Conditions: Presbyopia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 323
Healthy volunteers: no

Brief summary:
A study to evaluate the efficacy, safety, and pharmacokinetics of pilocarpine hydrochloride (HCl) ophthalmic solution (AGN-190584) when administered bilaterally, once daily for 30 days in participants with presbyopia.

Detailed description:

Arms:
arm 1: Participants received one drop of vehicle in each eye, once daily, for up to 30 days. arm 2: Participants received one drop of pilocarpine HCl ophthalmic solution 1.25% in each eye, once daily, for up to 30 days.

Interventions: intervention 1: Vehicle intervention 2: Pilocarpine HCl Ophthalmic Solution
Intervention descriptions: intervention 1: Vehicle, one drop in each eye, once daily, for up to 30 days. intervention 2: Pilocarpine HCl ophthalmic solution 1.25%, one drop in each eye, once daily, for up to 30 days.

Protocol document:
Prot_000.pdf: 
 
 
Approval Date: 
 
05-Dec-2018
 
Protocol 1883-301-013       
AGN-190584 
 
1 
Title Page 
Protocol Title: A Phase 3, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, 
Parallel-Group Study Evaluating the Safety and Efficacy of AGN-190584 in Participants 
with Presbyopia 
Protocol Number: 1883-301-013 
Amendment Number: 1 
Product: AGN-190584 
Brief Protocol Title: Phase 3 efficacy study of AGN-190584 in participants with presbyopia 
Development Phase: 3 
Sponsor Name: Allergan, Inc. 
Legal Registered Address:  
2525 Dupont Drive, Irvine, CA 92612, USA 
Serious Adverse Event Reporting:  
Allergan Medical Safety Physician Contact Information:  
Allergan Signatory:  
Vice President, Therapeutic Area Head 
Anterior Segment and Consumer Eye Care 
Allergan, Inc. 
Refer to the final page of this protocol for electronic signature and date of approval. 


 
 
Approval Date: 
 
05-Dec-2018
 
Protocol 1883-301-013       
AGN-190584 
 
2 
Protocol Amendment Summary of Changes 
DOCUMENT HISTORY 
Document 
Date 
Amendment 1 
05 December 2018 
Original Protocol 
13 October 2018 
Amendment 1 (05 December 2018) 
Overall Rationale for the Amendment: 
The following is a summary of changes made to the original protocol, some of which are based 
on communication with the FDA. 
Section No. and 
Name 
Description of Change 
Brief Rationale 
Throughout 
Update figures, tables, appendices, and 
text to a 30-day study intervention 
timeline 
A 30-day study intervention period is an adequate 
duration to demonstrate safety and efficacy of 
AGN-190584 
1.1. Synopsis; 1.3. 
Schedule of 
Activities; 3. 
Objectives and 
Endpoints; 8. 
Study 
Assessments and 
Procedures; 10.7. 
Appendix 7 
Add OD and OS measurements for 
mesopic and photopic CDVA, DCIVA, 
and DCNVA 
In addition to binocular measurements, individual 
eye measurements were added to mesopic and 
photopic CDVA, DCIVA, and DCNVA to 
provide a more complete assessment of these 
endpoints 
1.1. Synopsis; 4.1. 
Overall Design; 
9.2. Sample Size 
Determination 
Modify participant dropout rate to 10% 
and participants completing the study 
per study intervention group to 
approximately 135 
The participant dropout rate assumption was 
modified to 10% (versus 20%) as this is a 
sufficiently conservative estimate of participants 
who may not complete the 30-day study. 
Assumptions for the sample size calculation and 
their basis were clarified.  
1.1. Synopsis; 6.3. 
Measures to 
Minimize Bias: 
Randomization 
and Blinding; 
9.4.1.3. 
Secondary 
Analyses; 9.4.4.1. 
Subgroup 
Analyses 
Modify “baseline DCNVA” to 
“baseline binocular DCNVA” for 
randomization and analysis 
“Baseline DCNVA” was modified to “baseline 
binocular DCNVA” to clarify this stratification 
parameter during randomization and statistical 
analysis 
1.3. Schedule of 
Activities; 8.8. 
Biomarkers and 
Other 
Add determination of dominant eye 
Collection of participant dominant/nondominant 
eye data was clarified 


 
 
Approval Date: 
 
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Protocol 1883-301-013       
AGN-190584 
 
3 
Section No. and 
Name 
Description of Change 
Brief Rationale 
Assessments; 
10.7. Appendix 7 
1.3. Schedule of 
Activities; 10.7.1. 
Screening Visit 
(Days -30 to -1) 
Modify screening DCNVA assessment 
that will be repeated 3 times with 
different charts to OD only 
OD was added to clarify that the screening visit 
DCNVA (to be repeated 3 times with different 
charts) is for OD only 
7.1. 
Discontinuation 
of Study 
Intervention 
Added a guideline to encourage 
participants who discontinue the study 
intervention early to stay in the study 
for the safety assessments at Day 30 
This was added to promote a continuation of 
safety assessments if a participant discontinues 
study intervention before the end of the study 
9.1. Statistical 
Hypotheses 
Update of statistical hypotheses 
The statistical hypotheses for the primary and key 
secondary efficacy endpoints were clarified 
9.2. Sample Size 
Determination 
Update of sample size justification 
The vehicle group intervention effect was 
updated based on previous phase 2 study results; 
the intervention effect for the non-emmetropes 
group was added. The total number of 
participants to complete the study was changed to 
135 for each treatment group 
9.4.1. Efficacy 
Analyses 
Remove key secondary efficacy 
endpoint (change from baseline letters 
AUC0-10 in mesopic, high contrast, 
binocular DCNVA at Day 30) and its 
analysis method 
This key secondary efficacy endpoint is not 
required to demonstrate the efficacy of AGN-
190584 
9.4.1.1. Analysis 
Endpoints 
Remove secondary efficacy endpoint 
(photopic, high contrast, binocular 
DCIVA mean change from baseline 
letters AUC0-10 at Day 30) and its 
analysis method 
This secondary efficacy endpoint is not required 
to demonstrate the efficacy of AGN-190584 
9.4.1.1. Analysis 
Endpoints 
Add secondary efficacy endpoint 
(Change from baseline photopic, high 
contrast, binocular DCIVA letters at 
Day 30, Hour 3) 
This secondary efficacy endpoint was added to 
evaluate the efficacy of AGN-190584 for DCIVA 
9.4.1.3. 
Secondary 
Analyses 
Update change from baseline analysis 
(MMRM) 
The change from baseline analysis model 
(MMRM) was updated to include the following 
additional fixed effects: visit, visit by study 
intervention group interaction, and baseline value 
by visit interaction 
9.4.4.1 Subgroup 
Analyses 
Update subgroup analyses 
Subgroup analyses by gender and race was added 
Throughout 
Minor editorial and document 
formatting revisions 
Minor, therefore have not been summarized 
 


 
 
Approval Date: 
 
05-Dec-2018
 
Protocol 1883-301-013       
AGN-190584 
 
4 
Table of Contents 
Title Page ........................................................................................................................................1 
Protocol Amendment Summary of Changes ....................................................................................2 
Table of Contents ...........................................................................................................................4 
List of Tables ..................................................................................................................................7 
List of Figures .................................................................................................................................7 
1. 
Protocol Summary ..........................................................................................................8 
1.1. 
Synopsis ............................................................................................................................8 
1.2. 
Schema ............................................................................................................................10 
1.3. 
Schedule of Activities .....................................................................................................11 
2. 
Introduction ...................................................................................................................18 
2.1. 
Study Rationale ...............................................................................................................18 
2.2. 
Background .....................................................................................................................18 
2.3. 
Benefit/Risk Assessment ................................................................................................19 
3. 
Objectives and Endpoints ............................................................................................20 
4. 
Study Design ..................................................................................................................21 
4.1. 
Overall Design ................................................................................................................21 
4.1.1. 
Clinical Hypotheses ........................................................................................................21 
4.2. 
Scientific Rationale for Study Design ............................................................................21 
4.3. 
Justification for Dose ......................................................................................................21 
4.4. 
End of Study Definition ..................................................................................................21 
5. 
Study Population ...........................................................................................................23 
5.1. 
Inclusion Criteria ............................................................................................................23 
5.2. 
Exclusion Criteria ...........................................................................................................24 
5.3. 
Lifestyle Considerations .................................................................................................26 
5.4. 
Screen Failures ................................................................................................................26 
6. 
Study Intervention ........................................................................................................27 
6.1. 
Study Intervention(s) Administered ................................................................................27 
6.1.1. 
Study Supplies ................................................................................................................27 
6.1.2. 
Instructions for Use and Administration .........................................................................28 
6.2. 
Preparation/Handling/Storage/Accountability ................................................................28 
6.3. 
Measures to Minimize Bias: Randomization and Blinding ............................................29 
6.4. 
Study Intervention Compliance ......................................................................................30 
6.5. 
Concomitant Therapy .....................................................................................................30 
6.5.1. 
Prohibited Interventions and Washout Before the Study ................................................30 
6.5.2. 
Permitted Interventions ...................................................................................................31 
6.5.3. 
Rescue Medicine .............................................................................................................31 
6.5.4. 
Prohibited Interventions During the Study .....................................................................31 


 
 
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5 
6.6. 
Dose Modification ..........................................................................................................31 
6.7. 
Intervention after the End of the Study ...........................................................................31 
7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal........................................................................................32 
7.1. 
Discontinuation of Study Intervention ............................................................................32 
7.2. 
Participant Discontinuation/Withdrawal from the Study ................................................32 
7.3. 
Lost to Follow Up ...........................................................................................................33 
8. 
Study Assessments and Procedures.............................................................................34 
8.1. 
Efficacy Assessments .....................................................................................................34 
8.2. 
Safety Assessments .........................................................................................................37 
8.2.1. 
Vital Signs .......................................................................................................................37 
8.2.2. 
Pregnancy Testing ...........................................................................................................37 
8.2.3. 
Photopic and Mesopic, High Contrast Corrected Distance Visual 
Acuity for Each Eye and Binocularly .............................................................................38 
8.2.4. 
Near Contrast Sensitivity ................................................................................................38 
8.2.5. 
Study Intervention Tolerability and Drop Comfort Assessments ...................................38 
8.2.6. 
Temporal/Supraorbital Headache Visual Analog Scale .................................................38 
8.2.7. 
Intraocular Pressure ........................................................................................................39 
8.2.8. 
Slit-lamp Biomicroscopy ................................................................................................39 
8.2.9. 
Manifest Refraction ........................................................................................................42 
8.2.10.  Dilated Funduscopic Examination ..................................................................................42 
8.2.11.  Suicidal Risk Monitoring ................................................................................................43 
8.3. 
Adverse Events and Serious Adverse Events .................................................................43 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and 
Serious Adverse Event Information ................................................................................43 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse 
Events ..............................................................................................................................44 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events ...........................................44 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events ..................................44 
8.3.5. 
Pregnancy ........................................................................................................................45 
8.3.6. 
Medication Errors ...........................................................................................................45 
8.4. 
Treatment of Overdose ...................................................................................................45 
8.5. 
Pharmacokinetics ............................................................................................................46 
8.5.1. 
Blood Pharmacokinetic Sampling Procedure .................................................................46 
8.5.2. 
Pharmacokinetic Sample Bioanalysis .............................................................................47 
8.6. 
Pharmacodynamics .........................................................................................................47 
8.7. 
Genetics ..........................................................................................................................47 
8.8. 
Biomarkers and Other Assessments ...............................................................................47 
8.8.1. 
Biomarkers ......................................................................................................................47 
8.8.2. 
Determination of Dominant Eye .....................................................................................47 
8.9. 
Health Economics ...........................................................................................................48 
9. 
Statistical Considerations .............................................................................................48 


 
 
Approval Date: 
 
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AGN-190584 
 
6 
9.1. 
Statistical Hypotheses .....................................................................................................48 
9.2. 
Sample Size Determination ............................................................................................49 
9.3. 
Populations for Analyses ................................................................................................49 
9.4. 
Statistical Analyses .........................................................................................................49 
9.4.1. 
Efficacy Analyses ...........................................................................................................49 
9.4.2. 
Safety Analyses ...............................................................................................................51 
9.4.3. 
Pharmacokinetic Analyses ..............................................................................................52 
9.4.4. 
Other Analyses ................................................................................................................52 
9.5. 
Interim Analyses .............................................................................................................53 
9.5.1. 
Data Monitoring Committee ...........................................................................................53 
10. 
Supporting Documentation and Operational Considerations ..................................54 
10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations ................................................................................................................55 
10.1.1.  Regulatory and Ethical Considerations ...........................................................................55 
10.1.2.  Financial Disclosure ........................................................................................................55 
10.1.3.  Informed Consent Process ..............................................................................................56 
10.1.4.  Data Protection................................................................................................................56 
10.1.5.  Posting Clinical Study Data ............................................................................................56 
10.1.6.  Data Quality Assurance ..................................................................................................57 
10.1.7.  Source Documents ..........................................................................................................57 
10.1.8.  Study and Site Closure ....................................................................................................57 
10.1.9.  Publication Policy ...........................................................................................................58 
10.1.10.  Compliance with Protocol...............................................................................................58 
10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting .........................................................59 
Definition of AE ............................................................................................................................59 
Definition of SAE ..........................................................................................................................60 
Recording and Follow-Up of AEs and/or SAEs ............................................................................61 
Reporting of SAEs .........................................................................................................................63 
10.3. 
Appendix 3: Abbreviations .............................................................................................64 
10.4. 
Appendix 4: Standard Discontinuation Criteria..............................................................66 
10.5. 
Appendix 5: Study Tabular Summary ............................................................................68 
10.6. 
Appendix 6: Contraceptive Guidance and Collection of 
Pregnancy Information ...................................................................................................70 
Definitions: ....................................................................................................................................70 
Contraception Guidance: ...............................................................................................................70 
Pregnancy Testing: .........................................................................................................................72 
Collection of Pregnancy Information: ...........................................................................................72 


 
 
Approval Date: 
 
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Protocol 1883-301-013       
AGN-190584 
 
7 
10.8. 
Appendix 8: Patient Reported Outcomes Questionnaires, 
Descriptions, and Instructions.........................................................................................89 
10.8.1.  National Eye Institute Visual Function Questionnaire 25 ..............................................89 
10.8.2.  Near Vision Presbyopia Task-based Questionnaire ......................................................105 
10.8.3.  Presbyopia Impact and Coping Questionnaire ..............................................................110 
10.8.4.  Presbyopia Patient Satisfaction Questionnaire .............................................................119 
10.8.5.  Patient Global Impression of Status ..............................................................................122 
10.8.6.  Patient Global Impression of Change ...........................................................................123 
10.8.7.  Patient Expectations for Treatment Efficacy ................................................................124 
11. 
References ....................................................................................................................125 
 
List of Tables 
Table 1-1 
Schedule of Visits and Procedures: Screening to Visit 3 .................................. 11 
Table 1–2 
Schedule of Visits and Procedures: Visit 4 to Visit 5/Early Exit ...................... 15 
Table 8-1 
Efficacy Assessments ........................................................................................ 35 
Table 10–1 
Highly Effective Contraceptive Methods .......................................................... 71 
 
List of Figures 
Figure 1-1 
Study Schema .................................................................................................... 10 
 


 
 
Approval Date: 
 
05-Dec-2018
 
Protocol 1883-301-013       
AGN-190584 
 
8 
1. 
Protocol Summary 
1.1. 
Synopsis 
Protocol Title: A Phase 3, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, 
Parallel-Group Study Evaluating the Safety and Efficacy of AGN-190584 in Participants with 
Presbyopia  
Protocol Number: 1883-301-013 
Brief Title: Phase 3 efficacy study of AGN-190584 in participants with presbyopia 
Study Rationale:  
In previous studies, Allergan established the safety and efficacy of several (0.5% to 1.5%) 
concentrations of AGN-190584 dosed once daily, bilaterally or in the nondominant eye, over a 
period of up to 28 days in participants with presbyopia. Study 1883-301-013 is a multicenter, 
double-masked, randomized, vehicle-controlled, parallel group, Phase 3 study evaluating the 
efficacy, safety, and pharmacokinetics of AGN-190584 (1.25% pilocarpine) dosed once daily, 
bilaterally, over a period of 30 days in participants with presbyopia. 
Objectives and Measures: 
The objectives of this study are to evaluate the efficacy, safety, and pharmacokinetics of AGN-
190584 when administered bilaterally, once daily for 30 days in participants with presbyopia. 


