Conditions: Presbyopia
Keywords: loss of elasticity in lens lens lens disorder loss of near vision Presbyopia UNR844 farsightedness
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 234
Healthy volunteers: no

Brief summary:
Study of safety and efficacy of UNR844 in subjects with presbyopia.

Detailed description:
This was a randomized, placebo-controlled, double-masked,multi-arm, parallel-group, multi-center 13-month study which consisted of:

* A 1 week run-in period
* A 3-month treatment course with UNR844 and/or Placebo
* A 9-month treatment holiday period Participants were randomized equally to one of five treatment arms: UNR844 5 mg/mL,UNR844 13.3 mg/mL, UNR844 23 mg/mL, UNR844 30 mg/mL, or Placebo eye drops twice-a-day for three months.

Participants underwent a 1 week run-in period where they were assessed for entry criteria during the Screening visit. During the run-in period, participants self-administered 1 drop of artificial tears twice-a-day (1 drop in the morning and 1 drop in the evening) in each eye at home. This run-in period was designed to help minimize any potential variability in distance corrected near visual acuity (DCNVA) caused due to initial ocular surface issues and help to establish an accurate baseline prior to randomization. The run-in period was to help exclude participants with a change in DCNVA of 0.10 logMAR difference between Screening and Baseline.

This study was conducted to determine the optimum dose of UNR844 treatment and the duration of effect of UNR844 treatment for further development.

Arms:
arm 1: UNR844 5 mg/mL ophthalmic solution; one drop twice-a-day for three months arm 2: UNR844 13.3 mg/mL 1 ophthalmic solution; one drop twice-a-day for three months arm 3: UNR844 23 mg/mL ophthalmic solution; one drop twice-a-day for three months arm 4: UNR844 30 mg/mL ophthalmic solution; one drop twice-a-day for three months arm 5: placebo ophthalmic solution; one drop twice-a-day for three months

Interventions: intervention 1: UNR844 intervention 2: Placebo
Intervention descriptions: intervention 1: Ophthalmic solution for topical ocular administration intervention 2: Placebo

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
UNR844
Clinical Trial Protocol CUNR844A2202 / NCT04806503
A randomized, placebo-controlled, double-masked, multi-
center, dose-ranging study to evaluate the safety, and 
efficacy of UNR844 in subjects with presbyopia
Document type:
Amended Protocol Version
EUDRACT number:
N/A
Version number:
V02 Clean
Clinical Trial Phase:
IIb
Release date:
03-Sep-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis
Clinical Trial Protocol Template Version 3.0 dated 31-Jan-2020


Novartis
Confidential
Page 2 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Glossary of terms.................................................................................................................9
Amendment v02 (03-Sep-2021)...............................................................................................11
Amendment v01 (19-Jan-2021)................................................................................................13
Protocol summary..............................................................................................................15
1
Introduction .......................................................................................................................18
1.1
Background............................................................................................................18
1.2
Purpose ..................................................................................................................19
2
Objectives and endpoints...................................................................................................19
2.1
Primary estimands .................................................................................................20
2.2
Secondary estimands .............................................................................................20
3
Study design ......................................................................................................................21
4
Rationale............................................................................................................................22
4.1
Rationale for study design .....................................................................................22
4.1.1
Rationale for choice of background therapy.........................................22
4.2
Rationale for dose/regimen and duration of treatment ..........................................23
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................23
4.4
Purpose of Interim Analysis ..................................................................................23
4.5
Risks and benefits..................................................................................................23
5
Study Population ...............................................................................................................24
5.1
Inclusion criteria ....................................................................................................24
5.2
Exclusion criteria...................................................................................................25
6
Treatment...........................................................................................................................27
6.1
Study treatment......................................................................................................27
6.1.1
Investigational and control drugs..........................................................27
6.1.2
Additional study treatments ..................................................................27
6.1.3
Treatment arms/group ...........................................................................28
6.1.4
Treatment duration................................................................................28
6.2
Other treatment(s)..................................................................................................28
6.2.1
Concomitant therapy.............................................................................28
6.2.2
Prohibited medication ...........................................................................28
6.3
Participant numbering, treatment assignment, randomization ..............................30


Novartis
Confidential
Page 3 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
6.3.1
Participant numbering...........................................................................30
6.3.2
Treatment assignment, randomization ..................................................30
6.4
Treatment blinding.................................................................................................31
6.5
Dose escalation and dose modification..................................................................32
6.6
Additional treatment guidance...............................................................................32
6.6.1
Treatment compliance...........................................................................32
6.6.2
Emergency breaking of assigned treatment code..................................32
6.7
Preparation and dispensation.................................................................................33
6.7.1
Handling of study treatment and additional treatment..........................33
6.7.2
Instruction for prescribing and taking study treatment .........................34
7
Informed consent procedures ............................................................................................34
8
Visit schedule and assessments .........................................................................................35
8.1
Screening ...............................................................................................................39
8.1.1
Information to be collected on screening failures.................................39
8.2
Participant demographics/other baseline characteristics .......................................39
8.3
Efficacy..................................................................................................................39
40
41
8.3.3
Appropriateness of efficacy assessments..............................................41
8.4
Safety.....................................................................................................................41
8.4.1
Corneal fluorescein staining..................................................................43
8.4.2
Laboratory evaluations..........................................................................44
8.4.3
Pregnancy and assessments of fertility .................................................45
8.4.4
Appropriateness of safety measurements..............................................45
8.5
Additional assessments..........................................................................................46
8.5.1
Clinical Outcome Assessments (COAs) ...............................................46
47
9
Study discontinuation and completion ..............................................................................48
9.1
Discontinuation and completion............................................................................48
9.1.1
Study treatment discontinuation and study discontinuation..................48
9.1.2
Withdrawal of informed consent...........................................................49
9.1.3
Lost to follow-up...................................................................................49
9.1.4
Early study termination by the sponsor.................................................50
9.2
Study completion and post-study treatment ..........................................................50
10 Safety monitoring and reporting........................................................................................50
10.1
Definition of adverse events and reporting requirements......................................50


Novartis
Confidential
Page 4 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
10.1.1
Adverse events ......................................................................................50
10.1.2
Serious adverse events ..........................................................................52
10.1.3
SAE reporting........................................................................................53
10.1.4
Pregnancy reporting ..............................................................................53
10.1.5
Reporting of study treatment errors including misuse/abuse................54
10.2
Additional Safety Monitoring................................................................................54
11 Data Collection and Database management......................................................................54
11.1
Data collection.......................................................................................................54
11.2
Database management and quality control............................................................55
11.3
Site monitoring ......................................................................................................55
12 Data analysis and statistical methods ................................................................................56
12.1
Analysis sets ..........................................................................................................56
12.2
Participant demographics and other baseline characteristics.................................57
12.3
Treatments .............................................................................................................57
12.4
Analysis of the primary endpoint(s)/estimand(s) ..................................................57
12.4.1
Definition of primary endpoint(s)/estimand(s) .....................................57
12.4.2
Statistical model, hypothesis, and method of analysis..........................57
12.4.3
Handling of remaining intercurrent events of primary estimand..........60
12.4.4
Handling of missing values not related to intercurrent event ...............61
12.4.5
Sensitivity analyses for primary endpoint/estimand .............................61
12.4.6
Supplementary analysis.........................................................................61
12.4.7
Supportive analyses...............................................................................61
12.5
Analysis of secondary endpoints/estimands..........................................................61
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................61
12.5.2
Safety endpoints....................................................................................63
12.5.3
Patient reported outcomes.....................................................................63
63
64
65
12.7
Interim analyses.....................................................................................................65
12.8
Sample size calculation..........................................................................................66
12.8.1
Primary endpoint(s)...............................................................................66
13 Ethical considerations and administrative procedures ......................................................66
13.1
Regulatory and ethical compliance........................................................................66
13.2
Responsibilities of the investigator and IRB/IEC..................................................66
13.3
Publication of study protocol and results...............................................................66


Novartis
Confidential
Page 5 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
13.4
Quality Control and Quality Assurance.................................................................67
14 Protocol adherence ............................................................................................................67
14.1
Protocol amendments.............................................................................................67
15 References .........................................................................................................................69
70
70
75
75
76
78
79
80
List of tables
Table 2-1
Objectives and related endpoints ..........................................................19
Table 6-1
Investigational and control drug............................................................27
Table 6-2
Prohibited medications and therapies....................................................28
Table 6-3
Prohibited medication changes .............................................................29
Table 6-4
Masked and unmasked plan ..................................................................31
Table 8-1
Assessment Schedule ............................................................................36
Table 8-2
Safety assessment specification ............................................................41
Table 8-3
Corneal staining scale ...........................................................................44
Table 8-4
Laboratory evaluations..........................................................................45
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................54
Table 12-1
Primary, sensitivity, and supportive estimands.....................................60
70
73
73
73
74
74
Table 16-7
Binocular VA: objectives and related endpoints...................................76
Table 16-8
Monocular VA (right eye only): objectives and related endpoints.......77


Novartis
Confidential
Page 6 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
List of figures
Figure 3-1
Study design..........................................................................................21
Figure 8-1
Corneal staining scale ...........................................................................44
Figure 12-1
Dose-response shapes of the candidate models ....................................59
 
79


Novartis
Confidential
Page 7 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
List of abbreviations
AE
Adverse Event
ATC
Anatomical Therapeutic Chemical Classification System
BAC
Benzalkonium chloride
BCDVA
Best-corrected distance visual acuity
BP
Blood Pressure
BSE
Better-seeing eye
CFR
Code of Federal Regulations
ClinRO
Clinician Reported Outcomes
CO
Country Organization
COA
Clinical Outcome Assessment
COVID-19
Coronavirus Disease - 19
CRA
Clinical Research Associate
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CSR
Clinical study report
CTT
Clinical Trial Team
DCNVA
Distance-corrected near visual acuity
DDE
Direct Data Entry
DLT
Dose Limiting Toxicity
ED50
Effective dose
EDC
Electronic Data Capture
EMA
European Medicines Agency
Emax
Maximum Effect
EOS
End of Study
eSource
Electronic Source
ETDRS
Early Treatment Diabetic Retinopathy Study
EU
European Union
EudraCT
European Union Drug Regulating Authorities Clinical Trials Database
FAS
Full analysis set
GCP
Good Clinical Practice
GCS
Global Clinical Supply
HbA1C
Hemoglobin A1C
HPßCD
Hydroxypropyl ß cyclodextrin
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Council for Harmonization of Technical Requirements for Pharmaceuticals for 
Human Use
IDEEL
Impact of Dry Eye on Everyday Life
IEC
Independent Ethics Committee
IN
Investigator Notification
IOP
Intraocular Pressure
IRB
Institutional Review Board
IRT
Interactive Response Technology


Novartis
Confidential
Page 8 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
IUD
Intrauterine device
IUS
Intrauterine system
LA
Lipoic Acid
LoA
Limits of Agreement
MAR
Missing at Random
MCP-Mod
Multiple Comparison Procedure - Modeling
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
MMRM
Multilevel Modelling for Repeated Measures
NCNVA
Near corrected near visual acuity
ObsRO
Observer Reported Outcomes
OD
Oculus Dexter
OS
Oculus Sinister
OU
Oculus Uterque
PerfO
Performance Outcomes
PK
Pharmacokinetic(s)
QMS 
Quality Management System
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SD
standard deviation
SMQ
Standardized MedDRA Query
SOP
Standard Operating Procedure
SUSAR
Suspected Unexpected Serious Adverse Reaction
UI
Unmasked Individual
US
United States
VA
Visual Acuity
WHO
World Health Organization
WoC
Withdrawal of Consent
WSE
Worse-seeing eye


