Clinical trial NCT03809611
Conditions: Presbyopia
Keywords: Presbyopia, adults, randomized study, placebo
Sponsor: Novartis Pharmaceuticals
Start date: 2019-04-26; Completion date: 2019-12-16
Enrollment: 125 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to assess the effect of topical UNR844-Cl (lipoic acid choline ester chloride) ophthalmic solution on near visual function in presbyopic subjects.

Detailed description:
This was a multi-center, double-masked, placebo-controlled, randomized, parallel-group study. The total duration of the study was approximately 3 months. Approximately 120 presbyopic subjects were to be enrolled into the study.

Presbyopic subjects aged 45 to 55 years were the primary age group in this study.

Screening and Baseline: Subjects were screened for eligibility followed by a baseline visit after which they were randomized to receive either UNR844-Cl (1.5%, equivalent to 1.3% freebase) or Placebo, dosed one drop in each eye twice daily, for 3 months.

Randomized subjects attended the following study visits after baseline: at Week 2, Month 1, Month 2 and Month 3.

The primary objective of this study was to assess the efficacy of UNR844-Cl on binocular distance corrected near visual acuity (DCNVA) in presbyopic subjects aged 45 to 55 years with the primary endpoint being the change from baseline in binocular DCNVA in subjects aged 45 to 55 years at Month 3 after UNR844-Cl or Placebo treatment.

There were two secondary endpoints:

1. To assess the efficacy of UNR844-Cl on achieving 75 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letters in binocular DCNVA in presbyopic subjects aged 45 to 55 years with endpoint being the proportion of subjects aged 45 to 55 years achieving 75 or more ETDRS letters in binocular DCNVA at Month 3 after UNR844-Cl or Placebo treatment.
2. To assess the safety of UNR844-Cl in presbyopic subjects by the frequency of treatment emergent adverse events (AEs) and treatment emergent serious adverse events (SAEs) in all subjects after UNR844-Cl or Placebo treatment.

Arms: arm 1: 1.5% UNR844-Cl ophthalmic solution for twice-daily dosing arm 2: placebo ophthalmic solution for twice-daily dosing
Interventions: intervention 1: UNR844-Cl intervention 2: Placebo
Intervention descriptions: intervention 1: 1.5% Ophthalmic solution for topical ocular administration intervention 2: placebo

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development
UNR844
Clinical Trial Protocol CUNR844A2203 / NCT03809611
A 3-month, randomized, placebo-controlled, double-
masked, multi-center study to evaluate the safety and 
efficacy of topical ocular UNR844-Cl in subjects with 
presbyopia 
Document type:
Clinical Trial Protocol
EUDRACT number:
N/A
Version number:
01 (Amended Protocol)
Clinical Trial Phase:
II
Release date:
02-Jul-2019
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template version 1.0 dated 01-Dec-2017


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
List of abbreviations............................................................................................................6
Glossary of terms.................................................................................................................7
Amendment 01 ...........................................................................................................................8
Protocol summary..............................................................................................................10
1
Introduction .......................................................................................................................12
1.1
Background............................................................................................................12
1.2
Purpose ..................................................................................................................13
2
Objectives and endpoints...................................................................................................13
3
Study design ......................................................................................................................14
4
Rationale............................................................................................................................15
4.1
Rationale for study design .....................................................................................15
4.1.1
Rationale for choice of background therapy.........................................15
4.2
Rationale for dose/regimen and duration of treatment ..........................................15
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................16
4.4
Purpose and timing of interim analyses/design adaptations..................................16
4.5
Risks and benefits..................................................................................................16
5
Population..........................................................................................................................17
5.1
Inclusion criteria ....................................................................................................17
5.2
Exclusion criteria...................................................................................................17
6
Treatment...........................................................................................................................19
6.1
Study treatment......................................................................................................19
6.1.1
Investigational and control drugs..........................................................20
6.1.2
Additional study treatments ..................................................................20
6.1.3
Treatment arms/group ...........................................................................20
6.1.4
Treatment duration................................................................................20
6.2
Other treatment(s)..................................................................................................20
6.2.1
Concomitant therapy.............................................................................20
6.2.2
Prohibited medication ...........................................................................20
6.3
Subject numbering, treatment assignment, randomization....................................22
6.3.1
Subject numbering ................................................................................22
6.3.2
Treatment assignment, randomization ..................................................22
6.4
Treatment blinding.................................................................................................23


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6.5
Dose escalation and dose modification..................................................................23
6.5.1
Dose modifications................................................................................23
6.5.2
Follow-up for toxicities.........................................................................23
6.6
Additional treatment guidance...............................................................................23
6.6.1
Treatment compliance...........................................................................23
6.6.2
Emergency breaking of assigned treatment code..................................24
6.7
Preparation and dispensation.................................................................................24
6.7.1
Handling of study treatment and additional treatment..........................24
6.7.2
Instruction for prescribing and taking study treatment .........................25
7
Informed consent procedures ............................................................................................25
8
Visit schedule and assessments .........................................................................................26
8.1
Screening ...............................................................................................................29
8.1.1
Information to be collected on screening failures.................................29
8.2
Subject demographics/other baseline characteristics.............................................29
8.3
Efficacy..................................................................................................................29
8.3.1
Distance-corrected near visual acuity ...................................................29
30
30
8.4
Safety.....................................................................................................................30
8.4.1
Laboratory evaluations..........................................................................32
8.4.2
Electrocardiogram (ECG) .....................................................................33
8.4.3
Pregnancy and assessments of fertility .................................................33
8.4.4
Appropriateness of safety measurements..............................................33
33
33
9
Study discontinuation and completion ..............................................................................34
9.1
Discontinuation......................................................................................................34
9.1.1
Discontinuation of study treatment .......................................................34
9.1.2
Withdrawal of informed consent...........................................................35
9.1.3
Lost to follow-up...................................................................................35
9.1.4
Early study termination by the sponsor.................................................35
9.2
Study completion and post-study treatment ..........................................................36
10 Safety monitoring and reporting........................................................................................36
10.1
Definition of adverse events and reporting requirements......................................36
10.1.1
Adverse events ......................................................................................36
10.1.2
Serious adverse events ..........................................................................37
10.1.3
SAE reporting........................................................................................38


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10.1.4
Pregnancy reporting ..............................................................................39
10.1.5
Reporting of study treatment errors including misuse/abuse................39
10.2
Additional Safety Monitoring................................................................................40
11 Data Collection and Database management......................................................................40
11.1
Data collection.......................................................................................................40
11.2
Database management and quality control............................................................40
11.3
Site monitoring ......................................................................................................41
12 Data analysis and statistical methods ................................................................................42
12.1
Analysis sets ..........................................................................................................42
12.2
Subject demographics and other baseline characteristics......................................42
12.3
Treatments .............................................................................................................42
12.4
Analysis of the primary endpoint(s) ......................................................................42
12.4.1
Definition of primary endpoint(s).........................................................42
12.4.2
Statistical model, hypothesis, and method of analysis..........................43
12.4.3
Handling of missing values/censoring/discontinuations.......................43
12.4.4
Sensitivity and Supportive analyses......................................................44
12.5
Analysis of secondary endpoints ...........................................................................44
12.5.1
Efficacy endpoint ..................................................................................44
12.5.2
Safety endpoints....................................................................................45
45
12.7
Interim analyses.....................................................................................................46
12.8
Sample size calculation..........................................................................................46
12.8.1
Primary endpoint(s)...............................................................................46
12.8.2
Secondary endpoint(s)...........................................................................46
46
13 Ethical considerations and administrative procedures ......................................................47
13.1
Regulatory and ethical compliance........................................................................47
13.2
Responsibilities of the investigator and IRB/IEC..................................................47
13.3
Publication of study protocol and results...............................................................47
13.4
Quality Control and Quality Assurance.................................................................47
14 Protocol adherence ............................................................................................................47
14.1
Protocol Amendments ...........................................................................................48
15 References .........................................................................................................................49
16 Appendices ........................................................................................................................50


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List of tables
Table 2-1
Objectives and related endpoints ..........................................................13
Table 6-1
Investigational and control drugs..........................................................20
Table 6-2
Prohibited medications and therapies....................................................21
Table 6-3
Prohibited medication changes .............................................................21
Table 6-4
Dose and treatment schedule.................................................................25
Table 8-1
Assessment Schedule ............................................................................27
Table 8-2
Safety assessment specifications...........................................................30
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................40
List of figures
Figure 3-1
Study Design .........................................................................................14


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List of abbreviations
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC 
Anatomical Therapeutic Chemical
BCDVA
Best-corrected distance visual acuity
BP
Blood Pressure
CFR
Code of Federal Regulation
CIR
Copy Increment from Reference
Cl
Chloride
CRO
Contract Research Organization
DCNVA
Distance-corrected near visual acuity
ECG
Electrocardiogram
eCRF 
electronic Case Report Form
EDC
Electronic Data Capture
EOS
End of study
ETDRS
Early Treatment Diabetic Retinopathy Study
FAS
Full Analysis Set
GCP
Good Clinical Practice
IB
Investigator's Brochure
ICH
International Conference on Harmonization of Technical Requirements for Registration of 
Pharmaceuticals for Human Use
IRB
Institutional Review Board
IRT
Interactive Response Technology
LA
Lipoic Acid
LACE
Lipoic Acid Choline Ester
LDH
lactate dehydrogenase
MAR
Missing At Random
MedDRA
Medical dictionary for regulatory activities
MMRM
Mixed effect Model Repeat Measurement
No.
Number
SAE
Serious Adverse Event
SUSAR
Suspected Unexpected Serious Adverse Reactions
TEAE
Treatment Emergent Adverse Event
TESAE
Treatment Emergent Serious Adverse Event
WoC
Withdrawal of consent


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) which is used as a 
comparator to the investigational drug being tested in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g., 100 mg once a day, 
75 mg twice-daily)
EDC (electronic 
data capture)
Electronic data capture (EDC) is the electronic acquisition of clinical study data using data 
collection systems, such as Web-based applications, interactive voice response systems 
and clinical laboratory interfaces. EDC includes the use of Electronic Case Report Forms 
(eCRFs) which are used to capture data transcribed from source documents used at the 
point of care.
Enrollment
Point/time of subject entry into the study at which informed consent must be obtained (i.e. 
prior to starting any of the procedures described in the protocol)
Investigational 
drug
The study drug whose properties are being tested in the study; this definition is consistent 
with US CFR 21 Section 312.3 and is synonymous with “investigational new drug” or 
“investigational medicinal product”.
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as well as their 
associated treatment controls. This includes any placebos, any active controls, as well as 
approved drugs used outside of their indication/approved dosage or tested in a fixed 
combination. Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by the protocol 
when used within approved indication/dosage.
Medication 
number
A unique identifier on the label of each study drug package in studies that dispense study 
drug using an IRT system.
Patient
An individual with the condition of interest
Period
A minor subdivision of the study timeline; divides phases into smaller functional segments 
such as screening, baseline, titration, washout, etc.
Premature 
subject 
withdrawal
Point/time when the subject exits from the study prior to the planned completion of all 
study drug administration and assessments; at this time all study drug administration is 
discontinued and no further assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study drug was 
discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; may or may 
not also be the point/time of premature subject withdrawal.
Study 
drug/treatment
Any drug (or combination of drugs) administered to the subject as part of the required 
study procedures; includes investigational drug, active drug run-ins or background 
therapy.
Study Treatment
Any drug administered to the study participants as part of the required study procedures; 
includes investigational drug(s), control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to the defined study 
treatment completion date
Subject
An individual who has consented to participate in this study. The term Subject may be 
used to describe either a healthy volunteer or a patient.
Subject number
A unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and should be used to identify the 
subject throughout the study for all data collected, sample labels, etc.


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Treatment 
number
A unique identifier assigned in non-randomized studies to each dosed subject, 
corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific assessments and 
used in data analysis to evaluate the drug being tested in the study
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject does not want to 
participate in the study any longer, and does not want any further visits or assessments, 
and does not want any further study related contact, and does not allow analysis of 
already obtained biologic material
Amendment 01
Changes to the protocol
1.  Section 5.1 Inclusion criterion 3
Less than 70 ETDRS letters at baseline and no more than 5 ETDRS letters difference between 
screening and baseline is changed to apply to binocular DCNVA only.
2. Section 8 Visit Schedule and assessments
A sentence was added; “Screening visit assessments may be split on separate days as close as 
possible to each other, however all visual acuity and refraction assessments must be performed 
on the same day.”
 


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4. Table 8-2 Safety Assessments specifications
Editorial correction of the sentence “Vital signs include blood pressure (BP) and heart rate 
measurements at screening” by deleting “at screening” since vital signs are performed at all 
visits as correctly displayed in Table 8-1.
5. Section 6.3.1 Subject numbering
Editorial correction removing “...by the Interactive Response Technology (IRT)”
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. A copy of 
this amended protocol will be sent to the Institutional Review Board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities. The changes described in this amended protocol 
require IRB/IEC approval prior to implementation. 
The changes herein do NOT affect the trial specific model ICF. 