 
 
Approval Date: 
 
05-Dec-2018
 
Protocol 1883-301-013       
AGN-190584 
 
9 
Objectives 
Measures 
To evaluate the efficacy of AGN-190584 
when administered bilaterally, once daily for 
30 days in participants with presbyopia. 
• 
Mesopic and photopic, high contrast distance-corrected 
near visual acuity (DCNVA) for each eye and binocularly 
• 
Mesopic and photopic, high contrast distance-corrected 
intermediate visual acuity for each eye and binocularly 
• 
Patient reported outcomes questionnaires:  
o 
Mesopic and Photopic Near Vision Presbyopia Task-
based Questionnaire 
o 
Presbyopia Impact and Coping Questionnaire 
To evaluate the safety and tolerability of 
AGN-190584 when administered bilaterally, 
once daily for 30 days in participants with 
presbyopia 
• 
Adverse events 
• 
Photopic and mesopic high contrast corrected distance 
visual acuity for each eye and binocularly 
• 
Near Contrast sensitivity 
• 
Vital signs (blood pressure and heart rate) 
• 
Study drug tolerability and drop comfort assessments 
• 
Temporal/supraorbital headache visual analog scale 
• 
Intraocular pressure 
• 
Slit-lamp biomicroscopy 
• 
Manifest refraction 
• 
Dilated funduscopic examination 
• 
Pregnancy test for women of childbearing potential 
To evaluate the pharmacokinetics of 
AGN-190584 when administered bilaterally, 
once daily for 30 days in participants with 
presbyopia 
• 
Plasma concentrations of AGN-190584 (sampled at 
selected sites; approximately 10% of all enrolled 
participants) 
Overall Study Design: 
This is a multicenter, double-masked, randomized, parallel-group, vehicle-controlled, Phase 3 
study in participants with presbyopia. The study population will consist of adult male and female 
participants with objective and subjective evidence of presbyopia.  
Number of Participants: 
Approximately 150 participants per group will be enrolled to achieve at least 135 participants per 
group completing the study based on an assumed dropout rate of 10%. Participants who 
prematurely discontinue from the study will not be replaced. 


 
 
Approval Date: 
 
05-Dec-2018
 
AGN-19
 
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11 
1.3. 
Schedule of Activities 


 
 
 
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Table 1–2 
Schedule of Visits and Procedures: Visit 4 to Visit 5/Early Exit 


 
 
 
 
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18 
2. 
Introduction 
Allergan is investigating pilocarpine HCl ophthalmic solution 1.25% (AGN-190584) as a 
noninvasive, reversible, pharmacological treatment for presbyopia, a condition in which the eye 
exhibits a diminished ability to focus on near objects with increasing age. 
2.1. 
Study Rationale 
In previous studies, Allergan established the safety and efficacy of various concentrations of 
AGN-190584 dosed once daily, bilaterally or in the nondominant eye, over a period of up to 
28 days in participants with presbyopia. Study 1883-301-013 is a multicenter, double-masked, 
randomized, vehicle-controlled, parallel group, Phase 3 study evaluating the safety, efficacy, and 
tolerability of AGN-190584 dosed once daily, bilaterally, over a period of 30 days in participants 
with presbyopia. 
2.2. 
Background 
The impairment of near vision is common among older adults. In 2005, 1.044 billion people 
globally were estimated to have presbyopia, and prevalence is expected to increase to 1.782 
billion by 2050 (Holden 2008). Both nonsurgical and surgical methods for the correction of 
presbyopia are available. Traditional nonsurgical methods of refractive correction for presbyopia 
include the use of dedicated reading spectacles, bifocal or varifocal spectacles, and monovision 
or multifocal contact lenses. A number of surgical techniques are also used for the treatment of 
presbyopia, which include monovision PRK or LASIK, conductive keratoplasty, intraocular 
lenses, and corneal inlays. However, for each of the existing technologies mentioned above, 
visual quality is reduced at 1 or more viewing distances, and each comes with its own unique 
safety risks and associated complications. For example, bifocals and progressive lenses (eg, 
reading glasses, contacts) produce optical aberrations and can increase the risk of falls 
(Johnson 2007, Lord 2002). Multifocal optics reduce image quality uniformly at all viewing 
distances. For surgical technologies, surgical risks, and the need for repositioning and 
explantation, or regression of effect have limited their widespread adoption (Moshirfar 2017, 
Ruiz 2009, Tomita 2015). Thus, there remains a need for a noninvasive, reversible, 
pharmacological treatment for presbyopia. 
Pilocarpine is a muscarinic receptor agonist that mimics the actions of the parasympathetic 
neurotransmitter, acetylcholine, on smooth muscle. This causes 2 effects that enhance near 
vision: 1) constriction of the iris sphincter muscle, resulting in pupil constriction (miosis), and 
2) contraction of the ciliary muscle, resulting in central lens steepening and lens accommodation 
(focusing from distance to near) (García-Lázaro 2012). Reducing the pupil size has long been 
recognized as an effective way to increase the useful depth of focus, in part by reducing 
peripheral aberrations (Tucker 1975). 
Pilocarpine ophthalmic solutions are currently used for the reduction of elevated IOP in patients 
with open-angle glaucoma or ocular hypertension, management of acute-angle closure glaucoma, 


 
 
Approval Date: 
 
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Protocol 1883-301-013       
AGN-190584 
19 
prevention of postoperative elevated IOP associated with laser surgery, and induction of miosis 
(Pilocarpine HCl ophthalmic solution package insert 2011). Currently, the use of pilocarpine 
ophthalmic solution is limited by the commonly experienced AE of temporal and periorbital 
headache (ie, brow ache), which is believed to be due to the rapidity of the ciliary muscle 
contraction (Tsai 2009). However, Allergan has established an acceptable safety profile of 
AGN-190584 in 3 Phase 2 clinical studies (Studies 199201-007, 199201-009, and 199201-010). 
This is likely because the posology of pilocarpine evaluated for the treatment of presbyopia to 
date is of lower concentration (0.5% to 1.5%) and less frequently administered (once to twice 
daily) than for the treatment of glaucoma (1.0% to 4.0% administered up to 4 times daily). As a 
result, discontinuation rates for all Phase 2 clinical studies were generally low and safety 
parameters were not clinically significant between participants that received AGN-190584 
compared to participants that received vehicle or a combination therapy. The majority of AEs 
reported in any treatment group were mild to moderate in intensity.  
Efficacy measures for Phase 2 clinical studies included mesopic uncorrected near visual acuity 
line and letter improvement. Of the various concentrations of AGN-190584 evaluated, near 
vision was most improved compared with vehicle under mesopic and photopic conditions at the 
1.0% and 1.5% pilocarpine concentrations, respectively. 
More detailed information regarding clinical safety findings, clinical efficacy findings, chemistry, 
and pharmacology is provided in the IB. 
2.3. 
Benefit/Risk Assessment 
Currently available approaches to presbyopia correction include nonsurgical options (spectacles 
or contact lenses) and surgical options (PRK or LASIK, conductive keratoplasty, intraocular 
lenses, or corneal inlays). Each approach has its own risk-benefit ratio. Because the risk-benefit 
ratio with nonsurgical options is generally lower than that of surgical procedures, both historical 
and contemporary practice has been to attempt nonsurgical or pharmacological treatment before 
resorting to more invasive alternatives. 
Although the use of spectacles and contact lenses to correct presbyopia is widespread, this 
approach has limitations. Multifocal spectacles impair depth perception and edge-contrast 
sensitivity at critical distances for detecting obstacles in the environment (Lord 2002), and 
varifocal lenses have a corridor of nondistorted vision. For these reasons, older people are more 
than twice as likely to fall when wearing multifocal spectacles, and many participants have 
difficulty adjusting to using them (Johnson 2007, Lord 2002). As a result, Allergan 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. 


 
 
Approval Date: 
 
05-Dec-2018
 
 
Protocol 1883-301-013       
AGN-190584 
20 
3. 
Objectives and Endpoints 
Objectives 
Measures 
To evaluate the efficacy of AGN-190584 
when administered bilaterally, once daily for 
30 days in participants with presbyopia. 
• 
Mesopic and photopic, high contrast DCNVA for each eye 
and binocularly 
• 
Mesopic and photopic, high contrast DCIVA for each eye 
and binocularly 
• 
PRO questionnaires:  
o 
Mesopic and Photopic NVPTQ 
o 
PICQ 
To evaluate the safety and tolerability of 
AGN-190584 when administered bilaterally, 
once daily for 30 days in participants with 
presbyopia 
• 
AEs 
• 
Photopic and mesopic high contrast CDVA for each eye 
and binocularly 
• 
Near Contrast sensitivity 
• 
Vital signs (blood pressure and heart rate) 
• 
Study drug tolerability and drop comfort assessments 
• 
Temporal/supraorbital headache VAS 
• 
IOP 
• 
Slit-lamp biomicroscopy 
• 
Manifest refraction 
• 
Dilated funduscopic examination 
• 
Pregnancy test for WOCBP 
To evaluate the pharmacokinetics of 
AGN-190584 when administered bilaterally, 
once daily for 30 days in participants with 
presbyopia 
• 
Plasma concentrations of AGN-190584 (sampled at 
selected sites; approximately 10% of all enrolled 
participants) 
 


 
 
Approval Date: 
 
05-Dec-2018
 
 
Protocol 1883-301-013       
AGN-190584 
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4. 
Study Design 
4.1. 
Overall Design 
This is a multicenter, double-masked, randomized, parallel-group, vehicle-controlled, Phase 3 
study in participants with presbyopia. Participants will receive AGN-190584 or vehicle dosed 
once daily, bilaterally, for 30 days. Approximately 300 participants with presbyopia will be 
enrolled at approximately 50 sites in the United States. 
This study consists of the following visits: screening, Day 1 (baseline), and Days 3, 7, 14, and 30. 
A study schema is located in Section 1.2 and the SoA is located in Section 1.3. 
Approximately 150 participants per group will be enrolled to achieve at least 135 participants per 
group completing the study. Participants who prematurely discontinue from the study will not be 
replaced. 
4.1.1. 
Clinical Hypotheses 
• AGN-190584 ophthalmic solution dosed bilaterally, once daily for 30 days will 
demonstrate a significant improvement in DCNVA over vehicle. 
• AGN-190584 ophthalmic solution dosed bilaterally, once daily for 30 days will 
demonstrate an acceptable safety and tolerability profile. 
4.2. 
Scientific Rationale for Study Design 
The current Phase 3 clinical study is designed to evaluate the efficacy, safety, and tolerability of 
AGN-190584 versus vehicle over a 30-day study intervention period when administered once 
daily bilaterally in participants with presbyopia. 
Allergan Phase 2 Studies 199201-007 and 199201-009 support the administration of 
AGN-190584 monotherapy as an effective and safe treatment for presbyopia in doses up to 1.5%. 
The current Phase 3 study will evaluate AGN-190584 in an expanded participant population to 
establish efficacy and safety. 
4.3. 
Justification for Dose 
Through modeling and evaluation of the Phase 2 results (Studies 199201-007, 199201-009, and 
199201-010), Allergan has determined the optimal dose of AGN-190584 to be 1.25% for the 
treatment of presbyopia. 
4.4. 
End of Study Definition 
The EOS is defined as the date of the last visit of the last participant in the study. 


 
 
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A participant is considered to have completed the study if he/she has completed all phases of the 
study including the last visit. 


 
 
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5. 
Study Population 
The study population will consist of adult male and female participants with objective and 
subjective evidence of presbyopia. 
Prospective approval of protocol deviations to recruitment and enrollment criteria, also known as 
protocol waivers or exemptions, is not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. 
Age 
1.01 
Participant must be 40 to 55 years of age inclusive, at the time of the screening visit 
2. 
Type of Participant and Presbyopia Characteristics 
2.01 
In good general health at the screening visit, as determined by the investigator  
2.02 
Subjective complaints of poor near vision that impact activities of daily living,
3. 
Sex 


 
 
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3.01 
Male and female 
4. 
Informed Consent 
4.01 
Capable of giving signed informed consent, which includes compliance with the 
requirements and restrictions listed in the ICF and in this protocol 
4.02 
Written informed consent from the participant or a legally authorized representative 
has been obtained prior to any study-related procedures 
4.03 
Written documentation has been obtained in accordance with the relevant country 
and local privacy requirements, where applicable (eg, Written Authorization for Use 
and Release of Health and Research Study Information for the United States) 
5. 
Other 
5.01 
Able, as assessed by the investigator, and willing to follow study instructions and 
likely to complete all required study visits 
 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. 
Medical Conditions 
1.01 
Uncontrolled systemic disease 
1.03 
Any clinical condition or previous surgery that might affect the absorption, distribution, 
biotransformation, or excretion of AGN-190584. History of cataract surgery, phakic 
intraocular lens surgery, corneal inlay surgery, radial keratotomy, or any intraocular 
surgery. However, participants with history of PRK or LASIK with CDVA meeting 
inclusion criteria will be allowed to enroll. 
1.04 
Known allergy or sensitivity to the study intervention or its components or other 
cholinergic agonist medications 
2. 
Prior/Concomitant Therapy 


 
 
Approval Date: 
 
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Protocol 1883-301-013       
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2.01 
Concurrent use of any topical ophthalmic medications, including artificial tears, other 
than the study intervention during the course of the study 
2.02 
Concurrent use of temporary or permanent punctal plugs or history of punctal cautery in 
one or both eyes 
3. 
Prior/Concurrent Clinical Study Experience 
3.01 
Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of entry into this study 
3.02 
Participation in a blood or plasma donation program within 30 days prior to study 
intervention administration 
4. 
Diagnostic Assessments 
4.02 
Severe dry eye disease (defined as total corneal staining ≥ grade 3 on the 5-point Oxford 
scale and an OSDI score of > 33) at the screening visit 
4.03 
Corneal abnormalities (including keratoconus, corneal scar, Fuchs’ endothelial 
dystrophy, guttata, or edema) in either eye that are likely to interfere with visual acuity 
4.04 
Narrow iridocorneal angles (Shaffer grade ≤ 2 or lower on gonioscopy examination), 
history of angle-closure glaucoma, or previous iridotomy 
4.05 
History of iris trauma, Adie’s tonic pupil, abnormal pupil shape in either eye, or 
anisocoria > 1 mm between pupils under mesopic conditions at the screening visit 
4.06 
Lens opacity in either eye that is determined to cause significant disturbance of the 
central visual axis on screening biomicroscopy 
4.07 
Diagnosis of any type of glaucoma or ocular hypertension 
4.08 
Bifocal or multifocal spectacles or contact lenses for habitual correction. Participants 
willing to wear study-provided monofocal correction (either spectacles or contact lenses) 
during the study can be enrolled 
4.09 
Abnormal and clinically significant results according to the investigator or designee, on 
physical/ophthalmic examination or medical history 


 
 
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5. 
Other 
5.01 
Females who are pregnant, nursing, or planning a pregnancy during the study.
 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study. A minimal set of screen failure information is required to 
ensure transparent reporting of screen failure participants to meet the Consolidated Standards of 
Reporting Trials publishing requirements and to respond to queries from regulatory authorities. 
Minimal information includes demography, screen failure details, eligibility criteria, and any 
SAE. 
Individuals who do not meet the criteria for participation in this study (screen failures) may not 
be rescreened. 


 
 
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6. 
Study Intervention 
Study intervention is defined as any investigational intervention intended to be administered to a 
study participant according to the study protocol. 
6.1. 
Study Intervention(s) Administered 
Study Intervention Name 
AGN-190584 
Vehicle 
Dosage Formulation 
Topical eye drop 
Topical eye drop 
Identity of Formulation 
Pilocarpine HCl 1.25% Ophthalmic 
Solution 
Pilocarpine HCl Placebo Ophthalmic 
Solution 
Drug Substance 
Pilocarpine 1.25% 
Not applicable 
Route of Administration  
Topical eye drop 
Topical eye drop 
Dosing Instructions 
1 drop in each eye once daily 
1 drop in each eye once daily 
Manufacturer 
Allergan Sales, LLC. 
Allergan Sales, LLC. 
Number and Timing of 
Interventions 
1 drop bilaterally, once daily 
1 drop bilaterally, once daily 
 
As this is a double-masked study, AGN-190584 and Vehicle will be supplied in identically 
appearing bottles and cartons. 


 
 
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6.2. 
Preparation/Handling/Storage/Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study intervention received and any discrepancies are reported 
and resolved before use of the study intervention. 


