9.4.
Statistical Analyses
9.4.1.
Efficacy Analyses
The efficacy analyses will be based on the ITT population. Baseline for efficacy is defined as the 
last nonmissing efficacy assessment before the first dose of study intervention. All statistical 
tests will be 2-sided hypothesis tests performed at the 5% level of significance for main effects. 
All confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise.
 
 
 


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9.4.1.1.
Analysis Endpoints
The primary and other efficacy endpoints and associated analyses are summarized in the 
following sections.
Primary Efficacy Endpoint:

Overall composite driving Z score approximately 1 hour after study intervention 
instillation
Other Efficacy Analyses:
Other efficacy analyses will include road sign recognition score, lane-keeping score, pedestrian 
recognition distance, driving time, pupil diameter, halometer, and a night-driving experience 
questionnaire.
9.4.1.2.
Primary Analyses
Overall composite driving Z score will be analyzed using MMRM. The model will include study 
intervention group, study intervention sequence, and study period as fixed effects and participant 
nested within sequence of testing as a random effect. The within-participant correlation error 
structure is unstructured. Noninferiority of AGN-190584 will be concluded if the lower bound of 
the 95% confidence interval of the least square mean difference between AGN-190584 and 
vehicle is greater than -0.25.
9.4.1.3.
Other Efficacy Analyses
Detailed methods of analyses for other efficacy variables will be described in the SAP.
9.4.2.
Safety Analyses
The safety analyses will be performed using the safety population. For each safety parameter, the 
last nonmissing safety assessment before the first dose of study intervention will be used as the 
baseline.
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 treatment-emergent SAE if it is a TEAE that additionally meets any 
SAE criteria.
The number and percentage of participants with TEAEs during the study will be tabulated by 
system organ class and preferred term and by system organ class, preferred term, and severity.
The number and percentage of participants with ocular TEAEs during the study will be tabulated 
by preferred term.
 
 
 


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If more than 1 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 had such events. Listings of all AEs, SAEs, and AEs 
leading to discontinuation by participant will be presented.
9.4.2.2.
Other Safety Analyses
All other safety variables will be analyzed with descriptive statistics. Detailed methods for the 
analysis of other safety variables will be described in the SAP.
9.5.
Interim Analyses
No interim analysis is planned.
9.6.
Data Monitoring Committee
Not applicable.
 
 
 


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10.
Supporting Documentation and Operational Considerations
10.1.
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations
10.1.1.
Regulatory and Ethical Considerations

This study will be conducted in accordance with the 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, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated.

Any amendments to the protocol will require 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 subinvestigators 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.
 
 
 


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10.1.3.
Informed Consent Process

The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding 
the study. 

Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 
50, local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center. 

The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was 
obtained. The authorized person obtaining the informed consent must also sign the ICF.

Participants must be reconsented 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 or the participant’s legally 
authorized representative.
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 his/her 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 study 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 data and information may be published in nonpromotional, peer-reviewed 
publications either by or on behalf of the sponsor. 
 
 
 


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
Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required.

Company-sponsored study information and tabular study results will be posted on the 
United States National Institutes of Health’s website www.ClinicalTrials.gov and other 
publicly accessible sites.
10.1.6.
Data Quality Assurance

All participant data relating to the study will be recorded on printed or electronic CRFs
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.

The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.

The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.

Monitoring details describing strategy (eg, 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 plan.

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 (eg, 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.
 
 
 


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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 Section 4.0 of ICH E6, GCP: 
Consolidated Guidance and records must be attributable, legible, contemporaneous, 
original, and accurate.

During the COVID-19 pandemic, remote data review/verification may be employed if 
allowed by the local regulatory authority, IRB/IEC, and the study site.
10.1.8.
Study and Site Start and Closure
For the purpose of clinical trial registries, the study start date is the date on which the clinical 
study will be open for recruitment of participants.
The first act of recruitment is first participant first visit, which is considered the first act of 
recruitment and will be the study start date.
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.
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 
 
 
 


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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

The sponsor has proprietary interest in this study. Authorship and manuscript composition 
will reflect joint cooperation between multiple investigators and sites and sponsor 
personnel. Authorship will be established prior to the writing of the manuscript.

The sponsor will comply with the requirements for publication of study results.

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 
(including those that may be due to the COVID-19 pandemic) 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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10.3.
Appendix 3: Abbreviations
Abbreviation/Term
Definition
AE
adverse event
AESI
adverse event of special interest
BCDVA
best-corrected distance visual acuity
C/D
cup-to-disc
CDISC
Clinical Data Interchange Standards Consortium
CDVA
corrected distance visual acuity
CFR
Code of Federal Regulations
CIOMS
Council for International Organizations of Medical Sciences
COVID-19
coronavirus disease 2019
CRF
case report form
CSR
clinical study report
CTA
clinical trial agreement
DCNVA
distance-corrected near visual acuity
eCRF
electronic case report form
EDC
electronic data capture
EOS
end of study
EOT
end of treatment
FDA
Food and Drug Administration
FSH
follicle-stimulating hormone
GCP
Good Clinical Practice
GPS
global positioning system
HDVA
habitual distance visual acuity
HRT
hormone replacement therapy
IB
investigator’s brochure
ICF
informed consent form
ICH
International Council for Harmonization
ID
identification
IEC
independent ethics committee
IOP
intraocular pressure
IRB
institutional review board
ISO
International Organization for Standardization
ITT
intent-to-treat
IUD
intrauterine device
IUS
intrauterine system
IxRS
interactive electronic response system
LASIK
laser-assisted in situ keratomileusis 
 