Novartis
Confidential
Page 9 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Glossary of terms
Additional 
treatment
Medicinal products that may be used during the clinical trial as described in the protocol, 
but not as an investigational medicinal product (e.g. any background therapy)
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue, 
urine, stool, etc. taken from a study participant
Cohort
A specific group of participants fulfilling certain criteria and generally treated at the same 
time
Control drug
A study drug (active or placebo) used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, and/or evaluate 
comparative effects of the investigational drug
Dosage
Dose of the study treatment given to the participant in a time unit (e.g. 100 mg once a 
day, 75 mg twice a day)
Electronic Data 
Capture (EDC)
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 paper source 
forms used at the point of care
End of the clinical 
trial
The end of the clinical trial is defined as the last visit of the last participant or at a later 
point in time as defined by the protocol
Enrollment
Point/time of participant entry into the study at which informed consent must be obtained 
eSource (DDE)
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines source 
documents and case report forms (eCRFs) into one application, allowing for the real time 
collection of clinical trial information to sponsors and other oversight authorities, as 
appropriate
Estimand
A precise description of the treatment effect reflecting the clinical question posed by the 
trial objective. It summarizes at a population-level what the outcomes would be in the 
same patients under different treatment conditions being compared. Attributes of an 
estimand include the population, variable (or endpoint) and treatment of interest, as well 
as the specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable.
Healthy volunteer
A person with no known significant health problems who volunteers to be a study 
participant
Intercurrent events
Events occurring after treatment initiation that affect either the interpretation or the 
existence of the measurements associated with the clinical question of interest.
Investigational 
drug/ treatment
The drug whose properties are being tested in the study
Medication number
A unique identifier on the label of medication kits
Mis-randomized 
participants
Mis-randomized participants are those who were not qualified for randomization and who 
did not take study treatment, but have been inadvertently randomized into the study 
Other treatment
Treatment that may be needed/allowed during the conduct of the study (i.e. concomitant 
or rescue therapy)
Part
A sub-division of a study used to evaluate specific objectives or contain different 
populations. For example, one study could contain a single dose part and a multiple dose 
part, or a part in participants with established disease and in those with newly-diagnosed 
disease
Participant
A trial participant (can be a healthy volunteer or a patient)
Participant number
A unique number assigned to each participant upon signing the informed consent. This 
number is the definitive, unique identifier for the participant and should be used to 
identify the participant throughout the study for all data collected, sample labels, etc.


Novartis
Confidential
Page 10 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Period
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) which are 
described in the Protocol. Periods define the study phases and will be used in clinical 
trial database setup and eventually in analysis
Personal data
Participant information collected by the Investigator that is coded and transferred to 
Novartis for the purpose of the clinical trial. This data includes participant identifier 
information, study information and biological samples.
Premature 
participant 
withdrawal
Point/time when the participant exits from the study prior to the planned completion of all 
study drug administration and/or 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 participant
Run-in Failure
A participant who is screened but not randomized/treated after the run-in period (where 
run-in period requires adjustment to participant’s intervention or other treatment)
Screen Failure
A participant who did not meet one or more criteria that were required for participation in 
the study
Source 
Data/Document
Source data refers to the initial record, document, or primary location from where data 
comes. The data source can be a database, a dataset, a spreadsheet or even hard-
coded data, such as paper or eSource
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent by the first 
participant
Study treatment
Any drug or combination of drugs or intervention administered to the study participants 
as part of the required study procedures; includes investigational drug(s), control(s) or 
background therapy
Study treatment 
discontinuation
When the participant permanently stops taking any of the study drug(s) prior to the 
defined study treatment completion date (if any) for any reason; may or may not also be 
the point/time of study discontinuation
Treatment 
arm/group 
A treatment arm/group defines the dose and regimen or the combination, and may
consist of 1 or more cohorts.
Treatment of 
interest
The treatment of interest and, as appropriate, the alternative treatment to which 
comparison will be made. These might be individual interventions, combinations of 
interventions administered concurrently, e.g. as add-on to standard of care, or might 
consist of an overall regimen involving a complex sequence of interventions. This is the 
treatment of interest used in describing the related clinical question of interest, which 
might or might not be the same as the study treatment.
Variable (or 
endpoint)
The variable (or endpoint) to be obtained for each participant that is required to address 
the clinical question. The specification of the variable might include whether the 
participant experiences an intercurrent event.
Withdrawal of 
study consent 
(WoC)
Withdrawal of consent from the study occurs only when a participant does not want to 
participate in the study any longer and does not allow any further collection of personal 
data


Novartis
Confidential
Page 11 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Amendment v02 (03-Sep-2021) 
Amendment rationale
 
 
The 30 days phone call follow up and SAE reporting after 
end of study treatment is corrected to end of study visit. Further clarification for safety reporting 
is included for subjects who discontinue study treatment during the 3 month treatment period.  
The amendment also includes correcting a typographical error in inclusion # 5. There are also 
typographical errors and clarifications provided on other minor aspects of the protocol.
Changes to the protocol
1. Section 5.1 Inclusion Criteria
In inclusion criterion # 5, DCNVA is corrected to NCNVA since the VA is currently 
assessed using near correction at 40 cm. The same correction is made in the protocol 
summary.
2. Section 8-1 Assessment Schedule
Safety lab data will be transferred to Novartis database. Therefore, footnote # 1, 
assessment to be recorded in the source documentation only, is deleted for Hematology, 
Clinical Chemistry, Urinalysis and Pregnancy test (serum).
The assessment related to the Trial Feedback Questionnaire is removed from Table 8-1, 
since this is not a study assessment and will be used to collect overall experience with 
Novartis clinical trials. 
3. Section 8.2 Participant demographics/other baseline characteristics
Room illumination range for measuring non-dilated pupil size has been revised from 8-
15 lux to 25-60 lux.  This change has been made based on the calibration of the new 
light sensor on the electronic visual acuity system provide for use in the study.
 
 
 
5. Section 8.4 Safety, Table 8-2 Safety Assessment Specification
In the Refractive Status, Cyclopentolate 1% is now indicated as an example to give some 
flexibility to the sites.
6. Section 8.5.1 Clinical Outcome Assessments (COAs)
 
 
 


Novartis
Confidential
Page 12 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
 
 
 
8. Section 9.2 Study completion and post study treatment 
A correction was made to the treatment period, to reflect the correct length, which is 3 
months. The clarification about safety follow up for discontinued participants has been 
moved to Section 9.1.1.
9.
Section 10.1.1 Adverse events
A phrase was added stating that investigational device would be monitored for AE 
temporal or causality along with the investigational drug. Another statement was added 
that risks associated with the investigational device can be found in a separate 
investigational brochure.
10. Section 10.1.3 SAE reporting
Correction is made for the requirement of a 30 day safety follow up call after the last 
study visit instead of last study treatment. Additional clarification regarding urgency of 
SAE reporting is provided.
11. Section 12.4.3 Handling of remaining intercurrent events of primary estimand
Clarification is provided regarding handling of primary estimand in case of multiple 
intercurrent events. 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 and Health Authority 
approval according to local regulations prior to implementation. The changes herein do 
NOT affect the trial-specific model ICF.


Novartis
Confidential
Page 13 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Amendment v01 (19-Jan-2021) 
Amendment rationale 
 
 
The amendment also corrects typographical errors and provides clarifications on certain minor 
aspects of the protocol.
Changes to the protocol
1. Section 6.1.1 Treatment Compliance
Removed the statement that the frequency of artificial tears usage during the study will 
be captured in the e-diary as this will no longer be done.
 
 
 
 
 
3. Section 8.3.1 Distance-Corrected Near Visual Acuity using electronic system
Two binocular DCNVA assessments will be done at all study visits and not in a few 
visits as in the previous protocol. This change is now aligned with the data flagging 
planned in the M&S technologies VA system and will help to keep the number of 
assessments same across visits to avoid any confusion to the sites. The following 
sentence is added to address this change ‘At all study visits starting from Screening, for 
binocular Table 16-8 DCNVA (using letters) only, two assessments separated by at least 
10 min will be done’. 
 
 
 
 
The rest of the changes in Appendix 2 subsections were updated to align with the above-
mentioned change.


Novartis
Confidential
Page 14 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
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.


Novartis
Confidential
Page 15 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Protocol summary
Protocol 
number
CUNR844A2202
Full Title
A randomized, placebo-controlled, double-masked, multi-center, dose-ranging 
study to evaluate the safety, and efficacy of UNR844 in subjects with presbyopia
Brief title
Study of safety and efficacy of UNR844 in subjects with presbyopia
Sponsor and
Clinical Phase
Novartis
Phase IIb study
Investigation 
type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of the study is to determine the optimum dose of UNR844 
treatment and duration of effect of UNR844 treatment for further development.
Primary 
Objective(s)
The primary objective of this study is to characterize the dose-response of 
UNR844 treatment with respect to change from baseline in binocular distance-
corrected near visual acuity using letters, at Month 3.
Secondary 
Objectives
The secondary objectives includes, characterizing the dose-response of 
UNR844 based on monocular distance-corrected near visual acuity at Month 3 
and to assess the duration of effect after stopping UNR844 treatment using 
change in binocular and monocular distance-corrected near visual acuity from 
Month 4 to Month 12. Additionally, the study will also evaluate the proportion of 
participants gaining at least 0.3 logMAR in binocular and monocular DCNVA 
from baseline at Month 3.
Study design
This is a randomized, placebo-controlled, double-masked, multi-arm, parallel-
group, multi-center study.
Eligible subjects will be randomized 1:1:1:1:1 to receive:
UNR844 dose concentrations of 5 mg/mL, 13.3 mg/mL, 23 mg/mL and 30 
mg/mL or placebo dosed one drop in each eye twice-daily for 3 months.
Study 
population
Approximately 225 male or female presbyopic participants aged 45 to 55 years 
will be enrolled
Key Inclusion 
criteria

Phakic male or female participants aged 45 to 55 years, inclusive, at the 
Screening visit.

Monocular and binocular distance-corrected near visual acuity at 40 cm 
distance worse than 0.3 logMAR at the Screening and Baseline visits.

Binocular distance-corrected near visual acuity at baseline must not be 
different by more than 0.1 logMAR from the corresponding assessment at the 
Screening visit.

Need a minimum near addition prescription of +1.00 D or more to achieve 
binocular near-corrected near visual acuity (NCNVA) of at least 0.0 logMAR at 
40 cm distance, as assessed by the Investigator, at the Screening visit.


Novartis
Confidential
Page 16 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Key Exclusion 
criteria

Best-corrected distance visual acuity worse than 0.0 logMAR at 4 m distance 
in either eye at the Screening visit.

Spherical equivalent greater than +4.0 D or less than -4.0 D, based on 
manifest refraction, in either eye at the Screening visit.

Astigmatism of greater than 1.25 D, based on manifest refraction, in either 
eye at the Screening visit.

Difference in manifest refraction spherical equivalent of greater than 0.75 D 
between eyes at the Screening visit.

