Clinical trial NCT03201562
Conditions: Presbyopia
Sponsor: LENZ Therapeutics, Inc
Start date: 2017-04-30; Completion date: 2018-05-20
Enrollment: 58 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
To evaluate the safety and efficacy of PRX-100 compared with aceclidine alone and vehicle in the treatment of early to moderate presbyopia.

Detailed description:

Arms: arm 1: Aceclidine+tropicamide combination single dose (PRX-100 Ophthalmic Solution) arm 2: Aceclidine single dose arm 3: Vehicle single dose
Interventions: intervention 1: Aceclidine+tropicamide combination intervention 2: Aceclidine intervention 3: Vehicle
Intervention descriptions: intervention 1: Ophthalmic Solution intervention 2: Ophthalmic Solution intervention 3: Ophthalmic Solution

Protocol documents:
Prot_002.pdf: 


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dermatologic, hematologic, neurologic, or 
psychiatric disease.
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PRX-100 (aceclidine 
 and tropicamide 
) Ophthalmic Solution 
x
 Aceclidine Ophthalmic Solution
x
Vehicle Ophthalmic Solution (for PRX-100)
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Percentage of subjects who achieve a 3-line (15-
letters) or greater improvement from pre-treatment in 
the measurement of monocular best-corrected 
distance VA at 45 cm at 1h post-treatment in the 
study eye.
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The percentage of subjects who achieve a 1-line (5-
letter) to 3-line (15-letters) or greater improvement 
from pre-treatment by 1-letter increments in the 
measurement of monocular best-corrected distance 
VA at 45 cm in the study eye at each time point
o
0.5, 1, 3, 4, 5 and 7h post-treatment
x
Percentage of subjects with at least a 3-line (15-
letter) improvement in the study eye in the 
measurement of post-treatment monocular best-
corrected distance VA at 
compared to pre-
treatment monocular best-corrected distance VA  
 
x
Mean monocular best-corrected distance logMAR 
VA at near distances in the study eye
o
Post-treatment assessments compared to 
pre-treatment assessment
o
Two near testing distances will be 
assessed: 45 cm (all post-treatment time 
points [0.5, 1, 3, 4, 5 and 7h]) and 
x
Percentage of subjects with at least a 3-line (15-
letter) improvement in the measurement of post-
treatment binocular best-corrected distance VA at 45 


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cm compared to pre-treatment binocular best-
corrected distance VA at 45 cm
o
0.5, 1, 3, 4, 5 and 7h post-treatment
x
Percentage of subjects with at least a 3-line (15-
letter) improvement in the measurement of post-
treatment binocular best-corrected distance VA 
 
compared to pre-treatment binocular best-
corrected distance VA 
 
x
Mean binocular best-corrected distance logMAR VA
at near distance
o
Post-treatment assessments compared to 
pre-treatment assessment
o
Two near testing distances will be 
assessed: 45 cm (all post-treatment time 
points [0.5, 1, 3, 4, 5 and 7h]) and 
 
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Best-corrected VA
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Low-luminance best-corrected VA
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Slit lamp biomicroscopy
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Conjunctival redness
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IOP
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Adverse events (AEs) (reported, elicited, and 
observed)
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Pupillometry
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In general, quantitative/continuous data will be summarized using descriptive statistics (n, 
mean, SD, median, min, and max). Qualitative/categorical data will be summarized using 
frequencies and percentages. Statistical testing, unless otherwise indicated, will be performed 
at a 2-sided 0.10 significance level.  
The study eye, defined in section 8.3.1, will be used for all monocular analyses. The fellow 
eye will inherently be included in all binocular analyses.  Both eyes will be displayed and 
analyzed for all ophthalmic safety variables.
The primary and monocular secondary efficacy analyses will be conducted in the modified
intent-to-treat (mITT) population using statistical models which implicitly impute missing 
data.  The mITT population is defined in section 10.2.1.
 




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x
Random effect measure: subject within sequence, to account for the correlation 
between treatments and periods within a subject. 
x
Repeated measures correlation will be estimated with an unstructured variance-
covariance matrix in the GEE model. 
Standard errors and CIs (80 and 90%) will also be presented for each treatment group and the 
difference between treatment groups. Separate models will be built for each distance (with 45 
cm being primary and 
 being secondary) and time points. Pairwise comparisons among 
treatment groups will also be made at each distance and time point using McNemar’s tests. 
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For the secondary efficacy variable of monocular assessment of best-corrected distance VA, 
the percentage of subjects who achieve a 1-line (5-letter) to 3-line (15-letters) or greater 
improvement from pre-treatment by 1-letter increments in the measurement of monocular 
best-corrected distance VA will be evaluated at 45 cm for each time point (0.5, 1, 3, 4, 5 and 
7h post-treatment) using the mITT population.  Analyses will be repeated using the ITT 
population.
In addition,
will be compared to pre-treatment 
assessments in the study eye.
Descriptive statistics will be presented for each time point and distance as well as for the 
change from pre-dose at each time point and distance by treatment group. The same logistic 
regression models developed for the primary analyses will be used to test these secondary 
endpoints.  
For continuous secondary endpoints, similar mixed effect models will be employed.  Two-
sided one-sample t-tests from a mixed effects linear model with binocular best-corrected 
distance VA at near distance change from pre-dose as the response variable; sequence, period, 
and treatment as fixed effects; and subject within sequence as a random effect term with a 
variance component covariance matrix to account for the correlation among measures within 
a subject using α = 0.1. Two-sided 80% and 90% CI will be provided as additional descriptors 
of the data. Separate models will be constructed for each distance and time point separately. 
Pairwise comparisons between treatment groups will also be made at each distance and time 
point using one-sample t-tests.
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Exploratory efficacy endpoints will be analyzed for all available data similarly to the primary 
and secondary endpoints in the mITT population and in the ITT population for sensitivity. All 
exploratory variables will include percentage based and mean based analyses, similar to the 
primary and secondary endpoints. Pairwise treatment comparisons will be calculated where 
possible, along with changes from pre-treatment; otherwise, analyses will be limited to within 
treatment statistics. 
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Pupil diameter will be analyzed using similar statistical methods to that of the secondary 
efficacy variable best-corrected distance VA at near distance for each time point separately.  




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TABLE OF CONTENTS 
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6.1.1 
Primary Efficacy Variable ................................................................24 
6.1.2 
Secondary Efficacy Variable ............................................................24 
6.1.3 
Exploratory Efficacy Variables: .......................................................25 
6.1.4 
Criteria for Effectiveness ..................................................................26 
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7.1.1 
Study Treatment(s)/ Formulation(s) .................................................26 
7.1.2 
Instructions for Use and Administration ...........................................27 
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8.1.1 
Overview ...........................................................................................28 
8.1.2 
Informed Consent..............................................................................28 
8.1.3 
Washout Intervals .............................................................................28 
8.1.4 
Procedures for Final Study Entry ......................................................29 
8.1.5 
Pregnancy ..........................................................................................29 
8.1.6 
Methods for Assignment to Treatment Groups: ...............................29 
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8.2.1 
Prohibited Medications/Treatments ..................................................30 
8.2.2 
Escape Medications ..........................................................................30 
8.2.3 
Special Diet or Activities ..................................................................30 
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Procedures to be performed at the Study Visit with Regard to Study 
Objective(s) ....................................................................................................30 
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8.4.1 
Scheduled Visit .................................................................................34 
8.4.2 
Unscheduled Visits ...........................................................................34 
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8.6.1 
Completed Subjects ..........................................................................34 
8.6.2 
Withdrawn Subjects ..........................................................................34 
8.6.3 
Discontinued Subjects .......................................................................35 
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9.1.1 
Severity .............................................................................................36 
9.1.2 
Relationship to Investigational Product ............................................36 
9.1.3 
Expectedness .....................................................................................37 
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9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .....................39 
9.3.2 
Reporting a Serious Adverse Event ..................................................39 
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10.2.1 Modified Intent-to-Treat Population .................................................41 
10.2.2 Intent-to-Treat Population .................................................................42 
10.2.3 Modified Per Protocol Population ....................................................42
10.2.4 Per Protocol Population ....................................................................42 
10.2.5 Safety Population ..............................................................................42 
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11.1.1 Subject Informed Consent.................................................................47 
11.1.2 IRB Approval ....................................................................................48 
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11.4.1 Retention of Documentation .............................................................49 
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11.5.1 Labeling/Packaging...........................................................................49 
11.5.2 Storage of Investigational Product ....................................................50 
11.5.3 Accountability of Investigational Product ........................................50 
11.5.4 Return or Disposal of Investigational Product ..................................50 
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 ([SORUDWRU\ (IILFDF\ 9DULDEOHV .....................................................100 
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ADHD
Attention-Deficit/Hyperactivity Disorder
AE
adverse event
cd/m2
candela per square meter
CFR
Code of Federal Regulations
CI
confidence interval
CST
Clinical Trial Suite
eCRF
electronic case report form
D
diopter
EKG
electrocardiogram
ETDRS
Early Treatment of Diabetic Retinopathy Study
FDA
Food and Drug Administration
GCP
Good Clinical Practice
GEE
Generalized Estimating Equation
ICF
informed consent form
IEC
independent ethics committee
IND
investigational new drug application
IOL
intraocular lens
IOP
intraocular pressure
IP
investigational product
IRB
institutional/independent review board
ITT
intent to treat
LASEK
laser-assisted sub-epithelial keratectomy
LASIK
laser in situ keratomileusis
LOCF
last observation carried forward
logMAR
logarithm of the minimum angle of resolution
MAX
maximum
MedDRA
Medical Dictionary for Regulatory Activities
MIN
minimum
mmHg
millimeters of mercury
 


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NCS
not clinically significant
OD
right eye
OS
left eye
OU
both eyes
OTC
over the counter
PP
per protocol
PRK
photorefractive keratectomy
QD
once daily
RGP
rigid gas permeable
SAE
serious adverse event
SAP
statistical analysis plan
SD
standard deviation
SOP
standard operating procedure
VA
visual acuity

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Presbyopia is defined by a loss in the ability of the eye to adjust its focal length so that objects at 
different distances produce focused images on the retina. As the eye ages, the lens of the eye 
becomes less able to change shape. Hardening of the lens, along with weakening of the ciliary 
muscles, plays a major role in the pathogenesis of presbyopia and leads to symptoms such as 
blurred vision, eye strain and headache after reading or computer use (Truscott 2009; Helmholtz
1855; Ostrin and Glasser 2007; Scarcelli 2011).  
Presbyopia affects most people over 45 years of age and continues to worsen until approximately 
65 years of age. Based on data from 228 countries, it was estimated that in 2005, presbyopia 
affected more than 1 billion people worldwide. Presbyopia is projected to increase to 1.78 billion 
people by 2050.  More than half of the people with this condition do not have adequate treatment 
options, which results in some level of disability when performing tasks that require near visual 
acuity (Holden 2008).  
Current treatments available for presbyopia include the use of reading glasses, contact lenses, or 
refractive (including laser) or intraocular lens (IOL) surgery. Pharmaceutical therapies have been 
explored but, thus far, continue to be limited in treating presbyopia without being associated with 
undesirable adverse effects (Gilmartin 1995).  
PRX-100 is an ophthalmic solution that contains a low dose of aceclidine 
 and 
tropicamide 
. Both aceclidine and tropicamide have been used extensively in humans for 
ophthalmic indications. Aceclidine is a parasympathomimetic miotic agent that is approved for 
lowering IOP in Europe. In 1969, a 2% solution of aceclidine was approved in several European 
countries for the treatment of glaucoma. Furthermore, aceclidine has been used at concentrations 
of up to 4% in humans. Tropicamide is an anticholinergic drug that was approved for human use 
in the US in 1960. Tropicamide induces mydriasis (pupil dilation) and cycloplegia (paralysis of 
the ciliary muscle) and is used to facilitate ophthalmic patient examinations. Tropicamide is 










