Clinical trial NCT04983589
Conditions: Presbyopia
Keywords: Presbyopia AGN-190584 Pilocarpine HCl 1.25% Old Eye Aged Eye
Sponsor: Allergan
Start date: 2021-09-02; Completion date: 2022-02-11
Enrollment: 230 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Currently available treatments for presbyopia (old eye) include nonsurgical options (spectacles or contact lenses) and surgical options, however, each has its own risks and limitations. The purpose of this study is to evaluate how effective AGN-190584 is in treating presbyopia compared to vehicle (placebo).

AGN-190584 is an investigational drug being developed for the treatment of presbyopia. Participants are placed in 1 of 2 groups, called treatment arms. Each group receives a different treatment. There is a 1 in 2 chance that participants will be assigned to vehicle. Around 200 participants age 40-55 years with a diagnosis of presbyopia will be enrolled in the study in approximately 20 sites in the United States.

Participants will receive AGN-190584 or vehicle in each eye twice daily for 14 days.

There may be additional procedures for participants in this trial compared to their standard of care. Participants will attend regular visits during the study at a doctor's office. The effect of the treatment will be checked by medical assessments, vision/eye tests, checking for side effects and completing questionnaires.

Detailed description:

Arms: arm 1: Participants received vehicle, one drop bilaterally (in each eye), twice daily (BID), with a gap of 6 hours between both doses, for up to 14 days. arm 2: AGN-190584 ophthalmic solution, one drop bilaterally (in each eye), BID, with a gap of 6 hours between both doses, for up to 14 days.
Interventions: intervention 1: Pilocarpine HCl intervention 2: Vehicle
Intervention descriptions: intervention 1: Pilocarpine HCl ophthalmic solution 1.25% ocular drops. intervention 2: Oxymetazoline HCl and pilocarpine HCl placebo ocular drops.

Protocol documents:
Prot_000.pdf: 


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TABLE OF CONTENTS
1
SYNOPSIS
5
2
INTRODUCTION
7
2.1
BACKGROUND AND RATIONALE
7
2.2
BENEFITS AND RISKS TO SUBJECTS
8
3
OBJECTIVES AND ENDPOINTS
8
3.1
OBJECTIVES, HYPOTHESES, AND ESTIMANDS
8
3.2
PRIMARY ENDPOINT
11
3.3
SECONDARY ENDPOINTS
11
3.4
ADDITIONAL EFFICACY ENDPOINTS
11
3.5
PHARMACOKINETIC ENDPOINTS
12
3.6
SAFETY ENDPOINTS
12
3.7
PATIENT REPORTED OUTCOMES
12
4
INVESTIGATIONAL PLAN
13
4.1
OVERALL STUDY DESIGN AND PLAN
13
4.2
DISCUSSION OF STUDY DESIGN
13
5
STUDY ACTIVITIES
14
5.1
ELIGIBILITY CRITERIA
14
5.2
CONTRACEPTION RECOMMENDATIONS
17
5.3
PROHIBITED MEDICATIONS AND THERAPY
18
5.4
PRIOR AND CONCOMITANT THERAPY
19
5.5
WITHDRAWAL OF SUBJECTS AND DISCONTINUATION OF STUDY
20
5.6
FOLLOW-UP AFTER SUBJECT DISCONTINUATION OF STUDY DRUG OR FROM STUDY
21
5.7
STUDY DRUG
21
5.8
RANDOMIZATION/DRUG ASSIGNMENT
22
5.9
PROTOCOL DEVIATIONS
23
6
SAFETY CONSIDERATIONS
23
6.1
COMPLAINTS AND ADVERSE EVENTS
23
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7
STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
27
7.1
STATISTICAL AND ANALYTICAL PLANS
27
7.2
DEFINITION FOR ANALYSIS POPULATIONS
27
7.3
HANDLING POTENTIAL INTERCURRENT EVENTS FOR THE PRIMARY AND KEY SECONDARY ENDPOINTS
27
7.4
STATISTICAL ANALYSES FOR EFFICACY
27
7.5
PHARMACOKINETIC ANALYSIS
28
7.6
STATISTICAL ANALYSES FOR SAFETY
29
7.7
OVERALL TYPE I ERROR CONTROL
29
7.8
SAMPLE SIZE DETERMINATION
30
8
ETHICS
30
8.1
INDEPENDENT ETHICS COMMITTEE/INSTITUTIONAL REVIEW BOARD (IEC/IRB)
30
8.2
ETHICAL CONDUCT OF THE STUDY
30
8.3
SUBJECT CONFIDENTIALITY
31
9
SOURCE DOCUMENTS AND CASE REPORT FORM COMPLETION
31
10 DATA QUALITY ASSURANCE
31
11 COMPLETION OF THE STUDY
31
12 REFERENCES
31
LIST OF TABLES
TABLE 1.
HYPOTHESES FOR THE PRIMARY AND THE KEY SECONDARY EFFICACY ENDPOINTS
9
TABLE 2.
SUMMARY OF THE ESTIMAND ATTRIBUTES OF THE PRIMARY AND THE KEY SECONDARY 
EFFICACY ENDPOINTS
10
TABLE 3.
STUDY DRUG IDENTIFICATION
22
LIST OF FIGURES
FIGURE 1.
STUDY SCHEMA
13
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LIST OF APPENDICES
APPENDIX A.
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
33
APPENDIX B.
RESPONSIBILITIES OF THE INVESTIGATOR
35
APPENDIX C.
LIST OF PROTOCOL SIGNATORIES
36
APPENDIX D.
ACTIVITY SCHEDULE
37
APPENDIX E.
PROTOCOL SUMMARY OF CHANGES
42
APPENDIX F.
OPERATIONS MANUAL
44
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2 INTRODUCTION
2.1 Background and Rationale
Why Is This Study Being Conducted?
The decline 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 2050.1  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 photorefractive keratectomy 
(PRK) or laser-assisted in situ keratomilieusis (LASIK), conductive keratoplasty, intraocular lenses, and 
corneal inlays. However, for each of the existing technologies mentioned above, visual quality is 
reduced at 1 or more viewing distances (near, intermediate, or distance), and each comes with its own 
unique safety risks and associated complications. For example, bifocals and progressive lenses (e.g., 
reading glasses, contacts) produce optical aberrations and can increase the risk of falls.2,3  Multifocal 
optics reduce image quality uniformly at all viewing distances. For surgical technologies, surgical risks, 
the need for repositioning and explantation, and/or regression of effect have limited their widespread 
adoption.4-6  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) contraction of the iris sphincter muscle, resulting in pupil constriction (miosis); reducing the pupil size 
has long been recognized as an effective way to increase the useful depth of focus, in part by reducing 
peripheral aberrations7, and 2) contraction of the ciliary muscle, resulting in central lens steepening and 
lens accommodation (focusing from distance to near).8
Pilocarpine ophthalmic solutions are currently used for the reduction of elevated intraocular pressure 
(IOP) in patients with open-angle glaucoma or ocular hypertension, management of acute angle-closure 
glaucoma, prevention of postoperative elevated IOP associated with laser surgery, and induction of
miosis.9  Currently the use of pilocarpine ophthalmic solution is limited by the commonly experienced 
adverse event (AE) of temporal and periorbital headache (i.e., brow ache), which is believed to be due to 
the rapidity of the ciliary muscle contraction.10  However, AbbVie (formerly Allergan) has established an 
acceptable safety profile of AGN-190584 in 3 Phase 2 clinical studies (Studies 199201-007, 199201-009, 
and 199201-010) and 2 Phase 3 studies (1883-301-013 and 1883-302-013). 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 
clinical studies were generally low and safety parameters were not clinically significant between subjects 
who received AGN-190584 compared to subjects who received vehicle or a combination therapy. The 
majority of AEs reported in any treatment group were mild to moderate in severity. More detailed 
information regarding clinical safety findings, clinical efficacy findings, chemistry, and pharmacology is 
provided in the Investigator's Brochure (IB).
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2.2 Benefits and Risks to Subjects
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 environment3, and multifocal 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 subjects have difficulty adjusting to using them.2,3  As a result, AbbVie is developing a 
noninvasive, reversible, pharmacological treatment for presbyopia.
More detailed information about the known and expected benefits and risks and reasonably expected 
AEs of AGN-190584 may be found in the IB.
Considering the Coronavirus Disease - 2019 (COVID-19) pandemic, the benefits and risks to subjects 
participating in this study have been evaluated. Based on the limited information to date, no additional 
risk to study subjects is anticipated with the use of AGN-190584; however, the risk of study activity 
participation should be evaluated by the investigator.
3 OBJECTIVES AND ENDPOINTS
3.1 Objectives, Hypotheses, and Estimands
Objectives
The primary objective of this study is to evaluate the safety, efficacy, and pharmacokinetics of 
AGN-190584 when administered bilaterally, twice daily for 14 days in subjects with presbyopia.
Hypotheses
The clinical hypotheses are that AGN-190584 ophthalmic solution dosed bilaterally, twice daily (Hour 0 
and Hour 6) for 14 days will demonstrate a significant improvement in distance-corrected near visual 
acuity (DCNVA) over vehicle after the second dose, and AGN-190584 ophthalmic solution dosed 
bilaterally, twice daily for 14 days will demonstrate an acceptable safety and tolerability profile.
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Table 1.
Hypotheses for the Primary and the Key Secondary Efficacy Endpoints
Hypothesis 
Efficacy Endpoints
H1
Primary: The proportion of subjects gaining 3 lines or more in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the same 
refractive correction at Day 14, Hour 9 (3 hours after the second dose)
H2
Key Secondary: The proportion of subjects gaining 3 lines or more in photopic, 
high-contrast, binocular DCNVA with no more than 5-letter loss in photopic CDVA 
with the same refractive correction at Day 14, Hour 9 (3 hours after the second dose)
DCNVA = distance-corrected near visual acuity; CDVA = corrected distance visual acuity
Estimands
Estimand attributes are described in Table 2. 
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Table 2.
Summary of the Estimand Attributes of the Primary and the Key Secondary Efficacy Endpoints
Estimand Label
Attributes of the Estimand
Treatment
Endpoint
Population
Handling of 
Intercurrent Events
Statistical Summary
Estimand for the 
primary endpoint
AGN-190584 
or vehicle
The proportion of subjects 
gaining 3 lines or more in 
mesopic, high-contrast, 
binocular DCNVA with no 
more than 5-letter loss in 
mesopic CDVA with the 
same refractive correction 
at Day 14, Hour 9 (3 hours 
after the second dose)
ITT 
The composite 
strategy will be 
applied to handle 
the intercurrent 
events. Missing 
data will be 
regarded as a 
nonresponder for 
the primary 
endpoint.
The difference and the corresponding 95% 
confidence interval in the proportion of subjects 
gaining 3 lines or more in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in 
mesopic CDVA with the same refractive correction
at Day 14, Hour 9 between AGN-190584 and 
vehicle.
Estimand for the key 
secondary endpoint
AGN-190584 
or vehicle
The proportion of subjects 
gaining 3 lines or more in 
photopic, high-contrast, 
binocular DCNVA with no 
more than 5-letter loss in 
photopic CDVA with the 
same refractive correction 
at Day 14, Hour 9 (3 hours 
after the second dose)
ITT 
The composite 
strategy will be 
applied to handle 
the intercurrent 
events. Missing 
data will be 
regarded as a 
nonresponder for 
the key secondary 
endpoint.
The difference and the corresponding 95% 
confidence interval in the proportion of subjects 
gaining 3 lines or more in photopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in 
photopic CDVA with the same refractive correction
at Day 14, Hour 9 between AGN-190584 and 
vehicle. 
DCNVA = distance-corrected near visual acuity; CDVA = corrected distance visual acuity; ITT = intent to treat
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3.2 Primary Endpoint
The primary endpoint is the proportion of subjects gaining 3 lines or more in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the same refractive correction at 
Day 14, Hour 9 (3 hours after the second dose).
3.3 Secondary Endpoints
Key Secondary Endpoint
1.
Proportion of subjects gaining 3 lines or more in photopic, high-contrast, binocular DCNVA with 
no more than 5-letter loss in photopic CDVA with the same refractive correction at Day 14, 
Hour 9 (3 hours after the second dose)
Supportive Secondary Endpoints
1.
Proportion of subjects gaining 2 lines or more in mesopic, high-contrast, binocular DCNVA with 
no more than 5-letter loss in mesopic CDVA with the same refractive correction at Day 14, 
Hour 9 (3 hours after the second dose)
2.
Proportion of subjects achieving 20/40 or better in mesopic, high-contrast, binocular DCNVA 
with no more than 5-letter loss in mesopic CDVA with the same refractive correction at Day 14, 
Hour 9 (3 hours after the second dose)
3.4 Additional Efficacy Endpoints
1.
Change from baseline in mesopic Near Vision Presbyopia Task-based Questionnaire (NVPTQ) 
Performance score at Day 14, Hour 9 (3 hours after the second dose)
2.
Change from baseline in Presbyopia Impact and Coping Questionnaire (PICQ) Coping score at 
Day 14, Hour 3 
3.
Change from baseline in Visual Function Assessment application (VFA app) at Day 14, Hour 9 
(3 hours after the second dose) 

Change from baseline in average number of blinks per minute 

Change from baseline in median working distance (centimeters)

Change from baseline in median magnification level (%) from the original size

Change from baseline in reading speed (words per minute)

Change from baseline in median contrast level (%) based on the original value
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3.5 Pharmacokinetic Endpoints
Blood samples for the quantitation of AGN-190584 in subject's plasma will be collected from 
approximately 10% of enrolled subjects at selected sites.
3.6 Safety Endpoints
The safety measurements will include AE, vital signs (blood pressure and heart rate), mesopic and 
photopic, high-contrast, binocular CDVA, IOP, slit-lamp biomicroscopy, manifest refraction, dilated 
fundoscopic examination, postdose tolerability assessment, drop comfort questionnaire, and pregnancy 
test.
3.7 Patient Reported Outcomes
Patient-reported outcome (PRO) questionnaires are administered in this study. The VFA app should be 
administered as well.
At screening, subjects will answer questions on vision functioning and health-related quality of life using 
the NEI VFQ-25, including the near vision subscale items (Questions A3 to A5) from the Appendix of 
Optional Additional Questions.
Subjects will also complete the Ocular Surface Disease Index (OSDI) at screening, which assesses 
symptoms of ocular irritation and their impact on vision-related functioning.
Each subject will also perform 4 paper-based near vision reading tasks under mesopic conditions.
Subjects will subsequently rate their vision-related reading ability and satisfaction with their vision-
related reading ability by completing the NVPTQ.
Subjects will also answer questions assessing the impact of presbyopia on their life and need for 
compensatory coping mechanisms using the PICQ.
Subjects will also answer single-item questions on their overall global impression of status (PGIS) and 
their overall global impression of change (PGIC). 
After study drug administration, subjects will complete the Drop Comfort Questionnaire to evaluate 
comfort of the study drug after administration.
Finally, the VFA app will be used to assess the subject's ability to read on electronic devices.
For questionnaires completed on an electronic platform, if technical issues prevent the questionnaire 
from being completed, responses can be written down on source documents (preferably a paper copy of 
the questionnaire if available) and entered when the electronic platform is available.
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4 INVESTIGATIONAL PLAN
4.1 Overall Study Design and Plan
This is a Phase 3, multicenter, double-masked, parallel-group, vehicle-controlled study in subjects with 
presbyopia. Subjects will receive AGN-190584 or vehicle dosed twice daily, bilaterally, for 14 days. 
Approximately 200 subjects with presbyopia will be enrolled at approximately 20 sites in the United 
States.
The study consists of the following visits: screening (Days -30 to -1), Day 1 (baseline), Day 7 (± 2 days), 
and Day 14 (± 2 days). A study schema is shown in Figure 1. Subjects will receive either AGN-190584 or 
vehicle dosed twice daily, bilaterally, for 14 days beginning on Day 1. On nonvisit days, subjects will be 
instructed to instill one drop of the dispensed study drug in each eye twice daily, with each dose 
administered 6 hours apart. On visit days, study drug will be instilled bilaterally by designated site 
personnel at Hour 0 (8 AM ± 1 hour) and Hour 6 (time measured 6 hours from the time of completion of 
the Hour 0 study drug administration). Study procedures on visit days are provided in the Activity 
Schedule (Appendix D) and further guidance regarding study procedures are located in the Operations 
Manual (Appendix F). 
Adult subjects 40 to 55 years of age with objective and subjective evidence of presbyopia will be 
enrolled. See Section 5 for information regarding eligibility criteria.
Figure 1.
Study Schema
At selected sites, blood will be collected for pharmacokinetic (PK) on Days 1 and 14 at Hours 0, 0.25, 0.5, 1, 3, 6 [pre-dose], 6.25, 
6.5, 7, 9, 12
4.2 Discussion of Study Design
Choice of Control Group
A vehicle control group is a recognized comparative evaluator of safety and efficacy in clinical trials.
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Screening 
-30 to -1 
!visit # : 
1 
2 
3 
AGN-190584 BID OU, n: 100 
--, 
l_! Vehicle BID OU, n= 100 
[Hour(,ID 1, 3, @ 7, 9 
0 
Dosing Timepoints, done 
in office during visits 


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Appropriateness of Measurements
Standard statistical, PK, and clinical procedures will be used in this study. All efficacy and safety-related 
measurements in this study are commonly used for assessing presbyopia. All clinical procedures in this 
study are standard and generally accepted.
Suitability of Subject Population
The study population will include male and female adults 40 to 55 years of age with objective and 
subjective evidence of presbyopia. Subjects with any evidence of ocular conditions that could affect the 
safety of the subject or interpretation of efficacy parameters will not be enrolled.
Selection of Doses in the Study
The dose selection in this study is based on modeling and the analysis of safety and efficacy data from 
Phase 2 Studies 1991201-007, 199201-009, 199201-010 and Phase 3 Studies 1883-301-013 and 
1883-302-013. AGN-190584 (pilocarpine hydrochloride) 1.25% is expected to be efficacious with an 
acceptable safety profile.
5 STUDY ACTIVITIES
5.1 Eligibility Criteria
Subjects must meet all of the following criteria in order to be included in the study. Anything other than 
a positive response to the questions below will result in exclusion from study participation.
Consent
1. Subjects must voluntarily sign and date an informed consent, approved by an independent 
ethics committee (IEC)/institutional review board (IRB), prior to the initiation of any screening or 
study-specific procedures.
Demographic and Laboratory Assessments
2. Adult male or female, 40 to 55 years of age inclusive at the time of the screening visit
3. Are willing and able to comply with procedures required in this protocol.
Disease/Condition Activity
4. Subject meets the following ocular conditions:

Subjective complaints of poor near vision that impact activities of daily living, as defined by 
at least a moderate impact (score ≥ 3) on at least 1 question on the 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

Best cycloplegic distance correction at screening in the range of spherical -4.00 D to +1.00 D 
inclusively and cylinder ≤ ±2.00 D with photopic, high-contrast binocular CDVA of 20/25 or 
better at the screening and baseline visits
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
Photopic, high-contrast binocular CDVA of 20/32 or better by habitual monofocal correction 
(either spectacles or contact lenses), or willing to wear new monofocal correction spectacles 
to achieve photopic, high-contrast CDVA of 20/32 or better during the study

Mesopic, high-contrast binocular DCNVA of 20/40 (J3) to 20/100 (J10) at the screening and 
baseline visits

Photopic, high-contrast, near visual acuity correctable to 20/40 (J3+) or better in each eye at 
the screening visit

Mesopic pupil diameter < 8.0 mm in both eyes at the screening visit
5. Subject does not meet any of the following ocular conditions:

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

Corneal abnormalities (including keratoconus, corneal scar, Fuchs' endothelial dystrophy, 
guttata, or edema) in either eye that are likely to interfere with visual acuity

Narrow iridocorneal angles (Shaffer grade ≤ 2 or lower on gonioscopy examination), history 
of angle-closure glaucoma, or previous iridotomy

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

Lens opacity in either eye that is determined to cause significant disturbance of the central 
visual axis on screening biomicroscopy

Diagnosis of any type of glaucoma or ocular hypertension

Bifocal or multifocal spectacles or contact lenses for habitual correction. Subjects willing to 
wear study-provided monofocal correction (either spectacles or contact lenses) during the 
study can be enrolled.

Had cataract surgery, phakic intraocular lens surgery, corneal inlay surgery, radial 
keratotomy, or any intraocular surgery. However, subjects with history of PRK or LASIK with 
CDVA meeting inclusion criteria will be allowed to enroll.

Presence of any ocular condition that, in the opinion of the investigator, could affect the 
safety of the subject or interpretation of efficacy parameters (e.g., uveitis, retinal 
detachment)

Concurrent use of temporary or permanent punctal plugs or history of punctal cautery in 
one or both eyes
Subject History
6. No history of the following:

Uncontrolled systemic disease

Any clinical condition or previous surgery that might affect the absorption, distribution, 
biotransformation, or excretion of AGN-190584
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
A condition or a situation that, in the investigator's opinion, may put the subject at 
significant risk, may confound the study results, or may interfere significantly with 
the subject's participation in the study

Abnormal or clinically significant results according to the investigator or designee, on 
physical/ophthalmic examination or medical history

clinically significant (per investigator's judgment) drug or alcohol abuse within the last 
6 months

clinically significant medical conditions/disease state or any other reason that the 
investigator determines would interfere with the subject's participation in this study or 
would make the subject an unsuitable candidate to receive the study drug

allergic reaction or significant sensitivity to constituents of the study drug (and its 
excipients) and/or other products in the same class (cholinergic agonist)
7. No known active severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. If 
a subject has signs/symptoms suggestive of SARS-CoV-2 infection, the subject must have a 
negative molecular (e.g., polymerase chain reaction [PCR]) test result. Subjects who do not 
meet SARS-CoV-2 infection eligibility criteria must be screen failed, and may only rescreen after 
they meet the following SARS-CoV-2 infection viral clearance criterion:
8. At least 14 days since the first PCR test result have elapsed in an asymptomatic subject or 14 
days since recovery, defined as resolution of fever without use of antipyretics and improvement 
in symptoms
Contraception
9. For all females of childbearing potential; a negative urine pregnancy test at the screening visit 
and at baseline prior to the first dose of study drug
10. Female subjects of childbearing potential must practice at least 1 protocol-specified method 
of birth control, that is effective from Study Day 1 through study exit. Female subjects of 
nonchildbearing potential do not need to use birth control.
11. Female who is not pregnant or breastfeeding, and is not considering becoming pregnant or 
donating eggs during the study or for approximately 30 days after the last dose of study drug.
Concomitant Medications
12. Subject must not use any medications that may have a substantial effect on visual function 
or the optical properties of the eye (defined in Section 5.3) at least 2 weeks prior to the first 
dose of study drug, Day 1.
13. Subject must not use any ocular medications other than the study drug or medications 
administered to conduct study procedures at the screening and Day1 (baseline) visit 
14. Subject must not have been treated with any investigational drug within 30 days or 
5 half-lives of the drug (whichever is longer) prior to the first dose of study drug, be currently 
enrolled in another clinical study, or have been previously enrolled in this study.
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15. Subject must not have enrolled in the Phase 3 AGN-190584 Studies 1883-301-013 or 
1883-302-013.
5.2 Contraception Recommendations
Contraception Requirements for Females
Subjects must follow the following contraceptive guidelines as specified:

Females, Nonchildbearing Potential
Females do not need to use birth control during or following study drug treatment if considered 
of nonchildbearing potential due to meeting any of the following criteria:
1.
Premenopausal female with permanent sterility or permanent infertility due to one of the 
following:

Permanent sterility due to a hysterectomy, bilateral salpingectomy, bilateral 
oophorectomy

Nonsurgical permanent infertility due to Mullerian agenesis, androgen insensitivity, or 
gonadal dysgenesis; investigator discretion should be applied to determining study entry 
for these individuals.
2.
Postmenopausal female

Age ≤ 55 years with no menses for 12 or more months without an alternative medical 
cause

Females, of Childbearing Potential

Females of childbearing potential must avoid pregnancy while taking study drug(s) and for 
at least 30 days after the last dose of study drug.