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
Study 
treatment
Participants will be randomized equally to one of five treatment arms, consisting 
of:

Placebo eye drops, twice-a-day for three months

UNR844 5 mg/mL eye drops, twice-a-day for three months

UNR844 13.3 mg/mL eye drops, twice-a-day for three months

UNR844 23 mg/mL eye drops, twice-a-day for three months

UNR844 30 mg/mL eye drops, twice-a-day for three months
Key Efficacy 
assessments

Binocular distance-corrected near visual acuity at 40 cm
Key safety 
assessments

Adverse event monitoring

Ophthalmic examinations
 

Refractive status for each eye
Other 
assessments 

Distance-corrected near visual acuity using letters at 40 cm for each eye
 
Data analysis
The primary objective of the study is to characterize the dose response 
relationship among UNR844 doses 0 mg/mL, 5 mg/mL, 13.3 mg/mL, 23 mg/mL 
and 30 mg/mL dosed twice-daily at Month 3. This will be evaluated by measuring 
the binocular DCNVA (letters) in logMAR using the electronic visual acuity 
system.
The null hypothesis of flat dose-response relationship for change from baseline 
in binocular DCNVA at Month 3 as compared to placebo will be tested at a one-
sided significance level of 2.5% against the alternative hypothesis of a 
monotonic decreasing dose response relationship. MCP-Mod methodology is 
utilized to test for a dose-response signal and estimate the dose-response 
relationship.
One of the secondary objectives is to characterize the dose response 
relationship among various UNR844 doses at Month 3, with change from 
baseline in monocular DCNVA at Month 3 for the worse-seeing eye (WSE) and 
better-seeing eye (BSE) as the endpoints. The same null and alternative 


Novartis
Confidential
Page 17 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
hypotheses as the primary will be considered, by utilizing the MCP-Mod to test 
for a dose-response signal and estimate the dose-response relationship.
The other secondary objective is to evaluate the efficacy of improving DCNVA in 
presbyopic participants, with the corresponding endpoints gaining at least 3 lines 
(change from baseline of </= - 0.3 logMAR) in binocular, worse-seeing eye and 
better-seeing eye, respectively at Month 3. No formal testing will be done for the 
objective. A logistic regression model, by adjusting for baseline DCNVA and age 
(grouped as 45 to 50 years and 51 to 55 years), will be fitted to obtain pairwise 
comparison of each dose versus placebo.
The third secondary objective is to assess the duration of effect using change in 
DCNVA after Month 3 with various dose concentrations of UNR844. The 
corresponding endpoint is DCNVA during treatment and treatment holiday, i.e., 
from baseline till Month 12. No formal hypothesis testing will be undertaken. An 
individualized nonlinear mixed effect model will be fitted to assess the effect over 
time.
Key words
Presbyopia, near visual acuity, adults, randomized study, placebo


Novartis
Confidential
Page 18 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
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.
Alpha-R-lipoic acid choline ester eye drops solution (Novartis product code UNR844, formerly 
known as EV06), is being developed as a topical pharmacological treatment for presbyopia. 
UNR844's active ingredient, a salt of alpha-R-lipoic acid choline ester, has been shown to 
improve the topical ocular delivery of arlipoic acid (lipoic acid or LA) to the aqueous humor 
Garner and Garner 2016. Arlipoic acid is thought to be further metabolized in the lens fiber 
cells to dihydrolipoic acid that may act to reduce age-related disulfide bonds between lens 
proteins, restoring lens elasticity. Similarly, UNR844 is also expected to be metabolized in other 
ocular tissues such as cornea, iris and conjunctiva, with no known adverse effects 
Khan et al 2011.
UNR844 1.3% (13.3 mg/mL) eye drops solution was evaluated in a randomized, double-masked, 
placebo-controlled clinical study with 75 participants with presbyopia in Study EV-C-002 
(Novartis study code: CUNR844A2201). Fifty participants were treated with UNR844 one drop 
to each eye twice a day for up to three months, while 25 participants received placebo treatment. 
UNR844 was well tolerated and there were no safety issues identified. After three months, 
participants treated with UNR844 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. Of those participants who were followed up for seven months after completing 
the treatment, the mean improvement in DCNVA largely persisted throughout this period in 
Study EV-C-003 (Novartis study code: CUNR844A2201E1). Another study using UNR844 1.3% 
in 124 presbyopic participants of age 45 to 65 years was also completed (CUNR844A2203). 
No safety concerns were identified and the results supported further evaluation of the compound.
The previous studies evaluated the chloride salt of UNR844, and the tosylate form of UNR844 
will be evaluated in the current study (CUNR844A2202) for dose-finding purposes.


Novartis
Confidential
Page 19 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
1.2
Purpose
The purpose of the study is to determine the optimum dose of UNR844 tosylate treatment and 
duration of effect of UNR844 treatment for further development.
2
Objectives and endpoints
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Characterize dose-response of UNR844 for 
change from baseline in binocular DCNVA at 
Month 3.

Change from baseline in binocular DCNVA assessed 
using letters at Month 3
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Characterize dose response of UNR844 as 
measured by change from baseline in 
monocular DCNVA at Month 3

Change from baseline in monocular DCNVA, assessed 
using letters (i.e., worse-seeing eye and better-seeing eye) 
at Month 3

Assess the duration of effect using change in 
DCNVA after Month 3 with various dose 
concentrations of UNR844

Binocular and monocular DCNVA assessed using 
letters, over time after Month 3 (i.e., Month 4 to Month 12)

Evaluate the efficacy of improving DCNVA in 
presbyopic participants, as measured by 
proportion of participants gaining at least 0.3 
logMAR DCNVA at Month 3

Proportion of participants gaining at least 0.3 logMAR in 
binocular and monocular (worse-seeing eye and better-
seeing eye) DCNVA assessed using letters (without near 
correction) from baseline at Month 3


Novartis
Confidential
Page 20 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
2.1
Primary estimands
The clinical question of interest is:
What is the efficacy attributable to different doses of UNR844 received after 3 months of 
treatment, taking into account any unfavorable effect of the drug such as discontinuation due to 
unsatisfactory therapeutic effect or AE?
The primary estimand is described by the following attributes:
1. Population: Participants aged 45 to 55 years with presbyopia. Further details about the 
population are provided in Section 5.
2. Primary variable: Change from baseline in binocular DCNVA at Month 3
3. Treatment of interest: the randomized treatment (different doses) of the investigational 
treatment UNR844 administered or the placebo treatment) taken up to Month 3, assuming 
no further benefit after data collection for participants who discontinue treatment due to 
adverse events or unsatisfactory therapeutic events.
Handling of remaining intercurrent events, with the corresponding assumption that these 
intercurrent events had not occurred:

Use of prohibited medications or therapy, or changes in prohibited medication 
(hypothetical strategy)

Study treatment discontinuation due to other reasons (hypothetical strategy)
The summary measure: difference in variable means between treatments.
2.2
Secondary estimands
Not applicable.


Novartis
Confidential
Page 21 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
3
Study design
Figure 3-1
Study design
This is a randomized, placebo-controlled, double-masked, multi-arm, parallel-group, multi-
center study.
The 13-month study will consist of:

A 1 week run-in period

A 3-month treatment course with UNR844 and/or placebo

A 9-month treatment holiday period


Novartis
Confidential
Page 22 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Participants will be randomized equally to one of five treatment arms, consisting of:

Placebo eye drops, twice-a-day for three months

UNR844 5 mg/mL eye drops, twice-a-day for three months

UNR844 13.3 mg/mL eye drops, twice-a-day for three months

UNR844 23 mg/mL eye drops, twice-a-day for three months

UNR844 30 mg/mL eye drops, twice-a-day for three months
Participants will undergo a 1 week run-in period where they will be assessed for entry criteria 
during the Screening visit. During the run-in period, participants will administer 1 drop of 
artificial tears twice-a-day (1 drop in the morning and 1 drop in the evening) in each eye at 
home. This run-in period is designed to help minimize any potential variability in DCNVA 
caused due to initial ocular surface issues and help to establish an accurate baseline prior to 
randomization. The run-in period will help to exclude participants with a change in DCNVA of 
0.1 logMAR difference between Screening and Baseline.
Participants will be dosed with the various concentrations of UNR844 in both eyes for 3 months. 
An interim analysis will be performed on the 3-month safety and efficacy results. This analysis 
will be performed by a separate unmasked study team that will have no other involvement in 
the study. The results of this interim analysis will be used to select the optimum dose 
concentration.
The duration of effect of UNR844 (i.e., how long does the improvement in DCNVA last) with 
respect to DCNVA will be evaluated during the 9-month treatment holiday period.
4
Rationale
4.1
Rationale for study design
The study is designed as a randomized, parallel group, placebo-controlled, double-masked, 
multi-center study. Double-masking and randomization are used to minimize any bias 
associated with treatment knowledge. Randomization ratio is 1:1:1:1:1 to the five treatment 
arms, and randomization will be stratified by baseline binocular DCNVA to account for 
different near visual acuity starting levels, region to account for possible regional differences 
and age group 45 to 50 years and 51 to 55 years.
After the treatment course, participants will be followed for nine months. This duration is based 
on results from the previous CUNR844A2201E1 study, where the improvement in DCNVA 
due to UNR844 treatment persisted largely for approximately seven months on average.
4.1.1
Rationale for choice of background therapy
Currently, there are no pharmacological therapies approved for presbyopia. Participants will be 
able to use optical correction (i.e., spectacles), if needed, after completing study assessments.
Upon signing the informed consent form, participants who currently wear contact lenses 
(including multifocal contact lenses) will then be instructed to stop wearing soft contact lenses 
approximately 1 week prior to Screening visit and in the case of hard or toric contact lenses 


Novartis
Confidential
Page 23 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
approximately 2 weeks prior to Screening visit. Participants will be provided with spectacles to 
wear at home during the entire study period to replace their habitual contact lenses.
4.2
Rationale for dose/regimen and duration of treatment
The study will evaluate UNR844 dose concentrations of 5 mg/mL, 13.3 mg/mL, 23 mg/mL and 
30 mg/mL. The 5mg/mL is the lowest concentration tested in ocular nonclinical PK studies that 
showed adequate exposure, the 13.3 mg/mL concentration is equivalent in free base UNR844 
concentration to that previously assessed in the CUNR844A2201 and CUNR844A2203 clinical 
studies, and the 30 mg/mL concentration is the maximum feasible concentration of UNR844. 
The range of concentrations are expected to provide sufficient data to help model the dose-
response relationship of UNR844.
Twice-a-day administration will be evaluated in this study. This is a common dose frequency 
with ocular eye drops, and is in part based on rabbit pharmacokinetic studies which measured 
time dependent concentrations of UNR844 in the anterior chamber. More frequent dosing is 
associated with increased user inconvenience.
Treatment duration of three months will be evaluated. Results from previous clinical studies 
using UNR844 suggested that efficacy is achieved by a 3-month treatment course.
The selected dose regimens are supported by non-clinical toxicity study results in the rabbit and 
the dog species of up to 40 mg/mL, administered three times-a-day over three months.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
The control in this study is placebo eye drops, which comprise of the inactive ingredients in the 
UNR844 eye drop except hydroxypropyl-beta-cyclodextrin (HPβCD). The placebo also 
includes preservative benzalkonium chloride (BAC).
The aim of the study is to evaluate the safety and efficacy of UNR844 in presbyopia, hence 
placebo is an appropriate comparator in this non-serious condition with no approved 
pharmacological therapies.
4.4
Purpose of Interim Analysis
There are two interim analyses planned in the study. The objective of the first interim analysis 
is to determine whether the overall null hypothesis of a flat dose response can be rejected and 
will be done when all participants complete the Month 3 visit. The second interim analysis will 
be performed to assess the retention of the treatment effect over the 9 months treatment holiday 
period. Additional details are provided in Section 12.7.
4.5
Risks and benefits
In two previous clinical studies (CUNR844A2201 and CUNR844A2203), there were no safety 
concerns identified. There were no serious adverse events (SAEs) and no participants 
discontinued from the study because of an adverse event (AE). Please refer to the Investigator's 
Brochure for details on the reported AEs.


Novartis
Confidential
Page 24 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Non-clinical studies with UNR844, which will be evaluated in this study, did not show any 
safety or tolerability concerns. Safety of UNR844 is also being evaluated in a study in healthy 
participants and information from this study will be provided in an update to the Investigator's 
Brochure prior to the start of the CUNR844A2202 study.
The risk to participants 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 eye drops solution on fertility, pregnancy and lactation have not been 
studied. No safety concerns are expected based on the nature of UNR844. 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.
Although UNR844 exhibited a beneficial effect with respect to near visual acuity in presbyopic 
participants in a prior clinical study, it cannot be guaranteed that a similar effect would be 
observed in this study.
5
Study Population
Approximately 225 male or female presbyopic participants aged 45 to 55 years will be enrolled.
With an estimated 5% drop-out rate during the treatment period (i.e., 3 months) this would mean 
approximately 210 participants would complete 3 months of treatment period. All efforts would 
be taken to minimize/maintain the drop-out rate during the 9 months treatment holiday period. 
If the power of the study drops below 82%, additional participants will be enrolled to replace 
drop outs due to COVID-19.
5.1
Inclusion criteria
Participants eligible for inclusion in this study must meet all of the following criteria:
1. Written informed consent must be obtained before any assessment is performed.
2. Phakic male or female participants aged 45 to 55 years, inclusive, at the Screening visit.
3. Monocular and binocular distance-corrected near visual acuity at 40 cm distance worse 
than 0.3 logMAR at the Screening and Baseline visits.
4. Binocular distance-corrected near visual acuity at baseline must not be different by more 
than 0.1 logMAR from the corresponding assessment at the Screening visit.
5. Need a minimum near addition prescription of +1.00 D or more to achieve binocular near 
corrected near visual acuity (NCNVA) of at least 0.0 logMAR at 40 cm distance, as 
assessed by the Investigator, at the Screening visit.