 
 


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Abbreviation/Term
Definition
LED
light-emitting diode
logMAR
logarithm of the minimum angle of resolution
MMRM
mixed model for repeated measures
mRNA
messenger ribonucleic acid
NCI
National Cancer Institute
NEI VFQ-25
National Eye Institute Visual Function Questionnaire 25
OD
right eye
OS
left eye
OSDI
Ocular Surface Disease Index
OTC
over-the-counter
OU
both eyes
PCR
polymerase chain reaction
PK
pharmacokinetic
PRK
photorefractive keratectomy 
PRN
as needed
SAE
serious adverse event
SAP
statistical analysis plan
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SoA
schedule of activities
TEAE
treatment-emergent adverse event
USA
United States of America
WOCBP
women of childbearing potential
 
 
 


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10.4.
Appendix 4: 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)
Completed
To possess every necessary or normal part or component or step; 
having come or been brought to a conclusion (NCI)
Death
The absence of life or state of being dead (NCI)
Disease relapse
The return of a disease after a period of remission
Failure to meet randomization criteria
An indication that the subject has been unable to fulfill/satisfy the 
criteria required for assignment into a randomized group
Lack of efficacy
The lack of expected or desired effect related to a therapy (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)
Progressive disease
A disease process that is increasing in extent or severity (NCI)
Protocol deviation
An event or decision that stands in contrast to the guidelines set out 
by the protocol (NCI)
Recovery
A healing process and/or an outcome implying relative health. The 
term is typically used in the context of direct and indirect effects of 
sickness or injury. (NCI)
Screen failure
The potential subject who does not meet one or more criteria 
required for participation in a trial
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)
 
 
 


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CDISC Submission Value
CDISC Definition
Technical problems
A problem with some technical aspect of a clinical study, usually 
related to an instrument (NCI)
Withdrawal by parent/guardian
An indication that a study participant has been removed from the 
study by the parent or legal guardian
Withdrawal by subject
An indication that a study participant has removed itself from the 
study (NCI)
 
 
 


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10.5.
Appendix 5: Study Tabular Summary
Parameter Group
Parameter
Value
Trial information
Trial Title
Evaluating the Impact of AGN-190584 
on Night-driving Performance
Clinical Study Sponsor
Allergan Sales, LLC
Trial Phase Classification
Phase 3b
Trial Indication
Presbyopia
Trial Indication Type
Treatment
Trial Type
Efficacy
Safety
Trial Length
22 to 71 days, with a 30-day screening 
period
Planned Country of Investigational Site
Australia
Planned Number of Enrolled Participants
Approximately 54
FDA-regulated Device Study
No
FDA-regulated Drug Study
Yes
Pediatric Study
No
Participant 
information
Healthy Participant Indicator
No
Planned Minimum Age of Participants
40
Planned Maximum Age of Participants
55
Sex of Participants
Both
Stable Disease Minimum Duration
Not specified
Treatments
Investigational Therapy or Treatment
AGN-190584 (pilocarpine HCl 1.25% 
ophthalmic solution)
Intervention Type
Drug
Dose per Administration
1 bilaterally
Dose Units
Drop
Dosing Frequency
Once daily
Route of Administration
Topical eyedrop
Trial design
Study Type
Interventional
Intervention Model
Crossover
Planned Number of Arms
2
Trial Is Randomized
Yes
Trial Blinding Schema
Double-masked
Adaptive Design
No
 
 
 


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10.6.
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions:
Woman of Childbearing Potential
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below).
If fertility is unclear (eg, 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, (eg, Müllerian 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.
o
A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. 
However, in the absence of 12 months of amenorrhea, confirmation with more than 
1 FSH measurement is required.

Females on HRT and whose menopausal status is in doubt will be required to use one 
of the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment.
 
 
 


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Contraception Guidance:
Female Participants
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective or acceptable method of contraception consistently and correctly as described in 
Table 10–1.
Table 10–1
Highly Effective and Acceptable 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 ovulation

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 (ie, Nexplanon®)

Bilateral tubal occlusion (eg, Essure®, bilateral tubal ligation)

Intrauterine copper contraceptive (ie, 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.
Acceptable Methods
Acceptable birth control methods that result in a failure of more than 1% per year include:

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary mode of 
action

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide

Nonhormonal intrauterine device
A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.
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. 
 
 
 


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Pregnancy Testing:

WOCBP should only be included after a confirmed menstrual period, a negative highly 
sensitive urine pregnancy test at screening, and a negative test at Visit 2.

Additional pregnancy testing should be performed at study exit, and as required locally. 

Pregnancy testing will be performed whenever a menstrual cycle is missed or when 
pregnancy is otherwise suspected.