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Protocol No. CUNR844A2203
Protocol summary
Protocol 
number
CUNR844A2203
Full Title
A 3-month, randomized, placebo-controlled, double-masked, multi-center study to evaluate 
the safety and efficacy of topical ocular UNR844-Cl in subjects with presbyopia
Brief title
Study of safety and efficacy of UNR844-Cl eye drops in subjects with presbyopia
Sponsor and 
Clinical Phase
Novartis Phase II study
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
To assess the effect of topical UNR844-Cl (lipoic acid choline ester chloride) ophthalmic 
solution on near visual function in presbyopic subjects.
Primary 
Objective
The primary objective of this study is to assess the efficacy of topical lipoic acid choline 
ester chloride ophthalmic solution in presbyopic subjects aged 45 to 55 years by assessing 
the change in binocular distance-corrected near visual acuity from baseline when 
compared to placebo after 3 months of treatment.
Secondary 
Objectives
To assess the efficacy of topical lipoic acid choline ester chloride ophthalmic solution in 
presbyopic subjects aged 45 to 55 years by assessing the proportion of subjects achieving 
75 or more Early Treatment Diabetic Retinopathy Study (ETDRS) letter score in binocular 
distance-corrected near visual acuity when compared to placebo after 3 months of 
treatment.
To assess the safety of topical lipoic acid choline ester chloride ophthalmic solution by 
comparing the frequency of treatment emergent adverse events and treatment emergent 
serious adverse event in all subjects treated with lipoic acid choline ester chloride and 
placebo over a treatment period of 3 months.
Study design
This is a randomized, double-masked, placebo-controlled, parallel-group study.
Eligible subjects will be randomized 1:1 to receive either topical lipoic acid choline ester 
chloride ophthalmic solution 1.5% or placebo, dosed one drop in each eye twice-daily for 3 
months.
Population
Approximately 120 male or female subjects aged 45 to 65 years with presbyopia will be 
enrolled, of which approximately 72 subjects will be aged 45 to 55 years, and 48 subjects 
will be aged 56 to 65 years.
Key Inclusion 
criteria

Phakic presbyopic male or female subjects aged 45 to 65 years, inclusive

Distance-corrected near visual acuity at 40 cm of less than 70 ETDRS letters for each 
eye and for binocular vision

Need a minimum add of +1.00D or greater to achieve binocular distance-corrected 
near visual acuity at 40 cm of at least 85 ETDRS letters assessed by the investigator.
Key Exclusion 
criteria

Best-corrected distance visual acuity at 4 m of less than 85 ETDRS letters in either 
eye

Spherical equivalent greater than +4.0D or less than -4.0D in either eye based on 
manifest refraction at screening or baseline visit

Any other clinically significant visual, ocular or systemic conditions
Study 
treatment
Topical lipoic acid choline ester chloride ophthalmic solution (UNR844-Cl) 1.5%, 
administered as one drop in each eye twice-daily for three months


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Placebo (vehicle ophthalmic solution), administered as one drop in each eye twice-daily for
three months
Efficacy 
assessments

Binocular distance-corrected near visual acuity at 40 cm
Key safety 
assessments

Adverse event monitoring

Ophthalmic examinations

Best-corrected distance visual acuity at 4 m, for each eye and for binocular vision
Other 
assessments
Data analysis
The primary efficacy analysis will test the null hypothesis that there is no difference in the 
change from baseline in binocular distance-corrected near visual acuity for subjects aged 
45 to 55 years between the treatment groups at three months, and the alternative 
hypothesis that this change from baseline is greater for the UNR844-Cl group than for the 
placebo group. A mixed-effect model repeated measure model will be fitted and the 
comparison between the two treatment groups will be performed using a two-group t-test at 
a one-sided significance level of 5%.
The secondary efficacy analysis will test the null hypothesis that there is no difference in the 
proportion of subjects aged 45 to 55 years achieving 75 or more ETDRS letters in binocular 
distance-corrected near visual acuity between the treatment groups at three months, and the 
alternative hypothesis that this proportion is greater for the UNR844-Cl group than for the 
placebo group. The comparison between the two treatment groups will be performed using 
a stratified Cochran-Mantel-Haenszel test at a one-sided significance level of 5%.
 
Key words
Presbyopia, near visual acuity, adults, randomized study, placebo


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1
Introduction
1.1
Background
Presbyopia is a common age-related vision disorder characterized by a progressive inability to 
focus on near objects. Approximately 80% of people aged 40 years or older will likely develop 
presbyopia (Holden et al 2008). It is estimated that there were 1.8 billion people affected by 
presbyopia worldwide in 2015 and it is predicted that 1.9 billion people will be affected by 2050 
(Fricke et al 2018).
Current management of presbyopia relies on optical correction (e.g., spectacles, contact lens) 
or surgical intervention (e.g., corneal inlay, corneal refractive procedures, and intraocular lens 
replacement). A pharmacological approach may offer an alternative therapeutic option that can 
have advantages in terms of improving patient convenience and satisfaction.
There are various etiologies proposed for the cause of presbyopia such as loss of ciliary muscle 
activity, geometric changes in the lens and hardening of the lens with increasing age 
(Strenk et al 2005). However, it is generally accepted that crystalline lens hardening leads to 
less accommodation in presbyopes. Recent research suggests that age-dependent increase in 
lens protein disulfides may be related to the loss of lens elasticity that contributes to presbyopia, 
and treatment with an antioxidant agent can restore lens elasticity (Garner and Garner 2016).
 
 
 
 
 
 
 
 
UNR844-Cl 1.5% topical ophthalmic solution was evaluated in a randomized, double-masked, 
placebo-controlled clinical study with 75 subjects with presbyopia. Fifty subjects were treated 
with UNR844-Cl 1.5% one drop to each eye twice a day for up to three months, while 25 
subjects received placebo treatment. UNR844-Cl was well tolerated and there were no safety 
issues identified. After three months, subjects treated with UNR844-Cl had a mean 
improvement in distance-corrected near visual acuity (DCNVA) of 8.1 Early Treatment 
Diabetic Retinopathy Study (ETDRS) letter score in their first treated eye, compared to a mean 
improvement of 4.3 ETDRS letter score in the placebo group.
The current study is designed to further evaluate the efficacy as observed in this previous study 
in terms of improvement in binocular DCNVA. 
 
 
 
Distance-corrected near visual acuity is the measurement of near vision at 
40 cm while subjects are wearing their prescription to correct their distance vision, if any (i.e., 


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for myopia, hyperopia or astigmatism). Core score is a multi- factor combination visual score 
ranked in terms of difficulty to identify targets of varying contrast, size and presentation time.
1.2
Purpose
The primary purpose of this study is to assess the safety and efficacy of UNR844-Cl in 
presbyopic subjects aged 45 to 55 years, as measured by the improvement in DCNVA. 
 
 
 
 
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Assess the efficacy of UNR844-Cl 
on binocular DCNVA in presbyopic 
subjects aged 45 to 55 years

Change from baseline in binocular DCNVA in subjects 
aged 45 to 55 years at Month 3 after UNR844-Cl or 
placebo treatment
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Assess the efficacy of UNR844-Cl 
on achieving 75 or more ETDRS 
letters in binocular DCNVA in 
presbyopic subjects aged 45 to 55 
years

Proportion of subjects aged 45 to 55 years achieving 
75 or more ETDRS letters in binocular DCNVA 
at Month 3 after UNR844-Cl or placebo treatment

Assess the safety of UNR844-Cl in 
presbyopic subjects

Frequency of treatment emergent adverse events and 
treatment emergent serious adverse events in all 
subjects after UNR844-Cl or placebo treatment


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3
Study design
Figure 3-1
Study Design


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This is a multi-center, double-masked, placebo-controlled, randomized, parallel-group study. 
The total duration of the study will be approximately 3 months (Figure 3-1). Approximately 
120 presbyopic subjects will be enrolled into the study.
Screening and Baseline: Subjects will be screened for eligibility followed by a baseline visit 
after which they will be randomized to receive either UNR844-Cl or placebo, dosed one drop 
in each eye twice-daily, for 3 months.
Randomized subjects will attend the following study visits after baseline: at Week 2, Month 1, 
Month 2 and Month 3.
4
Rationale
4.1
Rationale for study design
The rationale for this study is to further evaluate the efficacy as observed in the previous study 
with UNR844-Cl. This will be a randomized, double-masked, multi-center, placebo-controlled 
study.
Age group
Presbyopic subjects aged 45 to 55 years will be the primary age group in this study as in the 
previous clinical study with UNR844-Cl. 
 
 
 
Number of arms and dosing
One concentration of UNR844-Cl was evaluated in a prior clinical study. Since this study is to 
evaluate the efficacy observed earlier, the same UNR844-Cl 1.5% concentration 
 
 will be evaluated and subjects will be dosed twice-daily with either UNR844-Cl 
or placebo (two arms).
Duration of treatment
 
 
Therefore, the total treatment duration in this study will be three months.
4.1.1
Rationale for choice of background therapy
Currently, there are no pharmacological therapies approved for presbyopia. Subjects will be 
able to wear their optical correction, if needed, when not undergoing study assessments. 
Subjects will be instructed not to wear contact lenses prior to completing the study assessments 
on the day of the study visits.
4.2
Rationale for dose/regimen and duration of treatment
 
 


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, subjects will receive twice-daily UNR844-Cl treatment, one drop 
in each eye, for three months.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The control in this study is placebo, which comprise the formulation vehicle of UNR844-Cl (all 
inactive ingredients except the active drug substance UNR844-Cl). There are no approved 
pharmacological treatment for presbyopia. The aim of this study is evaluate the impact of 
UNR844-Cl on near visual function and therefore placebo (vehicle) is an appropriate 
comparator.
4.4
Purpose and timing of interim analyses/design adaptations
Not applicable.
4.5
Risks and benefits
In a prior clinical study with UNR844-Cl, there were no safety concerns identified. There were 
no serious adverse events (SAEs) and no subjects discontinued from the study because of an 
adverse event (AE).
The most commonly reported AEs were:

Nasopharyngitis (16% UNR844-Cl subjects, 8% placebo subjects)

Dysgeusia (14% UNR844-Cl subjects, 0% placebo subjects)

Upper respiratory tract infection (2% UNR844-Cl subjects, 8% placebo subjects)

Headache (8% UNR844-Cl subjects, 0% placebo subjects)
The most commonly reported AEs in the "eye disorders" system organ class were:

Eye irritation (6% UNR844-Cl subjects, 0% placebo subjects)

Asthenopia (4% UNR844-Cl subjects, 0% placebo subjects)

Conjunctival hyperemia (0% UNR844-Cl subjects, 8% placebo subjects)

Eye pruritus (4% UNR844-Cl subjects, 0% placebo subjects)

Foreign body sensation in eyes (4% UNR844-Cl subjects, 0% placebo subjects)

Ocular hyperemia (4% UNR844-Cl subjects, 0% placebo subjects)
The risk to subjects in this study will be minimized by compliance with the eligibility criteria 
and study procedures, as well as periodic monitoring of safety data.
The effects of UNR844-Cl ophthalmic solution on fertility, pregnancy and lactation have not 
been studied. No safety concerns are expected based on the nature of UNR844-Cl. However, 
women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study, and agree that in order 
to participate in the study they must adhere to the contraception requirements outlined in the 
exclusion criterion. If there is any question that the subject will not reliably comply, they should 
not be entered or continue in the study.


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Although UNR844-Cl exhibited a beneficial effect with respect to DCNVA in presbyopic 
subjects in a prior clinical study, it cannot be guaranteed that a similar effect would be observed 
in this study.
5
Population
Approximately 120 male or female presbyopic subjects aged 45 to 65 years will be enrolled, of 
which approximately 72 subjects will be aged 45 to 55 years and approximately 48 subjects will 
be aged 56 to 65 years.
With an estimated 10% drop-out rate, this would mean approximately 66 subjects are 
anticipated to complete the study in the 45 to 55 years age group and 44 subjects in the 56 to 65 
years age group.
5.1
Inclusion criteria
Subjects eligible for inclusion in this study must meet all of the following criteria at the 
screening visit unless specified otherwise:
1. Written informed consent must be obtained before any assessment is performed.
2. Phakic presbyopic male or female subjects aged 45 to 65 years, inclusive.
3. DCNVA of each eye, as well as for binocular vision, less than 70 ETDRS letters at 40 cm 
distance at the screening visit.

In addition, DCNVA for binocular vision at baseline must also be less than 70 
ETDRS letters at this visit and not more than 5 ETDRS letters different from the 
corresponding assessment at the screening visit.
4. Subjects who need a minimum add of +1.00D or greater to achieve binocular DCNVA of 
at least 85 ETDRS letters at 40 cm distance, as assessed by the investigator.
5.2
Exclusion criteria
Subjects meeting any of the following criteria at the screening visit (or unless specified 
otherwise) are not eligible for inclusion into this study.
1. Best-corrected distance visual acuity (BCDVA) less than 85 ETDRS letters at 4 m 
distance in either eye.
2. Spherical equivalent greater than +4.0D or less than -4.0D, based on manifest refraction, 
in either eye at the screening or baseline visit.
3. Astigmatism of greater than 1.25D, based on manifest refraction, in either eye at the 
screening or baseline visit.
4. Difference of greater than 0.50D between manifest refraction spherical equivalent and the 
cycloplegic refraction spherical equivalent.
5. Anisometropia of spherical equivalent of greater than 0.75D at the screening or baseline 
visit.
6. Any clinically significant congenital malformation or acquired changes to the lens or iris 
in either eye that might have an impact on visual acuity (e.g., clinically significant 
cataractous lens changes) or clinically significant phacodonesis.


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7. Undilated pupillary diameter of less than 2.5 mm in either eye measured at an ambient 
light level of 8 to 15 lux.
8. Unequal pupil diameters with a difference of greater than 1 mm between eyes.
9. Non-circular pupil assessed by the investigator to be related to a pathological cause.
10. Contraindication to pupil dilation in either eye or a history of untreated narrow angles or 
currently occludable angles in either eye.
11. Prior history or current diagnosis of accommodative spasm, accommodative 
insufficiencies, or other accommodative issues that would preclude accurate measurement 
of lens accommodation (except accommodative issues related to presbyopia).
12. Secondary cause of presbyopia in either eye (e.g., damage to lens, zonules or ciliary 
muscle, multiple sclerosis, cardiovascular accidents, vascular insufficiency, myasthenia 
gravis, anemia, influenza, measles).
13. Any active ocular infection (i.e., bacterial, viral, parasitic or fungal), or inflammation, or a 
history of herpetic ocular infection in either eye at screening or baseline.
14. History of idiopathic or autoimmune uveitis in either eye.
15. Ocular surface disease from any cause (e.g., dry eye, blepharitis, exposure) in either eye at 
the screening visit that is greater than mild in severity and is not controlled by use of over-
the-counter artificial tear products.
16. History or current diagnosis of treated or untreated glaucoma of any type.
17. History of penetrating ocular trauma, significant blunt ocular trauma in either eye.
18. Prior intraocular surgery or laser surgery of any kind in either eye, including prior cataract 
extraction.
19. Planned intraocular or extra-ocular surgery (e.g., cataract extraction or refractive surgery) 
in either eye during the study period.
 
