Conditions: Presbyopia
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 163
Healthy volunteers: no

Brief summary:
This study will identify the optimum concentrations of AGN-199201 and AGN-190584 when dosed in combination once a day for the improvement of uncorrected near visual acuity in participants with presbyopia (inability to focus on items close-up).

Detailed description:

Arms:
arm 1: Participants will receive 5 different treatments as per protocol for 2 days each. Treatment 1: nondominant eye--1 drop AGN-199201 vehicle followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle; Treatment 2: nondominant eye--1 drop AGN-199201 Dose A followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle; Treatment 3: nondominant eye--1 drop AGN-199201 Dose B followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle; Treatment 4: nondominant eye--1 drop AGN-199201 Dose C followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle; Treatment 5: nondominant eye--1 drop fixed combination of AGN-199201 and AGN-190584 followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle. arm 2: Participants will receive 5 different treatments as per protocol for 2 days each. Treatment 1: nondominant eye--1 drop AGN-199201 vehicle followed by 1 drop AGN-190584 Dose A, dominant eye--2 drops AGN-190584 vehicle; Treatment 2: nondominant eye--1 drop AGN-199201 Dose A followed by 1 drop AGN-190584 Dose A, dominant eye--2 drops AGN-190584 vehicle; Treatment 3: nondominant eye--1 drop AGN-199201 Dose B followed by 1 drop AGN-190584 Dose A, dominant eye--2 drops AGN-190584 vehicle; Treatment 4: nondominant eye--1 drop AGN-199201 Dose C followed by 1 drop AGN-190584 Dose A, dominant eye--2 drops AGN-190584 vehicle; Treatment 5: nondominant eye--1 drop fixed combination of AGN-199201 and AGN-190584 followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle. arm 3: Participants will receive 5 different treatments as per protocol for 2 days each. Treatment 1: nondominant eye--1 drop AGN-199201 vehicle followed by 1 drop AGN-190584 Dose B, dominant eye--2 drops AGN-190584 vehicle; Treatment 2: nondominant eye--1 drop AGN-199201 Dose A followed by 1 drop AGN-190584 Dose B, dominant eye--2 drops AGN-190584 vehicle; Treatment 3: nondominant eye--1 drop AGN-199201 Dose B followed by 1 drop AGN-190584 Dose B, dominant eye--2 drops AGN-190584 vehicle; Treatment 4: nondominant eye--1 drop AGN-199201 Dose C followed by 1 drop AGN-190584 Dose B, dominant eye--2 drops AGN-190584 vehicle; Treatment 5: nondominant eye--1 drop fixed combination of AGN-199201 and AGN-190584 followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle. arm 4: Participants will receive 5 different treatments as per protocol for 2 days each. Treatment 1: nondominant eye--1 drop AGN-199201 vehicle followed by 1 drop AGN-190584 Dose C, dominant eye--2 drops AGN-190584 vehicle; Treatment 2: nondominant eye--1 drop AGN-199201 Dose A followed by 1 drop AGN-190584 Dose C, dominant eye--2 drops AGN-190584 vehicle; Treatment 3: nondominant eye--1 drop AGN-199201 Dose B followed by 1 drop AGN-190584 Dose C, dominant eye--2 drops AGN-190584 vehicle; Treatment 4: nondominant eye--1 drop AGN-199201 Dose C followed by 1 drop AGN-190584 Dose C, dominant eye--2 drops AGN-190584 vehicle; Treatment 5: nondominant eye--1 drop fixed combination of AGN-199201 and AGN-190584 followed by 1 drop AGN-190584 vehicle, dominant eye--2 drops AGN-190584 vehicle.

Interventions: intervention 1: AGN-199201 ophthalmic solution intervention 2: AGN-190584 ophthalmic solution intervention 3: AGN-190584 vehicle intervention 4: AGN-199201 + AGN-190584 Combination intervention 5: AGN-199201 vehicle
Intervention descriptions: intervention 1: 1 drop of AGN-199201 ophthalmic solution Doses A, B, C in the eye. intervention 2: 1 drop AGN-190584 ophthalmic solution doses A, B and C in the eye. intervention 3: Vehicle to AGN-190584 intervention 4: 1 drop AGN-199201 and AGN-190584 fixed combination ophthalmic solution in the eye. intervention 5: Vehicle to AGN-199201

Protocol document:
Prot_001.pdf: 
NCT02595528 
 
Study ID: 199201‐009 
 
 
Title: A Phase 2, Multicenter, Double‐masked, Randomized, Vehicle‐Controlled, Study of the Concurrent 
Use of AGN‐190584 and AGN‐199201 in Patients With Presbyopia 
 
Protocol Amendment 4 Date: 04Apr2016 
 
 
 


 
 
Approval Date: 
 
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Title Page 
ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
which is the property of Allergan 
 
STUDY TITLE 
A Phase 2, Multicenter, Double-masked, Randomized, Vehicle-Controlled, Study of the 
Concurrent Use of AGN-190584 and AGN-199201 in Patients With Presbyopia 
Protocol Number:   
199201-009 Amendment 4 
EudraCT Number (if applicable): 
Phase: 
2b 
Name of Investigational Products: 
AGN-199201 (oxymetazoline hydrochloride ophthalmic 
solution) and AGN-190584 (pilocarpine hydrochloride 
ophthalmic solution) 
Sponsor: 
 
Allergan (North America) 
2525 Dupont Drive 
Irvine, California USA 
92612 
 
 
 
Emergency Telephone Number(s): 
Refer to the Study Contacts Page.  
Serious Adverse Event Reporting:  
 
 
 
 
 
 
 


 
 
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Allergan Signatory: 
 
 
 
. 
Refer to the final page of this protocol for electronic signature 
and date of approval. 
 
The following information can be found on FDA Form 1572 and/or study contacts page:  
Name and contact information of Allergan study personnel and Emergency Telephone 
Numbers; name, address, and statement of qualifications of each investigator; name of each 
subinvestigator working under the supervision of the investigator; name and address of the 
research facilities to be used; name and address of each reviewing IRB; US 21 CFR 312.23 
section 6(iii)b. 
 


 
 
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INVESTIGATOR SIGNATURE PAGE 
INVESTIGATOR: 
 
 
 
 
I agree to: 
• Implement and conduct this study diligently and in strict compliance with the protocol, 
good clinical practices and all applicable laws and regulations. 
• Maintain all information supplied by Allergan in confidence and, when this information 
is submitted to an Institutional Review Board (IRB), Independent Ethics Committee 
(IEC) or another group, it will be submitted with a designation that the material is 
confidential. 
• Ensure that all persons assisting with the trial are adequately informed about the protocol, 
the investigational product(s), and their trial-related duties and functions. 
I have read this protocol in its entirety and I agree to all aspects. 
 
 
 
 
 
Investigator Printed Name 
 
Signature 
 
Date 
 
 


 
 
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Table of Contents 
Table of Contents ...................................................................................................................... 4 
List of Tables ............................................................................................................................. 7 
List of Figures ........................................................................................................................... 7 
Protocol Summary .................................................................................................................... 8 
1. 
Background and Clinical Rationale ................................................................................. 17 
1.1 
Background ............................................................................................................ 17 
1.2 
Preclinical Summary .............................................................................................. 20 
1.3 
Clinical Summary................................................................................................... 22 
1.4 
Rationale for Study Design .................................................................................... 24 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 26 
2.1 
Study Objectives .................................................................................................... 26 
2.2 
Clinical Hypotheses ............................................................................................... 27 
3. 
Study Design .................................................................................................................... 27 
4. 
Study Population and Entry Criteria ................................................................................ 28 
4.1 
Number of Patients ................................................................................................. 28 
4.2 
Study Population Characteristics ........................................................................... 28 
4.3 
Inclusion Criteria .................................................................................................... 28 
4.4 
Exclusion Criteria................................................................................................... 30 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 31 
4.5.1  Permissible Medications/Treatments ......................................................... 31 
4.5.2  Prohibited Medications/Treatments ........................................................... 32 
5. 
Study Treatments ............................................................................................................. 33 
5.1 
Study Treatments and Formulations ...................................................................... 33 
5.2 
Control Treatments ................................................................................................. 33 
5.3 
Methods for Masking ............................................................................................. 33 
5.4 
Treatment Allocation Ratio and Stratification ....................................................... 33 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 34 
5.6 
Treatment Regimen and Dosing ............................................................................. 35 
5.7 
Storage of Study Medications/Treatments ............................................................. 36 
5.8 
Treatment Administration ...................................................................................... 37 


 
 
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6. 
Response Measures and Summary of Data Collection Methods ..................................... 37 
6.1 
Efficacy Measures .................................................................................................. 37 
6.1.1  Primary Efficacy Measure .......................................................................... 37 
 
 
 
 
 
 
 
 
 
 
6.5 
Summary of Methods of Data Collection .............................................................. 44 
7. 
Statistical Procedures ....................................................................................................... 44 
7.1 
Analysis Populations .............................................................................................. 44 
7.2 
Collection and Derivation of Primary and Other Efficacy Assessments ............... 45 
7.2.1  Primary Efficacy Variable .......................................................................... 45 
 
 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 46 
7.3.1  Primary Efficacy Analyses ......................................................................... 46 
 
 
 
 
7.4 
Subgroup Analyses ................................................................................................. 47 
7.5 
Sample Size Calculation ........................................................................................ 47 
7.6 
Interim Analyses..................................................................................................... 47 
8. 
Study Visit Schedule and Procedures .............................................................................. 47 
8.1 
Patient Entry Procedures ........................................................................................ 48 
8.1.1  Overview of Entry Procedures ................................................................... 48 
8.1.2  Informed Consent and Patient Privacy ....................................................... 48 
8.2 
Washout Intervals ................................................................................................... 48 
8.3 
Procedures for Final Study Entry ........................................................................... 48 
 
 
 
 
 
 
 
 
8.5 
Instructions for the Patients .................................................................................... 52 
8.6 
Unscheduled Visits ................................................................................................. 53 
8.7 
Compliance with Protocol ...................................................................................... 53 


 
 
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8.8 
Early Discontinuation of Patients .......................................................................... 53 
8.9 
Withdrawal Criteria ................................................................................................ 53 
8.10  Study Termination .................................................................................................. 54 
9. 
Adverse Events ................................................................................................................ 54 
9.1 
Definitions .............................................................................................................. 54 
9.1.1  Adverse Event ............................................................................................ 54 
9.1.2  Serious Adverse Event ............................................................................... 55 
9.1.3  Severity ...................................................................................................... 55 
9.1.4  Relationship to Study Drug or Study Procedure ........................................ 56 
9.2 
Procedures for Reporting Adverse Events ............................................................. 56 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 56 
9.4 
Procedures for Unmasking of Study Medication ................................................... 57 
9.5 
Procedures for Pregnancy Follow-up and Reporting (If Applicable) .................... 57 
10.  Administrative Items ....................................................................................................... 58 
10.1  Protection of Human Patients ................................................................................ 58 
10.1.1  Compliance with Informed Consent Regulations (US 21 CFR Part 50) and 
Relevant Country Regulations ................................................................... 58 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 58 
10.1.3  Compliance With Good Clinical Practice .................................................. 58 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21CFR Part 11) ................................................................................... 58 
10.2  Changes to the Protocol ......................................................................................... 58 
10.3  Patient Confidentiality ........................................................................................... 59 
10.3.1  Patient Privacy ........................................................................................... 59 
10.4  Documentation ....................................................................................................... 59 
10.4.1  Source Documents ..................................................................................... 59 
10.4.2  Case Report Form Completion................................................................... 60 
10.4.3  Study Summary .......................................................................................... 61 
10.4.4  Retention of Documentation ...................................................................... 61 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments . 62 
10.5.1  Labeling/Packaging .................................................................................... 62 
10.5.2  Clinical Supply Inventory .......................................................................... 63 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 63 
10.6  Monitoring by the Sponsor .................................................................................... 63 
10.7  Publications ............................................................................................................ 63 


 
 
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10.8  Coordinating Investigator ...................................................................................... 64 
11.  References ........................................................................................................................ 64 
12.  Attachments ..................................................................................................................... 67 
 
 
 
 
 
 
 
 
 
 
12.10 Glossary of Abbreviations ...................................................................................... 91 
12.11 Protocol Amendment 1 Summary .......................................................................... 93 
12.12 Protocol Amendment 2 Summary .......................................................................... 97 
12.13 Protocol Amendment 3 Summary .......................................................................... 98 
12.14 Protocol Amendment 4 Summary .......................................................................... 98 
 
List of Tables 
Table 1 
Study Treatment Groups ................................................................................... 9 
 
 
 
 
 
List of Figures 
 
 
Figure 2 
Oxford Scale for Grading Corneal and Conjunctival Staining ....................... 86 
Figure 3 
Anterior Chamber Angle Grading ................................................................... 88 
 


 
 
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Protocol Summary 
 
Study Compounds:   
AGN-199201 (oxymetazoline hydrochloride ophthalmic solution)
 
AGN-190584 (pilocarpine hydrochloride ophthalmic solution)
   
Phase:  2 
Study Objective:  
To identify the optimum concentrations of AGN-199201 
 and AGN-190584 
 when dosed in combination once a day for the improvement of uncorrected near visual 
acuity (UNVA) in patients with presbyopia  
Clinical Hypotheses:   
At least one concurrently dosed combination of AGN-199201 and AGN-190584 will: 
1. demonstrate a significant improvement in UNVA over monotherapy with AGN-199201 and 
monotherapy with AGN-190584 when they are dosed at the same concentrations as the combination 
2. produce safety and tolerability findings no worse than cumulative findings with AGN-199201 
monotherapy and AGN-190584 monotherapy when they are dosed at the same concentrations as the 
combination  
Study Design 
Structure:  Multicenter, double-masked, randomized, vehicle-controlled 
Duration:  39 to 112 days per patient  
Study Treatment Groups:  Patients will receive AGN-199201 
 and:  
Group 1: 
AGN-190584 vehicle   
Group 2:   
AGN-190584 ophthalmic solution, 
  
Group 3:   
AGN-190584 ophthalmic solution, 
 
Group 4:   
AGN-190584 ophthalmic solution, 
   
All patients will receive the fixed combination of AGN-190584 ophthalmic solution 
 and AGN-199201 
ophthalmic solution 
 during one of the 5 dosing periods.  See Table 1 for details of the dosing groups.  
 


 
 
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Table 1 
Study Treatment Groups 
Group 
Nondominant eye 
Dominant eye 
 
Unfixed Combination(s) 
Fixed Combination 
 
1 
AGN-199201,
 
 
AGN-190584, 
0% (vehicle) 
(AGN-190584, 
/ AGN-199201,  
) + Vehicle 
Vehicle + Vehicle 
2 
AGN-199201,
 
 
AGN-190584, 
 
(AGN-190584, 
/ AGN-199201,  
) + Vehicle 
Vehicle + Vehicle 
3 
AGN-199201,
 
 
AGN-190584, 
 
(AGN-190584, 
AGN-199201,  
) + Vehicle 
Vehicle + Vehicle 
4 
AGN-199201,
 
 
AGN-190584, 
 
(AGN-190584, 
/ AGN-199201,  
) + Vehicle 
Vehicle + Vehicle 
   
 
 
   
 
 
 
 
    
Dosage/Dose Regimen:  This study is a controlled comparison of the unfixed combinations of AGN-199201 
and AGN-190584 
 ophthalmic solutions, and the 
fixed combination of AGN-190584 
 and AGN-199201 
) dosed in the nondominant eye.  Study 
medication will be administered once daily in each eye during office visits at hour 0 (8 AM ± 1 hour) for 2 
consecutive days during each dosing period.  Dosing periods will be separated by a washout period of 
14 ± 7 days.     
Eyes receiving both AGN-190584 and AGN-199201 are to receive a single drop of AGN-199201, followed 
approximately 5 to 7 minutes later by a single drop of AGN-190584.  Eyes receiving the fixed combination of 
AGN-190584
 and AGN-199201 
are to receive a single drop of the fixed combination drug, 
followed approximately 5 to 7 minutes later by a single drop of vehicle.  Eyes receiving vehicle alone are to 
receive 2 drops of vehicle, separated by approximately 5 to 7 minutes (see Table 1 and Figure 1).   
Randomization/Stratification:  At the baseline visit of the first dosing period, patients will be randomized in a 
1:1:1:1 ratio into 1 of the 4 study groups.  Randomization will be stratified at baseline by UNVA ≤ 20/80 and 
> 20/80. 
   