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b. bladder medication (eg Urecholine®, bethanechol) 
c.
antipsychotics 
d. antidepressants 
e.
attention –deficit/hyperactivity disorder (ADHD) medications 
f.
alpha-blockers (eg, tamsulosin, Flomax®, Jayln®, Uroxatral®, Rapaflo®) 
g. anticholinergics (eg, atropine, belladonna, benztropine, dicyclomine, donepezil, 
hyoscyamine, propantheline, scopolamine, trihexphenidyl) 
h. muscarinic receptor agonists or cholinergic agonists (eg, Salagen®, Evoxac®)
i.
over-the-counter (OTC) or prescription antihistamines or decongestants 
j.
any prescribed topical ophthalmic medications 
k. recreational drug use (eg, marijuana, methadone, heroin, cocaine); 
20. Have a diagnosis of diabetes mellitus or a history of elevated blood sugar; 
21. Have a condition or a situation, which in the Investigator’s opinion, may put the 
subject at increased risk, confound study data, or interfere significantly with the 
subject’s study participation, including but not limited to unstable: cardiovascular, 
hepatic, renal, respiratory, gastrointestinal, endocrine, immunologic, dermatologic, 
hematologic, neurologic, or psychiatric disease.  
5.5
:LWKGUDZDO &ULWHULD LI DSSOLFDEOH
Subjects will be withdrawn from the study if any of the following criteria are met: 
1. 
Be a female of childbearing potential who is currently pregnant, nursing or 
planning a pregnancy; tests positive to a urine pregnancy test at visit 2, 3 
or 4; or refuses to use an adequate method of contraception for the 
duration of the study; 
2. 
Have an active ocular infection at visit 2, 3 or 4 (bacterial, viral or fungal), 
positive history of an ocular herpetic infection, preauricular
lymphadenopathy, or ongoing, active ocular inflammation (eg, moderate 
to severe blepharitis, allergic conjunctivitis, peripheral ulcerative keratitis, 
scleritis, uveitis) in either eye.  
Subjects may also be withdrawn from the study for the following reasons: 
x
AE
x
Lost to follow-up 
x
Withdrawal of consent by subject 
x
Investigator discretion 
x
Death 
x
Subject not following required study procedures 


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x
Study terminated by the Sponsor 
x
Other 
Subject withdrawals will be documented clearly on the subject’s source 
document.   
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6.1
(IILFDF\ 0HDVXUHV
6.1.1
Primary Efficacy Variable 
x
Percentage of subjects who achieve a 3-line (15-letters) or greater 
improvement from pre-treatment in the measurement of monocular best-
corrected distance VA at 45 cm at 1h post-treatment in the study eye. 
6.1.2
Secondary Efficacy Variable 
x
The percentage of subjects who achieve a 1-line (5-letter) to 3-line (15-
letters) or greater improvement from pre-treatment by 1-letter 
increments in the measurement of monocular best-corrected distance VA 
will be evaluated at 45 cm for each time point 
o
0.5, 1, 3, 4, 5 and 7h post-treatment 
x
Percentage of subjects with at least a 3-line (15-letter) improvement in 
the study eye in the measurement of post-treatment monocular best-
corrected distance VA at 
 compared to pre-treatment monocular 
best-corrected distance VA at 
 
 
x
Mean monocular best-corrected distance logMAR VA at near distances 
in the study eye 
o
Post-treatment assessments compared to pre-treatment 
assessment 
o
Two near testing distances will be assessed: 45 cm (all post-
treatment time points [0.5, 1, 3, 4, 5 and 7h]) and 
 
  
x
Percentage of subjects with at least a 3-line (15-letter) improvement in 
the measurement of post-treatment binocular best-corrected distance VA 
at 
 compared to pre-treatment binocular best-corrected distance 
VA at 


03Jul2018 
CONFIDENTIAL 
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o
 
x
Percentage of subjects with at least a 3-line (15-letter) improvement in 
the measurement of post-treatment binocular best-corrected distance VA 
at 
 compared to pre-treatment binocular best-corrected distance 
VA at 
 
  
x
Mean binocular best-corrected distance logMAR VA at near distance 
o
Post-treatment assessments compared to pre-treatment 
assessment 
o
Two near testing distances will be assessed: 45 cm (all post-
treatment time points [0.5, 1, 3, 4, 5 and 7h]) and 
 
 
6.1.3
Exploratory Efficacy Variables: 
x
 
 
   
 
 
  
  
 
 
  
 
 
 
 
 
 
 


03Jul2018 
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o
 
 
 
  
 
 
 
  
 
6.1.4
Criteria for Effectiveness 
Changes in best-corrected distance VA at near distance will be calculated as 
the difference, in logMAR units, between the post-treatment monocular (study 
eye) and binocular best-corrected distance VA measurements at near (45 cm
and 
 minus the pre-treatment monocular (study eye) and binocular best-
corrected distance VA measurements at near (45 cm and 
  A 3-line 
improvement in VA is considered clinically meaningful. 
6.2
6DIHW\ 0HDVXUHV
x
Urine pregnancy test  
x
Best-corrected distance VA 
x
Low-luminance best-corrected distance VA 
x
Slit-lamp biomicroscopy 
x
Conjunctival redness 
x
IOP 
x
AEs (reported, elicited, and observed)  
6.3
2WKHU 0HDVXUHV
x
Pupillometry 
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7.1.1
Study Treatment(s)/ Formulation(s) 
The study treatments are as follows: 






03Jul2018 
CONFIDENTIAL 
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•
Muscarinic receptor agonists or cholinergic agonists (eg, Salagen®,
Evoxac®): 2 weeks
•
Over-the-counter and prescription antihistamines or decongestants: 2 
weeks
•
Artificial tears: on the day of or during visit 1, 2, 3 or 4  
•
Any prescribed topical ophthalmic medications: 2 weeks 
8.1.4
Procedures for Final Study Entry 
Subjects must satisfy all inclusion and none of the exclusion criteria in order 
to be entered into the study. 
8.1.5
Pregnancy 
Females must have a negative urine pregnancy test at visit 1, if female of 
childbearing potential (those who have experienced menarche and who are not 
surgically sterilized [bilateral tubal ligation, hysterectomy or bilateral 
oophorectomy] or post-menopausal [12 months after last menses]) and must 
use adequate birth control throughout the study period. Adequate birth control 
is defined as hormonal – oral, implantable, injectable, or transdermal 
contraceptives; mechanical – spermicide in conjunction with a barrier such as 
condom or diaphragm; intrauterine device (IUD); or surgical sterilization of 
partner. For non-sexually active females, abstinence may be regarded as an 
adequate method of birth control. 
In the event a female has a positive urine pregnancy test at visit 2, 3 or 4, the 
subject will be withdrawn from the study and the Investigator will notify Ora 
and the sponsor within 24 hours of knowledge of the event. 
8.1.6
Methods for Assignment to Treatment Groups: 
Each subject who signs an informed consent form will be assigned a screening 
number.  Screening numbers will be assigned in sequential order beginning 
with 001.  Once a subject meets all qualification criteria, he/she will be 
randomized in a 1:1:1 ratio to one of three Latin square design sequences 
[(1,2,3), (2,3,1), and (3,1,2)] detailing the order in which treatments (1: PRX-
100, 2: aceclidine, 3: vehicle) will be administered over the three study visits 
and will be assigned a 4-digit subject number.  Subject numbers will be 
assigned in a sequential order starting at the lowest number available.  No 
numbers will be skipped or omitted. Randomization will be used to avoid bias 
in the assignment of subjects to treatment, to increase the likelihood that 
known and unknown subject attributes (e.g., demographics and baseline 
characteristics) are evenly balanced across treatment groups, and to enhance 
the validity of statistical comparisons across treatment groups.  Masked 
treatment will be used to reduce potential of bias during data collection and 
evaluation of clinical endpoints.  




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x
Informed consent and HIPAA 
x
Demographics 
x
Medical/medication history 
x
Urine pregnancy test (for females of child-bearing potential) 
x
Inclusion/exclusion criteria review 
x
Screening assessments:  
o
Screening monocular best-corrected distance visual acuity (VA) at 45 cm* 
o
Screening monocular best-corrected distance VA* 
x
Slit-lamp biomicroscopy 
x
Fluorescein staining 
o
Subjects should wait at least 30 minutes with his/her eyes closed following 
fluorescein staining 
 
 
 
  
 
 
  
 
 
 
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x
Medical and medication history update  
x
Urine pregnancy test (for females of child-bearing potential) 
x
Subjects will be asked to read printed instructions about what will be completed at 
each visit prior to beginning baseline/pre-treatment assessments. 
x
Baseline/pre-treatment assessments:  
o
Pupillometry 
  
o
Monocular best-corrected distance VA at 
 
o
Binocular best-corrected distance VA at 
 
o
Monocular best-corrected distance visual acuity at 
* 
o
Binocular best-corrected distance VA at 
 


03Jul2018 
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o
Monocular best-corrected distance VA* 
o
Binocular best-corrected distance VA* 
o
Monocular low-luminance best-corrected distance VA* 
o
Binocular low-luminance best-corrected distance VA* 
o
 
  
  
  
  
 
  
o
Slit-lamp biomicroscopy
o
Conjunctival redness assessment 
x
Randomization will occur at visit 2 for all qualified subjects. All randomized 
subjects will receive each treatment once at each visit 2, 3 and 4 (crossover study 
design). Subjects randomization will dictate which treatment will be administered 
at each study visit. 
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x
Instillation of PRX-100, aceclidine, or vehicle OU 
o
 
 
 
 
3RVWWUHDWPHQW DVVHVVPHQWV
o
AE query post-treatment and 1 hour post-treatment 
o
The following assessments will be made 0.5, 1, 3, 4, 5 and 7 hours post-
treatment:  

Conjunctival redness assessment 

Pupillometry 
  

Monocular best-corrected distance VA at 
 

Binocular best-corrected distance VA at 
 

Monocular best-corrected distance VA*


03Jul2018 
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
Binocular best-corrected distance VA* 

Monocular low-luminance best-corrected distance VA* 

Binocular low-luminance best-corrected distance VA* 
o
The following assessments will be made 1, 4 and 5 hours post-treatment:  

Monocular best-corrected distance VA at 
 

Binocular best-corrected distance VA at 
 

All best-corrected distance VA at 
 assessments to be assessed 
immediately following best-corrected distance VA at 45 cm 
assessments 
o
The following assessments will be made 1 and 5 hours post-treatment 
following binocular low-luminance best-corrected distance VA:

 
  
  
  
  
 
 
o
Following the 7-hours post-treatment assessments: 

Slit lamp biomicroscopy 

IOP 

AE query 
$VVHVVPHQW IRU 6WXG\ ([LW
x Subjects will be assessed for study exit. Study exit can occur at either visit 1, 2, 3, 
or 4. If a subject completes the study, Study exit will occur at Visit 4. 
* VA to be assessed with best distance correction 
 
  
** Best effort will be made to adhere to 
 assessment time points. No 
minimum/maximum windows are defined for any post-treatment assessment time point. 


