Clinical trial NCT02780115
Conditions: Presbyopia
Sponsor: Allergan
Start date: 2016-05-26; Completion date: 2017-10-31
Enrollment: 151 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a safety, efficacy and pharmacokinetics study of the fixed combination of AGN-199201 and AGN-190584 in participants with presbyopia (inability to focus on items close-up).

Detailed description:

Arms: arm 1: Vehicle dosed in both eyes administered once daily during office visits 1 through 5. arm 2: Fixed combinations of AGN-199201 Dose A and AGN-190584 Dose A dosed in both eyes administered once daily during office visits 1 through 5. arm 3: Fixed combinations of AGN-199201 Dose B and AGN-190584 Dose B dosed in both eyes administered once daily during office visits 1 through 5. arm 4: Fixed combinations of AGN-199201 Dose C and AGN-190584 Dose C dosed in both eyes administered once daily during office visits 1 through 5. arm 5: Dominant eye dosed with Vehicle. Fixed combinations of AGN-199201 Dose C and AGN-190584 Dose C dosed in nondominant eye. Treatment administered once daily during office visits 1 through 5.
Interventions: intervention 1: AGN-199201 ophthalmic solution intervention 2: AGN-190584 ophthalmic solution intervention 3: AGN-199201 Vehicle intervention 4: AGN-190584 Vehicle
Intervention descriptions: intervention 1: 1 drop of AGN-199201 ophthalmic solution Doses A, B, C in the eye. intervention 2: 1 drop of AGN-190584 ophthalmic solution Doses A, B, C in the eye. intervention 3: Vehicle to AGN-199201 intervention 4: Vehicle to AGN-190584

Protocol documents:
Prot_001.pdf: 
NCT02780115 
 
Study ID: 199201‐010 
 
 
Title: A Phase 2, Multicenter, Double‐Masked, Randomized, Vehicle‐Controlled, Parallel‐Group Study 
Evaluating the Safety, Efficacy, and Pharmacokinetics of the Fixed Combination of AGN‐199201 and 
AGN‐190584 in Patients With Presbyopia 
 
Protocol Amendment 3 Date: 18Aug2016 
 
 
 


 
 
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ALLERGAN – CONFIDENTIAL 
The following contains confidential, proprietary information  
that is the property of Allergan 
 
STUDY TITLE 
A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, 
Parallel-Group Study Evaluating the Safety, Efficacy, and Pharmacokinetics of the 
Fixed Combination of AGN-199201 and AGN-190584 in Patients With Presbyopia 
 
Protocol Number:   
199201-010 Amendment 3 
Phase: 
2 
Name of Investigational Products: 
AGN-199201 (oxymetazoline hydrochloride ophthalmic 
solution) and AGN-190584 (pilocarpine hydrochloride 
ophthalmic solution) 
Emergency Telephone Number(s): 
Refer to the Study Contacts Page 
Serious Adverse Event Reporting: 
 
 
 
 
Allergan Medical Safety Physician 
Contact Information: 
 
 
 
Allergan Signatory: 
 
 
 
Refer to the final page of this protocol for electronic signature 
and date of approval. 


 
 
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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 ........................................................................................................................... 8 
Protocol Summary .................................................................................................................... 9 
1. 
Background and Clinical Rationale ................................................................................. 25 
1.1 
Background ............................................................................................................ 25 
1.2 
Preclinical Summary .............................................................................................. 28 
1.3 
Clinical Summary................................................................................................... 29 
1.4 
Rationale for Study Design .................................................................................... 32 
2. 
Study Objectives and Clinical Hypotheses ...................................................................... 33 
2.1 
Study Objectives .................................................................................................... 33 
2.2 
Clinical Hypotheses ............................................................................................... 34 
3. 
Study Design .................................................................................................................... 34 
4. 
Study Population and Entry Criteria ................................................................................ 34 
4.1 
Number of Patients ................................................................................................. 34 
4.2 
Study Population Characteristics ........................................................................... 35 
4.3 
Inclusion Criteria .................................................................................................... 35 
4.4 
Exclusion Criteria................................................................................................... 36 
4.5 
Permissible and Prohibited Medications/Treatments ............................................. 38 
4.5.1  Permissible Medications/Treatments ......................................................... 38 
4.6 
Prohibited Medications/Treatments ....................................................................... 38 
5. 
Study Treatments ............................................................................................................. 39 
5.1 
Study Treatments and Formulations ....................................................................... 39 
5.2 
Control Treatment .................................................................................................. 39 
5.3 
Methods for Masking ............................................................................................. 40 
5.4 
Treatment Allocation Ratio and Stratification........................................................ 40 
5.5 
Method for Assignment to Treatment Groups/Randomization .............................. 40 
5.6 
Treatment Regimen and Dosing ............................................................................. 41 
5.7 
Storage of Study Medications/Treatments ............................................................. 41 
5.8 
Treatment Administration ...................................................................................... 42 


 
 
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6. 
Response Measures and Summary of Data Collection Methods ..................................... 42 
6.1 
Efficacy Measures .................................................................................................. 42 
6.1.1  Primary Efficacy Measure .......................................................................... 42 
 
 
 
 
 
 
 
 
 
 
 
 
6.6 
Summary of Methods of Data Collection .............................................................. 58 
7. 
Statistical Procedures ....................................................................................................... 58 
7.1 
Analysis Populations .............................................................................................. 58 
7.2 
Collection and Derivation of Primary and Other Efficacy Assessments ............... 59 
7.2.1  Primary Efficacy Variable .......................................................................... 59 
 
 
7.3 
Hypothesis and Methods of Analysis ..................................................................... 61 
7.3.1  Primary Efficacy Analyses ......................................................................... 61 
 
 
 
 
 
 
7.4 
Subgroup Analyses ................................................................................................. 62 
7.5 
Sample Size Calculation ........................................................................................ 62 
7.6 
Interim Analyses..................................................................................................... 63 
8. 
Study Visit Schedule and Procedures .............................................................................. 63 
8.1 
Patient Entry Procedures ........................................................................................ 63 
8.1.1  Overview of Entry Procedures ................................................................... 63 
8.1.2  Informed Consent and Patient Privacy ....................................................... 63 
8.2 
Washout Intervals/Run-In ...................................................................................... 64 
8.3 
Procedures for Final Study Entry ........................................................................... 64 
 
 
 
 
 
 
 
 
 
 


 
 
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8.5 
Instructions for the Patients .................................................................................... 78 
8.6 
Unscheduled Visits ................................................................................................. 79 
8.7 
Compliance With Protocol ..................................................................................... 79 
8.8 
Early Discontinuation of Patients .......................................................................... 79 
8.9 
Withdrawal Criteria ................................................................................................ 79 
8.10  Study Termination .................................................................................................. 80 
9. 
Adverse Events ................................................................................................................ 80 
9.1 
Definitions .............................................................................................................. 80 
9.1.1  Adverse Event ............................................................................................ 80 
9.1.2  Serious Adverse Event ............................................................................... 81 
9.1.3  Severity ...................................................................................................... 81 
9.1.4  Relationship to Study Drug or Study Procedure ........................................ 81 
9.2 
Procedures for Reporting Adverse Events ............................................................. 82 
9.3 
Procedures for Reporting a Serious Adverse Event ............................................... 82 
9.4 
Procedures for Unmasking of Study Medication ................................................... 83 
9.5 
Procedures for Pregnancy Follow-up and Reporting (If Applicable) .................... 83 
10.  Administrative Items ....................................................................................................... 83 
10.1  Protection of Human Patients ................................................................................ 84 
10.1.1  Compliance With Informed Consent Regulations (US 21 Code of Federal 
Regulations [CFR] Part 50) and Relevant Country Regulations ............... 84 
10.1.2  Compliance With IRB or IEC Regulations ................................................ 84 
10.1.3  Compliance With Good Clinical Practice .................................................. 84 
10.1.4  Compliance With Electronic Records; Electronic Signatures Regulations 
(US 21 CFR Part 11) .................................................................................. 84 
10.2  Changes to the Protocol ......................................................................................... 84 
10.3  Patient Confidentiality ........................................................................................... 85 
10.3.1  Patient Privacy ........................................................................................... 85 
10.4  Documentation ....................................................................................................... 85 
10.4.1  Source Documents ..................................................................................... 85 
10.4.2  Case Report Form Completion................................................................... 86 


 
 
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10.4.3  Study Summary .......................................................................................... 86 
10.4.4  Retention of Documentation ...................................................................... 87 
10.5  Labeling, Packaging, and Return or Disposal of Study Medications/Treatments .. 87 
10.5.1  Labeling/Packaging .................................................................................... 87 
10.5.2  Clinical Supply Inventory .......................................................................... 87 
10.5.3  Return or Disposal of Study Medications/Treatments and/or Supplies ..... 88 
10.6  Monitoring by the Sponsor .................................................................................... 88 
10.7  Publications ............................................................................................................ 88 
10.8  Coordinating Investigator ...................................................................................... 88 
11.  References ........................................................................................................................ 89 
12.  Attachments ..................................................................................................................... 92 
 