 
  


 
 
Approval Date: 
 
04-Apr-2016
Allerg
 
 
 
 
 
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Key Exclusion Criteria:   
• 
Concurrent use of any topical ophthalmic medications, including artificial tears, other than the study 
medications, during the course of the study 
 
 
 
 
 
 
• 
Corneal abnormalities (including keratoconus, corneal scar, Fuchs’ endothelial dystrophy, guttata, or 
edema) in either eye which are likely to interfere with visual acuity  
• 
History of cataract surgery, phakic intraocular lens (PIOL surgery), corneal inlay surgery, or any 
intraocular 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
• 
Diagnosis of glaucoma or ocular hypertension 
• 
 
  
 
 
 
 
Response Measures 
Primary Efficacy:  
• 
Mesopic, high contrast UNVA  
  
 
 
 
 
 
 
  
 
 
 
 


 
 
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General Statistical Methods and Types of Analyses:   
The modified intent-to-treat (mITT) population is defined as all randomized patients with a baseline and at least 
1 post baseline assessment of mesopic, high contrast, UNVA and will be analyzed as randomized.  The efficacy 
variables will be analyzed using the mITT population.   
The per protocol (PP) population is defined as all randomized patients who have no significant protocol 
deviations that affect the primary efficacy variable and complete all study visits.  The PP population will be 
determined prior to database lock.  The primary efficacy variable will be analyzed using the PP population on 
an as-treated basis.  
The safety population is defined as all patients who received at least 1 dose of study treatment and will be 
analyzed as treated.  All safety measures will be analyzed using the safety population. 
In general, continuous data will be summarized with descriptive statistics (number of patients, mean, standard 
deviation, median, minimum, and maximum) and will be analyzed using mixed model techniques or 2-sample 
t-tests (for between-group comparisons) and paired t-tests (for within-group analyses).  Categorical variables 
will be summarized by sample size (N), frequency count and percent, and will be analyzed using Pearson’s 
chi-square test, Fisher’s exact test, or Cochran-Mantel-Haenszel (CMH) test. 
There will be no imputation of missing data for all analysis. 
Efficacy: 
The primary efficacy variable is the weighted average change from baseline in UNVA letters in the 
nondominant eye over two-day dosing periods between hour 1 and hour 10.  Baseline will be the hour 0 
measure for each dosing period.  For the primary efficacy analyses, the weighted average change from baseline 
will be analyzed by response surface approach using a mixed model with treatment group, dosing period, 
baseline UNVA, and iris color as fixed effects. 
A UNVA responder is defined as a patient with at least a 3 line improvement in mesopic, high contrast, UNVA 
from baseline (hour 0 of visit 1) at most of the postdose time points in the nondominant eye.  The proportion of 
the UNVA responders will be compared by frequency distribution.   
There will be no adjustment for multiple tests.    
Detailed descriptions will be documented in analysis plan. 


 
 
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Safety: 
Safety measures will be analyzed using the safety population.  Medical Dictionary for Regulatory Activities 
(MedDRA) nomenclature will be used to code adverse events.  Incidence rates of each treatment-emergent 
adverse event will be summarized by primary system organ class and preferred term.  Treatment-emergent 
adverse events are events that occur or worsen after the treatment.  Summary tables will be generated for all 
treatment-emergent adverse events regardless of causality as well as for those considered to be 
treatment-related.  The adverse events will be classified into ocular and nonocular types and will be summarized 
separately as described below.  Ocular adverse events and other ocular evaluations will be summarized using 
eye as the experimental unit by dosing group and dosing period.  Nonocular adverse events and other nonocular 
assessments (eg, vital signs) will be summarized using patient as the experimental unit by dosing group and 
dosing period. 
 
Detailed descriptions of the safety analyses for adverse events and other safety measures will be documented in 
analysis plan. 
Sample Size Calculation:   
The study consists of 4 parallel groups and 5 sequences of 2-day dosing periods within each group 
(see Figure 1).  Each dosing period is separated by a washout of 14 ± 7 days and each sequence is tested 8 times 
resulting in 40 patients per group. 
The sample size is deemed appropriate to build a response surface model that assesses the efficacy profile of the 
combination relative to monotherapies. 
 


 
 
 
 
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1. 
Background and Clinical Rationale 
1.1 
Background 
Presbyopia is a condition in which the eye exhibits a diminished ability to focus on near 
objects with age.  The exact cause of presbyopia is not known.  The most likely cause of 
progressive presbyopia is a loss of elasticity of the crystalline lens, although changes in the 
lens’s curvature from continual growth and loss of power of the ciliary muscles have also 
been postulated to contribute to its pathogenesis (Radhakrishnan and Charman, 2007; 
Ostrin and Glasser, 2004).  The consequence of presbyopia is that the eye’s near point (ie, the 
point nearest the eye at which an object is accurately focused on the retina when the 
maximum degree of accommodation is employed) gets progressively further away with age.  
The ability to focus on near objects declines throughout life, from an accommodation of 
about 20 diopters (D) (ability to focus at 50 mm away) in a child, to 10 diopters at age 25 
(100 mm), and plateaus at 0.5 to 1 diopter at age 60 (ability to focus down to 1 to 2 meters 
only).  The first signs of presbyopia are eyestrain, difficulty seeing in dim light, problems 
focusing on small objects and/or fine print, and are usually first noticed between the ages of 
40 and 50 (Radhakrishnan and Charman, 2007; Ostrin and Glasser, 2004).  
Traditional nonsurgical methods of refractive correction for presbyopia include the use of 
dedicated reading spectacles, bifocal, or varifocal spectacles, monovision contact lenses or 
multifocal contact lenses.  Multifocal spectacles impair depth perception and edge-contrast 
sensitivity at critical distances for detecting obstacles in the environment (Lord et al, 2002).  
Varifocal lenses, have a corridor of non-distorted vision.  For these reasons, older people are 
more than twice as likely to fall when wearing multi-focal spectacles (Lord et al, 2002; 
Johnson et al, 2007).  More recently, the United States Food and Drug Administration (US 
FDA) has approved conductive keratoplasty for correction of presbyopia,  multifocal 
intraocular lenses (IOLs) for visual correction of aphakia in adult patients with or without 
presbyopia, and the KAMRA® corneal inlay for the improvement of near vision in 
presbyopic eyes.   
Corneal inlays are placed within the corneal stroma beneath the surface to modify the way 
the cornea refracts light.  The Presby Flexivue Microlens contains a refractive power that 
adds +1 to +3 D, the ReVision Optics Raindrop induces a change in the central corneal 
curvature, and the Acufocus Kamra inlay is a pinhole aperture to facilitate greater depth of 
focus (Bethke 2013; García-Lázaro et al, 2012).  Of these, the KAMRA is the only FDA 
approved treatment for presbyopic eyes.  For each of the existing technologies, visual quality 
is reduced at one or more viewing distances and each strategy comes with its own unique  
safety risks.  For example, zonal bifocals (eg, zonal reading glasses, contacts) suffer from 


 
 
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optical aberrations, and multifocal optics reduce image quality uniformly at all viewing 
distances.  Thus there remains a need for a non-invasive, reversible pharmacological 
treatment for presbyopia.   
Allergan is developing a noninvasive, reversible pharmacological treatment for presbyopia 
based upon concurrent administration of pilocarpine hydrochloride (AGN-190584) and 
oxymetazoline hydrochloride (AGN-199201) ophthalmic solutions.  
Pilocarpine ophthalmic solutions (1.0% to 4.0%, 1 drop administered to both eyes up to 
4 times daily) are currently used for the reduction of elevated intraocular pressure (IOP) in 
patients with open-angle glaucoma or ocular hypertension, the management of acute-angle 
closure glaucoma, prevention of postoperative elevated IOP associated with laser surgery, 
and for induction of miosis (new drug application [NDA] 200-890, pilocarpine hydrochloride 
ophthalmic solution package insert).   
Pilocarpine is a muscarinic receptor agonist that mimics the actions of the parasympathetic 
neurotransmitter, acetylcholine, on smooth muscle. This causes 2 effects which enhance near 
vision: 1) constriction of the iris sphincter muscle, resulting in pupil miosis, and 
2) constriction of the ciliary muscle, resulting in central lens steepening and lens 
accommodation (focusing from distance to near) in humans (as well as in animal models) 
(García-Lázaro et al, 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 and Charman, 1975).  The current use of pilocarpine ophthalmic solution 
monotherapy for the treatment of presbyopia is limited by the commonly experienced 
adverse event of temporal and periorbital headache (ie, brow ache), which is believed to be 
due to the strength of the ciliary muscle contraction (Tsai and Forbes, 2009).  The side effects 
of pilocarpine monotherapy for treatment of glaucoma can be intolerable due to headache 
and visual disturbances (blurred vision and visual impairment described as dim, dark or 
jumping vision), resulting in a discontinuation rate of approximately 20% to 25% 
(NDA 200-890; Tsai and Forbes, 2009). 
Oxymetazoline hydrochloride (HCl) is currently approved by the US FDA as over-the-
counter (OTC) eye drops, under the brand names Visine® LR and Ocuclear®, at a 
concentration of 0.025% for topical (ocular) administration for the relief of redness of the eye 
due to minor eye irritations.  It is also available as an OTC nasal spray under the brand name 
Afrin® at a concentration of 0.05% for topical (intranasal) administration for temporary relief 
of nasal congestion, sinus congestion and pressure, and to shrink swollen nasal membranes. 


 
 
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Oxymetazoline is best known as a potent and selective α1a-adrenoceptor agonist with a half 
maximal effective concentration (EC50) in the range of 1 to 50 nM (Evans et al, 2011; Horie 
et al, 1995; Taniguchi et al, 1999).  Oxymetazoline is also a non-selective partial 
α2-adrenoceptor agonist (Audinot et al, 2002; Haenisch et al, 2010; Kukkonen et al, 1998; 
Pauwels et al, 2000).  All selective α1 agonists are vasoconstrictors, which is the basis for 
their therapeutic activity.  In addition to its α-adrenoceptor agonism, oxymetazoline is also a 
potent serotonin (5-HT1) receptor agonist.  Oxymetazoline was shown to be a full (or partial) 
agonist of 5-HT1A, 5-HT1B, and 5-HT1D receptors and a weak agonist of the 5-HT1C receptor 
(Schoeffter and Hoyer, 1991). 5-HT1 receptor agonists are also known to have 
vasoconstrictive properties (Hoyer et al, 1994).  5-HT1 receptors are mostly expressed in the 
central nervous system and some peripheral nerves.  Activation of central 5-HT1A receptors 
are known to trigger the release or inhibition of norepinephrine depending on species, 
presumably from the locus coeruleus, which then reduces or increases neuronal tone to the 
iris sphincter muscle by modulation of postsynaptic α2-adrenergic receptors within the 
Edinger-Westphal nucleus, resulting in pupil dilation in rodents, and pupil constriction in 
primates including humans (Yu et al, 2004; Prow et al, 1996; Fanciullacci et al, 1995).  A 
population of 5-HT1A receptors are present in the rabbit and human ciliary processes 
(Chidlow et al, 1995; Yang and Latt, 1998) suggesting that oxymetazoline could also directly 
affect lens accommodation. 
Alpha1 agonists are frequently co-administered with local anesthetics in order to:  delay 
anesthetic absorption, reduce anesthetic dosage, prolong anesthesia, and reduce systemic side 
effects (Burchum and Rosenthal, 2016).  These effects are attributed to alpha1-mediated 
vasoconstriction at the site of anesthetic administration.  Thus, coadminstration of 
oxymetazoline with pilocarpine may prolong pilocarpine’s duration of effect, allow for less 
pilocarpine administration which could improve its tolerability, and could enhance 
pilocarpine's ocular penetration modulating its effect on accommodation.   
Samson and colleagues (1980) evaluated the safety of oxymetazoline 0.025% in 20 normal 
patients and determined that topical ocular administration resulted in a small, clinically 
insignificant increase in pupil diameter (0.13 mm) and had no significant effect on the near 
point of accommodation.  These data suggest that oxymetazoline is not indicated as a 
monotherapy for the treatment of presbyopia at concentrations at or below 0.025% as it may 
slightly dilate the pupil.  Duzman and colleagues (1983) subsequently reported that 
oxymetazoline 0.025% had no significant effect on blood pressure, heart rate, IOP, pupil size, 
or visual acuity in two double-blind, randomized clinical trials.  They attributed the lack of 
intraocular findings to the poor ocular penetration of oxymetazoline following topical ocular 


 
 
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administration.  Consistent with the results reported by Samson and colleagues, Allergan 
Study 199201-007 found that oxymetazoline 0.125% monotherapy slightly dilated the pupil.   
Oxymetazoline has been coadministered with dexamethasone phosphate in a trans-scleral 
delivery device where it was shown to enhance the drug delivery of dexamethasone 
phosphate to the anterior chamber of the eye (Miller et al, 2008).  Taken together, these data 
lend support to the hypothesis that oxymetazoline may modulate the pharmacokinetics of 
pilocarpine providing synergistic benefits for the treatment of presbyopia akin to what is 
known for topical anesthetics.  Finally, oxymetazoline’s serotonin (5-HT1) receptor agonism 
may work synergistically with pilocarpine to improve uncorrected near visual acuity (UNVA) 
in younger presbyopia patients who still retain the ability to accommodate to near visual 
tasks.    
1.2 
Preclinical Summary 
Besides the abundance of scientific literature available on similar products containing the two 
active ingredients, the basis for efficacy and safety in support of the proposed clinical design 
was established in the following animal studies. 
In a 1-month ocular toxicity study, groups of 5 to 7 New Zealand White (NZW) rabbits per 
sex were administered a single topical drop (approximately 30 µL) of oxymetazoline 0.05%, 
0.125%, or 0.25% or vehicle into the left eye twice daily (6 hours apart) for 28 days 
(
.  At 2 minutes after dosing with oxymetazoline, 1 drop of pilocarpine 
1.0%, a commercially available formulation containing 0.5% hypromellose (a viscosity 
enhancing agent that is known to increase absorption), was administered to the same eye.  
The vehicle-treated eye did not receive any pilocarpine treatment.  All right eyes served as 
untreated controls.  Slow iris responses were noted in several treated females at week 2 and 
were confirmed to be present in both genders at all concentrations in a follow-up ophthalmic 
examination.  No histopathological findings were observed in any treatment group.  Based on 
minimal severity, reversibility of pupil/iris findings, and a lack of correlative 
histopathological changes, the observed effects were considered non-adverse and 
pharmacologic in nature.  The no-observed-adverse-effect-level (NOAEL) was 0.25% for 
oxymetazoline and 1.0% for pilocarpine (formulated with 0.5% hypromellose) when 
administered twice daily.  
A single dose ocular pharmacokinetic study in Dutch belted rabbits was conducted to 
compare the ocular pharmacokinetics of the fixed combination formulation planned for use in 
the Phase 2b study described herein to the unfixed formulation used previously in Phase 2a 
Study 199201-007.  Dutch belted rabbits were administered a single bilateral dose of 


 
 
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oxymetazoline 0.125% followed approximately 5 minutes later by a single bilateral dose of 
pilocarpine 1.0%  (with 0.5% hypromellose) in the same vehicles used in Study 199201-007.  
A second group of rabbits was administered a single bilateral drop of a fixed combination 
formulation (oxymetazoline 0.125% and pilocarpine 1.0%) containing the vehicle (without 
hypromellose) to be used in the proposed clinical study.  While only a slight reduction in 
pilocarpine exposure was noted with the fixed combination formulation in the iris-ciliary 
body (the purported site of action), this reduction was primarily driven by lower tissue 
concentrations at latter timepoints in the timecourse, potentially affecting clinical duration of 
action.  Thus, to compensate, the pilocarpine high dose for the phase 2b studies was 
increased from 1.0% to 1.5%. 
In a 14-day ocular tolerability study, groups of 5 female NZW rabbits were administered 
topical ocular drops (approximately 30 µL/drop) of combination formulations containing 
either 2% pilocarpine with 0.2 % oxymetazoline or 3% pilocarpine with 0.3% 
oxymetazoline, with or without 0.5% hypromellose, 1 or 2 times/day for 14 consecutive days 
(Study No. TX14097).  Right eyes were dosed 1 time/day and left eyes were dosed 
2 times/day.  All formulations were considered well tolerated with generally no more than 
minimal to mild discomfort and pupil dilation, including pupils that did not fully constrict in 
response to light.  
The data from the non-Good Laboratory Practice (GLP) tolerability study suggest that 
combination formulations of up to 3% pilocarpine with 0.3% oxymetazoline, with or without 
0.5% hypromellose, were well tolerated when given as frequently as twice per day.  This 
study and the comparison pharmacokinetic study provide further support, besides the 
1-month GLP study, for the safety of testing 1.5% pilocarpine in a formulation without 
hypromellose in the proposed clinical study. 
The accommodative apparatus of nonhuman primates is similar to that of humans, ie, the 
accommodative amplitude in primates declines with age on a comparable relative time course 
(Kaufman et al, 1982; Bito et al, 1982).  In a preclinical model to study the effect of 
oxymetazoline on the accommodative and miotic profile of pilocarpine in young adult 
monkey eyes, ophthalmic application of pilocarpine 0.5% caused a decrease in pupil size and 
an increase in accommodative amplitude.  Coadministration or pre-administration with 
topical ophthalmic oxymetazoline 0.1% delayed the time to maximal accommodative 
response induced by pilocarpine.  These preclinical findings are consistent with the 
hypothesis that oxymetazoline may reduce the incidence or severity of temporal or 
supraorbital headache by slowing the rate of pilocarpine-induced contraction of the ciliary 
muscle, and thus support clinical testing of this hypothesis.  