21. Prior participation in the EV-C-002 study or prior use of UNR844-Cl.
22. History of hypersensitivity to any of the study drugs or its inactive ingredients or to active 
ingredients of similar chemical classes.
23. Use of any medication known to affect accommodation, pupil size or intraocular pressure 
during the study, as listed in Table 6-3. Subjects who have been on a stable dose of such 
medication for at least 3 months prior to the screening visit and who are not expected to 
change the dose/regimen or discontinue the medication are eligible for the study.
24. Use of other investigational drugs within five half-lives or within 30 days of the screening 
visit (until the expected pharmacodynamic effect has returned to baseline, whichever is 
longer).
25. Prior therapy for presbyopia other than optical correction (e.g., supplements, medications, 
training exercises, ciliary body electrostimulation, corneal implants, surgery).
26. History of clinically significant cardiac abnormality.
27. History of diabetes mellitus.
28. History of malignancy of any organ system (other than localized squamous cell or basal 
cell carcinoma of the skin or in situ cervical cancer) within six months of the screening 
visit.


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29. Any ocular or systemic condition that, in the opinion of the investigator, would jeopardize 
subject safety, has an impact on visual acuity, affects study assessments or validity of 
study results.
30. Pregnant or nursing (lactating) women at screening.
31. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during the 
course of the study. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug. In case of oophorectomy alone, only when the reproductive 
status of the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least six months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Barrier methods of contraception: condom or occlusive cap (diaphragm or 
cervical/vault caps).

Use of oral (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate < 1%), for example hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device or intrauterine system
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking investigational drug.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g., age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child-bearing potential.
32. Subjects in a dependent or unequal relationship with the Sponsor or study site staff (e.g., 
employees of the Sponsor, employees or students under the direct supervision of the study 
site staff, immediate relatives of the study site staff)
No additional exclusions may be applied by the investigator, in order to ensure that the study 
population will be representative of all eligible subjects.
6
Treatment
6.1
Study treatment
Subjects will be randomized 1:1 to either UNR844-Cl or vehicle (placebo) dosed twice-daily 
for three months.


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6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drugs
Investigational/
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply Type
Sponsor (global 
or local)
UNR844-Cl 1.5%
Ophthalmic 
Solution
Topical ocular
Opaque plastic 
bottle
Novartis global
Placebo
Ophthalmic 
Solution
Topical ocular
Opaque plastic 
bottle
Novartis global
6.1.2
Additional study treatments
No additional treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
Subjects will be assigned at the baseline visit to one of the following two treatment arms in a 
1:1 ratio.

UNR844-Cl 1.5% ophthalmic solution - one drop in each eye twice-daily

Placebo ophthalmic solution - one drop in each eye twice-daily
6.1.4
Treatment duration
The planned treatment duration is three months.
6.2
Other treatment(s)
Not applicable.
6.2.1
Concomitant therapy
All medications, procedures and significant non-drug therapies (including physical therapy and 
blood transfusions) administered after the subject was enrolled into the study must be recorded 
in the concomitant medications/significant non-drug therapies or procedures electronic Case 
Report Form (eCRF) pages.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
randomized, contact Novartis to determine if the subject should continue participation in the 
study.
6.2.2
Prohibited medication
Use of the medications and therapies described in Table 6-2 are not allowed after screening.


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Table 6-2
Prohibited medications and therapies
Medication/therapy
Prohibition period
Action taken
Intraocular surgery or laser 
surgery of any kind in either 
eye, including cataract 
extraction
Any time after screening and 
throughout the study
Discontinue study treatment
 
 
 
Other investigational medicinal 
product or therapy
Any time after screening and 
throughout the study
Discontinue study treatment
Therapy for presbyopia other 
than optical correction (e.g., 
supplements, medications, 
training exercises, ciliary body 
electrostimulation, corneal 
implants, surgery)
Any time after screening and 
throughout the study
Discontinue study treatment
Subjects are not allowed to start, stop or change dosing of the following treatments after the 
screening visit, unless as part of the study protocol (Table 6-3).
Table 6-3
Prohibited medication changes
Medication
Prohibition period
Action taken
Antipsychotics
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Antidepressants
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Anticholinergics
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Calcium channel blockers
Any time after screening 
and throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Glaucoma medications
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug


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Medication
Prohibition period
Action taken
Psychostimulants
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Alpha-adrenergic agonists
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Any over-the counter or 
prescription ocular 
medications (except artificial 
tear products)
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Any other medications 
assessed by the investigator 
known to affect 
accommodation, pupil size or 
near vision
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Subjects who have prohibited medication/therapy or have prohibited medication changes during 
the study can continue in the study and their data will be handled as detailed in Section 12.4.3. 
6.3
Subject numbering, treatment assignment, randomization
6.3.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the study. The Subject No. consists of the Center 
Number (Center No.) (made of 4 numbers as assigned by Novartis to the investigative site) with 
a sequential subject number suffixed to it (made of 3 numbers), so that each subject is numbered 
uniquely across the entire database. Upon signing the informed consent form, the patient is 
assigned to the next sequential Subject No. available.
6.3.2
Treatment assignment, randomization
At baseline visit, all eligible subjects will be randomized via IRT to one of the treatment arms. 
The investigator or his/her delegate will contact the IRT after confirming that the subject fulfills 
all the inclusion/exclusion criteria. The IRT will assign a randomization number to the subject, 
which will be used to link the subject to a treatment arm and will specify a unique medication 
number for the first package of study treatment to be dispensed to the subject.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced by or under the responsibility of Novartis 


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Global Clinical Supplies using a validated system that automates the random assignment of 
medication numbers to packs containing the study treatment.
Randomization will be stratified based on binocular DCNVA (59 ETDRS letters or less; 60 
ETDRS letters or more) and age (45 to 50 years, 51 to 55 years and 56 to 65 years) at baseline.
Subjects will be randomized 1:1 within each stratum to either UNR844-Cl or placebo.
6.4
Treatment blinding
Subjects, investigator staff, those performing the assessments, and the Novartis study team will 
remain masked to the identity of the treatment from the time of randomization until database 
lock, using the following methods:
1. Randomization data are kept strictly confidential until the time of unmasking, and will not 
be accessible by anyone else involved in the study
2. The identity of the treatments will be concealed by the use of study treatments that are all 
identical in packaging, labeling and schedule of administration.
Unmasking will occur in the case of subject emergencies and at the conclusion of the study.
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
6.5.1
Dose modifications
Dose modifications are not allowed in this study. For subjects who do not tolerate the protocol-
specified dosing schedule, study treatment should be discontinued and, if possible, the subject 
is continued to be monitored in the study (Section 9.1.1).
6.5.2
Follow-up for toxicities
Not applicable.
6.6
Additional treatment guidance
Not applicable.
6.6.1
Treatment compliance
Subjects will be instructed at each on-therapy study visit to take the study treatment exactly as 
prescribed. Subjects will also be instructed to bring used/unused medication bottles to the study 
visits and the site staff will check compliance based on the number of bottles used.
The investigator must promote compliance by instructing the subject to take the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the investigator if he/she 
is unable for any reason to take the study treatment as prescribed. Compliance will be assessed 
by the investigator and/or study personnel at each visit. This information should be captured in 
the source document at each visit. All study treatment dispensed and returned must be recorded 
in the Drug Accountability Log.


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6.6.2
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide the 
requested subject identifying information and confirm the necessity to break the treatment code 
for the subject. The investigator will then receive details of the investigational drug treatment 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis monitor for the site and the study team that the code has been 
broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT/code break cards at any time in case of emergency. The investigator 
will provide:

Protocol number

Subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unblinding 
can be performed at any time.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label. Investigator staff will 
identify the study medication kits to dispense to the subject by contacting the IRT and obtaining 
the medication number(s). The study drug has a 2-part label (base plus tear-off or peel-off label), 
immediately before dispensing the medication kit to the subject, site personnel will detach the 
outer part of the label from the packaging and affix it to the source document.
6.7.1
Handling of study treatment and additional treatment
6.7.1.1
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure (IB). Clinical supplies are 
to be dispensed only in accordance with the protocol. Technical complaints are to be reported 
to the respective Novartis Country Organization Quality Assurance.
Medication labels will be in the local language and comply with local legal requirements. They 
will include storage conditions for the study treatment but no information about the subject 
except for the medication number.


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The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. Subjects will be asked 
to return all unused study treatment and packaging at the end of the study or at the time of 
discontinuation of study treatment.
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.7.1.2
Handling of additional treatment
Artificial tears are administered to subjects prior to certain visual function assessments in this 
study. Novartis will provide investigators with artificial tears for such use. These should be 
stored according to the manufacturers' instructions.
At the conclusion of the study, unused product can be disposed of by the investigator according 
to local practice.
6.7.2
Instruction for prescribing and taking study treatment
Table 6-4
Dose and treatment schedule
Investigational/Control Drug
(UNR844-Cl/ Placebo)
Dose
Frequency and/or Regimen
UNR844-Cl 1.5%
One drop in each eye
Twice-daily
Placebo
One drop in each eye
Twice-daily
Subjects should take the study treatment at approximately the same time each day twice-daily. 
For example, morning dose at approximately 8AM and evening dose at approximately 8PM. 
Contact lenses must be removed prior to administering the study treatment. Contact lenses may 
be worn approximately 15 minutes after administering the study treatment. If a dose is missed 
and it has been more than 6 hours from the approximate usual time of dosing, subjects should 
continue with the next scheduled dose.
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation) institutional review board (IRB) approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document.
Informed consent must be obtained before conducting any study-specific procedures (e.g., all 
of the procedures described in the protocol). The process of obtaining informed consent must 
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Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use (ICH) Good Clinical Practice (GCP) guidelines and regulatory 
requirements and is considered appropriate for this study. Any changes to the proposed consent 
form suggested by the investigator must be agreed by Novartis before submission to the IRB.
Information about common side effects already known about the investigational drug can be 
found in the IB. This information will be included in the subject informed consent and should 
be discussed with the subject during the study as needed. Any new information regarding the 
safety profile of the investigational drug that is identified between IB updates will be 
communicated as appropriate, for example, via an investigator notification or an aggregate 
safety finding. New information might require an update to the informed consent and then must 
be discussed with the subject.
Women of child-bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study they must adhere to the contraception requirements.
A copy of the approved version of all consent forms must be provided to Novartis after IRB 
approval.
 
8
Visit schedule and assessments
The assessment schedule (Table 8-1) lists all of the assessments and indicates with an “X” the 
visits when they are performed. All data obtained from these assessments must be supported in 
the subject’s source documentation.
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible. Screening visit assessments may 
be split on separate days as close as possible to each other, however all visual acuity and 
refraction assessments must be performed on the same day. Missed or rescheduled visits should 
not lead to automatic discontinuation. Subjects who prematurely discontinue the study for any 
reason should be scheduled for a visit as soon as possible, at which time all of the assessments 
listed for the final visit will be performed. At this final visit, all dispensed investigational 
product should be reconciled, and any adverse event and concomitant medications recorded on 
the eCRF.
All randomized and/or treated subjects should have a safety follow-up call conducted 30 days 
after last administration of study treatment (Section 9.2).


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Table 8-1
Assessment Schedule
Period
Screening
Treatment
Visit Name
Screening
Baseline
W2
M1
M1.5
M2
M2.5
M3/EOS
Days
-7
1
14
30
45
60
75
90
Informed consent
X
Demography
X
Study completion information
X
Medical history/current medical conditions
X
Inclusion/Exclusion criteria
X
X
Vital Signs
X
X
X
X
X
X
Physical Examination
X
Electrocardiogram (ECG)
X
Hematology
X
Clinical Chemistry
X
Urinalysis
X
Best-corrected distance visual acuity
X
X
X
X
X
X
Distance-corrected near visual acuity
X
X
X
X
X
X
Pregnancy Test (serum)
X
Pregnancy Test (urine)
X
Slit lamp biomicroscopy
X
X
X
X
X
X
Intraocular Pressure (IOP)
X
X
X
X
X
X
Dilated fundus exam
X
X
Adverse Events
X
X
X
X
X
X


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Period
Screening
Treatment
Visit Name
Screening
Baseline
W2
M1
M1.5
M2
M2.5
M3/EOS
Days
-7
1
14
30
45
60
75
90
Concomitant medications
X
X
X
X
X
X
Drug dispensation
X
X
X


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8.1
Screening
Screening
Re-screening is allowed once for those subjects who screen failed under the original Protocol 
v00 due to Inclusion criterion 3. All screening and baseline assessments must be repeated and 
Inclusion/Exclusion criteria as per amended Protocol v01 must be met for subjects who screen 
failed under original protocol. No other re-screenings are allowed.
8.1.1
Information to be collected on screening failures
Subjects who sign an informed consent form and subsequently found to be ineligible prior to 
randomization will be considered a screen failure. The reason for not starting on treatment will 
be entered on the screening phase disposition eCRF page. The demographic information, 
informed consent, and Inclusion/Exclusion eCRF pages must also be completed for screen 
failed patients. No other data will be entered into the clinical database for subjects who are 
screen failures, unless the subject experienced a SAE during the screening phase (see Serious 
Adverse Events Section 10.1.3 for reporting details). If the subject fails to be randomized, the 
IRT must be notified within two days of the screen fail that the subject was not randomized.
8.2
Subject demographics/other baseline characteristics
Patient demographic and baseline characteristic data to be collected on all subjects include: age, 
sex, race, ethnicity, relevant medical history/current medical condition (diagnosis and not 
symptoms will be recorded).
Investigators will have the discretion to record abnormal test findings on the Medical History 
eCRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
Baseline ocular characteristics include BCDVA, DCNVA,
 
 anterior and posterior eye segment 
health.
8.3
Efficacy
Efficacy assessments will be performed at the visits as specified in the assessment schedule 
(Table 8-1).
Instill one drop of artificial tear product in each eye approximately 5 minutes prior to starting 
visual acuity assessments. Additional drops may be used as needed. A period of approximately 
3 minutes should be observed between instillation of drops and restarting any visual 
assessments.
8.3.1
Distance-corrected near visual acuity
Distance-corrected near visual acuity at 40 cm at 100% contrast is measured binocularly and 
monocularly using an electronic near visual acuity testing system (M&S technologies Clinical 
Trial Suite). This assessment must be performed with subjects corrected for any distance 


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refractive errors. The system will provide the subject's DCNVA in ETDRS letter numerical 
score.
Novartis will provide the M&S Technologies Clinical Trial Suite system and training and 
certification on the system prior to the start of the study.
 