 
12.2  Package Insert ...................................................................................................... 108 
12.3  Glossary of Abbreviations .................................................................................... 109 
12.4  Protocol Amendment 1 Summary ......................................................................... 111 
12.5  Protocol Amendment 2 Summary ........................................................................ 114 
12.6  Protocol Amendment 3 Summary ........................................................................ 118 
 
List of Tables 
Table 1 
Study Treatment Groups ................................................................................. 10 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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List of Figures 
 
 
Figure 2 
Oxford Scale for Grading Corneal and Conjunctival Staining ....................... 52 
Figure 3 
Anterior Chamber Angle Grading ................................................................... 54 


 
 
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Protocol Summary 
 
Study Compounds:   
AGN-199201 (oxymetazoline hydrochloride [HCl] ophthalmic solution) 
 
AGN-190584 (pilocarpine HCl ophthalmic solution) 
 
Phase:  2 
Study Objectives:  
• 
To evaluate the safety, efficacy, and tolerability of fixed combinations of AGN-199201 and 
AGN-190584 over a 42-day observation period when administered bilaterally, once daily (QD) for 28 
days in patients with presbyopia 
• 
To compare the safety, efficacy, and tolerability of a fixed combination of AGN-199201 
 and 
AGN-190584 
 when administered monocularly to the nondominant eye versus bilaterally over a 
42-day observation period with QD dosing for the first 28 days in patients with presbyopia  
• 
To assess the systemic pharmacokinetics of AGN-199201 
 and 
AGN-190584 
 following single and multiple (QD for 28 days) ophthalmic 
administrations as a fixed combination in 1 or both eyes (OU), by analysis of plasma drug 
concentration-time profiles (maximum observed plasma concentration-time [Cmax], time to maximum 
observed plasma concentration-time [Tmax], area under the plasma concentration curve from time 0 to 
the last timepoint [AUC0-tlast], and area under the plasma concentration-time curve from time 0 to 
infinity [AUC0-inf]) 
• 
To evaluate the psychometric properties of the de novo patient-reported outcome (PRO) instruments 
developed for this program, including the near vision presbyopia performance tasks and task-based 
questionnaire under mesopic and photopic conditions, the presbyopia patient satisfaction questionnaire, 
and the presbyopia impact and coping questionnaire  
 
Clinical Hypotheses:   
At least 1 fixed combination of AGN-199201 and AGN-190584 ophthalmic solution dosed bilaterally, QD for 
28 days:  
1. will demonstrate a significant improvement in uncorrected near visual acuity (UNVA) over vehicle.  
2. will demonstrate acceptable safety and tolerability findings.  
3. will demonstrate an acceptable pharmacokinetic profile for AGN-199201 and AGN-190584 after 
single and repeat administrations. 
The fixed combination of AGN-199201 
and AGN-190584 
 can be administered either in the 
nondominant eye only or bilaterally for 28 days in patients with presbyopia without any significant difference in 
the observed safety, efficacy, tolerability, or pharmacokinetic profiles. 
Study Design: 
Structure:  Multicenter, double-masked, randomized, parallel-group, vehicle-controlled 
Duration:  38 to 65 days per patient  


 
 
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Study Treatment Groups:  See Table 1. 
Group 1: 
Vehicle Control, OU 
Group 2: 
Fixed combination AGN-199201 
 and AGN-190584 
 OU 
Group 3: 
Fixed combination AGN-199201 
 and AGN-190584 
, OU 
Group 4: 
Fixed combination AGN-199201 
 and AGN-190584 
 OU 
Group 5: 
Fixed combination AGN-199201 
 and AGN-190584 
, nondominant eye and 
vehicle to the dominant eye 
Table 1 
Study Treatment Groups 
Group 
AGN-199201 (%) 
AGN-190584 (%) 
Dosing 
1 
Vehicle control 
Vehicle control 
OU 
2 
 
 
OU 
3 
 
 
OU 
4 
 
 
OU 
5a 
 
 
Nondominant eye 
OU = both eyes 
a  Dominant eye dosed with vehicle 
 
Dosage/Dose Regimen:  This study will be a controlled comparison of fixed combinations of AGN-199201 and 
AGN-190584 at different concentrations and vehicle dosed in OU, and the fixed combination of AGN-199201 
 and AGN-190584 
dosed in OU or in the nondominant eye only.  Study medication will be 
administered QD in the morning.  During office visits 1 through 5, study medication will be administered at 
hour 0 (8 AM ± 1 hour). 
Patients receiving the fixed combination of AGN-199201 and AGN-190584 bilaterally will instill a single drop 
of the fixed combination drug into each eye.  Patients receiving the fixed combination of AGN-199201 and 
AGN-190584 in the nondominant eye only will instill a single drop of the fixed combination drug into the 
nondominant eye and a single drop of the vehicle into the dominant eye.  Patients receiving vehicle bilaterally 
will instill a single drop of the vehicle into each eye (see Table 1, Table 2, Table 3, Table 4, and Table 5). 
Randomization/Stratification:  At the baseline visit (visit 1), patients will be randomized in a 1:1:1:1:1 ratio into 
1 of the 5 study groups.  Randomization will be stratified by age (2 groups:  ≤ 50 and > 50) and iris color 
(2 groups:  brown and not-brown) at the baseline visit.  Approximately two-thirds of the enrolled patients will 
be ≤ 50 years old. 
Visit Schedule: 
• 
Screening visit  
• 
Dosing period:  each of the 5 parallel groups will have 28 (± 3) days of dosing as shown in Figure 1  
• 
Follow-up period:  following the dosing period, all patients will be seen for a 14 (± 2)-day follow-up 
period as shown in Figure 1 


 
 
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Study Population Characteristics: 
Number of Patients:  Approximately 150 patients (30 per group) will be enrolled at approximately 15 sites in 
the United States (US).  Approximately 26 patients per group are expected to complete the study based on an 
anticipated dropout rate of less than 12.5% (4 dropped patients per group). 
Condition/Disease:  The study population consists of adult patients who have objective and subjective evidence 
of presbyopia.  
Key Inclusion Criteria:  
• 
Male or female, between 40 and 55 years of age  
 
 
  
• 
Natural or corneal laser refractive surgery corrected 
 at distance with presbyopia in each 
eye and subjective complaints of poor near vision that impact activities of daily living,
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Key Exclusion Criteria:   
• 
Concurrent use of any topical ophthalmic medications, including artificial tears, other than the study 
medications during the course of the study 
• 
Presence of any ocular condition that, in the opinion of the investigator, could affect the safety of the 
patient or interpretation of efficacy parameters (eg, uveitis) 
• 
Dry eye disease (defined as total corneal staining ≥ grade 2 on the 5-point Oxford scale, or Schirmer’s 
score [with anesthesia] < 8 mm in 5 minutes) at the screening visit 


 
 
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• 
Corneal abnormalities 
 
in either eye that are likely to interfere with visual acuity  
• 
History of cataract surgery, phakic intraocular lens 
 surgery, corneal inlay surgery, 
 
 or any intraocular surgery;
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
  
 
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 will be defined as all randomized patients with a baseline and at 
least 1 postbaseline assessment of mesopic, high contrast UNVA and will be analyzed as randomized.  The 
efficacy variables will be analyzed using the mITT population.   
The safety population will be defined as all patients who received at least 1 dose of study treatment.  Safety 
analyses will be performed on an as-treated basis.  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 analysis of covariance (ANCOVA) or 
2-sample t-tests.  Categorical variables will be summarized by sample size (N) frequency count, and percent and 
will be analyzed using Pearson’s chi-square, Fisher’s exact, or the Cochran-Mantel-Haenszel (CMH) test. 
There will be no imputation of missing data for all analyses. 
Efficacy: 
The primary efficacy variable will be the weighted average change from baseline in mesopic, high contrast 
UNVA lines at day 28 in the nondominant eye.  Baseline will be the hour 0 measure at day 1. 
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 will be 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.  Detailed descriptions of the safety analyses for adverse events and other safety measures will be 
documented in the analysis plan (AP). 
Sample Size Calculation:   
A sample size of approximately 150 patients will be randomized in a 1:1:1:1:1 ratio into 1 of the 5 study groups.  
Approximately two-thirds of the enrolled patients will be younger patients (≤ 50 years old), and one-third of the 
enrolled patients will be older patients (> 50 years old).  
From the Study 199201-007 results, the treatment effect for the younger patients was on average 1.98 lines of 
change in mesopic, high contrast UNVA, with standard deviations for active and vehicle of 1.12 and 1.01, 


 
 
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respectively.  For older patients, the treatment effect was on average 0.72 lines of change in mesopic, high 
contrast UNVA with standard deviations for active and vehicle of 1.87 and 1.15 respectively.  The treatment 
effect for the younger patients was on average 1.02 lines of change in photopic, high contrast UNVA, with 
standard deviations for active and vehicle of 1.42 and 0.67, respectively.  For older patients, the treatment effect 
was on average 0.27 lines of change in photopic, high contrast UNVA, with standard deviations for active and 
vehicle of 1.10 and 0.93, respectively. 
Accounting for a 12.5% dropout rate, 26 patients per treatment group will provide 99% power to observe a 
difference between an active group and the vehicle group for ≥ 1 line of change from baseline in mesopic, high 
contrast UNVA and 68% power for ≥ 1 line of change from baseline in photopic, high contrast UNVA, with a 
type 1 error of 0.05. 
 






