 
 
Approval Date: 
 
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Only participants enrolled in the study may receive study intervention, and only authorized site 
staff may supply or administer study intervention. All study intervention must be stored in a 
secure, environmentally controlled, and monitored (manual or automated) area in accordance 
with the labeled storage conditions with access limited to the investigator and authorized site 
staff. All study intervention must be stored upright, in a refrigerator, and protected from freezing. 
Participants will be instructed on the proper storage of study intervention and to keep it out of the 
reach of children at all times. 
6.3. 
Measures to Minimize Bias: Randomization and Blinding 
All participants will be centrally assigned to randomized study intervention using the IxRS. 
Randomization and kit assignment will be conducted on Day 1 (baseline). At Day 1, participants 
will be randomized in a 1:1 ratio into 1 of the 2 study groups. This randomization will be 
stratified by age (2 groups: ≤ 50 years and > 50 years), baseline binocular DCNVA (2 groups: 
20/40 to 20/60 inclusively, and worse than 20/60), iris color (brown and non-brown), and 
emmetropes/non-emmetropes. A maximum of 50% (75 per arm) of the participants enrolled will 
have brown iris color, and a maximum of 25% (38 per arm) of the participants will be non-
emmetropes (a sphere outside of -0.50 D to +0.75 D and/or a cylinder greater than 0.75 D). 


 
 
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6.5. 
Concomitant Therapy 
The use of any concomitant medication, prescription or over-the-counter, is to be recorded on the 
participant’s eCRF at each visit along with the reason the medication is taken. 
From screening to the EOS, site staff will question each participant specifically on the use of 
concomitant medications. Site staff must notify the sponsor immediately if a participant 
consumes any concomitant medications not permitted by the protocol. Participants who used 
prohibited concomitant medications may be discontinued from the study at the discretion of the 
investigator or the sponsor. 
6.5.1. 
Prohibited Interventions and Washout Before the Study 
Use of medications that may have a substantial effect on visual function or the optical properties 
of the eye is prohibited 2 weeks prior to 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, pilocarpine, 
tetrahydrozoline, phenylephrine, naphazoline, cyclopentolate, atropine, beta-blockers, or 
antihistamines  
• systemic maprotiline, tricyclic antidepressants, or monoamine oxidase inhibitors 


 
 
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6.5.2. 
Permitted Interventions 
Any medication or vaccine (including over-the-counter or prescription medicines, vitamins, 
and/or herbal supplements) that the participant is receiving at the time of enrollment or receives 
during the study must be recorded along with: 
• Indication 
• Dates of administration including start and end dates 
• Dosage information including dose and frequency 
Therapy considered necessary for the participant’s welfare may be given at the discretion of the 
investigator. If the permissibility of a specific medication/intervention is in question, please 
contact the sponsor. 
The sponsor or designee should be contacted if there are any questions regarding concomitant or 
prior therapy. 
The concurrent use of nonocular medications that do not have a substantial effect on the pupil, 
accommodative properties, or retinal function of the eye will be permitted during the study if a 
stable dosing regimen is established. The dosing regimen is not considered to be stable if a 
participant starts, stops, or changes the dose/drug during the study. 
Any medication taken during the study between the date of the first dose of study intervention 
and the date of the EOS visit will be recorded in the eCRF as a concomitant medication; any 
medication started after the EOS visit will not be considered a concomitant medication and 
should not be captured in the eCRF. 
6.5.3. 
Rescue Medicine 
Rescue medicine is not applicable. 
6.5.4. 
Prohibited Interventions During the Study 
Use of ocular medications other than study intervention or medications administered to conduct 
study procedures are prohibited from the screening visit until study exit. 
The decision to administer a prohibited medication/treatment will be made with the safety of the 
study participant as the primary consideration. When possible, Allergan should be notified before 
the prohibited medication/treatment is administered. 
6.6. 
Dose Modification 
Dose modification is not applicable. 
6.7. 
Intervention after the End of the Study 
No interventions after the end of the study are planned. 


 
 
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7. 
Discontinuation of Study Intervention and Participant 
Discontinuation/Withdrawal 
A premature discontinuation will occur if a participant who signs the ICF and is dosed ceases 
participation in the study, regardless of circumstances, before the completion of the protocol-
defined study procedures. 
Reasons for discontinuation from the study intervention and/or the study may include the 
following: 
• AE 
• Lack of efficacy 
• Lost to follow-up 
• Noncompliance with study drug 
• Physician decision 
• Pregnancy 
• Protocol deviation 
• Site terminated by sponsor 
• Study terminated by sponsor 
• Withdrawal by subject 
• Death  
• Other 
7.1. 
Discontinuation of Study Intervention 
See the SoA (Section 1.3) for data to be collected at the time of early exit. 
Participants who discontinue the study intervention early will be encouraged to stay in the study 
for the safety assessments at Day 30. 
7.2. 
Participant Discontinuation/Withdrawal from the Study 
• A participant may withdraw from the study at any time at his/her own request or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, 
compliance, or administrative reasons. 


 
 
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• If the participant withdraws consent for disclosure of future information, the sponsor may 
retain and continue to use any data collected before such a withdrawal of consent. 
• If a participant withdraws from the study, he/she may request destruction of any samples 
taken and not tested, and the investigator must document this in the site study records. 
• See the SoA (Section 1.3) for data to be collected at the time of early exit. 
7.3. 
Lost to Follow Up 
A participant will be considered lost to follow-up if he or she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as soon as 
possible and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain whether or not the participant wishes to and/or should continue in the 
study. 
• Before a participant is deemed lost to follow-up, the investigator or designee must make 
every effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts will be documented in the participant’s medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 


 
 
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8. 
Study Assessments and Procedures 
• Study procedures and their timing are summarized in the SoA (Section 1.3). Protocol 
waivers or exemptions are not allowed. 
• Immediate safety concerns should be discussed with the sponsor promptly upon 
occurrence or awareness to determine if the participant should continue or discontinue 
study intervention. 
• Adherence to the study design requirements, including those specified in the SoA, is 
essential and required for study conduct. 
• All screening evaluations must be completed and reviewed to confirm that potential 
participants meet all eligibility criteria. The investigator will maintain a screening log to 
record details of all participants screened and to confirm eligibility or record reasons for 
screening failure, as applicable. 
• Procedures conducted as part of the participant’s routine clinical management (eg, blood 
count) and obtained before signing of the ICF may be utilized for screening or baseline 
purposes provided the procedures met the protocol-specified criteria and were performed 
within the timeframe defined in the SoA. 
• The maximum amount of blood collected for PK from each participant over the duration 
of the study, including any extra assessments that may be required, will not exceed 45 mL. 
Repeat or unscheduled samples may be taken for safety reasons or for technical issues 
with the samples. 
8.1. 
Efficacy Assessments 
Efficacy assessments are: mesopic and photopic, high contrast DCNVA for each eye and 
binocularly, mesopic and photopic, high contrast DCIVA for each eye and binocularly,
PRO questionnaires (NVPTQ, PICQ,


 
 
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Table 8-1 
Efficacy Assessments 
Assessment 
Timing 
Measurement 
Visual Acuity 
Mesopic, high contrast 
DCNVA for each eye and 
binocularly 
 
• Screening 
• Days 1, 14, and 30:  
Hours 0, 0.25, 0.5, 1, 3, 6, 8, and 10 
• Days 3 and 7:  
Hours 0, 1, and 3 
 
• 
Visual acuity for near (40-cm), intermediate 
(66-cm) and distance (4-meter) targets will be 
measured in mesopic and photopic conditions. 
• 
Mesopic condition is defined as lighting 3.2 to 
3.5 candelas per square meter (cd/m2; 10 to 
11 lux) measured at the target. 
Photopic condition is defined as lighting 
≥ 80 cd/m2 (251 lux) measured at the target. 
Photopic, high contrast 
DCNVA for each eye and 
binocularly 
 
• Screening 
• Days 1, 14, and 30:  
Hours 0, 0.25, 0.5, 1, 3, 6, 8, and 10 
• Days 3 and 7:  
Hours 0, 1, and 3 
 
 
Mesopic and photopic, 
high contrast DCIVA for 
each eye and binocularly 
• Screening 
• Days 1, 14, and 30:  
Hours 0, 1, 3, 6, 8, and 10 
• Days 3 and 7:  
Hours 0, 1, and 3 
 
 


 
 
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Assessment 
Timing 
Measurement 
PRO Questionnaires 
Mesopic and Photopic 
NVPTQ 
• Day 1, Hour 0 
• Day 14, Hour 1 
• Day 30, Hour 3 
 
• 
Comprised of 12 questions on 4 reading tasks 
(ie, reading a paragraph from a book, reading 
excerpts from an article in a newspaper, reading a 
portion of a nutrition label, and reading a section 
from a restaurant menu) 
• 
Participants will complete specific reading tasks 
under mesopic and photopic conditions without 
any near-vision correction  
• 
Participants will then answer 3 questions for each 
task, rating their vision-related reading ability and 
satisfaction with their vision-related reading 
ability 
• 
There is no explicit recall period used for the 
NVPTQ; the intention is for patients to complete 
the NVPTQ immediately after completing each 
task. 
• 
For more details on instructions and questions in 
NVPTQ, please see Appendix 8 
PICQ 
• Day 1, Hour 0 
• Day 30, Hour 3 
 
• 
Participants will answer 20 questions about the 
degree to which they were impacted by their 
difficulty seeing up close (eg, found daily near-
vision tasks difficult, or experienced self-
consciousness); or engaged in coping behaviors 
(eg, changed the font size on electronic screens) 
during the previous 7 days 
• 
For more details on instructions and questions in 
PICQ, please see Appendix 8 


 
 
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8.2. 
Safety Assessments 
Planned timepoints for all safety assessments are provided in the SoA (Section 1.3). 
8.2.1. 
Vital Signs 
Vital signs will be assessed as follows: 
• Blood pressure and pulse rate will be assessed. 
• Systolic and diastolic blood pressure will be measured using an appropriate 
sphygmomanometer after participants have been at rest (seated) for at least 5 minutes. 
Blood pressure will be recorded in mm Hg. 
• Heart rate will be measured in bpm after the participant has been in a resting state (seated) 
for at least 5 minutes. Pulse will be counted for 30 seconds, multiplied by 2, and recorded 
in bpm. 
• Blood pressure and pulse measurements will be assessed with a completely automated 
device. Manual techniques will be used only if an automated device is not available. 
Manual techniques will be used only by adequately trained personnel; whenever possible, 
the same person should perform all manual assessments as much as possible. 
• Participants should refrain from smoking or ingesting caffeine during the 30 minutes 
preceding the measurement. 
8.2.2. 
Pregnancy Testing 
Pregnancy test kits will be provided by the investigator and will be administered according to the 
instructions provided with the tests. WOCBP must have a negative test result before receiving 


 
 
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study intervention. This test will also be performed at the Day 30 (Early Exit) visit, and may be 
performed at any other visit, at the investigator’s discretion. At each visit, the investigator should 
discuss contraceptive use compliance with WOCBP. Additional details are provided in 
Appendix 6. 
8.2.3. 
Photopic and Mesopic, High Contrast Corrected Distance Visual Acuity for 
Each Eye and Binocularly 
Photopic and mesopic, high contrast CDVA, for each eye and binocularly, will be assessed using 
the provided visual acuity charts for distance vision in a room with mesopic lighting conditions 
(defined by lighting 3.2 to 3.5 candelas [cd]/m2 [10 to 11 lux] measured at the target) and 
photopic lighting conditions (defined by lighting ≥ 80 cd/m2 [251 lux] measured at the target). 
Forced choice letter by-letter scoring will be used for each test and the total number of correct 
letters or the highest value (number) of the grid identified (as applicable) will be recorded. 
Further details are outlined in the Procedure Manual. 
8.2.4. 
Near Contrast Sensitivity 
Near contrast sensitivity assessment will be conducted under photopic conditions. A 
Pelli-Robson contrast sensitivity chart will be used. The logarithmic contrast sensitivity value of 
the last triplet of which at least 2 letters are correctly read is marked as the contrast sensitivity. 
Further details are outlined in the Procedure Manual. 
8.2.5. 
Study Intervention Tolerability and Drop Comfort Assessments 
The presence and severity of ocular symptoms will be elicited from the participant for both eyes 
after dosing. Symptoms, including blurred vision, foreign body sensation, pain, burning/stinging, 
tearing, and itching, will be classified using a 5-point grading scale with 0 = none, +0.5 = trace, 
+1 = mild, +2 = moderate, and +3 = severe. The duration of symptoms (< 1 minute, 
1 to 5 minutes, > 5 minutes) will be captured once immediately after the second eye is instilled 
with a drop of study intervention. If any other ocular symptoms are present, these will also be 
captured. 
Participants will be asked to rate the overall comfort of the eye drops using a 6-point scale (ie, 
soothing, very comfortable, comfortable, uncomfortable, very uncomfortable, and intolerable) 
immediately after the second eye is instilled with a drop of study intervention, for both eyes. 
8.2.6. 
Temporal/Supraorbital Headache Visual Analog Scale 
Participants will be asked to rate the degree of temporal and supraorbital headache experienced 
after the second eye is instilled with a drop of study intervention, for the right and left eyes 
separately. Headache will be reported on an unmarked 100-mm wide VAS, ranging from no pain 
on the left to worst possible pain on the right. 


 
 
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8.2.7. 
Intraocular Pressure 
IOP must be measured after the biomicroscopic exam is completed and prior to pupil dilation. 
Measurements will be taken using a Goldmann applanation tonometer affixed to a slit-lamp with 
the participant seated. The participant and slit-lamp should be adjusted so that the participant’s 
head is firmly positioned on the chin rest and against the forehead rest without leaning forward 
or straining. Tight fitting neckwear should be loosened. Both eyes will be tested, with the right 
eye preceding the left eye. The 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. 
8.2.8. 
Slit-lamp Biomicroscopy 
Biomicroscopic examinations will be performed using a slit-lamp. The examinations will include 
evaluation of the condition of the eyelids, conjunctiva, cornea, anterior chamber, and iris/pupil. 


 
 
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Eyelid/Eyelid Margins/Lashes: 
Edema 
 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) 
= 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 
Erythema 
 
 
  0 
(None) 
= 
No erythema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) flush reddish color  
+1 
(Mild) 
= 
Localized, mild, flush reddish color 
+2 
(Moderate) 
= 
Diffuse reddish color encompassing the entire lid margin 
+3 
(Severe) 
= 
Deep diffuse reddish color of lid margins and superior 
and/or inferior eyelid 
Conjunctiva (Bulbar): 
Hyperemia  
  0 
(None) 
= 
No hyperemia 
+0.5 
(Trace) 
= 
Minimal (trace) flush, reddish color 
+1 
(Mild) 
= 
Mild flush, reddish color 
+2 
(Moderate) 
= 
Bright red color 
+3 
(Severe) 
= 
Deep, bright diffuse redness 
Edema 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) = 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 


 
 
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Conjunctiva (Palpebral): 
Hyperemia  
  0 
(None) 
= 
No hyperemia 
+0.5 
(Trace) 
= 
Minimal (trace) flush, reddish color 
+1 
(Mild) 
= 
Mild flush, reddish color 
+2 
(Moderate) 
= 
Bright red color 
+3 
(Severe) 
= 
Deep, bright diffuse redness 
Edema 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) swelling 
+1 
(Mild) 
= 
Localized, mild swelling 
+2 
(Moderate) = 
Diffuse, moderate swelling 
+3 
(Severe) 
= 
Diffuse, severe swelling 
Cornea: 
Edema 
 
  0 
(None) 
= 
No edema 
+0.5 
(Trace) 
= 
Localized, minimal (trace) epithelial haze 
+1 
(Mild) 
= 
Dull glass appearance of epithelium that may include fine 
localized microcystic changes 
+2 
(Moderate) = 
Dull glass appearance of the epithelium with large 
number of cystic changes with or without stromal edema 
 +3 
(Severe) 
= 
Epithelial bullae and/or stromal edema, localized or 
diffuse, with or without stromal striae 
Superficial Punctate Keratopathy 
 0 
= 
No superficial punctate keratopathy 
+0.5 
= 
Trace 
+1 
= 
Mild 
+2 
= 
Moderate 
+3 
= 
Severe 
Anterior Chamber: 
The anterior chamber will be evaluated for pathology. If pathology is present, it will be described. 