Females must commit to one of the following methods of birth control:

Combined (estrogen and progestogen containing) hormonal birth control (oral, 
intravaginal, transdermal, injectable) associated with inhibition of ovulation-initiated at 
least 30 days prior to study Baseline Day 1

Progestogen-only hormonal birth control (oral, injectable, implantable) associated with 
inhibition of ovulation initiated at least 30 days prior to study Baseline Day 1

Bilateral tubal occlusion/ligation (can be via hysteroscopy, provided a 
hysterosalpingogram confirms success of the procedure)

Intrauterine device

Intrauterine hormone-releasing system

Vasectomized partner (provided the partner has received medical confirmation of the 
surgical success of the vasectomy and is the sole sexual partner of the trial subject)

Practice true abstinence, defined as: refraining from heterosexual intercourse when this 
is in line with the preferred and usual lifestyle of the subject (periodic abstinence 
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[e.g., calendar, ovulation, symptothermal, post-ovulation methods] and withdrawal are 
not acceptable)

Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the 
primary mode of action, initiated at least 30 days prior to Study Day 1

Male or female condom with or without spermicide

Cap, diaphragm, or sponge with spermicide

A combination of male condom with cap, diaphragm, or sponge with spermicide 
(double-barrier method)
5.3 Prohibited Medications and Therapy
During the study, the following are prohibited.

Use of medications that may have a substantial effect on visual function or the optical 
properties of the eye is prohibited 2 weeks prior to the Day 1 visit and during the study:

Systemic medications with potential ocular side effects, including topiramate, 
hydroxychloroquine, ethambutol, phosphodiesterase 5 inhibitors (sildenafil, vardenafil, 
tadalafil), or tamoxifen

Ophthalmic, systemic, or intranasal anticholinergics and α-adrenergic receptor agonists with 
potential pupillary or accommodative effects, including oxymetazoline, tetrahydrozoline, 
phenylephrine, naphazoline, cyclopentolate, atropine

Cholinergic agonists such as pilocarpine, carbachol, and aceclidine

Alpha adrenergic antagonists including phentolamine mesylate

Tricyclic antidepressants

Use of systemic antihistamines (including those used in over-the-counter (OTC) cold and flu 
preparations) is prohibited within 3 days prior to a study visit and on visit days.

Use of selective serotonin and serotonin-norepinephrine reuptake inhibitors (SSRIs and SNRIs) is 
not prohibited if dosage is consistent for at least 30 days prior to randomization and throughout 
the study.

Use of ocular medications other than the study drug or medications administered to conduct 
study procedures is 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 
subject as the primary consideration. When possible, AbbVie should be notified before the prohibited 
medication/treatment is administered.
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5.4 Prior and Concomitant Therapy
Any medication or vaccine (including OTC or prescription medicines, vitamins, and/or herbal 
supplements) that the subject is receiving at the time of enrollment or receives during the study must be 
recorded through study exit.
Any questions regarding concomitant or prior therapy should be raised to the AbbVie emergency 
contact. Information regarding potential drug interactions with AGN-190584 can be located in the 
AGN-190584 IB.
Subjects must be able to safely discontinue any prohibited medications as described in the Eligibility 
Criteria (Section 5.1) and Prohibited Medications and Therapy (Section 5.3). Subjects must be consented 
for the study prior to discontinuing any prohibited medications for the purpose of meeting study 
eligibility.
COVID-19 Pandemic-related Vaccination Guidance
Given the ongoing COVID-19 pandemic, selected vaccines (e.g., messenger ribonucleic acid, 
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 subject.
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 AGN-190584, when possible, is preferred to be given at least ± 14 days from the
final SARS-CoV-2 vaccine administration.
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 subjects 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 electronic case 
report form. Refer to the Operations Manual for instructions on reporting any AEs associated with the 
COVID-19 vaccine.
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5.5 Withdrawal of Subjects and Discontinuation of Study
A subject may voluntarily withdraw or be withdrawn from the study at any time for reasons including, 
but not limited to, the following:

Clinically significant AEs, which rule out continuation of the study drug, as determined by the 
investigator or the AbbVie Therapeutic Area Medical Director

The investigator believes it is in the best interest of the subject.

The subject requests withdrawal from the study.

Eligibility criteria violation was noted after the subject started study drug and continuation of 
the study drug would place the subject at risk.

Introduction of prohibited medications or dosages and continuation of the study drug would 
place the subject at risk.

The subject becomes pregnant while on study drug.

Subject is significantly noncompliant with study procedures, which would put the subject at risk 
for continued participation in the trial.
For subjects to be considered lost to follow-up, reasonable attempts must be made to obtain 
information on the subject's final status. At a minimum, 2 telephone calls must be made and 1 certified 
letter must be sent and documented in the subject's source documentation.
AbbVie may terminate this study prematurely, either in its entirety or at any site. The investigator may 
also stop the study at his/her site if he/she has safety concerns. If AbbVie terminates the study for 
safety reasons, AbbVie will promptly notify the investigator.
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 subject safety and continuity of care. Acceptable mitigation strategies are 
identified and included in the Operations Manual in Appendix F.
The investigator should contact the sponsor medical contact before discontinuing a subject from the 
study for a reason other than described in the protocol to ensure all acceptable mitigation steps have 
been explored.
Interruption/Discontinuation of Study Drug Due to COVID-19 Infection
During the study drug dosing period, a subject with confirmed (viral test positive) or suspected 
COVID-19 infection will be discontinued. Follow subsequent protocol Section 5.6 for subjects who 
discontinue study drug.
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5.6 Follow-Up After Subject Discontinuation of Study Drug or from 
Study
Subjects who prematurely discontinue study drug treatment will be encouraged to stay in the study for 
safety assessments, unless subjects have decided to discontinue the study participation entirely 
(withdrawal of informed consent). Subjects should be advised on the continued scientific importance of 
their data even if they discontinue treatment with study drug early.
If a subject prematurely discontinues study participation (withdrawal of informed consent), the 
procedures outlined for the Premature Discontinuation visit should be completed as soon as possible, 
preferably within 2 weeks.
5.7 Study Drug
AGN-190584 or matching vehicle manufactured by AbbVie will be administered bilaterally twice daily 
beginning on Day 1 (Baseline) and should be taken at approximately the same time each day (6 hours 
apart). On the day before office visits, the study drug must be administered no less than 12 hours 
before the scheduled visit time. The study site personnel will document compliance and any missed 
doses should be reported to the investigator by the subject.
The subject will be instructed to return all drug containers (even if empty) to the study site personnel at 
each study visit. 
AbbVie will provide study drug for AGN-190584 or matching vehicle. AbbVie-provided study drug should 
not be substituted or alternately sourced unless otherwise directed by AbbVie.
AGN-190584 and matching vehicle will be packaged in bottles with quantities sufficient to accommodate 
the study design. Each kit will be labeled per local requirements and this label must remain affixed to 
the kit. Upon receipt, study drug should be stored as specified on the label and kept in a secure 
location. Each kit will contain a unique kit number. This kit number is assigned to a subject via 
interactive response technology (IRT) and encodes the appropriate study drug to be dispensed at the 
subject's corresponding study visit. Site staff will complete all blank spaces on the label before 
dispensing to subjects. Study drug will only be used for the conduct of this study.
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Table 3.
Study Drug Identification
Investigational Product
Investigational Product Vehicle
Investigational product name
AGN-190584
Vehicle
Active ingredient
Pilocarpine HCl 1.25%
Not applicable
Mode/Route of administration 
(ROA)
Topical eyedrop
Topical eyedrop
Formulation
Pilocarpine HCl 1.25% Ophthalmic 
Solution (011430X)
Lot T1484
Manufactured at Allergan Sales, 
LLC
Oxymetazoline HCl and Pilocarpine 
HCl Placebo Ophthalmic Solution 
(11258X)
Lot T1469
Manufactured at Allergan Sales, 
LLC
Dosage form
Topical eyedrop
Topical eyedrop
Dose and units
1 drop in each eye twice daily
1 drop in each eye twice daily
Drug preparation/packaging
Study drug will be provided in 
sterile, 5 mL bottles in a carton. 
Each bottle & carton will be labeled 
as required per country 
requirement.
Study drug will be provided in 
sterile, 5 mL bottles in a carton. 
Each bottle & carton will be labeled 
as required per country 
requirement.
Masking
Masked
Masked
Frequency of administration
Twice daily to each eye, 6 hours 
apart
Twice daily to each eye, 6 hours 
apart
Volume of study drug
3.5 mL per bottle
3.5 mL per bottle
Storage conditions
In a refrigerator, refrigerated: 2°C 
to 8°C
In a refrigerator, refrigerated: 2°C 
to 8°C
5.8 Randomization/Drug Assignment
All subjects will be assigned a unique identification number by the IRT at the screening visit. For 
subjects who rescreen, a new screening number will be assigned by the IRT. The IRT will assign a 
randomization number that will encode the subject's treatment group assignment according to the 
randomization schedule.
Subjects will be randomized in a 1:1 ratio to receive either AGN-190584 or vehicle dosed twice daily, in 
each eye, for 14 days.
Randomization will be further stratified by the following stratification factors:

Age group: ≤ 50 years and > 50 years 

Baseline binocular mesopic DCNVA severity: 20/63 or better, and worse than 20/63; with a 
maximum of 50% enrolled subjects with baseline binocular mesopic DCNVA of 20/63 or better 
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
Iris color: brown and nonbrown

Emmetrope status: emmetrope and nonemmetrope; with a maximum of 25% enrolled subjects 
with nonemmetrope. A subject will be considered as emmetrope if both eyes of the subject 
satisfy the 2 criteria: 1) -0.5D to +0.75D in sphere, inclusively; and 2) ≤ 0.75D in Cylinder.
All AbbVie personnel with direct oversight of the conduct and management of the study (with the 
exception of the AbbVie Drug Supply Management Team), the investigator, study site personnel, and the 
subject will remain masked to each subject's treatment throughout the study. To maintain the masking, 
the AGN-190584 and vehicle containers provided for the study will be identical in appearance. The IRT 
will provide access to unmasking subject treatment information in the case of a medical emergency.
5.9 Protocol Deviations
AbbVie does not allow intentional/prospective deviations from the protocol except when necessary to 
eliminate an immediate hazard to study subjects. The investigator is responsible for complying with all 
protocol requirements, written instructions, and applicable laws regarding protocol deviations. If a 
protocol deviation occurs (or is identified, including those that may be due to the COVID-19 pandemic), 
the investigator is responsible for notifying the IRB, regulatory authorities (as applicable), and AbbVie.
6 SAFETY CONSIDERATIONS
6.1 Complaints and Adverse Events
Complaints
A complaint is any written, electronic, or oral communication that alleges deficiencies related to the 
physical characteristics, identity, quality, purity, potency, durability, reliability, safety, effectiveness, or 
performance of a product/device. Complaints associated with any component of this investigational 
product must be reported to AbbVie.
Product Complaint
A product complaint is any complaint related to the biologic or drug component of the product or to the 
medical device component(s).
For a product this may include, but is not limited to, damaged/broken product or packaging, product 
appearance whose color/markings do not match the labeling, labeling discrepancies/inadequacies in the 
labeling/instructions (e.g., printing illegible), missing components/product, device damage or not 
working properly, or packaging issues.
Product complaints concerning the investigational product and/or device must be reported to AbbVie 
within 24 hours of the study site's knowledge of the event. Product complaints occurring during the 
study will be followed up to a satisfactory conclusion.
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Medical Complaints/Adverse Events and Serious Adverse Events: AGN-190584
An AE is defined as any untoward medical occurrence in a subject 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 unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not the event is considered causally related to the use of the 
product.
Such an event can result from use of the drug as stipulated in the protocol or labeling, as well as from 
"special situations" such as accidental or intentional overdose, medication error, occupational or 
accidental exposure, off-label use, drug abuse, drug misuse, or drug withdrawal, all which must be 
reported whether associated with an AE or not. Any worsening of a pre-existing condition or illness is 
considered an AE. Worsening in severity of a reported AE should be reported as a new AE. Changes in 
vital signs are considered to be AEs only if they result in discontinuation from the study, necessitate 
therapeutic medical drug, and/or if the investigator considers them to be AEs.
The investigators will monitor each subject for clinical evidence of AEs on a routine basis throughout the 
study. All AEs will be followed to a satisfactory conclusion.
An elective surgery/procedure scheduled to occur during a study will not be considered an AE if the 
surgery/procedure is being performed for a pre-existing condition and/or the surgery/procedure has 
been pre-planned prior to study entry. However, if the pre-existing condition deteriorates unexpectedly 
during the study (e.g., surgery performed earlier than planned), then the deterioration of the condition 
for which the elective surgery/procedure is being done will be considered an AE.
If an AE, whether associated with study drug or not, meets any of the following criteria, it is to be 
reported to AbbVie clinical pharmacovigilance or contract research organization (as appropriate) as a 
Serious adverse event (SAE) within 24 hours of the site being made aware of the SAE (refer to 
Section 4.3 of the Operations Manual for reporting details and contact information):
Death of Subject
An event that results in the death of a subject
Life-threatening
An event that, in the opinion of the investigator, would have 
resulted in immediate fatality if medical drug had not been taken. 
This does not include an event that would have been fatal if it had 
occurred in a more severe form.
Hospitalization or 
Prolongation of 
Hospitalization
An event that results in an admission to the hospital for any length 
of time or prolongs the subject's hospital stay. This does not include 
an emergency room visit or admission to an outpatient facility.
Congenital Anomaly
An anomaly detected at or after birth, or any anomaly that results in 
fetal loss
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Persistent or Significant 
Disability/Incapacity
An event that results in a condition that substantially interferes with 
the activities of daily living of a study subject. Disability is not 
intended to include experiences of relatively minor medical 
significance such as headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (e.g., sprained ankle).
Important Medical Event 
Requiring Medical or Surgical 
Drug to Prevent Serious 
Outcome
An important medical event that may not be immediately 
life-threatening or result in death or hospitalization but, based on 
medical judgment, may jeopardize the subject and may require 
medical or surgical drug to prevent any of the outcomes listed above 
(i.e., death of subject, life threatening, hospitalization, prolongation 
of hospitalization, congenital anomaly, or persistent or significant 
disability/incapacity). Additionally, any elective or spontaneous 
abortion or stillbirth is considered an important medical event along 
with any suspected transmission of an infectious agent via a 
medicinal product if no other serious criterion is applicable. 
Examples of such events include allergic bronchospasm requiring 
intensive treatment in an emergency room or at home, blood 
dyscrasias or convulsions that do not result in inpatient 
hospitalization, or the development of drug dependency or drug 
abuse.
All adverse events, whether solicited or spontaneously reported by the subject, will be collected from 
the time of study drug administration through study exit, unless spontaneously report after study exit. 
In addition, study procedure-related serious and nonserious adverse events will be collected from the 
time the subject signs the study-specific informed consent.
The following definitions will be used for serious adverse reaction (SAR) and suspected unexpected 
serious adverse reaction (SUSAR):
SAR
Defined as all noxious and unintended responses to an investigational medicinal 
product (IMP) related to any dose administered that result in an SAE as defined 
above
SUSAR
Refers to individual SAE case reports from clinical trials where a causal 
relationship between the SAE and the IMP was suspected by either the sponsor 
or the investigator, is unexpected (not listed in the applicable reference safety 
information), and meets one of the above serious criteria
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
requirements.
Adverse events will be monitored throughout the study to identify any of special interest that may 
indicate a trend or risk to subjects.
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Adverse Events of Special Interest
The following adverse events of special interest will be monitored during the study:

Headache

Visual disturbance
Subjects reporting a headache AE (including any AE related to headache or migraine) will be provided 
the supplemental headache AE assessment form to further assess the headache AE and grade the 
degree of severity.
Adverse Event Severity and Relationship to Study Drug
The investigators will rate the severity of each AE as mild, moderate, or severe.
The investigator will use the following definitions to rate the severity of each AE:
Mild
The adverse event is transient and easily tolerated by the subject.
Moderate
The adverse event causes the subject discomfort and interrupts the subject's 
usual activities.
Severe
The adverse event causes considerable interference with the subject's usual 
activities and may be incapacitating or life threatening.
The investigator will use the following definitions to assess the relationship of the AE to the use of study 
drug:
Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
sufficient evidence (information) to suggest a causal relationship.
No Reasonable 
Possibility
After consideration of factors including timing of the event, biologic 
plausibility, clinical judgment, and potential alternative causes, there is 
insufficient evidence (information) to suggest a causal relationship.
Pregnancy
While not an AE, pregnancy in a study subject must be reported to AbbVie within 24 hours after the site 
becomes aware of the pregnancy. Subjects who become pregnant during the study must be 
discontinued (Section 5.5). If a pregnancy occurs in a study subject or in the partner of a study subject, 
information regarding the pregnancy and the outcome will be collected.
The pregnancy outcome of an elective or spontaneous abortion, stillbirth, or congenital anomaly is 
considered an SAE and must be reported to AbbVie within 24 hours after the site becomes aware of the 
event.
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7 STATISTICAL METHODS & DETERMINATION OF SAMPLE SIZE
7.1 Statistical and Analytical Plans
The statistical methods provided in this protocol will be focused on primary and key secondary analyses. 
Complete and specific details of the statistical analysis will be described in the statistical analysis plan 
(SAP).
7.2 Definition for Analysis Populations
The intent to treat (ITT) population will consist of all randomized subjects. Subjects will be summarized 
according to the randomized study drug.
The safety population will consist of all subjects who received at least 1 administration of study drug.
Subjects will be summarized according to the study drug actually received.
The PK population will consist of all subjects with evaluable plasma concentrations of AGN-190584.
7.3 Handling Potential Intercurrent Events for the Primary and Key 
Secondary Endpoints
The following methods will be used to address potential intercurrent events for both the primary and 
key secondary endpoints:

Subjects who prematurely discontinued study drug before the Day 14 visit will be considered as 
nonresponders. 

Subjects who die before assessment of the endpoint will be considered as nonresponders for 
the endpoint.

Subjects who are lost to follow-up and are missing data for the endpoint will be considered as 
nonresponders for the endpoint. 
Missing data will be regarded as a nonresponder, for both the primary and key secondary endpoints.
7.4 Statistical Analyses for Efficacy
The efficacy analyses will be conducted on the ITT population based on treatment as randomized. 
Baseline for efficacy is defined as the last nonmissing efficacy assessment before the first dose of study 
drug or randomization if no study drug is given. All statistical tests will be 2-sided at a significance level 
of 0.05. All confidence intervals (CIs) will be 2-sided 95%.
Summary and Analysis of the Primary Endpoint
The proportion of subjects gaining 3 lines or more in mesopic, high-contrast, binocular DCNVA with no 
more than 5-letter loss in mesopic CDVA with the same refractive correction at Day 14, Hour 9 will be 
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summarized by treatment group using the ITT population. As presented in the estimand for the primary 
efficacy endpoint in Section 3.1, the composite strategy will be used to handle the intercurrent events. 
Subjects with intercurrent events prior to Day 14 Hour 9 will be considered as nonresponders for the 
primary efficacy endpoint. Subjects who have missing data for the primary efficacy endpoint will be 
categorized as nonresponders in the primary efficacy analysis.
The comparison of the proportions between AGN-190584 and Vehicle will be made using the Pearson's 
chi-square test. The treatment difference will be provided with a 2-sided 95% CI using the normal 
approximation based on the pooled variance without continuity correction. 
Summary and Analysis of Secondary Endpoints
Summary and Analysis of Key Secondary Endpoint
Similar as for the primary endpoint, the proportion of subjects gaining 3 lines or more in photopic, high-
contrast, binocular DCNVA with no more than 5-letter loss in photopic CDVA with the same refractive 
correction at Day 14, Hour 9 will be summarized by treatment group using the ITT population. As 
presented in the estimand for the key secondary efficacy endpoint in Section 3.1, the composite strategy 
will be used to handle the intercurrent events. Subjects with intercurrent events prior to Day 14 Hour 9 
will be considered as nonresponders for the key secondary efficacy endpoint. Subjects who have 
missing data for the key secondary efficacy endpoint will be categorized as nonresponders in the key 
secondary efficacy analysis.
The comparison of the proportions between AGN-190584 and vehicle will be made using the Pearson's 
chi-square test. The treatment difference will be provided with a 2-sided 95% CI using the normal 
approximation based on pooled variance without continuity correction.
Summary and Analysis of Supportive Secondary Endpoints
The supportive secondary endpoints will be analyzed using the same method as described in the analysis 
of the efficacy endpoints will be described in the SAP.
Subgroup Analysis for Efficacy
The primary and key secondary endpoints will be summarized by age group, sex, race, ethnicity, baseline 
binocular DCNVA severity, iris color, and emmetropes status.
7.5 Pharmacokinetic Analysis
Pharmacokinetic Parameters
Plasma PK parameters following the first and second doses on Day 1 and Day 14 will be calculated 
separately using standard Phoenix WinNonlin equations. PK parameters calculated after the first and 
second dose on Day 1 will include area under the concentration versus time curve from 0 to the end of 
the dosing interval (AUC0-tau), maximum observed concentration (Cmax), and time to maximum observed 
concentration (Tmax). Additionally, the observed concentration at the end of the dosing interval (Ctrough), 
and peak-to-trough ratio will be calculated after the first dose on Day 1. 
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Steady-state PK parameters calculated after the first and second dose on Day 14 will include AUC0-tau,ss, 
Cmax,ss, and Tmax,ss. Additionally, Ctrough,ss and peak-to-trough ratio will be calculated after the first dose on 
Day 14. Systemic accumulation will be assessed by calculating the accumulation index (AI) for AUC and 
Cmax on Day 14.
Additional PK parameters may be calculated, as necessary.
AUC0-tau will be calculated by using the linear-log trapezoidal rule.
Statistical Analyses of Pharmacokinetic Data
Details of the statistical analyses of PK data will be described in the PK analysis plan finalized before 
database lock.
7.6 Statistical Analyses for Safety
The safety analysis will be performed using the safety population; and subjects are assigned to a 
treatment group based on the treatment actually received, regardless of the treatment randomized.  
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or worsened 
(increased in severity or became serious) on or after the date of the first dose of study drug.
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 subjects with TEAEs during the study will be tabulated by system organ 
class and preferred term and by system organ class, preferred term, and severity.
If more than one AE is coded to the same preferred term for the same subject, the subject will be 
counted only once for that preferred term using the greatest severity and strictest causality for the 
summarizations by severity and by relationship to study drug.
Summary tables will be provided for subjects with SAEs and subjects with AEs leading to discontinuation
of study drug. Listings of all AEs, SAEs, and AEs leading to discontinuation of study drug by subject will 
be presented.
Adverse events of special interest will be summarized by treatment group and the details will be 
described in the SAP.
Detailed methods for the analysis of other safety variables will be described in the SAP.
7.7 Overall Type I Error Control
A fixed sequence testing procedure will be applied to control the overall familywise Type I error rate at 
α = 0.05 for the primary and secondary hypotheses sequentially. The hypotheses for primary endpoint 
and the secondary endpoints will be tested in a sequential order:
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
H1 Primary: The proportion of subjects gaining 3 lines or more in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the same refractive 
correction at Day 14, Hour 9 (3 hours after the second dose)

H2: Key Secondary: The proportion of subjects gaining 3 lines or more in photopic, high-
contrast, binocular DCNVA with no more than 5-letter loss in photopic CDVA with the same 
refractive correction at Day 14, Hour 9 (3 hours after the second dose)

H3 Supportive Secondary: The proportion of subjects gaining 2 lines or more in mesopic, high-
contrast, binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the same 
refractive correction at Day 14, Hour 9 (3 hours after the second dose)  