 
 
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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 (Ostrin and Glasser, 2004; 
Radhakrishnan and Charman, 2007).  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 D at age 25 (100 mm), 
and plateaus at 0.5 to 1 D 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, and problems focusing on 
small objects and/or fine print and are usually first noticed between the ages of 40 and 50 
(Ostrin and Glasser, 2004; Radhakrishnan and Charman, 2007).  
Traditional nonsurgical methods of refractive correction for presbyopia include the use of 
dedicated reading spectacles, bifocal or varifocal spectacles, or monovision 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 nondistorted vision.  For these reasons, older people are more than 
twice as likely to fall when wearing multifocal spectacles (Johnson et al, 2007; 
Lord et al, 2002).  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® inlay for the improvement of near vision in presbyopic eyes.  
PresbyLASIK and scleral expansion bands (SEBs) have also been evaluated in presbyopia.  
PresbyLASIK uses laser eye surgery and reshapes the cornea to create a multifocal cornea 
with 3 zones for near, intermediate, and far distances.  Each zone refracts light differently 
with the intent that the patients will learn to choose the correct zone for a given object’s 
distance.  SEBs use 4 thin segments positioned just beneath the surface of the sclera.  This 
creates more space between the circular ciliary muscle around the lens and the lens itself, 
potentially allowing more tension in the ciliary muscle, leading to greater contraction and 
greater steepening of the lens curvature for near vision.  SEBs have not been found to 
provide predictable or consistent results in the treatment of presbyopia 


 
 
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(Malecaze et al, 2001).  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).  For each of the 
existing technologies, visual quality is reduced at 1 or more viewing distances, and each 
strategy comes with its own unique challenges.  For example, zonal bifocals (eg, zonal 
reading glasses, contacts) produce optical aberrations, and multifocal optics 
(eg, PresbyLASIK) reduce image quality uniformly at all viewing distances.  Thus, there 
remains a need for a noninvasive, reversible, pharmacological treatment for presbyopia.   
Allergan is investigating the development of a noninvasive, reversible, pharmacological 
treatment for presbyopia based upon a fixed combination of pilocarpine hydrochloride (HCl) 
(AGN-190584) and oxymetazoline HCl (AGN-199201). 
Pilocarpine ophthalmic solutions (1.0% to 4.0%, 1 drop administered to both eyes [OU] 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, the prevention of postoperative elevated IOP associated with laser surgery, 
and for the induction of miosis (New Drug Application [NDA] 200-890, 
pilocarpine hydrochloride ophthalmic solution).   
Pilocarpine is a muscarinic receptor agonist that mimics the actions of the parasympathetic 
neurotransmitter, acetylcholine, on smooth muscle.  This causes 2 effects that enhance near 
vision:  1) constriction of the iris sphincter muscle, resulting in pupil 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 rapidity of the ciliary muscle contraction.  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). 


 
 
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Oxymetazoline 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 relief of eye redness due to irritation and conjunctivitis, as 
well as an OTC nasal spray under the brand name Afrin® at a concentration of 0.05% for 
topical (intranasal) administration for the treatment of allergic rhinitis. 
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 nonselective 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 (CNS) 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 (Fanciullacci et al, 1995; Prow et al, 1996; Yu et al, 2004).  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 directly 
affect lens accommodation. 
Alpha1 agonists are frequently coadministered with local anesthetics 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 that could improve its tolerability and enhance its 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, suggesting that oxymetazoline at concentrations of 0.025% or 


 
 
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lower has no direct mechanism of action for the treatment of presbyopia.  
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 2 
double-blind, randomized clinical trials.  They attributed the lack of intraocular findings to 
the poor ocular penetration of oxymetazoline following topical ocular administration.   
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.   
1.2 
Preclinical Summary 
Besides the abundance of scientific literature available on similar products containing the 2 
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 (BID) (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 BID.  
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 
this phase 2b study 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, once daily (QD) or BID for 14 
consecutive days (Study TX14097).  Right eyes were dosed QD and left eyes were dosed 
BID.  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 BID.  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. 
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. Juan Carlos 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 


 
 
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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 uncorrected near visual acuity (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%) and 
pilocarpine (1.0%) in a multicenter, double-masked, randomized, vehicle-controlled study in 
patients with presbyopia.  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 QD for 
3 days, and after a 5 ± 2-day washout period, BID for 3 days.  All dosing was performed by 
trained personnel in the clinic.  
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 
(oxymetazoline [0.125%]/pilocarpine [1.0%] dosed in OU).  In each group, patients were 
evenly distributed among the 4 strata of iris color and age.  Sixty-three of the 65 patients 
(96.9%) completed the study.  One patient in Group 2 and 1 patient in Group 4 discontinued 
from 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 timepoints postdose in the 
nondominant eye following both QD and 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 
timepoints postdose in the nondominant eye following QD dosing and was numerically 
superior following BID dosing.  Across all timepoints and visits, the mean change from 


 
 
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baseline in lines of UNVA numerically favored the combination groups over pilocarpine 
monotherapy at later timepoints 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% versus 11.8%) and BID (12.5% versus 
0%) dosing regimens, and in younger patients (ie, the 40- to 47-year age cohort per the 
prespecified 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-year age cohort 
per the prespecified cutoff), the difference was less pronounced between combination therapy 
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, providing a benefit over pilocarpine monotherapy for the treatment of 
presbyopia. 
Oxymetazoline monotherapy, pilocarpine monotherapy, and concurrent dosing of pilocarpine 
and oxymetazoline in 1 or OU 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” that 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 clinical development program is to develop a fixed-dose 
combination of oxymetazoline and pilocarpine for the treatment of presbyopia.  To date, 
preclinical studies in rabbits and nonhuman primates, 4 pilot clinical studies conducted by 
AltaVista Instituto del Investigation Medica at the clinic of Dr. Abad, and Study 199201-007 


 
 
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conducted by Allergan support the combination of pilocarpine and oxymetazoline for the 
treatment for presbyopia.   
1.4 
Rationale for Study Design 
The current phase 2 clinical study is designed to evaluate the safety, efficacy, and tolerability 
of fixed combinations of AGN-199201 and AGN-190584 over a 42-day observation period 
when administered QD, bilaterally, for 28 days in patients with presbyopia.   
Additionally, this study will evaluate the safety, efficacy, and tolerability of a fixed 
combination of AGN-199201 
 and AGN-190584
 when administered 
monocularly to the nondominant eye versus bilaterally for 28 days in patients with 
presbyopia.  The most widely used non-spectacle methods of presbyopia correction use is 
monovision.  In this technique, the eyes are dissociated by focusing 1 eye for distance vision 
and 1 eye for near vision.  Unfortunately, a significant proportion of patients cannot tolerate 
monovision (ie, ~ 40% for contact lenses and ~ 10% for laser treatments).  A pharmaceutical 
treatment for presbyopia that both increases depth of field by inducing miosis and enhances 
accommodation may allow patients to dose in 1 or OU without the significant optical 
limitations faced by current non-spectacle methods of presbyopia correction.    
There is widespread belief that prolonged use of decongestant sprays like oxymetazoline can 
result in a condition of decreased effectiveness called tolerance.  It is thought that with time 
they lose their effectiveness and more and more medication is needed to achieve the same 
level of decongestion.  It has also been proposed that once stopped, the patient experiences 
rebound congestion (Vaidyanathan et al, 2010).  Extending these finding from nasal 
application to ophthalmic application, the packaging for Visine LR reads, “overuse may 
cause more eye redness [rebound congestion].”  It is unknown if the findings of tolerance and 
rebound with extended use of oxymetazoline for eye redness or nasal congestion will impact 
the efficacy of a fixed combination of AGN-199201 (oxymetazoline HCl ophthalmic 
solution) and AGN-190584 (pilocarpine HCl ophthalmic solution) for the treatment of 
presbyopia.   
Allergan Study 199201-007 supports the unfixed combination of AGN-199201 
and 
AGN-190584 (
as a safe and effective short-term treatment for presbyopia.  The current 
study will evaluate fixed combinations of AGN-199201 and AGN-190584 that include the 
concentration of AGN-199201 and AGN-190584 that were unfixed  and used in Allergan 
Study 199201-007.   