 
 
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Iris/Pupil: 
The iris/pupil will be evaluated for pathology. If pathology is present, it will be described. 
8.2.9. 
Manifest Refraction 
Manifest refraction (distance and near) will be performed according to standard clinical practice 
in both mesopic and photopic conditions. 
If a participant loses ≥ 1 line of CDVA or DCNVA compared with Hour 0 of the same study 
visit at Hour 1 after dosing, a manifest refraction should be repeated under the same lighting 
conditions. 
Additional details are outlined in the Procedure Manual. 
8.2.10. 
Dilated Funduscopic Examination 
The fundus assessments should be conducted through a dilated pupil. The examinations will 
include evaluation of the lens, vitreous, fundus, and optic nerve. The C/D ratio will be assessed. 
The investigator should note if the pupil dilated normally. 
Lens: 
Lens Assessment: 
Use biomicroscopic examination, indirect lenses, direct/indirect ophthalmoscopy, etc., as 
appropriate, to visualize. 
Lens Status: 
The lens will be evaluated for pathology. If pathology is present, it will be described. 
Cataract Assessment: 
Under dilated examination, the presence and severity of nuclear, cortical, and posterior 
subcapsular cataract lens opacities will be evaluated. At the first dilated examination, each type 
of cataract, if present, will be graded using the scale below. At the last follow-up dilated 
examination, each type of cataract will be assessed for change from baseline and if changed, the 
current severity will be graded using the scale below: 
 0 
= 
None 
+1 
= 
Mild 
+2 
= 
Moderate 
+3 
= 
Severe 
Vitreous: 
The vitreous will be evaluated for pathology. If pathology is present, it will be described. It will 
be noted if the condition is not evaluable. 


 
 
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Fundus: 
The fundus (posterior pole; periphery, when dilated) will be evaluated for pathology. If 
pathology is present, it will be described. It will be noted if the condition is not evaluable. 
Optic Nerve: 
The optic nerve will be evaluated for pathology. If pathology is present, it will be described. It 
will be noted if the condition is not evaluable. 
C/D Ratio: 
C/D ratio will be reported using a 0.0 to 1.0 scale. It will be noted if the condition is not 
evaluable. 
8.2.11. 
Suicidal Risk Monitoring 
Suicidal risk monitoring is not applicable to this ophthalmology study. 
8.3. 
Adverse Events and Serious Adverse Events 
The definitions of an AE or SAE can be found in Appendix 2. 
AEs will be reported by the participant (or, when appropriate, by a caregiver, surrogate, or the 
participant’s legally authorized representative). 
The investigator and any qualified designees are responsible for detecting, documenting, and 
recording events that meet the definition of an AE or SAE and remain responsible for following 
up AEs that are serious, considered related to the study intervention or study procedures, or that 
caused the participant to discontinue the study intervention (ie, repeat treatment) or study (see 
Section 7). 
8.3.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse 
Event Information 
All SAEs from the signing of the ICF until 30 days after the last dose of study intervention will 
be collected at the timepoints specified in the SoA (Section 1.3), and as observed or reported 
spontaneously by study participants. 
All AEs from the signing of the ICF until 30 days after the last dose of study intervention will be 
collected at the timepoints specified in the SoA (Section 1.3), and as observed or reported 
spontaneously by study participants. 
Medical occurrences that begin before the start of study intervention, but after obtaining 
informed consent will be recorded in the AE section of the eCRF. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours, as indicated 
in Appendix 2. The investigator will submit any updated SAE data to the sponsor within 
24 hours of it being available. 


 
 
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Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation. However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study intervention or study participation, the investigator must promptly 
notify the sponsor. 
The methods of recording, evaluating, and assessing causality of AEs and SAEs and the 
procedures for completing and transmitting SAE reports are provided in Appendix 2. 
8.3.2. 
Method of Detecting Adverse Events and Serious Adverse Events 
Care will be taken not to introduce bias when detecting AEs and/or SAEs. Open-ended and 
non-leading verbal questioning of the participant is the preferred method to inquire about 
AE occurrences. 
8.3.3. 
Follow-up of Adverse Events and Serious Adverse Events 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts. All AEs/SAEs will be followed until resolution, stabilization, the 
event is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
The investigator is obligated to perform or arrange for the conduct of supplemental 
measurements and/or evaluations as medically indicated or as requested by Allergan to elucidate 
the nature and/or causality of the AE or SAE as fully as possible. This may include additional 
laboratory tests or investigations, histopathological examinations, or consultation with other 
health care professionals. 
If a participant dies during participation in the study, the investigator will provide Allergan with 
a copy of any postmortem findings including histopathology. 
If a participant is hospitalized and discharged, follow-up attempts must be made to obtain the 
discharge summary from the hospital and, if obtained, it should be sent to the sponsor. 
New or updated information will be recorded in the originally completed eCRF. 
The investigator will submit any updated SAE data to Allergan within 24 hours of receipt of the 
information. 
8.3.4. 
Regulatory Reporting Requirements for Serious Adverse Events 
• Prompt notification by the investigator to the sponsor of an SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of 
a study intervention under clinical investigation are met.  
• The sponsor has a legal responsibility to notify both the local regulatory authority and 
other regulatory agencies about the safety of a study intervention under clinical 
investigation. The sponsor will comply with country-specific regulatory requirements 
relating to safety reporting to the regulatory authority, IRBs/IECs, and investigators.  


 
 
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• Investigator safety reports must be prepared for suspected unexpected serious adverse 
reactions according to local regulatory requirements and sponsor policy and forwarded to 
investigators as necessary. 
• An investigator who receives an investigator safety report describing an SAE or other 
specific safety information (eg, summary or listing of SAEs) from the sponsor will review 
and then file it along with the IB and will notify the IRB/IEC, if appropriate according to 
local requirements. 
8.3.5. 
Pregnancy 
• If a pregnancy is confirmed after the participant has received the study intervention, the 
participant may choose to exit the study after appropriate safety follow-up or to remain in 
the study for all safety and efficacy follow-up assessments through the EOS visit. 
• Details of all pregnancies in female participants and, if indicated, female partners of male 
participants will be collected after the start of study intervention and through the duration 
of the pregnancy. 
• If a pregnancy is reported, the investigator should inform Allergan within 24 hours of 
learning of the pregnancy and should follow the procedures outlined in Appendix 6. 
• Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, 
congenital anomalies, ectopic pregnancy) or genetic abnormalities (whether leading to an 
elective abortion or not) are considered SAEs. 
8.3.6. 
Medication Errors 
Medication error refers to any unintended error in the dosing and/or administration of the study 
intervention as per instructions in the protocol. Medication errors generally fall into 4 categories 
as follows: 
• Wrong study drug 
• Wrong dose (including dosing regimen, strength, form, concentration, amount) 
• Wrong route of administration 
• Wrong participant (ie, not administered to the intended participant) 
8.4. 
Treatment of Overdose 
Treatment of overdose is not applicable to this ophthalmology study. 


 
 
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8.5. 
Pharmacokinetics 
Blood samples for quantitation of pilocarpine in participant’s plasma will be collected from 
approximately 10% of enrolled participants at selected sites. 
8.5.1. 
Blood Pharmacokinetic Sampling Procedure 
• A qualified phlebotomist will collect 5 mL of each participant’s blood via an indwelling 
catheter or venipuncture from either arm into one 6 mL vacutainer tube containing 
K2EDTA as an anticoagulant. 
• Plasma samples of approximately 2.5 mL will be separated from each blood sample 
collected for measurement of plasma concentrations of pilocarpine as specified in the SoA 
(Section 1.3). 
• Instructions for the collection and handling of biological samples will be provided by 
Allergan. The actual date and time (24-hour clock time) of each sample will be recorded. 
PK 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 eCRFs. 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, 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 Allergan’s standard operating procedures. Extreme care and diligence will be taken to 
ensure no other individuals outside the bioanalytical team will be unblinded. 


 
 
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Blood Volume Collected per Participant  
• Approximately 10% of participants at selected sites  
• PK blood samples: 45 mL (9 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. 
8.5.2. 
Pharmacokinetic Sample Bioanalysis 
Plasma concentrations of pilocarpine in plasma will be determined using validated liquid 
chromatography-tandem mass spectrometry methods. 
8.6. 
Pharmacodynamics 
Pharmacodynamic parameters are not evaluated in this study. 
8.7. 
Genetics 
Genetics are not evaluated in this study. 
8.8. 
Biomarkers and Other Assessments 
8.8.1. 
Biomarkers 
Biomarkers are not evaluated in this study. 
8.8.2. 
Determination of Dominant Eye 
Participants will be asked to extend their arms out in front of them at eye level, with their palms 
facing away, fingers together, and facing upward. Participants will bring their hands together, 
forming a small window by overlapping their thumbs and overlapping their fingers. Participants 
will select a small object at least 10 feet in front of them and look at it with both eyes through the 
view window in their hands. While remaining focused on the object, participants will close the 
right eye and take note of whether the image remains visible. If the image remains visible, the 
left eye is the dominant eye. If the image is no longer visible, the right eye is the dominant eye. 
This will be confirmed by closing the left eye and taking note of whether the image remains 
visible. Details will be outlined in the Procedure Manual. 


 
 
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8.9. 
Health Economics 
PRO instruments (questionnaires) are administered in this study
At screening, participants 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. 
Each participant will also perform four different near vision reading tasks under mesopic and 
photopic conditions. Participants will subsequently rate their vision-related reading ability, and 
satisfaction with their vision-related reading ability on the NVPTQ. 
Participants will also answer questions measuring overall satisfaction with the treatment using 
questions assessing the impact of presbyopia on their life – and need for 
compensatory coping mechanisms – using the PICQ. 
9. 
Statistical Considerations 
9.1. 
Statistical Hypotheses 
The null and alternative hypotheses for the primary efficacy endpoint are: 
• H0: AGN-190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 days 
have the same effect in the proportion of participants gaining 3 lines or more in mesopic, 
high contrast, binocular DCNVA at Day 30, Hour 3; 
• HA: AGN-190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 
days do not have the same effect in the proportion of participants gaining 3 lines or more 
in mesopic, high contrast, binocular DCNVA at Day 30, Hour 3. 
The null and alternative hypotheses for the key secondary efficacy endpoint are: 
• H0: AGN-190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 days 
have the same effect in the proportion of participants gaining 3 lines or more in mesopic, 
high contrast, binocular DCNVA at Day 30, Hour 6; 


 
 
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• HA: AGN-190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 
days do not have the same effect in the proportion of participants gaining 3 lines or more 
in mesopic, high contrast, binocular DCNVA at Day 30, Hour 6. 
9.2. 
Sample Size Determination 
The primary efficacy endpoint is the proportion of participants gaining 3 lines or more in 
mesopic, high contrast, binocular DCNVA at Day 30, Hour 3. The key secondary efficacy 
endpoint is the proportion of participants gaining 3 lines or more in mesopic, high contrast, 
binocular DCNVA at Day 30, Hour 6. The sample size calculation is based on the key secondary 
efficacy endpoint. The vehicle group intervention effect is assumed to be 3.6%, as observed in 
the Phase 2 study. AGN-190584 effect is assumed to be 16% in emmetropes and 12% in non-
emmetropes. This gives an overall AGN-190584 effect of 15% assuming emmetropes will be 
75% of the study population. 135 participants will be required in each study intervention group 
to detect the above difference with a power of 90% or greater at the 2-sided 
5% significance level. Assuming a 10% dropout rate, approximately 150 participants per study 
intervention group will be randomized. 
9.3. 
Populations for Analyses 
The analysis populations will consist of participants as defined below: 
• The ITT population includes all randomized participants. Participants will be summarized 
according to the randomized study intervention. 
• The safety population includes all treated participants who receive ≥ 1 administration of 
study intervention. Participants will be summarized according to the study intervention 
they actually received. 
9.4. 
Statistical Analyses 
The SAP will be developed and finalized before database lock and unmasking and will describe 
the participant populations to be included in the analyses, and procedures for accounting for 
missing, unused, and spurious data. This section is a summary of the planned statistical analyses 
of the primary and secondary endpoints. 
9.4.1. 
Efficacy Analyses 
The efficacy analyses will be based on the ITT population. Baseline for efficacy is defined as the 
last nonmissing efficacy assessment before the first dose of study intervention. All statistical 
tests will be 2-sided hypothesis tests performed at the 5% level of significance for main effects. 
All confidence intervals will be 2-sided 95% confidence intervals, unless stated otherwise.  


 
 
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9.4.1.1. 
Analysis Endpoints 
The primary and secondary efficacy endpoints are listed below and analyses will be described in 
the following sections. The analyses for other efficacy endpoints listed below will be described 
in the SAP. 
Primary Efficacy Endpoint: 
• Proportion of participants gaining 3 lines or more in mesopic, high contrast, binocular 
DCNVA at Day 30, Hour 3. 
Key Secondary Efficacy Endpoint: 
• Proportion of participants gaining 3 lines or more in mesopic, high contrast, binocular 
DCNVA at Day 30, Hour 6. 
Secondary Efficacy Endpoints: 
1. Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, 
DCNVA at Day 30, Hour 8. 
2. Change from baseline mesopic, high contrast, binocular DCNVA letters at Day 30, 
Hour 0.5. 
3. Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, 
DCNVA at Day 30, Hour 1. 
4. Mesopic NVPTQ Performance score mean change from baseline at Day 30, Hour 3. 
5. Change from baseline photopic, high contrast, binocular DCIVA letters at Day 30, Hour 3. 
6. Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, 
DCNVA at Day 30, Hour 10. 
7. Change from baseline mesopic, high contrast, binocular DCNVA letters at Day 30, 
Hour 0.25.  
8. Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, 
DCNVA at Day 30, Hour 3. 
9. Mesopic NVPTQ Satisfaction score mean change from baseline at Day 30, Hour 3. 
10. PICQ Coping score mean change from baseline at Day 30, Hour 3. 
11. PICQ Impact score mean change from baseline at Day 30, Hour 3. 


 
 
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9.4.1.2. 
Primary Analyses 
The proportion of participants gaining 3 lines or more in mesopic, high contrast, binocular 
DCNVA at Day 30, Hour 3 will be analyzed using chi-square test. Missing data will be regarded 
as 3-line gain failure. 
9.4.1.3. 
Secondary Analyses 
The key secondary efficacy endpoint is the proportion of participants gaining 3 lines or more in 
mesopic, high contrast, binocular DCNVA at Day 30, Hour 6.  
The key secondary efficacy endpoint will be analyzed using a chi-square test. Missing data will 
be regarded as 3-line gain failure.  
All analyses for other secondary efficacy endpoints will be based on observed data only. 
Secondary endpoints 1, 3, 6, and 8 will be analyzed using a chi-square test. Secondary endpoints 
2, 4, 5, and 7 will be analyzed using MMRM with study intervention group, visit, visit by study 
intervention group interaction, age group, baseline binocular DCNVA severity, iris color, 
emmetropes/non-emmetropes, baseline value, and baseline value by visit interaction as fixed 
effects. The within-participant correlation error structure is unstructured. Secondary endpoints 9, 
10, and 11 will be analyzed using analysis of covariance with study intervention group, age 
group, baseline binocular DCNVA severity, iris color, emmetropes/non-emmetropes, and 
baseline domain score as fixed effects. 
To control the overall Type 1 error rate in the efficacy analysis, a sequential testing procedure 
will be used. The test for the key secondary endpoint will be implemented only if the primary 
efficacy endpoint yields statistically significant results. All other secondary efficacy endpoints 
will be tested only if the key secondary efficacy endpoint is statistically significant. A proper 
multiple comparison procedure will be pre-specified in the SAP. 
9.4.2. 
Safety Analyses 
The safety analysis will be performed using the safety population and will be fully defined in the 
SAP. The safety parameters will include AEs, vital signs (blood pressure and heart rate), 
mesopic and photopic, high contrast, binocular CDVA, near contrast sensitivity, study 
intervention tolerability and drop comfort assessments, temporal/supraorbital headache 
assessment using VAS, IOP, slit-lamp biomicroscopy, manifest refraction, dilated funduscopic 
examination, and pregnancy test. For each safety parameter, the last nonmissing safety 
assessment before the first dose of study intervention will be used as the baseline. 