H4 Supportive Secondary: The proportion of subjects achieving 20/40 or better in mesopic, 
high-contrast, binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the same 
refractive correction at Day 14, Hour 9 (3 hours after the second dose)
If at any step a test fails, the test procedure will stop and no further hypotheses will be tested.
7.8 Sample Size Determination
The sample size calculation was considered for the primary efficacy endpoint, the response of gaining 
3 lines or more in mesopic, high-contrast, binocular DCNVA with no more than 5-letter loss in mesopic 
CDVA with the same refractive correction at Day 14, Hour 9 (3 hours after the second dose).
Assuming a responder rate of 25% in the AGN-190584 group and 7% in the vehicle group, and 5% 
dropout rate, a sample size of 100 subjects per study drug group will provide greater than 90% power 
using chi-square test at a 2-sided significance level of 5%.
8 ETHICS
8.1 Independent Ethics Committee/Institutional Review Board 
(IEC/IRB)
The protocol, informed consent form(s), recruitment materials, and all subject materials will be 
submitted to the Independent Ethics Committee/Institutional Review Board (IEC/IRB) for review and 
approval.  Approval of both the protocol and the informed consent form(s) must be obtained before any 
subject is enrolled.  Any amendment to the protocol will require review and approval by the IEC/IRB 
before the changes are implemented to the study.  In addition, all changes to the consent form(s) will be 
IEC/IRB approved.
8.2 Ethical Conduct of the Study
The study will be conducted in accordance with the protocol, Operations Manual, International Council 
for Harmonisation of Technical Requirements for Pharmaceuticals for Human Use (ICH) guidelines, 
applicable regulations, and guidelines governing clinical study conduct and the ethical principles that 
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have their origin in the Declaration of Helsinki.  Responsibilities of the investigator are specified in 
Appendix B.
In the event a significant disaster/crisis (e.g., epidemic/pandemic, natural disaster, conflict/combat) 
occurs leading to difficulties in performing protocol-specified procedures, AbbVie may engage with 
study site personnel in efforts to ensure the safety of subjects, maintain protocol compliance, and 
minimize risks to the integrity of the study while trying to best manage subject continuity of care.  This 
may include alternative methods for assessments (e.g., phone contacts or virtual site visits), alternative 
locations for data collection (e.g., use of a local lab instead of a central lab), and shipping investigational 
product and/or supplies direct to subjects to ensure continuity of treatment where allowed.  In all cases, 
these alternative measures must be allowed by local regulations and permitted by IRB/IEC.
8.3 Subject Confidentiality
To protect subjects' confidentiality, all subjects and their associated samples will be assigned numerical 
study identifiers or "codes."  No identifiable information will be provided to AbbVie.
9 SOURCE DOCUMENTS AND CASE REPORT FORM 
COMPLETION
The investigator is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the 
data reported.  All source documents should be attributable, legible, contemporaneous, original, 
accurate, and complete to ensure accurate interpretation of data.  Clinical site monitoring is conducted 
to ensure that the rights and well-being of human subjects are protected, that the reported trial data 
are accurate, complete, and verifiable, and that the conduct of the trial is in compliance with the 
currently approved protocol, ICH Good Clinical Practice (GCP), and applicable local regulatory 
requirement(s).
10
DATA QUALITY ASSURANCE
AbbVie will ensure that the clinical trial is conducted with a quality management system that will define 
quality tolerance limits in order to ensure human subject protection and reliability of study results.  Data 
will be generated, documented, and reported in compliance with the protocol, ICH GCP, and applicable 
regulatory requirements.
11
COMPLETION OF THE STUDY
The end-of-study is defined as the date of the last subject's last visit.
12
REFERENCES
1.
Holden BA, Fricke TR, Ho SM, et al. Global vision impairment due to uncorrected presbyopia. 
Arch Ophthalmol. 2008;126(12):1731-9.
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2.
Johnson L, Buckley JG, Scally AJ, et al. Multifocal spectacles increase variability in toe clearance 
and risk of tripping in the elderly. Invest Ophthalmol Vis Sci. 2007;48(4):1466-71.
3.
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(11):1760-6.
4.
Moshirfar M, Desautels JD, Wallace RT, et al. Comparison of FDA safety and efficacy data for 
KAMRA and Raindrop corneal inlays. Int J Ophthalmol. 2017;10(9):1446-51.
5.
Ruiz LA, Cepeda LM, Fuentes VC. Intrastromal correction of presbyopia using a femtosecond 
laser system. J Refract Surg. 2009;25(10):847-54.
6.
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):67-8.
7.
Tucker J, Charman WN. The depth-of-focus of the human eye for Snellen letters. Am J Optom 
Physiol Opt. 1975;52(1):3-21.
8.
Garcia-Lazaro S, Ferrer-Blasco T, Radhakrishnan H, et al. Visual function through 4 contact lens-
based pinhole systems for presbyopia. J Cataract Refract Surg. 2012;38(5):858-65.
9.
Pilocarpine hydrochloride ophthalmic solution 1%, 2%, and 4%. Fort Worth, TX; Alcon 
Laboratories, Inc., 2011.
10.
Tsai CJ, Forbes, M. Medical Management of Glaucoma. 3 ed. West Islip, New York: Professional 
Communications, Inc; 2009.
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APPENDIX A. STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
AI
accumulation index
AUC
area under the plasma concentration-time curve
AUC0-tau
area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval
AUC0-tau,ss
area under the plasma concentration-time curve from time 0 to the end of the dosing 
interval, steady state
BID
twice daily
CDVA
corrected distance visual acuity
CI
confidence interval
Cmax
maximum observed plasma concentration
Cmax,ss
maximum observed plasma concentration, steady state
COVID-19
Coronavirus Disease - 2019
Ctrough
observed plasma concentration at the end of the dosing interval
Ctrough,ss
observed plasma concentration at the end of the dosing interval, steady state
DCNVA
distance-corrected near visual acuity
GCP
Good Clinical Practice
IB
Investigator's Brochure
ICH
International Council for Harmonisation of Technical Requirements for Pharmaceuticals 
for Human Use
IEC
Independent Ethics Committee
IMP
investigational medicinal product
IRB
Institutional Review Board
IOP
intraocular pressure
IRT
interactive response technology
ITT
intent to treat
LASIK
laser-assisted in situ keratomilieusis
NEI VFQ-25
25-item National Eye Institute Visual Function Questionnaire
NVPTQ
Near Vision Presbyopia Task-based Questionnaire
OSDI
Ocular Surface Disease Index
OTC
over-the-counter
PCR
polymerase chain reaction
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PGIC
global impression of change
PGIS
global impression of status
PICQ
Presbyopia Impact and Coping Questionnaire
PK
pharmacokinetic(s)
PRK
photorefractive keratectomy
PRO
patient-reported outcome
SAE
serious adverse event
SAP
statistical analysis plan
SAR
serious adverse reaction
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
SUSAR
suspected unexpected serious adverse reactions
TEAE
treatment-emergent adverse event
Tmax
time to maximum observed concentration
Tmax,ss
time to maximum observed concentration, steady state
VFA app
Visual Function Assessment application
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APPENDIX B. RESPONSIBILITIES OF THE INVESTIGATOR
Protocol M21-195:  A Phase 3, Multicenter, Double-masked, Randomized, Vehicle-controlled, Parallel-
group Study Evaluating the Safety and Efficacy of BID Dosing of AGN-190584 in Subjects with Presbyopia
Protocol Date:  21 October 2021
Clinical research studies sponsored by AbbVie are subject to the International Council for Harmonisation 
of Technical Requirements for Pharmaceuticals for Human Use (ICH) Good Clinical Practices (GCP) and 
local regulations and guidelines governing the study at the site location.  In signing the Investigator 
Agreement, the investigator is agreeing to the following:
1.
Conducting the study in accordance with ICH GCP, the applicable regulatory requirements, 
current protocol and operations manual, and making changes to a protocol only after notifying 
AbbVie and the appropriate Institutional Review Board (IRB)/Independent Ethics Committee 
(IEC), except when necessary to protect the subject from immediate harm.
2.
Personally conducting or supervising the described investigation(s).
3.
Informing all subjects, or persons used as controls, that the drugs are being used for 
investigational purposes and complying with the requirements relating to informed consent and 
ethics committees (e.g., IEC or IRB) review and approval of the protocol and its amendments.
4.
Reporting complaints that occur in the course of the investigation(s) to AbbVie.
5.
Reading the information in the Investigator's Brochure/safety material provided, including the 
instructions for use and the potential risks and side effects of the investigational product(s).
6.
Informing all associates, colleagues, and employees assisting in the conduct of the study about 
their obligations in meeting the above commitments.
7.
Maintaining adequate and accurate records of the conduct of the study, making those records 
available for inspection by representatives of AbbVie and/or the appropriate regulatory agency, 
and retaining all study-related documents until notification from AbbVie.
8.
Maintaining records demonstrating that an ethics committee reviewed and approved the initial 
clinical protocol and all of its amendments.
9.
Reporting promptly, all changes in the research activity and all unanticipated problems involving 
risks to human subjects or others, to the appropriate individuals (e.g., coordinating investigator, 
institution director) and/or directly to the ethics committees and AbbVie.
10. Providing direct access to source data documents for study-related monitoring, audits, IEC/IRB 
review, and regulatory inspection(s).
Signature of Principal Investigator
Date
Name of Principal Investigator (printed or typed)
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APPENDIX C. LIST OF PROTOCOL SIGNATORIES
Name
Title
Functional Area
Senior Manager, Clinical Trial
Clinical Program Development
Associate Director, Medical Writing
Medical Writing
Therapeutic Area - Medical Director
Clinical Development
Statistics Therapeutic Area Head
Statistics 
Director
Statistics
VP, Non-Clinical and Translational 
Science
Non-Clinical and Translational 
Sciences
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APPENDIX D. ACTIVITY SCHEDULE
The following table shows the required activities across the study. The individual activities are described 
in detail in the Operations Manual.
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h.
5 to 10 minutes in mesopic conditions.
i.
If a subject loses ≥ 1 line (≥ 5 letters) of CDVA or DCNVA compared with Hour 0 of the same study visit at Hour 1 after dosing, a manifest refraction should be repeated under 
the same lighting conditions.
j.
Conducted with subject's best distance correction. CDVA to be measured binocularly. Pupil diameter must be measured in each individual eye.
k.
Conducted with subject's best distance correction. DCNVA to be measured binocularly. Pupil diameter must be measured in each individual eye.  
l.
Conducted with subject's best distance correction
m.
Conducted with subject's best distance correction. Half-eye style trial frames with full field trial lenses only.
n.
Distance, photopic. Minimum 30-minute wait after administration of dilating drops.
o.
Investigator should note if the pupil dilated normally. Minimum 30-minute wait after administration of dilating drops.
p.
Blood collection for PK at selected sites (on Days 1 and 14 at Hours 0, 0.25, 0.5, 1, 3, 6 [pre-dose], 6.25, 6.5, 7, 9, and 12).  Collection windows of ± 5 minutes should be used for 
Hours 0.25, 0.5, 6.25, and 6.5; and collection windows of ± 15 minutes should be used for all other blood collection timepoints.  Predose samples must be drawn within 
15 minutes of the dosing time.
q.
Hour 0 starts after study drug administration. Second dose should be applied within 15 minutes after Hour 6.  Site staff will administer study drug during study visits. Subjects 
will administer the study drug at home in between visits.
r.
Conducted 5 to 10 minutes post-dosing. Only those who reported ocular discomfort symptom(s) will be further queried on the severity and duration of each symptom.
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APPENDIX E. PROTOCOL SUMMARY OF CHANGES
Previous Protocol Versions 
Protocol 
Date
Version 1.0
17 June 2021
The purpose of this version is to make minor clarifications throughout the protocol and incorporate the 
following protocol updates and modifications:

Title Page – Study emergency contact and protocol version number were updated.

Synopsis – Postdose tolerability was added as a safety assessment (an inadvertent omission in 
the original protocol) and updated synopsis date.

Section 3.1 – Estimands (Table 2) updated for completeness. 

Section 3.4 – Detail was added to the additional efficacy endpoints for clarity.

Section 3.6 – Postdose tolerability was added as a safety measure (an inadvertent omission in 
the original protocol).

Section 3.7 – Instructions were added for cases of technical issues interfering with digital 
questionnaires completion.

Section 5.1 (Disease/Condition Activity) – Minor changes were made to the inclusion criteria as 
follows: timing of when cycloplegic distance correction criterion must be met (at screening) was 
added, and requirements for photopic, high-contrast, near visual acuity were clarified (this 
criterion applies to each eye separately, not both eyes).

Section 5.2 – Minor corrections were made related to contraception requirements for 
postmenopausal females.

Section 7.2 – PK population was added (an inadvertent omission in the original protocol).

Section 7.5 – PK analysis language clarified and updated to align with the current wording in the 
PK analysis plan

Section 7.6 – Planned summaries for AEs leading to discontinuation were corrected (AEs leading 
to discontinuation of study drug will be summarized and listed, not AEs leading to study 
discontinuation).

Appendix C – Protocol signatories were updated.

Appendix D – Collection windows for hourly assessments were clarified, the order of 
assessments was updated (the order that assessments are listed in the table now indicates the 
suggested order).  A footnote was added for OSDI and detail was added to the NEI VFQ-25 
footnote to indicate that these measures should be completed on paper. Footnote "p"
(previously "e") was put in correct order and applied to all PK timepoints for clarification; other 
footnotes were renumbered appropriately.

Appendix E – A summary of changes made to the original protocol was added.
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
Appendix F – The Operations Manual was updated as follows: study emergency contact and SAE 
reporting email were updated, clarifications about paper vs. electronic assessments and 
potential technical glitches were added, inclusion criteria were updated per changes made in 
Section 5.1, clarifying details related to the DCNVA assessment, NVPTQ administration, and 
Supplemental Headache-AE Assessment were added, SAE reporting information was updated, 
an OSDI scoring appendix was added, timing of Hours 7 and 9 in relation to the second dose was 
clarified (i.e., 1 and 3 hours after the second dose, respectively), and other minor corrections 
and clarifications were made.
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APPENDIX F. OPERATIONS MANUAL
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CONFIDENTIAL INFORMATION
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1 CONTACTS
Sponsor/
Emergency 
Medical Contact
 MD
AbbVie Inc.
1 North Waukegan Road
North Chicago, IL 60064
EMERGENCY 24 hour Number:
+1 (973) 784-6402
Mobile:
Email:
Safety Concerns
Ophthalmology Safety Team
1 North Waukegan Road
North Chicago, IL 60064
Toll Free: +1 (833) 942-2226
Email:
SafetyManagement_Ophthalmology@abbvie.com
SAE Reporting 
outside of EDC 
Email:
IR-Clinical-SAE@abbvie.com
Fax:
+1 (714) 796-9504
Back-up:
+1 (714) 246-5295
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TABLE OF CONTENTS
1
CONTACTS
2
2
PROTOCOL ACTIVITIES BY VISIT
6
2.1
INDIVIDUAL TREATMENT PERIOD VISIT ACTIVITIES
6
3
STUDY PROCEDURES
10
3.1
STUDY SUBJECT INFORMATION AND INFORMED CONSENT
10
3.2
MEDICAL AND OPHTHALMIC HISTORY
11
3.3
ADVERSE EVENT ASSESSMENT
11
3.4
DROP COMFORT QUESTIONNAIRE
11
3.5
POST-DOSE TOLERABILITY ASSESSMENT
11
3.6
PATIENT-REPORTED OUTCOMES
11
3.7
VITAL SIGNS
17
3.8
CLINICAL LABORATORY TESTS
17
3.9
LIGHTING CONDITIONS AND DISTANCE SPECIFICATIONS FOR EXAMINATIONS
18
3.10 PUPILLARY REACTION TO LIGHT
20
3.11 DETERMINATION OF DOMINANT EYE
21
3.12 MANIFEST REFRACTION
21
3.13 REPEATED MANIFEST REFRACTION
25
3.14 CYCLOPLEGIC REFRACTION
25
3.15 VISUAL ACUITY MEASURES
26
3.16 DISTANCE-CORRECTED NEAR VISUAL ACUITY (DCNVA)
28
3.17 PUPIL DIAMETER
29
3.18 SLIT-LAMP BIOMICROSCOPY
31
3.19 FLUORESCEIN CORNEAL STAINING
33
3.20 IOP
34
3.21 GONIOSCOPY
34
3.22 DILATED FUNDOSCOPIC EXAMINATION
35
3.23 PHARMACOKINETICS SAMPLING (SELECTED SITES ONLY)
36
3.24 DISPENSE STUDY DRUG
37
3.25 SUBJECT WITHDRAWAL FROM THE STUDY
38
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3.26 UNSCHEDULED VISITS
38
4
SAFETY MANUAL
38
4.1
METHODS AND TIMING OF SAFETY ASSESSMENT
38
4.2
REPORTING ADVERSE EVENTS AND INTERCURRENT ILLNESSES
39
5
COUNTRY-SPECIFIC REQUIREMENTS
41
5.1
SUSAR REPORTING
41
6
STUDY DRUG AND SUPPLIES
41
6.1
STUDY SUPPLIES
41
6.2
TREATMENTS ADMINISTERED
42
6.3
PACKAGING AND LABELING
42
6.4
SHIPMENT OF STUDY DRUG
44
6.5
METHOD OF ASSIGNING SUBJECTS TO TREATMENT GROUPS
45
6.6
SELECTION AND TIMING OF DOSE FOR EACH SUBJECT
46
7
APPENDICES
47
7.1
STUDY-SPECIFIC ABBREVIATIONS AND TERMS
47
7.2
VFA APP INSTRUCTIONS
49
7.3
OCULAR SURFACE DISEASE INDEX SCORING
64
7.4
VISUAL ACUITY CHARTS USED FOR EACH VISUAL ACUITY MEASURE
66
LIST OF TABLES
TABLE 1.
PRO CATEGORIES AND TESTING CONDITIONS
12
TABLE 2.
QUICK REFERENCE FOR PROCEDURES AND PERFORMANCE SPECIFICATIONS
18
TABLE 3.
TEXT CHOICE SELECTION GUIDE FOR ENGLISH LANGUAGE
62
TABLE 4.
TEXT CHOICE SELECTION GUIDE FOR SPANISH LANGUAGE
63
TABLE 5.
SCREENING VISIT VISUAL ACUITY CHARTS
66
TABLE 6.
DAY 1 (BASELINE), DAY 7 (VISIT 2), AND DAY 14 (EXIT/VISIT 3) VISUAL ACUITY CHARTS
67
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LIST OF FIGURES
FIGURE 1.
LIGHT METER
19
FIGURE 2.
VISUAL ACUITY CHART USE
23
FIGURE 3.
PUPILLOMETER ALIGNMENT AND EYECUP POSITIONING
30
FIGURE 4.
ADVERSE EVENT AND SERIOUS ADVERSE EVENT COLLECTION SCHEMA
38
FIGURE 5.
VISUAL ANALOG SCALE
40
FIGURE 6.
AGN-190584 BOTTLE AND CARTON
43
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2 PROTOCOL ACTIVITIES BY VISIT
Study visits may be impacted due to the Coronavirus Disease - 2019 (COVID-19) pandemic. This may 
include changes such as phone or virtual visits, visits at alternative locations, or changes in the visit 
frequency and timing of study procedures, among others. Additional details are provided in the 
subsequent section. Every effort should be made to ensure the safety of subjects and site staff, while 
maintaining the integrity of the study. If visits cannot be conducted onsite due to travel restrictions or 
other pandemic-related reasons, follow the updates below on how to proceed.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
During the COVID-19 pandemic, if it is not possible for all study procedures to be performed as specified 
due to travel restrictions or other reasons, the following modifications are allowed:

Study visits and/or activities should be performed as scheduled whenever possible. If it is not 
possible to do so due to the pandemic, reschedule the visit within the visit window if possible.  
2.1 Individual Treatment Period Visit Activities
This section presents a list of activities performed during each visit, organized by visit. The dot pattern 
on the upper right indicates the place of the visit in the overall Treatment Period Activity Schedule.
Activities are grouped by category (Interview, Exam, etc.). Further information about each activity is 
provided in Section 3.
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subject's medical record. An entry must also be made in the subject's dated source documents to 
confirm that informed consent was obtained prior to any study-related procedures and that the subject 
received a signed copy.
Information regarding benefits for subjects and information regarding provisions for treating and/or 
compensating subjects who are harmed because of participation in the study can be found in the 
informed consent form.
Due to the COVID-19 pandemic, it is possible that additional protocol modifications not outlined in this 
protocol may become necessary. If this situation arises, in addition to the study informed consent, 
additional verbal consent may be obtained prior to these adaptations or substantial changes in study 
conduct in accordance with local regulations.
3.2 Medical and Ophthalmic History
A complete medical history including demographics, history of tobacco, alcohol, and drug use will be 
taken at screening. The subject's medical history will be updated at the Study Day 1 visit. This updated 
medical history will serve as the baseline for clinical assessment. Any abnormal findings from screening 
assessments should be captured as medical history.
3.3 Adverse Event Assessment
Please refer to Section 4.1.
3.4 Drop Comfort Questionnaire
The questionnaire should be administered to the subjects immediately after drop instillation. The 
Subject Evaluation of Drop Comfort single-item question should be assessed immediately.
For questionnaires completed on an electronic platform, if technical issues prevent the questionnaire 
from being completed, responses can be written down on source documents (preferably a paper copy of 
the questionnaire if available) and entered when the electronic platform is available.
3.5 Post-Dose Tolerability Assessment
Five to ten minutes after administration of the study drug during the study visit, you should ask the 
subject how they are feeling about the eyedrops as indicated in the post-dose tolerability assessment 
guidance document.
3.6 Patient-Reported Outcomes
Subjects will be asked to complete patient-reported outcomes (PRO) questionnaires. Subjects should be 
instructed to follow the instructions provided with the instrument and to provide the best possible 
response to each item. Site personnel shall not provide interpretation to subjects other than 
encouragement to complete the tasks. Subjects who are functionally unable to read any of the 
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**
These questionnaires should be answered under normal room lighting, which would likely  meet the photopic cutoff of 
> 251 lux specified in the study protocol. For simplicity, photopic is used to define lighting conditions for these
questionnaires.
*** Detailed instructions for the VFA app are provided in Section 7.2.
Note:
The OSDI and NEI VFQ-25 questionnaires will be on paper. All other questionnaires will be administered on an 
electronic platform (i.e., cellphone or tablet).  The VFA app is administered on an iPhone provided by the site.  For 
questionnaires completed on an electronic platform, if technical issues prevent the questionnaire from being 
completed, responses can be written down on source documents (preferably a paper copy of the questionnaire if 
available) and entered when the electronic platform is available.  Please contact your clinical research associate to 
obtain a paper copy of the questionnaire if needed.
The PRO instruments should be completed prior to drug administration on Day 1, and prior to any 
discussion of Adverse event (AE) or any review of laboratory findings.
General Considerations
1.
The questionnaires should be completed in an area that is quiet and has adequate privacy.
2.
Make the subject as comfortable as possible and reassure the subject that his or her answers 
are confidential and will not impact the type of medical care he or she receives.
3.
Attempt to administer the questionnaire to the subject privately.
4.
The study site personnel should choose the correct visit number for the questionnaires to 
correspond to the visit day/schedule before administering the questionnaire (e.g., Visit 1, 
Day 1).
5.
When the questionnaires are finished, thank the subject for participating.
6.
Questionnaires for a visit should not be completed after the subject has left the investigator's 
office on that visit day (e.g., questionnaires for Visit 1 should not be completed at any other 
time than at Visit 1).
Visual Function Assessment application (VFA app)
The VFA app should be administered per the schedule specified in Table 1. Detailed instructions on the 
VFA app are provided in Section 7.2. Of note, this measure should be administered under photopic 
conditions, with best distance correction. Only half eye style trial frames with full field trial lenses are 
permitted for best distance correction while administering the VFA app.
OSDI 
The OSDI (Ocular Surface Disease Index) consists of 12 questions, graded on a 5-point scale from All of 
the Time (4) to None of the Time (0). The subject will complete the OSDI.
The OSDI is scored using the formula: (sum of scores x 25)/number of questions answered.
1.
Add the subtotals from questions 1-5, 6-9, and 10-12 to get the total score.
2.
Multiply this total by 25.
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3.
Divide this number by the number of questions answered (i.e., those questions that were scored 
on the 4-to-0 scale, not counting those marked 'N/A') to get the subject's OSDI score.
4.
You can also use the worksheet that AbbVie provided to calculate the OSDI score.
Sites will transcribe the subject's responses on the paper OSDI questionnaire into the electronic data 
capture (EDC).
Administration of the NEI VFQ-25
1.
Subjects should answer this questionnaire using their habitual distance correction.
2.
Explain that they will be asked a series of questions, and this is a necessary and important part 
of the clinical study in which they are participating.
3.
The questionnaire process may take up to 25 minutes, including time to review study 
instructions. However, this time may vary from subject to subject and from visit to visit. Please 
allow sufficient time to complete the questionnaires.
4.
The instructions for the VFQ-25 advise the subject to answer the questions as if he or she is
wearing his or her glasses or contacts without near correction. The purpose of this study is to 
assess subjects' difficulty with near vision when the subject is not wearing glasses or contacts 
with near correction. As a result, before administration of the VFQ-25 begins (i.e., before the 
initial instructions are read to the subject), please advise subjects that for this study 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.
5.
The VFQ-25, including all questions from the Appendix of Optional Additional Questions, will be 
administered by site personnel who have received documented training. However, particular 
items of interest for confirming inclusion criteria only include the near vision subscale (items 5-
7) and the near vision questions from the Appendix of Optional Additional Questions (items A3-
A5). Responses to all VFQ-25 items will be used in psychometric validation analyses of the VFA 
app.
During the NEI VFQ-25 Questionnaire Administration
1.
Read the instructions on the questionnaires to the subject.
2.
After reading the instructions to the subject, make sure that the subject understands the 
instructions (including the fact that any references to glasses or contacts should be interpreted 
as referring to distance correction only – if required); and is ready to begin the questionnaire.
3.
Read each question slowly, exactly as worded, followed by the appropriate answer choices (if 
applicable), and mark the answer choice for the subject.
4.
Repeat questions and answer choices as needed; do not rephrase the question.
5.
Do not "lead" the subject to a particular answer. Allow the subject to respond how he or she
feels. If the subject is unsure how to answer, explain that there are no right or wrong answers 
and ask him or her to answer to the best of his or her ability.
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6.
If the subject wants to change his or her answer to a question after the site has marked an 
answer choice, study site personnel can mark a different response and add a note to indicate 
the final answer.
7.
Continue to move the interview forward. Do not get "stuck" on a particular question.
8.
Reassure the subjects throughout the interview that they are doing well, as appropriate.
Checking the Questionnaire
Study site personnel should check the following before the subject leaves the site:
1.
In order to be eligible for the study, the subject must: have a score ≥ 3 on at least one item from 
either the VFQ-25 Near Vision Subscale (items 5-7) or from the Appendix of Optional Additional 
Questions (A3-A5) (i.e., a score of ≥ 3 on at least one out of these six questions). If the subject
does not have a score of 3 or above for at least one of these six items (items 5-7 or A3-5), the 
subject is not eligible to participate in the study.
2.
If a subject communicates information regarding AEs during the course of the interview, assure 
that these are documented appropriately.
Sites will transcribe the responses on the paper NEI VFQ-25 questionnaire into the EDC.
Subject Self-Administration of the Single-Item Subject Global Impression of Change, Single-Item 
Subject Global Impression of Status, and Presbyopia Impact and Coping Questionnaire
Instruct the subject to read the instructions at the top of the page carefully before answering the 
question.
Single Item PGIC Questionnaire
Subjects will be asked to complete a single-item questionnaire asking about their impression of the 
study medication's effect on their near vision. Subjects should answer this questionnaire under 
photopic conditions using their best distance correction.
Single Item PGIS Questionnaire
Subjects will be asked to complete a single-item questionnaire asking about their impression of their 
problems seeing up close over the past 7 days. Subjects should answer this questionnaire under 
photopic conditions using their best distance correction.
Presbyopia Impact and Coping Questionnaire
This questionnaire includes 14 questions about the degree to which subjects were impacted by their 
difficulty seeing up close; or engaged in coping behaviors during the previous 7 days. Subjects should 
answer this questionnaire using their habitual distance correction.
Near Vision Presbyopia Task-Based Questionnaire
The Near Vision Presbyopia Task-Based Questionnaire (NVPTQ) includes 12 questions on 4 paper-based 
reading tasks (book, newspaper, menu, nutrition label). Subjects will be asked to read a text passage, 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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and answer 3 questions about their ability to read, whether they squinted while reading, and 
satisfaction with their ability to read. After a subject has completed the task, the study staff should 
proceed with the next task (i.e., ask the subject to read the next text passage and answer the 3 
questions). Subjects should read text passages and answer questions under mesopic conditions, using 
their best distance correction.
Lighting Conditions 
Subjects should read text passages and answer questions under mesopic conditions, using their best 
distance correction. Please see definition of mesopic lighting (Section 3.9) for other efficacy measures.
Task Preparation
1.
Each of the four reading task examples (book, newspaper, menu, nutrition label) should be 
stacked upon a lectern facing the subject, in the following order:
a.
Paragraph from a book
b.
Newspaper article
c.
Menu
d.
Nutrition Label
2.
The lectern should be set so that the task examples are perpendicular to the table and so that 
the examples are at the subject's eye level. Do not adjust the lectern once the subjects have 
begun reading the tasks.
3.
Subjects should be given a different task example each time they are asked to complete the 
NVPTQ (i.e., at each visit). For instance, subjects should be given tasks labelled "Example A1, A2, 
etc." during their first assessment. At their next assessment, subjects should be given tasks 
labeled "Example B1, B2, etc.", and so on. Review the NVPTQ in Mesopic Conditions Worksheet 
history to ensure that subjects are not receiving the same task example during the course of the 
trial. Record the task example numbers for this assessment.
Subject Preparation
1.
Seat the subject so that the distance between the subject's eyes and the lectern is 40 cm. 
Ensure that the subject does not move his/her head significantly during the time he/she is
reading the tasks.
2.
Use the NVPTQ in Mesopic Conditions Worksheet provided to confirm proper setup of tasks 
(i.e., ensure tasks are on the lectern, and are in the correct order)
3.
Provide the NVPTQ to the subject. It may be helpful to provide the questionnaire on a fixed 
surface to minimize time spent re-adjusting the subject position between tasks. 
4.
Instruct the subject to read the NVPTQ instructions.
5.
Before administering the reading tasks, remind the subject of the following:
a.
Remember to read the text for each of the reading samples. You can read the tasks out loud 
or to yourself.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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b.
Do not move the reading material closer to or farther away from yourself.
c.
Do not adjust the location of where you are sitting or lean forward.
6.
Provide the subject with Task #1 (Book).
7.
After the subject has finished reading Task #1, instruct the subject to read and complete the 
questionnaire items pertaining to Task #1 (items 1-3 in the task-oriented questionnaire).
(IMPORTANT: Before giving the questions to the patient, adjust the brightness on the device to 
the lowest possible setting.)
8.
After completion of the Task #1 questions, provide the subject with Task #2 questions. Repeat 
steps 6 and 7 for Tasks #2-4.
Subject Vision Correction for Tasks
Subjects should read text passages and answer questions under mesopic conditions, using their best 
distance correction. Subjects are required to read the tasks on their own. Study staff are not permitted 
to provide assistance for the reading tasks. Subjects are not allowed to use their reading glasses, or any 
other form of near-vision correction, while reading the text passages or answering the questions. If the 
subject is unable to read the questionnaire after performing the tasks, site personnel may read the 
questionnaire to the subject and record their answers. Please note - site personnel are NOT allowed to 
assist subjects with reading the actual task examples, they may ONLY assist with the questionnaire 
about the task examples.
Once a subject requires interviewer assistance with the task-related questionnaire, the questionnaire 
must be interviewer administered (preferably by the same interviewer) at all subsequent assessments 
for the remainder of the study.
3.7 Vital Signs
Vital sign determinations of systolic and diastolic blood pressure and pulse rate will be obtained at visits 
as specified in Section 2.1. Blood pressure and pulse rate should be measured after the subject has 
been sitting for at least 5 minutes.
3.8 Clinical Laboratory Tests
Pregnancy Tests (Urine)
Pregnancy testing should not be performed for postmenopausal women.
A urine pregnancy test will be performed at screening, Day 1, and Day 14 (or upon confinement in each 
period) for all female subjects of childbearing potential. More frequent pregnancy tests can be
performed throughout the study at the investigator's discretion or if required per local/country 
requirements.
If the baseline urine pregnancy test is negative, then dosing with study drug may begin.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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Light Meter
The light meter provided by AbbVie should be used to measure room illumination at the target. Before 
taking any measurement, make sure the power switch is turned to the "on" position, and the range 
switch is turned to the "2000 position," as shown in Figure 1. 
Figure 1.
Light Meter
When measuring room illumination/lighting conditions: 
1.
Remove the light sensor cover.
2.
Position the light sensor in the middle of the (mounted) distance VA chart with the sensor facing 
outward to the room.
a.
Chart should either be mounted on the wall or on a stable stand.
3.
Adjust room lighting until light meter reading achieves the mesopic or photopic range required. 
4.
Lighting conditions on the distance VA chart confirms lighting for VA assessments associated 
regardless of distance;
a.
i.e., if mesopic lighting has been confirmed and mesopic VA measurements are being 
performed, lighting does not need to be checked from distance → intermediate → near and 
vice versa.
5.
Upon changing lighting conditions, lighting should be re-checked (as per steps 1 to 4) prior to 
performing the associated procedures (e.g., change from mesopic to photopic).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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a.
For mesopic procedures, subjects should be dark adapted at least 5-10 minutes prior to the 
start of procedures, once lighting conditions are confirmed.
3.10 Pupillary Reaction to Light
The 'swinging light test' is used to measure pupillary reaction to light. It is a means of detecting 
differences between the two eyes and how they respond to a light shone in one eye at a time. This test 
can be conducted under either photopic or mesopic conditions (it is easier to see under mesopic 
conditions). 
In a normal swinging light test, the pupils of both eyes will constrict equally regardless of which eye is 
stimulated by the light. In an abnormal test, there is less pupil constriction in the eye with retinal or 
optic nerve disease. 
Procedure:
Using a bright torch which can be focused to give a narrow, even beam of light. Perform the following: 

Ask the subject to focus on a distant object, such as a Snellen chart or a picture. This is to 
prevent the near-pupil response (pupil constriction when moving focus from distance to near).
While performing the test, take care not to get in the way of the fixation target.

Move the whole torch deliberately from side to side so that the beam of light is directed directly 
into each eye. Do not swing the beam from side to side around a central axis (e.g., by holding it 
in front of the person's nose), as this can also stimulate the near response.

Keep the light source at the same distance from each eye to ensure that the light stimulus is 
equally bright in both.

Keep the beam of light steadily on the first eye for at least 3 seconds. This allows the pupil size 
to stabilize. Note whether the pupil of the eye being illuminated reacts briskly and constricts 
fully to the light. Also note what happens to the pupil of the other eye: does it also constrict 
briskly?

Move the light quickly to shine in the other eye. Again, hold the light steady for 3 seconds. 
Note whether the pupil being illuminated stays the same size, or whether it gets bigger. Note 
also what happens to the other eye.

Repeat the test, observing what happens to the pupils of OU when one eye and then the other 
eye is illuminated.

Judge whether the subject's pupillary reaction to light is normal or abnormal. Enter into the 
source document and eCRF.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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3.11 Determination of Dominant Eye
1.
Participants will be asked to extend their arms out in front of them at eye level, with their palms 
facing away, fingers together and facing upward.
2.
With hands together, a small window will be formed by overlapping their thumbs and 
overlapping their fingers. 
3.
Participants will select a small object at least 10 feet in front of them and look at it with both 
eyes through the view window in their hands.
While remaining focused on the object, participants will close the OD and open the OS, taking care not 
to move the position of the hands, and take note of whether the image remains visible. If the image 
remains visible, the OS is the dominant eye. If the image is no longer visible, the OD is the dominant 
eye. This will be confirmed by closing the OS and opening the OD, taking care not to move the position 
of the hands, and taking note of whether the image remains visible.
3.12 Manifest Refraction
Manifest refraction should be conducted at the Screening visit under mesopic and photopic light 
conditions, for both distance and near (this is considered the "baseline manifest refraction"). Manifest 
refraction can be conducted per the site's standard clinical practice or following the procedures 
instructed below. The investigator may choose any appropriate method to conduct manifest refraction, 
including a phoropter, trial frames with loose lenses inserted. The prescriptions obtained from the 
manifest refraction conducted at the Screening visit (for mesopic and photopic distance, if not the same) 
will be used as the best distance correction during the study visits for:

Corrected Distance Visual Acuity (CDVA) and Distance-Corrected Near Visual Acuity (DCNVA)

Some PRO measures under each lighting condition 
Note: If the subject's habitual monofocal distance correction is the same as the manifest refractions 
under both mesopic and photopic conditions, then their habitual correction can be used for the 
procedures above.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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A repeat manifest refraction should be done under the same lighting condition in subjects who lose 
≥1 line (defined as 5 or more letters) at Hour 1 in either eye in CDVA or DCNVA compared with Hour 0 
of the same visit. The repeated manifest refraction should be conducted with the same method as at 
the screening visit. The results of the repeated manifest refraction need to be recorded in the source 
document and entered into EDC.
Determine Subject's Approximate Refraction
Prior to manifest refraction, measure the subject's current distance spectacles (habitual correction) with 
a lensometer, or perform autorefraction if the subject does not wear distance spectacles. This 
measurement will be the starting point for refracting the subject on the phoropter. 
New monofocal correction:
If subject's habitual distance correction (1) is insufficient to achieve distance visual acuity of 20/32 or 
better, or (2) are not monofocal lenses (i.e., if they are bifocal or progressive), then the study site should 
provide new, monofocal distance correction spectacles to achieve a corrected distance vision of 20/32 
or better. 
This new monofocal distance correction or subject's own habitual correction may be used for distance-
corrected visual acuity measures (i.e., in place of trial frames or phoropter) if they have the same 
prescription as their best correction under the corresponding lighting condition (e.g., some subjects may 
not tolerate best correction as habitual correction, but a new Rx may still get them to qualify at 20/32 or 
better – these subjects may not use their new Rx for visual acuity testing). However, if the subject's best 
distance correction is different between mesopic and photopic conditions, a trial frame is still needed 
for the condition that the new monofocal distance correction or subject's own habitual correction is 
different from the best distance correction.
Manifest Refraction
Manifest refraction is performed for distance (4 m) and near (40 cm), under both mesopic and photopic 
conditions. 
To start, the subject's current distance spectacles are measured with a lensometer; if no spectacles are 
worn, auto refraction is done. One of these measurements is used as the beginning approximate 
refraction. 
The investigator may use any appropriate method to conduct the manifest refraction, including 
phoropter, trial frames with loose lenses inserted, or loose lenses. The AbbVie-provided distance and 
near visual acuity charts should be used for each measure.
The distance and near visual acuity charts provided by AbbVie have three blocks of letters – one each for 
right eye (OD), left eye (OS), and OU (Figure 2). Please use the appropriate letters for distance and near 
measures. Note that only OD and OS blocks will be used for manifest refraction.
Note: In the rare case if a subject's best corrected vision is 20/63 or worse, subjects should read the 
central OU section because there are no corresponding letters for OD or OS on the charts.  If both OD 
and OS are 20/63 or worse, use a different chart to avoid memorizing. For vision better than 20/63, the 
subject should read the OD or OS sections of the chart as usual.  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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Figure 2.
Visual Acuity Chart Use
Manifest refraction should be done in the following order, beginning with the OD (OS occluded):
1.
Enter approximate refraction (from Determine Subject's Approximate Refraction) into the 
phoropter.
2.
Determine SPHERE power:
a.
With subject looking at the smallest legible line on the appropriate VA chart (near/distance), 
add +0.25 spherical lens.
i.
Ask the subject, is it "Better, worse, or is there no change?"
If BETTER or NO CHANGE:
Replace the +0.25 spherical lens with one with an additional +0.25 D. Check VA again, 
and repeat the process until adding +0.25 D makes the subject's VA worse. 
If WORSE:
Add a lens that is 0.25 D more minus or less plus than the previous lens. If this improves 
VA, even by one letter, continue to repeat the process until there is no more 
improvement in VA. 
ii.
Re-challenge with +0.25 sphere until the subject responds that the +0.25 sphere makes 
their VA worse. The final sphere is the most plus or least minus lens that achieves the 
best VA.
3.
Determine CYLINDER power and axis:
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.A. For OS 
.A. For OU 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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NOTE: The following description is for minus cylinder. Adjust accordingly for plus cylinder 
refraction by replacing the negative axis (red) with the positive axis (white) in the instructions 
for cylinder axis below.
Ask the subject to look at a line on the visual acuity chart, which is one line larger than the 
smallest line the subject can read. Ask the subject to focus on a round letter such as "C," "G," or 
"O" if one is present.
a.
IF CYLINDER WAS NOT PRESENT in the initial approximate refraction: 
i.
Place the cross-cylinder with the negative axis (red) first at 90°, then at 180°, then 45°
and 135°. If the subject states that the vision is improved at any one of these four axis 
positions, place cylindrical lens power in the refractor at the preferred axis and proceed 
to refine the axis. If the subject prefers none of the four positions, skip the refining 
cylinder power step.
IF CYLINDER WAS PRESENT in the initial approximate refraction: 
ii.
Position the cross-cylinder first with the negative axis 45° to the right of the cylinder 
axis (position one), and secondly with the negative axis at 45° to the left of the cylinder 
axis (position two). Flip the crossed cylinder and ask, which position improves the 
vision (position one or position two?).
b.
If subject responds that NEITHER POSITION IS BETTER and if this was the first test of the 
axis position, move the axis of the cylinder 15° to the right or left and repeat.
If the subject PREFERS ONE POSITION TO THE OTHER, rotate the cylinder axis toward the 
preferred axis of the cross-cylinder. (If the subject states that one position of the cross-cylinder 
is no better than the other position, proceed to refining cylinder power).
4.
Refine CYLINDER power:
a.
Ask the subject to look at the lowest line on the visual acuity chart that can be read.
b.
Align the cross-cylinder first with the positive axis and then with the negative axis coincident 
with the cylinder axis. Ask the subject which is better.
c.
If the subject prefers the positive (white) axis coincident with the cylinder axis, decrease the 
minus power of the cylinder by 0.25 diopter.
d.
If a subject indicates a change that would introduce positive cylinder power, remove all 
cylinder power and continue testing for negative cylinder power at an axis 90° away from 
the previous axis. 
e.
If the subject prefers the negative (red) axis coincident with the cylinder axis, increase the 
cylinder power by -0.25 diopters and retest. 
f.
For each 0.50 diopter change in cylinder power, adjust the sphere by 0.25 diopters of the 
opposite power.
5.
End the refraction:
a.
End the refraction by challenging with +0.25 spherical power and adjust the sphere until the 
subject responds that the additional positive sphere makes the vision worse.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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b.
Record the lens correction obtained in this refraction for the OD on the appropriate form.
c.
Record the visual acuity in Snellen Equivalents as the lowest line read with two, one, or no 
misses.
d.
REPEAT the entire refraction process for the OS.
Note: When determining whether refraction meets entry criteria, either plus OR minus 
cylinder notation may be used.
6.
Near Refraction:
a.
Best near add should be used when conducting near manifest refraction, including the near 
VA measurement.  The recorded near prescription should also include the near add. Both 
best near refraction and near add need to be captured and entered into EDC. 
b.
Inclusion criterion 7 "Photopic, high-contrast, near visual acuity correctable to 20/40 (J3+) or 
better in each eye at the screening visit" references the near VA measured by the near 
refraction. 
Note:
•
When determining whether refraction meets entry criteria, either plus OR minus 
cylinder notation may be used. Sites do not need to convert the sign when entering 
the data into the source worksheet of EDC. 
3.13 Repeated Manifest Refraction
A repeat manifest refraction should be done under the same lighting condition in subjects who lose 
≥1 line (defined as 5 or more letters) in either eye in CDVA or DCNVA at Hour 1 compared with Hour 0 
of the same visit. The investigator should choose the same method to conduct the repeat manifest 
refraction as at the screening visit. The results of the repeat manifest refraction must be recorded in the 
source document and entered into EDC; however, this new refraction is NOT used for the rest of the 
study. The original correction from the screening manifest refraction should continue to be used.
3.14 Cycloplegic Refraction
Cycloplegic refraction is used to confirm the manifest refraction and to determine emmetrope status. It 
is performed using distance VA charts, under photopic conditions, after subjects are dilated using 
1% tropicamide and 2.5% phenylephrine. Refraction is to be performed a minimum of 30 minutes after 
administration of dilating drops.
When determining whether refraction meets entry criteria, either plus OR minus cylinder notation may 
be used, and considered for each eye individually.
Example: An emmetrope may meet criteria in plus cylinder notation for one eye and minus cylinder 
notation in the other; however, if one eye in either notation does not meet emmetrope criteria, the 
subject would be a nonemmetrope.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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If a subject's cycloplegic refraction vision is 20/63 or worse, the subject should read the central OU 
section because there are no corresponding letters for OD or OS on the charts.  For vision better than 
20/63, the subject should read the OD or OS sections of the chart as usual.  
3.15 Visual Acuity Measures
General Considerations for all VA Measures
Sites should use a consistent evaluator to conduct all visual acuity measures. If a consistent evaluator is 
not possible, an overlap between two evaluators is required. This is a long and fatiguing study that 
involves multiple VA measurements at multiple timepoints. It is important for all evaluators to 
consistently allow subjects to take time to blink and consistently encourage them to try their best to 
read at each measurement across all timepoints at all study visits. 
For all VA measures, start with the lowest line the subject can read and move to the next line below if 
3 or more letters are read correctly. The Snellen equivalent is calculated as the last line when 3 or more 
letters are read correctly—that is, if only 0, 1, or 2 letters on a line can be read, do not proceed to the 
next line. The number of letters calculation should include all letters read correctly, including the letters 
on the line when 1 or 2 letters were read.  The VA score should be the last line on which 3 or more were 
read correctly. 
Use of Screening Manifest Refraction
Visual acuity measurements for CDVA and DCNVA are performed OU using the subject's best distance
correction based on the screening manifest refraction results per lighting condition: 

If screening (photopic/mesopic) manifest refraction requires correction, trial frames/lenses or 
phoropter (or new monofocal correction or habitual correction IF appropriate - see Section 3.12)
should be used to provide correction.