Urine pregnancy testing will be used unless the study site requires the use of serum 
testing, in which case serum testing will be used.
Collection of Pregnancy Information
Female Participants Who Become Pregnant

The investigator will collect pregnancy information on any female participant who 
becomes pregnant while participating in this study. In the event of pregnancy, the 
investigator will notify Clinical Pharmacovigilance within 24 hours of the site being made 
aware by entering the initial information into the EDC system (RAVE®). 

Pregnancies that occur prior to the site having access to the RAVE system, or if RAVE is 
not operable, should be documented on pregnancy paper forms and emailed (preferred 
route) or faxed to Clinical Pharmacovigilance within 24 hours of the site being made 
aware of the 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 (eg, 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 poststudy 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 or be withdrawn from the study.
 
 
 


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10.7.
Appendix 7: Night-driving Experience Questionnaire
This survey asks questions about your vision during the drive that you just completed. 
For questions 1-4, please circle the choice that best describes your answer to each question.
1- I was satisfied with the quality of my vision for driving.
Very 
dissatisfied
Dissatisfied
Neither 
satisfied 
nor 
dissatisfied
Satisfied
Very 
satisfied
2- My vision did not impact my confidence in driving.
Not at all
A little
Somewhat
Very
Extremely
3- I noticed a double image around distant objects.
Never
Rarely
Some of 
the time
Most of 
the time
All of the 
time
4- I experienced visual disturbance (glare, halo, starburst) in dim 
lighting.
Never
Rarely
Some of 
the time
Most of 
the time
All of the 
time
For questions 5-12, please mark an (X) in the box that best describes your 
answer to each question.
How difficult were the following driving tasks during the drive that you just
completed?
Not 
difficult at 
all
A little 
difficult
Moderately 
difficult
Very 
difficult
Extremely 
difficult
5- Seeing hazards on the road in time to avoid them
6- Keeping in my lane 
7- Seeing pedestrians at the roadside
8- Reading the road signs 
9- Judging distances
10- Reading car gauges (eg, speedometer) without straining my 
eyes
11- Adjusting my vision when looking from the road to the 
speedometer and back
12- Overall, how difficult was it to see during the driving task?
 
 
 


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11.
References
Buckhurst PJ, Naroo SA, Davies LN, et al. Tablet App halometer for the assessment of 
dysphotopsia. J Cataract Refract Surg. 2015;41:2424-2429.
García-Lázaro S, Ferrer-Blasco T, Radhakrishnan H, Cervino A, Charman WN, Montes-Mico R. 
Visual function through 4 contact lens-based pinhole systems for presbyopia. J Cataract Refract 
Surg. 2012;38:858-865.
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.
Kimlin JA, Black AA, Wood JM. Nighttime driving in older adults: effects of glare and 
association with mesopic visual function. Invest Ophthalmol Vis Sci. 2017;58:2796-2803.
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;10:1446-1451.
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;25:847-854.
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 
Physiol Opt. 1975;52:3-21.
 
 
 


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Wood JM. Age and visual impairment decrease driving performance as measured on a 
closed-road circuit. Human Factors. 2002;44:482-494.
Wood J, Chaparro A, Carberry T, Chu B. Effect of simulated visual impairment on nighttime 
driving performance. Optom Vis Sci. 2010;87:379-386.
Wood JM, Collins MJ, Chaparro A, Marszalek R, Carberry T, Lacherez P, Chu BS. Differential 
effects of refractive blur on day and nighttime driving performance. Invest Ophthalmol Vis Sci. 
2014;55:2284-2289.
Wood J, Chaparro A, Hickson L. Interaction between visual status, driver age and distracters on 
daytime driving performance. Vision Res. 2009;49:2225-2231.
Wood JM, Marszalek R, Carberry T, Lacherez P, Collins MJ. Effects of different levels of 
refractive blur on nighttime pedestrian visibility. Invest Ophthalmol Vis Sci. 2015;56:4480-4485.
 
 
 

SAP_001.pdf: 
AGN-190584
1883-306-013– Statistical Analysis Plan
Version 1.0– 26 Jul 2021
1
Statistical Analysis Plan for Study 1883-306-013
Evaluating the Impact of AGN-190584 on Night
Driving Performance
Date:  26 Jul 2021
Version 1.0
 
NCT04837482


AGN-190584
1883-306-013– Statistical Analysis Plan
Version 1.0– 26 Jul 2021
2
Table of Contents
1.0
Introduction .............................................................................5
2.0
Study Design and Objectives..................................................5
2.1
Objectives and Hypothesis.........................................................................5
2.2
Study Design Overview .............................................................................5
2.3
Treatment Assignment and Blinding .........................................................7
2.4
Sample Size Determination........................................................................7
3.0
Endpoints..................................................................................8
3.1
Primary Endpoint.......................................................................................8
3.2
Other Efficacy Endpoints...........................................................................8
3.3
Safety Endpoints ........................................................................................8
4.0
Analysis Populations ...............................................................8
5.0
Subject Disposition..................................................................9
6.0
Study Drug Duration.............................................................10
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications ....................10
7.1
Demographics and Baseline Characteristics............................................11
7.2
Medical History .......................................................................................11
7.3
Prior and Concomitant Medications ........................................................11
7.4
Data Collected but Not Analyzed ............................................................12
8.0
Efficacy Analyses...................................................................12
8.1
General Considerations............................................................................12
8.2
Handling of Missing Data........................................................................13
8.3
Primary Efficacy Endpoint and Analyses................................................13
Primary Efficacy Endpoint ......................................................................13
Handling of Missing Data for the Primary Efficacy Endpoint ................14
Primary Efficacy Analysis .......................................................................14
Additional Analyses of the Primary Efficacy Endpoint...........................15
8.4
Other Efficacy Analyses ..........................................................................15
8.5
Efficacy Subgroup Analyses....................................................................17
9.0
Safety Analyses ......................................................................17
9.1
General Considerations............................................................................17
 