 
 
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1.3 
Clinical Summary 
Four pilot clinical studies designed to evaluate the safety and efficacy of different 
combinations of topical pilocarpine and oxymetazoline ophthalmic solutions for the 
treatment of presbyopia and hyperopia were conducted between 2011 and 2013 by AltaVista 
Instituto del Investigation Medica at the clinic of Dr. Abad (Abad, 2013).  The concentration 
of pilocarpine tested in all 4 studies was 1.0%, while the concentrations of oxymetazoline 
tested ranged from 0.0125% to 0.125%.  Dosing frequency ranged from a single drop to 
1 drop 3 times daily for 6 months.  In the clinical data reported by AltaVista, topical ocular 
dosing of a fixed combination of pilocarpine and oxymetazoline solutions in patients resulted 
in no serious adverse events.  In a study of 65 patients who used a fixed combination of 
pilocarpine 1.0% and oxymetazoline 0.0125% up to 3 times daily for 6 months, 3 patients 
(4.6%) discontinued use of the drops due to brow ache or ocular pain (Abad, 2013).  This 
incidence is much lower than the reported 20% to 25% discontinuation rate with pilocarpine 
monotherapy for glaucoma and suggests that the administration of oxymetazoline with 
pilocarpine may improve the tolerability profile relative to pilocarpine monotherapy 
(NDA 200-890; Tsai and Forbes, 2009).  Minor, infrequent adverse events were also 
reported, including a sense of decreased illumination and ocular floaters.  AltaVista also 
reported that oxymetazoline prolonged the duration of the pilocarpine-induced improvement 
in UNVA from approximately 4 to 6 hours, with the greatest difference (approximately 1 
line) between the combination and pilocarpine monotherapy observed at 6 hours after dosing. 
Allergan Study 199201-007 evaluated the safety and efficacy of oxymetazoline (0.125%) 
monotherapy, pilocarpine (1.0%) monotherapy, or concurrent dosing of both in patients with 
presbyopia in a multicenter, double-masked, randomized, vehicle-controlled study.  
Oxymetazoline 0.125% and pilocarpine 1.0% ophthalmic solutions were concurrently 
administered as an “unfixed combination” in which the medications were administered 
separately.  For all treatment groups, study medications were dosed once daily for 3 days, and 
after a 5-day washout period, twice daily for 3 days.  All dosing was performed by trained 
personnel in the clinic.  The primary efficacy variable was a UNVA response at visit 3.  An 
UNVA responder was defined as a patient with at least a 2 line improvement in mesopic, high 
contrast, UNVA from baseline (hour 0 of visit 1) at a majority (at least 3) of time points 
postdose in the nondominant eye.  
A total of 65 patients were randomized, enrolled, and treated in this study.  Fifteen patients 
were randomized to Group 1 (oxymetazoline (0.125%) dosed in the nondominant eye), 17 to 
Group 2 (pilocarpine (1.0%) dosed in the nondominant eye), 16 to Group 3 (oxymetazoline 
(0.125%)/ pilocarpine (1.0%) dosed in the nondominant eye), and 17 to Group 4 


 
 
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(oxymetazoline (0.125%)/ pilocarpine (1.0%) dosed in both eyes).  In each group, patients 
were evenly distributed among the 4 strata of iris color and age.  Sixty-three patients (96.9%, 
63/65) completed the study.  One patient in Group 2 and one patient in Group 4 discontinued 
the study, both due to a nonocular adverse event.  There were no statistically significant 
differences among the treatment groups in any of the demographic variables.   
Concurrent dosing of pilocarpine and oxymetazoline provided a statistically significant 
greater response over vehicle in the percentage of patients achieving at least a 2 line 
improvement in mesopic, high-contrast UNVA at a majority of time points postdose in the 
nondominant eye following both once daily (QD) and twice daily (BID) dosing regimens.  
Pilocarpine monotherapy provided a statistically significant greater response over vehicle in 
the percentage of patients achieving at least a 2 line improvement in mesopic, high-contrast 
UNVA at a majority of time points postdose in the nondominant eye following QD dosing 
and was numerically superior following BID dosing.  Across all time points and visits, the 
mean change from baseline in lines of UNVA numerically favored the combination groups 
over pilocarpine monotherapy at later time points postdose (hour 8 of the QD dosing period 
and hour 11 of the BID dosing period) replicating the findings reported by AltaVista.  
Oxymetazoline monotherapy was found to have little effect on UNVA.    
The greatest differences in favor of the combination of pilocarpine and oxymetazoline dosed 
in the nondominant eye (Group 3) relative to pilocarpine monotherapy dosed in the 
nondominant eye (Group 2) were seen with more stringent response criteria, most notably 
with the percentage of patients achieving at least a 3 line gain in UNVA from baseline at all 
timepoints postdose at the end of both the QD (31.3% vs. 11.8%) and BID (12.5% vs. 0%) 
dosing regimens, and in younger patients (ie, the 40 to 47 age cohort per the pre-specified 
cutoff) who robustly responded to combination with 2.8 to 3.8 lines of improvement on 
average.  Younger patients on pilocarpine monotherapy responded with 1.2 to 2.5 lines of 
improvement on average.  In older patients (ie, the 48 to 55 age cohort per the prespecified 
cutoff) the difference was less pronounced between combination and pilocarpine 
monotherapy.  Both pilocarpine monotherapy and concurrent dosing of pilocarpine and 
oxymetazoline significantly reduced pupil diameter, with a maximal effect at approximately 
1 hour postdose (range across visits:  -2.56 to -2.73 mm) and a reduced effect 6 to 8 hours 
postdose (range across visits:  -1.05 to -1.66 mm).  Combined these results suggest that in 
younger patients the combination may be having a direct effect upon accommodation or 
modulation of the pharmacokinetics of pilocarpine providing a benefit over pilocarpine 
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Oxymetazoline monotherapy, pilocarpine monotherapy, and concurrent dosing of pilocarpine 
and oxymetazoline in one or both eyes were found to be safe and well tolerated.  No 
meaningful difference was seen between groups in the discontinuation rate or the incidence 
or severity of adverse events, with the exception of “eyelid retraction” which occurred most 
frequently in the oxymetazoline monotherapy group.  No meaningful differences were seen 
between groups in visual analog scale (VAS) scores for temporal or supraorbital headache.  It 
may require a larger sample size to detect ocular adverse events associated with pilocarpine 
monotherapy and to properly test AltaVista’s finding of improved tolerability with the 
combination of oxymetazoline and pilocarpine relative to pilocarpine monotherapy. 
The overall objective of this program is to develop a fixed-dose combination of pilocarpine 
and oxymetazoline for the treatment of presbyopia.  To date, preclinical studies in rabbits and 
non-human primates, 4 pilot clinical studies conducted by AltaVista Instituto del 
Investigation Medica at the clinic of Dr. Juan Carlos Abad, and Allergan study 199201-007 
support the combination of pilocarpine and oxymetazoline for the treatment for presbyopia.  
These studies are summarized in the sections below. 
1.4 
Rationale for Study Design 
Allergan Study 199201-007 achieved proof-of-concept for the current approach of treating 
presbyopia with a combination of oxymetazoline and pilocarpine ophthalmic solutions.  This 
phase 2 clinical study is a systematic dose-response study designed to identify the optimum 
concentrations of oxymetazoline HCl (0.0125%, 0.05%, or 0.125%) and pilocarpine HCl 
(0.5%, 1%, or 1.5%) ophthalmic solutions dosed in combination for the improvement of 
UNVA in patients with presbyopia.   
The results from Study 199201-007 suggest that pilocarpine improves UNVA in patients with 
presbyopia by decreasing pupil diameter which increases depth of focus.  Oxymetazoline 
may further modulate the miotic effect of pilocarpine on UNVA by increasing both 
accommodation and duration.  Study 199201-009 was designed to have more sensitivity to 
change in oxymetazoline concentration (ie, within patient comparison) than pilocarpine 
concentration (ie, between patient comparison).  Secondarily, the current study brackets the 
concentration of pilocarpine used in 199201-007, the higher concentration of pilocarpine in 
the current study may result in a greater discontinuation rate.  Thus, pilocarpine was selected 
as a between-patient variable to minimize any potential impact of patient discontinuation.   
This study was designed to dose in the nondominant eye of younger presbyopic patients 
based on the results of 199201-007, as the greatest improvements in UNVA were seen with 
these two conditions. Due to the large number of comparisons when crossing over two drugs 


 
 
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each with 3 concentrations as well as monotherapies, it is not practical to use fixed 
combinations for all dose combinations in the current study.  A fixed combination of 
pilocarpine 1% and oxymetazoline 0.125% was selected as the only fixed combination to 
enable bridging between the fixed combination used in this study and the unfixed 
combination used in this study and 199201-007.   
Rationale for Dose Range 
Oxymetazoline HCl has been marketed as an OTC medication for more than 3 decades in an 
intranasal spray containing 0.05% oxymetazoline HCl (under the brand name Afrin), and for 
over 2 decades in an eye drop solution containing 0.025% oxymetazoline HCl (under the 
brand names Visine LR and Ocuclear).  Oxymetazoline systemic exposure has been 
measured after a single administration of Afrin nasal spray (3 sprays [0.1 mL/spray] in each 
nostril of 0.05% oxymetazoline, equating to 0.3 mg/dose), which resulted in a mean plasma 
maximal concentration (Cmax) of 0.245 ng/mL and area under the curve from time 0 to 
12 hours (AUC0-12) of 1.74 ng·hr/mL (
  No serious adverse events 
were reported in this study and no patients discontinued prematurely due to an adverse event.  
There were no notable changes from predose to postdose in clinical laboratory tests, vital 
signs, electrocardiograms (ECGs), or IOP during the study. 
The 0.125% dose of oxymetazoline used in Study 199201-007 resulted in a lower dose by 
weight (approximately 0.1 mg/dose) when compared to Afrin (0.3 mg/dose), based on the 
smaller ophthalmic dosing volume (35 µL).  Results from Study 199201-007 showed that 
oxymetazoline monotherapy, pilocarpine monotherapy, and concurrent dosing of pilocarpine 
and oxymetazoline in one or both eyes were all safe and well tolerated.  No meaningful 
differences were found between groups in discontinuation rate or in the incidence or severity 
of adverse events, with the exception of “eyelid retraction” which occurred most frequently 
in the oxymetazoline monotherapy group.  No meaningful differences were found among 
groups in VAS scores for temporal or supraorbital headache.  It may require a larger sample 
size and/or higher dose strengths of pilocarpine to detect ocular adverse events associated 
with pilocarpine monotherapy and to properly test AltaVista’s finding of improved 
tolerability with the combination of oxymetazoline and pilocarpine relative to pilocarpine 
monotherapy. 
In the AltaVista studies, no systemic or ocular adverse events were observed in 15 patients 
who were exposed to up to 3 drops of ophthalmic oxymetazoline within a 15-minute time 
period at concentrations up to 0.125%.  Additionally, a nonclinical toxicology study 
demonstrated the safety of ophthalmic oxymetazoline at concentrations up to 0.25% when 


 
 
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administered BID for 28 days in combination with pilocarpine 1.0%.  A nonclinical 
pharmacokinetic study evaluating the unfixed vs. fixed combination formulations 
demonstrated that pilocarpine absorption into the iris-ciliary body was slightly lower 
following administration of the fixed combination.  This reduction in exposure was primarily 
driven by lower tissue concentrations at latter timepoints in the timecourse, potentially 
affecting clinical duration of action.  Therefore, to achieve similar pilocarpine exposure in the 
target tissue, this study will evaluate a maximum pilocarpine dose of 1.5%. 
Results from Study 199201-007 demonstrated that the combination of pilocarpine and 
oxymetazoline in the nondominant eye increased the peak effect and increased the duration 
of effect on UNVA in comparison to pilocarpine alone in the nondominant eye.  The 
combination of pilocarpine and oxymetazoline dosed only in the nondominant eye 
demonstrated greater improvements in uncorrected near vision than oxymetazoline or 
pilocarpine alone dosed in only one eye or the combination dosed bilaterally.  For both QD 
and BID dosing regimens, concurrent dosing of pilocarpine and oxymetazoline in either the 
nondominant eye (Group 3) or bilaterally (Group 4) showed consistent improvement over 
both oxymetazoline monotherapy (Group 1) and pilocarpine monotherapy (Group 2) in the 
percentage of patients achieving at least a 2 or 3 line improvement in mesopic, high-contrast, 
binocular UNVA at a majority of timepoints postdose.  The effect of pilocarpine alone was 
found to mostly return to a baseline level 6 hours after administration, while the combination 
showed a continued effect 6 to 8 hours after administration.  Oxymetazoline monotherapy 
was found to have little effect on UNVA.  Thus, Study 199201-007 replicated the findings 
reported by AltaVista.   
2. 
Study Objectives and Clinical Hypotheses  
2.1 
Study Objectives 
To identify the optimum concentrations of AGN-199201 (
 and 
AGN-190584 
 when dosed in combination once a day for the 
improvement of UNVA in patients with presbyopia  


 
 
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2.2 
Clinical Hypotheses 
At least one concurrently dosed combination of AGN-199201 and AGN-190584 will: 
1. demonstrate a significant improvement in UNVA over monotherapy with 
AGN-199201 and monotherapy with AGN-190584 when they are dosed at the same 
concentrations as the combination 
2. produce safety and tolerability findings no worse than cumulative findings with 
AGN-199201 monotherapy and AGN-190584 monotherapy when they are dosed at 
the same concentrations as the combination  
3. 
Study Design 
This study is a phase 2, multicenter, double-masked, parallel-group, randomized sequence, 
dose response, vehicle-controlled study in patients with presbyopia.  Four groups 
(see Table 1) of different concentrations of AGN-190584 
 will be 
used to compare unfixed combinations with AGN-199201 
 
and a fixed combination of AGN-190584 
) and AGN-199201 
) solutions dosed 
in the nondominant eye during 5 dosing periods.  For all 4 treatment groups, each dosing 
period will be once daily for 2 consecutive days, followed by a 7 to 21 day washout before 
the next 2-day dosing period, until exit after the fifth 2-day dosing period.  The study 
duration will be 39 to 112 days per patient. 
Following a screening visit (days -18 to -1) patients will be randomized at a baseline visit 
(visit 1) in a 1:1:1:1 ratio (stratified by the UNVA at baseline of ≤ 20/80 and > 20/80) to 1 of 
the following treatment groups (also summarized in Table 1):   
• Group 1:  AGN-199201 
 and AGN-190584 
vehicle 0% 
• Group 2:  AGN-199201 
 and AGN-190584 
ophthalmic solution 
  
• Group 3:  AGN-199201 
 and AGN-190584 
ophthalmic solution 
 
• Group 4:  AGN-199201 
 and AGN-190584 
ophthalmic solution 
   


 
 
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All patients will receive the fixed combination of AGN-199201 
 and AGN-190584 
 ophthalmic solutions within one of the 5 dosing periods.  Vehicles for AGN-190584, 
AGN-199201, and the fixed combination ophthalmic solutions all have the same formulation.   
Study medication will be administered once daily in each eye during office visits at hour 0 
(8 AM ± 1 hour) for 2 consecutive days during each dosing period.  Dosing periods will be 
separated by a washout period of 14 ± 7 days.  Eyes receiving both AGN-199201 and 
AGN-190584 are to receive a single drop of AGN-199201, followed approximately 5 to 
7 minutes later by a single drop of AGN-190584.  Eyes receiving the fixed combination of 
AGN-190584 
 and AGN-199201 
) are to receive a single drop of the fixed 
combination drug, followed approximately 5 to 7 minutes later by a single drop of vehicle.  
Eyes receiving vehicle alone are to receive 2 drops of vehicle, separated by approximately 
5 to 7 minutes.  The study design is depicted in Figure 1.  
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients  
Approximately 160 patients (40 per group) will be enrolled at approximately 15 US sites.  
Approximately 35 patients per group are expected to complete the study based on an 
anticipated dropout rate of 12.5% (5 dropped patients per group).   
4.2 
Study Population Characteristics 
The study population consists of adult patients who have objective and subjective evidence 
of presbyopia.  
4.3 
Inclusion Criteria 
The following are requirements for entry into the study:  
1. Male or female, ≥ 40 and < 51 years of age  
 
 
3. 
 at distance, either natural or post corneal laser refractive surgery cornea, 
with presbyopia in each eye and subjective complaints of poor near vision that impact 
activities of daily living, 
 
 


 
 
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4.4 
Exclusion Criteria 
The following are criteria for exclusion from the study: 
Ophthalmic: 
1. Concurrent use of any topical ophthalmic medications, including artificial tears, other 
than the study medications, during the course of the study 
 
  
 
 
4. Corneal abnormalities (including keratoconus, corneal scar, Fuchs’ endothelial dystrophy, 
guttata, or edema) in either eye which are likely to interfere with visual acuity  
5. History of cataract surgery, phakic intraocular lens (PIOL surgery), corneal inlay surgery, 
or any intraocular surgery.
 