Novartis
Confidential
Page 25 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
5.2
Exclusion criteria
Participants meeting any of the following criteria are not eligible for inclusion in this study.
1. Best-corrected distance visual acuity worse than 0.0 logMAR at 4 m distance in either eye 
at the Screening visit.
2. Spherical equivalent greater than +4.0 D or less than -4.0 D, based on manifest refraction, 
in either eye at the Screening visit.
3. Astigmatism of greater than 1.25 D, based on manifest refraction, in either eye at the 
Screening visit.
4. Difference of greater than 0.50D between manifest refraction spherical equivalent and the 
cycloplegic refraction spherical equivalent.
5. Difference in manifest refraction spherical equivalent of greater than 0.75 D between eyes 
at the Screening visit.
6. Unequal pupil diameters with a difference of greater than 1 mm between eyes.
7. Non-circular pupil assessed by the Investigator to be related to a pathologic cause.
8. Contraindication to pupil dilation in either eye or a history of untreated narrow angles or 
currently occludable angles in either eye.
9. Insufficient pupillary dilation that precludes observation of the fundus or lens in either 
eye, in the opinion of the investigator.
10. Contact lens wear within 1 week for soft lenses and 2 weeks for hard or toric lenses, prior 
to Screening visit and for the duration of the study.
11. Prior history or current diagnosis of accommodative spasm, accommodative 
insufficiencies or other accommodative issues, except age-related accommodative issues 
related to presbyopia.
12. 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.
13. Secondary cause of presbyopia in either eye (e.g., damage to lens, zonules or ciliary 
muscle, multiple sclerosis, and myasthenia gravis).
14. Any active ocular infection (i.e., bacterial, viral, parasitic or fungal), or inflammation, or a 
history of herpetic ocular infection in either eye at the Screening or Baseline visit.
15. History of idiopathic or auto-immune uveitis in either eye.
16. Ocular surface disease with a IDEEL blurry vision score greater than "slightly" AND 
corneal staining in the central zone greater than grade 1 at Screening visit.
17. History or current diagnosis of treated or untreated glaucoma of any type.
18. History of penetrating ocular trauma, significant blunt ocular trauma or uveitis in either 
eye.
19. Prior intraocular/extraocular surgery or laser surgery of any kind in either eye, including 
cataract surgery in either eye during the study period.
20. History of hypersensitivity to any of the study treatments (including placebo) or its 
inactive ingredients or to active ingredients of similar chemical classes.
21. Change in dose of any medication known to affect accommodation, pupil size or 
intraocular pressure during the study, as listed in Table 6-3. Participants who have been on 


Novartis
Confidential
Page 26 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
stable dose of such medications for at least three months before the Screening visit and 
who are not expected to change the dose/ regimen or discontinue the medication are 
eligible for the study.
22. Use of other investigational drugs within 5 half-lives or within 30 days of the Screening 
visit, until the expected pharmacodynamic effect has returned to baseline, whichever is 
longer.
23. Prior therapy for presbyopia other than physical optical correction (e.g., supplements, 
medications, training exercises, ciliary body electrostimulation, corneal implants surgery).
24. History of clinically significant cardiac abnormalities or cerebrovascular conditions.
25. Suboptimally controlled diabetes mellitus (i.e., HbA1c 7% or more at the Screening visit) 
or history of insulin autoimmune disease.
26. History of or current use of arlipoic acid or dihydrolipoic acid oral supplements or eye 
drops.
27. Prior participation in a clinical study evaluating UNR844 or EV06.
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.
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
31. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
participant. 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 bilateral 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 6 months prior to screening). For female participants 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). For UK: with spermicidal foam/gel/film/cream/ vaginal 
suppository

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 (IUD) or intrauterine system 
(IUS)


Novartis
Confidential
Page 27 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
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.
If local regulations deviate from the contraception methods listed above to prevent 
pregnancy, local regulations apply and will be described in the ICF
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 bilateral 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. Participants 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).
6
Treatment
6.1
Study treatment
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
Pharmaceutical 
Dosage Form
Route of 
Administration
Supply type
Sponsor (global 
or local)
UNR844 5 
mg/mL
Eye drops 
solution
Topical ocular
Opaque plastic 
bottle
Novartis global
UNR844 13.3 
mg/mL
Eye drops 
solution
Topical ocular
Opaque plastic 
bottle
Novartis global
UNR844 23 
mg/mL
Eye drops 
solution
Topical ocular
Opaque plastic 
bottle
Novartis global
UNR844 30 
mg/mL
Eye drops 
solution
Topical ocular
Opaque plastic 
bottle
Novartis global
Placebo
Eye drops 
solution
Topical ocular
Opaque plastic 
bottle
Novartis global
6.1.2
Additional study treatments
Novartis will provide artificial tears to the participants for administration of one-drop twice-
dailybetween screening and the baseline visits at home.
Artificial tears will also be administered to participants prior to any visual acuity assessments 
during the study visit days in the clinic. Instill one drop of artificial tears in each eye at least 30 
minutes before starting visual acuity assessments. Novartis will provide Investigators with 
artificial tears for such use at the site. These should be stored according to the manufacturer's 
instructions.


Novartis
Confidential
Page 28 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
At the conclusion of the study, unused product should be disposed of by the Investigator 
according to local practice.
6.1.3
Treatment arms/group
Participants will be assigned at the Baseline visit to one of the following five treatment arms in 
a ratio of 1:1:1:1:1.

Placebo eye drops, one drop twice-a-day for three months

UNR844 5 mg/mL eye drops, one drop twice-a-day for three months

UNR844 13.3 mg/mL eye drops, one drop twice-a-day for three months

UNR844 23 mg/mL eye drops, one drop twice-a-day for three months

UNR844 30 mg/mL eye drops, one drop twice-a-day for three months
6.1.4
Treatment duration
The planned treatment duration is three months.
6.2
Other treatment(s)
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 
enrolled, contact Novartis/sponsor 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 and 
for the entire duration of the study.
Table 6-2
Prohibited medications and therapies
Medication/therapy
Prohibition period
Action taken after baseline 
visit
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 
(see Section 9.1.1)
Arlipoic acid or dihydrolipoic 
acid oral supplements or eye 
drops (other than study 
treatment)
Any time after screening and 
throughout the study
Discontinue study treatment 
(see Section 9.1.1)


Novartis
Confidential
Page 29 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Medication/therapy
Prohibition period
Action taken after baseline 
visit
Other investigational medicinal 
product or therapy
Any time after screening and 
throughout the study
Discontinue study treatment 
(see Section 9.1.1)
Therapy for presbyopia other 
than physical 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 
(see Section 9.1.1)
Participants are not allowed to start, stop or change dosing of the following treatments after the 
screening visit and for the entire duration of the study, 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
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


Novartis
Confidential
Page 30 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Medication
Prohibition period
Action taken
Any over-the counter or 
prescription ocular 
medications (except artificial 
tear products
Any time after screening and 
throughout the study
No change in the brand and 
regimen of the artificial tears 
during 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
Participants who use their own artificial tears during the study after Baseline visit must wait at 
least 10-15 minutes after dosing study treatment, to avoid any washout of study drug. 
Participants 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
Participant numbering, treatment assignment, randomization
6.3.1
Participant numbering
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is enrolled for screening and is retained for the participant 
throughout his/her participation in the trial. The Participant No. consists of the Center Number 
(Center No.) (as assigned by Novartis to the investigative site) with a sequential participant 
number suffixed to it, so that each participant’s participation is numbered uniquely across the 
entire database. Upon signing the informed consent form, the participant is assigned to the next 
sequential Participant No. available. In situations where a participant is re-screened, a new 
Participant No. will be assigned.
6.3.2
Treatment assignment, randomization
At baseline visit, all eligible participants will be randomized via Interactive Response 
Technology (IRT) to one of the treatment arms. The investigator or his/her delegate will contact 
the IRT after confirming that the participant fulfills all the inclusion/exclusion criteria. The IRT 
will assign a randomization number to the participant, which will be used to link the participant 
to a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from participants and investigator staff. A 
participant randomization list will be produced by the IRT provider using a validated system 
that automates the random assignment of participant 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 Global Clinical Supply (GCS) using a validated system that automates the random 
assignment of medication numbers to packs containing the study treatment.


Novartis
Confidential
Page 31 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Randomization will be stratified based on binocular DCNVA (0.5 logMAR or less; 0.52
logMAR or more) and age (45 to 50 years and 51 to 55 years) at baseline, and region.
Participants will be randomized 1:1:1:1:1 within each stratum to either treatment arm. The 
randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Participants, investigator and site staff, persons performing the assessments, and monitors 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 unmasked 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 treatment that are all identical 
in packaging, labeling, schedule of administration and appearance. 
Unmasking will occur in the case of participant emergencies and at the conclusion of the study.
Table 6-4
Masked and unmasked plan
Time or Event
Role
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single participant 
unblinded)
Interim Analysis
Participants
M
M
M
M
Site staff
M
M
M*
M
Global Clinical 
Supply and 
Randomization 
Office
M
M
M
M
Unmasked sponsor 
staff e.g. for study 
treatment re-supply, 
unmasked 
monitor(s), sample 
analyst(s)
M
UI
UI
UI
Unmasked 
Pharmacovigilance 
sponsor staff
M
M
UI
M
Statistician/statistical 
programmer/ data 
analysts
M
M
M
UI
All other sponsor 
staff not identified 
above
M
M
M
M
Key:
UI: Allowed to be unmasked on individual participant level
M: Remains masked
*Investigator will be unmasked in case of emergency breaking of treatment code (Section 6.6.2)


Novartis
Confidential
Page 32 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
For participants who do not tolerate the protocol-specified dosing regimen, study treatment 
should be discontinued and, if possible, the subject is continued to be monitored in the study 
(Section 9.1.1).
6.6
Additional treatment guidance
6.6.1
Treatment compliance
Participants will be instructed at each on-therapy study visit to take the study treatment exactly 
as prescribed.
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. Participants will be provided 
with an ediary to complete every day after they administer study drug. Compliance will be
assessed by the investigator and/or study personnel at each visit. Participants 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 and ediary data. All study treatment dispensed 
and returned must be recorded in the Drug Accountability Log.
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 
participant safely. Masked codes may also be broken after a participant discontinues treatment 
due to disease progression if deemed essential to allow the investigator to select the participant’s 
next treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study participant who presents with an emergency condition. However, participants 
can continue to participate in the study (Section 9.1.1). Emergency treatment code breaks are 
performed using the IRT. When the investigator contacts the system to break a treatment code 
for a participant, he/she must provide the requested participant identifying information and 
confirm the necessity to break the treatment code for the participant. The investigator will then 
receive details of the investigational drug treatment for the specified participant 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

participant number


Novartis
Confidential
Page 33 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
In addition, oral and written information to the participant must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that unmasking 
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 participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. Study medication will be dispensed to the patient at the clinic as 
outlined in table of assessments in Section 8. In the event of COVID-19 pandemic it may be 
necessary to make alternative arrangements (e.g., curb-side pickup or home delivery) for the 
participant to obtain study medication at the designated study visit as allowed by local 
regulations, site capabilities and participant’s comfort level.
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 label.
Clinical supplies are to be dispensed only in accordance with the protocol. Technical complaints 
are to be reported to the respective Novartis CO Quality Assurance.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number.
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. Participants 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.