 
 
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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 observed plasma maximum concentration (Cmax) of 
0.245 ng/mL and area under the plasma concentration-time 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 
sign measurements, electrocardiograms (ECGs), or IOP during the study.  This study will 
determine the systemic pharmacokinetics of AGN-199201 
 and 
AGN-190584 
 following single and multiple (QD for 28 days) 
ophthalmic administrations as a fixed combination in 1 or OU, by analysis of plasma drug 
concentration-time profiles (Cmax, time to maximum plasma concentration [Tmax], and AUC).  
2. 
Study Objectives and Clinical Hypotheses 
2.1 
Study Objectives 
The objectives of this study will be: 
• To evaluate the safety, efficacy, and tolerability of fixed combinations of 
AGN-199201 and AGN-190584 over a 42-day observation period when administered 
bilaterally QD for 28 days in patients with presbyopia 
• To compare the safety, efficacy, and tolerability of a fixed combination of 
AGN-199201 
) and AGN-190584 
 when administered monocularly to 
the nondominant eye versus bilaterally over a 42-day observation period with QD 
dosing for the first 28 days in patients with presbyopia 
• To assess the systemic pharmacokinetics of AGN-199201 
 
) and AGN-190584 
 following single and multiple 
(QD for 28 days) ophthalmic administrations as a fixed combination in 1 or OU, by 
analysis of plasma drug concentration-time profiles (Cmax, Tmax, AUC from time 0 to 
the last timepoint [AUC0-last], and AUC from time 0 to infinity [AUC0-inf]). 
• To evaluate the psychometric properties of the de novo patient-reported outcome 
(PRO) instruments developed for this program, including the near vision presbyopia 
performance tasks and task-based questionnaire under mesopic and photopic 
conditions, the presbyopia patient satisfaction questionnaire, and the presbyopia 
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2.2 
Clinical Hypotheses 
At least 1 fixed combination of AGN-199201 and AGN-190584 ophthalmic solution dosed 
bilaterally QD for 28 days:  
1. will demonstrate a significant improvement in UNVA over vehicle.  
2. will demonstrate acceptable safety and tolerability findings.  
3. will demonstrate an acceptable pharmacokinetic profile for AGN-199201 and 
AGN-190584 after single and repeat administrations. 
The fixed combination of AGN-199201 
 and AGN-190584 
 can be 
administered either in the nondominant eye only or bilaterally for 28 days in patients with 
presbyopia without any significant difference in the observed safety, efficacy, tolerability or 
pharmacokinetic profiles. 
3. 
Study Design 
This multicenter, double-masked, randomized, parallel-group, vehicle-controlled study will 
be a controlled comparison of fixed combinations of AGN-199201 and AGN-190584 at 
different concentrations to vehicle dosed in OU, and the fixed combination of AGN-199201 
) and AGN-190584 (
 dosed in OU or in the nondominant eye only.  Study 
medication will be administered QD in the morning.  During office visits 1 through 5, study 
medication will be administered at hour 0 (8 AM ± 1 hour).  Following the treatment period, 
all patients will be seen for a 14 ± 2-day follow-up period as shown in Figure 1.  The study 
duration will be 38 to 65 days per patient. 
4. 
Study Population and Entry Criteria 
4.1 
Number of Patients 
Approximately 150 patients (30 per group) will be enrolled at approximately 15 sites in the 
US.  Approximately 26 patients per group are expected to complete the study based on an 
anticipated dropout rate of less than 12.5%.  Approximately two-thirds of the enrolled 
patients will be ≤ 50 years old.  


 
 
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4.2 
Study Population Characteristics 
The study population will consist of adult patients who have objective and subjective 
evidence of presbyopia.  
4.3 
Inclusion Criteria 
The following will be requirements for entry into the study:  
1. Male or female, between 40 and 55 years of age  
 
 
3. Natural or corneal laser refractive surgery corrected 
 at distance 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 will be 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 that are likely to interfere with visual acuity  
5. History of cataract surgery, phakic intraocular lens (PIOL surgery), corneal inlay 
surgery, 
 
 
 
 
 
 


 
 
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10. Diagnosis of any type of glaucoma or ocular hypertension 
 
 
 
 
 
 
 
 
 
  
 
 
 
  
 
 
 
 
 
 
 
  


 
 
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4.5 
Permissible and Prohibited Medications/Treatments 
4.5.1 
Permissible Medications/Treatments 
The concurrent use of nonocular medications that do not have a substantial effect on the 
pupil, accommodative properties, or retinal function of the eye will be permitted during the 
study if a stable dosing regimen is established.  The dosing regimen is not considered to be 
stable if a 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 (ie, 
hysterectomy). 
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. 
4.6 
Prohibited Medications/Treatments 
Use of ocular medications other than study medication or medications administered to 
conduct study procedures (see Section 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 2 weeks prior to the baseline visit and during the study: 


 
 
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• 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 will be made with the safety of 
the study participant as the primary consideration.  When possible, Allergan should be 
notified before the prohibited medication/treatment is administered. 
5. 
Study Treatments 
5.1 
Study Treatments and Formulations 
Fixed combination AGN-199201
 weight/volume (w/v) and AGN-190584 
 
 
 
 
Fixed combination AGN-199201
 w/v and AGN-190584 
 
 
 
 
Fixed combination AGN-199201 
 w/v and AGN-190584
 
 
 
 
5.2 
Control Treatment 
The vehicle of AGN-199201 and AGN-190584 
 
 
 


 
 
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5.3 
Methods for Masking 
Study medication will be administered to each randomized patient bilaterally by qualified site 
personnel during the study visits 1 to 5.  The patient will be instructed to continue using the 
dispensed study medication on the assigned eyes between visits.  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 1:1:1:1:1 ratio into 1 of 5 treatment groups: 
Group 1: 
Vehicle control, OU 
Group 2: 
Fixed combination AGN 199201 
 and AGN 190584 
, OU 
Group 3: 
Fixed combination AGN 199201 
 and AGN 190584 
, OU 
Group 4: 
Fixed combination AGN 199201 
) and AGN 190584 (
, OU 
Group 5: 
Fixed combination AGN 199201 (
) and AGN 190584 
, 
monocular dosing to the nondominant eye and vehicle to the dominant eye  
Randomization will be stratified by age (2 groups:  ≤ 50 and > 50) and iris color (2 groups:  
brown and not brown) at the baseline visit.  There will be a total of 4 strata; brown eyes and 
age ≤ 50 years, brown eyes and age > 50 years, not brown eyes and age ≤ 50 years, and not 
brown eyes and age > 50 years.  For the determination of stratification group assignment for 
each patient, sites will be required to enter iris color (ie, brown, blue, green, gray, or hazel) 
and age 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 4 strata as 
described in Section 5.4, and they will be assigned to 1 of the 5 treatment groups 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 a 


 
 
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medication kit number 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 the medication kit number, study number, and 
dominant or nondominant eye.  Each medication kit (carton) will contain 2 multidose bottles 
of study treatment .  The IxRS will provide the site with the specific medication kit 
number(s) for each randomized patient at the time of randomization.  Sites will assign study 
medication kits according to the IxRS instructions.  Sites will receive the IxRS confirmation 
notifications for each transaction.  All notifications will be maintained with the study source 
documents. 
5.6 
Treatment Regimen and Dosing 
Doses of study medication and/or vehicle will be instilled in the appropriate eyes by 
designated site personnel at hour 0 (8 AM ± 1 hour) of visits 1, 2, 3, 4, and 5.  In between 
office visits, patients will be instructed to continue using the dispensed study medication on 
the assigned eyes in the morning QD. 
Patients receiving the fixed combination of AGN-199201 and AGN-190584 bilaterally will 
instill a single drop of the fixed combination drug into each eye.  Patients receiving the fixed 
combination of AGN-199201 and AGN-190584 in the nondominant eye only will instill a 
single drop of the fixed combination drug into the nondominant eye and a single drop of the 
vehicle into the dominant eye.  Patients receiving vehicle bilaterally will instill a single drop 
of the vehicle into each eye (see Table 1 and Figure 1). 
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. 
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 
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Patients will be instructed on the proper storage of study medication and to keep it out of the 
reach of children at all times. 
5.8 
Treatment Administration 
Doses of study medication and/or vehicle will be instilled in the appropriate eyes by 
designated site personnel at hour 0 (8 AM ± 1 hour) of visits 1, 2, 3, 4, and 5.  In between 
office visits, patients will be instructed to apply the dispensed study medication in the 
morning QD into OU.  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 will be mesopic, high contrast UNVA. 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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epth of focus of the measured eye.  More details will be out 
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6.6 
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 will be 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 will be defined as all randomized patients 
with a baseline and at least 1 postbaseline assessment of mesopic, high contrast UNVA and 
will be analyzed as randomized.  The efficacy variables will be analyzed using the mITT 
population.   
The safety population will be defined as all patients who received at least 1 dose of study 
treatment.  Safety analyses will be performed on an as-treated basis.  All safety measures will 
be analyzed using the safety population. 


 
 
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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 analysis of covariance (ANCOVA) or 2-sample t-tests.  Categorical variables will be 
summarized by sample size (N), frequency count and percent, and will be analyzed using 
Pearson’s chi-square, Fisher’s exact, or the Cochran-Mantel-Haenszel (CMH) test. 
There will be no imputation of missing data for all analyses. 
7.2 
Collection and Derivation of Primary and Other Efficacy 
Assessments 
7.2.1 
Primary Efficacy Variable 
The primary efficacy variable will be the weighted average change from baseline in mesopic, 
high contrast UNVA lines at day 28 in the nondominant eye.  Baseline will be the hour 0 
measure at day 1.   
 
 
 
 
 
  
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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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 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 the CMH 
test. 
There will be no adjustment of type 1 error rate for the multiple tests.  There will be no 
imputation of missing data for all analyses.  
7.3.1 
Primary Efficacy Analyses 
For the primary efficacy analysis, the weighted average change from baseline will be 
analyzed by ANCOVA with treatment group, age group, and iris color as fixed effects.  A 
detailed algorithm for the derivation of the primary efficacy variables will be documented in 
the AP. 
 