 
 
 
 


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9.2
Adverse Events ........................................................................................17
Treatment-Emergent Adverse Events ......................................................18
Adverse Event Overview .........................................................................18
Treatment-Emergent Adverse Events by SOC and/or PT .......................19
SAEs (Including Deaths) and Adverse Events Leading to Study 
Drug Discontinuation...............................................................................19
Adverse Events of Special Interest ..........................................................19
9.3
Vital Signs................................................................................................20
9.4
Pregnancy.................................................................................................20
9.5
Ocular Safety Analyses............................................................................20
Slit-lamp Biomicroscopy and Ophthalmoscopy ......................................20
Mesopic and Photopic Binocular HDVA ................................................20
Intraocular Pressure .................................................................................21
10.0
Interim Analyses....................................................................21
10.1
Data Monitoring Committee....................................................................21
11.0
Overall Type-I Error Control ..............................................21
12.0
Version History......................................................................22
13.0
References...............................................................................22
14.0
Appendices .............................................................................23
Appendix A.
Protocol Deviations..................................................................................23
Appendix B.
Definition of Adverse Events of Special Interest (if applicable)............24
Appendix C.
List of Abbreviations ...............................................................................25
Appendix D.
Changes to Protocol-planned Analyses ...................................................26
List of Tables
Table 4-1
Definition of the Control Period ................................................................9
Table 8-1
Other Effectiveness Analyses ..................................................................16
Table 14-1
List of Preferred Terms for AEs of Special Interest1...............................24
 
 
 
 
 
 
 
 
 


AGN-190584
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List of Figures
Figure 2-1
Study Schema.............................................................................................7
 


AGN-190584
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Version 1.0– 26 Jul 2021
5
1.0
Introduction
This Statistical Analysis Plan (SAP) provides a technical and detailed elaboration of the 
statistical analyses of the efficacy and safety data as outlined and specified in protocol
amendment 1 for Study 1883-306-013 (approved on 15-Apr-2021). 
The SAP will not be updated in case of administrative changes or amendments to the 
protocol unless the changes impact the analysis.
Unless noted otherwise, all analyses will be performed using SAS version 9.4 (SAS 
Institute Inc, Cary, NC 27513) or later. 
2.0
Study Design and Objectives
2.1
Objectives and Hypothesis
The objectives are:

To evaluate night-driving performance in real-world driving conditions in 
participants with presbyopia treated with AGN-190584 versus vehicle

To evaluate safety in participants with presbyopia treated with AGN-190584 
versus vehicle
The primary efficacy endpoint is overall composite driving performance Z score 
approximately 1 hour after study intervention instillation. The null and alternative 
hypotheses for the primary efficacy endpoint are:

H0: The difference in mean overall composite driving performance Z score 
between AGN-190584 and vehicle (AGN-190584 minus vehicle) is < -0.25.

HA: The difference in mean overall composite driving performance Z score 
between AGN-190584 and vehicle (AGN-190584 minus vehicle) is ≥ -0.25.
2.2
Study Design Overview
This is a single-center, randomized, double-masked, crossover, Phase 3b study evaluating 
the effect of AGN-190584 compared with vehicle when dosed in both eyes on driving 
 


AGN-190584
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6
performance under real-world, night-lighting conditions in participants with objective and 
subjective evidence of presbyopia.
The study consists of 5 visits (screening [Visit 1], randomization/first dosing [Visit 2], 
first driving [Visit 3], second dosing [Visit 4], and second driving [Visit 5] visits) with a 
crossover of AGN-190584 and vehicle. There will be a 7- to 14-day study intervention 
adaptation period before each driving visit (Visits 3 and 5) and a 7- to 42-day washout 
period between Visits 3 and 4. Participants will require transport to and from both driving
visits.
Approximately 54 participants will be enrolled at one study site (Queensland University 
of Technology, Australia) and approximately 40 participants are expected to complete the 
study based on an anticipated dropout rate of 25% or less. Participants who prematurely 
discontinue from the study will not be replaced.
The dosing regimen and schedule for this study are as follows:
Study intervention sequence
Visit 2 through Visit 3
Washout Period
Visit 4 through Visit 5
Sequence 1
AGN-190584
Vehicle
Sequence 2
Vehicle
AGN-190584
 


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7
The schema of the study is shown in Figure 2-1.
Figure 2-1
Study Schema
2.3
Treatment Assignment and Blinding
Participants will be randomized to the following study intervention sequences in a 1:1
ratio:

AGN-190584 followed by vehicle 

vehicle followed by AGN-190584
The identity of study intervention will be masked to the participants and the study center.
2.4
Sample Size Determination
The sample size calculation is based on the primary efficacy endpoint. Assuming no 
difference between treatment groups and variance of 0.11, approximately 40 participants 
will be required to obtain 90% power for a 1-sided noninferiority test with type 1 error of 
0.025 and noninferiority margin of -0.25 units in mean overall composite driving 
performance Z score. Therefore, approximately 54 participants will be enrolled to achieve 
40 participants completing the study assuming an anticipated dropout rate of 25% or less.
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 
 
 
 
  
  
 
 
 
  
  
 
 
 
 
 
  
 
 
 
 


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3.0
Endpoints
3.1
Primary Endpoint
Primary efficacy endpoint is overall composite driving performance Z score 
approximately 1 hour after study intervention instillation.
3.2
Other Efficacy Endpoints

Hazard avoidance

Road sign recognition

Road sign recognition distance

Pedestrian recognition distance

Lane keeping

Driving time

Pupil diameter

Halometer

Night-driving experience questionnaire 
3.3
Safety Endpoints

Mesopic/photopic habitual distance visual acuity (HDVA)

Adverse events (AEs)

Pregnancy tests for women of childbearing potential (WOCBP)

Slit-lamp biomicroscopy

Intraocular pressure (IOP) measurements
4.0
Analysis Populations
The following populations are defined:
 


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Population
Description
Intent-to-Treat (ITT)
The ITT population includes all randomized participants.
Safety
The safety population includes all treated participants who
receive ≥ 1 administration of study intervention.
For analyses based on the ITT population, participants will be summarized according to 
the randomized study intervention. For analyses based on the Safety population, 
participants will be summarized according to the study intervention they actually receive
in each period.
Also, only statistical analyses of safety will be performed by study period as defined in 
Table 4-1.  
Table 4-1
Definition of the Control Period 
Period
Start Date
End Date
Period 1
Date of the first 
dose at Visit 2
For participants who do not receive the treatment at 
Visit 4: the end date is the study exit date.  
For participants who receive the treatment at Visit 4: the 
end date is the date when the treatment is received at 
Visit 4 minus 1 day.
Period 2
Dose date at Visit 4
Study exit date
5.0
Subject Disposition
The total number of participants who were screened, enrolled (randomized), and treated 
will be summarized.  Reasons for exclusion, including screen failure, will be summarized.
A summary of participant accountability will be provided where the number of 
participants in each of the following categories will be summarized for each intervention
group:
●
participants randomized in the study;
●
participants who took at least one dose of study drug;
 


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●
participants who completed protocol-specified treatment;
●
participants who prematurely discontinued study drug and reasons for 
discontinuation;
●
participants in each analysis population, as applicable.
Participant disposition will be summarized by study intervention sequence for the entire 
study and for Period 1 and Period 2.
6.0
Study Drug Duration
For the safety population, duration of treatment will be summarized by study intervention
group.  Duration of treatment for each intervention group is defined for each participant as 
the duration of treatment in Period 1 or Period 2, last dose date minus first dose date in 
each period +1. Duration of treatment will be summarized using the number of 
participants treated, mean, standard deviation, median, minimum and maximum.  In 
addition, the number and percentage of participants in each treatment duration interval (1 
to 7, 8 to 15, and > 15 days) will be summarized by study intervention group.
7.0
Demographics, Baseline Characteristics, Medical 
History, and Prior/Concomitant Medications
Demographics, medical history, ophthalmic history and prior and concomitant 
medications will be summarized by study intervention sequence and in total (e.g., across 
study intervention sequence) for the ITT population.  Categorical variables will be 
summarized with the number and percentage of participants; percentages will be 
calculated based on the number of non-missing observations.  Continuous variables will 
be summarized with descriptive statistics (number of non-missing observations, mean and 
standard deviation, median, minimum and maximum).
 


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7.1
Demographics and Baseline Characteristics
Continuous demographic variables include age, weight, height, and body mass index 
(BMI). Categorical demographic variables include sex, ethnicity, race and age (<=50 and 
> 50 years) when applicable
Demographic parameters will be summarized descriptively by study intervention 
sequence and in total for the ITT population.  Age is calculated from birthdate to the
informed consent date in years.
Corrected distance visual acuity (CDVA) and distance-corrected near visual acuity 
(DCNVA) at baseline will be summarized descriptively by study intervention sequence 
and in total for the ITT population.
7.2
Medical History
Medical and ophthalmic history data will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) dictionary. The actual version of the MedDRA coding 
dictionary will be noted in the statistical tables and clinical study report.
The number and percentage of participants in each medical history category (by MedDRA 
system organ class and preferred term) will be summarized in total and by study 
intervention sequence.  The system organ class (SOC) will be presented in alphabetical 
order, and the preferred terms will be presented in alphabetical order within each SOC.  
Participants reporting more than one condition/diagnosis will be counted only once in 
each row (SOC or preferred term).
Ophthalmic history will be summarized similarly. Medical and ophthalmic histories
include medical condition prior to Day 1 baseline visit, whether ongoing or resolved.
7.3
Prior and Concomitant Medications
Prior and concomitant medications will be summarized by generic name.  A prior 
medication is defined as any medication taken prior to the date of the first dose of study 
 