  
 
 
 
 
 
 
  
10. Diagnosis of any type of glaucoma or ocular hypertension 
 
 
 
 
 
 
 


 
 
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Systemic: 
 
  
 
 
  
 
 
 
 
 
 
 
  
 
 
 
4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
The concurrent use of non-ocular medications that do not have a substantial effect on the 
pupil, accommodative properties, or retinal function of the eye is permitted during the study 
if a stable dosing regimen is established.  The dosing regimen is not considered to be stable if 
a patient starts, stops, or changes the dose/drug during the study.    
4.5.1.1 
Definition of Females of (Non-)Childbearing Potential and/or 
Acceptable Contraceptive Methods 
For purposes of this study, females will be considered of childbearing potential unless they 
are naturally postmenopausal (see definition below) or permanently sterilized 
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Natural menopause is defined as the permanent cessation of menstrual periods, determined 
retrospectively after a woman has experienced 12 months of amenorrhea without any other 
obvious pathological or physiological cause.  For women of childbearing potential who may 
participate in the study, the following methods of contraception, if properly used, are 
generally considered reliable:  oral contraceptives, patch contraceptives, injection 
contraceptives, male condom with intravaginal spermicide, diaphragm or cervical cap with 
spermicide, vaginal contraceptive ring, intrauterine device, surgical sterilization (bilateral 
tubal ligation), vasectomized partner, or sexual abstinence. 
The investigator and each patient will determine the appropriate method of contraception for 
the patient during their participation in the study. 
4.5.2 
Prohibited Medications/Treatments 
Use of ocular medication(s) other than study medications administered to conduct study 
procedures (see Sections 6.3 and 6.4) are prohibited from the screening visit until study exit. 
Use of medications that may have a substantial effect on visual function or the optical 
properties of the eye is prohibited from 2 weeks prior to the baseline visit and during the 
study: 
• systemic medications with potential ocular side effects including topiramate, 
hydroxychloroquine, ethambutol, phosphodiesterase 5 (PDE5) 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 
(MAOIs) 
The decision to administer a prohibited medication/treatment is done with the safety of the 
study participant as the primary consideration.  When possible, Allergan should be notified 
before the prohibited medication/treatment is administered. 


 
 
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5. 
Study Treatments 
5.1 
Study Treatments and Formulations 
AGN-199201
) 
 
 
 
AGN-190584 
 
 
  
The fixed combination (AGN-199201
 w/v and AGN-190584 
 
 
 
 
5.2 
Control Treatments 
The vehicles of AGN-199201, AGN-190584, 
 
 
  
5.3 
Methods for Masking 
Study medication will be administered to each randomized patient at each dosing period by 
qualified site personnel.  The investigator, investigational staff, and patients will be fully 
masked to study drug and vehicle treatments.  All study treatments will be provided in 
identical multidose bottles and cartons.  
5.4 
Treatment Allocation Ratio and Stratification  
Patients will be randomized in a 1:1:1:1 ratio into 1 of 4 treatment groups: 
• Group 1:  AGN-199201 
 and AGN-190584 vehicle 
(0%) 
• Group 2:  AGN-199201 
 and AGN-190584 
ophthalmic solution 
  
• Group 3:  AGN-199201 (
 and AGN-190584 
ophthalmic solution 
 


 
 
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• Group 4:  AGN-199201 
 and AGN-190584 
ophthalmic solution 
   
All patients will receive the fixed combination of AGN-190584 ophthalmic solution 
 and 
AGN-199201 ophthalmic solution 
 within one of the 5 dosing periods.  The order of 
the dosing sequence in each group is shown in Table 3.  
Patients will be stratified by UNVA at baseline of ≤ 20/80 and > 20/80.  For determination of 
stratification group assignment for each patient, sites will be required to enter the UNVA at 
baseline into the interactive response system (IxRS), and the IxRS will assign the stratum.   
5.5 
Method for Assignment to Treatment Groups/Randomization 
Prior to initiation of study treatment, each patient who provides informed consent will be 
assigned a patient number that will serve as the patient identification number on all study 
documents. 
At the time of randomization on visit 1, eligible patients will be placed into 1 of 2 strata as 
described in Section 5.4, and they will be assigned to 1 of the 4 treatment groups, in a 
masked fashion based on the randomization scheme within the patient's stratum according to 
the order of enrollment.  The IxRS will assign the next available randomization number for 
the appropriate stratum to the patient at the time the investigator requests randomization.  The 
IxRS will report 2 medication kit numbers (one for nondominant eye and one for dominant 
eye) to use for each patient corresponding to the randomization number.  The randomization 
scheme will be prepared by Allergan Biostatistics.  
Study medication will be labeled with medication kit number, study number, and dominant or 
nondominant eye.  Each medication kit (carton) will contain 2 multidose bottles of study 
treatment; 1 bottle will be labeled with an ‘X’ and 1 bottle will be labeled with a ‘Y’.  The 
study treatment in each bottle will be administered in sequence (a single drop from bottle X 
first, followed 5 to 7 minutes later by a single drop from bottle Y).  The IxRS will provide the 
site with the specific medication kit number(s) for each randomized patient at the time of 
randomization (day 1 of the first dosing period) and on day 1 of each subsequent dosing 
period.  Sites will assign study medication kits according to the IxRS instructions.  Sites will 
receive the IxRS confirmation notifications for each transaction.  All notifications are to be 
maintained with the study source documents. 


 
 
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5.6 
Treatment Regimen and Dosing 
This study is a controlled comparison of the unfixed combinations of AGN-199201 (
 
and AGN-190584 
 ophthalmic 
solution, and the fixed combination of AGN-190584 
 and AGN-199201 
 dosed 
in the nondominant eye.  The dosing sequence of the nondominant eye in each group is 
shown in Table 3.  
Study medication or vehicle will be administered once daily in each eye during office visits 
by designated site personnel at hour 0 (8 AM ± 1 hour) for 2 consecutive days during each 
dosing period.  Dosing periods will be separated by a washout period of 14 ± 7 days.    
Eyes receiving both AGN-190584 and AGN-199201 are to receive a single drop of 
AGN-199201 
 followed approximately 5 to 7 minutes later by a single drop of 
AGN-190584 (
  Eyes receiving the fixed combination of AGN-190584 (
 and 
AGN-199201 (
are to receive a single drop of the fixed combination drug (
 
followed approximately 5 to 7 minutes later by a single drop of vehicle 
  Eyes 
receiving vehicle alone are to receive a single drop of vehicle (
 followed 
approximately 5 to 7 minutes later by a single drop of vehicle 
 


 
 
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5.7 
Storage of Study Medications/Treatments 
The study product must be stored in a secure area.  Only assigned study personnel, 
authorized by the investigator, may have access to study product.  Study product will be 
administered only to patients entered into the clinical study, at no cost to the patient, in 
accordance with the conditions specified in this protocol. 


 
 
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All study products must be stored upright, in a refrigerator and protected from freezing.  All 
study products will be stored within the temperature storage range limits required to ensure 
study product stability during the study.  Sites must report any temperature excursion to 
Allergan, and avoid administering the impacted study product, by isolating the product, until 
receiving further instructions from Allergan (see Study Procedure Manual for more 
information). 
5.8 
Treatment Administration 
Study medication or vehicle will be administered to each randomized patient once daily in 
each eye during office visits at hour 0 (8 AM ± 1 hour) for 2 consecutive days during each 
dosing period by site personnel not otherwise involved in measuring safety, tolerability, or 
efficacy parameters.  See Sections 5.3 and 5.6 for more detail.   
6. 
Response Measures and Summary of Data Collection Methods 
6.1 
Efficacy Measures 
6.1.1 
Primary Efficacy Measure 
The primary efficacy measure is mesopic, high contrast UNVA.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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6.5 
Summary of Methods of Data Collection 
This protocol will use eCRFs with remote data capture through a qualified third-party vendor.  
Data entered into the eCRF will correspond to, and be supported by, source documentation 
maintained at the sites.  The investigator is responsible for ensuring that data are properly 
recorded on each patient’s eCRF and related documents.  Data will be entered on the eCRFs 
in a timely manner and on an ongoing basis.  An IxRS will be used to assign patient 
identification numbers, randomize patients, and manage study medication inventory.  Data 
will be transferred to Allergan on a periodic basis throughout the study. 
7. 
Statistical Procedures 
One database lock is planned at the completion of the study.  A detailed analysis plan (AP) 
will be approved prior to database lock. 
7.1 
Analysis Populations 
The modified intent-to-treat (mITT) population is defined as all randomized patients with a 
baseline and at least 1 post baseline assessment of mesopic, high contrast, UNVA and will be 
analyzed as randomized.  The efficacy variables will be analyzed using the mITT population.   
The per protocol (PP) population is defined as all randomized patients who have no 
significant protocol deviations that affect the primary efficacy variable and complete all 
study visits.  The PP population will be determined prior to database lock.  The primary 
efficacy variable will also be analyzed using the PP population on an as-treated basis.  
The safety population is defined as all patients who received at least 1 dose of study 
treatment and will be analyzed as treated.  All safety measures will be analyzed using the 
safety population. 


 
 
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7.2 
Collection and Derivation of Primary and Other Efficacy 
Assessments 
7.2.1 
Primary Efficacy Variable  
The primary efficacy variable is the weighted average change from baseline in UNVA letter 
in the nondominant eye over 2-day periods between hour 1 and hour 10.  Baseline will be the 
hour 0 measure for each dosing period. 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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•
 
 
 
 
 
 
 
7.3 
Hypothesis and Methods of Analysis 
In general, continuous data will be summarized with descriptive statistics (number of 
patients, mean, standard deviation, median, minimum, and maximum) and will be analyzed 
using mixed model, analysis of variance (ANCOVA) techniques or 2-sample t-tests (for 
between-group comparisons) and paired t-tests (for within-group analyses).  Categorical 
variables will be analyzed using Pearson’s chi-square test, Fisher’s exact test, or 
Cochran-Mantel-Haenszel (CMH) test. 
There will be no adjustment of type I error rate for the multiple tests.  A 2-sided test with a 
p-value ≤ 0.05 will be considered statistically significant. 
There will be no imputation of missing data for the all analysis.  
7.3.1 
Primary Efficacy Analyses 
For the primary efficacy analysis, the weighted average change from baseline will be 
analyzed using a mixed model with treatment group, dosing period, baseline UNVA, and iris 
color as fixed effects.  
 
 
 
 
 
   
 
 
  
 


 
 
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7.4 
Subgroup Analyses 
Subgroup analyses will be performed for the primary efficacy variable by UNVA at baseline 
(UNVA ≤ 20/80 or > 20/80), iris color (brown or not brown), gender, race, and ethnicity.  
7.5 
Sample Size Calculation 
The study consists of 4 parallel groups and 5 sequences of 2-day dosing periods within each 
group (see Figure 1).  Each dosing period is separated by a washout of 14 ± 7 days and each 
sequence is tested 8 times resulting in 40 patients per group. 
The sample size is deemed appropriate to build a response surface model that assesses the 
efficacy profile of the combination relative to monotherapies. 
7.6 
Interim Analyses 
There will be no interim analyses. 
8. 
Study Visit Schedule and Procedures 
Please see Table 2 for a schematic of the schedule of visits and procedures and Figure 1 for a 
flowchart of the study visits. 


 
 
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8.1 
Patient Entry Procedures 
8.1.1 
Overview of Entry Procedures 
Prospective patients as defined by the criteria in Sections 4.3 and 4.4 (inclusion/exclusion 
criteria) will be considered for entry into this study. 
8.1.2 
Informed Consent and Patient Privacy 
The study will be discussed with the patient and a patient wishing to participate must give 
informed consent prior to any study-related procedures or change in treatment.  The patient 
must also give authorization and other written documentation in accordance with the relevant 
country and local privacy requirements (where applicable) prior to any study-related 
procedures or change in treatment. 
Each patient that provides informed consent and/or assent will be assigned a patient number 
that will be used on patient documentation throughout the study. 
8.2 
Washout Intervals 
Each dosing period will be separated by a washout of 14 ± 7 days.   
8.3 
Procedures for Final Study Entry 
The results from screening ocular examinations must be evaluated and determined to be 
acceptable to the investigator prior to the patient’s entry into the study.  Furthermore, all 
female patients of childbearing potential MUST have a negative urine pregnancy test at 
screening and baseline (day 1) prior to randomization and initiation of study treatment.  Each 
patient’s ocular examination findings at screening and baseline (day 1) will be evaluated with 
respect to the entry criteria specified in Sections 4.3 and 4.4 for final determination of 
eligibility before the patient is randomized.  
Patients will be considered to have enrolled in the study when they are randomized. 
See Section 5.5 for the method for assignment to treatment groups/randomization. 
8.4 
Visits and Associated Procedures 
Evaluations should be performed by the same evaluator throughout the study whenever 
possible.  If it is not possible to use the same evaluator to follow the patient, then evaluations 
should overlap (examine the patient together and discuss findings) for at least 1 visit. 


 
 
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The following section provides a list of procedures for each scheduled visit.  All ophthalmic 
procedures should be performed for each eye, unless otherwise noted.  Additional 
information on the examination procedures, equipment, and techniques for the measures 
listed in this section is presented in Section 6.3. 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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8.5 
Instructions for the Patients 
After patients have signed the informed consent, they will be instructed as follows: 
• Patients will be instructed to complete the study-related procedures as explained to 
them by the study site personnel. 
• Patients will be instructed to refrain from swimming, being exposed to smoke, or 
other exposure that might cause eye irritation during the study 
• If spectacles are worn for vision correction, patients should remember to bring the 
spectacles each time they visit the doctor’s office. 
• Patients must not read, use the computer, or look at cell phones/tablets without the 
use of reading glasses during any portion of the study visits. Note:  Patients will be 
required to refrain from using their glasses during the near-vision tasks and associated 
near-vision task questionnaires, but may use their glasses to fill out other study related 
questionnaires. 
• Patients will be instructed to strictly follow the study visit schedule and to report all 
changes in condition to the site. 