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8.4
6FKHGXOH RI 9LVLWV 0HDVXUHPHQWV DQG 'RVLQJ
8.4.1
Scheduled Visit 
Refer to Appendix 1 for a schedule of measurements at the Visit. 
8.4.2
Unscheduled Visits 
In the case of an AE, an Unscheduled Visit may be performed by the 
Investigator. Unscheduled Visit assessments can include any of the following: 

Medical/medication history 

Urine pregnancy test 

VA assessments 

Slit-lamp biomicroscopy 

Conjunctival redness 

IOP 

Fluorescein staining 

AE query 
The Investigator may perform additional assessments, if needed. All 
additional assessments will be documented in the subject’s source document. 
8.5
&RPSOLDQFH ZLWK 3URWRFRO
This study will be conducted in compliance with the protocol, the ethical principles 
that have their origin in the Declaration of Helsinki, the International Conference on 
Harmonisation (ICH) consolidated Guideline E6 for Good Clinical Practice (GCP) 
(CPMP/ICH/135/95), and applicable regulatory requirement(s), such as Food and 
Drug Administration (FDA) GCP Regulations and Code of Federal Regulations Title 
21, parts 11, 50, 54, 56 and 312, as appropriate. 
8.6
6XEMHFW 'LVSRVLWLRQ
8.6.1
Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2
Withdrawn Subjects 
A subject may be withdrawn for meeting any of the withdrawal criteria as 
described in Section 5.5. 


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8.6.3
Discontinued Subjects 
A discontinued subject is one who does not complete the four (4) protocol defined 
study visits. A subject MAY be discontinued at the discretion of the Investigator, 
Sponsor, and/or the IRB/IEC. Subjects will also be discontinued if the following 
criteria is met:
x
 
Prior to discontinuing a subject, every effort should be made to obtain as much 
follow-up data as possible, and to retrieve all study materials.  Adverse events 
(AEs) will be followed as described in Section 9.
8.7
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7KH VWXG\ PD\ EH WHUPLQDWHG DW DQ\ WLPH E\ WKH ,QYHVWLJDWRU WKH
VSRQVRU DQGRU 2UD ZLWK DSSURSULDWH QRWLILFDWLRQ
8.8
6WXG\ 'XUDWLRQ
This study is comprised of 4 visits over a total duration of approximately 7 weeks. 
8.9
0RQLWRULQJ DQG 4XDOLW\ $VVXUDQFH
During the course of the study an Ora, Inc. monitor, or designee, will make routine 
site visits to review protocol compliance, assess study drug accountability, and ensure 
the study is being conducted according to the pertinent regulatory requirements. The 
review of the subjects’ medical records will be performed in a manner that adequately 
maintains subject confidentiality. Further details of the study monitoring will be 
outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, Ora, Inc. quality assurance 
and/or its designees may carry out on-site inspections and/or audits which may 
include source data checks. Therefore, direct access to the original source data will be 
required for inspections and/or audits. All inspections and audits will be carried out 
giving consideration to data protection as well as subject confidentiality to the extent 
that local, state, and federal laws apply. 

$'9(56( (9(176
9.1
$GYHUVH (YHQW
An AE is defined as any untoward medical occurrence associated with the use of an 
investigational product (IP) in humans, whether or not considered IP-related. An AE 


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can be any unfavorable and unintended sign (e.g., an abnormal laboratory finding), 
symptom, or disease temporally associated with the use of an investigational product, 
without any judgment about causality. An AE can arise from any use of the 
investigational product (e.g., off-label use, use in combination with another drug or 
medical device) and from any route of administration, formulation, or dose, including 
an overdose. An AE can arise from any delivery, implantation, or use of a medical 
device, including medical device failure, patient characteristics that may impact 
medical device performance (e.g., anatomical limitations), and therapeutic parameters 
(e.g., energy applied, sizing, dose release) associated with a medical device. 
All AEs spontaneously reported by the subject and/or in response to an open question 
from study personnel or revealed by observation, physical examination or other 
diagnostic procedures will be recorded in the subject’s source document and eCRF. 
Any clinically relevant deterioration in clinical finding is considered an AE and must 
be recorded. When possible, signs and symptoms indicating a common underlying 
pathology should be noted as one comprehensive event. 
Documentation regarding the AE should be made as to the nature, date of onset, end 
date, severity, relationship to investigational product, expectedness, action(s) taken, 
seriousness, and outcome of any sign or symptom observed by the physician or 
reported by the patient upon indirect questioning. 
All AEs will be collected from the time a subject signs the informed consent form 
through the subject’s study exit visit. 
9.1.1
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of 
intensity of an AE as determined by the Investigator or reported to him/her by 
the patient/subject.  The assessment of severity is made irrespective of 
relationship to investigational product or seriousness of the event and should 
be evaluated according to the following scale: 
x
Mild: Event is noticeable to the subject, but is easily tolerated and does 
not interfere with the subject’s daily activities.
x
Moderate:  Event is bothersome, possibly requiring additional therapy, 
and may interfere with the subject’s daily activities.
x
Severe:  Event is intolerable, necessitates additional therapy or alteration 
of therapy, and interferes with the subject’s daily activities.
9.1.2
Relationship to Investigational Product 
The relationship of each AE to the investigational product should be 
determined by the Investigator using these explanations: 


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x
Suspected:  A reasonable possibility exists that the investigational product 
caused the AE.
x
Not Suspected: A reasonable possibility does not exist that the 
investigational product caused the AE. 
Suspected adverse reaction means any AE for which there is a reasonable 
possibility that the investigational product caused the AE.  “Reasonable 
possibility” means there is evidence to suggest a causal relationship between 
the investigational product and the AE.  Types of evidence that would suggest 
a causal relationship between the investigational product and the AE include:  
a single occurrence of an event that is uncommon and known to be strongly 
associated with investigational product exposure (e.g., angioedema, hepatic 
injury, Stevens-Johnson Syndrome); one or more occurrences of an event that 
is not commonly associated with investigational product exposure, but is 
otherwise uncommon in the population exposed to the investigational product 
(e.g., tendon rupture); an aggregate analysis of specific events observed in a 
clinical trial (such as known consequences of the underlying disease or 
condition under investigation or other events that commonly occur in the 
study population independent of drug therapy) that indicates those events 
occur more frequently in the investigational product-treatment group than in a 
concurrent or historical control group. 
9.1.3
Expectedness 
The expectedness of an AE should be determined based upon existing safety 
information about the investigational product using these explanations: 
x
Unexpected:  an AE that is not listed in the Investigator’s Brochure (IB) or 
is not listed at the specificity or severity that has been observed. 
x
Expected:  an AE that is listed in the IB at the specificity and severity that 
has been observed. 
x
Not applicable: an AE unrelated to the investigational product. 
Adverse events that are mentioned in the IB as occurring with a class of 
products or as anticipated from the pharmacological (or other) properties of 
the product, but are not specifically mentioned as occurring with the particular 
product under investigation are to be considered unexpected. 
The Investigator should initially classify the expectedness of an AE, but the 
final classification is subject to the Medical Monitor’s determination.


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9.2
6HULRXV $GYHUVH (YHQWV
An AE is considered serious if, in the view of either the Investigator or sponsor, it 
results in any of the following outcomes: 
x
Death; 
x
A life-threatening AE; 
o
Note:  An AE is considered “life-threatening” if, in the view of either the 
Investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a 
more severe form, might have caused death. 
x
Inpatient hospitalization or prolongation of existing hospitalization; 
o
Note:  The term “inpatient hospitalization” refers to any inpatient admission 
(even if less than 24 hours).  For chronic or long-term inpatients, inpatient 
admission includes transfer within the hospital to an acute/intensive care 
inpatient unit.  Inpatient hospitalization does not include:  emergency room 
visits; outpatient/same-day/ambulatory procedures; observation/short stay 
units; rehabilitation facilities; hospice facilities; nursing homes; or clinical 
research/phase 1 units. 
o
Note:  The term “prolongation of existing hospitalization” refers to any 
extension of an inpatient hospitalization beyond the stay anticipated or 
required for the reason for the initial admission as determined by the 
Investigator or treating physician. 
x
A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
o
Note:  A serious adverse event (SAE) specifically related to visual threat 
would be interpreted as any potential impairment or damage to the subject’s 
eyes (e.g., hemorrhage, retinal detachment, central corneal ulcer or damage to 
the optic nerve). 
x
A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 


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9.3
3URFHGXUHV IRU 5HSRUWLQJ $GYHUVH (YHQWV
All AEs and their outcomes must be reported to Ora, the study sponsor, and the 
IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities and recorded on the appropriate subject source document 
and eCRF. 
9.3.1
Reporting a Suspected Unexpected Adverse Reaction 
All AEs that are ‘suspected’ and ‘unexpected’ are to be reported to Ora, the 
study sponsor and the IRB/IEC as required by the IRB/IEC, federal, state, or 
local regulations and governing health authorities. 
9.3.2
Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the 
investigational product, must be immediately reported by the Investigator to 
Ora and the sponsor within 24 hours of becoming aware of the event.  All 
information relevant to the SAE must be recorded on the appropriate source 
document, SAE Report Form and eCRF.  The Investigator is obligated to 
pursue and obtain information requested by Ora and/or the sponsor in addition 
to the information reported on the source document, SAE Report Form and 
eCRF.  All subjects experiencing a SAE must be followed up and the outcome 
reported. 
In the event of a SAE, the Investigator must notify Ora and the sponsor 
immediately; 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 subject; provide Ora and the study sponsor 
with a complete case history, which includes a statement as to whether the 
event was or was not suspected to be related to the use of the investigational 
product; and inform the IRB of the AE within their guidelines for reporting 
SAEs. 
Contact information for reporting SAEs: 