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drug.  A concomitant medication is defined as any medication that started prior to the date 
of the first dose of study drug and continued to be taken after the first dose of study drug 
or any medication that started on or after the date of the first dose of study drug.  The 
number and percentage of participants taking medications will be summarized by generic 
drug name based on the World Health Organization (WHO) Drug Dictionary for both 
prior and concomitant medications. 
The number and percentage of participants reporting prior medications will be 
summarized by drug generic name in total and by study intervention sequence. If a 
participant took a specific medication multiple times or took multiple medication within 
the same generic name, the participant will be counted only once for the generic name.
The number and percentage of participants reporting concomitant medications will be 
summarized by drug generic name by study intervention group. The listings will be 
provided for prior and concomitant medications.
7.4
Data Collected but Not Analyzed
Iris color assessment, vital signs, ocular surface disease index, National Eye Institute 
Visual Function questionnaire 25, fluorescein corneal stain, gonioscopy/angle assessment, 
binocular mesopic and photopic high contrast, BCDVA and DCNVA assessments, 
manifest refraction and dilated fundoscopic examination results are collected only at 
Screening and will not be analyzed. Any clinically significant vital sign findings or 
abnormal pupil dilation findings will be captured as an adverse event and summarized 
accordingly.
8.0
Efficacy Analyses
8.1
General Considerations

The primary analysis will be performed after the database is locked and 
randomization schedule is released.

Efficacy endpoints will be analyzed using the ITT population. The 95% 
confidence intervals will be provided for the primary endpoint.
 


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
Baseline for efficacy is defined as the last nonmissing efficacy assessment before 
the first dose of study intervention in each period or randomization if no study 
drug is given when applicable.

Continuous variables will be summarized by number of participants with observed 
values (n), mean, standard deviation, median, 1st and 3rd quartiles, minimum, and 
maximum.

Categorical variables will be summarized by number of participants with observed 
values (n), frequency counts (n1) and percent of participants with observed values.
8.2
Handling of Missing Data
Missing continuous and categorical efficacy data will be analyzed based on observed data. 
Missing values will be not imputed.
8.3
Primary Efficacy Endpoint and Analyses
Primary Efficacy Endpoint
The night-driving evaluation will be performed approximately 1 hour following study 
intervention instillation at both driving visits.
The overall composite driving performance Z score for a participant is calculated using 
the average of Z scores for the following component driving measures: percent hazards 
hit, percent sign recognition and recognition distance, pedestrian recognition distance, lap 
duration and percent of time outside of the lane (lane-keeping).
A participant’s Z score for a given component driving measure is calculated using the 
mean and standard deviation from the pooled treatment data. Since a lower percent of 
hazards hit, lower percentage of time outside of the lane and a shorter lap duration is 
indicative of better performance, the Z scores of these three components are reversed 
(e.g., -1 x Z score) before computing the overall driving Z score.
The primary efficacy endpoint is overall composite driving performance Z score 
approximately 1 hour after study intervention instillation.
 
 


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Handling of Missing Data for the Primary Efficacy Endpoint
For primary analysis, the missing data will be handled using a MMRM model with the 
missing at random (MAR) assumption, in which both missingness of data and the 
correlation of the repeated measurements will be considered. 
Primary Efficacy Analysis
Primary efficacy endpoint (overall composite driving performance Z score approximately 
1 hour after study intervention instillation) will be analyzed using a linear mixed-effects 
model with repeated measures (MMRM). 
The model will use overall composite driving performance Z score approximately 1 hour 
after study intervention instillation as dependent variable, include study intervention 
group (AGN-190584, vehicle), study intervention sequence (Sequence 1: AGN-190584 
followed by vehicle, Sequence 2: vehicle followed by AGN-190584), and study period
(Period 1, Period 2) as fixed effects and participant nested within sequence of testing as a 
random effect. The covariance structure to model the within-participant correlation error 
structure will be unstructured. If the unstructured covariance matrix results in a lack of 
convergence, compound symmetry covariance structure will be used. The Kenward-Roger 
method will be used to estimate the denominator degrees of freedom. 
The least-square (LS) mean and 95% CI will be provided for each study intervention 
(AGN-190584, or vehicle) in overall composite driving performance driving Z score. 
The comparison between the two study interventions (AGN-190584 vs. vehicle) will be 
performed by providing LS mean and 95% CI for the between-group difference in the 
overall composite driving performance Z score. Noninferiority of AGN-190584 will be 
concluded if the lower bound of the 95% CI of the least square mean difference between 
AGN-190584 and vehicle is greater than -0.25.
 
 
 


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Additional Analyses of the Primary Efficacy Endpoint
The primary endpoint will also be summarized by descriptive statistics. The observed data 
will be used, and no imputation will be performed. 
8.4
Other Efficacy Analyses
The other effectiveness analyses will be performed using the ITT population for all 
variables listed in Table 8-1
The continuous efficacy endpoints will be summarized by descriptive statistics. The 
number and percentage of participants reporting each response will be provided for the 12 
questions in the night-driving experience questionnaire. The denominator will be the 
number of the participants with a non-missing response for the specific question. The 
results will be presented by study intervention group. The results for “AGN-190584” 
group will be based on Period 1 data for study intervention sequence “AGN-190584 
followed by vehicle”, and Period 2 data for study intervention sequence “vehicle followed 
by AGN-190584”.  The results for “vehicle” group will be based on Period 2 data for 
study intervention sequence “AGN-190584 followed by vehicle”, and Period 1 data for 
study intervention sequence “vehicle followed by AGN-190584”.
The other efficacy analysis results will be deemed supportive. No hypotheses will be 
tested on the other efficacy endpoints, and no multiplicity adjustment will be performed. 
 