Results from screening should be used to provide the correction throughout the trial; the 
screening best-corrected vision performed under (mesopic/photopic) conditions will be used 
post screening for 

mesopic results for mesopic VA measurements

photopic results for photopic VA measurements
If no correction is needed, the VA measurements should be completed without the trial lenses/frames.
Chart Usage
AbbVie will provide multiple charts for each type of visual acuity measurement. Charts for each VA 
measurement are labeled with specific identifiers and use different letters. Each chart contains a unique 
identifying number that corresponds to a worksheet provided. The worksheet is to be used to capture 
the results of each VA evaluation.
To ensure proper VA measurement, different charts should be used at each timepoint and no charts 
should be used in successive VA measures. This should prevent the memory effect. Please note that VA 
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worksheets labeled 'mesopic' and 'photopic' can refer to the same chart. When rotating different 
worksheets ensure rotation extends into both mesopic and photopic worksheets. 
The worksheets provided by AbbVie are labeled the same way as the corresponding charts. Section 7.3
contains tables of which VA charts should be used for each VA measure, according to timepoint and 
lighting conditions. Please refer to these tables for the preferred chart rotations to minimize learning 
effects. It may help to print this appendix for reference.
Corrected Distance Visual Acuity (CDVA)
1.
CDVA is performed with the best distance correction determined by the screening manifest 
refraction under the corresponding lighting conditions.
2.
Trial frames and trial lenses or phoropter (or new monofocal correction or habitual correction IF 
appropriate – see Section 3.12) should be used if correction is needed per the manifest 
refraction results. If no correction is needed, complete the CDVA without the trial frames or 
phoropter. 
3.
AbbVie will provide 3 double-sided distance charts labeled 23214-1 (Front and Back), 23214-2 
(Front and Back), and 23214-3 (Front and Back), found at the bottom right-hand corner of the 
front side. Charts are similar, only differing in letters.
a.
Site should refer to Section 7.3 on which chart should be used at each timepoint.
b.
Use the corresponding CDVA worksheet based on the chart selected.
4.
The chart should be mounted on the wall or stable stand (eg, lectern) that is 4 meters away 
from the subject's eyes and at approximately eye level to the average height of the seated 
subject.
5.
Conduct the CDVA measurement OU:
6.
Ask the subject to:
a.
Read the lowest line visible starting with the middle of the chart.
b.
If read correctly, count the number of letters and proceed to the next line noting letters 
correct per line, until 2 or fewer letters can be read correctly on that line, then stop.
c.
VA score (Snellen equivalent) is the lowest line on which 3 or more letters are read 
correctly. (Note: it is possible that there is more than one line of 3 or 4 correctly read 
letters; always record the lowest line as the VA score).
d.
Use the provided worksheet to calculate the number of letters read in the preceding lines 
and record the associated VA score (Snellen equivalent).
7.
CDVA measured under mesopic and photopic conditions as per protocol timepoints
8.
The number of letters, VA score, and chart number will be entered into the eCRF for OU. 
Identify the letters on the worksheet read correctly to enable you to score and verify the result 
(e.g., by crossing out incorrect letters).
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3.16 Distance-Corrected Near Visual Acuity (DCNVA) 
1.
DCNVA is performed with the best distance correction determined by the screening manifest 
refraction under the corresponding lighting conditions.
2.
Trial frames and trial lenses or phoropter (or new monofocal correction or habitual correction IF 
appropriate –see Section 3.12) should be used if correction is needed per the manifest 
refraction results. If no correction is needed, complete the DCNVA without the trial frames or 
phoropter. 
3.
AbbVie will provide 8 near charts that are labeled as 23213-1 (Front and Back), 23213-2 (Front 
and Back), 23213-3 (Front and Back), and 23213-4 (Front and Back), found at the bottom 
right-hand corner of the front side. All charts have the same settings and only differ in letters.
a.
Site should refer to Section 7.3 on which chart should be used at each timepoint.
b.
Use the corresponding DCNVA worksheet based on the chart selected. 
4.
The chart should be mounted on a lectern or held by the subject or site staff. Use the attached 
string to keep 40 cm from the chart by aligning the end of the string to the lateral canthus of the 
subject's OS. 
5.
For the measurement OU ask the subject to:
a.
Read the lowest line visible starting with the middle of the chart.
b.
If read correctly, count the number of letters and proceed to the next line, noting letters 
correct per line, until 2 or fewer letters can be read correctly on that line, then stop.
c.
VA score (Snellen equivalent) is the lowest line on which 3 or more letters are read 
correctly. (Note: It is possible that there is more than one line of 3 or 4 correctly read 
letters; always record the lowest line as the VA score).
d.
Use the provided worksheet to calculate the number of letters read in the preceding lines 
and record the associated VA score (Snellen equivalent).
6.
DCNVA needs to be measured under both mesopic and photopic conditions in the order 
specified and at the timepoints listed in the protocol. 
7.
The number of letters, VA score, and chart number will be entered into the eCRF for OU.
Note:

Mesopic DCNVA is repeated 3 times at the screening visit for practice. Please reference 
Section 7.3 for the charts that should be used. Evaluators should consistently allow subjects 
to take time to blink and consistently encourage them to try their best to read at each 
measurement.  The results of the three measurements are expected to be the same or very 
similar, and at least one of the three should meet the inclusion criteria on mesopic DCNVA. 
Please enter the last qualifying score into EDC.

Per inclusion criterion 3 (bullet 4), Mesopic, high-contrast DCNVA has to be 20/40 (J3) to 
20/100 (J10) at the screening and baseline visits. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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3.17 Pupil Diameter
The pupil diameter will be measured at the timepoints listed in the study protocol.
Pupil Diameter
AbbVie will provide a NeurOptics VIP-300 unilateral pupillometer to perform all pupil diameter 
measurements per protocol timepoints. The provided pupillometer is housed in a protective hard-shell 
case that includes the following:

Pupillometer

Lithium-ion battery

Two opaque rubber eyecups 

Medical grade power supply for the charging station

The charging station
Measuring Pupil Diameter
Pupil diameters should be measured with the provided pupillometer for distance/near VA and under 
mesopic/photopic conditions, per eye. The following VA charts should be utilized: 

Near pupil diameter: 40 cm (near) visual acuity chart

Distance pupil diameter: 4 meter (distance) visual acuity chart. 
Note: Pupillometer Use 

From the home screen, select 'settings' (the gear icon), and select LIGHTS OFF mode.

MUST BE in LIGHTS OFF mode NOT in "variable" mode (the current mode will be displayed)
While measuring pupil size in 1 eye, the fellow eye should remain open and focused on the appropriate 
distance or near vision chart. Pupil measurements will be measured over 2 seconds and the readings 
recorded. Ensure that the pupillometer eyecup does not cover the subject's eye, as sufficient ambient 
light is necessary for an accurate measurement. Holding the pupillometer so that approximately 
1-2 inches separates the subject's eye from the eyecup should allow sufficient ambient light entry.
Subject Preparation
1.
With any spectacles removed, instruct the subject to focus at the target distance with the eye 
that is not being tested.
2.
Ask the subject to keep his/her head straight and both eyes wide open during both targeting 
and measurement. In some cases, if targeting becomes a problem, it may be necessary to 
gently hold the subject's eye open with your finger.
3.
The operator should position the instrument at a right angle to the subject's axis of vision and 
any tilting of the instrument should be minimized (See Figure 3 below). When taking the 
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measurement, remember not to cover the subject's eye with the eyecup, so as to allow for 
sufficient ambient light to enter. 
4.
It may be helpful for the operator to be at the same level as the subject when performing the 
scan to minimize tilting. If necessary, both subject and operator can sit down facing each other 
during targeting and measurement. (See Figure 3 below).
5.
The pupillometer should not be used without the eyecup positioned correctly (see Figure 3
below). The eyecup has a tab in the rim that fits into the indentation in the lens shield of the 
pupillometer. Position the tab in the eyecup rim into the indent in the lens shield and press into 
place. The tabs on either side of the lens shield should also snap into holes on either side of the 
eyecup.
Figure 3.
Pupillometer Alignment and Eyecup Positioning
Pupil Measurement
1.
From the main screen, select settings icon (nut and bolt) and then the top left "eye" icon to 
toggle between "Light off" and "Variable" mode. Measurements must be performed using the 
LIGHT OFF MODE. 
2.
Position the pupillometer in front of the intended eye (do not cover the eye, hold to allow 
ambient light to enter), and ensure the subject is focused at the appropriate target (near or 
distance) with his/her other eye. 
3.
Press and hold either the OD or OS button until the eye is centered on the touchscreen and the 
display shows a circle around the pupil. Once the circle appears (green for OD and yellow for 
OS), release the button, holding the pupillometer in place for approximately 2 seconds, making 
sure the subject maintains an open eye position. 
4.
When the pupil measurement is complete, pupil data are analyzed, and results are displayed. If 
the measurement was affected by a tracking problem (e.g., excessive blinks), results are 
reported as NA. 
5.
Repeat this process for the other eye. 
6.
From the results page, you may select the Video icon to view playback of the scan. Records can 
also be deleted using the Delete icon. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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7.
All measurements will be recorded in the source worksheet and the eCRF, rounded to the 
nearest tenth. Printouts of pupil values do not need to be saved as long as values are recorded 
in the source. Please refer to the NeurOptics VIP-300 Pupillometer Instruction Manual for more 
detailed operating instructions.
3.18 Slit-lamp Biomicroscopy
Biomicroscopic examinations should be performed using a slit-lamp. The examinations will include 
evaluation of the condition of the eyelids, conjunctiva, cornea, anterior chamber, and iris/pupil.
Eyelid/Eyelid Margins/Lashes:
Edema
  0
(None)
=
No edema
+0.5
(Trace)
=
Localized, minimal (trace) swelling
+1
(Mild)
=
Localized, mild swelling
+2
(Moderate)
=
Diffuse, moderate swelling
+3
(Severe)
=
Diffuse, severe swelling
Erythema
  0
(None)
=
No erythema
+0.5
(Trace)
=
Localized, minimal (trace), flush reddish color 
+1
(Mild)
=
Localized, mild, flush reddish color
+2
(Moderate)
=
Diffuse reddish color encompassing the entire lid margin
+3
(Severe)
=
Deep diffuse reddish color of lid margins and superior and/or inferior 
eyelid
Crusting:
  0
(None)
+0.5
(Trace)
+1
(Mild)
+2
(Moderate)
+3
(Severe)
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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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
Note:
Subconjunctival hemorrhage, discharge, blanching, follicles, pterygium encroaching on visual axis, pterygium not 
encroaching on visual axis are graded as 0, + 0.5, +1, +2, +3.
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
Note:
Subconjunctival hemorrhage, discharge, blanching, follicles, pterygium encroaching on visual axis, pterygium not 
encroaching on visual axis are graded as 0, + 0.5, +1, +2, +3.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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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
Note:
Punctate epithelial staining, Filaments, Infiltrates, Edema, Cornea Gutatta, Endothelial Pigment, Keratic Precipitates, 
Neovascularization, Opacity(ies), Stromal Haze are graded 0, + 0.5, +1, +2, +3.
Anterior Chamber:
Cells, Flare, Anterior Synechiae, Hypopyon, Hyphema will be graded as 0,+ 0.5, +1, +2, +3, +4.
Iris/Pupil:
Rubeosis Iridis, anterior chamber angle involved, Rubeosis Iridis, anterior chamber not involved, 
Afferent Pupillary Defect, Posterior Synechiae, Transillumination Defects, Pseudoexfoliative Material, 
Peripheral Iridectomy, Laser Peripheral Iridotomy will be evaluated with no grading.
3.19 Fluorescein Corneal Staining
The corneal staining should be graded 2 minutes after instillation of the sodium fluorescein.  
Examination will be performed with the slit lamp at approximately 10X magnification.  Evaluate the 
entire cornea for staining using the supplied yellow barrier filter placed directly in front of the objective 
lens of slit lamp. The slit lamp's cobalt blue filter must be used to illuminate the cornea.  Corneal 
fluorescein staining must be evaluated at the 2-minute timepoint.  Refer to the Oxford Scheme outlined 
in the laminated chart provided to grade the staining.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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3.20 IOP
Intraocular pressure (IOP) should be measured after the biomicroscopic exam is completed and prior to 
pupil dilation. Measurements should be taken using a Goldmann applanation tonometer affixed to a 
slit-lamp with the participant seated. The participant and slit-lamp should be adjusted so that the 
participant's head is firmly positioned on the chin rest and against the forehead rest without leaning 
forward or straining. Tight fitting neckwear should be loosened. Both eyes will be tested, with the right 
eye preceding the left eye. The measurer will look through the binocular viewer of the slit lamp at low 
power. The tension knob will be preset at a low-pressure value (4 to 6 mm Hg). The measurer will 
follow the image of the fluorescein-stained semicircles while slowly rotating the tension knob until the 
inner borders of the fluorescein rings touch each other at the midpoint of their pulsation in response to 
the cardiac cycle. When this image is reached, the measurer will take his/her fingers off the tension 
knob and record the IOP reading along with the date and time of day.
3.21 Gonioscopy
Gonioscopy will be performed to assess the iridocorneal (anterior chamber) angle.  You may use your 
preferred indirect gonioscopy lens (e.g., Posner, Zeiss 4-mirror lens, etc.).  When gonioscopic 
photography is being performed you should use the appropriate gonioscopic lens for the photography.
General steps to performing gonioscopy:

Room lights should be turned off during the examination. All participants should be examined in 
the same room with the same slit lamp if possible to do so, and with consistent lighting 
conditions.

Perform the angle assessment under high magnification.

With the participant comfortable at the slit lamp, wet the corneal surface of your lens with an 
artificial tear or lubricating solution and place your gonioscopy lens on the participant's eye.

Direct a bright, narrow light beam away from the pupil to avoid inducing miosis.

Have the participant maintain their gaze in the primary position while you examine the 
iridocorneal angle.

Minimize tilting the lens; only minor movement of the lens is permissible. Otherwise, the angle 
findings may be distorted and a closed or narrow angle may appear open.  Do not apply 
pressure that may cause indentation.  The presence of corneal striations is an indication that 
the cornea is being indented.

Examine the iridocorneal angle for peripheral anterior synechiae and other angle pathology.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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3.22 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 should 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 should be evaluated. Capsular bag should also 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 should be evaluated for pathology. If pathology is present, it will be described. It will be 
noted if the condition is not evaluable.  Cells, Vitreous Haze, Vitreous Hemorrhage and Posterior 
Vitreous Detachment should be graded the severity grades: +0.5, +1, +2, +3, +4, not evaluable, not 
applicable).
Fundus:
The fundus (posterior pole; periphery, when dilated) will be evaluated for pathology. If pathology is 
present, it should be described. It will be noted if the condition is not evaluable.
Macula:
The macula will be evaluated for any of the following pathology: intraretinal fluid, subretinal fluid,
intraretinal hemorrhage, subretinal hemorrhage, rhegmatogenous detachment, tractional detachment, 
pigment epithelial detachment.  
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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Retina Periphery:
The retina periphery will be evaluated for any of the following pathology and the approximate clock 
location:
Retinal hemorrhage, retinal tear, rhegmatogenous retinal detachment macula center attached, 
rhegmatogenous retinal detachment macula center detached, tractional retinal detachment macula 
center attached, tractional retinal detachment macula center detached, and exudative retinal
detachment macula center attached, exudative retinal detachment macula center detached, other 
retinal detachment, round (atrophic) retinal hole, lattice degeneration.
Optic Nerve:
The optic nerve should be evaluated for pathology. If pathology is present, it will be described along 
with approximate clock location. It will be noted if the condition is not evaluable.
C/D Ratio:
C/D ratio should be reported using a 0.0 to 1.0 scale. It will be noted if the condition is not evaluable.
3.23 Pharmacokinetics Sampling (Selected Sites Only)
Pharmacokinetic (PK) samples for quantification of AGN-190584 in plasma will be collected at selected 
sites in approximately 10% of all enrolled subjects. Please refer to the Central Laboratory Manual for 
full collection, processing, and shipping information for pharmacokinetic blood samples.
Blood Pharmacokinetic Sampling Procedure
A qualified phlebotomist will collect 5 mL of each subject's blood via an indwelling catheter or 
venipuncture from either arm into one 6 mL vacutainer tube containing dipotassium 
ethylenediaminetetraacetic acid as an anticoagulant.

Plasma samples of approximately 2.5 mL will be separated from each blood sample collected for 
measurement of plasma concentrations of AGN-190584 as specified in the Protocol Activity 
Schedule (Appendix D).

Instructions for the collection and handling of biological samples will be provided by AbbVie.  
The actual date and time (24-hour clock time) of each sample will be recorded.  Pharmacokinetic 
blood samples to determine pilocarpine concentrations should be drawn at the nominal times, 
relative to the dosing time, and the actual time of the blood draw must be recorded in the 
source documents and Electronic case report form (eCRF).  Samples taken outside the allowable 
time window will be noted as protocol deviations, and the reason for deviation must be 
recorded in the source documents and eCRFs.  Predose samples must be drawn within 15 
minutes of the dosing time.

Study center staff will record the atomic clock times of all blood draws for each participant and 
will label vacutainer and polypropylene tubes with a coded label that corresponds to the 
participant number and blood draw time.  The central lab will supply the coded labels, 
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vacutainers, and polypropylene tubes.  The study center will be responsible for all other 
supplies.

Samples will be used to evaluate the pharmacokinetics of pilocarpine.  Each plasma sample will 
be divided into 2 aliquots (1 each for primary and backup PK samples).  Samples collected for 
analyses of pilocarpine plasma concentration may also be used to evaluate safety or efficacy 
aspects related to concerns arising during or after the study. 
Drug concentration information that would unmask the study will not be reported to investigative sites 
or blinded personnel until the study has been unmasked.
Bioanalytical representatives will be unmasked for PK sample bioanalysis during the conduct of the 
study.  The unmasking of bioanalytical representatives is to be carried out in a secure manner following 
AbbVie's standard operating procedure (SOP).  Extreme care and diligence will be taken to ensure no 
other individuals outside the bioanalytical team will be unblinded.
Blood Volume Collected per Participant
Approximately 10% of participants at selected sites
Pharmacokinetic blood samples: 110 mL (22 blood samples, 5 mL each)
Within 30 minutes from the time of the blood draw, blood samples must be centrifuged at no less than 
2000 g for 15 minutes at approximately 4°C.  After centrifugation, the plasma samples will be harvested 
and aliquoted into two approximately 1.25 mL samples in cryovials (one primary and one backup).  The 
samples should be placed on wet ice immediately after aliquoting and transferred to a –20°C freezer 
within one hour of processing to plasma.
Study center staff will send plasma samples to the central lab for storage at the end of each period.  
Before shipment and on the day of shipment, the sponsor and the central lab will be notified by email as 
to the time and method of shipment.  Primary and backup samples will be shipped to the central lab in 
separate shipments on separate days.
Pharmacokinetic Sample Bioanalysis
Plasma concentrations of AGN-190584 in plasma will be determined using validated liquid 
chromatography-tandem mass spectrometry methods.
3.24 Dispense Study Drug
Study drug will be dispensed to subjects beginning at Day 1 and as specified in Section 2.1. The first 
dose of study drug will be administered after all other Day 1 procedures are completed. At the visits 
specified in Section 2.1, the site personnel will review returned study drug kits, and empty study drug 
packaging to verify drug accountability.
Each site will be responsible for maintaining drug accountability records including product description, 
manufacturer, and lot numbers for all noninvestigational product (IP) dispensed by the site.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
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3.25 Subject Withdrawal from the Study
All attempts must be made to determine the date of the last study drug dose and the primary reason for 
discontinuation of study drug or study participation. The information will be recorded on the 
appropriate eCRF page. However, these procedures should not interfere with the initiation of any new 
treatments or therapeutic modalities that the investigator feels are necessary to treat the subject's 
condition. Following discontinuation of study drug, the subject will be treated in accordance with the 
investigator's best clinical judgment, irrespective of whether the subject decides to continue 
participation in the study.
3.26 Unscheduled Visits
An Unscheduled Visit should be performed when the subject comes in for a medical visit for evaluation 
and assessment. During Unscheduled Visits, ocular examinations may be performed at the 
investigator's discretion.
Visits for dispensing new study drug in case of temperature excursion, loss, or damage are not 
considered Unscheduled Visits.
4 SAFETY MANUAL
4.1 Methods and Timing of Safety Assessment
All adverse events, whether solicited or spontaneously reported by the subject, will be collected from 
the time of study drug administration through study exit, unless spontaneously report after study exit.  
In addition, study procedure-related serious and nonserious adverse events will be collected from the 
time the subject signs the study-specific informed consent.
Figure 4.
Adverse Event and Serious Adverse Event Collection Schema
AE = adverse event; SAE = serious adverse event
Note:
Spontaneous report only after study exit.
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Supplemental Headache AE Assessment
Whenever a headache AE is reported after the initial dosing at Day 1, the subject should be immediately 
followed up with a supplemental headache AE assessment form to further assess the headache.  The 
supplemental headache AE assessment form contains three visual analog scales (VAS) that the subject 
will complete to grade the overall severity, the temporal severity (if applicable), and the supraorbital 
severity (if applicable).  The subjects will be asked to make a vertical mark along each horizontal 100 mm 
long VAS, ranging from No Pain on the left to Worst Possible Pain on the right. 
Figure 5.
Visual Analog Scale
The evaluator should also ask the subject the additional questions on the headache AE assessment form.  
If a headache started after administration of both the first and second doses of study drug, then these 
additional questions should be answered about whichever headache had worse outcomes.  For 
example, "How long after taking the study drug did the headache/migraine start?" should reflect 
whichever headache had the quickest onset, and "How long did the headache/migraine last? (if 
intermittent, approximately how long did each event last)" should reflect whichever headache had the 
longest duration.
The evaluator should measure the distance from the end of the line to the mark that the subject made
with a ruler and record the length on the supplemental headache assessment worksheet.  
If a headache is classified as intermittent or recurrent with the same causality and severity, then one 
supplemental headache AE assessment form should be used. If the subject experiences multiple 
headaches with different causality or severity, then each headache should have its own supplemental 
headache AE assessment form.
COVID-19 Pandemic-Related Acceptable Protocol Modifications
Supplemental study CRFs should be completed in the event of COVID-19-related missed/virtual visits, 
study drug interruptions or discontinuations, or AEs (including capture of specific signs/symptoms of 
infection and testing results).
Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infections should be captured as AEs. If 
the event meets the criteria for a SAE, then follow the SAE reporting directions per the protocol and 
above. The following COVID-19-related supplemental eCRFs should be completed (for both serious and 
nonserious events):

COVID-19 Supplemental Signs/Symptoms

COVID-19 Status Form
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If a subject has a confirmed or suspected SARS-CoV-2 infection and study drug was interrupted, the 
investigator should contact the sponsor emergency medical contact listed above before reintroducing 
study drug.
Reactions known to be associated with the SARS-CoV-2 vaccine should be reported as AEs. If the event 
meets the criteria for an SAE, then follow the SAE reporting directions. All AEs associated with the SARS-
CoV-2 vaccine will be linked to the vaccine on the COVID-19 Vaccine eCRF.
5 COUNTRY-SPECIFIC REQUIREMENTS
5.1 SUSAR Reporting
AbbVie will be responsible for SUSAR reporting for the IMP in accordance with global and local 
guidelines and Appendix A of the Investigator Brochure will serve as the Reference safety information.
6 STUDY DRUG AND SUPPLIES
6.1 Study Supplies
AbbVie will supply the following:

Unilateral pupillometer

Pupillary distance ruler

Distance and near visual acuity charts

Light meters

Oxford scale

Yellow barrier filter for corneal fluorescein staining (if needed)

Sodium fluorescein DET strips (if needed)

Lectern

Paper OSDI and NEI VFQ-25 questionnaires

Tablet for electronic questionnaires

An iPhone with a screen size of 4.7 to 5.8 inches diagonally for the VFA app. The following 
iPhone models meet this specification: iPhone 6s, iPhone 6s Plus, iPhone 7, iPhone 7 Plus, 
iPhone 8, iPhone 8 Plus, iPhone X, iPhone Xs, iPhone 11 Pro, iPhone 12 Mini, and second-
generation iPhone SE (introduced in 2020). AbbVie must choose only one model and use across 
all sites. Subjects will not take the iPhone home, as the VFA app is only administered at site 
visits, using the site-provided iPhone.