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9.4
3URFHGXUHV IRU 8QPDVNLQJ LI DSSOLFDEOH
When medically necessary, the Investigator may need to determine what treatment 
has been assigned to a subject.  When possible (i.e., in non-emergent situations), Ora 
and/or the study sponsor should be notified before unmasking investigational product. 
A two-panel clinical label with scratch offs will be used for unmasking.  
9.5
7\SH DQG 'XUDWLRQ RI WKH )ROORZXS RI 6XEMHFWV DIWHU $GYHUVH
(YHQWV
The Investigator will follow unresolved AEs to resolution, until the subject is lost to 
follow-up or until the AE is otherwise explained.  Resolution means the subject has 
returned to baseline state of health or the Investigator does not expect any further 
improvement or worsening of the AE.  If the subject is lost to follow-up, the 
Investigator should make 3 reasonable attempts to contact the subject via telephone, 
post, or certified mail.  All follow-up will be documented in the subject’s source 
document. Non-serious AEs identified on the last scheduled contact must be recorded 
on the source document with the status noted.  
If the Investigator becomes aware of any new information regarding a SAE (i.e. 
resolution, change in condition, or new treatment), a new Serious Adverse Event 
Report Form must be completed and faxed to Ora and/or the study sponsor within 24 
hours.  The original SAE Report Form is not to be altered.  The Report Form should 
describe whether the event has resolved or continues and how the event was treated. 
 67$7,67,&$/ +<327+(6(6 $1' 0(7+2'6 2) $1$/<6(6
10.1
*HQHUDO &RQVLGHUDWLRQV
All quantitative/continuous study assessments will be summarized by treatment (or 
treatment sequence) and visit and time point (as applicable) using descriptive 
statistics (n, mean, SD, median, minimum, and maximum.  All qualitative/categorical 
study assessments will be summarized by treatment (or treatment sequence), visits, 
and time point (as applicable) using frequency counts and percentages.   
Statistical testing, unless otherwise indicated, will be performed at a 2-sided 0.10 
significance level.  When applicable, two-sided 80% and 90% CIs will be reported.  
All p-values (P) will be displayed to four decimal places, with P less than 0.0001 
presented as '< 0.0001' and P greater than 0.9999 presented as ‘> 0.9999’.  








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x
Percentage of subjects with at least a 3-line (15-letter) improvement in the study 
eye in the measurement of post-treatment monocular best-corrected distance VA
 compared to pre-treatment monocular best-corrected distance VA 
 
 
x
Mean monocular best-corrected distance logMAR VA at near distances in the 
study eye 
o
Post-treatment assessments compared to pre-treatment assessment 
o
Two near testing distances will be assessed: 
 (all post-treatment time 
points [0.5, 1, 3, 4, 5 and 7h]) and 
 
x
Percentage of subjects with at least a 3-line (15-letter) improvement in the 
measurement of post-treatment binocular best-corrected distance VA at 45 cm 
compared to baseline binocular best-corrected distance VA at 45 cm
o
0.5, 1, 3, 4, 5 and 7h post-treatment  
x
Percentage of subjects with at least a 3-line (15-letter) improvement in the 
measurement of post-treatment binocular best-corrected distance VA at 
 
compared to baseline binocular best-corrected distance VA at 
 
  
x
 Mean binocular best-corrected distance logMAR VA at near 
o
Post-treatment assessments compared to pre-treatment assessment 
o
Two near testing distances will be assessed: 
 (all post-treatment time 
points [0.5, 1, 3, 4, 5 and 7h]) and 
 
10.6 ([SORUDWRU\ (IILFDF\ 9DULDEOHV
The exploratory efficacy variables are: 
x
   
  
  
 
  
 
 
 




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Descriptive statistics will be presented for each time point and distance by treatment 
group. Testing of the percentage of subjects with at least a 3-line (15-letter)
improvement in the study eye from pre-dose will be completed accounting for the 
correlations between treatments and periods within a subject using a logistic 
(binomial error and logit link) model estimated by generalized estimating equation 
methods. Aspects of the model include: 
• Response measure: indicator of whether the subject had at least a 3-line (15-letter) 
improvement in the study eye from pre-dose in the monocular assessment of best-
corrected distance VA at 
. 
• Fixed effect explanatory measures: sequence, period, and treatment.  
• Random effect measure: subject within sequence, to account for the correlation 
between treatments and periods within a subject. 
• Repeated measures correlation will be estimated with an unstructured variance-
covariance matrix.  
Standard errors and CIs (80 and 90%) will also be presented for each treatment 
group and the difference between treatment groups. Separate models will be built for 
each distance (with 45 cm being primary and 
 being secondary) and time point 
separately. Pairwise comparisons among treatment groups will also be made at each 
distance and time point using McNemar’s tests. 
10.11
6HFRQGDU\ (IILFDF\ $QDO\VLV
Descriptive statistics will be presented for each time point and distance as well as 
for the change from pre-dose at each time point and distance by treatment group. 
The same logistic regression models developed for the primary analyses will be used 
to test secondary proportion endpoints.  For continuous secondary endpoints, similar 
mixed effect models will be employed.  Two-sided one-sample t-tests from a mixed 
effects linear model with monocular best-corrected distance VA at near from pre-
dose as the response variable; sequence, period, and treatment as fixed effect 
variables; and subject within sequence as a random effect term with a variance 
component covariance matrix to account for the correlation among measures within 
a subject using α = 0.10 and two-sided 80% and 90% CI will be provided as 
additional descriptors of the data.  Separate models will be built for each distance 
and time point separately. Pairwise comparisons among treatment groups will also 
be made at each distance and time point using one-sample t-tests.  
10.12
([SORUDWRU\ (IILFDF\ $QDO\VLV
Exploratory efficacy endpoints will be analyzed for all available data similarly to 
the primary and secondary endpoints in the mITT population and in the ITT 
population for sensitivity. All exploratory variables will include percentage based 




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enrollment into the study.  If the subject is under the legal age of consent, the 
consent form must be signed by a legal guardian or as required by state and/or 
local laws and regulations. 
All informed consent/assent forms must be approved for use by the sponsor 
and receive approval/favorable opinion from an IRB/IEC prior to their use.  If 
the consent form requires revision (e.g., due to a protocol amendment or 
significant new safety information), it is the Investigator’s responsibility to 
ensure that the amended informed consent is reviewed and approved by Ora 
prior to submission to the governing IRB/IEC and that it is read, signed and 
dated by all subjects subsequently enrolled in the study as well as those 
currently enrolled in the study. 
If informed consent is taken under special circumstances (oral informed 
consent), then the procedures to be followed must be determined by Ora 
and/or study sponsor and provided in writing by Ora and/or study sponsor 
prior to the consent process. 
11.1.2 IRB Approval 
This study is to be conducted in accordance with IRB regulations (U.S. 21 
CFR Part 56.103).  The Investigator must obtain appropriate IRB approval 
before initiating the study and re-approval at least annually. 
Only an IRB/ERC approved version of the ICF will be used. 
11.2
(WKLFDO &RQGXFW RI WKH 6WXG\
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
11.3
6XEMHFW &RQILGHQWLDOLW\
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the Investigator and his/her staff with adequate precautions 
as to ensure that the confidentiality of the data in accordance with local, state, and 
federal laws and regulations. 
Monitors, auditors and other authorized representatives of Ora, the sponsor, the 
IRB/IEC approving this study, the Food and Drug Administration (FDA), the 
Department of Health and Human Services (DHHS), other domestic government 
agencies, and other foreign regulatory agencies will be granted direct access to the 
study subject’s original medical and study records for verification of the data and/or 
clinical trial procedures.  Access to this information will be permitted to the 
aforementioned individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the investigational product may ultimately be 
marketed, but the subject’s identity will not be disclosed in these documents.




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Clinical label texts for the primary packaging (glass vials) and secondary 
packaging (clinical kits) meet applicable regulatory requirements and include 
the statement “Caution: New Drug-Limited by Federal Law to Investigational 
Use.”     
11.5.2 Storage of Investigational Product 
Investigational drug must be stored in a secure area of the investigative site, 
accessible only to Investigator or designees, at room temperature between 15° 
- 25°C (59-77°F).  The investigational product will be administered only to 
subjects entered into the clinical study, in accordance with the conditions 
specified in this protocol.  All investigational drugs will be returned to 
inventory after use. 
11.5.3 Accountability of Investigational Product 
The investigational product is to only be administered by the principal 
Investigator or his/her named sub Investigator(s), and is to only be used in 
accordance with this protocol.  The investigational product must only be 
distributed to subjects properly qualified under this protocol to receive 
investigational product. 
The Investigator must keep an accurate accounting of the investigational 
product received from the supplier.  This includes the amount of 
investigational product administered to subjects and the amount returned or 
disposed upon the completion of the study.  A detailed inventory must be 
completed for the investigational product. 
11.5.4 Return or Disposal of Investigational Product 
All investigational products will be returned to the sponsor or their designee 
or destroyed.  The return or disposal of investigational product will be 
specified in writing. 
11.6 5HFRUGLQJ RI 'DWD RQ 6RXUFH 'RFXPHQWV DQG (OHFWURQLF &DVH
5HSRUWV )RUPV H&5)V
The Investigator is responsible for ensuring that study data is completely and 
accurately recorded on each subject’s source document, eCRF and all study-related 
material.  All study data should also be attributable, legible, contemporaneous, and 
original.  Recorded datum should only be corrected in a manner that does not 
obliterate, destroy, or render illegible the previous entry (e.g., by drawing a single line 
through the incorrect entry and writing the revision next to the corrected data).  An 
individual who has corrected a data entry should make clear who made the correction 
and when, by adding to the correction his/her initials as well as the date of the 
correction. 


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11.7 +DQGOLQJ RI %LRORJLFDO 6SHFLPHQV
Not applicable 
11.8 3XEOLFDWLRQV
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study. Authorship will be established before writing the manuscript.  
Ora and the study sponsor will have the final decision regarding the manuscript and 
publication. 
 5()(5(1&(6
Francois J. and Goes F. Ultrasonic study of the effect of different miotics on the eye components. 
Ophthalmologica Basel 1977;175(6):328-338. 
Gilmartin B, Amer A, Ingleby S. Reversal of tropicamide mydriasis with single instillations of 
pilocarpine can induce substantial pseudo-myopia in young adults. Ophthalmic & Physiological 
Optics 1995;15(5):475-479. 
Helmholtz, H.v. Uber die akkommodation des auges. A. v. Graefe’s Arch. Klin. Ophthalmol. 
1855;1, 1–74.
Holden B, Fricke T, Ho S, Wong R, Schlenther G, Cronje´ S, Burnett A, Papas E, Naidoo K, 
Frick K. Global vision impairment due to uncorrected presbyopia. Archives of Ophthalmology 
2008;126(12):1731-1739. 
Ostrin, L.A. and Glasser, A Edinger-Westphal and pharmacologically stimulated accommodative 
refractive changes and lens and ciliary process movements in rhesus monkeys. Experimental Eye 
Research 2007;84: 302-313. 
Randazzo A, Nizzola F, Rossetti L, Orzalesi N, Vinciquerra P. Pharmacological management of 
night vision disturbances after refractive surgery – Results of a randomized clinical trial. J Cataract 
Refract Surg 2005;31(9): 1764-1772.  
Romano, J. H. Double-blind cross-over comparison of aceclidine and pilocarpine in open-angle 
glaucoma. British Journal of Ophthalmology 1970;54: 510-521.
Scarcelli, G., Kim, P., and Yun, S.H. In vivo measurement of age-related stiffening in the 
crystalline lens by brillouin optical microscopy. Biophysical Journal 2011;101: 1539-1545. 
Truscott, R. J. Presbyopia. Emerging from a blur towards an understanding of the molecular 
basis for this most common eye condition. Experimental Eye Research 2009;88: 241-247. 


