 
 
 
 
 
 
8.4
Safety
Safety assessments are specified below (Table 8-2) with the assessment schedule (Table 8-1) 
detailing when each assessment is to be performed. A detailed description about how to perform 
the assessments will be provided in the site operations manual.
Instill one drop of artifical tear product in each eye approximately 5 minutes prior to starting 
visual acuity assessments. Additional drops may be used as needed. A period of approximately 
3 minutes should be observed between instillation of drops and restarting any visual 
assessments.
For details on AE collection and reporting, refer to Adverse Events Section 10.1.
Table 8-2
Safety assessment specifications
Assessment
Specification
Physical examination
A routine physical examination will be performed 
at the baseline visit and will include an 
evaluation of the general appearance (e.g., skin, 
peripheral blood perfusion, extremities, lymph 
nodes).


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Assessment
Specification
Information for all physical examinations should 
be included in the source documentation at the 
study site. Clinically relevant findings that are 
present prior to signing informed consent must 
be included in the Medical History part of the 
eCRF. Significant findings made after first 
administration of investigational drug that meet 
the definition of an Adverse Event must be 
recorded on the Adverse Event section of the 
eCRF.
Vital sign
Vital signs include blood pressure (BP) and 
heart rate measurements. After the patient has 
been sitting for five minutes, with back 
supported and both feet placed on the floor, 
systolic and diastolic BPs will be measured once 
using an automated validated device (e.g., 
OMRON) with an appropriately sized cuff. If the 
investigator has any concerns with the single 
measurement, BP measurements should then 
be repeated after at least 10 minutes from the 
first measurement. All individual measurements 
should be entered in the source document. In 
case the cuff sizes available are not large 
enough for the patient's arm circumference, a 
sphygmomanometer with an appropriately sized 
cuff may be used.
Best-corrected distance visual acuity (BCDVA)
BCDVA will be measured binocularly and 
monocularly at 100% contrast at 4 m at the visits 
as detailed in the assessment schedule. An 
electronic visual acuity testing system will be 
used for this assessment.


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Assessment
Specification
Ophthalmic Examination
The following ocular assessments will be 
performed as per the schedule assessment:
1. Slit-lamp examination include evaluation of 
the lids/lashes, conjunctiva, cornea, anterior 
chambers aqueous reactions (cells and flare), 
iris, lens and anterior part of the vitreous body 
and assessment of phacodonesis in both eyes. 
Slit-lamp examination will be performed before 
study treatment and throughout the study. 
Phacodonesis should be assessed after dilation 
at Screening and Month 3 visits. The results will 
be recorded in the source documents only and 
any clinically significant findings must be 
documented in the eCRF.
2. Intraocular pressure will be assessed in both 
eyes with Goldmann applanation tonometer or 
Tonopen. This assessment must be performed 
after any visual acuity assessments.
3. Dilated fundus examination will be performed 
in both eyes. Any clinically significant findings 
must be documented in the eCRF.
8.4.1
Laboratory evaluations
A central laboratory will be used for analysis of all specimens collected.
The central laboratory will flag laboratory values falling outside of the normal ranges on the 
central laboratory reports. Investigators are responsible for reviewing these abnormal values for 
clinical significance, signing the laboratory reports to indicate their review, and reporting values 
considered clinically significant in the appropriate eCRF page.
Clinically significant abnormalities at screening must be recorded as medical history/current 
medical conditions.
Any clinically significant abnormal laboratory value should be evaluated and followed-up by 
the investigator until normal or a cause for the abnormality is determined.
8.4.1.1
Hematology
Hemoglobin, platelets, white blood cells, differential (basophils, eosinophils, lymphocytes, 
monocytes, neutrophils, other)
8.4.1.2
Clinical chemistry
Albumin, alkaline phosphatase, serum alanine aminotransferase (ALT), serum aspartate 
aminotransferase 
(AST), 
lactate 
dehydrogenase 
(LDH), 
calcium, 
magnesium, 
phosphorus, sodium, potassium, creatinine, direct bilirubin, total bilirubin, urea, uric acid, 
amylase, lipase, glucose (non-fasting).


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8.4.1.3
Urinalysis
Macroscopic (Dipstick) panel - color, bilirubin, blood, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity, urobilinogen
Microscopic panel - red blood cells, white blood cells, casts, crystals, bacteria and epithelial 
cells.
8.4.2
Electrocardiogram (ECG)
Electrocardiograms must be recorded after 10 minutes rest in the supine position to ensure a 
stable baseline. The preferred sequence of cardiovascular data collection during study visits is 
ECG collection first, followed by vital signs, and blood sampling. The Fridericia QT correction 
formula should be used for clinical decisions.
A single 12-lead ECG is collected. The original ECGs on non-heat-sensitive paper or a certified 
copy on non-heat sensitive paper, appropriately signed, must be collected and archived at the 
study site. If a patient had an ECG performed within 6 months of screening, the results of this 
ECG can be used in lieu of performing the screening ECG. A copy of the historical ECG will 
be retained in the patient's source documentation.
Clinically significant abnormalities must be recorded on the eCRF as either medical 
history/current medical conditions or adverse events as appropriate.
8.4.3
Pregnancy and assessments of fertility
All pre-menopausal women who are not surgically sterile will have pregnancy testing. 
Additional pregnancy testing might be performed if requested by local requirements. A serum 
pregnancy test is performed at screening and a urinary pregnancy test is sufficient at the end of 
study visit.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are appropriate evaluations of ocular and systemic health in 
presbyopic subjects administered UNR844-Cl ophthalmic solution.


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9
Study discontinuation and completion
9.1
Discontinuation
9.1.1
Discontinuation of study treatment
Discontinuation of study treatment for a subject occurs when study treatment is stopped earlier 
than the protocol planned duration, and can be initiated by either the subject or the investigator.
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being.
Study treatment must be discontinued under the following circumstances:

Subject decision

Pregnancy

Use of prohibited medications or therapies as described in Table 6-2

Unsatisfactory therapeutic effect

Any situation in which study participation might result in a safety risk to the subject

Following emergency unmasking
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of study treatment 
and record this information.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see Section 9.1.2). Where possible, they should return for the assessments 
indicated in the assessment schedule. If they fail to return for these assessments for unknown 
reasons, every effort (e.g., telephone, e-mail, or letter) should be made to contact the 
subject/pre-designated contact as specified in the lost to follow-up section. This contact should 
preferably be done according to the study visit schedule.
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule.


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After study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New/concomitant treatments

AEs/SAEs
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment.
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code section (Section 6.6.2).
9.1.2
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject:

Does not want to participate in the study anymore, AND

Does not allow further collection of personal data, AND

Does not want any further study-related contacts
In this situation, the investigator should make a reasonable effort (e.g., telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table (Table 8-1).
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation.
9.1.3
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject (e.g., dates of telephone 
calls, registered letters). A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study.
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. In taking the decision to terminate, 
Novartis will always consider the subject welfare and safety. Should early termination be 
necessary, subjects must be seen as soon as possible (provide instruction for contacting the 


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subject, when the subject should stop taking drug, when the subject should come for a final 
visit) and treated as a prematurely withdrawn subject. The investigator may be informed of 
additional procedures to be followed in order to ensure that adequate consideration is given to 
the protection of the subject’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes their Study Completion visit, and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision.
All randomized and/or treated subjects should have a safety follow-up call conducted 30 days 
after last administration of study treatment. The information collected is kept as source 
documentation. All SAEs reported during this time period must be reported as described in 
Section 10.1.3. Documentation of attempts to contact the subject should be recorded in the 
source documentation.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An AE is any untoward medical occurrence (e.g., any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product.
The investigator has the responsibility for managing the safety of individual subject and 
identifying AEs.
Novartis qualified medical personnel will be readily available to advise on trial-related medical 
questions or problems.
The occurrence of AE must be sought by non-directive questioning of the subject at each visit 
during the study. Adverse events also may be detected when they are volunteered by the subject 
during or between visits or through physical examination findings, laboratory test findings, or 
other assessments.
Adverse events must be recorded in the Adverse Events eCRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to Section 10.1.2):
1. The severity grade 

Mild: usually transient in nature and generally not interfering with normal activities

Moderate: sufficiently discomforting to interfere with normal activities

Severe: prevents normal activities


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2. Its relationship to the study treatment 

If the event is due to lack of efficacy or progression of underlying illness (i.e., 
progression of the study indication) the assessment of causality will usually be ‘Not 
suspected’. The rationale for this guidance is that the symptoms of a lack of efficacy 
or progression of underlying illness are not caused by the trial drug, they happen in 
spite of its administration and/or both lack of efficacy and progression of underlying 
disease can only be evaluated meaningfully by an analysis of cohorts, not on a single 
subject
3. Its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported.
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with study treatment. All adverse events must be treated 
appropriately. Treatment may include one or more of the following: 

dose not changed

drug interrupted/withdrawn
6. Its outcome (i.e., its recovery status or whether it was fatal)
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject.
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days (or end of study visit, 
whichever is longer) following the last dose of study treatment.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g., continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the study treatment, the interventions required to treat it, and the outcome.
Information about adverse drug reactions for the investigational drug can be found in the IB.
Abnormal laboratory values or test results constitute AEs only if they fulfill at least one of the 
following criteria:

They induce clinical signs or symptoms

They are considered clinically significant

They require therapy
Clinically significant abnormal laboratory values or test results must be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values, which are considered to be non-typical in subjects with 
the underlying disease. 
10.1.2
Serious adverse events
A SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s) or medical conditions(s) which meets any one of the following criteria:


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
Fatal

Life-threatening 

Life-threatening in the context of a SAE refers to a reaction in which the subject was 
at risk of death at the time of the reaction; it does not refer to a reaction that 
hypothetically might have caused death if it were more severe (please refer to the 
ICH-E2D Guidelines).

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

Is medically significant (i.e., defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above)
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction.
All reports of intentional misuse and abuse of the product are also considered SAEs irrespective 
if a clinical event has occurred (Section 10.1.5).
10.1.3
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last administration of study 
treatment   must be reported to Novartis Safety within 24 hours of learning of its occurrence. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator site file provided to each site.


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All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
If the SAE is not previously documented in the IB (i.e., a new occurrence) and is thought to be 
related to the study treatment, a Novartis Safety Department associate may urgently require 
further information from the investigator for health authority reporting. Novartis may need to 
issue an Investigator Notification to inform all investigators involved in any study with the same 
study treatment that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees as per national regulatory 
requirements in participating countries.
Any SAEs experienced after the 30-day period following the last administration of study 
treatment should only be reported to Novartis Safety if the investigator suspects a causal 
relationship to study treatment.
10.1.4
Pregnancy reporting
Pregnancies
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications.
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety. Pregnancy follow-up should be recorded on the same form and should 
include an assessment of the possible relationship to the study treatment of any pregnancy 
outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the "Study treatment (Summary)" eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Novartis Safety only if associated with an SAE. Misuse or abuse will 


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be collected and reported in the safety database irrespective of it being associated with an 
AE/SAE within 24 hours of investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Study 
treatment (Summary) 
eCRF
Document in AE 
eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with 
an AE
Only if associated with 
an SAE
Misuse/abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections (Section 10.1.1, Section 10.1.2 and Section 10.1.3).
10.2
Additional Safety Monitoring
Not applicable.
11
Data Collection and Database management
11.1
Data collection
Designated investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
Code of Federal Regulation (CFR) Part 11 requirements. Investigator site staff will not be given 
access to the electronic data capture (EDC) system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs, allow modification and/or 
verification of the entered data by the investigator staff.
The investigator/designee is responsible for assuring that the data entered into the eCRF is 
complete and accurate, and that entry and updates are performed in a timely manner. The 
investigator must certify that the data entered are complete and accurate
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site.
Automatic validation programs check for data discrepancies and, by generating appropriate 
error messages, allow the data to be confirmed or corrected before transfer of the data to the 
vendor working on behalf of Novartis.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
11.2
Database management and quality control
Novartis personnel or designated contract research organization (CRO) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 


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site staff are required to respond promptly to queries and to make any necessary changes to the 
data.
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization Drug Reference List, which employs the Anatomical Therapeutic 
Chemical (ATC) classification system. Medical history/current medical conditions and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology.
Randomization codes and data about all study treatment(s) dispensed to the subject will be 
tracked using IRT. The system will be supplied by a vendor, who will also manage the database. 
The data will be sent electronically to Novartis (or a designated CRO) at specific timelines.
Each occurrence of a code break via IRT will be reported to Novartis personnel. The code break 
functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unmasked and made 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management.
11.3
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e., eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The field monitor will 
visit the site to check the completeness of subject records, the accuracy of data capture/data 
entry, the adherence to the protocol and to GCP, the progress of enrollment, and to ensure that 
study treatment is being stored, dispensed, and accounted for according to specifications. Key 
study personnel must be available to assist the field monitor during these visits. Continuous 
remote monitoring of each site’s data may be performed by Novartis or designated CRO. 
Additionally, a central analytics organization may analyze data and identify risks and trends for 
site operational parameters, and provide reports to Novartis clinical teams to assist with trial 
oversight.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original informed consent form signed by the 
subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the eCRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
subjects will be disclosed.