 
 
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9.4.2.1. 
Adverse Events 
An AE will be considered a TEAE if the AE began or worsened (increased in severity or became 
serious) on or after the date of the first dose of study intervention. However, an AE that occurs 
more than 30 days after the last dose of study intervention will not be counted as a TEAE. 
An AE will be considered a treatment-emergent SAE if it is a TEAE that additionally meets any 
SAE criteria. 
The number and percentage of participants reporting TEAEs during the study will be tabulated 
by system organ class and preferred term and by system organ class, preferred term, and severity. 
If more than one AE is coded to the same preferred term for the same participant, the participant 
will be counted only once for that preferred term using the most severe and most related 
occurrence for the summarizations by severity and by relationship to study intervention. 
Summary tables will be provided for participants with SAEs and participants with AEs leading to 
discontinuation if 5 or more participants reported such events. Listings of all AEs, SAEs, and 
AEs leading to discontinuation by participant will be presented. 
9.4.2.2. 
Other Safety Analyses 
All other safety variables will be analyzed with descriptive statistics. Detailed methods for the 
analysis of other safety variables will be described in the SAP. 
9.4.3. 
Pharmacokinetic Analyses 
9.4.3.1. 
Pharmacokinetic Parameters 
The following PK parameters will be calculated based on standard Phoenix WinNonlin 
equations: AUC0-last.ss, maximum plasma drug concentration at steady state, time of maximum 
plasma drug concentration at steady state, Cmin,ss, and peak-to-trough ratio. 
Cmin,ss will be determined observationally as the drug concentration during the dosing interval at 
steady state. 
AUC0-last,ss will be calculated by using the linear-log trapezoidal rule. 
9.4.3.2. 
Statistical Analyses of Pharmacokinetic Data 
Details of the statistical analyses of PK data will be described in the pharmacokinetic analysis 
plan finalized before database lock.  


 
 
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9.5. 
Interim Analyses 
No interim analysis is planned. 
9.5.1. 
Data Monitoring Committee 
Not applicable. 


 
 
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10. 
Supporting Documentation and Operational Considerations 


 
 
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10.1. 
Appendix 1: Regulatory, Ethical, and Study Oversight 
Considerations 
10.1.1. 
Regulatory and Ethical Considerations 
• This study will be conducted in accordance with the protocol and with the following: 
o Consensus ethical principles derived from international guidelines including the 
Declaration of Helsinki and Council for International Organizations of Medical Sciences 
International Ethical Guidelines 
o Applicable ICH/International Organization for Standardization GCP guidelines 
o Applicable laws and regulations 
• The protocol, protocol amendments, ICF, IB, and other relevant documents (eg, 
advertisements) must be submitted to an IRB/IEC by the investigator and reviewed and 
approved by the IRB/IEC before the study is initiated. 
• Any amendments to the protocol will require IRB/IEC approval before implementation of 
changes made to the study design, except for changes necessary to eliminate an immediate 
hazard to study participants.  
• The investigator will be responsible for the following: 
o Providing written summaries of the status of the study to the IRB/IEC annually or more 
frequently in accordance with the requirements, policies, and procedures established by 
the IRB/IEC 
o Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures 
o Providing oversight of the overall conduct of the study at the site and adherence to 
requirements of applicable local regulations, for example 21 CFR, ICH guidelines, the 
IRB/IEC, and European regulation 536/2014 for clinical studies (if applicable) 


 
 
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10.1.3. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions regarding the 
study.  
• Participants must be informed that their participation is voluntary. Participants will be 
required to sign a statement of informed consent that meets the requirements of 21 CFR 50, 
local regulations, ICH guidelines, Health Insurance Portability and Accountability Act 
requirements, where applicable, and the IRB/IEC or study center.  
• The medical record must include a statement that written informed consent was obtained 
before the participant was enrolled in the study and the date the written consent was obtained. 
The authorized person obtaining the informed consent must also sign the ICF. 
• Participants must be re-consented to the most current version of the ICF(s) during their 
participation in the study.  
• A copy of the ICF(s) must be provided to the participant or the participant’s legally 
authorized representative. 
10.1.4. 
Data Protection 
• Participants will be assigned a unique identifier. Any participant records or datasets that are 
transferred to the sponsor will contain the identifier only; participant names or any 
information which would make the participant identifiable will not be transferred.  
• The participant must be informed that his/her personal study-related data will be used by the 
sponsor in accordance with local data protection laws. The level of disclosure must also be 
explained to the participant.  
• The participant must be informed that his/her medical records may be examined by Clinical 
Quality Assurance auditors or other authorized personnel appointed by the sponsor, by 
appropriate IRB/IEC members, and by inspectors from regulatory authorities. 
10.1.5. 
Posting Clinical Study Data 
• Study data and information may be published in nonpromotional, peer-reviewed publications 
either by or on behalf of the sponsor.  
• Clinical study reports, safety updates, and annual reports will be provided to regulatory 
authorities as required. 
• Company-sponsored study information and tabular study results will be posted on the United 
States National Institutes of Health's website www.ClinicalTrials.gov and other publicly 
accessible sites 


 
 
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10.1.6. 
Data Quality Assurance 
• All participant data relating to the study will be recorded on printed or electronic CRFs 
unless transmitted to the sponsor or designee electronically (eg, laboratory data). The 
investigator is responsible for verifying that data entries are accurate and correct by 
physically or electronically signing the CRF.  
• The investigator must maintain accurate documentation (source data) that supports the 
information entered in the CRF.  
• The investigator must permit study-related monitoring, audits, IRB/IEC review, and 
regulatory agency inspections and provide direct access to source data documents.  
• The sponsor or designee is responsible for the data management of this study including 
quality checking of the data.  
• Study monitors will perform ongoing source data verification to confirm that data entered 
into the CRF by authorized site personnel are accurate, complete, and verifiable from source 
documents; that the safety and rights of participants are being protected; and that the study is 
being conducted in accordance with the currently approved protocol and any other study 
agreements, ICH GCP, and all applicable regulatory requirements.  
• Records and documents, including signed ICFs, pertaining to the conduct of this study must 
be retained by the investigator as stated in the clinical trial agreement. No records may be 
destroyed during the retention period without the written approval of the sponsor. No records 
may be transferred to another location or party without written notification to the sponsor.  
10.1.7. 
Source Documents 
• Source documents provide evidence for the existence of the participant and substantiate the 
integrity of the data collected. Source documents are filed at the investigator’s site. 
• Data reported on the CRF or entered in the eCRF that are transcribed from source documents 
must be consistent with the source documents or the discrepancies must be explained. The 
investigator may need to request previous medical records or transfer records, depending on 
the study. 
• Definition of what constitutes source data can be found in Section 4.0 of ICH E6, GCP: 
Consolidated Guidance and records must be attributable, legible, contemporaneous, original, 
and accurate. 


 
 
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10.1.9. 
Publication Policy 
• Allergan as the sponsor has proprietary interest in this study. Authorship and manuscript 
composition will reflect joint cooperation between multiple investigators and sites and 
Allergan personnel. Authorship will be established prior to the writing of the manuscript. As 
this study involves multiple centers, no individual publications will be allowed prior to 
completion of the final report of the multicenter study except as agreed with Allergan. 
• The sponsor will comply with the requirements for publication of study results. In 
accordance with standard editorial and ethical practice, the sponsor will generally support 
publication of multicenter studies only in their entirety and not as individual site data. 
• Authorship will be determined by mutual agreement and in line with International Committee 
of Medical Journal Editors authorship requirements. 
10.1.10. 
Compliance with Protocol 
The investigator is responsible for compliance with the protocol at the investigational site. A 
representative of the sponsor will make frequent contact with the investigator and his/her 
research staff and will conduct regular monitoring visits at the site to review participant and 
study intervention accountability records for compliance with the protocol. Protocol deviations 
will be discussed with the investigator upon identification. The use of the data collected for the 
participant will be discussed to determine if the data are to be included in the analysis. The 
investigator will enter data that may be excluded from analysis as defined by the protocol 
deviation specifications. Significant protocol deviations will be reported to the IRB/IEC 
according to the IRB/IEC’s reporting requirements. 


 
 
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10.2. 
Appendix 2: Adverse Events: Definitions and Procedures for 
Recording, Evaluating, Follow-up, and Reporting 
Definition of AE 
AE Definition 
• 
An AE is any untoward medical occurrence in a patient or clinical study participant, 
temporally associated with the use of study intervention, whether or not considered 
related to the study intervention. 
• 
An AE can therefore be any unfavorable and unintended sign (including an abnormal 
laboratory finding), symptom, or disease (new or exacerbated) temporally associated 
with the use of study intervention. 
AESI 
An AESI (serious or nonserious) is one of scientific and medical concern specific to the 
sponsor’s study drug/device or program, which warrants ongoing monitoring and rapid 
communication by the investigator to the sponsor. Such an event might warrant further 
investigation in order to characterize and understand it.  
There are no AESIs identified for the study intervention AGN-190584. 
 
Events Meeting the AE Definition  
• 
Exacerbation of a chronic or intermittent pre-existing condition including either an 
increase in frequency and/or intensity of the condition 
• 
New condition detected or diagnosed after study intervention administration even 
though it may have been present before the start of the study 
• 
Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction 
• 
Lack of efficacy or failure of expected pharmacological action per se will not be 
reported as an AE or SAE. Such instances will be captured in the efficacy 
assessments. However, the signs, symptoms, and/or clinical sequelae resulting from 
the lack of efficacy will be reported as AEs or SAEs if they fulfill the definition of an 
AE or SAE. 
 


 
 
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Events NOT Meeting the AE Definition  
• 
Any clinically significant abnormal laboratory findings or other abnormal safety 
assessments that are associated with the underlying disease or disease progression, 
unless judged by the investigator to be more severe than expected for the 
participant’s condition. Merely repeating an abnormal test, in the absence of any of 
the above conditions. Any abnormal test result that is determined to be an error does 
not require recording as an AE. 
• 
Medical or surgical procedure (eg, endoscopy, appendectomy): the condition that 
leads to the procedure is the AE 
• 
Situations in which an untoward medical occurrence did not occur (social and/or 
convenience admission to a hospital) 
• 
Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present 
or detected at the start of the study that do not worsen 
Definition of SAE 
SAEs must meet both the AE criteria described above and the seriousness criteria listed below. 
An SAE is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life threatening 
The term life threatening in the definition of serious refers to an event in which the 
participant was at risk of death at the time of the event. It does not refer to an event, 
which hypothetically might have caused death, if it were more severe. 
c. 
Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually 
involving at least an overnight stay) at the hospital or emergency ward for observation 
and/or intervention that would not have been appropriate in the physician’s office or 
outpatient setting. Complications that occur during hospitalization are AEs. If a 
complication prolongs hospitalization or fulfills any other serious criteria, the event is 
serious. When in doubt as to whether hospitalization occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective intervention of a pre-existing condition that did not worsen 
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d. Results in persistent disability/incapacity 
• 
The term disability means a substantial disruption of a person’s ability to conduct 
normal life functions. 
• 
This definition is not intended to include experiences of relatively minor medical 
significance such as uncomplicated headache, nausea, vomiting, diarrhea, influenza, 
and accidental trauma (eg, sprained ankle) which may interfere with or prevent 
everyday life functions but do not constitute a substantial disruption. 
e. 
Is a congenital anomaly/birth defect 
f. 
Other situations: 
• 
Medical or scientific judgment should be exercised in deciding whether SAE 
reporting is appropriate in other situations such as important medical events that may 
not be immediately life threatening or result in death or hospitalization but may 
jeopardize the participant or may require medical or surgical intervention to prevent 
one of the other outcomes listed in the above definition. These events should usually 
be considered serious. 
Examples of such events include invasive or malignant cancers, intensive 
intervention in an emergency room or at home for allergic bronchospasm, blood 
dyscrasias or convulsions that do not result in hospitalization, or development of 
drug dependency or drug abuse. 
Recording and Follow-Up of AEs and/or SAEs 
AE and SAE Recording 
• 
When an AE or SAE occurs, it is the responsibility of the investigator to review all 
documentation (eg, hospital progress notes, laboratory reports, and diagnostics 
reports) related to the event. 
• 
The investigator will then record all relevant AE or SAE information in the eCRF. 
• 
It is not acceptable for the investigator to send photocopies of the participant’s 
medical records to Allergan in lieu of completion of the AE or SAE eCRF page. 
• 
There may be instances when copies of medical records for certain cases are 
requested by Allergan. In this case, all participant identifiers, with the exception of 
the participant number, will be redacted on the copies of the medical records before 
submission to Allergan. 
• 
The investigator will attempt to establish a diagnosis of the event based on signs, 
symptoms, and/or other clinical information. Whenever possible, the diagnosis (not 
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Assessment of Intensity 
MILD 
A type of AE that is usually transient and may require only minimal treatment 
or therapeutic intervention. The event does not generally interfere with usual 
activities of daily living. 
MODERATE 
A type of AE that is usually alleviated with additional specific therapeutic 
intervention. The event interferes with usual activities of daily living, causing 
discomfort but poses no significant or permanent risk of harm to the research 
participant. 
SEVERE 
A type of AE that interrupts usual activities of daily living, or significantly 
affects clinical status, or may require intensive therapeutic intervention. 
An event is defined as serious when it meets at least one of the predefined outcomes as 
described in the definition of an SAE, NOT when it is rated as severe. 
 
Assessment of Causality 
• 
The investigator is obligated to assess the relationship between study intervention 
and each occurrence of each AE or SAE. 
• 
A reasonable possibility of a relationship conveys that there are facts, evidence, 
and/or arguments to suggest a causal relationship, rather than a relationship cannot 
be ruled out. 
• 
The investigator will use clinical judgment to determine the relationship. 
• 
Alternative causes, such as underlying disease(s), concomitant therapy, and other 
risk factors, as well as the temporal relationship of the event to study intervention 
administration will be considered and investigated. 
• 
The investigator will also consult the IB and/or product information, for marketed 
products, in his/her assessment. 
• 
For each AE or SAE, the investigator must document in the medical notes that 
he/she has reviewed the AE or SAE and has provided an assessment of causality. 
• 
There may be situations in which an SAE has occurred and the investigator has 
minimal information to include in the initial report to Allergan. However, it is very 
important that the investigator always make an assessment of causality for 
every event before the initial transmission of the SAE data to Allergan. 
• 
The investigator may change his/her opinion of causality in light of follow-up 
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assessment. 
• 
The causality assessment is one of the criteria used when determining regulatory 
reporting requirements. 
Reporting of SAEs 
SAE/SADE Reporting 
• 
Email is the preferred method to transmit SAE information. The email address is 
IR-Clinical-SAE@allergan.com. 
• 
Facsimile transmission of the SAE information is also acceptable. The fax number is 
+1-714-796-9504 (backup number is +1-714-246-5295).  
• 
In rare circumstances and in the absence of facsimile equipment, notification by 
telephone is acceptable with a copy of the SAE form, sent by overnight mail or 
courier service. 
• 
Initial notification via telephone does not replace the need for the investigator to 
complete and sign the SAE form within the designated reporting time frames. 
• 
Contacts for SAE reporting can be found on the protocol title page. 
 