Novartis
Confidential
Page 34 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
6.7.1.2
Handling of additional treatment
Artificial tears will be provided to the participants for use at home between the Screening and 
Baseline visits. Participants will return artificial tears at the Baseline visit.
6.7.2
Instruction for prescribing and taking study treatment
Participants should take the study treatment at approximately the same time each day, twice-a-
day. For example, morning dose at approximately 8 am and evening dose at approximately 
8 pm. If a dose is missed and it has been more than six hours from the approximate usual time 
of dosing, participants 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 participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant 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 be 
documented in the participant source documents.
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH 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/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the 
participant informed consent and should be discussed with the participant 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 participant.
The following informed consents are included in this study:

Main study consent

As applicable, Pregnancy Outcomes Reporting Consent for female Participants.
 
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.


Novartis
Confidential
Page 35 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
Participants might be asked to complete an optional questionnaire to provide feedback on their 
clinical trial experience.
8
Visit schedule and assessments
The Assessment Schedule (Table 8-1) lists all of the assessments when they are performed. All 
data obtained from these assessments must be supported in the participant’s source 
documentation.
Participants 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. Missed or rescheduled visits 
should not lead to automatic discontinuation. Participants 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 the adverse event and concomitant 
medications recorded on the CRF.
Assessments assigned to the screening visit can be conducted on separate days as close to each 
other as possible. Visual acuity and refraction assessments must be performed on the same day.
According to evaluation performed for this study all visits must be performed at site. No 
evaluation at home is possible with the exception of the 
, in case of COVID pandemic.
If the COVID-19 pandemic limits or prevents on-site study visits and other study assessments 
may not be performed, alternative methods of safety monitoring may be implemented. 
Depending on local regulations, site capabilities and participant’s visit status in the study, phone 
calls or virtual contacts (e.g., teleconsult) can be performed for safety follow-up for the duration 
of the pandemic, until it is safe for the participant to visit the site again.
If a participant is unable to attend the scheduled baseline visit due to illness, the run-in period 
could be extended up to 2 weeks from the Screening visit. During this extended run-in period, 
participants will continue to administer the Sponsor provided artificial tears as directed.


Novartis
Confidential
Page 36 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Table 8-1
Assessment Schedule
Period
Run-in
Treatment
Treatment holiday period
Visit Name
Screening
Baseline
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12/EOS
Days
-7
1
14
30
60
90
120
150
180
210
240
270
300
330
360
Informed consent
X
Demography
X
Medical history/current 
medical conditions
X
Prior medications
X
X
Concomitant medications
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Inclusion/Exclusion criteria
X
X
Vital Signs
X
X
X
X
X
X
Physical Examination1
X
X
Distance-corrected near 
visual acuity (letters)3
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X


Novartis
Confidential
Page 37 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Period
Run-in
Treatment
Treatment holiday period
Visit Name
Screening
Baseline
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12/EOS
Days
-7
1
14
30
60
90
120
150
180
210
240
270
300
330
360
IDEEL blurry vision 
question1
X
Cycloplegic refraction
X
Pupil size (non-dilated)
X
Slit lamp biomicroscopy
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Corneal Staining
X
X
X
X
X
X
Intraocular Pressure (IOP)
X
X
X
X
X
X
X
X
X
X
Dilated fundus exam
X
X
X
Hematology
X
X
Clinical Chemistry
X
X
Urinalysis
X
X
Pregnancy Test (serum)
X
Pregnancy Test (urine)1
X
X
Adverse Events
X
X
X
X
X
X
X
X
X
X
X
X
X
X
X
Drug dispensation
X
X
X
Study completion 
information
X
eDiary compliance 
assessment
X
X
X
X
X


Novartis
Confidential
Page 38 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Period
Run-in
Treatment
Treatment holiday period
Visit Name
Screening
Baseline
W2
M1
M2
M3
M4
M5
M6
M7
M8
M9
M10
M11
M12/EOS
Days
-7
1
14
30
60
90
120
150
180
210
240
270
300
330
360
X Assessment to be recorded in the clinical database or received electronically from a vendor
1 Assessment to be recorded in the source documentation only
3 Duplicate binocular DCNVA assessments will be completed at all visits
 
 


Novartis
Confidential
Page 39 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
8.1
Screening
Screening
If a participant is unable to attend the baseline visit after the extended run-in period due to 
prolonged recovery from an illness, the participant can be re-screened once at a later time after 
discussion with the Sponsor.
8.1.1
Information to be collected on screening failures
Participants who sign an informed consent but fail to be started on treatment for any reason will 
be considered a screen failure. The reason for not being started on treatment will be entered on 
the screening phase disposition page. The demographic information, informed consent, and 
Inclusion/Exclusion pages must also be completed for screen failure patients. No other data will 
be entered into the clinical database for participants who are screen failures, unless the 
participant experienced a serious adverse event during the screening period (see SAE section 
for reporting details). If the participant fails to be randomized, the IRT must be notified within 
2 days of the screen fail, that the participant was not randomized.
8.2
Participant demographics/other baseline characteristics
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
Subject demographic and baseline characteristic data to be collected on all participants 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 
CRF whenever in their judgment, the test abnormality occurred prior to the informed consent 
signature.
Participants will provide their response to the blurry vision question from the IDEEL symptom 
bother questionnaire at Screening visit. Non-dilated pupil size will be assessed in a room 
illumination of 25 to 60 lux at Screening visit for eligibility.
Baseline ocular characteristics, including DCNVA, 
 will be 
collected.
8.3
Efficacy
Efficacy assessments will be performed at the visits as specified in the assessment schedule 
(Table 8-1).
At the clinic during the scheduled study visits, instill one drop of Novartis provided artificial 
tear product in each eye at least 30 minutes prior to starting visual acuity assessments. The time 
of artificial tears administration should be recorded in the source. Participants are encouraged 
not to engage in near work such as reading books or continuous use of mobile phone for texting 
or browsing while waiting at the site for study assessments. Participants should minimize the 


Novartis
Confidential
Page 40 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
use of their near correction (i.e., multifocal spectacles or reading glasses), prior to all study 
assessments during their clinic visits, including Screening visit.


Novartis
Confidential
Page 41 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
8.3.3
Appropriateness of efficacy assessments
Presbyopia manifests as difficulty with near vision tasks, such as reading. Hence the use of 
DCNVA is an appropriate measure to evaluate if UNR844 can benefit participants with 
presbyopia.
Similarly, currently optical correction is used to improve near vision in presbyopia. 
 
 
 
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.
For details on AE collection and reporting, refer to Section 10.1.
Table 8-2
Safety assessment specification
Assessment
Specification
Physical examination
A routine physical examination will be performed 
at the screening visit and at Month 12 and will 
include an evaluation of the general appearance 
(e.g., skin, peripheral blood perfusion, 
extremities, lymph nodes). 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 signs
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 


Novartis
Confidential
Page 42 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Assessment
Specification
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.


Novartis
Confidential
Page 43 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Assessment
Specification
Ophthalmic Examination
The following ocular assessments will be 
performed as per the schedule assessment:
1. Slit-lamp biomicroscopy include evaluation of 
the lids/lashes, conjunctiva, cornea (including 
corneal staining using the grading scale below), 
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 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
Corneal fluorescein staining
Corneal fluorescein staining will be determined on a scale of 0 - 3 as the average from each of 
5 zones (central plus 4 quadrants). Results will be recorded for each zone. This test will be 
performed using 5 µL of non-preserved 2% sodium fluorescein or equivalent per country 
instilled into the lower palpebral conjunctiva of both eyes.


Novartis
Confidential
Page 44 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Table 8-3
Corneal staining scale
OD
OS
Degree of Staining
Region
Degree of Staining
0....1....2....3
C-Central
0....1....2....3
0....1....2....3
S-Superior
0....1....2....3
0....1....2....3
T-Temporal
0....1....2....3
0....1....2....3
N-Nasal
0....1....2....3
0....1....2....3
I-Inferior
0....1....2....3
Figure 8-1
Corneal staining scale
8.4.2
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. All abnormal lab 
results must be evaluated for criteria defining an adverse event and reported as such if the 
criteria are met.


Novartis
Confidential
Page 45 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Table 8-4
Laboratory evaluations
Test Category
Test Name
Hematology
Hemoglobin, platelets, white blood 
cells, differential (basophils, eosinophils, 
lymphocytes, monocytes, neutrophils, and 
other)
Chemistry
Albumin, alkaline phosphatase, serum alanine 
aminotransferase, serum aspartate 
aminotransferase, lactate dehydrogenase, 
calcium, magnesium, phosphorus, sodium, 
potassium, creatinine, direct bilirubin, total 
bilirubin, urea, uric acid, amylase, lipase, 
glucose (non-fasting), and glycated hemoglobin 
(HbA1c).
Urinalysis
Macroscopic (Dipstick) panel - color, bilirubin, 
blood, glucose, ketones, leukocyte esterase, 
nitrite, pH, protein, specific gravity, and 
urobilinogen
Microscopic panel - red blood cells, white blood 
cells, casts, crystals, bacteria and epithelial 
cells. Microscopic analysis is only required if any 
parameter of the macroscopic panel is 
abnormal.
Pregnancy Test
serum pregnancy test at screening/ urine 
pregnancy test will be done at the other required 
time points.
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 urine pregnancy test is sufficient at other 
timepoints. However, a positive urinary pregnancy test needs to be confirmed with a serum 
pregnancy test.
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child-
bearing potential must also be available as source documentation in the following cases:
1. Surgical bilateral oophorectomy without a hysterectomy
2. Reported 12 months of natural (spontaneous) amenorrhea with an appropriate clinical 
profile.
In the absence of the above medical documentation, FSH testing is required of any female 
participant regardless of reported reproductive/menopausal status at screening/baseline.
8.4.4
Appropriateness of safety measurements
The safety assessments selected are appropriate evaluations of ocular and systemic health in 
presbyopic participants administered UNR844 ophthalmic solution.


Novartis
Confidential
Page 46 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)
Clinician Reported Outcomes (ClinRO)
Not applicable.


Novartis
Confidential
Page 47 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 48 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
9
Study discontinuation and completion
9.1
Discontinuation and completion
9.1.1
Study treatment discontinuation and study discontinuation
Discontinuation of study treatment for a participant occurs when study treatment is stopped 
earlier than the protocol planned duration and can be initiated by either the participant or the 
investigator.
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being.
Study treatment must be discontinued under the following circumstances:

Participant/guardian decision

Pregnancy

Unsatisfactory therapeutic effect

Use of prohibited treatment as per recommendations in Section 6.2.2

Any situation in which study participation might result in a safety risk to the participant

Following emergency unmasking
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information.
Participants 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, letter) should be made to contact the 
participant/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 participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the participant. 
This telephone contact should preferably be done according to the study visit schedule.
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

Adverse Events / Serious Adverse Events


Novartis
Confidential
Page 49 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment.
If discontinuation occurs because treatment code has been broken, please refer to
Section 6.6.2.
All randomized and/or treated participants who discontinued the study during the 3 month 
treatment period 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.
9.1.2
Withdrawal of informed consent
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant:

Does not want to participate in the study anymore, and

Does not want any further visits or assessments 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 participant’s decision to withdraw his/her consent and 
record this information.
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data.
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 participant are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table.
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 participants 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 participant, e.g., dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study.


Novartis
Confidential
Page 50 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
9.1.4
Early study termination by the sponsor
The study can be terminated by Novartis at any time.
Reasons for early termination

Unexpected, significant, or unacceptable safety risk to participants enrolled in the study

Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data

Discontinuation of study drug development
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, Participants must be seen as soon as possible 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 local regulation will be responsible 
for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last participant 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.
10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a 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 or an investigational device  
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events.
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems.
The occurrence of adverse events 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 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):


Novartis
Confidential
Page 51 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
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
2. Its relationship to the study treatment. If the event is due to lack of efficacy the assessment 
of causality will usually be ‘Not suspected.’ The rationale for this guidance is that the 
symptoms of a lack of efficacy are not caused by the trial drug, they happen in spite of its 
administration and/or lack of efficacy 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
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 interventions required to treat it, and the outcome.
 
 
Abnormal laboratory values or test results constitute adverse events 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 subject with 
the underlying condition.