Laboratory supplies for pharmacokinetic samples for selected sites. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
The investigator will supply the following:

Dilating eyedrops (1.0% tropicamide ophthalmic solution and 2.5% phenylephrine ophthalmic 
solution)

Artificial tears/lubricating solution for gonioscopy

Topical anesthetic (0.5% proparacaine ophthalmic solution)

Occluder

Urine pregnancy test kits

Stopwatch

Ruler/tape measure to measure 4-meter lane

Internet connection (high-speed connection for eCRF completion) equipment for all other 
examinations and measures
Subjects who wear bifocal or multifocal spectacles or contact lenses will be provided with a pair of 
monofocal spectacles with the same or improved distance correction (20/32 or better) as their new 
habitual correction. Subjects whose distance habitual corrections are worse than 20/32 will also be 
provided with a pair of new spectacles with improved distance correction (20/32 or better). Subjects 
are required to wear the newly provided spectacles for at least 7 days before Day 1 and during the 
study, and no bifocal or multifocal or old habitual correction lenses should be used. Either monofocal 
spectacles or contact lenses can be worn between study visits, but only spectacles can be worn on the 
study visit days. Reading glasses are allowed between visits when needed.
6.2 Treatments Administered
The study drug (AGN-190584) will be dispensed and administered in the form of eyedrops at designated
study visits by site personnel. On nonvisit days, subjects will be instructed to take the study drug as 
described in Section 5.7 of the protocol.
AGN-190584 will be administered in both eyes twice daily in the morning and the afternoon. On the day 
before office visits, the study drug should not be administered less than 12 hours before the scheduled 
visit time.
Study drug can only be dispensed to subjects enrolled in the study through the IRT system. At the end 
of the Treatment Period or at the Premature D/C visit, the site will contact the IRT system to provide 
visit date information and study drug return information for each kit.
6.3 Packaging and Labeling
As this is a double-masked study, AGN-190584 and vehicle will be supplied in identically appearing 
bottles and cartons (Figure 6).
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Figure 6.
AGN-190584 Bottle and Carton

1 carton = 1 kit 

Each kit/carton 

Labeled Carton:  Site to complete blank spaces on the carton label

Contains one (1) sterile 5 mL bottle with a 3.5 mL fill

Affixed label that corresponds to the outer carton/kit label 

IRT will assign one (1) kit/carton per dispensing.
Subjects will be dispensed a carton (1 kit) of IP upon completion of all Day 1 procedures. Subjects 
should keep the bottle in the outer carton and must bring all used and unused kit(s) for on-site visits as 
these will be used to perform on-site administration. 
All used and unused IP MUST BE returned by the subject to the site at study completion; IP should be 
destroyed onsite per site SOPs or return to depot.
Page 87 of 113
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Ophthalmlc SOI.-, or Vehicle 
:•, 
Stt:rlle 
Kit # : XXXXXXX 
Lot # : LL-LLLLLL 
Subject # : ______ _ 
Date Dispensed: ____ _ 
AbbVle, North Chicago, IL 60064 USA 
M21-195 
AGN 190584 Pilo HCI 1.25% Ophthalmic Solution or Vehicle 
3.5 ml 
/ 
Bottle 
For Topical Ophtha lmlc Use Only 
Administer as directed by your Investigator. 
Store between 2°c to s0 c (36°F to 46°F). 
Keep out of the reach of children. 
Keep bottle In outer carton. 
Sterile 
Caution: New Drug - Limited by United States law to lnvestigational use. 


p. 44 of 67
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.4 Shipment of Study Drug
Shipments will be shipped in preconditioned shippers (no temperature monitors will be included), 
including packing list and study intervention. Upon receipt of the shipment the site should 
confirm/verify the shipment contents against the packing list: 

Site # / PI name 

Kit numbers

Quantity of kits 

Condition of kits 

Expiry (if applicable) 

Lot No. 
The original packing list should be filed in the site ISF. Any discrepancies should be reported to the 
assigned site monitor.
IP Shipment – Temperature Monitoring
No temperature monitors will be included with shipments because the shippers that the study drugs are 
sent in will be prequalified shippers that will maintain the temperature between 2 °C and 8 °C. 
Registering Shipments (Consignments) into IRT
Each shipment of IP has a corresponding consignment assignment as noted on the packing list. These 
consignments must be registered into the EndPoint IRT system immediately upon receipt.
Storage and Disposition of Study Drug
The IPs are for investigational use only and are to be used only within the context of this study. The 
study drug supplied for this study must be maintained under adequate security and stored under the 
conditions specified on the label until dispensed for subject use or destroyed on site as appropriate.
Excursion Reporting
Physically set aside affected study intervention under labeled storage conditions, then enter the 
temperature excursion into ATEMS; ATEMS will automatically provide an assessment and show the new 
study intervention status. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
6.5 Method of Assigning Subjects to Treatment Groups
Subjects will be randomized in a 1:1 ratio into the following treatment groups: 
Treatment
Dosing Schedule
AGN-190584 1.25%
1 drop OU, twice daily, 6 hours apart for 14 days
Vehicle
Stratification is based on the following factors at either screening or Baseline/Day 1: 
Age at Screening 

≤50 years 

> 50 years
Screening 
Binocular Mesopic DCNVA Severity

20/63 or Better (≤50%)

Worse than 20/63
Baseline/Day 1
Iris color 

Brown 

Nonbrown
Screening 
Emmetrope status* 

Emmetrope 

Nonemmetrope (≤25%) 
Screening
* Emmetrope status is confirmed via screening cycloplegic refraction.  See Section 3.14 for details.
If correction for each eye is within sphere range of -0.50 D to +0.75 D inclusive and ≤ 0.75 D in Cylinder, 
the subject is considered an emmetrope. If one or both eyes are out of the range, the subject should be 
considered a nonemmetrope. 
Note: Refractions may be transcribed in plus or minus cylinder notation to determine whether 
inclusion criteria and/or emmetrope definitions are met.
At the screening visit, all subjects will be assigned a unique subject number using the IRT. For subjects 
who do not meet the study selection criteria, the site personnel must contact the IRT system and 
identify the subject as a screen failure.
Sites are to enter required information into IRT either in real time or shortly after a reportable event to 
ensure timely reporting of the overall study status. Interactive response technology will provide the 
subject identification number per consented subject; this number will identify the subject throughout 
the course of the trial. Contact information and user guidelines for IRT use will be provided to each site.
Interactive response technology will control the stratification for the trial. Once a stratum cap has been 
reached, no additional subjects can be enrolled; therefore, screening entries of age, iris color, and 
emmetrope status will determine the general stratification, which is confirmed on Baseline/Day 1 with 
the entry of the 1-hour DCNVA, OU. Once a stratum has been filled no additional subjects meeting 
those stratum factors can be randomized/enrolled. Therefore, sites must review the screening entries 
prior to Baseline/Day 1 to ensure proper stratification (with corresponding documentation), updating 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
IRT entries if needed. Upon randomization these factors cannot be updated and will affect the stratum 
population.
* NOTE- ERRORS IN ENTERING THE STRATUM GROUP IN IRT MAY IMPACT THE RANDOMIZATION OF THE 
SUBJECT AND DATA ANALYSIS. PLEASE ENSURE THAT THE ASSIGNED STRATUM GROUP YOU SELECTED 
IN IRT IS ACCURATE BEFORE PROCEEDING IN THE SYSTEM. AFTER YOU PROCEED, YOU CANNOT CHANGE 
THE STRATUM GROUP.
6.6 Selection and Timing of Dose for Each Subject
Baseline/Day 1
Upon randomization in IRT, site staff should perform the following prior to administration/dispensing to 
ensure per kit/carton: 

Verify against carton/kits pulled against assigned carton/kits via IRT printout 

Verify carton/kit label against affixed bottle label 
Any discrepancies should be reported to the site monitor upon identification.
Baseline/Day 1 IP administration: Upon completion of all Hour 0 procedures (immediately after VAS if 
applicable) and prior to the tolerability assessment/drop comfort questionnaire, site staff will administer 
one (1) drop in each eye with one of the two (2) drop bottles at 8AM ± 1 hour and no sooner than
6 hours + 15 minutes after the first administration.
Site staff will demonstrate the IP administration to educate the subject about the at-home dosing 
procedures. The site will review the subject instructions for at-home and in-office study visit 
administration, IP storage/transport, and any warnings. Printed subject dosing instructions should be 
provided with the IP when dispensed prior to the end of the visit, with any subject education noted 
within source.
Study Visits: IP Administration/Compliance
On visit days site staff will administer IP at Hour 0 in a similar fashion to Baseline/Day 1 at 8AM ± 1 hour 
and again 6 hours after the first administration within + 15 minutes.
Subjects are to bring all used and unused IP for study visits, returning all by the end of their 
participation. On-site administration will occur with the IP dispensed during the Baseline/Day 1 visit 
that is returned. Therefore, subjects should be instructed to bring all used and unused IP for study visits. 
At the conclusion of participation all IP dispensed (used and unused) must be returned to the site for
destruction.
Subjects should not self-administer IP prior to the visit on the visit day, and should provide staff the 
approximate time of their last self-administration (last self-administration should occur no sooner on 
the day before a study visit than 12 hours prior to their scheduled visit time). During study visits, site 
staff should discuss compliance with daily IP administration and assess reasons for not administering for 
safety and/or re-education needs, documenting discussion accordingly.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7 Appendices
7.1 STUDY-SPECIFIC ABBREVIATIONS AND TERMS
Abbreviation
Definition
AE
adverse event
BID
twice daily
CDVA
corrected distance visual acuity
COVID-19
Coronavirus Disease - 2019
CRF
case report form
DCNVA
distance-corrected near visual acuity
EC
Ethics Committee
eCRF
electronic case report form
EDC
electronic data capture
IL
interleukin
IMP
Investigational Medicinal Product
IOP
intraocular pressure
IP
investigational product
IRT
interactive response technology
N/A
not applicable
NEI VFQ-25
25-item National Eye Institute Visual Function Questionnaire
NVPTQ
Near Vision Presbyopia Task-Based Questionnaire
OD
right eye
OS
left eye
OSDI
Ocular Surface Disease Index
OU
both eyes
PD
premature discontinuation
PGIC
patient global impression of change
PGIS
global impression of status
PICQ
Presbyopia Impact and Coping Questionnaire
PK
pharmacokinetic
PRO
patient-reported outcome
SAE
serious adverse event
SARS-CoV-2
severe acute respiratory syndrome coronavirus 2
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
SE
study eye
SOP
standard operating procedure
SUSAR
Suspected Unexpected Serious Adverse Reactions
VAS
visual analog scales
VFA app
Visual Function Assessment application
Page 92 of 113
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
7.2 VFA App Instructions
Background
The VFA app is a custom-developed iOS application that will be used in clinic, in the presence of a 
clinician, to assess a clinical trial subject's ability to read on electronic devices. 
Subjects are asked to read a prespecified text passage on an iPhone. The app will capture coping 
behaviors adopted by users to help them read better (e.g., blinking, squinting, screen tilt), as well as 
metrics on their reading performance (e.g., reading speed).
No videos or images are stored permanently within the app, on the device, or transmitted to any 
external storage.
Conditions for Use
iPhone Specification
Sites should be provided one or more iPhones, depending on the expected maximum number of 
subjects per a site visit.
A single device needs to be chosen from the candidates provided below and used across all sites:
An iPhone with a screen size of 4.7 to 5.8 inches diagonally. The following iPhone models meet this 
specification: iPhone 6s, iPhone 6s Plus, iPhone 7, iPhone 7 Plus, iPhone 8, iPhone 8 Plus, iPhone X, 
iPhone Xs, iPhone 11 Pro, iPhone 12 Mini, and second-generation iPhone SE (introduced in 2020)
Subjects will not take the iPhone home, as the VFA app is only administered at site visits, using the 
site-provided iPhone.
Light Setting and Correction 
VFA should be administered under photopic conditions, with the subject's best distance correction. No 
near-vision correction is allowed.
Only half-eye style trial frames or full-field trial lenses can be used for best distance correction while 
subjects are performing the VFA task. Other forms of correction would interfere with the camera's 
ability to detect subjects' faces.
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Instructions for Downloading the VFA App on iPhone
Before providing sites with iPhones, AbbVie should download the VFA app on each device.
The unique device IDs of the phones need to be e-mailed to 
 – this further 
adds to the app security. A Microsoft's App Center link for the app will be provided for it to be 
downloaded. You will be asked to select your preferred language the first time you open the app.
Page 94 of 113
abbvie 
'1 App Center 
Latest release 
Version 1.03 (1) 
ar 26, 2021 at 16:40 
217 MB 
Sign In 


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Detailed Instructions
Study Site Personnel: Screens 1 to 3
Screen 1: Site login

Login using provided unique site username and password. If 
lost please email 

Choose between English or Spanish language, depending on 
subject preference
Page 95 of 113
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temp 
Login 
Change Language 
Lost Password? 


p. 52 of 67
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Screen 2: Subject identification 
and pupillary distance setting

Enter the subject ID

Select a text passage based on subject ID and visit 
number, per the table provided in the Text Choice 
Selection Guides below. This is to make sure that each 
subject is assigned a different text passage at each visit 
(to avoid the learning bias), and text passages are 
distributed evenly across subjects and visits. 
E.g., for Subject 6, for Visit 1 select text 4.

Measure the subject's pupillary distance and adjust the 
PD dial accordingly.
Page 96 of 113
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Logout 
Home 
q 
Subject 10: 
study subject ID 
Text Selection 
Pupillary 
Distance 
Stan reading test 
'ID' 
IDRA 
w e 
r 
t 
y u 
a 
s d 
g 
h 
z 
X 
C 
V 
b n 
123 
@ 
0 
space 
IDEALLY 
D 
p 
k 
m 
<El 
fOttJm 
1,,y_._,. 
-
Pai-ID 
1_1,.,.__t.on 
PD 
k#ll1--..q ,_ 
qwa 
t
v
u
lo
p 
Pupil Centre to P1.lpil Cerr e 
lnmm 


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Screen 3: Subject instructions

Read the instructions on screen 3 to the subject clearly, 
and press continue. 

Then hand the smartphone to the subject.
Page 97 of 113
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Introduction 
Aspa,1or 
• 
• 
a 
that 
you use this 
artide 
and 31"1SV/Cf 
about the 
he words 
in tho ande 
them. 
wantto 
bi 
to 
the words s you read. 
You will have the opportunity before you 
beg n reading to adjust the size 
nd 
contrast ( 
ol t 
t 
You 
can also 
ts o the text 
whloyou 
¥tide. 
You can M'ligate tlvough th s app nd 
us 
the touchscr en th 
w y you 
normaly do 
your sma,tphone. 
I« )'OU 
r 
q.iestJ0n 
about the alticle, the app wit ask you to 
two mul ple-chooot 
lions 
about your abllty to road tho t 


p. 54 of 67
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Subject: Screens 4 to 13
Screen 4: Screen manipulation 
details

Ask the subject to read the instructions and press 
continue to progress.
Page 98 of 113
abbvie 
( 
Pago 2/S 
Instructions 
On tho noxt 
n, you w II bo gi n 
bit of samplo toxt that you c.in adju t 
to ppe r tho way you want the text of 
the rtlc to ppe r. 
To chango lhe to 
size, pinch to zoom 
on your smartphono 
set n. 
To 
the text 
dark r, move tho 
Contra slider I 
the bottom of tho 
to~ 
tlg 
your linger on 
Yl)l.w touchscreento 
SCfoll up nd down. 
Pie se mak the text only as big a.nd 
as dark as you need tor ad 
comfortably. In o~ words, 
s ndmg 
canbefo, 
it 
With no problem. 
You may 
adJUStmon s to tho IOX1 ol 
the 
iclo 
any ume. 


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Screen 5: Initial size/contrast setting

Explain to the subject that he/she can pinch to 
change size and move the slider to change contrast. 

Ask him/her to take a moment to apply these 
adjustments if needed. Remind him/her to make text 
only as dark and large as he/she needs to read it 
easily.
Screen 6: Phone orientation:

The subject must hold the smartphone so the screen 
is directed towards his/her face – if not, a tone will 
bleep. A tone during the task will warn him/her that 
the phone position needs to be adjusted.

If the face is not detected once he/she is holding the 
phone in the right position, the operator should 
check the lighting level and that the lens angle in the 
trial frame is not causing reflections.
Page 99 of 113
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I 
( 
Page3/8 
Adjust Text Size and Contrast 
Adjust the size of the text below ("Can 
you read this?") using pinch to zoom on 
your touchscreen. 
Make the text only as large as you need 
to read it easily. 
Can you read this? 
Adjust the contrast (darkness) of the 
text by moving the slider to the left or 
nght. 
Make the text only as dark as you need 
to read it easily. 
. 
( 
Page3/6 
Center your face 
Please keep the screen directed at your 
face throughout the test. 
K] 
At the start of the test you will hear an 
audible tone to signify that the test is 
collecting data. If you hear a tone after 
this then the device is not able to 
recognise your face. Please return your 
face to the middle of the screen. 


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Screen 7: Confirmation of being 
ready to start reading

The subject clicks "OK" when ready to start reading 
the text passage.
Screen 8: Reading task

The subject reads silently, scrolling to the 
bottom of the screen and pressing 
"Finished" once he/she has read all the 
text.

He/she can adjust the text size and 
contrast at any time as practiced.
Page 100 of 113
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Ready to begin reading? 
Press OK and read the article silently 
to yourself. 
When you are finished, press the 
"FINISHED" button 
---
Henri Matisse 
One ol lhe mos, Imponan1 
artists of the 1wentielh 
cenlury was Frenchman Henn 
Matisse. He led an art 
movement called post-
Impressionism and was one of 
the fIrs1 famous collage artists 
Throughout his career. 
Matisse experimented with 
different colors, art lonms, and 
mediums. He did not follow 
the established rules of art-
he created his own. 
. . . . 
Matisse was a man with a 
mischievous personality and 
keen sense of humor-
characteristics that are 
reflected in his artwork. As a 
master of color, he brought a 
special joyfulness and a 
childlike perspective to his art. 
When Matisse died in 1954, 
he left a part of himself behind 
for all future generations to 
enjoy. -


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Screen 9: Reading completion 
confirmation

Confirmation that reading has been completed
Screen 10: Question on text 
comprehension

The subject answers a simple true/false question 
about the text he/she has read – click the box to 
tick.
Page 101 of 113
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Page 6/6 
Please answer the following question 
about the article you just read. 
1. True or false: Matisse is considered 
the founder of a new style of art that 
uses bold colors and shapes. 
True D 
False D 
*''* 


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Screen 11: Question on ability to 
read the text

The subject answers two questions about the 
subject's ability to read the article – click the box to 
tick.
Screen 12: Answer review and 
confirmation

This screen gives subjects the opportunity to 
confirm/change responses before submitting them. 

Explain to subjects that once they click the 'Confirm'
button, they cannot go back and change responses.
Page 102 of 113
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( 
Page 5/6 
' 
Please answer the following questions 
about your ability to read the text. 
2. How would you rate your ability to 
read the text in the article? 
I could not read any of the text 
due to problems seeing up close 
Poor 
Fair 
Good 
Very Good 
Excellent 
3. How satisfied are you with your 
( 
Page B/8 
Confirm Answers 
Please take a moment to review your 
answers. Once you confirm your answers, 
you cannot change them anymore. 
1. True or false: Researchers are cenain 
that the stone tablet is an ancient map. 
False 
2. How would you rate your ability to read 
the text in the article? 
Fair 
3. How satisfied are you with your ability 
to read the text in the article? 
Neither satisfied nor dissatisfied 
Conhrm 
Back 


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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Screen 13: Task completion 
confirmation

At this point, the subject should hand the phone 
back to the study site personnel. 
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OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Study Site Personnel: Screens 14, 15
Screen 14: Video processing

This screen represents a short delay while face video is 
processed and features extracted – the video is not 
saved.

Press 'OK' to continue.
Screen 15: Summary report

Results are displayed and automatically 
saved and transmitted to the Cloud. 

If the Wi-Fi fails, the data will 
automatically be transmitted when the 
phone is next in contact with a Wi-Fi 
connection.
Page 104 of 113
abbvie 
RaulUSummlly 
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di>t..-.:e 355cm 
MM d<slMlce 38.1 cm 
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01) True 
02)E•-
031 Yery .. llSI_, 


p. 61 of 67
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Handling Wi-Fi Connectivity Issues During the VFA App Administration
Wi-Fi issue while data is being transferred to the cloud-based storage
Every app on iOS has local storage called an app sandbox. No other app or even the user can get into 
this app sandbox, only the app itself. This is a fundamental feature of the iOS operating system, and 
why it is so secure. The data get temporarily stored in the app's sandbox if the app does not have an 
internet connection, and will try again periodically; we call this secure 'Caching.' If the internet 
connection resumes and a response from the server is received the data get sent and cleared from the 
cache or successfully submitted. The app can only access the specific user's cache if the user is logged 
in. So once the connection is resolved, the site study personnel need to log in to the app again for data 
to be transferred to the cloud storage.
Wi-Fi issue at some point before subjects complete the task
The app will continue as normal once connection is restored. Any data that can't be sent will be stored 
in the cache, waiting for two things, one for internet connection, and two for the right authenticated 
user to be logged in before sending again. So once the connection is resolved, the site study personnel 
should log in to the app again, and the subject can complete the task.
Page 105 of 113
abbvie 


p. 62 of 67
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Text Choice Selection Guides
Table 3.
Text Choice Selection Guide for English Language
SUBJECT ID*
Visit 1 Text No.
Visit 2 Text No.
Visit 3 Text No.
1
EN 1
EN 2
EN 5
2
EN 5
EN 4
EN 1
3
EN 3
EN 4
EN 2
4
EN 2
EN 1
EN 3
5
EN 5
EN 1
EN 4
6
EN 4
EN 3
EN 5
7
EN 2
EN 3
EN 1
8
EN 1
EN 5
EN 2
9
EN 4
EN 5
EN 3
10
EN 3
EN 2
EN 4
11
EN 1
EN 3
EN 4
12
EN 2
EN 4
EN 5
13
EN 3
EN 5
EN 1
14
EN 4
EN 1
EN 2
15
EN 5
EN 2
EN 3
*
This column should be filled with unique study subject IDs at each site.
Page 106 of 113
abbvie 


p. 63 of 67
OPERATIONS MANUAL FOR CLINICAL STUDY PROTOCOL M21-195 Version 2.0
CONFIDENTIAL INFORMATION
No use or disclosure outside AbbVie is permitted without prior written authorization from AbbVie.
Table 4.
Text Choice Selection Guide for Spanish Language
SUBJECT ID*
Visit 1 Text No.
Visit 2 Text No.
Visit 3 Text No.
1
SP 1
SP 2
SP 5
2
SP 5
SP 4
SP 1
3
SP 3
SP 4
SP 2
4
SP 2
SP 1
SP 3
5
SP 5
SP 1
SP 4
6
SP 4
SP 3
SP 5
7
SP 2
SP 3
SP 1
8
SP 1
SP 5
SP 2
9
SP 4
SP 5
SP 3
10
SP 3
SP 2
SP 4
11
SP 1
SP 3
SP 4
12
SP 2
SP 4
SP 5
13
SP 3
SP 5
SP 1
14
SP 4
SP 1
SP 2
15
SP 5
SP 2
SP 3
*
This column should be filled with unique study subject IDs at each site.
Page 107 of 113
abbvie 









SAP_001.pdf: 
AGN-190584 
M21-195 – Statistical Analysis Plan 
Version 1.0 – 19 November 2021 
 
 
1 
Statistical Analysis Plan for Study M21-195 
A Phase 3, Multicenter, Double-Masked, 
Randomized, Vehicle-Controlled, Parallel-Group 
Study Evaluating the Safety and Efficacy of BID 
Dosing of AGN-190584 in Subjects with Presbyopia 
 
Date:  19 November 2021 
 
Version 1.0 
 
 
NCT04983589


AGN-190584 
M21-195 – Statistical Analysis Plan 
Version 1.0 – 19 November 2021 
 
 
2 
Table of Contents 
1.0 
Introduction ............................................................................. 5 
2.0 
Study Design and Objectives .................................................. 5 
2.1 
Objectives, Hypotheses and Estimands .....................................................5 
2.1.1 
Objectives ..................................................................................................5 
2.1.2 
Hypotheses .................................................................................................5 
2.1.3 
Estimands ...................................................................................................6 
2.2 
Study Design Overview .............................................................................6 
2.3 
Treatment Assignment and Blinding .........................................................8 
2.4 
Sample Size Determination ........................................................................8 
3.0 
Endpoints .................................................................................. 9 
3.1 
Primary Endpoint(s) ...................................................................................9 
3.2 
Secondary Endpoint(s) ...............................................................................9 
3.2.1 
Key Secondary Endpoint ...........................................................................9 
3.2.2 
Supportive Secondary Endpoints ...............................................................9 
3.3 
Additional Efficacy Endpoint(s) ..............................................................10 
3.4 
Safety Endpoint(s) ...................................................................................10 
3.5 
Pharmacokinetic Endpoints .....................................................................10 
3.6 
Patient Reported Outcomes ......................................................................11 
4.0 
Analysis Populations ............................................................. 12 
5.0 
Subject Disposition ................................................................ 12 
6.0 
Study Treatment Duration ................................................... 13 
7.0 
Subject Characteristics ......................................................... 13 
7.1 
Demographics and Baseline Characteristics ............................................14 
7.2 
Medical History .......................................................................................14 
7.3 
Prior and Concomitant Medications ........................................................15 
7.4 
Protocol Deviations ..................................................................................16 
8.0 
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints .............................. 16 
9.0 
Efficacy Analyses ................................................................... 17 
9.1 
General Considerations ............................................................................17 
9.2 
Handling of Missing Data ........................................................................18 