 
 
   


 
 
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7.4 
Subgroup Analyses 
Subgroup analyses will be performed for the primary efficacy variable by UNVA at baseline 
(20/40 to 20/80 and 20/100 to 20/200), age group, and iris color (brown or not brown).  
7.5 
Sample Size Calculation 
A sample size of approximately 150 patients will be randomized in a 1:1:1:1:1 ratio into 1 of 
the 5 study groups.  Approximately two-thirds of the enrolled patients will be younger 
patients (≤ 50 years old), and approximately one-third of the enrolled patients will be older 
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From the Study 199201-007 results, the treatment effect for the younger patients was on 
average 1.98 lines of change in mesopic, high contrast UNVA, with standard deviations for 
active and vehicle of 1.12 and 1.01, respectively.  For older patients, the treatment effect was 
on average 0.72 lines of change in mesopic, high contrast UNVA, with standard deviations 
for active and vehicle of 1.87 and 1.15, respectively.  The treatment effect for the younger 
patients was on average 1.02 lines of change in photopic, high contrast UNVA, with standard 
deviations for active and vehicle of 1.42 and 0.67, respectively.  For older patients, the 
treatment effect was on average 0.27 lines of change in photopic, high contrast UNVA, with 
standard deviations for active and vehicle of 1.10 and 0.93, respectively. 
Accounting for a 12.5% dropout rate, 26 patients per treatment group will provide 99% 
power to observe a difference between an active group and the vehicle group for ≥ 1 line of 
change from baseline in mesopic, high contrast UNVA and 68% power for ≥ 1 line of change 
from baseline in photopic, high contrast UNVA, with a type 1 error of 0.05. 
7.6 
Interim Analyses 
There will be no interim analyses. 
8. 
Study Visit Schedule and Procedures 
Please see Table 2, Table 3, Table 4, and Table 5 for a schematic of the schedule of visits and 
procedures and Figure 1 for a flowchart of the study visits. 
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 US only), data protection consent (Europe only), 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. 


 
 
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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/Run-In 
This study will not include a washout period.   
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. 
 
 
 
   
The following section provides a list of procedures for each scheduled visit.  All ophthalmic 
procedures should be performed for each eye, unless otherwise noted.  It is recommended, 
but not required, that the procedures occur in the order presented.  Additional information on 
the examination procedures, equipment, and techniques for the measures listed in this section 
are presented in Section 6.4 and the Procedure Manual. 


 
 
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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 glasses are worn for vision correction, patients should remember to bring the 
glasses 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. 
• 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 4.6). 


 
 
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• Patients will be reminded that study medication must be stored out of the reach of 
children at all times. 
• Patients will be provided a dosing card for additional instructions on study drug 
administration. 
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 been 
compliant with study medication use, have used any concomitant medications, or have had 
any medical procedures performed since the previous visit. 
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 Allergan and will be clearly documented on the appropriate eCRF. 
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. 
If the patient withdraws prior to completing the study, the procedures outlined for the 
visit 8/study exit should be performed at the last visit attended (see Section 8.4.9). 
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 4.5.1.1). 


 
 
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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 eCRF.  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 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, 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 eCRF. 


 
 
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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 
 
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. 


 
 
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9.2 
Procedures for Reporting Adverse Events 
Any adverse event must be recorded on the appropriate eCRF. 
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 
Allergan 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 
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. 


 
 
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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 
calling 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. 
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. 


 
 
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10.1 
Protection of Human Patients 
10.1.1 
Compliance With Informed Consent Regulations (US 21 Code 
of Federal Regulations [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.   
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 21 CFR 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 
to study patients, or when the changes involve only logistical or administrative aspects of the 
study (eg, change in monitors, change of telephone numbers). 


 
 
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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 ECGs.  The investigator's copy of the eCRFs 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 
• 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. 


 
 
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• 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 
• 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, the results of urine pregnancy 
tests) 
• 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.   
The investigator is responsible for ensuring that data are properly recorded on each patient's 
eCRFs and related documents.  An investigator who has signed the protocol signature page 
should personally sign for eCRFs (as indicated in the case report forms) to ensure that the 
observations and findings are recorded on the eCRFs correctly and completely.  The eCRFs 
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. 


 
 
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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 eCRFs should be maintained on file. 
For countries falling within the scope of the ICH guidelines, the Allergan-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 Allergan. 
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. 
10.5 
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 multidose bottles of 
study treatment; 1 bottle will be labeled Dominant (
 and 1 bottle 
will be labeled Non-Dominant (
  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 


 
 
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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 multidose 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’s designee for destruction. 
10.6 
Monitoring by the Sponsor 
A representative of Allergan 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 
onsite 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 a 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. 
10.8 
Coordinating Investigator 
A signatory Coordinating Investigator will be designated prior to the writing of the Clinical 
Study Report. 


 
 
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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. 
Burchum JR, Rosenthal LD.  Lehne’s pharmacology for nursing care.  9th ed.  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. 
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.  


 
 
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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. 
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. 
Malecaze FJ, Gazagne CS, Tarroux MC, Gorrand JM.  Scleral expansion bands for 
presbyopia.  Ophthalmology.  2001;108:2165-2171. 
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.  
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. 


 
 
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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. 
Vaidyanathan S, Williamson P, Clearie K, Khan F, Lipworth B.  Fluticasone reverses 
oxymetazoline-induced tachyphylaxis of response and rebound congestion.  Am J Respir Crit 
Care Med.  2010;182:19–24. 
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. 
Attachments 
 


 
 
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12.2 
Package Insert 
The appropriate package insert will be supplied to investigators in countries where the 
product is marketed. 


 
 
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12.3 
Glossary of Abbreviations 
Term/Abbreviation 
Definition 
5-HT 
serotonin 
ANCOVA 
analysis of covariance 
AP 
analysis plan 
AUC 
area under the plasma concentration-time curve 
AUC0-12 
area under the plasma concentration-time curve from time 0 to 12 
hours 
AUC0-inf 
area under the plasma concentration-time curve from time 0 to 
infinity 
AUC0-tlast 
area under the plasma concentration curve from time 0 to the last 
timepoint 
BID 
twice daily 
bpm 
beats per minute 
Cmax 
plasma maximum concentration 
C/D 
cup to disc 
cd/m2 
candelas per square meter 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel 
CNS 
central nervous system 
D 
diopters 
DET 
dry eye test 
EC50 
maximal effective concentration 
ECGs 
electrocardiograms 
eCRF 
electronic case report form 
EDC 
electronic data capture 
EU 
European Union 
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 


 
 
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IOP 
intraocular pressure 
IRB 
Institutional Review Board 
IxRS 
interactive response system 
LASIK 
laser-assisted in situ keratomileusis 
LC-MS/MS 
liquid chromatography tandem mass spectrometry 
MAOIs 
monoamine oxidase inhibitors 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
NDA 
New Drug Application 
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 
OCT 
Optical Coherence Tomography 
OD 
right eye 
OS 
left eye 
OTC 
over-the-counter 
OU 
both eyes 
PDE5 
phosphodiesterase 5 
PGIC 
Patient Global Impression of Change 
PIOL 
phakic intraocular lens 
PRK 
photorefractive keratectomy 
PRO 
patient-reported outcome 
QD 
once daily 
RK 
radial keratotomy 
SEB 
scleral expansion band 
T1/2 
half-life 
UDVA 
uncorrected distance visual acuity 
UNVA 
uncorrected near visual acuity 
US 
United States 
VAS 
visual analog scale 
w/v 
weight/volume 


 
 
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12.4 
Protocol Amendment 1 Summary 
Title:  A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Parallel 
Group Study Evaluating the Safety, Efficacy, and Pharmacokinetics of the Fixed 
Combination of AGN 199201 and AGN 190584 in Patients With Presbyopia 
Protocol 199201-010 Amendment 1 
Date of Amendment:  February 2016 
Amendment Summary 
This summary includes changes made to Protocol 199201-010 (October 2015).  Grand Seiko 
autorefraction is no longer a mandated method for pupil diameter measurement, since not all 
sites have this autorefractor.  Only selected sites will use this measurement. 
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, an e-mail address was 
added for serious adverse event 
reporting, and the Allergan Medical 
Safety Physician contact information 
was changed 
To reflect the current Therapeutic Area Head 
and Safety Physician and to facilitate serious 
adverse event reporting 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Section4.5.1.1 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 5.7 
Text referring to a temperature 
monitoring device was deleted 
To apply to sites that may not have a 
temperature monitoring device 
 
 
 
 
 
 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
  
 
Section 8.5 
Deleted instruction for patients to 
remain at the study site for the 
duration of the visit 
To minimize patient inconvenience 
Section 9.5 
This section was added to describe 
the procedures for pregnancy 
follow-up and reporting  
To be consistent with the Informed Consent 
Form 


 
 