Novartis
Confidential
Page 52 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
10.1.2
Serious adverse events
An SAE is defined as any adverse event [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:

fatal

life-threatening
Life-threatening in the context of a SAE refers to a reaction in which the participant 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 participant’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, e.g. defined as an event that jeopardizes the participant 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 participant 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 (please refer to the ICH 
E2D Guidelines).
All new 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 serious adverse 
event irrespective if a clinical event has occurred. (Section 10.1.5)


Novartis
Confidential
Page 53 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
10.1.3
SAE reporting
To ensure participant safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit 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 folder provided to 
each site.
Information about all SAEs is collected and recorded on the appropriate eSAE CRF pages. In 
the event that the eSAE CRF pages are not available (after last study visit), SAEs must be 
reported using the paper SAE Report Form. All applicable sections of the form must be 
completed in order to provide a clinically thorough report.
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 
immediately, without undue delay, and under no circumstances later than 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 Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a Chief Medical Office and 
Patient Safety Department associate may urgently require further information from the 
investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) 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 in accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries.
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment, unless 
otherwise specified by local law/regulations.
10.1.4
Pregnancy reporting
Pregnancies
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign pregnancy consent form to allow the Study 
Doctor ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 
signing the informed consent must be reported by the investigator to Novartis Safety within 24 
hours of learning of its occurrence, including pregnancies where the participant was exposed 
to placebo. 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. Standard Novartis Safety 
follow-ups are conducted for reports of pregnancy and data on health of newborns are collected 
for one year after delivery. In case of any congenital abnormality, birth defect or maternal and 
newborn complications, the possible relationship to the Novartis drug should be reported. 


Novartis
Confidential
Page 54 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Information on whether the baby was breast fed should be included where appropriate. 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 recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE. Misuse or abuse will 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 Dosing 
CRF (Yes/No)
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.
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 Electronic 
Case Report Forms (eCRF). The eCRFs have been built using fully validated secure web-
enabled software that conforms to 21 CFR Part 11 requirements, Investigator site staff will not 
be given access to the 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.


Novartis
Confidential
Page 55 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, 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 participant data for 
archiving at the investigational site.
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 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 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 (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology.
Dates of screenings, randomizations, screen failures and study completion, as well as 
randomization codes and data about all study treatment (s) dispensed to the participant and all 
dosage changes will be tracked using an Interactive Response Technology (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 the clinical team and monitor. 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. 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. eSource DDE or 
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 participant records, the 
accuracy of data capture / data entry, the adherence to the protocol and to Good Clinical Practice, 
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 


Novartis
Confidential
Page 56 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
performed by a centralized Novartis CRA organization. Additionally, a central analytics 
organization may analyze data & identify risks & 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 participant in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, and the results of any other tests or assessments. All information 
on CRFs must be traceable to these source documents in the participant's file. The investigator 
must also keep the original informed consent form signed by the participant (a signed copy is 
given to the participant).
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 CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed.
12
Data analysis and statistical methods
The final analysis for the primary efficacy endpoint will be performed when at least 225 
randomized participants have completed all assessments of the treatment period at Month 3 visit 
or discontinued from the study.
Additional analysis may be also conducted to evaluate the impact of COVID-19 pandemic.
Further technical details and discussions of the statistical considerations will be provided in the 
SAP.
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 Participants to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, Participants will be 
analyzed according to the treatment and strata (if applicable) 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 Participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized/assigned treatment if the patient took at least one dose of 
that treatment or the first treatment received if the randomized/assigned treatment was never 
received.


Novartis
Confidential
Page 57 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
12.2
Participant 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, 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 Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group.
12.4
Analysis of the primary endpoint(s)/estimand(s)
The primary objective of the study is to characterize the dose response relationship among 
UNR844 doses 0 (placebo), 5 mg/mL, 13.3 mg/mL, 23 mg/mL and 30 mg/mL dosed twice-
daily at Month 3. This will be evaluated by measuring the DCNVA (letters) in logMAR using 
the electronic visual acuity system.
12.4.1
Definition of primary endpoint(s)/estimand(s)
The primary efficacy variable is defined as the change from baseline in binocular DCNVA at 
Month 3.
12.4.2
Statistical model, hypothesis, and method of analysis
MCP-Mod methodology is utilized to test for a dose-response signal and estimate the dose-
response relationship.
Testing an overall dose-response signal
The null hypothesis of flat dose-response relationship for change from baseline in binocular 
DCNVA at Month 3 as compared to placebo will be tested at a one-sided significance level of 
2.5% against the alternative hypothesis of a monotonic decreasing dose response relationship.
Five candidate models to describe the potential dose-response shape (defined in terms of change 
from baseline in binocular DCNVA at Month 3 as compared to placebo) were selected (see
Figure 12-1 of the plot of the candidate models)


Novartis
Confidential
Page 58 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
1. Emax model 1 (with ED50 = 0.079%)
2. Emax model 2 (with ED50 = 0.375% )
3. Sigmoid-Emax model 1 (with ED50 = 1.500% and Hill coefficient= 4.301)
4. Sigmoid-Emax model 2 (with ED50 = 1.089% and Hill coefficient= 2.643 )
5. Exponential model (with delta=1.770)
For each of the underlying candidate models an optimal contrast will be derived. Then for each 
contrast (m, m=1,…,5), a t-statistic Tm based on multiplying mean responses per dose group 
with model-derived contrast vectors will be derived. For the purpose of derivation of the 
contrasts, the dose is used to allow calculation of optimal contrasts.
Response estimates at the dose will be based on the least square means per dose based on an 
MMRM model.
The model will include the change from baseline in binocular DCNVA (mean of the two 
assessments) as the dependent variable, binocular DCNVA at the baseline as the covariate, 
region, dose, age group, assessment visit, interaction of dose and assessment visit as the fixed 
effect and participant 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.
Under a normality assumption on the primary endpoint based on the least-squared estimates 
across the doses, a critical value q for testing each individual candidate model contrast is 
determined under the null hypothesis and under the constraint that the family-wise error rate is 
controlled at the desired one-sided 2.5% level. If Tmax = maxm Tm > q, the overall null hypothesis 
of a flat dose-response curve is rejected and the procedure will move on to the next step of dose-
response curve estimation as well as estimation of the dose that achieves a decrease of 0.08 
logMAR correct as compared to placebo (if there are multiple such doses, the smallest is 
chosen).
Otherwise, if no contrast test is statistically significant, then no overall dose response signal can 
be detected from the observed data and the procedure stops without proceeding to dose 
estimation.
Bootstrap model averaging will be used to estimate the dose-response curve, the target dose and 
to derive confidence intervals. Parametric bootstrap simulation will be performed using the 
least-squares dose group estimates based on their multivariate normal distribution.
Each simulated vector of dose estimates will be fitted by generalized least-squares fitting of the 
resulting simulated values (see Pinheiro et al 2014 for details) with the Emax model, the 
sigmoid Emax model and the exponential model. The best model for each simulated bootstrap 
sample will be recorded and used for prediction of the dose-response curve and the target dose. 
The final reported estimates will be based on the median of the so obtained predictions. 
Approximate confidence intervals for the dose-response curve and the target dose will be 
calculated based on the bootstrap quantiles.
In addition to the information collected during the 3 months treatment period for MCP-Mod 
analysis, the information collected during the 9 months treatment free period for the estimation 
of duration of effect will be taken into consideration for the selection of dose for future studies.


Novartis
Confidential
Page 59 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Figure 12-1
Dose-response shapes of the candidate models
The primary, sensitivity and two supportive estimands are noted in the table below together 
with their key attributes. The estimands outlined will be discussed in further detail in the SAP.


Novartis
Confidential
Page 60 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Table 12-1
Primary, sensitivity, and supportive estimands
Primary Estimand
Supportive Estimand 1
Supportive Estimand 2
Question
What is the efficacy 
attributable to different 
doses of UNR844 
received after 3 months 
of treatment, taking into 
account any unfavorable 
effect of the drug such as 
discontinuation due to 
unsatisfactory therapeutic 
effect or AE?
What is the true efficacy 
of different doses of 
UNR844, when 
administered as planned 
for 3 months, in 
Participants who had no 
relevant intercurrent 
events such as 
discontinuation or use of 
prohibited medications?
What is the efficacy 
attributable to the 
randomly assigned doses 
of UNR844 after 3 
months of treatment, 
considering the impact of 
any intercurrent events 
as inherent part of the 
assign treatment?
Estimand Definition
Dose-specific difference 
in mean change from 
baseline in DCNVA at 
Month 3 attributable to 
the initially randomized 
medication accounting for 
beneficial and detrimental 
effect of the drug
Dose-specific difference 
in mean change from 
baseline in DCNVA at 
Month 3 attributable to 
the study treatment 
received, excluding the 
effect of intercurrent 
events such as 
discontinuation or use of 
prohibited medications
Dose-specific difference 
in mean change from 
baseline in DCNVA at 
Month 3 attributable to 
randomized treatment
Discontinuation due to 
unsatisfactory therapeutic 
effect or AE
Primary: Include data 
collected post 
discontinuation if 
available. If not available, 
impute assuming no 
further benefit
Sensitivity: Exclude data 
collected post 
discontinuation and 
impute assuming no 
further benefit
Exclude data collected 
post discontinuation;
treat as missing and 
impute assuming missing 
at random
Include data collected 
post discontinuation, if 
available. If not available, 
impute assuming no 
further benefit
Discontinuation due to 
other reasons
Exclude data collected 
post discontinuation; treat 
as missing and impute 
assuming missing at 
random
Exclude data collected 
post discontinuation; treat 
as missing and impute 
assuming missing at 
random
Include data collected 
post discontinuation, if 
available. If not available, 
impute assuming no 
further benefit
Use of Prohibited 
medication or therapy, or 
changes in prohibited 
medication – Potentially 
affect efficacy
Exclude data collected 
post-use of prohibited 
medication; treat as 
missing and impute 
assuming missing at 
random
Exclude data collected 
post-use of prohibited 
medication; treat as 
missing and impute 
assuming missing at 
random
Include data collected 
post-use of prohibited 
medication, if available. If 
not available, impute 
assuming no further 
benefit
12.4.3
Handling of remaining intercurrent events of primary estimand
For participants who discontinued study treatment permanently with reason for discontinuation 
being either adverse event or unsatisfactory therapeutic event, the data collected post 
discontinuation will be included, if available. If not available, impute assuming no further 
benefit. For all other intercurrent events, data collected post intercurrent events will be removed; 
treat as missing and impute assuming missing at random.
If a subject has multiple intercurrent events, treatment discontinuation due to unsatisfactory 
therapeutic effect or AE will be considered as the priority intercurrent event, and data handling 


Novartis
Confidential
Page 61 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
following this intercurrent event will be according to what’s specified above, by ignoring the 
other intercurrent event(s) of the same subject. If only the other (non-priority) two intercurrent 
events happen to the same subject, the earliest event will be considered. Data handling following 
this first intercurrent event will be according to what’s specified above.
12.4.4
Handling of missing values not related to intercurrent event
In the case of missing data occurring in other scenarios, i.e., independent of intercurrent events 
related to response to study treatment, the estimand based on MAR approach will be considered 
specifically for each treatment arm the participants are assigned. This will result in a reasonable 
estimate of the true outcome based on the treatment effect observed at 7 months after study 
treatment discontinuation in CUNR844A2201E1 study.
12.4.5
Sensitivity analyses for primary endpoint/estimand
There will be one sensitivity analysis:
The efficacy endpoint is the same as the primary efficacy analysis, with the only change to 
exclude data collected post discontinuation and impute assuming no further benefit.
12.4.6
Supplementary analysis
Not applicable.
12.4.7
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. The only difference between this analysis and the primary efficacy analysis is the 
exclusion of the data collected post discontinuation or post-use of prohibited medications; treat 
as missing and impute assuming missing at random.
Supportive analysis #2
The efficacy endpoint for Supportive analysis #2 is change from baseline in binocular DCNVA 
at Month 3. The only difference between this analysis and the Supportive analysis #1 is the 
inclusion of data collected post discontinuation or post-use of prohibited medication, if 
available. If not available, impute assuming no further benefit.
12.5
Analysis of secondary endpoints/estimands
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
There are three secondary endpoints:
1. Change from baseline in monocular DCNVA (i.e., worse-seeing eye and better-seeing 
eye) at Month 3;


Novartis
Confidential
Page 62 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202

MCP-Mod as described in Section 12.4.2 will be applied to change from baseline in 
monocular DCNVA at Month 3 for the worse-seeing eye (WSE) and better-seeing eye 
(BSE), with intercurrent events and missing data handled in the same way as the for 
the primary estimand and supportive estimand 2 (Section 12.4)


Novartis
Confidential
Page 63 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
2. Gain of 3 lines (change from baseline of </= - 0.3 logMAR) in binocular, worse-seeing 
eye and better-seeing eye respectively at Month 3;

For monocular DCNVA, gaining of 3 lines is defined as change from baseline ≤ - 0.3 
logMAR in DCNVA and < + 0.1 logMAR in BCDVA.