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12
Data analysis and statistical methods
The analysis will be conducted on all subject data at the time the study ends.
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation.
12.1
Analysis sets
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. FAS 
will be used for all efficacy variables, unless otherwise stated.
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized/assigned treatment if the subject took at least one dose of that treatment or 
the first treatment received if the randomized/assigned treatment was never administered.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group.
12.3
Treatments
The Safety Set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented.
The duration of exposure in days to UNR844-Cl or placebo will be summarized by means of 
descriptive statistics using the Safety Set.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the ATC classification system, by 
treatment group.
12.4
Analysis of the primary endpoint(s)
The primary objective of the study is to assess the efficacy of UNR844-Cl on binocular DCNVA 
in presbyopic subjects aged 45 to 55 years.
12.4.1
Definition of primary endpoint(s)
The primary estimand is defined as follows:

Population - subjects aged 45 to 55 years in the FAS with at least one post-baseline 
binocular DCNVA assessment  


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
Variable - change in ETDRS letter score from baseline in binocular DCNVA

Intercurrent events - data collected after any use of prohibited medications or therapies 
(Table 6-2), after prohibited medication changes (Table 6-3) or after discontinuation of 
study treatment will not be included in the estimand and will be treated as missing and 
imputed as described in Section 12.4.3

Population level summary - difference in variable means between treatment conditions at 
Month 3
12.4.2
Statistical model, hypothesis, and method of analysis
The primary efficacy endpoint, change from baseline in binocular DCNVA, will be analyzed at 
Month 3 based on the data observed in the FAS population, according to the treatment group 
subjects were randomized and the strata that were assigned at randomization. The strata 
information will be based on the data obtained from IRT that was utilized for randomization. 
The comparison between the two treatment groups will be performed using a two group t-test 
at one-sided 5% level of significance.
Assuming general linear model for change from baseline in binocular DCNVA, the following 
hypotheses will be tested:
H0: δ1 = 0 vs. Ha: δ1 > 0
where δ1 is the difference of change from baseline in numbers of letters read correctly between 
the UNR844-Cl and placebo at Month 3.
The model will include the change from baseline in binocular DCNVA at Month 3 as the 
dependent variable, binocular DCNVA at baseline as the covariate and treatment group and age 
group stratum at randomization as factors.
12.4.3
Handling of missing values/censoring/discontinuations
A mixed effect model repeat measurement (MMRM) model with the change from baseline in 
binocular DCNVA will be fitted. The model will include the change from baseline in binocular 
DCNVA as the dependent variable, binocular DCNVA at baseline as the covariate, treatment 
group and age group, assessment visit, interaction of treatment group and assessment visit as 
the fixed effect and subject as a random effect. For subjects who do not have a binocular 
DCNVA assessment at Month 3, the predicted values of the individual subject based on the 
multiple imputation will be used as dependent variable for the primary endpoint analysis and 
one of the supportive analysis.
The details of data handling for the primary efficacy endpoint are described below.
For subjects who either (1) fulfilled the protocol definition of having taken prohibited 
medications or therapy, or made prohibited medication changes (Section 6.2.2), or (2) 
discontinued study treatment permanently, the data collected following either scenario (1) or 
(2) will be excluded and treated as missing and imputed as follows:

For scenario (1) and (2) with reason for discontinuation being either adverse event or 
unsatisfactory therapeutic effect, Copy Increment from Reference (CIR) method will be 
used for imputation.

For all others, Missing at Random (MAR) method will be used for imputation.


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12.4.4
Sensitivity and Supportive analyses
There will be two supportive analyses
Supportive analysis #1:
The efficacy endpoint for Supportive analysis #1 is change from baseline in binocular DCNVA 
at Month 3 regardless of whether or not the intercurrent events occurred. The only difference 
between this analysis and the primary efficacy analysis is the inclusion of the data points after 
use of prohibited medications or therapy, prohibited medication changes or treatment 
discontinuation.
All data collected will be included in this analysis and the same imputation methods as those 
for the primary efficacy endpoint will be used to impute the time points that the data was truly 
missing.
Supportive analysis #2:
The efficacy endpoint for Supportive analysis #2 is change from baseline in binocular DCNVA 
at the end of treatment, which is always observed. There is no missing data imputation for the 
efficacy endpoint of this supportive analysis. 
12.5
Analysis of secondary endpoints
There are two secondary endpoints, one for efficacy and one for safety.
The secondary endpoint for efficacy is the proportion of subjects aged 45 to 55 years achieving 
75 or more ETDRS letters in binocular DCNVA at Month 3 after UNR844-Cl or placebo 
treatment.
The secondary endpoint for safety is the frequency of treatment-emergent AEs (TEAEs) and 
treatment-emergent SAEs (TESAEs) in all subjects after UNR844-Cl or placebo treatment.
12.5.1
Efficacy endpoint
The secondary efficacy endpoint, the proportion of subjects aged 45 to 55 years achieving 75 
or more ETDRS letters in binocular DCNVA at Month 3, is based on the data observed in the 
FAS population, according to the treatment group patients was randomized and the DCNVA 
stratum that was assigned at randomization. The comparison between the two treatment groups 
will be performed using stratified Cochran-Mantel-Haenszel test at one-sided 5% level of 
significance.
Assuming the following hypotheses will be tested:
H0: δ2 = 0 vs. Ha: δ2 > 0
where δ2 is the difference of proportion of subjects achieving 75 or more ETDRS letters in 
binocular DCNVA between the UNR844-Cl and placebo at Month 3.
The estimand for the secondary efficacy endpoint is closely related to the estimand for the 
primary efficacy endpoint. For subjects who has a DCNVA assessment at Month 3, the observed 
letter score will be used to derive the endpoint of achieving 75 or more ETDRS letters or not. 
For subjects who has no DCNVA assessment at Month 3, the predicted value of the estimand 


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for the primary efficacy endpoint will be used to derive the endpoint of achieving 75 or more 
ETDRS letters or not.
12.5.2
Safety endpoints
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.
Summary tables for AEs will summarize only on-treatment events, with a start date during the 
on-treatment period (TEAEs). The on-treatment period lasts from the date of first administration 
of study treatment to 30 days after the date of the last actual administration of any study 
treatment.
The secondary endpoint for safety is the frequency of TEAEs and TESAEs in all subjects.
The number (and proportion) of subjects with TEAE will be summarized in the following ways:

Overall summary of subjects with any TEAE, any severe TEAE, any study drug related 
TEAE, any TEAE leading to study drug discontinuation, any TESAE, any study drug 
related TESAE

TEAE by primary system organ class and preferred term

TEAE by descending frequency and preferred term for ocular and non-ocular respectively

TEAE by maximum severity

TESAE by primary system organ class and preferred term

Study drug related TESAE by system organ class and preferred term
Any other AEs or SAEs will be listed.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class.
Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time. Summary statistics 
will be provided by treatment and visit/time.


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12.7
Interim analyses
Not applicable.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Assuming a mean difference of 4.9 ETDRS letters with a common standard deviation of 6.02 
ETDRS letters in change from baseline in binocular DCNVA at 3 months between UNR844 
and placebo, based on the results of the prior study in presbyopic subjects, 66 subjects (33 in 
each arm) aged 45 to 55 years are required to complete the study to achieve an approximate 
power of 94% at 5% (one-sided) significance level. Assuming about 90% subjects will complete 
the study, a total of 72 subjects for the primary efficacy endpoint will be enrolled.
12.8.2
Secondary endpoint(s)
Assuming the proportion of subjects achieving 75 or more ETDRS letters in binocular DCNVA 
at Month 3 are 40.5% and 10.5% for UNR844-Cl and placebo, respectively, based on the results 
of the prior study in presbyopic subjects, 66 subjects (33 in each arm) aged 45 to 55 years are 
required to be completed to achieve an approximate power of 82% at 5% (one-sided) 
significance level.


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13
Ethical considerations and administrative procedures
13.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH GCP, with applicable local regulations (including European Directive 2001/20/EC, 
US CFR 21), and with the ethical principles laid down in the Declaration of Helsinki.
13.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the IRB for the trial protocol, written informed consent form, consent form updates, subject 
recruitment procedures (e.g., advertisements) and any other written information to be provided 
to subjects. Prior to study start, the investigator is required to sign a protocol signature page 
confirming his/her agreement to conduct the study in accordance with these documents and all
of the instructions and procedures found in this protocol and to give access to all relevant data 
and records to Novartis monitors, auditors, Novartis Quality Assurance representatives, 
designated agents of Novartis, IRBs, and regulatory authorities as required. If an inspection of 
the clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
13.3
Publication of study protocol and results
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov. In 
addition, after study completion (defined as last patient last visit) and finalization of the study 
report the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g., clinicaltrials.gov).
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that are provided prior to study start.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System that includes all activities involved in 
quality assurance and quality control, to ensure compliance with written Standard Operating 
Procedures as well as applicable global/local GCP regulations and ICH Guidelines.
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach.
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal standard operating procedures, and are performed according to written 
Novartis processes.
14
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of subjects should be 


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administered as deemed necessary on a case-by-case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB and health authorities, where required, it cannot be implemented.
14.1
Protocol Amendments
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB prior to 
implementation.
Only amendments that are required for subject safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, Novartis should 
be notified of this action and the IRB at the study site should be informed according to local 
regulations.


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15
References
References are available upon request
 
 
 
 


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16
Appendices
Not applicable.

SAP_001.pdf: 
Clinical Development
UNR844
CUNR844A2203 / NCT03809611
A 3-month, randomized, placebo-controlled, double-
masked, multi-center study to evaluate the safety and 
efficacy of topical ocular UNR844-Cl in subjects with 
presbyopia 
Statistical Analysis Plan (SAP)
Author:
Statistician, 
; Statistician, 
Document type:
SAP Documentation
Document status:
Final 2.0
Release date:
15-Jan-2020
Number of pages:
36
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
Jan 
3, 
2020
Prior 
to 
DB 
lock
To 
document 
changes to 
the 
original 
SAP
….


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................9
2.2
Analysis sets ..........................................................................................................11
12
2.3
Subject disposition, demographics and other baseline characteristics ..................12
2.3.1
Subject disposition ................................................................................12
2.3.2
Subject demographics and other baseline characteristics .....................12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................12
2.4.1
Study treatment / compliance................................................................12
2.4.2
Prior, concomitant and post therapies...................................................13
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoint...................................................................................15
2.5.2
Statistical hypothesis, model, and method of analysis..........................15
2.5.3
Handling of missing values/ multiple values/ censoring/ 
discontinuations.....................................................................................16
2.5.4
Supportive analyses...............................................................................16
2.6
Analysis of the key secondary objective ...............................................................17
2.7
Analysis of secondary efficacy objectives.............................................................17
2.7.1
Secondary endpoints .............................................................................17
2.7.2
Statistical hypothesis, model, and method of analysis..........................17
2.7.3
Handling of missing values/censoring/discontinuations.......................17
2.8
Safety analyses.......................................................................................................18
2.8.1
Adverse events (AEs)............................................................................18
2.8.2
Deaths....................................................................................................18
2.8.3
Laboratory data .....................................................................................18
2.8.4
Other safety data ...................................................................................19
2.9
Pharmacokinetic endpoints....................................................................................19
2.10
PD and PK/PD analyses.........................................................................................19
2.11
Biomarkers.............................................................................................................19


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19
19
20
2.13
Interim analysis......................................................................................................21
3
Sample size calculation .....................................................................................................21
3.1.1
Primary endpoint...................................................................................21
3.1.2
Secondary endpoints .............................................................................21
21
4
Change to protocol specified analyses ..............................................................................22
5
Appendix ...........................................................................................................................22
5.1
Imputation rules of missing dates..........................................................................22
5.1.1
AE date imputation ...............................................................................22
5.1.2
Concomitant medication date imputation .............................................24
5.2
Statistical models...................................................................................................25
5.2.1
Primary analysis and supportive analyses.............................................25
5.2.2
Secondary analysis................................................................................27
30
5.3
Rule of exclusion criteria of analysis sets..............................................................32
6
Reference...........................................................................................................................36


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
BCDVA
Best-corrected distance visual acuity
BP
Blood pressure
CIR
CMH
Copy Increment from Reference
Cochran-Mantel-Haenszel
CSR
Clinical Study report
DCNVA
Distance-corrected near visual acuity
FAS
Full Analysis Set
ECG
Electrocardiogram
ETDRS
Early Treatment Diabetic Retinopathy Study
eCRF
Electronic Case Report Form
IRT
Interactive Response Technology
IVR
Interactive Voice Response
MAR
Missing At Random
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MMRM
Mixed effect Model Repeat Measurement
RAP
PD
Report and Analysis Process
Protocol Deviation
SAE
Serious Adverse Event
SAF
SAP
Safety Set
Statistical Analysis Plan
SOC
TEAE
TESAE
System Organ Class
Treatment Emergent Adverse Event
Treatment Emergent Serious Adverse Event
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
The purpose of the Statistical Analysis Plan (SAP) is to describe the implementation of 
statistical analysis planned in the study protocol, and to provide detailed statistical methods that 
will be used for the Clinical Study Report (CSR) of study CUNR844A2203.
The analysis will be conducted on all subject data at the time the study ends.
Data will be analyzed according to the data analysis plan described in this document that will 
be incorporated into Section 9.7 and Appendix 16.1.9 of the CSR. 
1.1
Study design
Figure 1-1
Study Design
This is a multi-center, double-masked, placebo-controlled, randomized, parallel-group study. 
The total duration of the study will be approximately 3 months (Figure 1-1). Approximately 
120 presbyopic subjects will be enrolled into the study.
Screening and Baseline: Subjects will be screened for eligibility followed by a baseline visit 
after which they will be randomized to receive either lipoic acid choline ester chloride 
(UNR844-Cl) or placebo, dosed one drop in each eye twice-daily for 3 months.
Randomization will be stratified based on binocular distance-corrected near visual acuity 
(DCNVA) (59 Early Treatment Diabetic Retinopathy Study [ETDRS] letters or less; 60 ETDRS 
letters or more) and age (45 to 50 years, 51 to 55 years and 56 to 65 years) at baseline.
Subjects will be randomized 1:1 within each stratum to either UNR844-Cl or placebo.
Randomized subjects will attend the following study visits after baseline: at Week 2, Month 1, 
Month 2 and Month 3.
The primary objective of this study is to evaluate the efficacy of topical UNR844-Cl ophthalmic 
solution in presbyopic subjects aged 45 to 55 years by assessing the change in binocular 
DCNVA from baseline when compared to placebo after three months of treatment.