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Not applicable 












































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03Jul2018 
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$SSHQGL[  6SRQVRU DQG 2UD $SSURYDOV
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A Single-Center, Double-Masked Evaluation of the Efficacy and 
Safety of PRX-100 in the Treatment of Early to Moderate Presbyopia
3URWRFRO 1XPEHU
PRX100.FDAIIb
)LQDO 'DWH
03Jul2018
This clinical study protocol was subject to critical review and has been approved by the sponsor.  
The following personnel contributed to writing and/or approving this protocol. 
Signed
Signed





SAP_001.pdf: 
Study #PRX100.FDAIIb 
 
Sponsor: Presbyopia Therapies, LLC 
Clinical Study Report Appendix 
 
IND #120,609 
16.1.9. 
DOCUMENTATION OF STATISTICAL METHODS (STATISTICAL 
ANALYSIS PLAN) 
 
 
 


 
 
STATISTICAL ANALYSIS PLAN  
A Single-Center, Double-Masked Evaluation of the Efficacy and 
Safety of PRX-100 in the Treatment of Early to Moderate Presbyopia  
 
 
Sponsor:   
 
Presbyopia Therapies, LLC 
 
 
 
 
 
915 Ocean Blvd. 
Coronado, CA 92118 
 
 
Protocol Number: 
PRX100.FDAIIb 
 
 
 
Author:   
 
 
 
 
 
 
 
 
Statistics & Data Corporation 
 
 
Date:    
 
3Jul2018 
Version:  
 
Final v1.0 
 






Protocol PRX100.FDAIIb, SAP Version 1.0 
 
3JUL2018  
    Confidential & Proprietary   
 
           Page 3 of 38 
 
Table of Contents 
1. 
Introduction .............................................................................................................................. 6 
2. 
Study Objectives ...................................................................................................................... 6 
3. 
Study Variables ........................................................................................................................ 6 
3.1 Primary Variables ..................................................................................................................... 6 
3.2 Secondary Variables ................................................................................................................ 6 
3.3 Exploratory Efficacy Variables ................................................................................................. 7 
3.4 Other Measures ....................................................................................................................... 8 
3.5 Safety Variables ....................................................................................................................... 8 
3.6 Statistical Hypotheses .............................................................................................................. 8 
4. 
Study Design and Procedures ................................................................................................. 8 
4.1 General Study Design .............................................................................................................. 8 
4.2 Study Eye Definition: ................................................................................................................ 9 
4.3 Study Visit Schedule ................................................................................................................ 9 
4.4 Schedule of Assessments ...................................................................................................... 13 
5. 
Study Treatments ................................................................................................................... 15 
5.1 Method of Assigning Subjects to Treatment .......................................................................... 15 
5.2 Masking and Unmasking ........................................................................................................ 15 
6. 
Sample Size and Power Considerations ............................................................................... 16 
7. 
Data Preparation .................................................................................................................... 16 
8. 
Analysis Populations .............................................................................................................. 17 
8.1 Modified Intent-to-Treat Populations ...................................................................................... 17 
8.2 Intent-to-Treat Population ...................................................................................................... 17 
8.3 Per Protocol Population ......................................................................................................... 18 
8.4 Safety Population ................................................................................................................... 18 
8.5 Exploratory Population ........................................................................................................... 18 
9. 
General Statistical Considerations ......................................................................................... 18 
9.1 Unit of Analysis ...................................................................................................................... 19 
9.2 Definition of Baseline ............................................................................................................. 19 
9.3 Adjustments for Multiplicity .................................................................................................... 19 
9.4 General Imputation Methods.................................................................................................. 20 
10. 
Disposition of Subjects ........................................................................................................... 20 
11. 
Demographic and Pretreatment Variables ............................................................................. 21 
11.1 Demographic Variables .......................................................................................................... 21 
11.2 Pretreatment Variables .......................................................................................................... 21 
12. 
Medical History and Concomitant Medications ...................................................................... 22 
12.1 Medical History ...................................................................................................................... 22 


Protocol PRX100.FDAIIb, SAP Version 1.0 
 
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           Page 4 of 38 
12.2 Concomitant Medications ....................................................................................................... 22 
13. 
Dosing Compliance and Treatment Exposure ....................................................................... 22 
13.1 Dosing Compliance ................................................................................................................ 22 
14. 
Efficacy Analyses ................................................................................................................... 22 
14.1 Primary Analysis .................................................................................................................... 22 
14.2 Secondary Efficacy Analyses................................................................................................. 24 
14.3 Exploratory Efficacy Analyses................................................................................................ 26 
15. 
Safety Analyses ..................................................................................................................... 27 
15.1 Adverse Events ...................................................................................................................... 27 
15.2 Best-Corrected Distance Visual Acuity (BCVA) ..................................................................... 31 
15.3 Low-Luminance Best-Corrected Distance Visual Acuity ....................................................... 31 
15.4 Slit Lamp Biomicroscopy Examination ................................................................................... 31 
15.5 Intraocular Pressure (IOP) ..................................................................................................... 31 
15.6 Conjunctival Redness ............................................................................................................ 32 
15.7 Urine Pregnancy Test ............................................................................................................ 32 
16. 
Changes from Protocol-Stated Analyses ............................................................................... 32 
16.1 Sensitivity Analyses ............................................................................................................... 32 
17. 
References ............................................................................................................................. 33 
18. 
Revision History ..................................................................................................................... 34 
19. 
Tables .................................................................................................................................... 34 
20. 
Listings ................................................................................................................................... 37 
21. 
Figures ................................................................................................................................... 38 
 
 
 


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List of Abbreviations 
AE 
Adverse Event 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best-Corrected Distance Visual Acuity 
CI 
Confidence Interval 
CRF 
Case Report Form 
CS 
Clinically Significant 
eCRF 
Electronic Case Report Form 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
GEE 
Generalized Estimating Equations 
IB 
Investigators’ Brochure 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
IP 
Investigational product 
ITT 
Intent-to-Treat 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
N 
Number of observations 
NCS 
Not clinically significant 
OD 
Right eye 
OS 
Left eye 
OU 
Both eyes 
p 
p-value 
PDF 
Portable Document Format 
PP 
Per Protocol 
PT 
Preferred Term 
ROPI 
Report of Prior Investigations 
RTF 
Rich Text Format 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SDC 
Statistics and Data Corporation, Incorporated 
SOC 
System Organ Class 
TEAE 
Treatment-Emergent Adverse Event 
VA 
Visual Acuity 
WHO 
World Health Organization  
 
 


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1. Introduction 
The purpose of this statistical analysis plan (SAP) is to describe the planned analyses and reporting for 
protocol PRX100.FDAIIb, amendment 5 dated 3Jul2018. 
This SAP is being written with due consideration of the recommendations outlined in the most recent 
International Conference on Harmonization (ICH) E9 Guideline entitled Guidance for Industry: Statistical 
Principles for Clinical Trials and the most recent ICH E3 Guideline, entitled Guidance for Industry: 
Structure and Content of Clinical Study Reports. 
This SAP describes the data that will be analyzed and the subject characteristics, efficacy, and safety 
assessments that will be evaluated. This SAP provides details of the specific statistical methods that will 
be used. The statistical analysis methods presented in this document will supersede the statistical 
analysis methods described in the clinical protocol. If additional analyses are required to supplement 
the planned analyses described in this SAP, they may be completed and will be identified in the clinical 
study report. 
2. Study Objectives 
The objective of the study is to evaluate the safety and efficacy of PRX-100 compared with 
 
Aceclidine and Vehicle in the treatment of early to moderate presbyopia. 
3. Study Variables 
All best-corrected distance visual acuity measures in the protocol utilize the subject’s manifest refraction 
obtained within three months of Visit 1 and will hereby be referred to as best-corrected visual acuity 
(BCVA) at whichever distance is applicable. Efficacy variables include monocular BCVA at 45 cm and 
a
 and binocular BCVA at 45 cm and 
 The 45 cm distances will be repeated for pre-
treatment and at 0.5, 1, 3, 4, 5 and 7 hours post-treatment. The 
 
. Primary analyses will use the number of subjects who 
meet or exceed 3-lines of improvement from pre- to post-treatment in the monocular 45 cm BCVA, 
Monocular BCVA at 45 cm also be analyzed by 1-letter increments in this phase 1 trial. LogMAR units 
will be used for all visual acuity safety and efficacy measures. Pupillometry will also be measured. 
3.1 
Primary Variables 
Percentage of subjects who achieve a 3-line (15-letter) or greater improvement from pre-treatment 
(baseline) in the study eye measured with monocular best-corrected VA (BCVA) at 45 cm at 1 hour 
post-treatment. 
3.2 
Secondary Variables 
The secondary variables are: 




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o 
 
3.4 
Other Measures 
• 
 
 
3.5 
Safety Variables 
The safety variables include the following: 
• 
Adverse events (AE) (reported, elicited, and observed) 
• 
Monocular and binocular BCVA (10 feet) 
• 
Monocular and binocular low-luminance BCVA (10 feet)  
• 
Slit lamp biomicroscopy 
• 
Conjunctival redness 
• 
Intraocular pressure (IOP)  
• 
Urine pregnancy test  
3.6 
Statistical Hypotheses 
The statistical hypotheses are as follows:  
Null: There is no difference in the percentage of subjects with a 3-line (15-letter) or greater improvement 
from baseline in BCVA at 45 cm between PRX-100 versus Vehicle or 
 Aceclidine versus Vehicle 
at 1-hour post-treatment.  
Alternative: The percentage of subjects with a 3-line (15-letter) or greater improvement from baseline in 
BCVA at 45 cm is different for the PRX-100 compared to Vehicle or for the 
 Aceclidine compared 
to Vehicle at 1 hour post-treatment. 
4. Study Design and Procedures 
4.1 
General Study Design 
This is a randomized, double-masked, cross-over design, single-center evaluation of the efficacy and 
safety of PRX-100 ophthalmic solution compared to 
 Aceclidine and Vehicle ophthalmic solution 
for PRX-100. Subjects will receive all 3 treatments over the course of 3 visits, noting a 2-week gap of 
no treatment in-between dosing. The study will screen approximately 60 subjects to complete 30 
subjects per treatment arm to evaluate the safety of PRX-100 and the magnitude and duration of effects 
on improving near-vision acuity. Subjects will be randomly assigned to receive 1 of the following 
treatment sequences and will receive a different treatment at each visit taken bilaterally. The treatment 
sequences are shown in the table below. 
 