 
 
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• Patients will be instructed to maintain a stable dose of any concomitant medication 
used chronically. 
• Patients will be instructed to report any changes to their medication at their next study 
visit, or to report any new medication(s) initiated during the study.  Patients will also 
be reminded to contact the study site if they are experiencing any difficulties during 
their study participation. 
• Patients will be reminded of the systemic and ocular medications/treatments that are 
prohibited for the duration of the study (see Section 4.5.2). 
8.6 
Unscheduled Visits 
Additional examinations may be performed as necessary to ensure the safety and well-being 
of the patients during the study period.  Unscheduled visit eCRFs should be completed for 
each unscheduled visit.  For all parameters not measured, indicate “not done”. 
8.7 
Compliance with Protocol 
Patients will be scheduled for follow-up visits, and these should occur as close as possible to 
the day specified in the visit schedule. 
At each postbaseline visit, the investigator or designee will ask patients if they have used any 
concomitant medications or had any procedures performed since the previous visit. 
All doses of study medication will be administered by study personnel, therefore patient 
compliance with the study medication regime will not be monitored. 
8.8 
Early Discontinuation of Patients 
Patients may voluntarily withdraw from the study at any time.   
Notification of early patient discontinuation from the study and the reason for discontinuation 
will be made to the sponsor and will be clearly documented on the appropriate case report 
form. 
8.9 
Withdrawal Criteria 
A patient may be withdrawn from the study if it is deemed by the investigator or Allergan 
that it is unsafe for the patient to continue in the study.  Patients who are withdrawn from the 
study will not be replaced. 


 
 
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If the patient withdraws prior to completing the study, the procedures outlined for the 
visit 2/study exit should be performed at the last visit attended (see Section 8.4.3). 
If a female patient becomes pregnant during the study, the investigator will notify Allergan 
immediately after the pregnancy is confirmed and the patient will be exited from the study 
(see Section 9.5). 
8.10 
Study Termination 
The study may be stopped at his/her study site at any time by the site investigator.  Allergan 
may stop the study (and/or the study site) for any reason with appropriate notification. 
9. 
Adverse Events 
Adverse events occurring during the study will be recorded on an adverse event case report 
form.  If adverse events occur, the first concern will be the safety of the study participants. 
9.1 
Definitions 
9.1.1 
Adverse Event 
An adverse event is any untoward medical occurrence in a patient or clinical investigation 
patient administered a pharmaceutical product and that does not necessarily have a causal 
relationship with this  treatment.  An adverse event can therefore be any unfavorable and 
unintended sign (including an abnormal laboratory finding), symptom, or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related to the 
medicinal (investigational) product.  In addition, during the screening period, adverse events 
will be assessed regardless of the administration of a pharmaceutical product. 
Note:  Adverse events must be collected once informed consent has been obtained, regardless 
of whether or not the patient has been administered study drug. 
Progression of treatment indication including new or worsening of anticipated clinical signs 
or symptoms, which are collected as clinical efficacy variables and assessed as unequivocally 
associated with the disease progression and /or lack of efficacy, should NOT be reported as 
adverse events unless the disease progression is greater than anticipated in the natural course 
of the disease. 
Adverse events will be assessed, documented, and recorded in the electronic case report form 
(eCRF) throughout the study (ie, after informed consent has been obtained).  At each visit, 
the investigator will begin by querying for adverse events by asking each patient a general, 


 
 
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non-directed question such as “How have you been feeling since the last visit?”  Directed 
questioning and examination will then be done as appropriate.  All reported adverse events 
will be documented on the appropriate case report form. 
9.1.2 
Serious Adverse Event 
A serious adverse event is any adverse event occurring at any dose that results in any of the 
following outcomes:  death, a life-threatening adverse event, inpatient hospitalization or 
prolongation of existing hospitalization, a persistent or significant disability/incapacity, or a 
congenital anomaly/birth defect.  Important medical events that may not result in death, be 
life-threatening, or require hospitalization may be considered a serious adverse event when, 
based upon appropriate medical judgment, they may jeopardize the patient or patient and 
may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition.  (See Section 9.3 for procedures for reporting a serious adverse event.) 
Allergan considers all cancer adverse events as serious adverse events.  In addition, Allergan 
considers any abortion (spontaneous or nonspontaneous) as a serious adverse event. 
Preplanned surgeries or procedures for pre-existing, known medical conditions for which a 
patient requires hospitalization is not reportable as a serious adverse event. 
Any preplanned surgery or procedure should be clearly documented in the site source 
documents by the medically qualified investigator at the time of the patient’s entry into the 
study.  If it has not been documented at the time of the patient’s entry into the study, then it 
should be documented as a serious adverse event and reported to Allergan. 
9.1.3 
Severity 
A clinical determination will be made of the intensity of an adverse event.  The severity 
assessment for a clinical adverse event must be completed using the following definitions as 
guidelines: 
Mild 
Awareness of sign or symptom, but easily tolerated. 
Moderate 
Discomfort enough to cause interference with usual activity. 
Severe 
Incapacitating with inability to work or do usual activity. 
 


 
 
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9.1.4 
Relationship to Study Drug or Study Procedure 
A determination will be made of the relationship (if any) between an adverse event and the 
study drug or study procedure, as applicable.  A causal relationship is present if a 
determination is made that there is a reasonable possibility that the adverse event may have 
been caused by the drug or study procedure. 
9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate case report form. 
All adverse events that are drug-related and unexpected (not listed as treatment-related in the 
current Investigator's Brochure) must be reported to the governing Institutional Review 
Board/Independent Ethics Committee (IRB/IEC) as required by the IRB/IEC, local 
regulations, and the governing health authorities.  Any adverse event that is marked ‘ongoing’ 
at the exit visit must be followed-up as appropriate. 
9.3 
Procedures for Reporting a Serious Adverse Event 
Any serious adverse event occurring during the study period (beginning with informed 
consent) and for at least 28 days after the last dose of study drug must be immediately 
reported but no later than 24 hours after learning of a serious adverse event.  Serious adverse 
events must be reported to Allergan (or Agent of Allergan as listed on the Allergan Study 
Contacts Page and recorded on the serious adverse event form.  All patients with a serious 
adverse event must be followed up and the outcomes reported.  The investigator must supply 
the sponsor and the IRB/IEC with any additional requested information (eg, autopsy reports 
and discharge summaries). 
In the event of a serious adverse event, the investigator must: 
1. Notify Allergan immediately by fax or email using the  serious adverse event form 
(contact details can be found on page 1 of the serious adverse event form); phone 
numbers and relevant Allergan personnel contacts are also on the front page of 
protocol and Study Contacts Page. 
2. Obtain and maintain in his/her files all pertinent medical records, information, and 
medical judgments from colleagues who assisted in the treatment and follow-up of 
the patient. 
3. Provide Allergan with a complete, written description of the adverse event(s) on the 
serious adverse event form describing the event chronologically, including any 


 
 
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treatment given (eg, medications administered, procedures performed) for the adverse 
event(s).  Summarize relevant clinical information about the event:  signs, symptoms, 
diagnosis, clinical course and relevant clinical laboratory tests, etc.  Include any 
additional or alternative explanation(s) for the causality which includes a statement as 
to whether the event was or was not related to the use of the investigational drug. 
4. Promptly inform the governing IRB/IEC of the serious adverse event as required by 
the IRB/IEC, local regulations, and the governing health authorities. 
9.4 
Procedures for Unmasking of Study Medication 
When necessary for the safety and proper treatment of the patient, the investigator can 
unmask the patient’s treatment assignment to determine which treatment has been assigned 
and institute appropriate follow-up care.  When possible, the sponsor (Allergan Medical 
Safety Physician) should be notified prior to unmasking study medication.  The investigator 
should inform the sponsor (Allergan Medical Safety Physician) of the unmasking if there is 
no notification prior to the unmasking. 
The treatment assignment for the patient can be determined by designated site personnel 
logging into the IxRS via password protected access.  The reason for breaking the code must 
be recorded in the patient’s source documents. 
9.5 
Procedures for Pregnancy Follow-up and Reporting (If 
Applicable) 
If a female becomes pregnant during the study, the investigator will notify Allergan 
immediately after the pregnancy is confirmed, and the patient will be exited from the study 
after appropriate safety follow-up.  The investigator will (1) notify the patient’s physician 
that the patient was enrolled in this study and treated with an investigational drug ocular 
oxymetazoline, ocular pilocarpine, or the combination of oxymetazoline and pilocarpine, and 
(2) follow the progress of the pregnancy.  The investigator must document the outcome of the 
pregnancy and provide a copy of the documentation to Allergan.   
It is not known if the investigational products may have teratogenic or mutagenic effects, as 
studies to evaluate these effects in humans have not been done.  There are no adequate and 
well-controlled studies of pilocarpine or oxymetazoline administration in pregnant women.  
In addition, it is not known if these products are excreted in human milk. 


 
 
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10. 
Administrative Items 
This protocol is to be conducted in accordance with the applicable Good Clinical Practice 
(GCP) regulations and guidelines, eg, the International Conference on Harmonisation (ICH) 
Guideline on GCP. 
10.1 
Protection of Human Patients 
10.1.1 
Compliance with Informed Consent Regulations (US 21 CFR 
Part 50) and Relevant Country Regulations 
Written informed consent is to be obtained from each patient prior to any study-related 
activities or procedures in the study, and/or from the patient's legally authorized 
representative.  If the patient is under the legal age of consent, the consent form must be 
signed by the legally authorized representative in accordance with the relevant country and 
local regulatory requirements. 
10.1.2 
Compliance With IRB or IEC Regulations 
This study is to be conducted in accordance with IRB regulations (US 21 CFR Part 56.103) 
or applicable IEC regulations.  The investigator must obtain approval from a properly 
constituted IRB/IEC prior to initiating the study and re-approval or review at least annually.  
Allergan is to be notified immediately if the responsible IRB/IEC has been disqualified or if 
proceedings leading to disqualification have begun.  Copies of all IRB/IEC correspondence 
with the investigator should be provided to Allergan. 
10.1.3 
Compliance With Good Clinical Practice 
This protocol is to be conducted in accordance with the applicable GCP regulations and 
guidelines. 
10.1.4 
Compliance With Electronic Records; Electronic Signatures 
Regulations (US 21CFR Part 11) 
This study is to be conducted in compliance with the regulations on electronic records and 
electronic signature. 
10.2 
Changes to the Protocol 
The investigator must not implement any deviation from or changes of the protocol without 
approval by Allergan and prior review and documented approval/favorable opinion from the 
IRB/IEC of a protocol amendment, except where necessary to eliminate immediate hazards 


 
 
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to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 
10.3 
Patient Confidentiality 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the study drug may ultimately be marketed, but the 
patient’s name will not be disclosed in these documents.  The patient's name may be 
disclosed to the Sponsor of the study, Allergan, or the governing health authorities or the 
FDA if they inspect the study records.  Appropriate precautions will be taken to maintain 
confidentiality of medical records and personal information. 
10.3.1 
Patient Privacy 
Written authorization (US sites only), data protection consent (European sites only), and 
other documentation in accordance with the relevant country and local privacy requirements 
(where applicable) is to be obtained from each patient prior to enrollment into the study, 
and/or from the patient's legally authorized representative in accordance with the applicable 
privacy requirements (eg, the Health Insurance Portability and Accountability Act Standards 
for Privacy of Individually Identifiable Health Information (“HIPAA”), European Union Data 
Protection Directive 95/46/EC [“EU Directive”]). 
In accordance with HIPAA requirements, additional purposes of this study may include 
publishing of anonymous patient data from the study. 
10.4 
Documentation 
10.4.1 
Source Documents 
Source documents may include a patient's medical records, hospital charts, clinic charts, the 
investigator's patient study files, as well as the results of diagnostic tests such as X-rays, 
laboratory tests, and electrocardiograms.  The investigator's copy of the case report forms 
serves as part of the investigator's record of a patient's study-related data. 
The following information should be entered into the patient's medical record: 
• Patient’s name. 
• Patient’s contact information. 


 
 
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• The date that the patient entered the study, patient number, and patient randomization 
[or medication kit] number. 
• The study title and/or the protocol number of the study and the name of Allergan. 
• A statement that informed consent was obtained (including the date).  A statement that 
written authorization (US sites only), data protection consent (EU sites only), or other 
country and local patient privacy required documentation for this study has been 
obtained (including the date). 
• Dates of all patient visits, time of day, and protocol designated hours for all patient 
visits/timepoints. 
• All concurrent medications (List all prescription and non-prescription medications 
being taken at the time of enrollment.  At each subsequent visit, changes to the list of 
medications should be recorded.) 
• Occurrence and status of any adverse events. 
• The date the patient exited the study, and a notation as to whether the patient 
completed the study or reason for discontinuation. 
• The results of laboratory tests performed by the site (ie, results of urine pregnancy 
tests).   
• Patient medical, surgical, and ophthalmic histories (including demographics); 
screening ophthalmological assessments; and for females, documentation of 
non-childbearing potential or results of pregnancy test. 
• Key study variables 
Source documentation practices must follow Section 4.0 of ICH E6, Good Clinical Practice: 
Consolidated Guidance and ALCOA (ie, records must be Attributable, Legible, 
Contemporaneous, Original, and Accurate). 
10.4.2 
Case Report Form Completion 
This protocol will use electronic data capture (EDC) through a qualified third party vendor.  
The data will be entered in the EDC system in a timely manner on an ongoing basis.   


 
 
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The investigator is responsible for ensuring that data are properly recorded on each patient's 
case report forms and related documents.  An investigator who has signed the protocol 
signature page should personally sign for the case report forms (as indicated in the case 
report forms) to ensure that the observations and findings are recorded on the case report 
forms correctly and completely.  The case report forms are to be submitted to Allergan in a 
timely manner at the completion of the study, or as otherwise specified by Allergan and will 
be maintained in a central data repository. 
10.4.3 
Study Summary 
An investigator's summary will be provided to Allergan within a short time after the 
completion of the study, or as designated by Allergan.  A summary is also to be provided to 
the responsible IRB/IEC. 
10.4.4 
Retention of Documentation 
All study related correspondence, patient records, consent forms, patient privacy 
documentation, records of the distribution and use of all investigational products, and copies 
of case report forms should be maintained on file. 
For countries falling within the scope of the ICH guidelines, the sponsor-specific essential 
documents should be retained until at least 2 years after the last approval of a marketing 
application in an ICH region and until there are no pending or contemplated marketing 
applications in an ICH region or at least 2 years have elapsed since the formal 
discontinuation of clinical development of the investigational product.  These documents 
should be retained for a longer period, however, if required by the applicable regulatory 
requirement(s) or if needed by the sponsor. 
In addition, for countries not falling within the scope of the ICH guidelines, local regulatory 
requirements should be followed regarding the retention of clinical study documentation. 
Allergan requires that it be notified in writing if the investigator wishes to relinquish 
ownership of the data so that mutually agreed-upon arrangements can be made for transfer of 
ownership to a suitably qualified, responsible person. 
10.4.4.1 
Study Site 
The study site should retain the essential documents to be kept at the study site, such as 
source documents, contracts, informed consent form, protocol, records on control of the 
investigational product, or other study-related documents until either item 1 or 2 listed below, 
whichever is later.  However, when the sponsor requires that these documents are to be 


 
 
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retained for longer period, the study site should discuss it with Allergan about the period and 
method of preservation.  The record retainer designated for each record should be responsible 
for the preservation. 
1. The date of approval for manufacturing and marketing applications of the relevant 
investigational products (in case of discontinuing its development, until at least 
3 years after the date of development discontinuation). 
2. The day at least 3 years after the date of the termination or completion of the clinical 
study. 
The study site and the record retainer should take measures in such a way that these records 
are not lost or abandoned during the designated period of preservation and that they are 
presented upon request. 
10.4.4.2 
Institutional Review Board (IRB) 
The IRB should retain all relevant records such as standard operating procedures (SOPs), 
membership lists (including qualifications of the members), submitted documents, minutes of 
meetings, and correspondence until either item 1 or 2 listed below, whichever is later.   
1. The date of approval for manufacturing and marketing applications of the relevant 
investigational products (in case of discontinuing its development, until at least 
3 years after the date of development discontinuation). 
2. The day at least 3 years after the date of the termination or completion of the clinical 
study. 
When the study site or the sponsor requests the SOPs and membership lists, the IRB should 
comply with the request. 
10.5 
Labeling, Packaging, and Return or Disposal of Study 
Medications/Treatments 
10.5.1 
Labeling/Packaging 
The study medication will be packaged and supplied by Allergan.  The medication will be 
identified as an investigational compound. 
The study medication will be provided in sealed study kits containing 2 multi-dose bottles of 
study treatment; one bottle will be labeled with an 
and one bottle will be labeled with a 


 
 
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  The study number and kit number, at a minimum, will be printed on the outer carton 
and bottle labels.  Additional labeling will be in accordance with local regulations.   
10.5.2 
Clinical Supply Inventory 
The investigator must keep an accurate accounting of the number of investigational units 
received from Allergan, dispensed or administered to the patients, the number of units 
returned to the investigator by the patient (if applicable), and the number of units returned to 
Allergan during and at the completion of the study.  A detailed inventory must be completed 
for the study medication.  The study medication must be dispensed or administered only by 
an appropriately qualified person to patients in the study.  The medication is to be used in 
accordance with the protocol for patients who are under the direct supervision of an 
investigator.  A unit is defined as a study kit that is comprised of 2 multi-dose bottles of study 
medication. 
10.5.3 
Return or Disposal of Study Medications/Treatments and/or 
Supplies 
All clinical study medications/treatments and/or supplies will be returned to Allergan or 
Allergan designee for destruction. 
10.6 
Monitoring by the Sponsor 
A representative of the sponsor will monitor the study on a periodic basis.  The determination 
of the extent and nature of monitoring will be based on considerations such as the objective, 
purpose, design, complexity, blinding, size, and endpoints of the study. 
Authorized representatives of Allergan or regulatory authority representatives will conduct 
on-site visits to review, audit and copy study-related documents.  These representatives will 
meet with the investigator(s) and appropriate staff at mutually convenient times to discuss 
study-related data and questions. 
10.7 
Publications 
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. 