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There is no interim analysis planned.
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objectives
Endpoints
Primary objective
Endpoint for primary objective

Assess the efficacy of 
UNR844-Cl on binocular 
DCNVA in presbyopic 
subjects aged 45 to 55 years

Change from baseline in binocular DCNVA in 
subjects aged 45 to 55 years at Month 3 after 
UNR844-Cl or placebo treatment
Secondary objectives
Endpoints for secondary objectives

Assess the efficacy of 
UNR844-Cl on achieving 75 
or more ETDRS letters in 
binocular DCNVA in 
presbyopic subjects aged 45 to 
55 years

Proportion of subjects aged 45 to 55 years 
achieving 75 or more ETDRS letters in binocular 
DCNVA at Month 3 after UNR844-Cl or placebo 
treatment

Evaluate the safety of 
UNR844-Cl in presbyopic 
subjects

Frequency of treatment-emergent adverse events 
and treatment-emergent serious adverse events in 
all subjects after UNR844-Cl or placebo treatment


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2
Statistical methods
2.1
Data analysis general information
The analysis will be performed by the Biostatistics and statistical programming groups of 
Novartis, using SAS 9.4.
For categorical variables, frequencies and percentages will be computed. For continuous 
variables, descriptive statistics, including number of non-missing observations, mean, standard 
deviation, median, and range will be produced, where appropriate, point estimates and 
confidence intervals of treatment group differences will be provided.
These summary statistics will be presented by treatment group unless otherwise specified.
The randomization stratification factors in general will be included as factors in the primary 
efficacy analysis, and the corresponding supportive analyses.


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2.1.1
General definitions
2.1.1.1     Study treatment
Any drug administered to the study participants as part of the required study procedures, 
including investigational drug and control, which are:

Topical UNR844-Cl ophthalmic solution 1.5%, administered as one drop in each eye 
twice a day for three months

Placebo (vehicle ophthalmic solution), administered as one drop in each eye twice a day 
for three months
2.1.1.2
Baseline and post-Baseline
Baseline (Day 1) is the date of randomization. The baseline value for efficacy and 
safety variables is the last available value collected prior to or at the first date of study 
treatment. 
All data collected after the first date of treatment are defined as post-baseline. The study 
day for a baseline or post-baseline scheduled or unscheduled visit is defined as:
Study day = (Date of visit) – (Date of randomization) + 1;
The study day for a scheduled or unscheduled visit before baseline is defined as 
Study day = (Date of visit) – (Date of randomization).
2.1.1.3
End of study/end of treatment/unscheduled visit day mapping
The end of study date (from ‘Study disposition’ CRF) is the date when a subject completes or 
discontinues the study. The end of treatment date (from ‘Treatment disposition’ CRF) is the 
date of the last study treatment prior to/on the end of study date. For reporting data by visit in 
outputs, the end of study with discontinuation (Subject status from ‘Study disposition’ CRF 
NOT being ‘Completed’)/end of treatment with discontinuation (Subject status from ‘Treatment 
disposition’ CRF NOT being ‘Completed’)/unscheduled visit date will be allocated to the 
nearest planned main visit, by a 1/3 – 2/3 rule. To be more specific, suppose such a visit falls 
in two adjacent scheduled visits (e.g., visits A and B) of an assessment corresponding to visit 
days of X and Y. If the assessment day of such a visit falls within rounding (1/3*(Y-X+1)) after 
Day X, then it will be allocated to visit A, and to visit B otherwise. Figure 2-1 shows a graphical 
illustration of how this 1/3 – 2/3 rule of visit allocation is done. Table 2-1 shows an example of 
the allocation of end of study/end of treatment/unscheduled visit to a scheduled main visit, when 
an assessment is scheduled to be done at every scheduled visit; and Table 2-2 shows another
example of visit allocation when an assessment is only done at Baseline, Month 1, 2 and 3.


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Figure 2-1
Graphical illustration of visit allocation using the 1/3 – 2/3 rule
Table 2-1
Allocation of end of study/end of treatment/unscheduled visit for an 
assessment to be done at each scheduled visit
Scheduled 
main visit 
name/label
Scheduled 
visit study 
day
Scheduled visit 
window in days
Comment
Screening
-7
-7 – -1
Screening 
Baseline 
1
1
Baseline 
W2
14
2 – 19
M1
30
20 – 35
M1.5
45
36 – 50 
M2
60
51 – 65
M2.5
75
66 – 80
M3
90
>= 81
Table 2-2
Allocation of end of study/end of treatment/unscheduled visit for an 
assessment to be done at Baseline, Month 1, 2 and 3
Scheduled 
main visit 
name/label
Scheduled 
visit study 
day
Scheduled visit 
window in days
Comment
Baseline 
1
1
Baseline 
M1
30
2 – 40
M2
60
41 – 70
M3
90
>= 71
After allocation, if the nearest planned main visit already exists: for assessments with 
continuous scale, the mean value of all values from the scheduled planned main visit, and the 
end of study/end of treatment/unscheduled visit(s) allocated to that main visit will be used for 
tabulation or analyses by visit; for assessments with binary/categorical scale: data of the 
allocated value will only be used for tabulation and analyses by visit, if data of the 
corresponding scheduled visit is missing. If there are multiple entries of data for a scheduled 
visit of an assessment with binary/categorical scale, the last entry of the data will be used.


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2.1.1.4
Unscheduled visits
For tabulation and analyses by visit, all data collected at the unscheduled visits will 
first be allocated to a nearest planned main visit, then taken into account as the data (or 
part of the data) for that visit (Section 2.1.1.3). For analyses showing abnormalities, 
data from unscheduled visits will be considered individually, without mapping to a 
main visit. 
All data collected at unscheduled visits will be listed. 
2.1.1.5
On-treatment period
The on-treatment period lasts from the date of first administration of study treatment to 
30 days after the date of the last actual administration of any study treatment, i.e., date 
of the last actual administration of any study treatment (from ‘Study treatment’ CRF) 
– date of first administration of study treatment (from ‘Study treatment’ CRF) +1 + 30.
2.1.1.6
Missing baseline data
Missing baseline data will not be imputed.
2.1.1.7
Missing post-baseline data 
Observations with values ‘not done’, ‘not evaluable’, ‘not applicable’ will be treated as missing 
values. 
2.1.1.8
Better-seeing and worse-seeing eyes
The worse-seeing eye is defined as the eye that has the lower monocular DCNVA ETDRS letter 
score at baseline and the better-seeing eye is defined as the eye that has the higher ETDRS letter 
score. For subjects with identical monocular DCNVA ETDRS letter scores for both eyes at 
baseline, the right eye is defined as the worse-seeing eye.
2.2
Analysis sets
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. FAS 
will be used for all efficacy variables, unless otherwise stated.
The Safety Set (SAF) includes all subjects who received at least one dose of study treatment. 
Subjects will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized/assigned treatment if the subject took at least one dose of that 
treatment or the first treatment received if the randomized/assigned treatment was never 
administered.
Rules of exclusion criteria of analysis sets with protocol deviations and subject classification
are specified in Appendix 5.3.
The number and percentage of subjects within each of the above analysis sets will be 
summarized.


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2.3
Subject disposition, demographics and other baseline 
characteristics
2.3.1
Subject disposition
Subject disposition will be summarized separately by treatment group and total for the FAS. 
Specifically, the number and proportion of subjects who discontinued the study will be 
summarized by treatment and total. The primary reason for premature study discontinuation 
will be summarized in the table.
In addition, protocol deviations (PDs) will be summarized through presenting the number and 
percentage of subjects with each deviation.
2.3.2
Subject demographics and other baseline characteristics
Demographic (including age, sex, race, ethnicity) and other baseline data including disease 
characteristics (including DCNVA, best-corrected distance visual acuity [BCDVA], 
) will be 
listed and summarized descriptively by treatment group for the FAS.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class, preferred term and treatment group separately for ocular and non-ocualr 
histories/conditions. This includes any abnormalities noted during baseline evaluation of 
anterior and posterior eye segment health.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The SAF will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented.
2.4.1
Study treatment / compliance
The duration of exposure in days to UNR844-Cl or placebo will be summarized by 
means of descriptive statistics. The duration of exposure in days to UNR844-Cl or 
placebo is defined as: date of the last actual administration of UNR844-Cl or placebo 
(from ‘Study treatment’ CRF) – date of first administration of UNR844-Cl or placebo
(from ‘Study treatment’ CRF) +1.
Moreover, the on-treatment period (corresponding to the safety observation period) 
will also be summarized descriptively. The definition of the on-treatment period can be 
found from Section 2.1.1.5.


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Compliance will be presented by summarizing the total number of days with any 
treatment by treatment group. Reason of premature discontinuation from study 
treatment will also be summarized.
Total number of days with any treatment is calculated from ‘Study treatment’ CRF, by 
summing number of days ‘Dose interrupted’ and number of days from ‘Dose 
permanently discontinued’ to study end (the total number of days without treatment), 
then subtracted by duration of exposure. Suppose a subject has twice with ‘Dose 
interrupted’ and later ‘Dose permanently discontinued’ as recorded on ‘Study treatment’ 
CRF, then this subject’s total number of days without treatment is: (Start date of dose 
after the first dose interruption – stop date of dose before the first dose interruption) + 
(Start date of dose after the second dose interruption – Stop date of dose before the 
second dose interruption) + (end of study date – stop date of dose when ‘Dose 
permanently discontinued’).
2.4.2
Prior, concomitant and post therapies
Prior medications are defined as drugs taken and stopped prior to the first dose of study 
treatment. Any medication given at least once between the day of the first dose of the study 
treatment and the last study visit will be a concomitant medication, including those that were 
started pre-baseline visit and continued into the treatment period. Prior or concomitant 
medication will be identified based on recorded or imputed start and end dates of taking the 
medication.
Prior and concomitant medications and concomitant significant non-drug therapies will be 
summarized by treatment group (separately for ocular and non-ocular medications/therapies), 
presented in alphabetical order by ATC classification codes and preferred term. The tables will 
be presented with overall number and percentage of subjects receiving at least one drug of a 
particular ATC code and at least one drug in a particular preferred term. Medications will be 
coded according to the WHO Drug Reference List dictionary. In addition, all information will 
be listed including the reported name, laterality, and treatment start/end date, etc. 
Moreover, concomitant medications as well as significant non-drug therapies that are 
prohibited as per protocol (refer to Table 2-3 below) and given during the conduct of 
the study will be provided, separately for ocular and non-ocular medications/therapies. 
Summary tables on the start, stop or change dosing of the following treatments (Table 
2-4) after the screening visit, unless as part of the study protocol will also be shown.
Table 2-3
Prohibited medications and therapies
Medication/therapy
Prohibition period
Action taken
Intraocular surgery or laser 
surgery of any kind in either 
eye, including cataract 
extraction
Any time after screening and 
throughout the study
Discontinue study treatment
 
 
 
Other investigational medicinal 
product or therapy
Any time after screening and 
throughout the study
Discontinue study treatment


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Therapy for presbyopia other 
than optical correction (e.g., 
supplements, medications, 
training exercises, ciliary body 
electrostimulation, corneal
implants, surgery)
Any time after screening and 
throughout the study
Discontinue study treatment
Table 2-4
Prohibited medication changes
Medication
Prohibition period
Action taken
Antipsychotics
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Antidepressants
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Anticholinergics
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Calcium channel blockers
Any time after screening and
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Glaucoma medications
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Psychostimulants
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Alpha-adrenergic agonists
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
Any over-the counter or 
prescription ocular 
medications (except artificial 
tear products)
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug


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Medication
Prohibition period
Action taken
Any other medications 
assessed by the investigator 
known to affect 
accommodation, pupil size or 
near vision
Any time after screening and 
throughout the study
Record changes in the 
concomitant medication eCRF 
and report this protocol 
violation; subject can stay on 
study drug
2.5
Analysis of the primary objective
The primary objective of the study is to assess the efficacy of UNR844-Cl on binocular DCNVA 
in presbyopic subjects aged 45 to 55 years.
2.5.1
Primary endpoint
The primary estimand is defined as follows:

Population - subjects aged 45 to 55 years in the FAS with at least one post-baseline 
binocular DCNVA assessment  

Variable - change in ETDRS letter score from baseline in binocular DCNVA

Intercurrent events - data collected after any use of prohibited medications or therapies 
(Table 2-3), after prohibited medication changes (Table 2-4) or after discontinuation of 
study treatment will not be included in the estimand and will be treated as missing and 
imputed as described in Section 2.5.3.