Visit 2 
Visit 3 
Visit 4 
Sequence A 
PRX-100 
 Aceclidine 
Vehicle 
Sequence B 
 Aceclidine 
Vehicle 
PRX-100 






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o 
 
 
Post-Treatment Assessments***  
o 
AE query post-treatment and 1 hour post-treatment 
o 
The following assessments will be made 0.5, 1, 3, 4, 5 and 7 hours post-
installation of the test agent:  
 
Conjunctival redness assessment 
 
Pupillometry 
  
 
Monocular BCVA at 45 cm* 
 
Binocular BCVA at 45 cm* 
 
Monocular BCVA* 
 
Binocular BCVA* 
 
Monocular low-luminance BCVA* 
 
Binocular low-luminance BCVA* 
o 
 
 
  
 
 
 
 
o 
The following assessments will be made 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
o 
Following the 7 hour post-treatment assessments: 
 
Slit lamp biomicroscopy 
 
IOP 
 
AE query 
Assessment for Study Exit 
• 
Subjects will be assessed for study exit. Study exit can occur at either Visit 1, 2, 3, or 4. 
If a subject completes the study, study exit will occur at Visit 4.  


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* VA to be assessed with best distance-correction 
 
  
 
  






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5. Study Treatments 
The study treatments are PRX-100 (Aceclidine 
 and Tropicamide 0.01%) Ophthalmic Solution, 
 Aceclidine Ophthalmic Solution and Vehicle Ophthalmic Solution for PRX-100 (sterile saline 
solution). An unmasked trained study technician will prepare study drugs immediately prior to 
administration. 
 
 
 
 
  
 
 
5.1 
Method of Assigning Subjects to Treatment  
Each subject who signs an informed consent form will be assigned a screening number. Screening 
numbers will be assigned in sequential order beginning with 001 and proceed with the assessment 
schedule.  At Visit 2, once a subject meets all qualification criteria, he/she will be randomized into one 
of three treatment sequences in a 1:1:1 ratio (Sequence A: Sequence B: Sequence C), and assigned a 
4-digit subject number.  Each sequence will follow a pre-defined schedule where subjects will receive 
one drug at each visit.  
• Sequence A: PRX-100 (at Visit 2); 
 Aceclidine (at Visit 3); Vehicle (at Visit 4) 
• Sequence B: 
 Aceclidine (at Visit 2); Vehicle (at Visit 3); PRX-100 (at Visit 4) 
• Sequence C: Vehicle (at Visit 2); PRX-100 (at Visit 3); 
 Aceclidine (at Visit 4); 
Subject numbers will be assigned in a sequential order starting at the lowest number available.  No 
numbers will be skipped or omitted.  
A trained technician will be instructed to dispense the appropriate bottle of investigational drug that 
corresponds to the assigned subject number according to the randomization list. 
The 4-digit subject number will be used to identify subjects in all datasets and listings for this study.  
5.2 
Masking and Unmasking 
An independent unmasked designee who is not otherwise involved in the trial will generate the complete 
randomized study drug kit list. The subject, Sponsor, Investigators, and study staff will be masked during 
the randomization process and throughout the study. 
When medically necessary, the Investigator may need to determine what treatment has been assigned 
to a subject.  When possible (i.e., in non-emergent situations), Ora and/or the Sponsor should be notified 


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before unmasking investigational product (IP). A two-panel clinical label with scratch offs will be used 
for unmasking. 
In emergency situations, the investigator must notify the sponsor within 24 hours after determining that 
it is necessary to unmask the treatment assignment.  If the investigator determines that emergency 
unmasking is necessary, the investigator should identify and scratch off the emergency unmasking drug 
label for the given subject. The investigator must also indicate in source documents and in the eCRF 
that the mask was broken and provide the date, time, and reason for breaking the mask. 
5.2.1 
Unmasking to Monitor mITT Enrollment 
To ensure there are 30 completed subjects per treatment arm in the mITT population, an unmasked 
statistician from SDC will monitor mITT qualification criteria and provide a recommendation regarding 
how many additional subjects to enroll into the study. The unmasked statistician will only evaluate pre-
treatment monocular best-corrected distance VA at 45 cm at visits 2, 3 and 4 to make enrollment 
recommendations. No mention of which treatments, if any, have reached 30 subjects will be made. At 
most twice monthly enrollment projections will be made with 
 
 as requested by the Sponsor.   
6. Sample Size and Power Considerations 
Approximately 60 subjects will be screened to complete at least 30 evaluable subjects per treatment 
arm in the mITT population at a single site. As this is a phase 2 trial and 
 
onservative power estimations were calculated assuming a non-cross over, 2 
independent group, 
 Under these conservative assumptions the primary endpoint 
will have 84.7% power if 
 (
 of the PRX-100 treated subjects have a 3-line (15-
letter) or greater improvement from the pre-dose measurement of monocular BCVA while the 
Vehicle arm has 
 with a 3-line improvement. With these same 
assumptions, the study will have 90.1% power to show a difference between treatments if the PRX-
100 arm has 
 of the subjects with a 3-line or greater improvement. 
7. Data Preparation 
All reported study data will be recorded on the electronic case report forms (eCRFs) supplied by 
Statistics & Data Corporation (SDC) using iMedNet™. Only the Principal Investigator and authorized 
study staff according to the Delegation of Responsibilities log are entitled to make entries in the eCRF.   
After data are entered into the clinical study database, electronic edit checks, and data review will be 
performed.  All data validation specifications and procedures are detailed in the Data Validation Manual 
as a separate document. When the database has been declared to be complete and accurate, the 
database will be locked.  Any changes to the database after data have been locked can only be made 
with the approval of the Sponsor and Ora in consultation with SDC.  


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Final analyses outlined in this document will be carried out after the following have occurred:  
• 
All data management requirements are met according to SDC standard operating procedures, 
including data entry, performance of edit and validation checks, documentation and resolution 
of data queries, and database lock with written authorization provided by appropriate SDC and 
Sponsor personnel; 
• 
Protocol deviations have been identified and status defined (major/minor deviations);  
• 
Analysis populations have been determined; and 
• 
Randomized treatment codes have been unmasked. 
8. Analysis Populations 
8.1 
Modified Intent-to-Treat Populations 
The modified Intent-to-Treat (mITT) population consists of the study eye with baseline/pre-treatment 
monocular best-corrected distance VA 
 
 for each visit of all subjects 
who are randomized. 
 
. The mITT population will be analyzed as treated and will 
be the primary population used for the primary and monocular secondary efficacy analyses. 
Pairwise comparisons between treatment groups and changes from pre-treatment will use the mITT 
population using only those study eyes which have baseline/pre-treatment monocular best-corrected 
distance VA at 
. Because inclusion in the mITT 
is assessed at each treatment visit separately it is possible subjects are included at some 
visits/treatments but not at others. 
All mITT populations will use the dynamic study definition for the study eye. 
For exploratory purposes another analysis will use the monocular eye from mITT above for baseline 
(pre-treatment) and binocular post-treatment BCVA.  
Other modified populations will be defined similarly to mITT but at other specified baseline (pre-
treatment) cutoffs, per visit, below: 
• 
 
 
 
8.2 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population consists of the study eye of all subjects who are randomized.  All 
data will be included and no subjects will be excluded because of protocol violations/deviations. The ITT 
population will be analyzed as randomized and will be used for sensitivity analyses on the primary and 


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secondary monocular efficacy endpoints. The ITT population will be the primary population used to 
assess the secondary binocular efficacy endpoints. 
8.3 
Per Protocol Population 
The Per Protocol (PP) population is a subset of the ITT population and includes the study eye of subjects 
with no major protocol violations/deviations likely to affect the primary efficacy endpoint. This population 
will be analyzed as treated using observed data only for confirmatory and sensitivity analyses. 
8.4 
Safety Population 
The Safety population includes all randomized subjects who receive at least one dose of the study 
medication.  The safety population will be analyzed as treated and will be used for the safety analyses.  
No data will be excluded for any reason. 
8.5 
Exploratory Population 
Data analysis for some exploratory populations will be done at sponsor discretion. Known populations 
of interest include 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
9. General Statistical Considerations 
All data analysis will be performed by SDC after the study is completed and the database has been 
locked and released for unmasking.  Statistical programming and analyses will be performed using SAS® 
Version 9.4 or higher. Outputs will be provided in rich text format (RTF) for tables and portable document 
format (PDF) for tables, listings, and figures using landscape orientation.  All study data will be listed by 


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subject, treatment (or treatment sequence where applicable), visit, and time point (where applicable) 
based on all randomized subjects. Screen failures will not be captured in the database. 
All quantitative/continuous study assessments will be summarized by treatment (or treatment sequence) 
and time point (as applicable) using descriptive statistics (number of observations [n], mean, SD, 
median, minimum, and maximum). Minima and maxima will be reported with the same precision as the 
raw values; means and medians will be presented to one additional decimal place than reported in the 
raw values. Standard deviations will be presented to two additional decimal places than reported in the 
raw values. All qualitative/categorical study assessments will be summarized by treatment (or treatment 
sequence), and where applicable time point using frequency counts and percentages. All percentages 
will be rounded to one decimal place (i.e., XX.X%). 
Statistical testing, unless otherwise indicated, will be performed at a two-sided alpha = 0.10 significance 
level.  When applicable, two-sided 80% and 90% CIs will be reported.  All p-values (p) will be displayed 
to four decimal places, with p less than 0.0001 presented as ‘< 0.0001’ and p greater than 0.9999 
presented as ‘> 0.9999’.  
 Unless otherwise specified, summaries will be presented by treatment or treatment sequence, and, 
where appropriate visit and time point. 
9.1 
Unit of Analysis 
For measurements taken at the subject level, the unit of analysis will be the individual subject and for 
measurements taken at the eye level, the unit of analysis will be the study eye defined in Section 4.1 
and the exploratory study eyes defined in Section 8.5. The only exception is pupil diameter for which 
the unit of analysis is the average of three measurements in each of the subjects’ eyes at each time 
point. 
9.2 
Definition of Baseline 
For all variables, baseline is defined as the pre-treatment measurement taken prior to administration of 
study drug at each Visit. If the pre-treatment measurement is not available, then screening will be used 
as baseline for all treatments/visits. Change from baseline will be calculated as follow-up measure minus 
baseline/pre-treatment measure.  
9.3 
Adjustments for Multiplicity 
There will be no adjustments for multiplicity in testing the primary efficacy endpoint in this proof of 
concept study. There will be no adjustments for multiplicity for multiple treatment arms and multiple 
comparisons to Vehicle either. 