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12.5 
Protocol Amendment 2 Summary 
Title:  A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Parallel 
Group Study Evaluating the Safety, Efficacy, and Pharmacokinetics of the Fixed 
Combination of AGN-199201 and AGN-190584 in Patients With Presbyopia 
Protocol 199201-010 Amendment 2 
Date of Amendment:  March 2016 
Amendment Summary 
This summary includes changes made to Protocol 199201-010 Amendment 1 
(February 2016).  The order of the Grand Seiko automated refraction was corrected in 
Table 2, the description of the primary efficacy variable was clarified, and selected sites are 
now to use only the Zeiss Visante OCT model. 
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 
Summary, Key 
Inclusion 
Criteria 
• 
Natural or corneal laser 
refractive surgery corrected 
 
presbyopia in each eye and 
subjective complaints of poor 
near vision that impact activities 
of daily living, 
 
 
 
 
 
 
 
 
 
 
For clarification 
Protocol 
Summary, 
Efficacy, and 
Section 7.2.1 
The primary efficacy variable will 
be the weighted average change 
from baseline in mesopic, high 
contrast UNVA lines at day 28 in 
the nondominant eye.   
For clarification 


 
 
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Section 
Revision 
Rationale 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
Photopic pupil diameter (both eyes, 
distance and near) 
Correction 
Section 4.3 
3. Natural or corneal laser 
refractive surgery corrected 
 
presbyopia in each eye and 
subjective complaints of poor 
near vision that impact activities 
of daily living, 
 
 
 
 
 
 
For clarification 


 
 
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Section 
Revision 
Rationale 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 


 
 
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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 during the near-vision 
tasks and associated near-vision 
task questionnaires, but may use 
their glasses to fill out other 
study-related questionnaires. 
For clarification 


 
 
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12.6 
Protocol Amendment 3 Summary 
Title:  A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, 
Parallel-Group Study Evaluating the Safety, Efficacy, and Pharmacokinetics of the Fixed 
Combination of AGN-199201 and AGN-190584 in Patients With Presbyopia 
Protocol 199201-010 Amendment 3 
Date of Amendment:  June 2016 
Amendment Summary 
This summary includes changes made to Protocol 199201-010 Amendment 2 (March 2016).  
Mesopic and photopic DCNVA in the nondominant eye was added at baseline and day 28, 
and a statement was added that the investigator should note if the pupil dialated normally 
after the funduscopic examination at screening and visit 6. 
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 
 
 
 
 
 
 
 
d 
Section 7.3.1 
A detailed algorithm for the 
derivation of the primary efficacy 
variables will be documented in the 
AP. 
For clarification 
 
 
 
 
  
 
Section 7.4 
Subgroup analyses will be 
performed for the primary efficacy 
variable by UNVA at baseline 
(20/40 to 20/80 and 20/100 to 
20/200), age group, and iris color 
(brown or not brown), gender, race, 
and ethnicity. 
Gender, race, and ethnicity subgroup 
analyses will not be performed 
Sections 8.4.2 
 
 
 
 
 
 
 


 
 
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Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
 
            
 
           
 
            
 
           
 
            
 
           
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
Protocol 199201-010 Amd 3

SAP_000.pdf: 
NCT02780115 
 
Study ID: 199201‐010 
 
 
Title: A Phase 2, Multicenter, Double‐Masked, Randomized, Vehicle‐Controlled, Parallel‐Group Study 
Evaluating the Safety, Efficacy, and Pharmacokinetics of the Fixed Combination of AGN‐199201 and 
AGN‐190584 in Patients With Presbyopia 
 
Statistical Analysis Plan Amendment 2 Date: 15Dec2017 
 
 
 


Allergan Confidential 
SAP  199201-010 
AGN-199201 and AGN-190584 
1. 
Title Page 
STATISTICAL ANALYSIS PLAN 
A Phase 2, Multicenter, Double-Masked, Randomized, Vehicle-Controlled, Parallel-Group Study 
Evaluating the Safety, Efficacy, and Pharmacokinetics of the Fixed Combination of AGN-199201 
and AGN-190584 in Patients With Presbyopia 
Amendment 2.0: 2017-12-15 
 
Study Number: 
199201-010 
Development Phase: 
2 
Product Name: 
AGN-199201 (oxymetazoline hydrochloride 
ophthalmic solution) and AGN-190584 (pilocarpine 
hydrochloride ophthalmic solution) 
Study Statistician: 
 
Sponsor: 
Allergan PLC 
2525 Dupont Drive, Irvine, California USA 92612 
+1-714-246-4500 
 
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.


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 
2. 
Table of Contents 
1. 
Title Page ................................................................................................................................. 1 
2. 
Table of Contents ..................................................................................................................... 2 
2.1 
List of Tables .................................................................................................................. 3 
2.2 
List of Figures ................................................................................................................ 5 
3. 
List of Abbreviations and Definition of Terms ........................................................................ 6 
4. 
Introduction .............................................................................................................................. 8 
4.1 
Study Design Summary ................................................................................................. 8 
4.2 
Study Objectives ............................................................................................................ 9 
4.3 
Schedule of Activities .................................................................................................. 10 
5. 
Statistical Methodology and Study Endpoints ....................................................................... 20 
5.1 
Statistical Methods Planned in the Protocol and Determination of Sample Size ........ 20 
5.1.1  Statistical and Analytical Plans ........................................................................ 20 
5.1.1.1  Common Conventions ....................................................................... 20 
5.1.1.2  Demographics .................................................................................... 22 
5.1.1.3  Efficacy Analyses .............................................................................. 25 
5.1.1.4  Safety Analyses ................................................................................. 30 
 
 
 
 
5.1.1.7  Interim Analyses ................................................................................ 38 
5.1.2  Determination of Sample Size ......................................................................... 38 
5.2 
Changes in the Conduct of the Study or Planned Analyses ......................................... 39 
5.2.1  Changes in the Conduct of the Study ............................................................... 39 
5.2.2  Changes to Analyses Prior to Database Lock .................................................. 39 
6. 
Data Handling and Analysis Conventions ............................................................................. 39 
6.1 
Study Treatment Conventions ...................................................................................... 39 
6.1.1  Analysis Days .................................................................................................. 39 
6.1.2  Missing/Incomplete Treatment End Date ........................................................ 40 
6.2 
Analysis Visit Windows ............................................................................................... 40 
6.2.1  Safety ............................................................................................................... 40 
6.3 
Site Pooling .................................................................................................................. 41 
6.4 
Missing/Incomplete Date Conventions ........................................................................ 41 
6.4.1  Missing/Incomplete AE Start Date .................................................................. 41 
6.4.2  Missing/Incomplete Medication Start Date ..................................................... 41 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 
6.4.3  Missing/Incomplete AE/Medication End Date ................................................ 42 
6.5 
Efficacy Endpoint Conventions ................................................................................... 42 
6.6 
Safety Endpoint Conventions ....................................................................................... 42 
6.6.1  Adverse Events ................................................................................................ 42 
6.6.1.1  Missing Intensity or Relationship ...................................................... 42 
6.6.1.2  Possible Distant Spread of Toxin (PDSOT) ...................................... 42 
6.6.1.3  AE Group of Interest ......................................................................... 42 
 
 
 
 
 
 
6.6.4  Electrocardiograms .......................................................................................... 43 
6.7 
Imputed Value Listing Conventions ............................................................................. 43 
6.8 
Analysis Plan Amendment 1 Summary ....................................................................... 43 
6.9 
Analysis Plan Amendment 2 Summary ....................................................................... 44 
 
2.1 
List of Tables 
Table 3-1 
Abbreviations and Definitions of Terms ................................................................. 6 
Table 4-1 
Study Treatment Group ........................................................................................... 9 
Table 4-2 
Study Objectives ..................................................................................................... 9 
 
 
 
 
 
 
 
 
Table 5-1 
Analysis Populations ............................................................................................. 20 
Table 5-2 
Statistical Methodology ........................................................................................ 21 
Table 5-3 
Missing Data Handling by Endpoint Type ............................................................ 22 
Table 5-4 
Analysis Population Summaries ........................................................................... 22 
Table 5-5 
Subject Disposition Summaries ............................................................................ 23 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 
Table 5-6 
Protocol Deviation Summary ................................................................................ 23 
Table 5-7 
Demographic Summaries ...................................................................................... 23 
Table 5-8 
Baseline Characteristics Summaries ..................................................................... 23 
Table 5-9 
Medical History Summary .................................................................................... 24 
Table 5-10 
Ophthalmic History and Ophthalmic Surgery History Summary ......................... 24 
Table 5-11 
Medication Summaries ......................................................................................... 25 
 
 
 
 
Table 5-14 
Mesopic, High Contrast UNVA ............................................................................ 26 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 5-24 
AE Terms .............................................................................................................. 31 
Table 5-25 
AE Summaries ...................................................................................................... 31 
 
 
 
 
 
 
 
 
 
 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Table 6-1 
Analysis Day Definitions ...................................................................................... 39 
 
 
 
 
Table 6-4 
Imputation Scenarios ............................................................................................ 41 
Table 6-5 
Initial Imputed Date Algorithm ............................................................................. 41 
Table 6-6 
Missing AE Intensity and Relationship Imputation Algorithms ........................... 42 
 
 
 