 


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Table 8-1
Other Effectiveness Analyses
Endpoint
Description
Derivation
Methodology
Hazard avoidance
Percentage of hazards hit for each 
participant
Calculated from the reported total number of 
hazards and the number of hazards hit.
Continuous 
descriptive statistics
Sign recognition 
Percentage of sign recognition for each 
participant
Calculated from the reported total number of 
signs and the number of signs correctly 
identified
Continuous 
descriptive statistics
Sign recognition distance
Recognition distance in meters to one 
specific sign
Reported distance
Continuous 
descriptive statistics
Lane-keeping 
Percentage of time outside of the lane 
(lane-keeping)
Calculated post-testing from the reported 
total driving time and reported time outside 
of lane. Lane crossings where the participant 
is responding to a hazard on the road are not 
included.
Continuous 
descriptive statistics
Pedestrian recognition distance
Distance for pedestrian recognition
Reported distance
Continuous 
descriptive statistics
Driving time
The time to complete the road course
Reported time (min, sec) converted to 
seconds
Continuous 
descriptive statistics
Pupil diameter 
Measured before dosing, after dosing at 
driving test visit in each eye
Reported value
Continuous 
descriptive statistics
Halometer 
The area of the halo surrounding the 
LED glare source
Reported value
Continuous 
descriptive statistics
Night-driving experience 
questionnaire
12 questions to evaluate the
participants’ night driving experience
Reported responses to each question
Ordinal descriptive 
statistics and response 
frequencies 
 


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8.5
Efficacy Subgroup Analyses
No efficacy subgroup analyses will be performed for this study.
9.0
Safety Analyses
9.1
General Considerations

The safety endpoints will be analyzed with descriptive statistics using the safety 
population.

The safety results will be presented by study intervention group. 

The results for “AGN-190584” group will be based on Period 1 data for study 
intervention sequence “AGN-190584 followed by vehicle”, and Period 2 data for 
study intervention sequence “vehicle followed by AGN-190584”. 

The results for “vehicle” group will be based on Period 2 data for study intervention 
sequence “AGN-190584 followed by vehicle”, and Period 1 data for study 
intervention sequence “vehicle followed by AGN-190584”.

For each study period, the baseline for safety parameters will be the last assessment 
prior to the first administration of study intervention in the period unless specified 
otherwise.

For each study period, the change from baseline values will be computed as the 
postbaseline value minus the baseline value (defined above) for that study period. 

Continuous variables will be summarized by number of participants with observed 
values (n), mean, standard deviation, median, 1st and 3rd quartiles, minimum, and 
maximum.

Categorical variables will be summarized by number of participants with observed 
values (n), frequency counts (n1) and percent of participants with observed values.
9.2
Adverse Events
Adverse events (AEs) will be summarized and presented using primary MedDRA System 
Organ Classes (SOCs) and preferred terms (PTs) according to the version of the MedDRA 
coding dictionary used for the study at the time of database lock. The actual version of the 
MedDRA coding dictionary used will be noted in the AE tables and in the clinical study 
report.
 


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Treatment-Emergent Adverse Events
An AE will be considered a treatment emergent adverse events (TEAE) if the AE began 
or worsened (increased in severity or became serious) on or after the date of the first 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. Per the AE/SAE training manual, a new AE 
record will be created with a new AE onset date for any AE that worsens.  Therefore, 
TEAEs can simply be identified as those AEs with recorded onset date on or after the date 
of the first study intervention and within 30 days after the last dose of study intervention.
An AE will be considered a treatment emergent serious adverse event (TESAE) if it is a 
TEAE that additionally meets any serious adverse event (SAE) criterion.
Adverse Event Overview
Adverse events will be classified into ocular AEs and nonocular AEs. An ocular AE will
be determined as indicated on the AE form of eCRF (marked “OD” or “OS” to the 
question of “what was the location of the adverse event?”), and thus are not limited to 
AEs with primary SOCs of eyes.
An overview of AEs will be presented consisting of the number and percentage of 
participants experiencing at least one event for each of the following AE categories:
●
Any treatment-emergent AE (ocular and non-ocular)
●
Any treatment-emergent AE with reasonable possibility of being related to 
study drug according to the investigator (ocular and non-ocular)
●
Any serious treatment-emergent AE
●
Any treatment-emergent AE leading to discontinuation of study drug
●
Any treatment-emergent AE leading to death
●
Any treatment-emergent AE: headache of special interest
●
Any treatment-emergent AE: visual disturbance of special interest
●
All deaths
 
 
 