For the endpoints of gaining of 3 lines (change from baseline of 0.3 logMAR) in 
binocular, worse-seeing eye and better-seeing eye respectively at Month 3, missing 
data imputation will be done in the same way as for the primary endpoint
(Section 12.4), defined for the primary estimand, based on their corresponding 
continuous endpoints, i.e., binocular and monocular DCNVA. After the imputation, 
these endpoints will be dichotomized to generate the endpoints of gaining of 3 lines in 
both eyes, worse-seeing eye and better-seeing eye, respectively at Month 3. Then a 
logistic regression model, by adjusting for baseline DCNVA and age (grouped as 45 
to 50 years and 51 to 55 years), will be fitted to each imputed data set for each of the 
three endpoints. By applying Rubin’s rule to combine results of these individual data 
sets, pairwise comparison of each dose versus placebo will be obtained for each of the 
three endpoints.
3. Change from Month 3 in binocular and monocular (worse-seeing and better-seeing eyes) 
DCNVA over time after Month 3 (i.e., Month 4 to Month 12).
For binocular, worse-seeing and better-seeing eyes, DCNVA over time after Month 3 will be 
summarized by treatment group and scheduled visits.
For DCNVA data (during treatment and treatment holiday), an individualized nonlinear mixed 
effect model will be used to describe the data and results will be provided in a separate modeling 
analysis report and not in the study CSR.
12.5.2
Safety endpoints
Not applicable.
12.5.3
Patient reported outcomes
Not applicable.


Novartis
Confidential
Page 64 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 65 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
12.7
Interim analyses
Two interim analyses will be planned for the study:
The first interim analysis will be performed when all patients complete (or discontinue prior to) 
the Month 3 visit as described in Section 12.4. The major objective of this interim analysis is to 
determine if the overall null hypothesis of a flat dose-response curve can be rejected.
The second interim analysis will be performed when 60% of the participants complete 6 months 
(i.e., Month 9) of treatment holiday period. The major objective of this interim analysis is to 
assess the retention of the treatment effect over the 9 months treatment holiday period.


Novartis
Confidential
Page 66 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
A total sample size of 210 randomized participants (in 1:1:1:1:1 allocation ratios corresponding 
to five UNR844 dosing regimens [placebo, 5 mg/mL, 13.3 mg/mL, 23 mg/mL, 30 mg/mL, 
respectively, treated twice-daily for 3 months)] is required to ensure a average power of 86% 
to detect the presence of dose response under the set of candidate models considered in MCP-
Mod, assuming a maximum effect for mean binocular change from baseline in logMAR over 
placebo of -0.08 (SD = 0.14) for an UNR844 arm. To allow for a ~5% drop-out rate during the 
treatment period (i.e., 3 months), 225 participants (45 in each of the 5 treatment groups) will be 
randomized. The power calculations leading to the sample size determination were based on 
simulations using all five candidate models considered in MCP-Mod. The maximum t-statistic 
contrast test was applied to each of the simulated data set to assess the presence of a dose 
response signal. It is the average power of this test that is ensured to be 86% under two of the 
candidate models (the most likely and the worst case) considered for the sample size of 225 
participants.
If participants dropping out due to COVID-19 leads to power reduction to be below 82% based 
on the above assumptions, additional participants will be recruited to ensure adequate power.
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 Harmonized Tripartite Guidelines for Good Clinical Practice, 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 Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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/IECs, 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 and 
as required in EudraCT. In addition, after study completion and finalization of the study report 


Novartis
Confidential
Page 67 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
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, EudraCT etc.)
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings.
13.4
Quality Control and Quality Assurance
Novartis maintains a robust Quality Management System (QMS) 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 SOPs, 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 participants should be 
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/IEC 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/IEC prior to 
implementation.
Only amendments that are required for participant safety may be implemented immediately 
provided the health authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified.


Novartis
Confidential
Page 68 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant 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/IEC at the study site should be informed according to 
local regulations.


Novartis
Confidential
Page 69 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202
15
References
References are available upon request
Fricke TR, Tahhan N, Resnikoff S, et al (2018) Global Prevalence of Presbyopia and Vision 
Impairment from Uncorrected Presbyopia: Systematic Review, Meta-analysis, and Modelling. 
Ophthalmology; 125:1492-9.
Garner WH, Garner MH (2016) Protein Disulfide Levels and Lens Elasticity Modulation: 
Applications for Presbyopia. Invest Ophthalmol Vis Sci; 57(6):2851-63.
Holden BA, Fricke TR, Ho SM, et al (2008) Global vision impairment due to uncorrected 
presbyopia. Arch. Ophthalmol; 126(12):1731-9.
Khan A, Iqbal Z, Watson DG, et al (2011) Simultaneous determination of lipoic acid (LA) 
and dihydrolipoic acid (DHLA) in human plasma using high-performance liquid 
chromatography coupled with electrochemical detection. J. Chromatogr. B Analyt. Technol. 
Biomed. Life Sci; 879:1725-31.
Pinheiro J, Bornkamp B, Glimm E, et al (2014) Model-based dose finding under model 
uncertainty using general parametric models. Stat Med:1646-61.
Strenk SA, Strenk LM, Koretz JF (2005) The mechanism of presbyopia. Prog Retin Eye Res; 
24:379-93.
Zou GY (2013) Confidence interval estimation for the Bland-Altman limits of agreement with 
multiple observations per individual. Stat Methods Med Res p. 630-42.


Novartis
Confidential
Page 70 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 71 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 72 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 73 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 74 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 75 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 76 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 77 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 78 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 79 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 80 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 81 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202


Novartis
Confidential
Page 82 of 82
Amended Protocol v02 Clean
Protocol No. CUNR844A2202

SAP_001.pdf: 
Clinical Development 
UNR844 
CUNR844A2202 / NCT04806503
A randomized, placebo-controlled, double-masked, multi-center, 
dose-ranging study to evaluate the safety, and efficacy of UNR844 
in subjects with presbyopia 
Statistical Analysis Plan (SAP) 
Document type: 
SAP Documentation 
Document status: 
Final 3.0 
Release date: 
23-November-2022
Number of pages: 
47 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 
Template Version 3.0, Effective from 01-Jul-2020 


Novartis 
For business use only 
Page 2 of 46 
SAP 
 
CUNR844A2202 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and 
title impacted 
(Current) 
21-May-
2021 
Prior 
to 
DB 
lock 
Creation of 
final 
version 
N/A - First version 
NA 
28-July-
2022 
Prior 
to 
DB 
lock 
Creation of 
amendment 
1 
Update the list of abbreviations 
 
 
 
 
Clarify the second interim analysis 
Section 1 
 
 
 
Clarify the data analyses scope of this 
document (IA1 and final CSR) 
Section 1 
Section 2.1 
 
 
 
Clarify 
the 
responsibilities 
of 
different 
teams 
on 
the 
interim 
analyses and final CSR 
Section 1 
Section 1.1 
Section 2.7 
 
 
 
Change the decimal of logMAR and 
revise typos   
Section 1.1 
Section 1.2 
Section 2.2.1 
Section 2.4  
Section 2.7  
Section 2.13  
Section 2.14.1 
 
 
 
Clarify the exclusion criteria in run-
in period  
Section 1.1 
 
 
 
Change in the definition of Baseline 
and study day  
Section 2.1.1.2 
 
 
 
Modify the allocation rule for 
unplanned visit 
Section 2.1.1.3 
 
 
 
Exclude unscheduled visits from 
‘by-visit’ tabulations, graphs, or 
analyses 
Section 2.1.1.4 
 
 
 
Add the rule for multiple unscheduled 
visits 
Section 2.1.1.4 


Novartis 
For business use only 
Page 3 of 46 
SAP 
 
CUNR844A2202 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and 
title impacted 
(Current) 
 
 
 
Change in the definition of on-
treatment period and post-treatment 
period  
Section 2.1.1.5 
Section 2.8 
Section 2.8.1 
 
 
 
Add a rule to deal with cases with 
multiple 
entries 
for 
the 
same 
assessment 
and 
exclude 
physiologically implausible DCNVA  
Section 2.1.1.8 
 
 
 
Change the definition of FAS 
Section 2.2 
 
 
 
Use PD terms to identify subjects 
infected by COVID-19 
Section 2.2.1 
Section 2.5.3.1 
 
 
 
Delete summary of prior, concomitant 
and post therapies by SOC 
Section 2.4.1 
 
 
 
Add descriptions for candidate dose-
response model assumptions and 
update the dose-response curve 
Section 2.5.2 
 
 
 
Refine the descriptions for primary 
and supportive estimands 
Section 2.5.3.1 
 
 
 
Add one sensitivity analysis to 
investigate the impact of subjects with 
unexpected fluctuations 
Section 2.5.4 
 
 
 
Delete the paragraphs for supportive 
analyses 
Section 2.5.5 
 
 
 
Change the success criteria for 
gaining of 3 lines in binocular 
DNCVA 
Section 2.7.2 
Section 2.13  
Section 4 
 
 
 
 
 
 
Add required part for CTSD 
Section 2.8.1 
 
 
 
Remove the summary and shifting 
tables 
Section 2.8.3 
Section 2.8.4.2 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 4 of 46 
SAP 
 
CUNR844A2202 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and 
title impacted 
(Current) 
 
 
 
 
 
 
 
  
1 
 
 
 
Update the interim analysis team 
members 
Section 2.14.2 
 
 
 
Add the description of Five Macros 
for multiple imputation 
Section 5.4.1 
 
 
 
Remove the Type III analysis in 
logistic regression and add the 
sample code  
Section 5.4.2 
 
 
 
23-
November-
2022 
Prior 
to 
DB 
lock 
Creation of 
amendment 
2 
Reflect early study termination 
 
Section 1, 
Section 2.14, 
Section 4 
 
 
 
Delete second interim analysis 
Section 1.1, 
Section 2.14 
 
 
 
Define end of study/end of treatment 
mapping rule 
Section 
2.1.1.3 
 
 
 
Define the wording of unscheduled 
visits mapping rule 
Section 2.1.14 
 
 
 
Delete the summary of significant 
non-drug therapies and procedures 
Section 2.4.1 
 
 
 
Define secondary endpoints 
Section 2.7 
 
 
 
Defined safety endpoints 
Section 2.8.1 
 
 
 
Delete “ i.e. until 1 day after the date 
of the last study treatment” 
Section 2.8.1 
 
 
 
Add ophthalmic examinations and 
refractive status in the listings 
Section 2.8.4.3 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 5 of 46 
SAP 
 
CUNR844A2202 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section 
and 
title impacted 
(Current) 
 
 
 
Define changes to protocol analyses 
Section 4 
 
 
 
Delete the imputation of CM end date 
for ongoing record 
Section 5.1.2.1 
 
 
 
Delete medical history partial date of 
diagnosis imputation 
 
Section 5.1.2.3 


 
 
 
 
 
 