Population level summary - difference in variable means between treatment conditions at 
Month 3.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary efficacy endpoint, change from baseline in binocular DCNVA, will be analyzed at 
Month 3 based on the data observed in the FAS population, according to the treatment group 
subjects were randomized to and the strata that were assigned at randomization. The strata 
information will be based on the data obtained from Interactive Response Technology (IRT)
that was utilized for randomization. The comparison between the two treatment groups will be 
performed using a two group t-test at one-sided 5% level of significance.
Assuming general linear model for change from baseline in binocular DCNVA, the following
hypotheses will be tested:
H0: δ1 = 0 vs. Ha: δ1 > 0
where δ1 is the difference of change from baseline in numbers of letters read correctly between 
the UNR844-Cl and placebo at Month 3.
A mixed effect model repeat measurement (MMRM) model with the change from baseline in 
binocular DCNVA will be fitted. The model will include the change from baseline in binocular 
DCNVA as the dependent variable, binocular DCNVA at baseline (on its original continuous 
scale) as the covariate, treatment group and age group stratum at randomization, assessment 
visit, interaction of treatment group and assessment visit as the fixed effects and subject as a 
random effect. For subjects who do not have a binocular DCNVA assessment at Month 3, the 
predicted values of the individual subject based on the multiple imputation will be used as 


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dependent variable for the primary endpoint analysis and one of the supportive analysis (Section 
2.5.3).
The p-value will be adjusted to one-sided, and is calculated as follows:

0.5*(original two-sided p-value) if the least squares mean difference of UNR844 versus 
placebo is greater than 0

1-0.5*(original two-sided p-value) if the least squares mean difference of UNR844 versus 
placebo is smaller than or equal to 0.
2.5.3
Handling of missing values/ multiple values/ censoring/
discontinuations
The details of data handling for the primary efficacy endpoint are described below.
If more than one DCNVA score is recorded for each eye or both eyes at a scheduled visit, this 
will be handled as follows:

Any score of “100” will be ignored;

Of the remaining scores, the one that was entered last will be used.
For subjects who either (1) fulfilled the protocol definition of having taken prohibited 
medications or therapy, or made prohibited medication changes (Section 2.4.2), or (2) 
discontinued study treatment permanently, the data collected following either scenario (1) or (2) 
will be excluded and treated as missing and imputed as follows.

For scenario (1) and (2) with reason for discontinuation being either adverse event or 
unsatisfactory therapeutic effect, Copy Increment from Reference (CIR) method will be 
used for imputation.

For all others, the Missing at Random (MAR) imputation approach with the Five Macros 
(Carpenter et al. 2013) will be used for imputation.
The prohibited medications and therapies, as well as prohibited medication changes will be 
identified through PDs. Data after (identified through PD start date) the use of prohibited 
medications or therapies will be excluded. Also, data after the prohibited medication change 
(identified through PD start date of a new PD for the changed prohibited medication) will be 
excluded.
2.5.4
Supportive analyses
There will be two supportive analyses
Supportive analysis #1:
The efficacy endpoint for Supportive analysis #1 is change from baseline in binocular DCNVA 
at Month 3 regardless of whether or not the intercurrent events occurred. The only difference 
between this analysis and the primary efficacy analysis is the inclusion of the data points after 
use of prohibited medications or therapy, prohibited medication changes or treatment 
discontinuation.
All data collected will be included in this analysis and the same imputation methods as those 
for the primary efficacy endpoint will be used to impute the time points that the data was truly 
missing.


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Supportive analysis #2:
The efficacy endpoint for Supportive analysis #2 is change from baseline in binocular DCNVA 
at the end of treatment, i.e., the time when last study treatment is administered, which is always 
observed. There is no missing data imputation for the efficacy endpoint of this supportive 
analysis. 
2.6
Analysis of the key secondary objective
There is no key secondary objective for the study. 
2.7
Analysis of secondary efficacy objectives
The secondary endpoint for efficacy is the proportion of subjects aged 45 to 55 years achieving 
75 or more ETDRS letters in binocular DCNVA at Month 3 after UNR844-Cl or placebo 
treatment.
2.7.1
Secondary endpoints
The secondary efficacy endpoint is the proportion of subjects aged 45 to 55 years achieving 75 
or more ETDRS letters in binocular DCNVA at Month 3.
2.7.2
Statistical hypothesis, model, and method of analysis
The analysis of the secondary efficacy endpoint is based on the data observed in the FAS
population, according to the treatment group subjects was randomized and the DCNVA stratum 
that was assigned at randomization. The comparison between the two treatment groups will be 
performed using stratified Cochran-Mantel-Haenszel (CMH) test at one-sided 5% level of 
significance, with stratified baseline DCNVA and age group as the stratification factors.
Alternatively, if the cell count for any of the strata is too small (e.g., <5), the analysis will be done 
separately for each of the two stratification factors.
Assuming the following hypotheses will be tested:
H0: δ2 = 0 vs. Ha: δ2 > 0
where δ2 is the difference of proportion of subjects achieving 75 or more ETDRS letters in 
binocular DCNVA between the UNR844-Cl and placebo at Month 3.
2.7.3
Handling of missing values/censoring/discontinuations
The estimand for the secondary efficacy endpoint is closely related to the estimand for the 
primary efficacy endpoint (refer to Section 2.5.3). For subjects who has a DCNVA assessment 
at Month 3 and do not have intercurrent event (as defined in Section 2.5.1), the observed letter 
score will be used to derive the endpoint of achieving 75 or more ETDRS letters or not. For 
subjects who has no DCNVA assessment at Month 3 or have intercurrent event (Section 2.5.1), 
the predicted value of the estimand for the primary efficacy endpoint will be used to derive the 
endpoint of achieving 75 or more ETDRS letters or not.


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2.8
Safety analyses
For all safety analyses, the SAF will be used. All listings and tables will be presented by 
treatment group.
2.8.1
Adverse events (AEs)
Summary tables for AEs and SAEs will summarize only on-treatment events, with a start date 
during the on-treatment period (TEAEs and TESAEs, respectively). The on-treatment period 
lasts from the date of first administration of study treatment to 30 days after the date of the last 
actual administration of any study treatment (Section 2.1.1.5).
The secondary endpoint for safety is the frequency of TEAEs and TESAEs in all subjects.
The number (and proportion) of subjects with TEAE will be summarized for ocular and non-
ocular AEs separately, by treatment group and overall in the following ways:

Overall summary of subjects with any TEAE, any severe TEAE, any study drug related 
TEAE, any TEAE leading to study drug discontinuation, any TESAE, any study drug 
related TESAE

TEAE by primary system organ class and preferred term

TEAE by primary system organ class, preferred term and maximum severity

TESAE by primary system organ class and preferred term

Study drug related TESAE by system organ class and preferred term

TEAE leading to study drug discontinuation by primary system organ class and preferred 
term

TEAE leading to study drug interruption by primary system organ class and preferred term
Except for the first table, all the above AE summaries will be provided by descending frequency 
in the UNR844-Cl group. A subject with multiple adverse events within a primary system organ 
class is only counted once towards the total of the primary system organ class.
Any other AEs or SAEs will be listed.
All these analyses will be based on the most updated MedDRA version available prior to the 
database lock.
2.8.1.1
Adverse events of special interest / grouping of AEs
Not applicable.
2.8.2
Deaths
Death will not be individually listed, or tabulated, but will be included as part of the AE analyses.
2.8.3
Laboratory data
It is not applicable, as data will only be recorded in the source document.


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2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
It is not applicable, as data will only be recorded in the source document.
2.8.4.2
Vital signs
All vital signs data (including systolic/diastolic blood pressure (BP), and heart rate 
measurements) will be listed by treatment group, subject, and visit/time. Summary statistics (n, 
mean, median, standard deviation, min, max) for the absolute value and the change from 
baseline will be provided by treatment and visit/time.
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Biomarkers
Not applicable.


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2.13
Interim analysis
Not applicable.
3
Sample size calculation
3.1.1
Primary endpoint
Assuming a mean difference of 4.9 ETDRS letters with a common standard deviation of 6.02 
ETDRS letters in change from baseline in binocular DCNVA at 3 months between UNR844 
and placebo, based on the results of the prior study in presbyopic subjects, 66 subjects (33 in 
each arm) aged 45 to 55 years are required to complete the study to achieve an approximate 
power of 94% at 5% (one-sided) significance level. Assuming about 90% subjects will complete 
the study, a total of 72 subjects for the primary efficacy endpoint will be enrolled.
3.1.2
Secondary endpoints
Assuming the proportion of subjects achieving 75 or more ETDRS letters in binocular DCNVA 
at Month 3 are 40.5% and 10.5% for UNR844-Cl and placebo, respectively, based on the results 
of the prior study in presbyopic subjects, 66 subjects (33 in each arm) aged 45 to 55 years are 
required to be completed to achieve an approximate power of 82% at 5% (one-sided) 
significance level.


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4
Change to protocol specified analyses
Not applicable.
5
Appendix
Statistical methods are described in the main part of the clinical study report. This appendix 
provides further details on the statistical derivation and practical implementation.
5.1
Imputation rules of missing dates
The general approach to handling missing dates is shown below for dates of AEs,medical 
history diagnosis, and concomitant treatment. The imputation of missing dates for surgery or 
procedures will use the same rules as for concomitant treatment.
The detailed algorithms will appear in Programming Dataset Specifications. 
For the purpose of date imputation, the treatment follow up period date is defined as the last 
available visit date.
5.1.1
AE date imputation
5.1.1.1
Adverse event end date imputation
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (treatment follow up period date, 31DECYYYY, date of death, cut-off date if available). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(the last visit date, last day of the month, date of death, cut-off date if available). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
4. In case the imputed AE end date is before AE start date, then use AE start date as imputed 
AE end date.
5.1.1.2
Adverse event start date imputation
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.


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MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.c )
Before Treatment 
Start
( 2.c )
Before Treatment 
Start
( 2.c )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.c )
Before Treatment 
Start
( 4.d )
Uncertain
( 4.d )
After Treatment Start
YYYY > TRTY
( 3.a )
After Treatment Start
( 3.c )
After Treatment Start
( 3.c )
After Treatment Start
( 3.c )
After Treatment Start
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min (informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Impute AE start date -
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date.  Therefore, if the AE year value is missing, the imputed AE start date is set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment.  Therefore:
a.
If AE day and month are missing, the imputed AE start date is set to the mid-year 
point (01JulYYYY).
b. If AE month is missing but day is not missing, the observed start date will be used 
with month imputed as JulYYYY.
c.
Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment.  Therefore:
a.
If the AE day and month are missing, the imputed AE start date is set to the year 
start point (01JanYYYY).
b. If AE month is missing but day is not missing, the observed start date will be used 
with month imputed as JulYYYY.
c.
Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE day and month are missing the imputed AE start date is set to the AE 
reference start date + 1 day.


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b. If AE month is missing and day is not missing, the observed start date will be used 
with month imputed as the reference start month.
c.
Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).
d. Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
5.1.2
Concomitant medication date imputation
5.1.2.1
Concomitant treatment end date imputation
1. If CM end day is missing and CM month/year are non-missing then impute CM day as 
the minimum of treatment end date and the last day of the month.
2. If CM end day/month are missing and CM year is non-missing then impute CM day as 
the minimum of treatment end date and the end of the year (31DECYYYY).
3. Only include if ongoing records will have an imputed CM end date. If CM 
day/month/year is missing then use the treatment end date + 1 day as the imputed CM 
end date. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.
5. If imputed CM end date is greater than date of death, date of cutoff, or the last visit date, 
then use the minimum of date of death, date of cutoff, and the last visit date as the 
imputed CM end date.
5.1.2.2
Concomitant treatment start date imputation 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
YYYY < TRTY
( 2.a ) 
Before Treatment Start
( 2.c )
Before Treatment Start
( 2.c )
Before Treatment Start
( 2.c )
Before Treatment Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment Start
( 4.a )
Uncertain
( 4.c )
After Treatment Start


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YYYY > TRTY
( 3.a )
After Treatment Start
( 3.c )
After Treatment Start
( 3.c )
After Treatment Start
( 3.c )
After Treatment Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date. 
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment.  Therefore:
a.
If the CM day and month are missing, the imputed CM start date is set to the 
mid-year point (01JulYYYY).
b. If CM month is missing but day is not missing, the observed start date will be 
used with month imputed as JulYYYY.
c.
Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a.
If the CM day and month are missing, the imputed CM start date is set to the 
year start point (01JanYYYY).
b. If CM month is missing but day is not missing, the observed start date will be 
used with month imputed as JanYYYY.
c.
Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a.
And the CM day and CM month are missing or the CM day is missing and CM 
month is equal to the treatment start date month, then the imputed CM start date 
is set to one day prior treatment start date.
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY).
c.
Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
5.2
Statistical models
5.2.1
Primary analysis and supportive analyses
The multiple imputation for the primary analysis and the supportive analyses will be done using 
the Five Macros (Carpenter et al. 2013). The code of the Mixed Model with Repeated Measures 


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(MMRM) is included in macro ‘part3_55’ for the primary analysis and the supportive analyses.
To get the 90% confidence intervals, the default of ‘Alpha’ as an input parameter of the macro 
‘part3_55’ can be changed to 0.1:
%part3(Jobname=<XXX>
,anref=0
,alpha=0.1
,Label=<YYY>);
The model fitting part included in the macro is essentially equivalent to fitting the MMRM 
model to each individually imputed data set using the following SAS code:
Change from baseline in binocular DCNVA = intercept + treatment + baseline binocular 
DCNVA + visit + age group + treatment*visit + error.
The following SAS code can be used to perform these analyses:
PROC MIXED DATA=<Dataset> order=Internal;
   CLASS USUBJID <Treatment> <VISIT> <AGE GROUP>;
   MODEL <Chg_DCNVA> = <Treatment> <VISIIT> <VISIT by Treatment>
                    <Baseline binocular DCNVA> <Age group> / 
DDFM=KENWARDROGER
                    ALPHA=0.05;
   REPEATED <VISIT>/type=UN subject=USUBJID;
   LSMEANS  <VISIT>*<Treatment> / DIFF CL ALPHA = 0.05;
   ODS OUTPUT LSMEANS=outLsm
             DIFFS=Diffs;
RUN;
The terms in the brackets are to be adjusted according to the real data set and variable names. 
Names of the output data sets from the Five Macros are: &jobname._datafinal (final multiply 
imputed data sets) and &jobname._out (model fitting statistics of the multiply imputed data 
sets). The two-sided p-value provided by the ESTIMATE statement will be converted to one-
sided p-value as follows:

If the mean difference is ≥0, the one-sided p-value = two-sided p-value/2;

If the mean difference is < 0, the one-sided p-value = 1 – two-sided p-value/2.
The summary statistics of the primary variable based on the multiply imputed data sets can be 
obtained using the following SAS macro:
%macro prim_sum(datain,Visit,Trt,Resp,Imput,dataout) ;
PROC SORT DATA=&datain;
BY &Visit &Imput &Trt;
RUN;
ODS OUTPUT ConfLimits=SUM;
PROC TTEST DATA = &datain;
BY &Visit &Imput;
CLASS &Trt;


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VAR &Resp;
RUN;
DATA SUM;
SET SUM;
BY &Visit &Imput;
where method^="Satterthwaite";
keep &Visit &Imput Class Mean StdDev;
RUN;
PROC SORT data=SUM;
BY &Visit Class &Imput;
RUN;
PROC MIANALYZE data=SUM alpha=0.1; *for the 90% confidence intervals;
BY &Visit Class;
ODS OUTPUT PARAMETERESTIMATES=&dataout;
MODELEFFECTS Mean;
STDERR StdDev;
RUN;
%mend  ;
To call the above macro, &datain should be &jobname._datafinal, &visit is the variable used to 
indicate different visits <Visit>, &trt is the variable indicating treatment arms <Treatment>, 
&Resp is the response variable < Chg_DCNVA>, &imput is the variable indicating sets of 
different imputed data. If only data at Month 3 needs to be presented, shown by stratum, the 
<Visit> variable can be supplied by stratification variable when calling the macro.
5.2.2
Secondary analysis
The secondary analysis results can be performed by running the following SAS macro
(Ratitch et al. 2013):
/*This macro performs all needed secondary analyses for UNR844A2203 study*/
%macro secondary(datain,Trt,Visit,Imput,Strata,Resp,method,dataout_sum,dataout_cmh,dataout_p) ;
PROC SORT data=&datain;
BY &Visit &Trt &Imput;
RUN;
/************************************************************************
**************Summary statistics of secondary endpoint at M3*************
************************************************************************/
/*Estimate proportions of responders in each arm*/


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PROC FREQ DATA=&datain;
TABLES Resp_MA / cl binomial(level=2);
BY &Visit &Trt &Imput;
ODS OUTPUT BINOMIAL=prop;
RUN;
run;
*** From ODS output dataset BINOMIAL, create a dataset
containing estimated proportion of responders in each
treatment arm and their standard errors;
DATA prop_trt;
MERGE
prop(WHERE=(Label1="Proportion")
KEEP=&Imput &Visit &Trt nValue1 Label1
RENAME=(nValue1=prop))
prop(WHERE=(Label1="ASE")
KEEP=&Imput &Visit &Trt nValue1 Label1
RENAME=(nValue1=prop_se));
BY &Visit &Trt &Imput;
RUN;
*** Combine proportion estimates;
PROC SORT DATA=prop_trt; BY &Visit &Trt &Imput; RUN;
PROC MIANALYZE DATA=prop_trt alpha=0.1;
MODELEFFECTS prop;
STDERR prop_se;
BY &Visit &Trt;
ODS OUTPUT PARAMETERESTIMATES=&dataout_sum;
RUN;
/*******************************************************************
*****************Perform CMH test***********************************
********************************************************************/
*** Step I: Obtain Mantel-Haenszel estimate of the common odds ratio adjusted for
&Strata ***;
PROC SORT DATA=&datain;
by &Visit &Imput;
RUN;
PROC FREQ DATA=&datain;
TABLES &Strata*&Trt*&Resp / CMH;
ODS OUTPUT COMMONRELRISKS=comrrout;
BY &Visit &Imput;
RUN;
*** Log-transform odds ratio estimates
and obtain standard error from confidence intervals ***;
DATA ormh_t; SET comrrout(WHERE=(StudyType="Case-Control"));
log_or_mh_value=log(VALUE);
log_or_mh_se=(log(UPPERCL)-log(LOWERCL))/(2*quantile('Normal',.975));
RUN;
*** Combine proportion estimates;
PROC SORT DATA=ormh_t; BY &Visit &Imput; RUN;


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PROC MIANALYZE DATA=ormh_t alpha=0.1;
MODELEFFECTS log_or_mh_value;
STDERR log_or_mh_se;
BY &Visit;
ODS OUTPUT PARAMETERESTIMATES=log_cmh;
RUN;
data &dataout_cmh ;
set log_cmh ;
Common_or = exp(Estimate);
*Or_upper = exp(Estimate+quantile('Normal',.95)*StdErr);
*Or_lower = exp(Estimate-quantile('Normal',.95)*StdErr);
e_lcl = exp(LCLMean);
e_ucl = exp(UCLmean);
Keep &Visit Common_or e_lcl e_ucl;
run;
PROC FREQ DATA=&datain;
TABLES &Strata*&Trt*&Resp / CMH;
ODS OUTPUT CMH=cmh;
BY &Visit &Imput;
RUN;
%if &method=1 %then %do;
/******Step II/Option 1: To obtain p-values, perform CMH test
by applying Wilson-Hilferty transformation to the CMH statistic*******/
*** Apply Wilson-Hilferty transformation to the CMH statistic and
standardize the resulting normal variable;
DATA cmh_wh; SET cmh(WHERE=(AltHypothesis="General Association"));
cmh_value_wh=((VALUE/DF)**(1/3) - (1-2/(9*DF)))/SQRT(2/(9*DF));
cmh_sterr_wh = 1.0;
RUN;
*** Combine results;
PROC MIANALYZE DATA=cmh_wh;
by &Visit;
ODS OUTPUT PARAMETERESTIMATES=mian_cmh_wh;
MODELEFFECTS cmh_value_wh;
STDERR cmh_sterr_wh;
RUN;
*** Compute one-sided p-value;
DATA &dataout_p; SET mian_cmh_wh;
IF tValue > 0 THEN Probt_WH = Probt/2;
ELSE Probt_WH = 1-Probt/2;
KEEP &Visit Probt_WH;
RUN;
%end;
%if &method=2 %then %do;
/******Step II/Option 2: To obtain p-values, perform CMH test
by applying Rubin & Li et al's transformation to the CMH statistic*******/
DATA cmh_rub; SET cmh(WHERE=(AltHypothesis="General Association"));
KEEP &Visit &Imput DF Value;
RUN;
PROC SORT DATA=cmh_rub ;


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BY &Visit &Imput;
RUN;
*** Implement pooling procedure described in equations (3) and (4);
PROC IML;
USE cmh_rub ;
READ ALL VAR {Value} INTO chval;
READ ALL VAR {&Visit} INTO vis;
Read ALL VAR "DF";
close;
uvis=unique(vis);
n_vis=ncol(uvis);
df=unique(df);
n=nrow(chval);
m=n/n_vis;
Prob_Rub={};
VisitN={};
do i=1 to n_vis;
VisitN=VisitN//uvis[1,i];
st=(i-1)*m+1;
   en=i*m;
cvalroot_m = sum(chval[st:en]##0.5)/m;
   cval_m = sum(chval[st:en])/m;
   a=(chval[st:en]##0.5-j(m,1,1)*cvalroot_m)##2;
   rx = sum(a)*(1+1/m)/(m-1);
   Dx=(cval_m/df - (m+1)/(m-1)*rx)/(1+rx);
   df_den=(df**(-3/m))*(m-1)*(1+1/rx)**2;
   Pval1=1-CDF("F",Dx,df,df_den);
   Prob_Rub=Prob_Rub//Pval1;
end; *endc;
create &dataout_p var {Prob_rub VisitN} ;
APPEND;
close &dataout_p;
RUN; QUIT;
%end;
%mend  ;
Before calling the above macro, first create a ‘Strata’ variable for the interaction term of 
stratified baseline binocular DCNVA and age group <Stratified baseline binocular DCNVA by 
age group interaction>, which will result in four strata/levels. The response variable should be 
dichotomized based on the multiply imputed data set created by the Five Macros 
&jobname._datafinal. Set ‘method=2’ as Rubin and Li et al.’s approach will be used. The macro 
contains three output data sets: &dataout_sum contains summary statistics of the binary 
variable; &dataout_cmh contains point estimate(s) and standard error(s) of the combined CMH 
test; &dataout_p includes the corrected p-value(s) after combining CMH statistics from the 
multiply imputed data sets.


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5.3
Rule of exclusion criteria of analysis sets 
The following table provides the definitions of the protocol deviations of the study, together 
with the exclusion rules. 
Table 1
Protocol Deviations
PD ID
Deviation Text
Data exclusion
INCL01
Informed consent not obtained
Exclude from all 
analysis sets


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PD ID
Deviation Text
Data exclusion
INCL02
Phakic presbyopic male or female subjects aged 45 to 
65 years at baseline
Include in all analysis 
sets
INCL03
DCNVA at 40 cms less than 70 ETDRS letters
Include in all analysis 
sets
INCL04
Near add of +1.00D or greater
Include in all analysis 
sets
EXCL01
Distance visual acuity of less than 85 ETDRS letters 
at 4m
Include in all analysis 
sets
EXCL02
Distance refractive error spherical equivalent greater 
than +4.0D or less than -4.0D
Include in all analysis 
sets
EXCL03
Astigmatism of greater than 1.25D
Include in all analysis 
sets
EXCL04
Difference of greater than 0.50D between manifest 
and cycloplegic refraction spherical equivalent
Include in all analysis 
sets
EXCL05
Anisometropia of greater than 0.75D
Include in all analysis 
sets
EXCL06
Clinically significant congenital or acquired changes 
to the lens or iris in either eye or clinically significant 
phacodonesis.
Include in all analysis 
sets
EXCL07
Undilated pupillary diameter of less than 2.5 mm in 
either eye
Include in all analysis 
sets
EXCL08
Unequal pupil diameters with a difference of greater 
than 1 mm between eyes
Include in all analysis 
sets
EXCL09
Non-circular pupil assessed related to a pathological 
cause
Include in all analysis 
sets
EXCL10
Contraindication to pupil dilation
Include in all analysis 
sets
EXCL11
Prior history or current diagnosis of any 
accommodative issues
Include in all analysis 
sets
EXCL12
Secondary cause of presbyopia in either eye
Include in all analysis 
sets
EXCL13
Any active ocular infection  in either eye at screening 
or baseline.
Include in all analysis 
sets
EXCL14
History of idiopathic or autoimmune uveitis in either 
eye.
Include in all analysis 
sets
EXCL15
Ocular surface disease from any cause  that is greater 
than mild in severity and is not controlled by OTC 
artificial tears
Include in all analysis 
sets


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PD ID
Deviation Text
Data exclusion
EXCL16
History or current diagnosis of treated or untreated 
glaucoma of any type.
Include in all analysis 
sets
EXCL17
History of ocular trauma in either eye.
Include in all analysis 
sets
EXCL18
Prior intraocular surgery or laser surgery including 
prior cataract extraction.
Include in all analysis 
sets
EXCL19
Planned intraocular or extra-ocular surgery (e.g., 
cataract extraction or refractive surgery)
in either eye during the study period.
Include in all analysis 
sets
EXCL20
History of or current use of
Include in all analysis 
sets
EXCL21
Prior participation in the EV-C-002 study or prior use 
of UNR844-Cl.
Include in all analysis 
sets
EXCL22
Hypersensitivity to any of the study drugs or its 
inactive ingredients
Include in all analysis 
sets
EXCL23
Use of any medication known to affect 
accommodation, pupils or intraocular pressure
Include in all analysis 
sets
EXCL24
Use of other investigational drugs within five half-
lives or within 30 days of the screening visit
Include in all analysis 
sets
EXCL25
Prior therapy for presbyopia other than optical 
correction
Include in all analysis 
sets
EXCL26
History of clinically significant cardiac abnormality
Include in all analysis 
sets
EXCL27
History of diabetes mellitus
Include in all analysis 
sets
EXCL28
History of malignancy of any organ system within 6 
months of screening
Include in all analysis 
sets
EXCL29
Any ocular or systemic condition that, in the opinion 
of the investigator, would jeopardize subject safety
Include in all analysis 
sets
EXCL30
Pregnant or nursing (lactating) women at screening
Include in all analysis 
sets
EXCL31
Women of child-bearing potential,unless they are 
using basic methods of contraception during the
course of the study
Include in all analysis 
sets
EXCL32
Subjects in a dependent or unequal relationship with 
the Sponsor or study site staff
Include in all analysis 
sets


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PD ID
Deviation Text
Data exclusion
TRT01
Randomized but wrong IP administered during the 
study
Include in all analysis 
sets
TRT02
Investigational or other study treatment dose
adjustments and/or interruptions made
Include in all analysis 
sets
TRT03
Subject missed a visit not allowed in the study
Include in all analysis 
sets
OTH01
Any other protocol deviation without impact on the 
safety of the patient
Include in all analysis 
sets
COMD01
Prohibited medication and/or procedure as per 
protocol
Include in all analysis 
sets
COMD02
Prohibited medication change as per protocol
Include in all analysis 
sets
WITH01
Subject withdrew consent but continue to receive 
study medication.
Include in all analysis 
sets
WITH02
Subject not tolerating the protocol prescribed dosing 
schedule but not withdrawn from the study.
Include in all analysis 
sets


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6
Reference
Carpenter JR, Roger JH, and Kenward MG (2013) Analysis of longitudinal trials with 
protocol deviation: a framework for relevant, accessible assumptions, and inference via 
multiple imputation. Journal of Biopharmaceutical Statistics; 23:1352-71.
Ratitch B, Lipkovich I, and O’Kelly M (2013). Combining analysis resutls from multiply 
imputed categorical data. PharmaSUG 2013: Paper SP03.