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9.3 
Primary Efficacy Endpoint(s) and Analyses ............................................ 18 
9.3.1 
Primary Efficacy Endpoint ......................................................................18 
9.3.2 
Main Analysis of Primary Efficacy Endpoint .......................................... 18 
9.3.3 
Sensitivity and Supplementary Analyses of the Primary Efficacy 
Endpoint ...................................................................................................20 
9.4 
Secondary Efficacy Endpoints and Analyses ..........................................21 
9.4.1 
Key Secondary Efficacy Endpoint ........................................................... 21 
9.4.2 
Main Analyses of Key Secondary Efficacy Endpoint .............................21 
9.4.3 
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoint ....................................................................................23 
9.4.4 
Supportive Secondary Efficacy Endpoints and Analyses ........................24 
9.5 
Additional Efficacy Endpoints and Analyses ..........................................24 
9.6 
Exploratory Efficacy Endpoints and Analyses ........................................ 25 
9.7 
Efficacy Subgroup Analyses .................................................................... 26 
10.0 
Safety Analyses ...................................................................... 27 
10.1 
General Considerations ............................................................................27 
10.2 
Adverse Events ........................................................................................27 
10.2.1 
Treatment-Emergent Adverse Events ......................................................28 
10.2.2 
Adverse Event Overview .........................................................................28 
10.2.3 
Treatment-Emergent Adverse Events by SOC and/or PT .......................29 
10.2.4 
SAEs (Including Deaths) and Adverse Events Leading to Study 
Treatment Discontinuation .......................................................................30 
10.2.5 
Adverse Events of Special Interest .......................................................... 30 
10.2.6 
Headache Assessment ..............................................................................31 
10.3 
Analysis of Laboratory Data ....................................................................33 
10.4 
Analysis of Vital Signs ............................................................................ 33 
10.5 
Other Safety Analyses ..............................................................................33 
10.5.1 
Mesopic, High-Contrast, Binocular CDVA .............................................33 
10.5.2 
Photopic, High-Contrast, Binocular CDVA ............................................33 
10.5.3 
Intraocular Pressure .................................................................................33 
10.5.4 
Slit Lamp Biomicroscopy ........................................................................34 
10.5.5 
Manifest Refraction .................................................................................34 
10.5.6 
Dilated Fundoscopic Examination ...........................................................34 


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10.5.7 
Post-DoseTolerability ..............................................................................35 
10.5.8 
Drop Comfort ...........................................................................................35 
10.6 
Safety Subgroup Analyses .......................................................................35 
11.0 
Other Analyses ....................................................................... 36 
12.0 
Interim Analyses .................................................................... 36 
12.1 
Data Monitoring Committee ....................................................................36 
13.0 
Overall Type-I Error Control .............................................. 36 
14.0 
Version History ...................................................................... 37 
15.0 
References ............................................................................... 37 
 
List of Tables 
Table 1. 
Summary of the Estimand Attributes of the Primary Efficacy 
Endpoint ...................................................................................................19 
Table 2. 
Summary of the Estimand Attributes of the Key Secondary 
Efficacy Endpoint ....................................................................................22 
Table 3. 
SAP Version History Summary ...............................................................37 
 
List of Figures 
Figure 1. 
Study Schema .............................................................................................7 
 
List of Appendices
Appendix A. 
PRO Scoring Algorithm ...........................................................................38 
Appendix B. 
Definition of Adverse Events of Special Interest ....................................39 
Appendix C. 
List of MedDRA Preferred Terms for COVID-19 Infection ................... 40 
 
 
 


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1.0 
Introduction 
This Statistical Analysis Plan (SAP) describes the statistical analyses for AGN-190584 
Study M21-195 with the protocol title of "A Phase 3, Multicenter, Double-Masked, 
Randomized, Vehicle-Controlled, Parallel-Group Study Evaluating the Safety and 
Efficacy of BID Dosing of AGN-190584 in Subjects with Presbyopia." 
Pharmacokinetic analyses are not covered in this SAP. 
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 under the Linux operating system. 
2.0 
Study Design and Objectives 
2.1 
Objectives, Hypotheses and Estimands 
2.1.1 
Objectives 
The primary objective of this study is to evaluate the safety, efficacy, and 
pharmacokinetics of AGN-190584 when administered bilaterally, twice daily for 14 days 
in subjects with presbyopia. 
2.1.2 
Hypotheses 
The clinical hypotheses are that AGN-190584 ophthalmic solution dosed bilaterally, twice 
daily (Hour 0 and Hour 6) for 14 days will demonstrate a significant improvement in 
distance-corrected near visual acuity (DCNVA) over vehicle after the second dose, and 
AGN-190584 ophthalmic solution dosed bilaterally, twice daily for 14 days will 
demonstrate an acceptable safety and tolerability profile. 


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The hypotheses for primary endpoint and the secondary endpoints will be tested in a 
sequential order:  
● H1 Primary:  The proportion of subjects gaining 3 lines or more in mesopic, 
high-contrast, binocular DCNVA with no more than 5-letter loss in mesopic 
corrected distance visual acuity (CDVA) with the same refractive correction at 
Day 14, Hour 9 (3 hours after the second dose) 
● H2: Key Secondary:  The proportion of subjects gaining 3 lines or more in 
photopic, high-contrast, binocular DCNVA with no more than 5-letter loss in 
photopic CDVA with the same refractive correction at Day 14, Hour 9 (3 hours 
after the second dose) 
● H3 Supportive Secondary:  The proportion of subjects gaining 2 lines or more 
in mesopic, high-contrast, binocular DCNVA with no more than 5-letter loss in 
mesopic CDVA with the same refractive correction at Day 14, Hour 9 (3 hours 
after the second dose) 
● H4 Supportive Secondary:  The proportion of subjects achieving 20/40 or 
better in mesopic, high-contrast, binocular DCNVA with no more than 5-letter 
loss in mesopic CDVA with the same refractive correction at Day 14, Hour 9 (3 
hours after the second dose) 
 
2.1.3 
Estimands 
The details of estimands are listed in Table 1 (Section 9.3.2) for the primary efficacy 
endpoint and Table 2 (Section 9.4.2) for the key secondary efficacy endpoint. 
2.2 
Study Design Overview 
This is a Phase 3, multicenter, double-masked, parallel-group, vehicle-controlled study in 
subjects with presbyopia.  Subjects will receive AGN-190584 or vehicle dosed twice 
daily, bilaterally, for 14 days.  Approximately 200 subjects with presbyopia will be 
enrolled at approximately 20 sites in the United States. 
The study consists of the following visits: screening (Days -30 to -1), Day 1 (baseline), 
Day 7 (± 2 days), and Day 14 (± 2 days).  A study schema is shown in Figure 1.  Subjects 


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7 
will receive either AGN-190584 or vehicle dosed twice daily, bilaterally, for 14 days 
beginning on Day 1.  On nonvisit days, subjects will be instructed to instill one drop of 
the dispensed study treatment in each eye twice daily, with each dose administered 
6 hours apart.  On visit days, study treatment will be instilled bilaterally by designated site 
personnel at Hour 0 (8 AM ± 1 hour) and Hour 6 (time measured 6 hours from the time of 
completion of the Hour 0 study treatment administration).  Study procedures on visit days 
are provided in the Activity Schedule (Protocol Appendix D), and further guidance 
regarding study procedures is located in the Operations Manual (Protocol Appendix E).  
Adult subjects 40 to 55 years of age with objective and subjective evidence of presbyopia 
will be enrolled.  See Protocol Section 5 for information regarding eligibility criteria. 
The schematic of the study is shown in Figure 1. 
Figure 1. 
Study Schema 
 
BID = twice daily; OU = both eyes 
Note: 
At selected sites, blood will be collected for pharmacokinetics (PK) on Days 1 and 14 at Hours 0, 0.25, 0.5, 1, 
3, 6 (pre-dose), 6.25, 6.5, 7, 9, and 12. 
 


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2.3 
Treatment Assignment and Blinding 
Subjects will be randomized in a 1:1 ratio to receive either AGN-190584 or vehicle dosed 
twice daily, in each eye, for 14 days. 
Randomization will be further stratified by the following stratification factors: 
● Age group: ≤ 50 years and > 50 years  
● Baseline binocular mesopic DCNVA severity: 20/63 or better, and worse than 
20/63; with a maximum of 50% enrolled subjects with baseline binocular 
mesopic DCNVA of 20/63 or better  
● Iris color: brown and nonbrown 
● Emmetrope status: emmetrope and nonemmetrope; with a maximum of 
25% enrolled subjects with non-emmetrope.  A subject will be considered as 
emmetrope if both eyes of the subject satisfy the 2 criteria based on best 
cycloplegic distance correction: 1) -0.5D to +0.75D in sphere, inclusively; 
and 2) ≤ 0.75D in Cylinder. 
 
All AbbVie personnel with direct oversight of the conduct and management of the study 
(with the exception of the AbbVie Drug Supply Management Team), the investigator, 
study site personnel, and the subject will remain masked to each subject's treatment 
throughout the study.  To maintain the masking, the AGN-190584 and vehicle containers 
provided for the study will be identical in appearance.  The IRT will provide access to 
unmasking subject treatment information in the case of a medical emergency. 
2.4 
Sample Size Determination 
The sample size calculation was considered for the primary efficacy endpoint, proportion 
of subjects gaining 3 lines or more in mesopic, high-contrast, binocular DCNVA with no 
more than 5-letter loss in mesopic CDVA with the same refractive correction at Day 14, 
Hour 9 (3 hours after the second dose). 
Assuming a responder rate of 25% in the AGN-190584 group and 7% in the vehicle 
group, and a 5% dropout rate, a sample size of 100 subjects per study treatment group will 


AGN-190584 
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9 
provide greater than 90% power using chi-square testing at a 2-sided significance level 
of 5%. 
3.0 
Endpoints 
3.1 
Primary Endpoint(s) 
The primary endpoint is the proportion of subjects gaining 3 lines or more in mesopic, 
high-contrast, binocular DCNVA with no more than 5-letter loss in mesopic CDVA with 
the same refractive correction at Day 14, Hour 9 (3 hours after the second dose). 
3.2 
Secondary Endpoint(s) 
3.2.1 
Key Secondary Endpoint 
Proportion of subjects gaining 3 lines or more in photopic, high-contrast, binocular 
DCNVA with no more than 5-letter loss in photopic CDVA with the same refractive 
correction at Day 14, Hour 9 (3 hours after the second dose). 
3.2.2 
Supportive Secondary Endpoints 
1. 
Proportion of subjects gaining 2 lines or more in mesopic, high-contrast, binocular 
DCNVA with no more than 5-letter loss in mesopic CDVA with the same 
refractive correction at Day 14, Hour 9 (3 hours after the second dose) 
2. 
Proportion of subjects achieving 20/40 or better in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the 
same refractive correction at Day 14, Hour 9 (3 hours after the second dose) 
 


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3.3 
Additional Efficacy Endpoint(s) 
The additional efficacy endpoints are: 
1. 
Change from baseline in mesopic Near Vision Presbyopia Task-based 
Questionnaire (NVPTQ) Performance score at Day 14, Hour 9 (3 hours after the 
second dose) 
2. 
Change from baseline in Presbyopia Impact and Coping Questionnaire (PICQ) 
Coping score at Day 14, Hour 3  
3. 
Change from baseline in Visual Function Assessment application (VFA app) at 
Day 14, Hour 9 (3 hours after the second dose): 
● Change from baseline in average number of blinks per minute  
● Change from baseline in median working distance (centimeters) 
● Change from baseline in median magnification level (%) from the original size 
● Change from baseline in reading speed (words per minute) 
● Change from baseline in median contrast level (%) based on the original value 
 
3.4 
Safety Endpoint(s) 
The safety measurements will include adverse events (AEs), vital signs (blood pressure 
and heart rate), mesopic and photopic, high-contrast, binocular CDVA, intraocular 
pressure (IOP), slit-lamp biomicroscopy, manifest refraction, dilated fundoscopic 
examination, post-dose tolerability, drop comfort, and pregnancy test. 
3.5 
Pharmacokinetic Endpoints 
Blood samples for the quantitation of AGN-190584 in subject plasma will be collected 
from approximately 10% of enrolled subjects at selected sites. 
The analyses of pharmacokinetic endpoints will be covered in a separate analysis plan. 


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3.6 
Patient Reported Outcomes 
At screening, subjects will answer questions on vision functioning and health-related 
quality of life using the NEI VFQ-25, including the near vision subscale items 
(Questions A3 to A5) from the Appendix of Optional Additional Questions. 
Subjects will also complete the Ocular Surface Disease Index (OSDI) at screening, which 
assesses symptoms of ocular irritation and their impact on vision-related functioning. 
Each subject will also perform 4 paper-based near vision reading tasks under mesopic 
conditions.  Subjects will subsequently rate their vision-related reading ability and 
satisfaction with their vision-related reading ability by completing the NVPTQ. 
Subjects will also answer questions assessing the impact of presbyopia on their life and 
need for compensatory coping mechanisms using the PICQ. 
Subjects will also answer single-item questions on their overall global impression of 
status (PGIS) and their overall global impression of change (PGIC).  
After study treatment administration, subjects will complete the Drop Comfort 
Questionnaire to evaluate comfort of the study treatment after administration. 
Finally, the VFA app will be used to assess the subject's ability to read on electronic 
devices. 
In summary, patient-reported outcomes (PROs) are in the following types: 
● Collected at screening visit only for screening purpose, including NEI VFQ-25 
and OSDI.  
● As additional efficacy endpoints, including NVPTQ, PICQ, and VFA app 
individual scores (Section 3.3 and Section 9.5) 
● As safety endpoints, including the Drop Comfort Questionnaire (Section 3.4 
and Section 10.5.8)  


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● The other PROs including NVPTQ Satisfaction domain, PICQ Impact domain, 
PGIS, PGIC, and composite scores from VFA app (Appendix A) are not 
efficacy or safety endpoints.  They are not covered in this SAP (Section 11.0).  
 
4.0 
Analysis Populations 
The following population sets will be used for the analyses. 
The intent-to-treat (ITT) population will consist of all randomized subjects.  Subjects will 
be summarized according to the randomized study treatment. 
The safety population will consist of all subjects who received at least 1 administration of 
study treatment.  Subjects will be summarized according to the study treatment that they 
actually received. 
5.0 
Subject Disposition 
The total number of subjects who were screened will be summarized.  
Subject disposition will be provided for all screened subjects.  The number and percentage 
of subjects in each of the following categories will be summarized in total and for each 
treatment group: 
● Enrolled (randomized) 
○ Never received any study treatment  
○ Received randomized study treatment  
○ Received study treatment other than randomized 
● Treated (took at least one dose of study treatment) 
● Completed the study 
● Discontinued from the study  
● Primary reasons for discontinuation from the study by reason 
 


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Primary reasons for study treatment discontinuation will be provided for all treated 
subjects (the safety population).  The number and percentage of subjects will be 
summarized in total and for each treatment group by reason. 
In addition, disposition by investigator will be provided for the ITT population.  The 
number and percentage of subjects in each of the following categories will be summarized 
in total and for each treatment group by investigator: 
● Enrolled (randomized) in the study 
● Treated (took at least one dose of study treatment) 
● Completed the study 
● Discontinued from the study 
 
6.0 
Study Treatment Duration 
Study treatment duration will be summarized by treatment group for the safety population.   
Duration of treatment is defined for each subject as the last dose date minus the first dose 
date + 1.  Duration of treatment will be summarized using the number of subjects treated, 
mean, standard deviation, median, Q1, Q3, minimum, and maximum.   
In addition, the number and percentage of subjects in each treatment duration interval 
(≥ 7 and ≥ 14 days) will be summarized. 
7.0 
Subject Characteristics 
Demographics, baseline disease characteristics, medical/ophthalmic history, and prior and 
concomitant medications will be summarized for the ITT population overall and by 
treatment group.   
Categorical variables will be summarized with the number and percentage of subjects; 
percentages will be calculated based on the number of nonmissing observations.  
Continuous variables will be summarized with descriptive statistics (number of 


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non-missing observations, mean and standard deviation, median, 1st and 3rd quartiles, 
minimum and maximum. 
7.1 
Demographics and Baseline Characteristics 
Continuous demographic variables include:  
● Age 
 
Categorical demographic variables include: 
● Age group (≤ 50, > 50 years) 
● Sex  
● Ethnicity  
● Race  
 
Baseline disease characteristics include:  
● Baseline binocular mesopic DCNVA severity (20/63 or better, worse than 
20/63)  
● Iris color (brown, non-brown; and within nonbrown: blue, grey, green, and 
hazel) 
● Emmetrope status (emmetrope, nonemmetrope) 
 
For more details on emmetrope status, see Section 3.14 in Protocol Appendix F. 
7.2 
Medical History 
Medical history including prior procedures data will be coded using the Medical 
Dictionary for Regulatory Activities (MedDRA), version 24.1 or higher.  The actual 
version of the MedDRA coding dictionary will be noted in the statistical tables and 
clinical study report.   


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The number and percentage of subjects in each medical history category (by MedDRA 
primary system organ class and preferred term) will be summarized.  The system organ 
class (SOC) will be presented in alphabetical order, and the preferred terms (PTs) will be 
presented in alphabetical order within each SOC.  Subjects reporting more than one 
condition/diagnosis will be counted only once in each row (SOC or PT). 
The following summaries will be provided: 
● Medical history: number (%) of subjects with history ongoing at screening 
● Medical history: number (%) of subjects with history resolved as of screening 
● Ophthalmic medical history: number (%) of subjects with history ongoing at 
screening 
● Ophthalmic medical history: number (%) of subjects with history resolved as of 
screening 
 
An ophthalmic history will be determined as indicated on the Medical History form of 
eCRF (marked "OD," "OS," or "OU" to the question of "What was the location of the 
medical history condition/event?") 
7.3 
Prior and Concomitant Medications 
Medication terms will be coded using the World Health Organization (WHO) Drug 
Dictionary (Version WHODDMAR21B3G).  The version of the dictionary will be noted 
in the statistical tables and clinical study report. 
A prior medication is defined as any medication taken prior to the date of the first dose of 
study treatment.  A concomitant medication is defined as any medication that started prior 
to the date of the first dose of study treatment and continued to be taken after the first dose 
of study treatment or any medication that started on or after the date of the first dose of 
study treatment but not after the last study treatment dose date.   


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The number and percentage of subjects taking medications will be summarized by 
preferred drug name based on the WHO Drug Dictionary for both prior and concomitant 
medications, respectively. 
7.4 
Protocol Deviations 
According to ICH E3 2012 guideline, only important protocol deviations will be reported 
in CSR. 
The number and percentage of randomized subjects with important protocol deviations 
will be summarized overall and by treatment group for subjects reported by protocol 
deviation categories. 
● Subjects who entered the study even though they did not satisfy the entry 
criteria 
○ Subjects with inclusion criteria not met, overall and by inclusion criteria 
○ Subjects with exclusion criteria met, overall and by exclusion criteria 
● Subjects developed withdrawal criteria during the study but were not 
withdrawn 
● Subjects received wrong treatment or incorrect dose of study treatment 
● Subjects took prohibited concomitant medication
● Subjects with any other important deviations 
 
A listing of subjects with important protocol deviations will be provided. 
8.0 
Handling of Potential Intercurrent Events for the 
Primary and Key Secondary Endpoints 
The primary efficacy endpoint (defined in Section 3.1) and the key secondary efficacy 
endpoint (defined in Section 3.2) will be analyzed based on the ITT population and the 
following methods will be used to address potential intercurrent events (IE): 
● Subjects who prematurely discontinued study treatment before the Day 14 visit 
will be considered as nonresponders.  


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● Subjects who die before assessment of the endpoint will be considered as 
nonresponders for the endpoint. 
● Subjects who are lost to follow-up and are missing data for the endpoint will be 
considered as non-responders for the endpoint.  
 
9.0 
Efficacy Analyses 
9.1 
General Considerations 
All efficacy analyses will be conducted for all efficacy endpoints in the ITT population at 
the end of the study and after the database has been locked.  All tests will be 2-sided at an 
alpha level of 0.05.  All confidence intervals (CIs) will be at least 2-sided 95% 
confidence. 
Unless otherwise specified, the comparison of the proportions between AGN-190584 and 
vehicle will be made using the Pearson's chi-square test, and the treatment difference will 
be provided with a 2-sided 95% CI using the normal approximation based on the pooled 
variance without continuity correction. 
Continuous variables will be analyzed using an analysis of covariance (ANCOVA) model 
that includes treatment, age group, baseline DCNVA severity group, iris color group, and 
emmetrope status as factors as well as corresponding baseline value as a covariate. 
Unless otherwise specified, any mis-stratified subject will be analyzed based on the actual 
stratum the subject should have been randomized. 
"Baseline" refers to the last non-missing observation before the first administration of 
study treatment or randomization if no study treatment is given.  The change from 
baseline values will be computed as the postbaseline value minus the baseline value. 


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For descriptive analyses: 
● Categorical variables will be summarized with the number and percentage of 
subjects; unless otherwise stated, percentages will be calculated based on the 
number of non-missing observations. 
● Continuous variables will be summarized with descriptive statistics (number of 
nonmissing observations, mean and standard deviation, median, 1st and 3rd 
quartiles, minimum, and maximum. 
 
9.2 
Handling of Missing Data 
Unless otherwise specified, for the main analyses of primary and secondary efficacy 
endpoints and the other efficacy endpoints based on the binary data, subjects with missing 
data will be regarded as nonresponders.  Other efficacy endpoints will be analyzed as 
observed. 
9.3 
Primary Efficacy Endpoint(s) and Analyses 
9.3.1 
Primary Efficacy Endpoint 
The primary endpoint is the proportion of subjects gaining 3 lines or more in mesopic, 
high-contrast, binocular DCNVA with no more than 5-letter loss in mesopic CDVA with 
the same refractive correction at Day 14, Hour 9 (3 hours after the second dose). 
9.3.2 
Main Analysis of Primary Efficacy Endpoint 
The attributes of the estimand corresponding to the primary efficacy endpoint are 
summarized in Table 1. 
 


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Table 1. 
Summary of the Estimand Attributes of the Primary Efficacy Endpoint 
Estimand Label 
Attributes of the Estimand 
Treatment 
Endpoint 
Population 
Handling of 
Intercurrent Events 
Statistical Summary 
Estimand for the 
primary endpoint 
AGN-190584 or 
vehicle 
The proportion of subjects gaining 
3 lines or more in mesopic, high 
contrast, binocular DCNVA with no 
more than 5-letter loss in mesopic 
CDVA with the same refractive 
correction at Day 14, Hour 9 
(3 hours after the second dose) 
ITT 
The composite strategy 
will be applied to 
handle the intercurrent 
events.  Missing data 
will be regarded as a 
non-responder for the 
endpoint. 
The difference and the 
corresponding 95% 
confidence interval in the 
proportion of subjects 
gaining 3 lines or more in 
mesopic, high-contrast, 
binocular DCNVA with no 
more than 5-letter loss in 
mesopic CDVA with the 
same refractive correction at 
Day 14, Hour 9 between 
AGN-190584 and vehicle. 
DCNVA = distance-corrected near visual acuity; CDVA = corrected distance visual acuity; ITT = intent-to-treat 


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As presented in the estimand for the primary efficacy endpoint in Table 1, the composite 
strategy will be used to handle the intercurrent events.  Subjects with intercurrent events 
prior to Day 14, Hour 9 will be considered as non-responders for the primary efficacy 
endpoint.  Subjects who have missing data for the primary efficacy endpoint will be 
categorized as non-responders in the primary analysis. 
The comparison of the proportions between AGN-190584 and vehicle will be made using 
the Pearson's chi-square test.  The treatment difference will be provided with a 2-sided 
95% CI using the normal approximation based on the pooled variance without continuity 
correction. 
If the proportions of subjects with reported IEs are considered unbalanced between the 
treatment groups and are higher in the vehicle group than in the AGN-190584 group, the 
subjects with IEs will not be considered as nonresponders for the primary efficacy 
analysis.  
9.3.3 
Sensitivity and Supplementary Analyses of the Primary 
Efficacy Endpoint 
As a sensitivity analysis, a 2-sided 95% confidence interval using the Wilson-Newcombe 
method will be presented. 
In addition, the following sensitivity analyses with respect to missing data handling 
approaches will be conducted to explore the robustness of the primary efficacy analysis 
results: 
● Observed data without imputation: The comparison between AGN-190584 and 
vehicle for the primary efficacy endpoint will be made using the Pearson's 
chi-square test based on observed data without imputation.  
● Last observation carried forward (LOCF): Missing data for the primary efficacy 
endpoint at Day 14, Hour 9 will be imputed using a time matched LOCF, and 
the comparison between AGN-190584 and Vehicle for the primary efficacy 
endpoint will be conducted based on the data after imputation. 
 