2.2 
List of Figures 
 
 
 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 
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 
CMH 
Cochran-Mantel-Haenszel 
DCNVA 
distance corrected near visual acuity 
eCRF 
electronic case report form 
GCP 
Good Clinical Practice 
ICH 
International Conference on Harmonisation 
IOP 
intraocular pressure 
IxRS 
interactive response system 
LOCF 
last observation carried forward 
LS 
least squares 
MedDRA 
Medication Dictionary for Regulatory Activities 
mITT 
modified intent-to-treat 
N 
number of patients 
N/A 
not applicable 
NEI 
national eye institute  
NVPT 
near vision presbyopia task 
OC 
observed cases 
OCT 
optical coherence tomography 
OU 
both eyes 
PCS 
potentially clinically significant 
PICO PRO 
presbyopia impact and coping questionnaire patient-reported outcome 
PO 
primary objective 
PP 
per-protocol 
PPSQ PRO 
presbyopia patient satisfaction questionnaire patient-reported outcome 
PRO 
patient-reported outcome 
PT 
preferred term 
QD 
once daily 
SAE 
serious adverse event 
SADE 
serious adverse device effect 
SAP 
statistical analysis plan 
SD 
standard deviation 
SE 
standard error 
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 


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SAP 199201-010 
AGN-199201 and AGN-190584 
Abbreviation/Term 
Definition 
  
WHO 
World Health Organization 


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SAP 199201-010 
AGN-199201 and AGN-190584 
Table 4-1 
Study Treatment Group 
Treatment Group 
AGN-199201 (%) 
AGN-190584 (%) 
Dosing 
1 
Vehicle control 
Vehicle control 
OU 
2 
 
 
OU 
3 
 
 
OU 
4 
 
 
OU 
5a 
 
 
Nondominant eye 
OU = both eyes 
a  Dominant eye dosed with vehicle 
 
4.2 
Study Objectives  
Each study primary objective (PO), and secondary objective (SO) are presented below: 
Table 4-2 
Study Objectives  
Objectives 
PO To evaluate the safety, efficacy, and tolerability of fixed combinations of AGN-199201 and AGN-190584 
over a 42-day observation period when administered bilaterally, once daily (QD) for 28 days in patients with 
presbyopia 
 
SO1 To compare the safety, efficacy, and tolerability of a fixed combination of AGN-199201 
 and 
AGN-190584 
 when administered monocularly to the nondominant eye versus bilaterally over a 42-day 
observation period with QD dosing for the first 28 days in patients with presbyopia 
 
SO2 To assess the systemic pharmacokinetics of AGN-199201 
 and AGN-190584 
 following single and multiple (QD for 28 days) ophthalmic administrations as a fixed 
combination in 1 or both eyes (OU)  
 
SO3 To evaluate the psychometric properties of the de novo patient-reported outcome (PRO) instruments 
developed for this program, including the near vision presbyopia performance tasks and task-based 
questionnaire under mesopic and photopic conditions, the presbyopia patient satisfaction questionnaire, and the 
presbyopia impact and coping questionnaire  
PO = primary objective, SO1 = first secondary objective, SO2 = second secondary objective, SO3 = third secondary 
objective 


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SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 
 
 


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SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 


Allergan Confidential 
SAP 199201-010 
AGN-199201 and AGN-190584 
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 patients as defined below: See Table 5-1. 
Table 5-1 
Analysis Populations 
Population 
Definition 
Study Treatment 
Screened 
All screened patients who sign informed consent 
— 
Modified Intent-to-
Treat (mITT) 
All randomized patients  with a baseline and at least 1 post 
baseline assessment of mesopic, high contrast, UNVA and will 
be analyzed as randomized 
Randomized assignment 
Safety 
All patients who received ≥ 1 administration of study treatment 
and will be analyzed as treated 
Actual received 
 
The efficacy variables will be analyzed using the mITT population. All safety measures will be 
analyzed using the safety population. 
5.1.1.1.2 
Study Treatments 
The following treatment groups are defined for this study, also presented in Table 4-1, as group 1, 
2, 3, 4 and 5: 
• Group 1:  Vehicle Control, OU 
• Group 2:  Fixed combination AGN-199201 
 and AGN-190584 
), OU 
• Group 3:  Fixed combination AGN-199201 
 and AGN-190584
 OU 
• Group 4:  Fixed combination AGN-199201 
 and AGN-190584 
, OU 
• Group 5:   Fixed combination AGN-199201 
 and AGN-190584 
), 
Non-dominant eye and vehicle to the dominant eye 


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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 5-2 
Statistical Methodology 
Methodology 
Description 
M1 
Categorical 
counts 
• 
Number of patients in individual categories 
o 
Patients with ≥ 1 qualifying event counted once per individual category 
M2 
Categorical 
descriptives 
• 
Number and percentage of patients in individual categories 
o 
Patients with ≥ 1 qualifying event counted once per individual category 
• 
(Optional) N included if percentage denominator ≠ number of patients in the 
population (standard percentage denominator). 
M3 
PCS 
descriptives 
• 
Number and percentage of patients meeting potentially clinically significant 
(PCS) criteria 
o 
Patients with ≥ 1qualifying event counted once per PCS category  
• 
Percentage denominator = number of patients 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 = patients with non-missing value 
M5 
CFB 
descriptives 
• 
Continuous descriptives for baseline, postbaseline, and change from baseline 
(CFB) values 
• 
N included = patients 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 treatment 
group and covariates (baseline UNVA severity, iris color and age group) 
o 
Least squares (LS) means and standard errors 
o 
P-values and confidence intervals from contrast t-test comparing active 
AGN-199201 treatment groups vs AGN-199201 vehicle 
• 
N included = patients with non-missing values at both baseline and the 
postbaseline analysis visit 
M7 
CFB figure 
• 
Plot of CFB LS means and SE bars for each treatment group 
M8 
Responder 
• 
Categorical descriptives for responders and nonresponders 
o 
Nonresponders include: 
 
Patients who do not meet responder criteria 
• 
CMH test comparing active AGN-199201 treatment groups vs AGN-199201 
vehicle 
ANCOVA = analysis of covariance; N = number of patients. CMH = Cochran-Mantel-Haenszel 
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 
There will be no imputation of missing data for all analyses. 


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Table 5-3 
Missing Data Handling by Endpoint Type 
Endpoint type 
Timing 
Missing Data Handling 
Responder 
Treatment Period 
• 
All patients included 
• 
Patients with no postbaseline values will be excluded 
CFB ANCOVA 
 
Treatment Period 
• 
If missing covariates (including baseline if applicable)  
o 
Subject excluded 
• 
If missing 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 
ANCOVA = analysis of covariance; CFB = change from baseline 
 
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 treatment group.  Nonocular adverse events and other nonocular 
assessments will be summarized using patient as the experimental unit by treatment group. 
5.1.1.2 
Demographics 
5.1.1.2.1 
Analysis Populations 
The distribution of patients within the analysis populations will be summarized as follows: 
Table 5-4 
Analysis Population Summaries 
Population 
Description 
Timing 
Methodology 
Screened Population 
Distribution overall and within 
countries/regions/sites in total 
Screening Period 
Categorical counts 
mITT 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 
Participant Disposition 
Subject disposition encompasses the distribution of patients who enter, complete, and 
discontinue each specified analysis period, along with electric case report form (eCRF)-reported 
discontinuation reasons from each respective analysis period. Subject disposition will be 
summarized as follows: 


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SAP 199201-010 
AGN-199201 and AGN-190584 
Table 5-5 
Subject Disposition Summaries 
Parameter 
Description 
Timing 
Methodology 
Screening disposition 
Distribution in the Screened 
Population in total 
Screening Period 
Categorical descriptive 
Study disposition 
Distribution in the mITT Population 
in total and by treatment group 
Treatment Period 
Categorical descriptive 
mITT = modified intent-to-treat 
 
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 5-6 
Protocol Deviation Summary 
Parameter 
Description 
Timing 
Methodology 
Important protocol 
deviations 
Distribution in the mITT Population 
in total and by treatment group 
Treatment Period 
Categorical descriptive 
 
 
5.1.1.2.4 
Demographics 
Demographics will be summarized for the Screened Population, and in total and by treatment 
group for the mITT and Safety populations, as follows: 
Table 5-7 
Demographic Summaries 
Parameter 
Description 
Timing 
Methodology 
Age 
Age (years) relative to informed consent 
date 
Informed consent 
Continuous 
descriptives 
Age group 
• 
≤ 50 years 
• 
> 50 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 and 
Safety populations as follows: 
Table 5-8 
Baseline Characteristics Summaries 
Parameter 
Description 
Timing 
Methodology 
Baseline characteristics 
• 
Iris color 
Latest assessment in 
Categorical 


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Parameter 
Description 
Timing 
Methodology 
 
Screening Period or 
Pretreament Period 
descriptives 
Randomization strata 
• 
UNVA severity at baseline 
(≤ 20/80 and  > 20/80) 
Randomization date 
Categorical 
descriptives 
Baseline efficacy 
• 
Mesopic pupil diameter with 
Grand Seiko sites vs without 
Grand Seiko sites 
• 
UNVA severity at baseline 
with Grand Seiko sites vs 
without Grand Seiko sites 
Randomization date 
Continuous 
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 patients who report medical history events will be summarized by 
MedDRA system organ class (SOC) and preferred term (PT) by treatment group for the Safety 
Population as follows: 
Table 5-9 
Medical History Summary 
Parameter 
Description 
Timing 
Methodology 
Medical and surgical 
history 
Abnormalities and surgeries occurring 
before the Screening Visit 
Screening Period 
Categorical 
descriptive 
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
 