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Overall summary of TEAEs will be provided by study intervention group on a per-
participant level.
Treatment-Emergent Adverse Events by SOC and/or PT
Treatment-emergent adverse events will be summarized by SOC and PT; by maximum 
relationship to study drug as assessed by the investigator (e.g., reasonable possibility or no 
reasonable possibility) and SOC and PT; by maximum severity and SOC and PT.  
Specific adverse events will be counted once for each participant for calculating 
percentages, unless stated otherwise. In addition, if the same adverse event occurs 
multiple times within a participant, the highest severity and level of relationship to 
investigational product will be reported.
Nonocular TEAEs will also be summarized by SOC and PT. 
Ocular TEAEs will be summarized by preferred term and maximum relationship to study 
drug assessed by investigator. 
SAEs (Including Deaths) and Adverse Events Leading to 
Study Drug Discontinuation
All the SAEs (including deaths) and AEs leading to study drug discontinuation will be 
summarized by SOC and PT and presented in listing format. The listing will indicate if an 
AE is ocular or nonocular. All nonocular SAEs (including deaths) and nonocular AEs 
leading to study drug discontinuation will be summarized by SOC and PT.
Adverse Events of Special Interest
Headache of special interest and visual disturbance of special interest are the adverse 
events of special interest. List of PT for AEs of special interest is provided in Appendix B. 
The TEAEs of special interest will be summarized by study intervention group.
A similar summary will be provided for visual disturbance TEAEs of special interest. The 
definition of these adverse events of special interest is described in Appendix B. The list 
of preferred terms used for the analysis will be reviewed and finalized prior to database 
lock.
 
 
 
 


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9.3
Vital Signs
Vital signs are collected only at screening and data will not be analyzed.
9.4
Pregnancy
Positive test results for women of childbearing potential will be listed. 
9.5
Ocular Safety Analyses
Slit-lamp Biomicroscopy and Ophthalmoscopy
All biomicroscopy and ophthalmoscopy examinations findings will be coded using the
MedDRA dictionary.
The number and percentage of participants with biomicroscopy or ophthalmoscopy 
findings of greater than 1-grade severity increase from baseline for findings with a 
severity grade, or a positive status change from absence at baseline to presence at 
postbaseline (not associated with a severity grade), will be summarized by preferred term
and study intervention group. 
Mesopic and Photopic Binocular HDVA 
Binocular HDVA will be tested using logMAR charts at 4 m under 2 lighting conditions: 
mesopic luminance (10 to 11 lux) and photopic luminance (≥ 251 lux) under normal room 
lighting. Testing will be conducted with the optimal distance refractive correction. Forced 
choice letter-by-letter scoring will be used for each test and the total number of correct 
letters or the highest value (number) of the grid identified (as applicable) will be collected 
for each eye.
The total number of correct letters or the highest value (number) of the grid identified (as 
applicable) will be summarized by study intervention group, at the participant level for the 
screening test, before dosing at each driving test visit, and after dosing at each driving test 
visit for each lighting condition. The change at each driving test (post dosing assessment 
 
 
 


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minus pre dosing assessment) will also be summarized by study intervention group, at the 
participant level.
Intraocular Pressure
Intraocular pressure (IOP) will be measured for each eye, IOP change from baseline will be 
calculated for each eye and the summary will be based on the eye with greater decrease 
from baseline. 
10.0
Interim Analyses
No interim analysis is planned for this study.
10.1
Data Monitoring Committee  
Data monitoring committee is not required for this study.
11.0
Overall Type-I Error Control
There is only 1 statistical hypothesis on primary endpoint in this study. No multiplicity 
adjustment will be performed.
 
 


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12.0
Version History
SAP Version History Summary
SAP 
Version
Approval 
Date
Change
Rationale
1
Not Applicable
Original version
13.0
References
 


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14.0
Appendices
Appendix A.
Protocol Deviations
The number and percentage of subjects who reported at least one of the following 
protocol deviation categories will be provided.

Subject entered the study even though s/he did not satisfy entry criteria.

Subject developed withdrawal criteria during the study and was not withdrawn.

Subject received wrong treatment or incorrect dose of study.

Subject took prohibited concomitant medication.
 


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Appendix B.
Definition of Adverse Events of Special Interest (if applicable)
Table 14-1
List of Preferred Terms for AEs of Special Interest1
Area of Safety Interest
Preferred Term
Headache of special interest
Headache
Migraine
Migraine with aura
Sinus headache
Other PT related to headache of special interest
Visual Disturbance of Special 
Interest
Dyschromatopsia
Glare
Halo vision 
Metamorphopsia
Photophobia
Photopsia
Pseudomyopia
Vision blurred
Visual acuity reduced
Visual field defect
Visual impairment
Other PT related to vision impairment of special 
interest
1The final list of PTs to be used will be reviewed and finalized prior to database lock.
 


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Appendix C.
List of Abbreviations
Abbreviation/Term
Definition
AE
adverse event
BCDVA
distance-corrected distance visual acuity
DCNVA
distance-corrected near visual acuity
HDVA
habitual distance visual acuity
ITT
intent-to-treat
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
mixed model for repeated measures
SAE
serious adverse event
SAP
statistical analysis plan
SOC
System Organ Class
TEAE
treatment-emergent adverse event
TESAE
treatment emergent serious adverse event
WOCBP
women of childbearing potential
 


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Appendix D.
Changes to Protocol-planned Analyses
There are no changes from the protocol-planned analyses.