 
 
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10.3. 
Appendix 3: Abbreviations 
Abbreviation/Term 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
AUC0-last,ss 
area under the plasma concentration versus time curve from time 0 to the last 
measurable concentration, at steady state 
bpm 
beats per minute 
C/D 
cup to disc 
CDISC 
Clinical Data Interchange Standards Consortium 
CDVA 
corrected distance visual acuity 
CFR 
Code of Federal Regulations 
Cmin,ss 
minimum plasma drug concentration at steady state  
CRF 
case report form 
DCIVA 
distance-corrected intermediate visual acuity 
DCNVA 
distance-corrected near visual acuity 
DET 
dry eye test 
eCRF 
electronic case report form 
EOS 
end of the study 
FDA 
Food and Drug Administration 
FSH 
follicle-stimulating hormone 
GCP 
Good Clinical Practice 
HRT 
hormonal replacement therapy 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
ID 
identification 
IEC 
independent ethics committee 
IOP 
intraocular pressure 
IRB 
institutional review board 
ITT 
intent-to-treat 
IxRS 
interactive electronic response system 
LASIK 
laser-assisted in situ keratomileusis  
MMRM 
mixed model repeated measure 
NCI 
National Cancer Institute 
NEI VFQ-25 
National Eye Institute Visual Function Questionnaire 25 
NVPTQ 
Near Vision Presbyopia Task-based Questionnaire  
OD 
right eye 
OS 
left eye 
OSDI 
Ocular Surface Disease Index 


 
 
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Abbreviation/Term 
Definition 
PICQ 
Presbyopia Impact and Coping Questionnaire  
PK 
pharmacokinetic 
PRK 
photorefractive keratectomy  
PRO 
patient reported outcomes 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SoA 
schedule of activities 
TEAE 
treatment-emergent adverse event 
VAS 
visual analog scale 
WOCBP 
women of childbearing potential 
 


 
 
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10.4. 
Appendix 4: Standard Discontinuation Criteria 
CDISC Submission Value 
CDISC Definition 
AE 
Any untoward medical occurrence in a patient or 
clinical investigation subject administered a 
pharmaceutical product and which does not 
necessarily have a causal relationship with this 
treatment. An AE can therefore be any unintended 
sign (including an abnormal laboratory finding), 
symptom, or disease temporally associated with the 
use of a medicinal (investigational) product, 
whether or not related to the medicinal 
(investigational) product. For further information, 
see the ICH Guideline for Clinical Safety Data 
Management: Definitions and Standards for 
Expedited Reporting (modified from ICH E2A) 
Synonyms: side effect, adverse experience. See 
also SAE, serious adverse experience. (CDISC 
glossary) 
Completed 
To possess every necessary or normal part or 
component or step; having come or been brought to 
a conclusion (NCI) 
Death 
The absence of life or state of being dead (NCI) 
Lack of efficacy 
The lack of expected or desired effect related to a 
therapy (NCI) 
Lost to follow-up 
The loss or lack of continuation of a subject to 
follow-up 
Non-compliance with study drug 
An indication that a subject has not agreed with or 
followed the instructions related to the study 
medication (NCI) 
Other 
Different than the one(s) previously specified or 
mentioned (NCI) 
Physician decision 
A position, opinion or judgment reached after 
consideration by a physician with reference to 
subject (NCI) 
Pregnancy 
Pregnancy is the state or condition of having a 
developing embryo or fetus in the body (uterus), 
after union of an ovum and spermatozoon, during 
the period from conception to birth. (NCI) 
Progressive disease 
A disease process that is increasing in extent or 
severity (NCI) 
Protocol deviation 
An event or decision that stands in contrast to the 
guidelines set out by the protocol (NCI) 
Screen failure 
The potential subject who does not meet one or 
more criteria required for participation in a trial 


 
 
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CDISC Submission Value 
CDISC Definition 
Site terminated by sponsor 
An indication that a clinical study was stopped at a 
particular site by its sponsor (NCI) 
Study terminated by sponsor 
An indication that a clinical study was stopped by 
its sponsor (NCI) 
Withdrawal by subject 
An indication that a study participant has removed 
itself from the study (NCI) 
 


 
 
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10.5. 
Appendix 5: Study Tabular Summary 
Parameter Group 
Parameter 
Value 
Trial information 
Trial Title 
A Phase 3, Multicenter, Double-Masked, 
Randomized, Vehicle-Controlled, Parallel-
Group Study Evaluating the Safety and 
Efficacy of AGN-190584 in Participants 
with Presbyopia 
 
Clinical Study Sponsor 
Allergan, Inc. 
 
Trial Phase Classification 
Phase 3 Trial 
 
Trial Indication 
Presbyopia 
 
Trial Indication Type 
Treatment 
 
Trial Type 
Efficacy 
Safety 
Pharmacokinetics 
 
Trial Length 
30 days plus up to 30-day screening period 
 
Planned Country of Investigational Sites 
United States 
 
Planned Number of Participants 
300 
 
FDA-Regulated Device Study 
No 
 
FDA-Regulated Drug Study 
Yes 
 
Pediatric Study 
No 
Participant 
information 
Diagnosis Group 
Presbyopia 
 
Healthy Participant Indicator 
No 
 
Planned Minimum Age of Participants 
40 
 
Planned Maximum Age of Participants 
55 
 
Sex of Participants 
Male or female 
 
Stable Disease Minimum Duration 
Not specified 


 
 
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Parameter Group 
Parameter 
Value 
Treatments 
Investigational Therapy or Treatment 
AGN-190584 (Pilocarpine HCl 1.25% 
Ophthalmic Solution) 
 
Intervention Type 
Drug 
 
Pharmacological Class of Invest. Therapy 
Cholinergic agonist 
 
Dose per Administration 
1 bilaterally 
 
Dose Units 
Drop 
 
Dosing Frequency 
Once daily 
 
Route of Administration 
Topical eye drop 
 
Current Therapy or Treatment 
No 
 
Added on to Existing Treatments 
No 
 
Control Type 
Vehicle 
 
Comparative Treatment Name 
AGN-190584 Vehicle 
Trial design 
Study Type 
Interventional 
 
Intervention Model 
Parallel 
 
Planned Number of Arms 
2 
 
Trial is Randomized 
Yes 
 
Randomization Quotient 
1:1 
 
Trial Blinding Schema 
Double-masked 
 
Stratification Factors 
Age (2 groups: ≤ 50 years and > 50 years); 
baseline binocular DCNVA (2 groups: 
20/40 to 20/60 inclusively, and worse than 
20/60); iris color (brown and non-brown), 
and emmetropes/non-emmetropes 
 
Adaptive Design 
No 
 
Study Stop Rules 
None 
 
 


 
 
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10.6. 
Appendix 6: Contraceptive Guidance and Collection of Pregnancy 
Information 
Definitions: 
WOCBP 
A woman is considered fertile following menarche and until becoming postmenopausal unless 
permanently sterile (see below). 
Women in the following categories are not considered WOCBP: 
1. Premenarchal 
2. Premenopausal female with 1 of the following: 
• Documented hysterectomy 
• Documented bilateral salpingectomy 
• Documented bilateral oophorectomy 
Note: Documentation can come from the site personnel’s: review of the participant’s 
medical records, medical examination, or medical history interview. 
3. Postmenopausal female 
• A postmenopausal state is defined as no menses for 12 months without an alternative 
medical cause. A high FSH level in the postmenopausal range may be used to confirm a 
postmenopausal state in women not using hormonal contraception or HRT. However, in 
the absence of 12 months of amenorrhea, a single FSH measurement is insufficient.  
• Females on HRT and whose menopausal status is in doubt will be required to use one of 
the nonestrogen hormonal highly effective contraception methods if they wish to 
continue their HRT during the study. Otherwise, they must discontinue HRT to allow 
confirmation of postmenopausal status before study enrollment. 
Contraception Guidance: 
Female Participants 
Female participants of childbearing potential are eligible to participate if they agree to use a 
highly effective method of contraception consistently and correctly as described in Table 10–1. 


 
 
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10.8.2. 
Near Vision Presbyopia Task-based Questionnaire 
Near Vision Presbyopia Task-based Questionnaire (NVPTQ) 
Instructions: This questionnaire includes 12 questions on four reading tasks that you are about 
to complete.  
 
You will be asked to read text from the following examples: 
• Paragraph from a book 
• Newspaper article 
• Menu 
• Nutrition label 
 


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


 
 
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Date (DD/MMM/YYYY)/Time (PT) 
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1883-301-013 Protocol Amendment 1
05-Dec-2018 10:58 GMT-080
Clinical Development Approval

SAP_001.pdf: 
 
   Statistical Analysis Plan    1883-301-013
AGN-190584 
Page 1 of 44 
 
Title Page 
Protocol Title: A Phase 3, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, 
Parallel-Group Study Evaluating the Safety and Efficacy of AGN-190584 in Participants with 
Presbyopia 
Protocol Number:  1883-301-013 
Compound Number: AGN-190584 
 
 
Short Title: Phase 3 efficacy study of AGN-190584 in participants with presbyopia 
 
 
Sponsor Name: Allergan, Inc. 
Legal Registered Address: 2525 Dupont Drive, Irvine, CA 92612, USA 
 
 
Enter 
Registry 
Name 
Phase 3 efficacy study of AGN-190584 in participants with presbyopia 
 
Approval Date: January 30, 2020 
 
 
 
 


 
 
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Table of Contents 
Title Page .........................................................................................................................................1 
Table of Contents .............................................................................................................................2 
List of Tables ...................................................................................................................................3 
List of Figures ..................................................................................................................................3 
SAP Version History........................................................................................................................4 
1. 
Introduction .......................................................................................................................5 
1.1. 
Study Design .....................................................................................................................7 
2. 
Statistical Hypotheses .....................................................................................................17 
3. 
Sample Size Determination ............................................................................................18 
4. 
Populations for Analysis .................................................................................................19 
5. 
Statistical Analyses .........................................................................................................20 
5.1. 
General Considerations ...................................................................................................20 
5.2. 
Participant Disposition ....................................................................................................21 
5.3. 
Primary Endpoint(s) Analysis .........................................................................................21 
5.3.1. 
Definition of Endpoint(s) ................................................................................................21 
5.3.2. 
Main Analytical Approach ..............................................................................................21 
5.3.3. 
Sensitivity Analysis ........................................................................................................21 
5.4. 
Secondary Endpoint(s) Analysis .....................................................................................21 
5.4.1. 
Key Secondary Analysis .................................................................................................21 
5.4.2. 
Other Secondary Analyses ..............................................................................................22 
5.4.3. 
Multiplicity Adjustment ..................................................................................................23 
5.6. 
Safety Analyses...............................................................................................................26 
5.6.1. 
Extent of Exposure ..........................................................................................................26 
5.6.2. 
Adverse Events ...............................................................................................................26 
5.6.3. 
Vital Signs .......................................................................................................................27 
5.6.4. 
Mesopic, High Contrast, Binocular CDVA ....................................................................27 
5.6.5. 
Photopic, High Contrast, Binocular CDVA ....................................................................27 
5.6.6. 
Study Intervention Tolerability and Drop Comfort Assessments ...................................27 
5.6.7. 
Temporal/Supraorbital Headache Visual Analog Scale .................................................27 
5.6.8. 
Intraocular Pressure ........................................................................................................28 
5.6.9. 
Slit Lamp Biomicroscopy ...............................................................................................28 
5.6.10. Pregnancy Tests ..............................................................................................................28 
5.7.1. 
Health Outcomes Analyses .............................................................................................28 
5.7.2. 
Subgroup Analyses for Efficacy Parameters ..................................................................28 
5.8. 
Interim Analyses .............................................................................................................28 
5.8.1. 
Data Monitoring Committee ...........................................................................................29 


 
 
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6. 
Supporting Documentation .............................................................................................30 
6.1. 
Appendix 1 List of Abbreviations ..................................................................................31 
6.2. 
Appendix 2: Changes to Protocol-Planned Analyses .....................................................33 
6.3. 
Appendix 3: Supporting Study Information ...................................................................34 
6.3.1. 
Demographics .................................................................................................................34 
6.3.2. 
Baseline Characteristics ..................................................................................................34 
6.3.3. 
Protocol Deviations .........................................................................................................34 
6.3.4. 
Medical History ..............................................................................................................34 
6.3.5. 
Prior/Concomitant medications ......................................................................................34 
6.4. 
Appendix 4: Pro Scoring Algorithm ...............................................................................35 
6.4.1. 
NVPTQ Performance Domain Score ..............................................................................35 
6.4.2. 
NVPTQ Satisfaction Domain Score ...............................................................................36 
6.4.3. 
PICQ Coping Score.........................................................................................................37 
6.4.4. 
PICQ Impact Score .........................................................................................................38 
6.5. 
Data handling convention ...............................................................................................39 
6.5.1. 
Visit Time Windows .......................................................................................................39 
6.5.2. 
Missing Date of the Last Dose of Study Intervention .....................................................40 
6.5.3. 
Missing Severity Assessment for Adverse Events..........................................................40 
6.5.4. 
Missing Causal Relationship to Study Drug for Adverse Events ...................................40 
6.5.5. 
Missing Date Information for Adverse Events ...............................................................40 
6.5.6. 
Missing Date Information for Prior or Concomitant Medications ..................................42 
6.5.6.1. 
Incomplete Start Date .........................................................................................42 
6.5.6.2. 
Incomplete Stop Date .........................................................................................43 
7. 
References .......................................................................................................................44 
 
List of Tables 
Table 1-1 
Schedule of Visits and Procedures: Screening to Visit 3 .................................... 8 
Table 1-2 
Schedule of Visits and Procedures: Visit 4 to Visit 5/Early Exit ...................... 13 
Table 5-1 
Hypotheses and Corresponding Efficacy Parameters ....................................... 24 
 
List of Figures 
Figure 1-1 
Study Schema ...................................................................................................... 7 
Figure 5-1 
Graphical Testing Procedure ......................................................................... 25 
 


 
 
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SAP Version History  
This SAP for study 1883-301-013 is based on the protocol amendment 1, dated December 
02018.  
 
SAP Version History Summary 
SAP 
Version 
Approval 
Date 
Change 
Rationale 
1 
07/16/2019 
Not Applicable 
Original version 
2 
10/23/2019 
Multiplicity 
Adjustment 
Amendment 1 to update the secondary 
endpoints multiplicity adjustment 
3 
1/21/2020 
Used 
TransCelerate 
template 
Updated to new format using TransCelerate 
template 
4 
1/30/2020 
Added 2 line 
gainer analysis 
Added 2 line gainer analysis with mesopic 
DCNVA 
 
 
 


 
 
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1. 
Introduction 
This SAP provides a technical and detailed elaboration of the statistical analyses of the efficacy 
and safety data as outlined and specified in the protocol amendment 1 of study 1883-301-013 
(dated 05 December 2018). Specifications of tables, figures, and data listings are contained in a 
separate document. The SAP for health economics data will be prepared separately. 


 
 
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Objectives and Endpoints 
The objectives of this study are to evaluate the efficacy, safety, and pharmacokinetics of 
AGN-190584 when administered bilaterally, once daily for 30 days in participants with 
presbyopia. Details of the study objectives and corresponding endpoints are described in the 
table below: 
Objectives 
Endpoints 
To evaluate the efficacy of AGN-190584 
when administered bilaterally, once daily 
for 30 days in participants with presbyopia. 
• 
Mesopic and photopic, high contrast DCNVA for each eye 
and binocularly 
• 
Mesopic and photopic, high contrast DCIVA for each eye and 
binocularly 
• 
PRO questionnaires:  
o 
Mesopic and Photopic NVPTQ 
o 
PICQ 
To evaluate the safety and tolerability of 
AGN-190584 when administered 
bilaterally, once daily for 30 days in 
participants with presbyopia 
• 
AEs 
• 
Photopic and mesopic high contrast CDVA for each eye and 
binocularly 
• 
Near Contrast sensitivity 
• 
Vital signs (blood pressure and heart rate) 
• 
Study drug tolerability and drop comfort assessments 
• 
Temporal/supraorbital headache VAS 
• 
IOP 
• 
Slit-lamp biomicroscopy 
• 
Manifest refraction 
• 
Dilated funduscopic examination 
 
To evaluate the pharmacokinetics of 
AGN-190584 when administered 
bilaterally, once daily for 30 days in 
participants with presbyopia 
• 
Plasma concentrations of AGN-190584 (sampled at selected 
sites; approximately 10% of all enrolled participants) 
 
 


 
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Table 1-1 
Schedule of Visits and Procedures: Screening to Visit 3 


 
 
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Table 1-2 
Schedule of Visits and Procedures: Visit 4 to Visit 5/Early Exit 


 
 
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2. 
Statistical Hypotheses 
For the primary efficacy analysis, the null hypothesis is that there is no difference between AGN-
190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 days in the 
proportion of participants gaining 3 lines or more from baseline in mesopic, high contrast, 
binocular DCNVA at Day 30, Hour 3. The alternative hypothesis is that there is a difference 
between AGN-190584 ophthalmic solution and vehicle. 
For the key secondary efficacy analysis, the null hypothesis is that there is no difference between 
AGN-190584 ophthalmic solution and vehicle dosed bilaterally, once daily for 30 days in the 
proportion of participants gaining 3 lines or more from baseline in mesopic, high contrast, 
binocular DCNVA at Day 30, Hour 6. The alternative hypothesis is that there is a difference 
between AGN-190584 ophthalmic solution and vehicle. 
The hypotheses will be tested using chi-square tests at a significance level of 5%. 


 
 
 
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3. 
Sample Size Determination 
The primary efficacy parameter is the proportion of participants gaining 3 lines or more from 
baseline in mesopic, high contrast, binocular DCNVA at Day 30, Hour 3. The key secondary 
efficacy parameter is the proportion of participants gaining 3 lines or more from baseline in 
mesopic, high contrast, binocular DCNVA at Day 30, Hour 6. The sample size calculation is 
based on the key secondary efficacy parameter. 
The vehicle group intervention effect is assumed to be 3.6%, as observed in the Phase 2 study. 
AGN-190584 effect is assumed to be 16% in emmetropes and 12% in non-emmetropes. This 
gives an overall AGN-190584 effect of 15% assuming emmetropes will be 75% of the study 
population. One hundred thirty-five (135) participants will be required in each study intervention 
group to detect the above difference with a power of 90% or greater at the 2-sided 
5% significance level. Assuming a 10% dropout rate, approximately 150 participants per study 
intervention group will be randomized. 
 