 
 
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10.8 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 
11. 
References 
Abad, Juan Carlos, inventor; AltaVista Instituto de Investigation Medica SAS, assignee.  
Compositions and methods for treating presbyopia, mild hyperopia, and irregular 
astigmatism.  International patent WO2013/041967 A2.  March 28, 2013. 
Audinot V, Fabry N, Nicolas JP, Beauverger P, Newman-Tancredi A, Millan MJ, et al. Ligand 
modulation of [35S]GTPγS binding at human α2A, α2B and α2C adrenoceptors. Cellular 
Signal. 2002;14(10):829-837.  
Bethke W. Three new ways to tackle presbyopia: a review of several intracorneal inlays 
vying for Food and Drug Administration approval to treat emmetropic presbyopes. Review of 
Ophthalmology. Apr 2013;104-106. 
Bito LZ, DeRousseau CJ, Kaufman PL, Bito JW.  Age-dependent loss of accommodative 
amplitude in rhesus monkeys:  an animal model for presbyopia.  Invest Ophthalmol Vis Sci.  
1982;23(1):23-31. 
Burchum JR, Rosenthal LD. Lehne’s pharmacology for nursing care. St. Louis, Missouri: 
Elsevier;2016. 
Chidlow G, De Santis M, Sharif NA, Osborne NN. Characteristics of [3H] 5-
hydroxytryptamine binding to iris-ciliary body tissue of the rabbit. Invest Opthalmol Vis Sci. 
1995;36:2238-2245.  
Duzman E, Anderson J, Vita JB, Lue JC, Chen C-C, Leopold IH. Topically applied 
oxymetazoline. Ocular vasoconstrictive activity, pharmacokinetics, and metabolism. Arch 
Ophthalmol. 1983;101(7):1122-1126.  
Evans BA, Broxton N, Merlin J, Sato M, Hutchinson DS, Christopoulos A, et al. 
Quantification of functional selectivity at the human α(1A)-adrenoceptor. Mol Pharmacol. 
2011;79(2):298-307.  
Fanciullacci M, Sicuteri R, Alessandri M, Geppetti P. Buspirone, but not sumatriptan, induces 
miosis in humans: relevance for a serotoninergic pupil control.  Clin Pharmacol Ther. 
1995;57(3):349-355. 


 
 
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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.   
Haenisch B, Walstab J, Herberhold S, Bootz F, Tschaikin M, Ramseger R, et al. Alpha-
adrenoceptor agonistic activity of oxymetazoline and xylometazoline. Fundam Clin 
Pharmacol. 2010;24(6):729-739.  
Horie K, Obika K, Foglar R, Tsujimoto G. Selectivity of the imidazoline alpha-adrenoceptor 
agonists (oxymetazoline and cirazoline) for human cloned alpha 1-adrenoceptor subtypes. Br 
J Pharmacol. 1995;116(1):1611-1618.  
Hoyer D, Clarke DE, Fozard JR, Hartiq PR, Martin GR, Mylecharane EJ, et al. International 
Union of Pharmacology classification of receptors for 5-hydroxytryptamine (Serotonin). 
Pharmacol Rev. 1994;46(2):157-203. 
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(4):1466-1471. 
Kaufman PL, Bito LZ, DeRousseau CJ.  The development of presbyopia in primates.  Trans 
Opthalmol Soc UK. 1982;102(3):323-326. 
Kukkonen JP, Renvaktar A, Shariatmadari R, Akerman KE. Ligand- and subtype-selective 
coupling of human alpha-2 adrenoceptors to Ca++ elevation in Chinese hamster ovary cells. 
J Pharmacol Exp Ther. 1998;287(2):667-671.  
Lord SR, Dayhew J, Howland A. Multifocal glasses impair edge-contrast sensitivity and 
depth perception and increase the risk of falls in older people. J Am Geriatr Soc. 
2002;50(11):1760-1766. 
Miller DJ, Li SK, Tuitupou AL, Kochambilli RP, Papangkorn K, Mix DC Jr, et al. Passive 
and oxymetazoline-enhanced delivery with a lens device: pharmacokinetics and efficacy 
studies with rabbits. J Ocular Pharm and Ther. 2008;24(4):385-391. 
Ostrin LA, Glasser A.  Accommodation measurements in a prepresbyopic and presbyopic 
population.  J Cataract Refract Surg. 2004;30(7):1435-1444.  


 
 
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Pauwels PJ, Finana F, Tardif S, Colpaert FC, Wurch T. Agonist efficacy at the α2A-
adrenoceptor: Gα15 fusion protein: an analysis based on Ca2+ responses. Naunyn-
Schmiedeberg’s Arch Pharmacol. 2000;361(6):672-679.  
Pilocarpine ophthalmic solution NDA 200-890. 
Prow MR, Martin KF, Heal DJ. 8-OH-DPAT-induced mydriasis in mice: a pharmacological 
characterisation. Eur J Pharmacol. 1996;317(1):21-28. 
Radhakrishnan H, Charman WM.  Age-related changes in static accommodation and 
accommodative miosis.  Ophthalmic Physiol Opt. 2007;27(4):342-352. 
Samson CR, Danzig MR, Sasovetz D, Thompson HS.  Safety and toleration of 
oxymetazoline ophthalmic solution.  Pharmatherapeutica.  1980;2:347-352. 
Schoeffter P, Hoyer D. Interaction of the α-adrenoceptor agonist oxymetazoline with 
serotonin 5-HT1A, 5-HT1B, 5-HT1C and 5-HT1D receptors. Eur J Pharmacol. 
1991;196(2):213-216. 
Taniguchi T, Inagaki R, Murata S, Akiba I, Muramatsu I. Microphysiometric analysis of 
human α1a-adrenoceptor expressed in Chinese hamster ovary cells. Br J Pharmacol. 
1999;127(4):962-968.  
Tsai JC, Forbes M.  Medical Management of Glaucoma. 3rd ed. West Islip, New York: 
Professional Communications, Inc.; 2009.   
Tucker J, Charman WN.  The depth-of-focus of the human eye for Snellen letters.  Am J 
Optom Physiol Opt.  1975;52:3-21. 
Yang X, Latt JE. Prejunctional 5-HT receptors enhance cholinergic neurosecretion in the 
rabbit and human iris-ciliary body. Yan Ke Xue Bao. 1998;14(3):149-155. 
Yu Y, Ramage AG, Koss MC. Pharmacological studies of 8-OH-DPAT-induced pupillary 
dilation in anesthetized rats. Eur J Pharmacol. 2004;489(3):207-213. 
 


 
 
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12.10 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
5-HT 
serotonin 
ANCOVA 
analysis of covariance 
AP 
analysis plan 
AUC0-12 
area under the curve from time 0 to 12 hours 
BID 
twice daily 
bpm 
beats per minute 
Cmax 
maximal concentration 
C/D 
cup to disc 
cd/m2 
candelas per square meter 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
D 
diopters 
DET 
dry eye test 
ECGs 
electrocardiograms 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practices 
GLP 
Good Laboratory Practice 
HCl 
hydrochloride 
HIPAA 
Health Insurance Portability and Accountability Act Standards for 
Privacy of Individually Identifiable Health Information 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IOLs 
intraocular lenses 
IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IxRS 
interactive response system 
LASIK 
laser-assisted in situ keratomileusis 
MAOIs 
monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
NDA 
new drug application 


 
 
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NEI VFQ-25 
National Eye Institute Visual Function Questionnaire 25 
NOAEL 
no-observed-adverse-effect-level 
NVPT 
near vision task-based presbyopia 
NZW 
New Zealand White 
OD 
right eye 
OS 
left eye 
OTC 
over-the-counter 
PDE5 
phosphodiesterase 5 
PGIC 
Patient Global Impression of Change 
PIOL 
phakic intraocular lens 
PP 
per protocol 
PRK 
photorefractive keratectomy 
PRO 
patient reported outcome 
QD 
once daily 
SOP 
standard operating procedure 
UDVA 
uncorrected distance visual acuity 
UNVA 
uncorrected near visual acuity 
US 
United States 
VAS 
visual analog scale 
 
 


 
 
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12.11 
Protocol Amendment 1 Summary 
Title:  A Phase 2, Multicenter, Double-masked, Randomized, Vehicle-Controlled, Study of 
the Concurrent Use of AGN-190584 and AGN-199201 in Patients With Presbyopia 
Protocol 199201-009 Amendment 1 
Date of Amendment:  October 2015 
Amendment Summary 
This summary includes changes made to Protocol 199201-009 (September 2015).  The study 
duration was changed from 47 to 109 to 44 to 117 days,  Table 3 was corrected to include the 
fixed combination of AGN-199201 
 and AGN-190584 
, and measurement of 
the crystal lens thickness was changed to measurement of the anterior chamber depth.   
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
Protocol 
 
 
 
 
 
 
 
Protocol 
 
 
 
 
 
Protocol 
Summary and 
Sections 7.2.1 
and 7.3.1 
“Average change from baseline” 
was revised to “weighted average 
change from baseline” for the 
primary efficacy analysis 
To clarify the definition of the primary 
efficacy variable 
Section 5.5 
Study medication will be labeled 
with medication kit number, study 
number, dominant or nondominant 
eye, and lot number all possible 
concentrations of AGN-199201, 
AGN 190584, and vehicle.   
Text was revised to match study medication 
labels 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 


 
 
Approval Date: 
 
04-Apr-2016
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Protocol 199201-009 Amendment 4 
 
 
95 
GDD-TA-T-004 v2015.10 
 
Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 


 
 
Approval Date: 
 
04-Apr-2016
Allergan Confidential 
Protocol 199201-009 Amendment 4 
 
 
96 
GDD-TA-T-004 v2015.10 
 
Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
Section 7.4 
Ethnicity was added to the subgroup 
analyses 
To match the eCRF 
 
 
 
 
 
 
 
 
Section 9.1.3 
The “Not Applicable” category was 
deleted from the severity assessment 
for an adverse event 
This category will not be used in this study 
Section 11 
Prow, 1996 was added to the 
reference list 
Inadvertently omitted 
 
 
 
 
   
 
 


 
 
Approval Date: 
 
04-Apr-2016
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GDD-TA-T-004 v2015.10 
 
12.12 
Protocol Amendment 2 Summary 
Title:  A Phase 2, Multicenter, Double-masked, Randomized, Vehicle-Controlled, Study of 
the Concurrent Use of AGN-190584 and AGN-199201 in Patients With Presbyopia 
Protocol 199201-009 Amendment 2 
Date of Amendment:  December 2015 
Amendment Summary 
This summary includes changes made to Protocol 199201-009 Amendment 1 (October 2015).  
The Allergan Medical Safety Physician contact information was changed and “lot number” 
was deleted from the description on how study medication will be labeled. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Title Page 
The Allergan Medical Safety 
Physician contact information was 
changed 
To reflect the current physician supporting 
the protocol 
Section 5.5 
Study medication will be labeled 
with medication kit number, study 
number, and dominant or 
nondominant eye, and lot number.   
Text was revised to match study medication 
labels 


 
 
Approval Date: 
 
04-Apr-2016
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98 
GDD-TA-T-004 v2015.10 
 
12.13 
Protocol Amendment 3 Summary 
Title:  A Phase 2, Multicenter, Double-masked, Randomized, Vehicle-Controlled, Study of 
the Concurrent Use of AGN-190584 and AGN-199201 in Patients With Presbyopia 
Protocol 199201-009 Amendment 3 
Date of Amendment:  February 2016 
Amendment Summary 
This summary includes changes made to Protocol 199201-009 Amendment 2 
(December 2015).  Visit 3 of each dosing period, the OCT measure, and the electrical device 
PRO measure was removed from the study; the order of the Grand Seiko measurements was 
reversed to perform UDVA first and then UNVA; and the macroscopic hyperemia assessment 
was moved to be performed before the slit lamp biomicroscopy. 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Title Page 
The Allergan Signatory was 
changed, and an e-mail address was 
added for serious adverse event 
reporting 
To reflect the current Therapeutic Area 
Head, and to facilitate serious adverse event 
reporting 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Approval Date: 
 
04-Apr-2016
Allergan Confidential 
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99 
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Section 
Revision 
Rationale 
 
 
 
 
Section 4.5.1.1 If a female becomes pregnant during 
the study, the investigator will 
notify the sponsor immediately after 
the pregnancy is confirmed, and the 
patient will be exited from the study 
after appropriate safety follow-up.  
The investigator will (1) notify the 
patient’s physician that the patient 
was enrolled in this study and 
treated with an investigational drug 
ocular oxymetazoline, ocular 
pilocarpine, or the combination of 
oxymetazoline and pilocarpine, and 
(2) follow the progress of the 
pregnancy.  The investigator must 
document the outcome of the 
pregnancy and provide a copy of the 
documentation to Allergan.   
To be consistent with the Informed Consent 
Form 
Section 5.5 
The IxRS will provide the site with 
the specific medication kit 
number(s) for each randomized 
patient at the time of randomization. 
(day 1 of the first dosing period) and 
on day 1 of each subsequent dosing 
period.   
For clarification 
 
 
 
 
Section 5.7 
Text referring to a temperature 
monitoring device was deleted 
To apply to sites that may not have a 
temperature monitoring device 
 
 
 
 
 
 
 
 
 
 
 


 
 
Approval Date: 
 
04-Apr-2016
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Protocol 199201-009 Amendment 4 
 
 
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GDD-TA-T-004 v2015.10 
 
Section 
Revision 
Rationale 
 
 
 
 
 
 
Section 7.2.1 
The primary efficacy variable is the 
weighted average change from 
baseline in UNVA letter in the 
nondominant eye over three 2-day 
periods between hour 1 and hour 10. 
To reflect the removal of visit 3 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Approval Date: 
 
04-Apr-2016
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Section 
Revision 
Rationale 
measurements were added at hours 
 
 
 
 
Section 8.5 
Deleted instruction for patients to 
remain at the study site for the 
duration of the visit 
To minimize patient inconvenience 
Section 8.9 
Visit 3/study exit was changed to 
visit 2/study exit 
To reflect the removal of visit 3 
Section 9.5 
A section on the procedures for 
pregnancy follow-up and reporting 
was added 
To be consistent with the Informed Consent 
Form 


 
 
Approval Date: 
 
04-Apr-2016
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12.14 
Protocol Amendment 4 Summary 
Title:  A Phase 2, Multicenter, Double-masked, Randomized, Vehicle-Controlled, Study of 
the Concurrent Use of AGN-190584 and AGN-199201 in Patients With Presbyopia 
Protocol 199201-009 Amendment 4 
Date of Amendment:  April 2016 
Amendment Summary 
This summary includes changes made to Protocol 199201-009 Amendment 3 
(February 2016).  Table 2 and relevant sections of the protocol were corrected to include a 
photopic pupil measurement (both eyes, distance) at screening and near manifest refraction at 
baseline/visit 1, and the order of the sodium fluorescein corneal staining (Oxford scale), 
Schirmer’s tear test (with anesthesia), IOP, and gonioscopy/angle assessment was revised for 
optimal collection during the conduct of the study.  
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
 
Section 
Revision 
Rationale 
 
 
 
 
 
  
 
 
   
 
Protocol 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
Approval Date: 
 
04-Apr-2016
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 8.5 
• Patients must not read, use the 
computer, or look at cell 
phones/tablets without the use of 
reading glasses during any 
portion of the study visits.  Note:  
Patients will be required to 
refrain from using their glasses 
For clarification 


 
 
Approval Date: 
 
04-Apr-2016
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Protocol 199201-009 Amendment 4 
 
 
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Section 
Revision 
Rationale 
during the near-vision tasks and 
associated near-vision task 
questionnaires, but may use their 
glasses to fill out other study 
related questionnaires. 
 