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9.4 
General Imputation Methods 
As sensitivity analyses of the primary endpoint, missing data will be imputed once as failures in the study 
eye which do not meet the mITT criteria at either 1 or both treatments in the pairwise treatment 
comparisons. A similar imputation will be done imputing missing data (data not meeting the mITT 
criteria) as successes in the mITT GEE analysis. Additionally, analysis on the primary efficacy variable 
will be performed on the ITT and PP populations will be analyzed as treated using observed data only. 
Secondary binocular efficacy analyses and pupillometry will not be imputed. Any analyses on the fellow 
eye will not be imputed. 
10. Disposition of Subjects 
Subject disposition will be presented in terms of the numbers and percentages of subjects who were 
randomized, completed the study, and discontinued from the study.  Subjects who are not discontinued 
from the study will be considered study completers.  Disposition will be summarized by treatment 
sequence for all randomized subjects. 
The number and percentage of subjects prematurely discontinued from the study and the reasons for 
study discontinuation will be summarized by treatment sequence for all randomized subjects.  The 
reasons for study discontinuation that will be summarized include: AE, protocol violation, administrative 
reasons, sponsor termination of study, withdrew consent, and Investigator’s discretion, and other.  A 
subject listing will be provided which includes the date and reason for premature study discontinuation. 
The number of subjects in each of the analysis populations (ITT, PP and Safety) will be displayed by 
treatment and percentages of number of subjects will be calculated using randomized subjects as the 
denominator. Additionally, the number of subjects in each mITT will be listed by treatment and visit. 
The number and percentage of subjects with major protocol deviations will be summarized by treatment 
sequence and overall for all randomized subjects.  Protocol deviations will be classified as major or 
minor prior to the closure of the database during a masked review of each protocol deviation.  Major 
deviations will be defined as those deviations that potentially impact the primary outcome of the study.  
The protocol deviations and their associated codes that will be summarized include:   
Deviation Code = Deviation Category 
1 = Informed Consent 
2 = Inclusion/Exclusion and Randomization 
3 = Test Article/Study Drug Instillation 
4 = Improper Protocol Procedures at Site (missed, repeated, not per protocol) 
5 = Site’s Failure to Report SAE/AE 
6 = Visit out of Window (missed, early, late) 
7 = Subject Use of Prohibited Concomitant Medication(s) 


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8 = Subject’s Failure to Follow Instructions 
9 = Other 
A subject listing will be provided which includes the date of the deviation, the deviation description and 
the classification of whether the deviation was judged to be major or minor. 
In addition, subject listings will include randomization/treatment sequence (actual vs assigned), informed 
consent date and exclusions from the PP population. 
11. Demographic and Pretreatment Variables 
11.1 
Demographic Variables 
The demographic variables collected in this study include age, gender, race, ethnicity, and iris color.  
Subjects who record more than one race will be grouped into a single category denoted as multi-racial. 
Iris color will be presented at the subject level with a category for heterochromia. Sex, race, ethnicity, 
and iris color will be presented using descriptive summary statistics with counts and percentages. Age 
(years) will be summarized, overall and by treatment sequence, using continuous descriptive statistics. 
Age will be reported in years and calculated using the following formula: 
Age = (informed consent date – date of birth) / 365.25 truncated as an integer 
Demographic variables will be summarized for the ITT by treatment sequence and overall in tables. A 
subject listing that includes all demographic variables will be provided.  
11.2 
Pretreatment Variables 
Pretreatment variables are measured to ensure the safety and eligibility of subjects at Visit 1 and to 
confirm their previous results taken within 3 months of Visit 1 have not changed. Subject level listings 
will be used to present pretreatment information from the ITT population at the eye level when 
appropriate. The baseline pretreatment characteristic variables will be included on listings only and 
include the following variables:  
• 
Fluorescein Staining (pre-placebo instillation) 
• 
Manifest Refraction 
• 
Dark Adaptive Pupillometry 
Pre-treatment best-corrected distance visual acuity (BCVA) measured using an ETDRS chart in 
logMAR units will be assessed for screening and study eye selection at Visit 1 pre- and post-placebo 
instillation and will be presented with the Safety Population on the listings and tables of appropriate 
distances. A pre-placebo measurement of BCVA (at 10 feet) will confirm the BCVA assessed with 
 A pre- and 0.5 hours post-placebo measurement of 
BCVA at 45 cm is measured for screening purposes and selection of the study eye further explained 
in Section 4.1. The Investigator will indicate on the CRF whether VA was measured with or without 
correction, and if pin-hole was used. 


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12. Medical History and Concomitant Medications 
12.1 
Medical History 
Medical history will be coded using Medical Dictionary for Regulatory Activities (MedDRA) Version 20.0. 
Non-ocular medical history will be summarized using discrete summary statistics and presented by 
treatment sequence at the subject level by System Organ Class (SOC) and Preferred Term (PT) using 
the ITT population.  Ocular medical history will be similarly summarized at the subject level.  If a subject 
reports the same PT multiple times within the same SOC, that PT will only be reported once within that 
SOC.  As with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only 
be reported once. 
Listings of medical history will be generated separately for ocular and non-ocular data. 
12.2 
Concomitant Medications 
Concomitant medications will be coded using World Health Organization (WHO) Drug Dictionary, 
Version Enhanced B2, March 2017 and summarized to the therapeutic drug class (Anatomical 
Therapeutic Chemical [ATC] 4 classification) and preferred name (generic drug name). 
All medications taken 30 days prior to Visit 1 until the study end will be collected in the database. Prior 
medications are defined as those with an end date before the first treatment (Visit 2) in the sequence. 
Concomitant medications for each treatment are defined as those that are in use during dosing or started 
after dosing but ended before the next treatment in the sequence or study completion/discontinuation. 
Both ocular and non-ocular concomitant medications will be summarized using the ITT population.  
Medications will be tabulated for each treatment using frequencies and percentages.  Subjects may 
have more than one medication per ATC text.  At each level of subject summarization, a subject will be 
counted once if he/she reports one or more medications.  Percentages will be based on the number of 
subjects in each treatment.   
Listings of concomitant medications will be generated separately for ocular and non-ocular data. 
13. Dosing Compliance and Treatment Exposure 
13.1 
Dosing Compliance 
The study drug will be administered as a single dose by a trained study technician; therefore, dosing 
compliance and exposure cannot be calculated. Treatment administration will be listed by subject. 
14. Efficacy Analyses 
14.1 
Primary Analysis 
The primary efficacy variable in this study is the proportion of subjects with at least a 3-line (15-letter) 
improvement from the pre-treatment measurement of BCVA at 45 cm (monocular assessment) to 1 hour 








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Pairwise comparisons among treatment will also be made at each distance and time point using 
two-sample t-tests. The ITT population with no imputation is used for all secondary efficacy 
variables. All monocular assessments will analyze the study eye and fellow eye separately. For all 
secondary efficacy variables, descriptive statistics will be presented for each time point and distance 
as well as for the change from pre- to each post-treatment time point and distance by treatment. All 
secondary efficacy endpoints will also be presented in listings. The 45 cm and 
 BCVA listings 
will include a variable that indicates if a subject had a 3-line (15-letter) improvement from baseline. 
14.3 
Exploratory Efficacy Analyses 
Exploratory efficacy measures include the following: 
1. Proportion of subjects with at least a 3-line (15-letter) improvement in the study eye in the 
measurement of BCVA at 45 cm comparing baseline to 
a. 0.5, 1, 3, 4, 5 and 7 hours post-treatment 
2. 
 
 
 
 
   
 
  
 
 
 
 
 
 
  
 
  
 
Exploratory efficacy endpoints will be analyzed for all available data similarly to the primary and 
secondary endpoints in the mITT population and in the ITT population for sensitivity. All exploratory 
variables will include percentage based and mean based analyses, similar to the primary and 
secondary endpoints. Pairwise treatment comparisons will be calculated where possible, along with 
changes from pre-treatment; otherwise, analyses will be limited to within treatment statistics. 


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15. Safety Analyses 
All safety analyses will be conducted using the Safety Population. The percentage of subjects with 
treatment-emergent adverse events (TEAEs) will be summarized for each treatment.  Incidence will 
be tabulated by MedDRA SOC and PT within each SOC.  Slit lamp biomicroscopy, IOP, conjunctival 
redness, BCVA, low-luminance BCVA will be summarized descriptively using quantitative and 
qualitative summary statistics by visit and time point, as appropriate. 
15.1 
Adverse Events 
An AE is defined as any untoward medical occurrence associated with the use of an IP in humans, 
whether or not considered IP-related. An AE can be any unfavorable and unintended sign (e.g., an 
abnormal laboratory finding), symptom, or disease temporally associated with the use of an 
investigational product, without any judgment about causality. An AE can arise from any use of the 
IP (e.g. off-label use, use in combination with another drug or medical device) and from any route of 
administration, formulation, or dose, including an overdose. An AE can arise from any delivery, 
implantation, or use of a medical device, including medical device failure, patient characteristics that 
may impact medical device performance (e.g. anatomical limitations), and therapeutic parameters 
(e.g. energy applied, sizing, dose release) associated with a medical device.  
All AEs spontaneously reported by the subject and/or in response to an open question from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will be 
recorded in the source document and in the eCRF. Any clinically relevant deterioration in clinical finding 
is considered an AE and will be recorded. When possible, signs and symptoms indicating a common 
underlying pathology should be noted as one comprehensive event.  
Documentation regarding the AE should be made as to the nature, date of onset, end date, severity, 
relationship to investigational product, expectedness, action(s) taken, seriousness, and outcome of any 
sign or symptom observed by the physician or reported by the patient upon indirect questioning.  
AEs will be collected from the time the informed consent is signed through study exit. 
Severity 
Severity of an AE is defined as a qualitative assessment of the degree of intensity of an adverse event 
as determined by the Investigator or reported to him/her by the patient/subject.  The assessment of 
severity is made irrespective of relationship to IP or seriousness of the event and should be evaluated 
according to the following scale: 
• 
Mild: Event is noticeable to the subject, but is easily tolerated and does not interfere with the 
subject’s daily activities. 


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• 
Moderate: Event is bothersome, possibly requiring additional therapy, and may interfere with 
the subject’s daily activities. 
• 
Severe: Event is intolerable, necessitates additional therapy or alteration of therapy, and 
interferes with the subject’s daily activities. 
Relationship to Investigational Product 
The relationship of each AE to the IP should be determined by the Investigator using these explanations: 
• 
Suspected: A reasonable possibility exists that the IP caused the AE. 
• 
Not Suspected: A reasonable possibility does not exist that the IP caused the AE. 
Suspected adverse reaction means any AE for which there is a reasonable possibility that the IP caused 
the AE.  “Reasonable possibility” means there is evidence to suggest a causal relationship between the 
IP and the AE. Types of evidence that would suggest a causal relationship between the IP and the AE 
include:  a single occurrence of an event that is uncommon and known to be strongly associated with 
IP exposure (e.g., angioedema, hepatic injury, Stevens-Johnson Syndrome); one or more occurrences 
of an event that is not commonly associated with IP exposure, but is otherwise uncommon in the 
population exposed to the IP (e.g. tendon rupture); an aggregate analysis of specific events observed 
in a clinical trial (such as known consequences of the underlying disease or condition under investigation 
or other events that commonly occur in the study population independent of drug therapy) that indicates 
those events occur more frequently in the investigational product-treatment group than in a concurrent 
or historical control group. 
Expectedness 
The expectedness of an AE should be determined based upon existing safety information about the IP 
using these explanations: 
• 
Unexpected: an AE that is not listed in the Investigator’s Brochure (IB) or Report of Prior 
Investigations (ROPI) or is not listed at the specificity or severity that has been observed. 
• 
Expected: an AE that is listed in the IB or ROPI at the specificity and severity that has been 
observed. 
• 
Not applicable: an AE unrelated to the investigational product. 
Adverse events that are mentioned in the IB or ROPI as occurring with a class of products or as 
anticipated from the pharmacological/ mechanical (or other) properties of the product, but are not 
specifically mentioned as occurring with the particular product under investigation are to be considered 
unexpected. 
The Investigator will initially classify the expectedness of an AE, but the final classification is subject to 
the Medical Monitor’s determination. 