 


 
 
 
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4. 
Populations for Analysis 
Two analysis populations were defined for this study as follows: 
• ITT population will consist of all randomized participants.  The analysis using the ITT 
population will be based on the study intervention assigned. 
• The safety population will consist of all participants who received at least 1 
administration of study intervention.  The analysis using the safety population will be 
based on the actual study intervention received. 
 
 


 
 
 
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5. 
Statistical Analyses 
5.1. 
General Considerations 
• Efficacy endpoints will be analyzed using the ITT population, and the safety endpoints 
will be analyzed using the safety population. 
• The baseline for efficacy and safety will be the last non-missing assessment prior to the 
first administration of study intervention. For participants who were randomized but not 
treated, the baseline value will be the assessment collected on or prior to the 
randomization date, whichever is later. 
• The change from baseline values will be computed as the post-baseline value minus the 
baseline value. 
• Continuous variables will be summarized by number of participants with observed values 
(n), mean, standard deviation (SD), median, 1st and 3rd quartiles (Q1, Q3), minimum 
(min), and maximum (max). 
• Categorical variables will be summarized by number of participants with observed values 
or events (n), frequency count (n1), and percentage of participants with observed values 
or events. 
• All statistical hypothesis tests will be performed at the 2-sided 5% significance level, 
unless stated otherwise. All confidence intervals will be at least 2-sided 95% confidence 
intervals. 
• In general, statistical analyses will be performed using SAS version 9.4 or higher. 
MedDRA version 22.1 will be used to code adverse events, biomicroscopy, and medical 
history. WHODRUG Enhanced B2 will be used to code medications. 
To control the overall Type 1 error rate in the efficacy analysis, a sequential testing strategy will 
be used for the primary efficacy endpoint and key secondary efficacy endpoint. The test for the 
key secondary endpoint will be implemented only if the primary efficacy endpoint, yields 
statistically significant results. There are 11 other secondary efficacy endpoints which will be 
tested only if the key secondary efficacy endpoint is statistically significant using the graphical 
procedure described in Section 5.5.   
For primary and key secondary analyses, participants with missing data will be regarded as non-
responders. Analyses for other secondary efficacy endpoints will be based on observed data only. 


 
 
 
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5.2. 
Participant Disposition 
Number of participants screened for the study will be provided.  
Summary of study disposition post randomization will be provided by study intervention group 
as randomized for the following: 
• Number of participants randomized; this frequency count will be used as the denominator 
to calculate the percentages described below 
• Number and percentage of participants treated  
• Number and percentage of participants who completed the study 
• Number and percentage of participants who discontinued the study 
• Reasons for discontinuation from the study  
5.3. 
Primary Endpoint(s) Analysis 
5.3.1. 
Definition of Endpoint(s) 
The primary efficacy parameter will be the proportion of participants gaining 3 lines or more 
from baseline in mesopic, high contrast, binocular DCNVA at Day 30, Hour 3.  
5.3.2. 
Main Analytical Approach 
The primary efficacy parameter will be analyzed using a chi-square test with 2-sided 95% 
confidence interval based on the normal approximation based on pooled variance without 
continuity correction.   
5.3.3. 
Sensitivity Analysis 
As a sensitivity analysis a 2-sided 95% confidence interval using Wilson-Newcombe method 
will be presented 
5.4. 
Secondary Endpoint(s) Analysis 
5.4.1. 
Key Secondary Analysis 
The key secondary efficacy endpoint will be the proportion of participants gaining 3 lines or 
more from baseline in mesopic, high contrast, binocular DCNVA at Day 30, Hour 6.  The key 
secondary efficacy parameter will be analyzed with the same way as the primary efficacy 
parameter. 
 


 
 
 
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5.4.2. 
Other Secondary Analyses 
Other secondary efficacy endpoints include: 
1. Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, 
DCNVA at Day 30, Hour 8. 
2. Change from baseline in mesopic, high contrast, binocular DCNVA letters at Day 30, 
Hour 0.5. 
3. Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, 
DCNVA at Day 30, Hour 1. 
4. Change from baseline in Mesopic NVPTQ Performance score at Day 30, Hour 3. 
5. Change from baseline in photopic, high contrast, binocular DCIVA letters at Day 30, Hour 
3. 
6. Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, 
DCNVA at Day 30, Hour 10. 
7. Change from baseline in mesopic, high contrast, binocular DCNVA letters at Day 30, 
Hour 0.25.  
8. Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, 
DCNVA at Day 30, Hour 3. 
9. Change from baseline in Mesopic NVPTQ Satisfaction score at Day 30, Hour 3. 
10. Change from baseline in PICQ Coping score at Day 30, Hour 3. 
11. Change from baseline in PICQ Impact score at Day 30, Hour 3. 
All secondary endpoints related to proportion of participants gaining 3 lines or more or achieving 
20/40 better (endpoints 1, 3, 6 and 8) will be analyzed with the same way as the primary efficacy 
parameter. 
Timepoints are defined as scheduled measurement times made for each visit. Change from 
baseline in mesopic, high contrast, binocular DCNVA letters (endpoints 2 and 7) will be 
analyzed using MMRM by timepoint that includes treatment, visit, treatment  by visit interaction, 
age group, baseline DCNVA severity, iris color, and emmetropes/non-emmetropes as factors as 
well as baseline DCNVA value, and baseline DCNVA value by visit interaction as covariates 
under the assumption of MAR. An unstructured covariance matrix will be used as the covariance 
structure for repeated measurements.  A sensitivity analysis will be implemented with the 


 
 
 
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missing data imputed with the average outcome of the vehicle arm under the assumption of 
MANR. Change from baseline in photopic, high contrast, binocular DCIVA letters (endpoints 4) 
will be analyzed with the similar way as change from baseline in mesopic, high contrast, 
binocular DCNVA letters. Baseline DCIVA will be included as the covariate instead of baseline 
DCNVA. 
NVPTQ and PICO scoring algorithm are provided in Appendix 4.  Change from baseline in the 
mesopic NVPTQ Performance score, Mesopic NVPTQ Satisfaction score, PICQ Coping score, 
and PICQ Impact score (endpoints 4, 9, 10 and 11) will be analyzed using an ANCOVA model 
that include treatment, age group, baseline DCNVA severity, iris color, and emmetropes/non-
emmetropes as factors as well as baseline PRO score as covariate. Also, the CDF curves will be 
presented for each of the change from baseline PRO domain scores. The CDF curves (one per 
domain score for a total of four) represent the cumulative proportion of patients with any 
particular level of CFB in PRO domain scores at Day 30 Hour 3, by treatment arm. Curves will 
be produced with a vertical line drawn at the responder threshold. 
5.4.3. 
Multiplicity Adjustment 
The graphical procedure displayed in Figure 5-1 will be employed to control the overall 
familywise error rate at α=0.05 for the following hypotheses testing. Let H1, H2, H3, H4, H5, 
H6, H7, H8, H9, H10, and H11 represent the treatment effect comparisons of AGN-190584 with 
vehicle. Details of the hypotheses and corresponding efficacy parameters are described in 
Table 5-1. 


 
 
 
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Table 5-1 
Hypotheses and Corresponding Efficacy Parameters 
Hypothesis 
Efficacy Parameter 
1ry 
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA at 
Day 30, Hour 3 
2ry 
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA at 
Day 30, Hour 6 
H1 
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA at 
Day 30, Hour 8 
H2 
Change from baseline in mesopic, high contrast, binocular DCNVA letters at Day 30, Hour 0.5 
H3 
Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, DCNVA 
at Day 30, Hour 1 
H4 
Change from baseline in photopic, high contrast, binocular DCIVA letters at Day 30, Hour 3 
H5 
Change from baseline in Mesopic NVPTQ Performance score at Day 30, Hour 3 
H6 
Proportion of participants gaining 3-lines or more in mesopic, high contrast, binocular, DCNVA at 
Day 30, Hour 10 
H7 
Change from baseline mesopic, high contrast, binocular DCNVA letters at Day 30, Hour 0.25 
H8 
Proportion of participants achieving 20/40 or better in photopic, high contrast, binocular, DCNVA 
at Day 30, Hour 3 
H9 
Change from baseline in Mesopic NVPTQ Satisfaction score at Day 30, Hour 3 
H10 
Change from baseline in PICQ Coping score at Day 30, Hour 3 
H11 
Change from baseline in PICQ Impact score at Day 30, Hour 3 
 
 


 
AGN-1
 
Figure 5-1
Specifically
will then be
 
90584 
1 
Graph
y, H1, H2, H3, H
 tested. If H9 is 
 
hical Testing P
H4 and H5 will b
rejected, H10 an
Pag
Procedure 
e tested at a=0.0
nd H11 will then
   
ge 25 of 44
01 separately. If H
n be tested. 
Statistical A
H1, H2, H3, H4
Analysis Plan
4 or H5 is rejecte
n    1883-302
 
ed, H6, H7, H8 o
2-013
or H9 


 
 
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The proportion of participants gaining 2 lines or more from baseline in mesopic, high contrast, 
binocular DCNVA will be analyzed.  
 
5.6. 
Safety Analyses 
The safety analyses will be performed using the safety population. The safety parameters will 
include AEs, vital signs (blood pressure and heart rate), mesopic and photopic, high contrast, 
CDVA, for each eye and binocularly, near contrast sensitivity, study intervention tolerability and 
drop comfort assessments, temporal/supraorbital headache assessment using VAS, IOP, slit-lamp 
biomicroscopy, manifest refraction, dilated funduscopic examination, and pregnancy test. For 
each safety parameter, the last non-missing safety assessment before the first dose of study 
intervention will be used as the baseline for all analyses of that safety parameter.  
5.6.1. 
Extent of Exposure 
The exposure to study intervention, calculated as (last study intervention date - first study 
intervention date + 1), will be summarized using descriptive statistics by treatment for the safety 
population. 
5.6.2. 
Adverse Events 
 An AE will be considered a TEAE if the AE began or worsened (increased in severity or 
became serious) after the first administration of study intervention. However, an AE that occurs 
more than 30 days after the last administration of study intervention will not be counted as a 
TEAE.  
The number and percentage of participants reporting TEAEs in each treatment group will be 
tabulated by descending percentage in any group, by SOC and PT, and further categorized by 
severity and causal relationship to the study intervention. If more than 1 AE is coded to the same 
PT for the same participant, the participant will be counted only once for that PT using the 
greatest severity and strictest causality for the summarization by severity and causal relationship. 
The incidence of common (≥ 5% of participants in any treatment group) TEAEs will be 
summarized by SOC, PT, and treatment group. 
The total number of TEAEs by severity will be summarized by treatment group. The total 
number of TEAEs by causal relationship to the study intervention will be summarized by 


 
 
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treatment group. The number and percentage of participants reporting study intervention related 
TEAE will be tabulated by SOC and PT. 
A TESAE is defined as an SAE that is also a TEAE. The number and percentage of participants 
who have TESAEs will be summarized by PT and treatment group. In addition, the incidence of 
on-therapy SAEs that lead to death will be summarized separately by PT for each treatment 
group. 
Summary tables will be provided for TEAEs leading to discontinuation and TESAEs. Listings of 
all TEAEs, SAEs, and AEs leading to discontinuation by participant will be presented. 
5.6.3. 
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. 
5.6.4. 
Mesopic, High Contrast, Binocular CDVA 
Change from baseline in number of letters in binocular mesopic, high contrast, CDVA will be 
summarized descriptively for each assessment timepoint by treatment group. 
5.6.5. 
Photopic, High Contrast, Binocular CDVA 
Change from baseline in number of letters in binocular photopic, high contrast, CDVA will be 
summarized descriptively for each assessment timepoint by treatment group. 
5.6.6. 
Study Intervention Tolerability and Drop Comfort Assessments 
Ocular tolerability assessment will be performed at each visit. Symptoms of blurred vision, 
foreign body sensation, pain, burning/stinging, tearing, and itching will be assessed using a 
5-point scale (0 = none, 0.5 = trace, 1 = mild, 2 = moderate, and 3 = severe) for the severity and 
a 3-point scale (<1 min, 1 to 5 min, and >5 min) for the duration. Drop comfort will be assessed 
using a 6-point scale (soothing, very comfortable, comfortable, uncomfortable, very 
uncomfortable, and intolerable). For the severity, duration, and drop comfort, the number and 
percentage of participants in each category will be tabulated for each time point by treatment 
group. 
5.6.7. 
Temporal/Supraorbital Headache Visual Analog Scale 
Temporal and supraorbital headache will be separately assessed for each eye using a VAS at 
each visit. The reported values and the changes from baseline will be summarized using 
descriptive statistics for each time point for each eye by treatment group. 


 
 
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5.6.8. 
Intraocular Pressure 
IOP is measured for each eye using the Goldmann applanation tonometer at each visit. 
Tabulations will be based on the worst change (greater increase from baseline) between 2 eyes 
assessed at each visit. Descriptive statistics for IOP and changes from baseline at each 
assessment timepoint will be presented by treatment group.  
5.6.9. 
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 lids/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 participants with clinically significant biomicroscopy findings 
will be tabulated by finding category, assessment timepoint and treatment group. A clinically 
significant finding is defined as more than one severity grade increase (worsening) from baseline 
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). 
5.6.10. 
Pregnancy Tests 
Positive test results for WOCBP will be listed. 
5.8. 
Interim Analyses  
No interim analysis is planned for this study. 


 
 
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5.8.1. 
Data Monitoring Committee 
Data monitoring committee is not required for this study.


 
 
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6. 
Supporting Documentation 


 
 
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6.1. 
Appendix 1 List of Abbreviations 
 
AE 
adverse event 
ANCOVA 
analysis of covariance 
bpm 
beats per minute 
CDF 
cumulative distribution function 
CDVA 
corrected distance visual acuity 
DCIVA 
distance-corrected intermediate visual acuity 
DCNVA 
distance-corrected near visual acuity 
eCRF 
electronic case report form 
ID 
identification 
IOP 
intraocular pressure 
ITT 
intent-to-treat 
IxRS 
interactive electronic response system 
MAR 
missing at random 
MedDRA 
Medical Dictionary for Regulatory Activities 
mm Hg 
millimeters of mercury 
MMRM 
mixed model repeated measure 
MNAR 
missing not at random 
NEI VFQ-25 
National Eye Institute Visual Function Questionnaire 25 
NVPTQ 
Near Vision Presbyopia Task-based Questionnaire  
OD 
right eye 
OS 
left eye 
OSDI 
Ocular Surface Disease Index 
PCS 
potentially clinically significant 
PICQ 
Presbyopia Impact and Coping Questionnaire  
PRO 
patient reported outcomes 


 
 
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PT 
preferred term 
SAE 
serious adverse event 
SAP 
statistical analysis plan 
SD 
standard deviation 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
TESAE 
treatment-emergent serious adverse event 
VAS 
visual analog scale 
WHO DDE 
World Health Organization Drug Dictionary Enhanced  
WOCBP 
women of childbearing potential 
 
 


 
 
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6.2. 
Appendix 2: Changes to Protocol-Planned Analyses 
The subgroup analyses for the primary and key secondary endpoints by gender and race groups 
will not be conducted.  
 
 
 


 
 
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6.3. 
Appendix 3: Supporting Study Information 
6.3.1. 
Demographics 
Demographic parameters (age; age groups of ≤ 50 years and > 50 years; sex; race; ethnicity) will 
be summarized descriptively by treatment group for the ITT populations.  
6.3.2. 
Baseline Characteristics 
Baseline binocular DCNVA (2 groups: 20/40 to 20/60 inclusively, and worse than 20/60), iris 
color (brown and non-brown), and emmetropes/non-emmetropes will be summarized 
descriptively with frequency and percentage by treatment group for the ITT population. 
6.3.3. 
Protocol Deviations 
Unique participants reporting significant protocol deviations will be summarized in total and by 
treatment group for all randomized participants. 
6.3.4. 
Medical History 
Medical and surgical history will be summarized by treatment group for the Safety Population. 
Medical history includes prior medical history (prior to Day 1, first dose date) and still ongoing.  
6.3.5. 
Prior/Concomitant medications  
Prior medication is defined as any medications taken prior to the start of study intervention.  
Concomitant medication is defined as any medication taken on or after the start of study 
intervention regardless of the start date of the medication.  
 The number and percentage of participants with prior and concomitant medication use will be 
summarized by treatment group and Anatomical Therapeutic Chemical code for the Safety 
Population. If a participant took a specific medication multiple times or took multiple 
medications within the same therapeutic class, the participant will be counted only once for the 
coded drug name or therapeutic class. Formulations (including salts, esters, etc.) containing the 
same active ingredient will be pooled under the coded drug name of the base compound. 
Medications containing multiple active ingredients of different coded drug names will be 
reviewed during the course of the study and may be pooled under a single coded drug name 
for analyses. No statistical comparisons will be performed. 
 