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9.4 
Secondary Efficacy Endpoints and Analyses 
9.4.1 
Key Secondary Efficacy Endpoint 
Proportion of subjects gaining 3 lines or more in photopic, high-contrast, binocular 
DCNVA with no more than 5-letter loss in photopic CDVA with the same refractive 
correction at Day 14, Hour 9 (3 hours after the second dose). 
9.4.2 
Main Analyses of Key Secondary Efficacy Endpoint 
The attributes of the estimand corresponding to the key secondary efficacy endpoint are 
summarized in Table 2. 
 


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Table 2. 
Summary of the Estimand Attributes of the Key Secondary Efficacy Endpoint 
Estimand Label 
Attributes of the Estimand 
Treatment 
Endpoint 
Population 
Handling of 
Intercurrent Events 
Statistical Summary 
Estimand for the 
key secondary 
endpoint 
AGN-190584 or 
vehicle 
The proportion of subjects 
gaining 3 lines or more in 
photopic, high-contrast, 
binocular DCNVA with 
no more than 5-letter loss 
in photopic CDVA with 
the same refractive 
correction at Day 14, 
Hour 9 (3 hours after the 
second dose) 
ITT 
The composite strategy 
will be applied to handle 
the intercurrent events.  
Missing data will be 
regarded as a non-
responder for the 
endpoint. 
The difference and the 
corresponding 95% confidence 
interval in the proportion of 
subjects gaining 3 lines or more 
in photopic, high-contrast, 
binocular DCNVA with no more 
than 5-letter loss in photopic 
CDVA with the same refractive 
correction at Day 14, Hour 9 
between AGN-190584 and 
vehicle. 
DCNVA = distance-corrected near visual acuity; CDVA = corrected distance visual acuity; ITT = intent to treat 


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As presented in the estimand for the key secondary efficacy endpoint in Table 2, the 
composite strategy will be used to handle the intercurrent events.  Subjects with 
intercurrent events prior to Day 14, Hour 9 will be considered as non-responders for the 
key secondary efficacy endpoint.  Subjects who have missing data for the key secondary
efficacy endpoint will be categorized as non-responders in the primary analysis. 
The comparison of the proportions between AGN-190584 and vehicle will be made using 
the Pearson's chi-square test.  The treatment difference will be provided with a 2-sided 
95% CI using the normal approximation based on the pooled variance without continuity 
correction. 
If the proportions of subjects with reported IEs are considered unbalanced between the 
treatment groups and are higher in the vehicle group than in the AGN-190584 group, the 
subjects with IEs will not be considered as nonresponders for the key secondary efficacy 
analysis.  
9.4.3 
Sensitivity and Supplementary Analyses for Key Secondary 
Efficacy Endpoint 
Similar as for the primary efficacy endpoint, a 2-sided 95% confidence interval using 
Wilson-Newcombe method will be presented for the key secondary efficacy endpoint. 
In addition, the following sensitivity analyses with respect to missing data handling 
approaches will be conducted to explore the robustness of the key secondary efficacy 
analysis results: 
● Observed data without imputation: The comparison between AGN-190584 and 
vehicle for the key secondary efficacy endpoint will be made using the 
Pearson's chi-square test based on observed data without imputation.  
● Last observation carried forward (LOCF): Missing data for the key secondary 
efficacy endpoint at Day 14, Hour 9 will be imputed using a time matched 
LOCF, and the comparison between AGN-190584 and vehicle for the key 
secondary efficacy endpoint will be conducted based on the data after 
imputation. 


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9.4.4 
Supportive Secondary Efficacy Endpoints and Analyses
Supportive Secondary Endpoints: 
1. 
Proportion of subjects gaining 2 lines or more in mesopic, high-contrast, binocular 
DCNVA with no more than 5-letter loss in mesopic CDVA with the same 
refractive correction at Day 14, Hour 9 (3 hours after the second dose) 
2. 
Proportion of subjects achieving 20/40 or better in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the 
same refractive correction at Day 14, Hour 9 (3 hours after the second dose) 
 
The same analysis method as described in Section 9.3.2 for the primary efficacy endpoint 
will be applied for the above supportive secondary endpoints.  The comparison of the 
proportions between AGN-190584 and vehicle will be made using the Pearson's chi-
square test.  The treatment difference will be provided with a 2-sided 95% CI using the 
normal approximation based on the pooled variance without continuity correction. 
9.5 
Additional Efficacy Endpoints and Analyses 
The additional efficacy endpoints are: 
1. 
Change from baseline in mesopic Near Vision Presbyopia Task-based 
Questionnaire (NVPTQ) Performance score at Day 14, Hour 9 (3 hours after the 
second dose) 
2. 
Change from baseline in Presbyopia Impact and Coping Questionnaire (PICQ) 
Coping score at Day 14, Hour 3  
3. 
Change from baseline in Visual Function Assessment application (VFA app) at 
Day 14, Hour 9 (3 hours after the second dose): 
● Change from baseline in average number of blinks per minute  
● Change from baseline in median working distance (centimeters) 
● Change from baseline in median magnification level (%) from the original size 


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● Change from baseline in reading speed (words per minute) 
● Change from baseline in median contrast level (%) based on the original value 
 
The PRO scoring algorithms for the NVPTQ, PICQ, and VFA app are provided in 
Appendix A. 
The additional efficacy endpoints will be analyzed using an ANCOVA model that 
includes treatment, age group, baseline DCNVA severity group, iris color group, and 
emmetrope status as factors as well as corresponding baseline PRO score as a covariate.  
The same analysis will be applied for these PRO scores at other visits/timepoints. 
Additionally, for the PRO domain mesopic NVPTQ Performance score at Day 14 Hour 9 
and the PRO domain PICQ Coping score at Day 14 Hour 3, the cumulative distribution 
function (CDF) curves representing the cumulative proportion of subjects with any 
particular level of change from baseline in a PRO domain will be presented by treatment 
group. 
9.6 
Exploratory Efficacy Endpoints and Analyses 
Exploratory efficacy endpoints are not defined in the protocol and will be included for 
exploratory analyses: 
● Change from baseline in mesopic near pupil diameter 
● Change from baseline in mesopic distance pupil diameter 
● Change from baseline in photopic near pupil diameter 
● Change from baseline in photopic distance pupil diameter 
 
Descriptive statistics for pupil diameter (mesopic near, mesopic distance, photopic near 
and photopic distance) and changes from baseline values at each assessment timepoint 
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Additionally, similar analysis methods as described for primary (Section 9.3.2) and 
secondary efficacy endpoints (Section 9.4.2) will be used for the following exploratory 
efficacy endpoints based on observed data.  
● The proportion of subjects gaining 3 lines or more in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the 
same refractive correction at all visits/timepoints other than Day 14, Hour 9 
(3 hours after the second dose) 
● The proportion of subjects gaining 3 lines or more in photopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in photopic CDVA with the 
same refractive correction at all visits/timepoints other than Day 14, Hour 9 
(3 hours after the second dose) 
● The proportion of subjects gaining 2 lines or more in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the 
same refractive correction at all visits/timepoints  
● The proportion of subjects achieving 20/40 or better in mesopic, high-contrast, 
binocular DCNVA with no more than 5-letter loss in mesopic CDVA with the 
same refractive correction at all visits/timepoints 
 
9.7 
Efficacy Subgroup Analyses 
Subgroup analyses will be conducted for the primary and key secondary endpoints for the 
following subgroups: 
● Age group (≤ 50, > 50 years) 
● Sex (male, female) 
● Race (white, black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander, and multiple.) 
● Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
● Baseline binocular DCNVA (20/63 or better, worse than 20/63) 
● Iris color (brown, non-brown) 
● Emmetrope status (emmetropes, non-emmetropes) 
 


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Descriptive summary statistics and 95% confidence intervals will be provided; no 
statistical hypothesis test will be performed. For any subgroup with < 10 subjects in a 
treatment group, only descriptive summary statistics will be provided. 
10.0 
Safety Analyses 
10.1 
General Considerations 
The safety measurements will include AEs; vital signs (blood pressure and heart rate); 
mesopic and photopic, high-contrast, binocular CDVA; IOP; slit lamp biomicroscopy; 
manifest refraction; dilated fundoscopic examination; post-dose tolerability (for subjects 
reporting specific ocular symptoms), drop comfort; and pregnancy test. 
Safety data will be summarized using the Safety population based on the treatment 
actually received, regardless of the treatment randomized.  A subject's actual treatment 
will be determined by the first dose of study drug. 
AEs and findings from biomicroscopy and ophthalmoscopy examinations will be coded 
using the Medical Dictionary for Regulatory Activities (MedDRA), 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 
tables/listings and in the clinical study report. 
10.2 
Adverse Events 
AEs will be summarized and presented using primary MedDRA SOCs and PTs.  Specific 
adverse events will be counted once for each subject for calculating percentages, unless 
stated otherwise.  In addition, if the same adverse event occurs multiple times for a 
subject, the highest severity and level of relationship to investigational product will be 
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10.2.1 
Treatment-Emergent Adverse Events 
An AE will be considered a treatment-emergent adverse event (TEAE) if the AE began or 
worsened (increased in severity or became serious) on or after the date of the first dose of 
study treatment.  Events where the onset date is the same as the study treatment start date 
are assumed to be treatment emergent.  
In general, the number and percentage of subjects experiencing TEAEs will be 
summarized overall, as well as by primary MedDRA SOC and PT.  The SOCs will be 
presented in alphabetical order, and the PTs will be presented in decreasing frequency 
order on active study treatment within each SOC.  The number and percentage of subjects 
experiencing TEAEs will also be summarized by PT regardless of the SOC.  TEAEs by 
PT summaries will be presented in decreasing frequency order on active study treatment. 
10.2.2 
Adverse Event Overview 
Adverse events will be classified into ocular AEs and non-ocular AEs.  An ocular AE will 
be determined as indicated on the AE form of eCRF (marked "OD" and/or "OS" to the 
question of "what was the location of the adverse event?"), and thus are not limited to AEs 
with primary SOC of eye disorders. 
An overview of AEs will be presented consisting of the number and percentage of 
subjects experiencing at least one event for each of the following AE categories: 
● TEAEs 
○ Ocular TEAEs 
○ Nonocular TEAEs 
● TEAEs with reasonable possibility of being related to study treatment 
according to the investigator 
○ Ocular TEAEs with reasonable possibility of being related to study 
treatment according to the investigator 
○ Nonocular TEAEs with reasonable possibility of being related to study 
treatment according to the investigator 


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● Severe TEAEs
● Serious TEAEs 
○ Ocular serious TEAEs 
○ Nonocular serious TEAEs 
● TEAEs leading to withdrawal of study treatment 
○ Ocular leading to withdrawal of study treatment   
○ Nonocular leading to withdrawal of study treatment   
● TEAEs leading to death 
● Adverse events of special interest (AESIs) within the following 2 categories 
(AESIs will be based on the search criteria in Appendix B): 
○ Headache AESIs 
○ Visual disturbance AESIs 
● All deaths 
● COVID-19 Infection   
 
10.2.3 
Treatment-Emergent Adverse Events by SOC and/or PT 
Treatment-emergent adverse events will be summarized for each of the following AE 
categories: 
● TEAEs by SOC and PT 
○ Ocular TEAEs by SOC and PT 
○ Nonocular TEAEs by SOC and PT 
● TEAEs by PT 
● TEAEs with reasonable possibility of being related to study treatment by SOC 
and PT 
○ Ocular TEAEs with reasonable possibility of being related to study 
treatment by SOC and PT  
○ Nonocular TEAEs with reasonable possibility of being related to study 
treatment by SOC and PT 
● TEAEs by SOC, PT, and maximum severity 


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Specific adverse events will be counted once for each subject for calculating percentages, 
unless stated otherwise. 
If the same adverse event occurs multiple times for a subject, the highest severity and 
level of relationship to investigational product will be reported. 
10.2.4 
SAEs (Including Deaths) and Adverse Events Leading to 
Study Treatment Discontinuation 
SAEs (including deaths) and AEs leading to study treatment discontinuation will be 
summarized by SOC and PT and in listing format. 
10.2.5 
Adverse Events of Special Interest 
Adverse events of special interest in the following categories will be based on the search 
criteria in Appendix B: 
● Headache AESIs 
● Visual disturbance AESIs 
 
The following treatment-emergent AESIs will be summarized overall and by PT: 
● Headache AESIs 
○ Headache AESIs with reasonable possibility of being related to study 
treatment  
○ Headache AESIs with no reasonable possibility of being related to study 
treatment 
● Visual disturbance AESIs 
 
For each of the above categories of AESIs, descriptive summaries will be presented by 
treatment group for the following parameters: 
● Any AESI 
● Severity (mild, moderate, severe) 


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● Duration (days) 
● Duration category (1 day, 2 to 5 days, 6 to 20 days, > 20 days) 
● Onset day category (Day 1, Day 2 to Day 10, > Day 10) 
● Pattern (continuous, intermittent)  
● Outcome (recovered/resolved, recovered/resolved with sequelae, rot 
recovered/not resolved, fatal, unknown)  
● Concomitant medication or therapy (yes, no) 
○ Yes, Outcome (recovered/resolved, recovered/resolved with sequelae, not 
recovered/not resolved, fatal, unknown) 
○ No, Outcome (recovered/resolved, recovered/resolved with sequelae, not 
recovered/not resolved, fatal, unknown) 
● Discontinuation from the study treatment  
● Ongoing at exit  
 
In addition, concomitant medications or therapy started on or after the first study 
treatment date for the indication of headache AESIs will be summarized by preferred drug 
name and by treatment group.  
The following listings will be provided: 
● Headache AESIs: with reasonable possibility of being related to study 
treatment 
● Headache AESIs: with no reasonable possibility of being related to study 
treatment 
● Visual disturbance AESIs. 
 
10.2.6 
Headache Assessment 
Whenever a headache AE is reported after the initial dosing at Day 1, the subject will be 
followed up with a supplemental headache assessment form to further assess the 
headache.  Severity score will be assessed using a visual analog scale (VAS) (0 – 100 for 
No pain – Worst possible pain): 


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● Overall headache/migraine severity score (0 – 100) 
● Temporal headache/browache severity score (0 – 100) 
● Supraorbital headache/browache severity score (0 – 100) 
 
The number and percentage of subjects who had any of the above 3 VAS assessments will 
be summarized by treatment group for overall/temporal/supraorbital, respectively.  In 
addition, the total number of assessments of overall headache/migraine, temporal 
headache/browaches, and supraorbital headache/browache will be summarized by 
treatment group. 
In addition to the severity scores, the following information will be assessed for overall 
headache/migraine: 
● Onset after the first or second dose of study medication (after first dose, after 
second dose, both, unsure) 
● Intermittent status (yes, no)   
● Onset time after taking the study medication (0-1 hour, > 1-2 hours, > 2-
4 hours, > 4-6 hours, > 6 hours) 
● How long did the headache/migraine last?  (0-1 hour, > 1-2 hours, > 2-4 hours, 
> 4-6 hours, > 6 hours) 
 
All headache assessments for TEAEs will be summarized using descriptive statistics by 
treatment group.  The percentages will be based on the total number of assessed events by 
treatment group, whenever applicable.  For intermittent status, only the category of "Yes" 
will be summarized. 
Additionally, similar summaries will be provided for the following 2 subsets: 
● Supplemental headache assessments for TEAEs with reasonable possibility of 
being related to study treatment 
● Supplemental headache assessments for TEAEs with no reasonable possibility 
of being related to study treatment 
 


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10.3 
Analysis of Laboratory Data 
Urine pregnancy test will be performed at Screening, Day 1, and Day 14 for women of 
childbearing potential only. 
10.4 
Analysis of Vital Signs 
Descriptive statistics for vital signs (systolic and diastolic blood pressure, and pulse rate) 
and changes from baseline values at each assessment timepoint will be presented by 
treatment group. 
10.5 
Other Safety Analyses 
10.5.1 
Mesopic, High-Contrast, Binocular CDVA 
Mesopic, high-contrast, binocular CDVA is assessed at each visit.  
Change from baseline in number of letters in mesopic, high-contrast, binocular CDVA 
will be summarized descriptively for each assessment timepoint by treatment group. 
10.5.2 
Photopic, High-Contrast, Binocular CDVA 
Photopic, high-contrast, binocular CDVA is assessed at each visit.  
Change from baseline in number of letters in photopic, high-contrast, binocular CDVA 
will be summarized descriptively for each assessment timepoint by treatment group. 
10.5.3 
Intraocular Pressure 
IOP is measured for each eye using the Goldmann applanation tonometer at Hour 0, 
Hour 1, and Hour 7 (1 hour after the second dose) at each visit.  
Tabulations will be based on the eye with a greater magnitude of change from baseline 
assessed at each assessment time point of a visit.  In case of both eyes have same 
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chosen.  Descriptive statistics for IOP and changes from baseline at each assessment 
timepoint will be presented by treatment group.  
10.5.4 
Slit Lamp Biomicroscopy 
Biomicroscopy will be performed in each eye at each visit, by slit lamp examination, 
without pupil dilation, including but not limited to eyelids/lashes, conjunctiva, cornea, and 
anterior chamber.  Observations for the examination will be graded on a 5-point scale (0 = 
none, 0.5 = trace, 1 = mild, 2 = moderate, 3 = severe) except for the anterior chamber (in 
cells: 0 = 0 cells, + 0.5 = 1 - 5 cells, + 1 = 6 - 15 cells, + 2 = 16 - 25 cells, + 3 = 26 - 50 
cells, and + 4 = > 50 cells; in flare: 0 = none, + 1 = faint, + 2 = moderate, + 3 = marked 
and + 4 = intense). 
The number and percentage of subjects with clinically significant biomicroscopy findings 
will be tabulated by PT, assessment timepoint and treatment group.  A clinically 
significant finding is defined as more than one severity grade increase (worsening) from 
baseline, or a positive status change from absence at baseline to presence at postbaseline 
(not associated with a severity grade) in one or both eyes.  If a pathology is recorded at a 
follow-up visit but not at baseline, the baseline will be imputed with the same pathology, 
with a grade of zero (none). 
10.5.5 
Manifest Refraction  
Both mesopic manifest refraction (distance and near) and photopic manifest refraction 
(distance and near) will be assessed in each eye at Screening.  If a subject loses ≥ 1 line (≥ 
5 letters) of CDVA or DCNVA compared with Hour 0 of the same study visit at Hour 1 
after dosing, a manifest refraction should be repeated under the same lighting conditions. 
Manifest refraction assessments will be listed. 
10.5.6 
Dilated Fundoscopic Examination 
Dilated fundoscopic examination will be performed in each eye at Screening and at Hour 
9 on Day 14/early exit. 


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Findings from dilated fundoscopic examination will be listed.  
10.5.7 
Post-DoseTolerability  
Post-dose tolerability will be assessed after each dose at each visit in all subjects who 
report any of the following ocular symptoms after drop instillation: 
● blurred vision/vision disturbance 
● foreign body sensation/grittiness 
● pain 
● burning/stinging/irritation 
● tearing/watery eyes/discharge 
● itching 
 
These subjects will rate each of these symptoms using a 5-point scale (0 = none, 0.5 = 
trace, 1 = mild, 2 = moderate, and 3 = severe) for severity and a 3-point scale (< 1 min, 1 
to 5 min, and > 5 min) for duration.  The number and percentage of subjects who report 
each category of severity and duration will be tabulated for each time point by treatment 
group. 
10.5.8 
Drop Comfort 
Drop comfort will be assessed in all subjects after each dose at each visit.  
Subjects will rate the overall comfort of the treatment drops using a 6-point scale 
(soothing, very comfortable, comfortable, uncomfortable, very uncomfortable, and 
intolerable).  The number and percentage of subjects who report each category will be 
tabulated for each time point by treatment group. 
10.6 
Safety Subgroup Analyses 
Ocular TEAEs will be summarized by preferred term for each of the following subgroups:
● Age group (≤ 50, > 50 years) 


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● Sex (male, female) 
● Race (white, black or African American, Asian, American Indian or Alaska 
Native, Native Hawaiian or other Pacific Islander, and multiple.) 
● Ethnicity (Hispanic or Latino, not Hispanic or Latino) 
 
11.0 
Other Analyses 
Plasma concentrations of AGN-190584 will be assessed at selected sites in approximately 
10% of all enrolled subjects.  Details of the statistical analyses of PK data will be 
described in the PK analysis plan finalized before database lock. 
Additional PRO exploratory analyses other those described in Section 9.5 will be 
described in a separate analysis plan (Appendix A). 
12.0 
Interim Analyses 
Not applicable. 
12.1 
Data Monitoring Committee 
Not applicable. 
13.0 
Overall Type-I Error Control 
A fixed sequence testing procedure will be applied to control the overall familywise 
Type I error rate at α = 0.05 for the primary and secondary hypotheses sequentially.  The 
hypotheses for primary endpoint and the secondary endpoints will be tested in a sequential 
order:  
●
H1 Primary: The proportion of subjects gaining 3 lines or more in mesopic, 
high-contrast, binocular DCNVA with no more than 5-letter loss in mesopic 
CDVA with the same refractive correction at Day 14, Hour 9 (3 hours after the 
second dose) 


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● H2: Key Secondary: The proportion of subjects gaining 3 lines or more in 
photopic, high-contrast, binocular DCNVA with no more than 5-letter loss in 
photopic CDVA with the same refractive correction at Day 14, Hour 9 (3 hours 
after the second dose) 
● H3 Supportive Secondary: The proportion of subjects gaining 2 lines or more 
in mesopic, high-contrast, binocular DCNVA with no more than 5-letter loss in 
mesopic CDVA with the same refractive correction at Day 14, Hour 9 (3 hours 
after the second dose) 
● H4 Supportive Secondary:  The proportion of subjects achieving 20/40 or 
better in mesopic, high-contrast, binocular DCNVA with no more than 5-letter 
loss in mesopic CDVA with the same refractive correction at Day 14, Hour 9 (3 
hours after the second dose) 
 
If the statistical test at any step fails, the test procedure will stop and no further hypotheses 
will be tested.  
14.0 
Version History 
Table 3. 
SAP Version History Summary
Version 
Date 
Summary 
1.0 
19 NOV 2021 
Original version 
 
15.0 
References 


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Appendix A. 
PRO Scoring Algorithm 
The NVPTQ and the PICQ scoring algorithms can be found in: 
● Scoring Algorithms for Presbyopia Patient-Reported Outcome Instruments 
December 9, 2019 by Outcometrix 
 
VFA app coping behavior metric scores and candidate composite scores can be found in: 
● Psychometric Evaluation of the Visual Function Assessment Scores in 
Presbyopia Final Psychometric Analysis Plan 
June 17, 2021 by RTI Health Solutions 
 


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Appendix B. 
Definition of Adverse Events of Special Interest 
AESIs will be identified using the following search criteria1: 
Area of Safety Interest 
Search Criteria – Preferred Term (PT) 
PT Code 
Headache 
Headache 
10019211 
Migraine 
10027599 
Migraine with aura 
10027607 
Sinus headache 
10040744 
Other PT(s) related to headache of special interest 
(TBD) 
Visual disturbance 
Dyschromatopsia 
10013892 
Glare 
10052128 
Halo vision 
10019099 
Metamorphopsia 
10063341 
Photophobia 
10034960 
Photopsia 
10034962 
Pseudomyopia 
10075919 
Vision blurred 
10047513 
Visual acuity reduced 
10047531 
Visual field defect 
10047555 
Visual impairment 
10047571 
Other PT(s) related to visual disturbance of special 
interest 
(TBD) 
1. 
The final list of PTs to be used will be reviewed and finalized prior to database lock. 
 


AGN-190584 
M21-195 – Statistical Analysis Plan 
Version 1.0 – 19 November 2021 
 
 
40 
Appendix C. 
List of MedDRA Preferred Terms for COVID-19 Infection  
Area of Safety Interest  
Search Criteria  
COVID-19 Infection 
MedDRA 24.1 COVID-19 SMQ 20000237 (narrow search)