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Serious Adverse Events (SAE) 
An AE is considered serious if, in the view of either the Investigator or sponsor, it results in any of the 
following outcomes: 
• 
Death; 
• 
A life-threatening AE; 
o 
Note: An AE is considered “life-threatening” if, in the view of either the Investigator or 
sponsor, its occurrence places the patient or subject at immediate risk of death.  It does not 
include an AE that, had it occurred in a more severe form, might have caused death. 
• 
Inpatient hospitalization or prolongation of existing hospitalization; 
o 
Note: The term “inpatient hospitalization” refers to any inpatient admission (even if 
less than 24 hours).  For chronic or long-term inpatients, inpatient admission includes transfer 
within the hospital to an acute/intensive care inpatient unit.  Inpatient hospitalization does not 
include:  emergency room visits; outpatient/same-day/ambulatory procedures; 
observation/short stay units; rehabilitation facilities; hospice facilities; nursing homes; or 
clinical research/phase 1 units. 
o 
Note: The term “prolongation of existing hospitalization” refers to any extension of an 
inpatient hospitalization beyond the stay anticipated or required for the reason for the initial 
admission as determined by the Investigator or treating physician. 
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions; 
o 
Note: An SAE specifically related to visual threat would be interpreted as any potential 
impairment or damage to the subject’s eyes (e.g. hemorrhage, retinal detachment, central 
corneal ulcer or damage to the optic nerve). 
• 
A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require hospitalization may 
be considered serious when, based upon appropriate medical judgment, they may jeopardize the patient 
or subject and may require medical or surgical intervention to prevent one of the outcomes listed in this 
definition. 
AE Summaries 
All AEs will be coded using the MedDRA Version 20.0.   


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TEAEs are defined as any event that occurs or worsens on or after the day that randomized study 
treatment is initiated.  All AEs collected in the eCRFs will be presented in data listings, but only TEAEs 
will be summarized. 
An overall summary will be presented that includes the number of TEAEs and the number and 
percentage of subjects who experienced at least one TEAE, by treatment.  This summary will also 
include breakdowns of TEAEs further categorized as ocular or non-ocular, expected or unexpected 
TEAEs, treatment-emergent SAEs, TEAEs by maximum severity, related TEAEs, TEAEs leading to 
study treatment withdrawal, and TEAEs leading to death. 
Additional summaries of TEAEs will be provided showing the number and percentage of subjects who 
experienced at least one TEAE. These summaries will be presented by SOC and PT.  Non-ocular TEAEs 
will be summarized using discrete summary statistics and presented by treatment at the subject level 
by SOC and PT. Ocular TEAEs will be similarly summarized at the subject level.  If a subject reports the 
same PT multiple times within the same SOC, that PT will only be reported once within that SOC.  As 
with the PT, if a subject reports multiple conditions within the same SOC, that SOC will only be reported 
once.  In the summary, SOC will be listed in ascending alphabetical order; PTs will be listed in order of 
descending frequency for all subjects within each SOC.  The occurrence of non-ocular and ocular 
TEAEs will also be tabulated by SOC and PT for the following: maximal severity and suspected 
relationship to study drug. Expected and unexpected TEAEs and treatment-emergent SAEs will also be 
summarized by SOC and PT. 
Separate summaries will be provided for the following categories of AEs:  
• 
All AEs 
• 
Ocular TEAEs  
• 
Non-ocular TEAEs  
• 
Expected TEAEs  
• 
Unexpected TEAEs  
• 
Treatment-related TEAEs 
• 
Serious TEAEs 
• 
TEAEs leading to study discontinuation 
• 
TEAEs by Maximum Severity 
All AEs will be presented in a subject listing, with ocular AEs listed separately from non-ocular AEs.  
TEAEs leading to study treatment discontinuation will be listed separately.  In addition, all serious AEs 
will be presented in a separate listing. 


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15.2 
Best-Corrected Distance Visual Acuity (BCVA) 
Best-Corrected Distance Visual Acuity measured at the three meters or 10 feet distance is a safety 
variable. Measurements are done monocularly and binocularly pre-treatment and at 0.5, 1, 3, 4, 5, 
and 7 hours post treatment at each visit. The Investigator will indicate on the CRF whether VA was 
measured with or without correction, and if pin-hole was used. Monocular assessments will refer to a 
study eye and fellow eye. 
The sites will convert number of letters read correctly to the logMAR scores, which will be used for all 
summaries.  The observed and change from baseline in BCVA will be summarized by treatment using 
continuous descriptive summary statistics.  
Best-Corrected Distance Visual Acuity data will be also presented in a listing. Listings for the 10 feet 
BCVA will be displayed separately from 45 cm and 
 BCVA.  
15.3 
Low-Luminance Best-Corrected Distance Visual Acuity  
Binocular low-luminance BCVA and monocular low-luminance BCVA using an ETDRS chart calibrated 
for testing at three meters (10 feet) is conducted at baseline and at 0.5, 1, 3, 4, 5 and 7 hours post-
treatment. Results will be recorded in logMAR units.  
The observed and change from baseline low-luminance BCVA will be summarized for each eye (study 
eye and fellow eye for monocular low-luminance BCVA) and both eyes (for binocular low-luminance 
BCVA) using continuous descriptive statistics by time point for each treatment.  A subject listing of low-
luminance visual acuity will also be produced.  
15.4 
Slit Lamp Biomicroscopy Examination 
A slit lamp biomicroscopy examination will be conducted on both eyes at all scheduled visits pre-
treatment and at the last time point for each visit in the eyelid, conjunctiva, cornea, anterior chamber, 
iris, and lens. The results will be graded as normal, not clinically significant (NCS), or clinically 
significant (CS). 
A table will summarize results using counts and percentages for each treatment at each time point and 
location for each eye.  Percentages will be based on the number of subjects in each treatment with 
responses.  Shift tables and subject level listings will also be provided. 
15.5 
Intraocular Pressure (IOP) 
Intraocular pressure is measured at the end of every visit. IOP will be summarized by treatment for the 
study and fellow eye separately, using continuous descriptive summary statistics in a table. Change 
from baseline will also be calculated and summarized using descriptive summary statistics in a table.  
The data for IOP examinations will be presented in a listing. 


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15.6 
Conjunctival Redness  
Conjunctival redness is measured pre- and post-treatment at Visits 2, 3, and 4. Conjunctival redness 
will be summarized by treatment, for the right and left eye separately, using continuous descriptive 
summary statistics) in a table. Change from baseline will also be calculated and summarized using 
descriptive summary statistics in a table.  The data for Conjunctival redness will be presented in a listing. 
15.7 
Urine Pregnancy Test 
Female subjects of childbearing potential will have a urine pregnancy test at the site on the day of study 
visit 1, 2, 3, and 4. A subject level listing by visit will be produced. 
16. Changes from Protocol-Stated Analyses 
There are several changes from the protocol-stated analyses which include new populations, changes 
to the populations used for analyses and corresponding sensitivity analyses. 
New analysis populations not mentioned in the protocol but specified in Section 8.1 of this SAP: 
• 
monocular pre-treatment study eye compared to binocular post-treatment eyes 
• 
 
 
 
The following endpoints are analyzed in the ITT population, with no sensitivity populations, per the 
Protocol but will now be analyzed in the mITT to keep consistent with the other primary and secondary 
endpoints. Additionally, the ITT is moved to sensitivity analysis for the variables below: 
• 
Binocular BCVA 45 
• 
Binocular BCVA 
 
• 
Pupillometry 
Imputation sensitivity analysis methods specified in the protocol will no longer be used. The following 
endpoints will no longer be analyzed by imputing missing data once as a success and once as a failure: 
• 
Monocular BCVA 45 (includes primary endpoint) 
• 
Monocular BCVA 
 
These changes from protocol-stated analyses are Sponsor driven for this exploratory phase 2b study 
and based on the interest of other subgroup and population analyses. 
16.1 
Sensitivity Analyses 
Protocol specified sensitivity analyses may be performed as specified below on rare occasions if 
sensitivity analysis is needed.   






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14.3.1.1 
Overall Summary of Treatment-Emergent Adverse Events 
Safety Population 
14.3.1.2  
Ocular Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.3  
Non-Ocular Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.4  
Treatment-Related Ocular Treatment-Emergent Adverse Events by System 
Organ Class and Preferred Term 
Safety Population 
14.3.1.5  
Treatment-Related Non-Ocular Treatment-Emergent Adverse Events by 
System Organ Class and Preferred Term 
Safety Population 
14.3.1.6  
Expected Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.7  
Unexpected Treatment-Emergent Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.8  
Treatment-Emergent Serious Adverse Events by System Organ Class and 
Preferred Term 
Safety Population 
14.3.1.9  
Ocular Treatment-Emergent Adverse Events by System Organ Class, 
Preferred Term, and Maximal Severity 
Safety Population 




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16.2.7.1 
All Adverse Events 
Safety Population 
16.2.7.2 
Ocular Treatment-Emergent Adverse Events 
Safety Population 
16.2.7.3 
Non-Ocular Treatment-Emergent Adverse Events 
Safety Population 
16.2.7.4 
Expected Treatment-Emergent Adverse Events 
Safety Population 
16.2.7.5 
Unexpected Treatment-Emergent Adverse Events 
Safety Population 
16.2.7.6 
Treatment-Related Treatment-Emergent Adverse Events 
Safety Population 
16.2.7.7 
Serious Treatment-Emergent Adverse Events 
Safety Population 
16.2.7.8 
Treatment-Emergent Adverse Events Leading to Study Discontinuation 
Safety Population 
16.2.8.1 
Best-Corrected Visual Acuity (logMAR) at 3 meters (10 feet) 
Safety Population 
16.2.8.2 
Low-luminance Best-Corrected Distance Visual Acuity (logMAR) 
Safety Population 
16.2.8.3 
Slit Lamp Biomicroscopy 
Safety Population 
16.2.8.4 
Conjunctival Redness 
Safety Population 
16.2.8.5 
Intraocular Pressure (mmHg)  
Safety Population 
16.2.8.6 
Urine Pregnancy Test Results 
All Female Subjects 
 
21. Figures 
Figures will be produced for BCVA (logMAR) and pupillometry at 45 cm for different study eye 
definitions and different subgroups in the mITT population. Other figures will be produced at 
Sponsor discretion.