 


 
 
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6.4. 
Appendix 4: Pro Scoring Algorithm  
6.4.1. 
NVPTQ Performance Domain Score 
To account for the impact of squinting on performance, the responses to the pair of performance 
and squinting items on each task is combined into a new testlet variable informed by a series of 
item response theory models. For performance and squinting, this new testlet variable is created 
by combining all possible response categories according to Table 1. 
 
Table 1.Testlet variable values based on combining performance item responses and 
squinting item responses 
                                                 
Squinting 
 
Performance 
Yes, but I still 
could not read 
any of the text 
(2) 
Yes, and squinting 
helped me read some 
or all of the text (1) 
No, I did 
not squint 
(0) 
I could not read any of the text due 
to problems seeing up close (0) 
0 
0 
0 
Poor (1) 
0 
1 
Fair (2) 
1 
2 
Good (3) 
2 
3 
Very Good (4) 
3 
4 
Excellent (5) 
4 
5 
Note. The values in parentheses are the raw values corresponding to the item response. These are 
the variable values in the ADaM datasets.  
 
If the response to either the performance or squinting item within a task is missing, then the 
corresponding testlet is assigned a missing value. Because the four tasks are highly related, there 
is no limit on the number of missing testlet scores to be able to calculate the performance domain 
score. The performance domain score is calculated as the average of the non-missing testlet 
values as follows:  
NVPTQ Performance Score = (Book testlet + Newspaper testlet + Menu testlet + Nutrition Label 
testlet) / (# testlets with non-missing responses) 
 


 
 
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The NVPTQ Performance Score ranges from 0 to 5, with 0 corresponding to poorest 
performance and 5 corresponding to best performance. Thus, higher scores correspond to better 
outcomes  This algorithm puts the performance score on the original performance item response 
metric, which also ranges from 0 to 5, so the performance item responses can be referenced when 
interpreting the score. Individual-level score changes of 0.75 points or greater can be considered 
clinically meaningful; i.e., an individual whose NVPTQ Performance Score increases by at least 
0.75 points from baseline can be considered a responder. 
 
6.4.2. 
NVPTQ Satisfaction Domain Score 
To account for the impact of squinting on satisfaction, the responses to the pair of satisfaction 
and squinting items on each task is combined into a new testlet variable informed by a series of 
item response theory models. For satisfaction and squinting, this new testlet variable is created 
by combining all possible response categories according to Table 2. 
 
Table 2.Testlet variable values based on combining satisfaction item responses and 
squinting item responses 
                                                 
Squinting 
 
Satisfaction 
Yes, but I still 
could not read 
any of the text 
(2) 
Yes, and squinting 
helped me read some 
or all of the text (1) 
No, I did 
not squint 
(0) 
Very dissatisfied (0) 
0 
0 
0 
Dissatisfied (1) 
0 
1 
Neither satisfied nor dissatisfied (2) 
1 
2 
Satisfied (3) 
2 
3 
Very satisfied (4) 
3 
4 
Note. The values in parentheses are the raw values corresponding to the item response. These are 
the variable values in the ADaM datasets.  
 
If the response to either the satisfaction or squinting item within a task is missing, then the 
corresponding testlet is assigned a missing value. Because the four tasks are highly related, there 
is no limit on the number of missing testlet scores to be able to calculate the satisfaction domain 
score. The satisfaction domain score is calculated as the average of the non-missing testlet values 
as follows: 


 
 
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NVPTQ Satisfaction Score = (Book testlet + Newspaper testlet + Menu testlet + Nutrition Label 
testlet) / (# testlets with non-missing responses) 
 
The NVPTQ Satisfaction Score ranges from 0 to 4, with 0 corresponding to greatest 
dissatisfaction and 4 corresponding to greatest satisfaction . Thus, higher scores correspond to 
better outcomes. This algorithm puts the satisfaction score on the original satisfaction item 
response metric, which also ranges from 0 to 4, so the satisfaction item responses can be 
referenced when interpreting the score. Individual-level score changes of 1.00 points or greater 
can be considered clinically meaningful; i.e., an individual whose NVPTQ Satisfaction Score 
increases by at least 1.00 points from baseline can be considered a responder. 
6.4.3. 
PICQ Coping Score 
 
The coping domain consists of the following 8 items:  
• Item 1: Normal-sized text  
•  Item 2: Small-sized text  
• Item 3: Information on a computer  
•  Item 4: Information on a cell phone  
• Item 5: Increase font size  
• Item 6: Use glasses to read close  
•  Item 12: Hold reading materials farther out or closer  
•  Item 13: Squint to read  
 
Each of these items includes response categories ranging from 0, corresponding to “Never”, to 4, 
corresponding to “All of the time.” Items 3, 4, 5, and 6 include additional response categories, 
labeled with values of 9 or 10, to indicate that the question is not applicable because the subject 
did not use the object being evaluated (e.g., “I did not use a computer over the past 7 days”) or 
because the subject did not have the opportunity to change his behavior (e.g., “I permanently 
increased the font size on my computer, tablet, or cell phone prior to the past 7 days”). 
Responses in these “not applicable” categories labeled 9 or 10 are assigned missing values.  
 
Because of the similarity of the content of certain item pairs, two new testlet variables are 
created prior to scoring. The testlet variable for Item 1 and Item 2 is calculated by computing the 
mean of the non-missing responses to the two items. The testlet variable for Item 3 and Item 4 is 
calculated by computing the mean of the non-missing responses to the two items. If either item 
in the testlet pair has a missing value, the testlet value is assigned the value of the non-missing 
item. If both items in the testlet pair have missing values, then the testlet is assigned a missing 
value. 
 


 
 
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Items 1&2 Testlet = (Item 1 + Item 2)/ # non-missing responses to Item 1 and Item 2 
Items 3&4 Testlet = (Item 3 + Item 4) /# non-missing responses to Item 3 and Item 4  
 
After the testlet variables have been created, the coping domain score is calculated as the mean 
of the non-missing values to the coping testlets and single coping items. Because the coping 
items are well-related and internally consistent, and because missing data are expected for some 
items due to the “not applicable” response categories, there is no limit on the number of missing 
item responses to be able to calculate the coping domain score.  
 
PICQ Coping Score = (Item 1&2 Testlet + Item 3&4 Testlet + Item 5 + Item 6 + Item 12 + Item 
13) /# non-missing responses to the 6 components of the coping score  
 
The PICQ Coping Score ranges from 0 to 4, with 0 corresponding to least amount of coping and 
4 corresponding to the greatest amount of coping. Thus, higher scores correspond to poorer 
outcomes. This algorithm puts the coping score on the original item response metric, which also 
ranges from 0 to 4, so the coping item responses can be referenced when interpreting the score. 
Individual-level score changes of 1.00 points or greater can be considered clinically meaningful; 
i.e., an individual whose PICQ Coping Score decreases by at least 1.00 points from baseline can 
be considered a responder.  
6.4.4. 
PICQ Impact Score 
The impacts domain consists of the following 6 items:  
• Item 9: Rely on others  
• Item 15: Rest eyes  
• Item 16: Feel older  
• Item 17: Feel self-conscious  
• Item 19: Take longer to complete a task  
• Item 20: Inconvenient  
 
The first five impacts items include response categories ranging from 0, corresponding to 
“Never”, to 4, corresponding to “All of the time.” Item 20 uses response categories ranging from 
0, corresponding to “Not at all”, to 4, corresponding to “Extremely.” Item 9 includes an 
additional response category, labeled with a value of 9, to indicate that the question is not 
applicable because the subject did not have the opportunity to experience the impact (i.e., “Never 
because I used or did something to help”). Responses in this “not applicable” category labeled 9 
are assigned missing values.  
 


 
 
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Because of the similarity of the content of Item 16 and Item 17, a new testlet variable is created 
prior to scoring by computing the mean of the non-missing responses to the two items. If either 
item in the testlet pair has a missing value, the testlet is assigned the value of the non-missing 
item. If both items in the testlet pair have missing values, then the testlet is assigned a missing 
value.  
 
Items 16&17 Testlet = (Item 16 + Item 17) /# non-missing responses to Item 16 and Item 17  
 
After the testlet variable has been created, the impacts domain score is calculated as the mean of 
the non-missing values to the impacts testlet and single impacts items. Because the impacts items 
are well-related and internally consistent, and because missing data are expected for some items 
due to the “not applicable” response categories, there is no limit on the number of missing item 
responses to be able to calculate the impacts domain score.  
 
PICQ Impacts Score = (Item 9 + Item 15 + Items 16&17 Testlet + Item 19 + Item 20) /# non-
missing responses to the 5 components of the impacts score  
 
The PICQ Impacts Score ranges from 0 to 4, with 0 corresponding to least amount of impacts 
and 4 corresponding to the greatest amount of impacts. Thus, higher scores correspond to poorer 
outcomes. This algorithm puts the impacts score on the original item response metric, which also 
ranges from 0 to 4, so the impacts item responses can be referenced when interpreting the score. 
Individual-level score changes of 1.00 points or greater can be considered clinically meaningful; 
i.e., an individual whose PICQ Impacts Score decreases by at least 1.00 points from baseline can 
be considered a responder. 
 
6.5. 
Data handling convention 
6.5.1. 
Visit Time Windows 
For ITT and safety by-visit analyses, all follow-up visits or the exit visit, participants will be 
reassigned with the visit number based on the number of days from the first dose date according 
to the following windows corresponding to relevant analysis. 
Analysis Phase 
Analysis Visit 
(Derived) 
Study Visit (eCRF) 
Statistical Analyses Window 
Pretreatment 
Baseline 
Day 1 (Visit 1) 
Treatment Day ≤ 1,  
pre-dose/randomization 
Treatment 
Day 1 
Day 1 (Visit 1) 
Treatment Day 1,  
post dose/randomization 
 
Day 3 
Day 3 (Visit 2) 
Treatment Day [2, 4] 


 
 
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Analysis Phase 
Analysis Visit 
(Derived) 
Study Visit (eCRF) 
Statistical Analyses Window 
 
Day 7 
Day 7 (Visit 3) 
Treatment Day [5, 10] 
 
Day 14 
Day 14 (Visit 4) 
Treatment Day [11, 21] 
 
Day 30 
Day 30 (Visit 5) 
Treatment Day [22, 45] 
 
If multiple assessments were taken within an analysis window, the assessment obtained on the 
day closest to the target day will be used; in the case of a tie, the assessment obtained on the later 
day will be used in the analysis.  
6.5.2. 
Missing Date of the Last Dose of Study Intervention 
When the date of the last dose of study intervention is missing for a participant in the safety 
population, all efforts should be made to obtain the date from the investigator. If after all efforts 
are made it is still missing, the last available dosing record date will be used as the last dose date. 
6.5.3. 
Missing Severity Assessment for Adverse Events 
If severity is missing for an AE that started before the date of the first dose of study intervention, 
an intensity of mild will be assigned.  If the severity of a TEAE is missing, the maximum 
severity will be assigned to the event for the summarization by severity. The value will be 
displayed as missing in the data listing. 
6.5.4. 
Missing Causal Relationship to Study Drug for Adverse Events 
If the relationship to the study intervention is missing for a TEAE, the event will be considered 
related to the study intervention for the summarization. The value will be displayed as missing in 
the data listing. 
6.5.5. 
Missing Date Information for Adverse Events 
The following imputation rules only apply to cases in which the start date for AEs is incomplete 
(ie, partly missing): 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to 
the missing fields. 


 
 
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• If the year of the incomplete start date is before the year of the first dose of study 
intervention, December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the first dose of study 
intervention, January 1 will be assigned to the missing fields. 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure. 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study intervention, the day of the first dose of study intervention will be 
assigned to the missing day. 
• If either the year of the incomplete start date is before the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is before the month of the date of the first dose of study intervention, the last day of 
the month will be assigned to the missing day. 
• If either the year of the incomplete start date is after the year of the date of the first dose of 
study intervention or if both years are the same but the month of the incomplete start date 
is after the month of the date of the first dose of study intervention, the first day of the 
month will be assigned to the missing day. 
If the stop date is complete and the imputed start date as above is after the stop date, the start 
date will be imputed by the stop date. 
If the start date is completely missing and the stop date is complete, the following algorithm will 
be used to impute the start date: 
• If the stop date is after the date of the first dose of study intervention, the date of the first 
dose of study intervention will be assigned to the missing start date. 
• If the stop date is before the date of the first dose of study intervention, the stop date will 
be assigned to the missing start date. 


 
 
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6.5.6. 
Missing Date Information for Prior or Concomitant Medications 
For prior or concomitant medications, including rescue medications, incomplete (ie, partly 
missing) start dates and/or stop dates will be imputed. When the start date and the stop date are 
both incomplete for a participant, the start date will be imputed first. 
6.5.6.1. 
Incomplete Start Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication start date. If the stop date is complete (or imputed) and the imputed 
start date is after the stop date, the start date will be imputed using the stop date. 
Missing month and day 
• If the year of the incomplete start date is the same as the year of the first dose of study 
intervention, the month and day of the first dose of study intervention will be assigned to 
the missing fields. 
• If the year of the incomplete start date is before the year of the first dose of study 
intervention, December 31 will be assigned to the missing fields. 
• If the year of the incomplete start date is after the year of the first dose of study 
intervention, January 1 will be assigned to the missing fields. 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure. 
Missing day only 
• If the month and year of the incomplete start date are the same as the month and year of 
the first dose of study intervention, the day of the first dose of study intervention will be 
assigned to the missing day. 
• If either the year of the incomplete start date is before the year of the date of the first dose 
of study intervention or if both years are the same but the month of the incomplete start 
date is before the month of the date of the first dose of study intervention, the last day of 
the month will be assigned to the missing day. 
• If either the year of the incomplete start date is after the year of the date of the first dose of 
study intervention or if both years are the same but the month of the incomplete start date 
is after the month of the date of the first dose of study intervention, the first day of the 
month will be assigned to the missing day. 


 
 
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6.5.6.2. 
Incomplete Stop Date 
The following rules will be applied to impute the missing numeric fields for an incomplete prior 
or concomitant medication stop date. If the date of the last dose of study intervention is missing, 
impute it as descripted in Section 6.5.3. If the imputed stop date is before the start date (imputed 
or non-imputed start date), the imputed stop date will be equal to the start date. 
Missing month and day 
• If the year of the incomplete stop date is the same as the year of the last dose of study 
intervention, the month and day of the last dose of study intervention will be assigned to 
the missing fields. 
• If the year of the incomplete stop date is before the year of the last dose of study 
intervention, December 31 will be assigned to the missing fields. 
• If the year of the incomplete stop date is after the year of the last dose of study 
intervention, January 1 will be assigned to the missing fields. 
Missing month only 
• If only the month is missing, the day will be treated as missing and both the month and the 
day will be replaced according to the above procedure. 
Missing day only 
• If the month and year of the incomplete stop date are the same as the month and year of 
the last dose of study intervention, the day of the last dose of study intervention will be 
assigned to the missing day. 
• If either the year of the incomplete stop date is before the year of the date of the last dose 
of study intervention or if both years are the same but the month of the incomplete stop 
date is before the month of the date of the last dose of study intervention, the last day of 
the month will be assigned to the missing day. 
• If either the year of the incomplete stop date is after the year of the date of the last dose of 
study intervention or if both years are the same but the month of the incomplete stop date 
is after the month of the date of the last dose of study intervention, the first day of the 
month will be assigned to the missing day. 
 


 
 
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7. 
References 
Not Applicable. 
 
 
 


ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
1883-301-013 Statistical Analysis Plan
30-Jan-2020 16:21 GMT-080
Biostatistics Approval
31-Jan-2020 08:59 GMT-080
Clinical Development Approval
31-Jan-2020 10:08 GMT-080
Biostatistics Approval
03-Feb-2020 07:42 GMT-080
Management Approval