 
 
Approval Date: 
 
04-Apr-2016
ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 199201-009 Amd 4

SAP_000.pdf: 
NCT02595528 
 
Study ID: 199201‐009 
 
 
Title: A Phase 2, Multicenter, Double‐masked, Randomized, Vehicle‐Controlled, Study of the Concurrent 
Use of AGN‐190584 and AGN‐199201 in Patients With Presbyopia 
 
Statistical Analysis Plan Amendment 2 Date: 09Nov2017 
 
 
 


 
1. 
Title Page 
STATISTICAL ANALYSIS PLAN 
 
A Phase 2, Multicenter, Double-masked, Randomized, Vehicle-Controlled, Study of the 
Concurrent Use of AGN-190584 and AGN-199201 in Patients with Presbyopia 
 
Amendment 2.0: 2017-11-09 
 
Study Number: 
199201-009 
Development Phase: 
2b 
Product Name: 
AGN-199201 (oxymetazoline hydrochloride 
ophthalmic solution) and AGN-190584 (pilocarpine 
hydrochloride ophthalmic solution) 
Study Statistician: 
 
Sponsor: 
Allergan (North America) 
2525 Dupont Drive, Irvine, California USA 92612 
 
 
This document is the property of Allergan PLC and may not, in full or part, be passed on, 
reproduced, published, distributed to any person, or submitted to any regulatory authority 
without the express written permission of Allergan PLC.


2. 
Table of Contents 
1. 
Title Page ................................................................................................................................. 1 
2. 
Table of Contents ..................................................................................................................... 2 
2.1 
List of Tables .................................................................................................................. 3 
2.2 
List of Figures ................................................................................................................ 4 
3. 
List of Abbreviations and Definition of Terms ........................................................................ 5 
4. 
Introduction .............................................................................................................................. 6 
4.1 
Study Design Summary ................................................................................................. 6 
4.2 
Study Objectives and Endpoints .................................................................................... 7 
 
 
5. 
Statistical Methodology and Study Endpoints ....................................................................... 11 
5.1 
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 11 
5.1.1  Statistical and Analytical Plans ........................................................................ 11 
5.1.1.1  Common Conventions ....................................................................... 11 
5.1.1.2  Demographics .................................................................................... 15 
5.1.1.3  Efficacy Analyses .............................................................................. 18 
 
 
 
 
 
 
5.1.2  Determination of Sample Size ......................................................................... 27 
5.2 
Changes in the Conduct of the Study or Planned Analyses ......................................... 27 
5.2.1  Changes in the Conduct of the Study ............................................................... 27 
5.2.2  Changes to Analyses Prior to Database Lock .................................................. 27 
6. 
Data Handling and Analysis Conventions ............................................................................. 27 
6.1 
Study Treatment Conventions ...................................................................................... 27 
6.1.1  Analysis Days .................................................................................................. 27 
6.1.2  Missing/Incomplete Treatment End Date ........................................................ 28 
6.2 
Analysis Visit Windows ............................................................................................... 28 
6.2.1  Efficacy ............................................................................................................ 28 
 
 
6.3 
Site Pooling .................................................................................................................. 29 
6.4 
Missing/Incomplete Date Conventions ........................................................................ 29 
6.4.1  Missing/Incomplete AE Start Date .................................................................. 29 
6.4.2  Missing/Incomplete Medication Start Date ..................................................... 30 


6.4.3  Missing/Incomplete AE/Medication End Date ................................................ 30 
6.5 
Efficacy Endpoint Conventions ................................................................................... 30 
6.6 
Safety Endpoint Conventions ....................................................................................... 30 
6.6.1  Adverse Events ................................................................................................ 30 
6.6.1.1  Missing Intensity or Relationship ...................................................... 30 
6.6.1.2  Possible Distant Spread of Toxin (PDSOT) ...................................... 30 
6.6.1.3  AE Group of Interest ......................................................................... 30 
6.6.2  Clinical Laboratory Assessments ..................................................................... 30 
6.6.3  Vital Signs ........................................................................................................ 31 
6.6.3.1  Potentially Clinically Significant Criteria ......................................... 31 
6.6.3.2  Continuous Descriptives and Shift Table Parameters ....................... 31 
6.6.4  Electrocardiograms .......................................................................................... 31 
6.7 
Imputed Value Listing Conventions ............................................................................. 31 
6.8 
Analysis Plan Amendment 1 Summary ....................................................................... 31 
 
2.1 
List of Tables 
Table 3-1 
Abbreviations and Definitions of Terms ................................................................. 5 
Table 4-1 
Study Objectives and Corresponding Endpoints .................................................... 7 
 
 
Table 5-1 
Analysis Populations ............................................................................................. 11 
 
 
Table 5-3 
Statistical Methodology ........................................................................................ 14 
Table 5-4 
Missing Data Handling by Endpoint Type ............................................................ 15 
Table 5-5 
Analysis Population Summaries ........................................................................... 15 
Table 5-6 
Subject Disposition Summaries ............................................................................ 16 
Table 5-7 
Protocol Deviation Summary ................................................................................ 16 
Table 5-8 
Demographic Summaries ...................................................................................... 16 
Table 5-9 
Baseline Characteristics Summaries ..................................................................... 17 
Table 5-10 
Medical History Summary .................................................................................... 17 
Table 5-11 
Medication Summaries ......................................................................................... 17 


Table 5-12 
NEI VFG-25 Summary ......................................................................................... 18 
 
 
 
 
Table 5-15 
Mesopic, High Contrast UNVA Analyses ............................................................. 19 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5-23 
AE Terms .............................................................................................................. 22 
 
 
Table 6-1 
Analysis Day Definitions ...................................................................................... 28 
 
 
 
 
Table 6-4 
Imputation Scenarios ............................................................................................ 29 
Table 6-5 
Initial Imputed Date Algorithm ............................................................................. 29 
Table 6-6 
Missing AE Intensity and Relationship Imputation Algorithms ........................... 30 
 
 
 
2.2 
List of Figures 
 
 


3. 
List of Abbreviations and Definition of Terms 
Table 3-1 
Abbreviations and Definitions of Terms 
Abbreviation/Term 
Definition 
AE 
adverse event 
AGN 
Allergan 
ANCOVA 
analysis of covariance 
ANOVA 
analysis of variance 
ATC 
Anatomical Therapeutic Chemical 
CFB 
change from baseline 
eCRF 
electronic case report form 
EO 
exploratory objective 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
LOCF 
last observation carried forward 
LS 
least squares 
MedDRA 
Medication Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
MMRM 
mixed-effects model for repeated measures 
NEI 
national eye institute (NEI) visual function questionnaire - 25 (VFQ-25) 
OC 
observed cases 
PCS 
potentially clinically significant 
PO 
primary objective 
PP 
per-protocol 
PRO 
patient reported outcome 
PT 
preferred term 
SAE 
serious adverse event 
SADE 
serious adverse device effect 
SAP 
statistical analysis plan 
SID 
subject identification 
SO 
secondary objective 
SOC 
system organ class 
TEAE 
treatment-emergent adverse event 
UDVA 
uncorrected distance vision acuity 
UNVA 
uncorrected near vision acuity 
VAS 
visual analog scale 
VFQ-25 
visual function questionnaire - 25  
WHO 
World Health Organization 


4. 
Introduction 
This statistical analysis plan (SAP) details comprehensive, technical specifications of the 
statistical analyses of the efficacy and safety data outlined and/or specified in the final protocol 
of Study 199201-009 (version dated 2015-09-15) and the most recent amendment (version 4 
dated 2016-04-04). Specifications of tables, figures, and data listings are contained in a separate 
document.  
This document is organized into 3 main sections: 
1. Study overview 
2. Statistical Methodology and Study Endpoints 
3. Data Handling and Analysis Conventions 
 
4.1 
Study Design Summary 
This study is a phase 2b, multicenter, double-masked, parallel-group, randomized sequence, dose 
response, vehicle-controlled study in patients with presbyopia.  Sixteen unfixed combination of 
AGN-190584 
 and AGN-199201 (
 
and a fixed combination of AGN-190584 
 and AGN-199201 
 solutions will be 
dosed in the nondominant eye during 5 dosing periods.  For 17 different treatment combinations, 
each dosing period will be once daily for 2 consecutive days, followed by a 7 to 21 day washout 
before the next 2-day dosing period, until exit after the fifth 2-day dosing period.  The study 
duration will be 39 to 112 days per patient. 
Following a screening visit (days -18 to -1) patients will be randomized at a baseline visit (visit 
1) in a 1:1:1:1 ratio (stratified by uncorrected near vision acuity at baseline of ≤ 20/80 and > 
20/80) to 1 of the following treatment groups:   
• Group 1:  AGN-199201 
 and AGN-190584 
vehicle 0% 
• Group 2:  AGN-199201 
 and AGN-190584 
ophthalmic solution
  
• Group 3:  AGN-199201 
 and AGN-190584 
ophthalmic solution 
 
• Group 4:  AGN-199201 
 and AGN-190584 
ophthalmic solution 
   


All patien
 oph
for AGN
formulati
4.2 
Each stud
presented
Table 4-1 
Objectives
Primary 
PO1 To id
AGN-19
and AGN
dosed in 
improvem
(UNVA) 
 
nts will rece
hthalmic solu
-199201, an
ion.   
Study
dy primary o
d with corres
s 
dentify the o
9201 
N-190584
combination
ment of unco
in patients w
eive the fixed
utions within
d the vehicle
y Objectiv
objective (PO
sponding end
Study Obje
ptimum con
, 
 
n once a day
orrected near
with presbyo
d combinatio
n one of the 
e for fixed c
ves and En
O), secondar
dpoint(s) be
ctives and Co
ncentrations o
 
when
y for the 
r vision acui
opia 
on of AGN-1
5 dosing per
ombination 
ndpoints 
ry objective 
low: 
rresponding E
 
of 
n 
ity 
199201
riods.  Vehic
ophthalmic 
(SO), and ex
Endpoints 
The prima
weighted a
baseline in
nondomin
between h
will be the
dosing per
 and AG
cle for AGN-
solution hav
xploratory o
Endpoints 
ary efficacy v
average chan
n UNVA lett
nant eye over
hour 1 and ho
e hour 0 mea
riod. 
GN-190584 
-190584, veh
ve the same 
objective (EO
variable is th
nge from 
ter in the 
r 2-day perio
our 10.  Base
asure for eac
hicle 
O) is 
he 
ods 
eline 
ch 


4.3 
Schedule of Activities 






5. 
Statistical Methodology and Study Endpoints 
5.1 
Statistical Methods Planned in the Protocol and Determination of 
Sample Size 
This statistical analysis plan (SAP) will be approved prior to database lock. The SAP expands the 
statistical section of the protocol and contains a detailed description of methods to analyze data 
collected in the study. The text portion of the SAP will be included in the CSR report as 
Appendix 16.1.9.  
5.1.1 
Statistical and Analytical Plans 
Statistical analyses will be conducted using 
 
5.1.1.1 
Common Conventions 
5.1.1.1.1 
Analysis Populations 
The analysis populations will consist of subjects as defined below: 
Table 5-1 
Analysis Populations 
Population 
Definition 
Study Treatment 
Screened 
All screened subjects who sign informed consent 
— 
Modified Intent-to-
Treat (mITT) 
All randomized subjects with a baseline and at least 1 post 
baseline assessment of mesopic high contrast UNVA, with 
baseline vary not more than 3 lines across the 5 dosing period, 
and will be analyzed as randomized. 
Randomized assignment 
Per Protocol (PP) 
All randomized patients who have no significant protocol 
deviations that affect the primary efficacy variable and complete 
all study visits for each dosing period. 
Actual received 
Safety 
All subjects who received ≥ 1 administration of study treatment 
Actual received 
 
5.1.1.1.2 
Study Treatments 
The following treatment groups are defined for this study: 
• AGN-199201
 AGN-190584 
 
• AGN-199201 
+ AGN-190584 
 
• AGN-199201 
+ AGN-190584 
 
• AGN-199201
 AGN-190584 
 
• Fixed Combo  + Fixed Combo 
 
• AGN-199201 0% + AGN-190584 
 
• AGN-199201 
+ AGN-190584 
 


• AGN-199201
 + AGN-190584 
 
• AGN-199201 
+ AGN-190584
 
• AGN-199201 
 + AGN-190584 
 
• AGN-199201 
 + AGN-190584 
 
• AGN-199201 
+ AGN-190584 
 
• AGN-199201 
 + AGN-190584 
 
• AGN-199201 
 + AGN-190584 
 
• AGN-199201 
 + AGN-190584 
 
• AGN-199201 
 + AGN-190584 
 
• AGN-199201 
 + AGN-190584 
 
 
The following treatment sequences are defined for this study: 


5.1.1.1.3 
Statistical Methodology 
The methodologies defined below apply as specified to individual endpoints defined in this SAP. 
When indicated, 95% two-sided confidence intervals and two-sided p-values will be presented. 


Individual endpoint analyses may specify exceptions (additions or deletions) to these general 
definitions. 
Table 5-3 
Statistical Methodology 
Methodology 
Description 
M1 
Categorical 
counts 
• 
Number of subjects in individual categories 
o 
Subjects with ≥ 1 qualifying event counted once per individual category 
M2 
Categorical 
descriptives 
• 
Number and percentage of subjects in individual categories 
o 
Subjects with ≥ 1 qualifying event counted once per individual category 
• 
(Optional) N included if percentage denominator ≠ number of subjects in the 
population (standard percentage denominator). 
M3 
PCS 
descriptives 
• 
Number and percentage of subjects meeting potentially clinically significant (PCS) 
criteria 
o 
Subjects with ≥ 1qualifying event counted once per PCS category  
• 
Percentage denominator = number of subjects with non-missing baseline and >=1 
non-missing postbaseline assessment 
• 
Unevaluable assessments considered missing 
M4 
Continuous 
descriptives 
• 
N included, mean, standard deviation (SD), median, minimum, maximum 
• 
N included = subjects with non-missing value 
M5 
CFB 
descriptives 
• 
Continuous descriptives for baseline, postbaseline, and change from baseline (CFB) 
values 
• 
N included = subjects with non-missing values at both baseline and the specified 
postbaseline analysis visit 
M6 
CFB 
ANCOVA 
• 
Continuous descriptives and standard error (SE) for baseline, postbaseline, and CFB 
values 
• 
Estimates derived from mixed model for CFB value controlling for factors 
(pilocarpine dose, oxymetazoline dose) and covariates (baseline UNVA severity, iris 
color) 
o 
Least squares (LS) means and standard errors 
o 
P-values from contrast t-test comparing active AGN-199201 treatment 
groups vs AGN-199201 vehicle 
• 
N included = subjects with non-missing values at both baseline and the postbaseline 
analysis visit 
M7 
CFB 
MMRM 
• 
Continuous descriptives and SE for baseline, postbaseline, and CFB values at each 
analysis visit 
o 
N included = subjects with non-missing values at both baseline and the 
postbaseline analysis visit 
• 
Estimates derived from mixed model for CFB value controlling for fixed factors 
(pilocarpine dose, oxymetazoline dose,), covariates (baseline UNVA severity, iris 
color), and interactions (pilocarpine dose and oxymetazoline dose interaction), with 
an compound symmetry covariance matrix 
o 
LS means and standard errors 
o 
N included = subjects with non-missing values at both baseline and  
postbaseline analysis visit 
M8 
CFB figure 
• 
Plot of CFB LS means and SE bars for each treatment group. 
M9 
CFB RS 
figure 
• 
Plot of CFB response surface in 3 dimension. 
M10 Responder 
• 
Categorical descriptives for responders and nonresponders 
o 
Nonresponders include: 
 