5.1.1.2.7 
Ophthalmic History and Ophthalmic Surgical History 
Ophthalmic history, encompassing abnormalities and ophthalmic surgeries reported as occurring 
before the Screening Visit, will be coded using MedDRA, version 19.0 or newer. Unique patients 
who report ophthalmic history events will be summarized by MedDRA SOC and PT by 
treatment group for the Safety Population as follows: 
Table 5-10 
Ophthalmic History and Ophthalmic Surgery History Summary  
Parameter 
Description 
Timing 
Methodology 
Ophthalmic history and 
ophthalmic surgery 
history 
Abnormalities and surgeries occurring 
before the Screening Visit 
Screening Period 
Categorical 
descriptive 
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
 
5.1.1.2.8 
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 patients who reported medications will be summarized by 


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Anatomical Therapeutic Chemical (ATC) 4 class and PT by treatment group for the Safety 
Population as follows: 
Table 5-11 
Medication Summaries 
Parameter 
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 end date will be listed 
but excluded from analysis 
Treatment Period, 
Follow-up Period 
 
Categorical 
descriptives 
ATC4 classes will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose 
group. 
5.1.1.3 
Efficacy Analyses 
Efficacy analyses will be based on the mITT Population. 
The following efficacy assessments are defined: 


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Baseline assessments for applicable efficacy endpoints defined as follows: 
Table 5-13 
Efficacy Endpoint Baseline Definitions 
Endpoint 
Description 
Timing 
• 
Mesopic, high 
contrast UNVA 
 
 
 
 
 
Non-missing measurements at Day 1 Hour 0 
• 
Patients with no Day 1 Hour 0 measurement will be 
excluded from CFB analyses1 
Day 1 Hour 0 
5.1.1.3.1 
Study Success Criteria 
There will be no adjustment of type 1 error rate for the multiple tests. There will be no 
imputation of missing data for all analyses. 
5.1.1.3.2 
Mesopic, High Contrast UNVA  
Mesopic, high contrast UNVA endpoints will be summarized by treatment group for mITT 
Population.  
Table 5-14 
Mesopic, High Contrast UNVA 
Endpoint 
Description 
Timing 
Methodology 
Average change from 
baseline in UNVA 
letters (Primary efficacy 
variable) 
Average change from baseline in UNVA lines in the 
nondominant eye at day 28.  
Treatment 
Period Day 
28 
CFB 
ANCOVA1 
CFB figure 
 
 
 
 
 
 
 
 
 
 
 
 


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5.1.1.4.2 
Adverse Events 
The following adverse event (AE) terms are defined: 
Table 5-24 
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 ≤ treatment end date + 30 
On-therapy 
An event where: 
• 
Treatment start date ≤ event start date ≤ treatment end date + 30 
 
AEs, encompassing abnormalities and surgeries reported as occurring after the Screening Visit, 
will be coded using MedDRA version 19.0 or newer. Unique patients reporting AEs in the 
following AE categories will be summarized by treatment group and overall for the Safety 
Population as follows: 
Table 5-25 
AE Summaries 
Parameter 
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 Period 
Categorical 
descriptives 
TEAEs 
Overall summary and by SOC and PT 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Ocular TEAEs 
Summary by SOC and PT for ocular 
TEAEs 
 
dominant eye 
 
nondominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Non-ocular TEAEs 
Summary by SOC and PT for non-ocular 
TEAEs 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Common TEAEs 
Summary by PT 
• 
Includes TEAEs occurring in ≥ 
5.0% of patients in any treatment 
group 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Common Ocular 
TEAEs 
 
Summary by PT for common ocular 
TEAEs 
 
dominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 


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Parameter 
Description 
Timing 
Methodology 
 
nondominant eye 
Common Non-ocular 
TEAEs 
 
Summary by PT for common non-ocular 
TEAEs 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
TEAEs by intensity 
Overall summary and by SOC, PT, and 
intensity 
• 
Patients categorized overall and 
within each SOC and PT for the 
most intense occurrence 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Ocular TEAEs by 
intensity 
Overall summary and by SOC, PT, and 
intensity for ocular TEAEs 
• 
Patients categorized overall and 
within each SOC and PT for the 
most intense occurrence 
 
dominant eye 
 
nondominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Non-ocular TEAEs by 
intensity 
Overall summary and by SOC, PT, and 
intensity for non-ocular TEAEs 
• 
Patients categorized overall and 
within each SOC and PT for the 
most intense occurrence 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Treatment-related 
TEAEs 
Overall summary and by PT 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Ocular Treatment-
related TEAEs  
Overall summary and by PT for ocular 
TEAEs 
 
dominant eye 
 
nondominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Non-ocular Treatment-
related TEAEs  
Overall summary and by PT for non-ocular 
TEAEs 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Study-procedure-related 
TEAEs 
Overall summary and by PT 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Ocular Study-
procedure-related 
TEAEs 
Overall summary and by PT for ocular 
TEAEs 
 
dominant eye 
 
nondominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Non-ocular Study-
procedure-related 
TEAEs 
Overall summary and by PT for non-ocular 
TEAEs 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
On-therapy SAEs1 
Overall summary and by PT 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
On-therapy ocular 
SAEs 
Overall summary and by PT for ocular 
SAEs 
 
dominant eye 
 
nondominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
On-therapy non-ocular 
SAEs 
Overall summary and by PT for non-ocular 
SAEs 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
On-therapy fatal SAEs1 
Overall summary and by PT 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
On-therapy fatal ocular 
SAEs 
Overall summary and by PT for ocular 
fatal SAEs 
 
dominant eye 
 
nondominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
On-therapy fatal 
non-ocular SAEs 
Overall summary and by PT for non-ocular 
fatal SAEs 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 


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Parameter 
Description 
Timing 
Methodology 
AEs leading to study 
discontinuation1 
Overall summary and by PT 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Ocular AEs leading to 
study discontinuation 
Overall summary and by PT for ocular 
AEs leading to discontinuation 
 
dominant eye 
 
nondominant eye 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
Non-ocularAEs leading 
to study discontinuation 
Overall summary and by PT for non-ocular 
AEs leading to discontinuation 
Treatment Period, 
Follow-up Period 
Categorical 
descriptives 
1 Patients who report ≥ 1 AE in the AE category and all AEs for those patients will be listed. 
SOCs will be sorted alphabetically; PTs will be sorted in descending frequency in the highest dose group. 
 
 


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5.1.1.7 
Interim Analyses 
Not applicable 
5.1.2 
Determination of Sample Size 
A sample size of approximately 150 patients will be randomized in a 1:1:1:1:1 ratio into 1 of the 
5 study groups. Approximately two-thirds of the enrolled patients will be younger patients 
(≤ 50 years old), and approximately one-third of the enrolled patients will be older patients 
(> 50 years old). 
From the Study 199201-007 results, the treatment effect for the younger patients was on average 
1.98 lines of change in mesopic, high contrast UNVA, with standard deviations for active and 


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vehicle of 1.12 and 1.01, respectively. For older patients, the treatment effect was on average 
0.72 lines of change in mesopic, high contrast UNVA, with standard deviations for active and 
vehicle of 1.87 and 1.15, respectively. The treatment effect for the younger patients was on 
average 1.02 lines of change in photopic, high contrast UNVA, with standard deviations for 
active and vehicle of 1.42 and 0.67, respectively. For older patients, the treatment effect was on 
average 0.27 lines of change in photopic, high contrast UNVA, with standard deviations for 
active and vehicle of 1.10 and 0.93, respectively. 
Accounting for a 12.5% dropout rate, 26 patients per treatment group will provide 99% power to 
observe a difference between an active group and the vehicle group for lines of change from 
baseline in mesopic, high contrast UNVA, and 68% power for lines of change from baseline in 
photopic, high contrast UNVA, with a type I error of 0.05 
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 not be performed. 
6. 
Data Handling and Analysis Conventions 
6.1 
Study Treatment Conventions 
6.1.1 
Analysis Days 
Treatment is 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 
 


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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 
as the last available dosing record date/last available efficacy assessment date 


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•
 
 
 
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: 


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• 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 
 
 
 
 
 
 
 
 


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6.6.4 
Electrocardiograms 
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 5.2.2 
UNVA responder analyses with 
at least a 2-line improvement 
in mesopic, high contrast 
UNVA from baseline at a 
majority of postdose 
Added additional analysis 


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Section 
Revision 
Rationale 
timepoints (6 or more) in the 
nondominant eye will be 
added. 
 
 
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 
Section 5.1.1.3 
 
Added the baseline of depth of 
focus 
For clarification 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ALLERGAN 
 
 
 
 
 
 
 
 
 
Date (DD/MMM/YYYY)/Time (PT) 
Signed by: 
Justification 
  
 
           
 
            
 
           
 
            
 
           
 
            
 
 
     
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
           
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
            
 
        
 
 
199201-010 Statistical Analysis Plan