Subjects who do not meet responder criteria 
CFB = change from baseline; ANCOVA = analysis of covariance; ANOVA = analysis of variance. 
MMRM = mixed model for repeated measures; RS=response surface 
 


Raw and derived data listings will be provided, and will be fully defined in the table, figure, and 
data listing specification document. 
5.1.1.1.4 
Missing Data 
General missing data handling conventions are specified for methodologies in Section 5.1.1.1.3 
and summarized as follows: 
Table 5-4 
Missing Data Handling by Endpoint Type 
Endpoint type 
Timing 
Missing Data Handling 
Responder 
Treatment Period 
• 
All subjects included 
• 
Subjects with no postbaseline values will be excluded 
CFB ANCOVA 
 
Treatment Period 
• 
If missing covariates (including baseline if applicable)  
o 
Subject excluded 
• 
If missing weighted average change from baseline UNVA 
letters: 
o 
Subject excluded 
CFB MMRM 
Treatment Period 
• 
If missing covariates (including baseline if applicable) or 
missing values at all postbaseline analysis visits 
o 
Subject excluded 
• 
If missing weighted average change from baseline UNVA 
letters: 
o 
Subject excluded 
CFB Posebaseline 
Treatment Period 
• 
If missing value at the specified postbaseline analysis visit: 
o 
Available cases 
 
Subject excluded 
 
5.1.1.1.5 
Site Pooling 
Data from all sites will be pooled for analysis. 
5.1.1.1.6 
Other Common Conventions 
Ocular adverse events and other ocular evaluations will be summarized using eye as the 
experimental unit by dosing group and dosing period.  Nonocular adverse events and other 
nonocular assessments will be summarized using patient as the experimental unit by dosing 
group and dosing period. 
5.1.1.2 
Demographics 
5.1.1.2.1 
Analysis Populations 
The distribution of subjects within the analysis populations will be summarized as follows: 
Table 5-5 
Analysis Population Summaries 
Endpoint 
Description 
Timing 
Methodology 
Screened Population 
Distribution overall and within 
countries/regions/sites in total 
Screening Period, 
Categorical counts 


mITT, PP and Safety 
populations 
Distribution overall and within 
countries/regions/sites in total and by 
treatment group 
Treatment Period 
Categorical counts 
 
5.1.1.2.2 
Subject Disposition 
Subject disposition encompasses the distribution of subjects who enter, complete, and 
discontinue each specified analysis period, along with eCRF-reported discontinuation reasons 
from each respective analysis period. Subject disposition will be summarized as follows: 
Table 5-6 
Subject Disposition Summaries 
Endpoint 
Description 
Timing 
Methodology 
Screening and 
pretreatment disposition 
Distribution in the Screened Population in 
total 
Screening Period, 
Pretreament Period 
Categorical 
descriptives 
Study disposition 
Distribution in the mITT Population in 
total and by treatment group 
Treatment Period 
Categorical 
descriptives 
 
5.1.1.2.3 
Protocol Deviations 
Protocol deviations will be defined in a separate document, including importance classification. 
Protocol deviations will be summarized as follows: 
Table 5-7 
Protocol Deviation Summary 
Endpoint 
Description 
Timing 
Methodology 
Important protocol 
deviations 
Distribution in the mITT Population in 
total and by treatment group 
Treatment Period 
Categorical 
descriptives 
 
5.1.1.2.4 
Demographics 
Demographics will be summarized for the Screened Population, and in total and by treatment 
group for the mITT, PP and Safety populations, as follows: 
Table 5-8 
Demographic Summaries 
Endpoint 
Description 
Timing 
Methodology 
Age 
Age (years) relative to informed consent 
date 
Informed consent 
Continuous 
descriptives 
Age group 
• 
40-47 years 
• 
48-51 years 
Informed consent 
Categorical 
descriptives 
Sex, race, and ethnicity 
• 
eCRF categories 
• 
Race group 
o 
White 
o 
Non-white 
• 
Ethnicity 
o 
Hispanic 
o 
Non-hispanic 
Screening Period 
Categorical 
descriptives 
 


5.1.1.2.5 
Baseline Characteristics 
Baseline characteristics will be summarized in total and by treatment group for the mITT, PP and 
Safety populations as follows: 
Table 5-9 
Baseline Characteristics Summaries 
Endpoint 
Description 
Timing 
Methodology 
Baseline characteristics 
• 
Iris color 
 
Latest assessment in 
Screening Period or 
Pretreament Period 
Categorical 
descriptives 
Randomization strata 
• 
UNVA at baseline of ≤  20/80 
• 
UNVA at baseline of  > 20/80 
Randomization date 
Categorical 
descriptives 
 
5.1.1.2.6 
Medical History 
Medical history, encompassing abnormalities and surgeries reported as occurring before the 
Screening Visit, will be coded using the Medical Dictionary for Regulatory Activities (MedDRA), 
version 19.0 or newer. Unique subjects who report medical history events will be summarized by 
MedDRA system organ class (SOC) and preferred term (PT) in total and by treatment group for 
the Safety Population as follows: 
Table 5-10 
Medical History Summary 
Endpoint 
Description 
Timing 
Methodology 
Medical history 
Abnormalities and surgeries occurring 
before the Screening Visit 
Screening Period 
Categorical 
descriptives 
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
 
5.1.1.2.7 
Prior and Concomitant Medications 
Medications will be listed for the Safety Population as follows: 
Medications will be coded using the World Health Organization (WHO) Drug Dictionary, 
version 14.0 or newer. Unique subjects who reported medications will be summarized by 
Anatomical Therapeutic Chemical (ATC) 4 class and PT in total and by treatment group for the 
Safety Population as follows: 
Table 5-11 
Medication Summaries 
Endpoint 
Description 
Timing 
Methodology 
Prior medications 
Medications taken ≥ 1 time before the 
study treatment start date, regardless of 
medication end date 
 
Screening Period, 
Pretreament Period 
Categorical 
descriptives 
Concomitant 
medications 
Medications taken ≥ 1 time on or after the 
study treatment start date, regardless of 
medication start date 
• 
Medications starting 1 day after  
Treatment Period 
Categorical 
descriptives 


Endpoint 
Description 
Timing 
Methodology 
treatment end date will be listed 
but excluded from analysis 
ATC4 classes will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
 
5.1.1.2.8 
National Eye Institute Visual Function Questionnaire 
National eye institute (NEI) visual function questionnaire - 25 (VFQ-25) that will be 
administered at screening to determine patient-reported near and distance vision functioning. 
NEI VFQ-25 will be summarized for the Safety Population. 
Table 5-12 
NEI VFG-25 Summary  
Endpoint 
Description 
Timing 
Methodology 
NEI VFQ-25 
NEI VFQ-25 questionnaires 
Screening Period 
Categorical 
descriptives 
 
 
 
5.1.1.3 
Efficacy Analyses 
Efficacy analyses will be based on the mITT Population.  The primary efficacy variable, 
weighted average change from baseline in UNVA letter,  will also be analyzed based on the PP 
population. 
The following efficacy assessments are defined: 
: 


5.1.1.3.1 
Study Success Criteria 
There will be no adjustment of type 1 error rate for the multiple tests.  
5.1.1.3.2 
Mesopic, High Contrast UNVA  
General description of mesopic, high contrast UNVA endpoints.  
Table 5-15 
Mesopic, High Contrast UNVA Analyses 
Endpoint 
Description 
Timing 
Methodology 
Average change from 
baseline in UNVA 
letters (Primary efficacy 
variable) 
Average change from baseline in UNVA letters1 in the 
nondominant eye over two-day dosing periods between 
hour 1 and hour 10.  
Treatment 
Period 
CFB MMRM2  
CFB ANCOVA3 
CFB RS figure 
CFB figure 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 






5.1.1.4.2 
Adverse Events 
The following adverse event (AE) terms are defined: 
Table 5-23 
AE Terms 
Term 
Description 
Treatment-
emergent  
An event that initially occurs or increases in intensity on or after the treatment start date, where: 
• 
Treatment start date ≤ event start date ≤ following washout period before the next 2-day 
dosing period or last dose date + 30 days 
On-therapy 
An event where: 
• 
Treatment start date ≤ event start date ≤ following washout period before the next 2-day 
dosing period or last dose date + 30 days 
 
AEs, encompassing abnormalities and surgeries reported as occurring after the Screening Visit, 
will be coded using MedDRA version 19.0 or newer. Unique subjects reporting AEs in the 


following AE categories will be summarized by treatment group and overall for the Safety 
Population as follows: 
Table 5-21 
AE Summaries 
Endpoint 
Description 
Timing 
Methodology 
Overall summary 
Overall summary only for the following 
categories: 
• 
Treatment-emergent AEs 
(TEAEs) 
• 
Treatment-related TEAEs 
• 
Study-procedure-related TEAEs 
• 
On-therapy serious adverse events 
(SAEs) 
• 
On-therapy fatal SAEs 
• 
AEs leading to discontinuation 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
TEAEs 
Overall summary and by SOC and PT 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
Common TEAEs 
Summary by PT 
• 
Includes TEAEs occurring in ≥ 
5.0% of subjects in any treatment 
group 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
TEAEs by intensity 
Overall summary and by SOC, PT, and 
intensity 
• 
Subjects categorized overall and 
within each SOC and PT for the 
most intense occurrence 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
Treatment-related 
TEAEs 
Overall summary and by PT 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
Study-procedure-related 
TEAEs 
Overall summary and by PT 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
On-therapy SAEs1 
Overall summary and by PT 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
On-therapy fatal SAEs1 
Overall summary and by PT 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
AEs leading to study 
discontinuation1 
Overall summary and by PT 
Treatment Period, 
Follow-up 
Categorical 
descriptives 
1 Subjects who report ≥ 1 AE in the AE category and all AEs for those subjects will be listed. 
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 


 






5.1.1.5 
Subgroup Analyses 
Subgroup analyses will be performed for the primary efficacy variable by UNVA severity at 
baseline  and iris color (brown or not brown). 
5.1.1.6 
Interim Analyses 
Not applicable. 
5.1.2 
Determination of Sample Size 
The study consists of 4 parallel groups and forty patients per each parallel group will be enrolled. 
With a 1:1:1:1 parallel group allocation and 10% dropout rate, a total of 160 patients are to be 
enrolled in order to have 144 patients complete the study.  The sample size is deemed appropriate 
to assesses the efficacy profile of the combination relative to monotherapies. 
5.2 
Changes in the Conduct of the Study or Planned Analyses 
5.2.1 
Changes in the Conduct of the Study 
Not applicable. 
5.2.2 
Changes to Analyses Prior to Database Lock 
The term of  ‘average change from baseline in UNVA letters’ instead of ‘weighted average 
change from baseline in UNVA letters’ will be used since weighted average concept only applies 
when missing mid-timepoint values are imputed. UNVA responder analyses with at least a 2-line 
improvement in mesopic, high contrast UNVA from baseline at a majority of postdose timepoints 
(6 or more) in the nondominant eye will be added. 
Subgroup analyses by gender, race and ethnicity will be performed .  
mITT definition will be change to ‘All randomized subjects with a baseline and at least 1 post 
baseline assessment of mesopic high contrast UNVA, with baseline vary not more than 3 lines 
across the 5 dosing period, and will be analyzed as randomized.’ 
6. 
Data Handling and Analysis Conventions 
6.1 
Study Treatment Conventions 
6.1.1 
Analysis Days 
Treatments are defined as follows: 


Table 6-1 
Analysis Day Definitions 
Term 
Description 
Treatment Day 
Relative to treatment start date 
If analysis date ≥ treatment start date: 
• 
Day = analysis date – treatment start date + 1 
o 
Day 1 = treatment start date 
 
 
6.1.2 
Missing/Incomplete Treatment End Date 
If the investigator is unable to provide the treatment end date, treatment end date will be imputed 
to the last available dosing record date/last available efficacy assessment date. 


 
 
 
 
 
 
6.3 
Site Pooling 
Data from all sites will be pooled for analysis. 
6.4 
Missing/Incomplete Date Conventions 
Dates may be imputed with year, month, and day values under certain scenarios: 
Table 6-4 
Imputation Scenarios 
 
 
Complete
 
Scenario 
Year 
Month 
Day 
Imputable 
1 
Yes 
Yes 
Yes 
Complete 
2 
Yes 
Yes 
— 
Yes 
3 
Yes 
— 
Yes 
No1 
4 
Yes 
— 
— 
Yes 
5 
— 
Yes 
Yes 
No1 
6 
— 
Yes 
— 
No1 
7 
— 
— 
Yes 
No1 
8 
— 
— 
— 
Yes 
1 Not allowed per database design. 
 
Dates will be imputed initially toward a specified target date for imputable scenarios 2, 4, and 8, 
and adjusted against the latest reasonable dates. The initial imputed date is determined by the 
following algorithm: 
Table 6-5 
Initial Imputed Date Algorithm 
Available Year 
Available Month (MM) 
(YYYY) 
Missing 
< Target Month 
= Target Month 
> Target Month 
Missing 
Target Date 
 
— 
 
< Target Year 
YYYY-12-31 
 
YYYY-MM-LD 
 
= Target Year 
Target Date 
YYYY-MM-LD 
Target Date 
YYYY-MM-01 
> Target Year 
YYYY-01-01 
 
YYYY-MM-01 
 
YYYY = available start date year; MM = available start date month; LD = last day of the month. 
 
6.4.1 
Missing/Incomplete AE Start Date 
AE start dates will be imputed as the minimum of the following: 
• Initial imputed date, where target date = Treatment start date 
• Complete end date 


6.4.2 
Missing/Incomplete Medication Start Date 
Medication start dates will be imputed as the minimum of the following: 
• Initial imputed date, where target date = Treatment start date – 1 
• Complete end date 
6.4.3 
Missing/Incomplete AE/Medication End Date 
AE and medication end dates will be imputed as the minimum of the following: 
• Initial imputed date, where target date = Treatment end date + 30 
• Death date 
6.5 
Efficacy Endpoint Conventions 
Not applicable. 
6.6 
Safety Endpoint Conventions 
6.6.1 
Adverse Events 
6.6.1.1 
Missing Intensity or Relationship 
If the investigator is unable to provide the actual values, the following imputations will be 
applied: 
Table 6-6 
Missing AE Intensity and Relationship Imputation Algorithms 
Missing Value 
Imputation 
Timing 
Intensity 
Mild 
Screening Period, Pretreatment Period 
 
Severe 
Treatment Period 
Relationship 
— 
Screening Period, Pretreatment Period 
 
Related 
Treatment Period 
 
6.6.1.2 
Possible Distant Spread of Toxin (PDSOT) 
Not applicable. 
6.6.1.3 
AE Group of Interest 
Not applicable. 
6.6.2 
Clinical Laboratory Assessments 
Not applicable 


6.7 
Imputed Value Listing Conventions 
In general, listings will present the actual partial or missing values rather than the imputed values 
that may be used in endpoint derivation. In instances where imputed values will be presented, 
imputed values will be flagged. Actual rules will be fully defined in the table, figure, and data 
listing specification document. 
 
6.8 
Analysis Plan Amendment 1 Summary 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
Section 
5.1.1.1.1 
mITT definition is changed to 
‘All randomized subjects 
with a baseline and at least 1 
post baseline assessment of 
mesopic high contrast 
UNVA, with baseline vary 
not more than 3 lines across 
the 5 dosing period, and will 
be analyzed as randomized.’ 
Correction for the primary efficacy 
baseline data issue.  
Section 
Age group 
Correction 


Section 
Revision 
Rationale 
5.1.1.2.4 
• 40-47 years 
• 48-51 years  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section 5.2.2 
UNVA responder analyses with 
at least a 2-line improvement in 
mesopic, high contrast UNVA 
from baseline at a majority of 
postdose timepoints (6 or more) 
in the nondominant eye will be 
added. 
Added additional analysis 
 
6.9 
Analysis Plan Amendment 2 Summary 
Following is a summary of content-oriented changes that were made to each section of the 
protocol, and a brief rationale for these changes.  Minor editorial and document formatting 
revisions have not been summarized. 
Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 


ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
           
 
            
 
           
 
            
 
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
199201-009 Statistical Analysis Plan