 
Table of contents 
Table of contents ..................................................................................................................................... 6 
List of tables ........................................................................................................................................... 8 
List of figures .......................................................................................................................................... 8 
List of abbreviations ............................................................................................................................... 9 
1 
Introduction ........................................................................................................................................... 11 
1.1 
Study design ............................................................................................................................ 11 
1.2 
Study objectives and endpoints ............................................................................................... 13 
2 
Statistical methods ................................................................................................................................ 15 
2.1 
Data analysis general information ........................................................................................... 15 
2.1.1 
General definitions ............................................................................................... 15 
2.2 
Analysis sets ............................................................................................................................ 18 
2.2.1 
Subgroups of interest ............................................................................................ 18 
2.3 
Patient disposition, demographics and other baseline characteristics ..................................... 19 
2.3.1 
Subject disposition ................................................................................................ 19 
2.3.2 
Subject demographics and other baseline characteristics ..................................... 19 
2.4 
Treatments (study treatment, concomitant therapies, compliance) ......................................... 19 
2.4.1 
Prior, concomitant and post therapies ................................................................... 20 
2.5 
Analysis of the primary objective ............................................................................................ 20 
2.5.1 
Primary endpoint .................................................................................................. 20 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................................... 21 
2.5.3 
Handling of missing values/censoring/discontinuations ....................................... 22 
2.5.4 
Sensitivity analyses for primary endpoint/estimand ............................................. 25 
2.5.5 
Supportive analyses .............................................................................................. 25 
2.6 
Analysis of the key secondary objective ................................................................................. 25 
2.7 
Analysis of secondary efficacy objective(s) ............................................................................ 26 
2.7.1 
Secondary endpoints ............................................................................................. 26 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................................... 26 
2.7.3 
Handling of missing values/censoring/discontinuations ....................................... 27 
2.8 
Safety analyses ........................................................................................................................ 27 
2.8.1 
Adverse events (AEs) ........................................................................................... 27 
2.8.2 
Deaths ................................................................................................................... 28 
2.8.3 
Laboratory data ..................................................................................................... 29 
2.8.4 
Other safety data ................................................................................................... 29 
2.9 
Pharmacokinetic endpoints ...................................................................................................... 29 


Novartis 
For business use only 
Page 7 of 46 
SAP 
 
CUNR844A2202 
 
2.10 
PD and PK/PD analyses .......................................................................................................... 29 
 
 29 
2.12 
Biomarkers .............................................................................................................................. 30 
 
 30 
2.14 
Interim analysis ....................................................................................................................... 31 
2.14.1 
Planned Interim analysis ....................................................................................... 31 
2.14.2 
Interim Analysis Team ......................................................................................... 32 
2.14.3 
Conflict of interest ................................................................................................ 33 
2.14.4 
Insider Trading ..................................................................................................... 33 
2.14.5 
Responsibilities ..................................................................................................... 33 
2.14.6 
Confidentiality Agreement ................................................................................... 35 
2.14.7 
Organizational diagram ........................................................................................ 35 
2.14.8 
Data Review Meetings .......................................................................................... 37 
2.14.9 
Recommendations from the IAT .......................................................................... 37 
3 
Sample size calculation ......................................................................................................................... 38 
3.1 
Primary endpoint(s) ................................................................................................................. 38 
4 
Change to protocol specified analyses .................................................................................................. 38 
5 
Appendix ............................................................................................................................................... 39 
5.1 
Imputation rules of missing dates ............................................................................................ 39 
5.1.1 
AE partial date imputation .................................................................................... 39 
5.1.2 
Concomitant medication partial date imputation .................................................. 41 
5.2 
AEs coding/grading ................................................................................................................. 42 
5.3 
Laboratory parameters derivations .......................................................................................... 43 
5.4 
Statistical models ..................................................................................................................... 43 
5.4.1 
Primary analysis ................................................................................................... 43 
5.4.2 
Secondary analysis ............................................................................................... 45 
 
 46 
5.5 
Rule of exclusion criteria of analysis sets ............................................................................... 46 
6 
Reference .............................................................................................................................................. 46 
 
 
 


Novartis 
For business use only 
Page 8 of 46 
SAP 
 
CUNR844A2202 
 
List of tables 
Table 1-1 
Objectives and related endpoints .......................................................... 13 
Table 2-1 
Allocation of unscheduled visit for an assessment to be done at each 
scheduled visit ....................................................................................... 16 
Table 2-2 
Allocation of unscheduled visit for an assessment to be done at 
Baseline, Month 1-4, 7, 10, and 12 ....................................................... 17 
Table 2-5 
Interim Analysis Team Members .......................................................... 32 
Table 5-1 
Subject Classification ............................................................................ 46 
 
 
List of figures 
Figure 1-1 
Study Design ......................................................................................... 13 
Figure 2-1 
Graphical illustration of visit allocation using the 1/3 – 2/3 rule .......... 16 
Figure 2-2 
Dose-response shapes of the candidate models .................................... 22 
Figure 2-3 
Organization diagram ............................................................................ 36 
 


Novartis 
For business use only 
Page 9 of 46 
SAP 
 
CUNR844A2202 
 
List of abbreviations 
AE 
Adverse Event 
AIC 
Akaike information criterion 
ATC 
Anatomical Therapeutic Chemical Classification System 
 
 
BSE 
Better-seeing eye 
CIR 
Copy Increment from Reference 
COVID-19 
Coronavirus Disease - 19 
CTT 
Clinical Trial Team 
CRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical study report 
DBL 
Database Lock 
DCNVA 
Distance-corrected near visual acuity 
DI-C&S 
Novartis Development Informatics – Clinical and Safety Systems 
ED50 
Median Effective dose 
EMA 
European Medicines Agency 
Emax 
Maximum Effect 
EOS 
End of Study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
GPH 
Global Program Head 
IA 
Interim Analysis 
ICE 
Intercurrent event 
IRT 
Interactive Response Technology 
IAT 
Interim Analysis Team 
MAR 
Missing at Random 
MCP-Mod 
Multiple Comparison Procedure - Modeling 
MedDRA 
Medical dictionary for regulatory activities 
mg 
milligram(s) 
mL 
milliliter(s) 
MMRM 
Multilevel Modelling for Repeated Measures 
 
 
 
 
 
 
 
 
PD 
Protocol Deviation 
 
 
 
 
 
 
PT 
Preferred term 
SAE 
Serious Adverse Event 
SAF 
Safety Set 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 


Novartis 
For business use only 
Page 10 of 46 
SAP 
 
CUNR844A2202 
 
 
 
 
 
VA 
Visual Acuity 
WSE 
Worse-seeing eye 


 
 
 
 
 
 
1 
Introduction 
The study is being terminated early as Novartis has made the decision to stop UNR844A2202 
for the treatment of presbyopia based on the results from the interim analysis. All subjects who 
are ongoing at the time of the decision of study termination will be discontinued from the study 
at their next visit.  
The purpose of the Statistical Analysis Plan (SAP) is to describe the implementation of the 
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 CUNR844A2202.  
The analyses will be conducted at two time points as described below: 
• The Interim Analysis (IA) will be conducted on data from all subjects up to the Month 
3 Visit, when all subjects complete (or discontinue prior to) the Month 3 Visit;  
• The final analysis will be conducted on data obtained after Month 3 Visit once all active 
subjects have terminated the study and final Database Lock (DBL) achieved.  
This document refers to the data analysis for: 
• the Interim Analysis (at Month 3 visit), which is also the final analysis of the Month-3 
endpoints; 
• the final analysis for some key endpoints determined by the team, including data 
collected beyond Month-3.  
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. 
The Interim Analysis has been completed according to the plan on 24th August 2022.  
1.1 
Study design 
This is a randomized, placebo-controlled, double-masked, multi-arm, parallel-group, multi-
center study. The total duration of the study will be approximately 13 months and there will be 
around 225 male or female presbyopic participants aged 45 to 55 years enrolled in this study. 
The 13-month study will consist of: 
• A 1-week run-in period 
• A 3-month treatment course with UNR844 and/or placebo 
• A 9-month treatment holiday period 
Participants will be randomized equally to one of five treatment arms, consisting of: 
• Placebo eye drops, twice-a-day for three months 
• UNR844 5 mg/mL eye drops, twice-a-day for three months 
• UNR844 13.3 mg/mL eye drops, twice-a-day for three months 


Novartis 
For business use only 
Page 12 of 46 
SAP 
 
CUNR844A2202 
 
• UNR844 23 mg/mL eye drops, twice-a-day for three months 
• UNR844 30 mg/mL eye drops, twice-a -day for three months 
Participants will undergo a 1-week run-in period where they will be assessed for entry criteria 
during the Screening visit. During the run-in period, participants will administer 1 drop of 
artificial tears twice-a-day (1 drop in the morning and 1 drop in the evening) in each eye at 
home. This run-in period is designed to help minimize potential variability in distance-corrected 
near visual acuity (DCNVA) caused by initial ocular surface issues and help to establish an 
accurate baseline prior to randomization. The run-in period will exclude participants with a 
change in DCNVA more than 0.10 logMAR (5 letters) difference between Screening and 
Baseline. The study design is schematically depicted in Figure 1-1. 
Randomization will be stratified based on binocular DCNVA (0.50 logMAR or less; 0.52 
logMAR or more) and age (45 to 50 years and 51 to 55 years) at baseline, and region. 
Participants will be randomized 1:1:1:1:1 within each stratum to one treatment arm. The 
randomization scheme for participants will be reviewed and approved by a member of the 
Randomization Office.  


Novartis 
For business use only 
Page 13 of 46 
SAP 
 
CUNR844A2202 
 
Figure 1-1 
Study Design 
 
The primary objective of this study is to characterize dose-response of UNR844 in presbyopic 
subjects aged 45 to 55 years by assessing the change in binocular DCNVA from baseline after 
three months of treatment.  
The interim analysis will be performed when all subjects completed (or discontinue prior to) 
the Month 3 visit to assess the primary objective. The analysis was completed and the outcome 
led to the discontinuation of the program due to lack of efficacy.  
 
1.2 
Study objectives and endpoints 
Table 1-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 


Novartis 
For business use only 
Page 14 of 46 
SAP 
 
CUNR844A2202 
 
Objective(s) 
Endpoint(s) 
• Characterize the dose-response of 
UNR844 for change from baseline in 
binocular DCNVA at Month 3 
• Change from baseline in binocular DCNVA 
assessed using letters at Month 3 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• Characterize the dose response of 
UNR844 as measured by change from 
baseline in monocular DCNVA at Month 3 
• Change from baseline in monocular DCNVA, 
assessed using letters (i.e. worse-seeing eye and 
better-seeing eye) at Month 3 
• Assess the duration of effect using 
change in DCNVA after Month 3 
with various dose concentrations of 
UNR844  
• Binocular and monocular DCNVA assessed using 
letters, over time after Month 3 (i.e. Month 4 to Month 
12) 
• Evaluate the efficacy of improving 
DCNVA in presbyopic participants, as 
measured by proportion of participants 
gaining at least 0.30 logMAR DCNVA at 
Month 3 
• Proportion of participants gaining at least 0.30 
logMAR in binocular and monocular (worse-seeing eye 
and better-seeing eye) DCNVA assessed using letters 
(without near correction) from baseline at Month 3 
 


Novartis 
For business use only 
Page 15 of 46 
SAP 
 
CUNR844A2202 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The Interim Analysis will be performed by independent Analytics and statistical programming 
group of Novartis, while the final analysis will be performed by the Biostatistics and statistical 
programming of the CTT. 
This document refers to the data analysis for the Interim Analysis (at Month 3 visit), which is 
also the final analysis of the Month-3 endpoints, as well as the final analysis, including data 
beyond Month-3. Analyses will be performed using SAS 9.4. In addition, the dose finding R 
package will be used for the dose finding analysis focusing on Month-3 endpoint.   
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. These summary 
statistics will be presented by treatment group unless otherwise specified. Where appropriate, 
point estimates and confidence intervals of treatment group differences will be provided. 
In general, the randomization stratification factors will be included as factors in the primary 
efficacy analysis, and the corresponding supportive analyses. 
2.1.1 
General definitions  
2.1.1.1 
Study treatment  
The following treatment groups will be presented: 
• Placebo eye drops, one drop twice-a-day for three months 
• UNR844 5 mg/mL eye drops, one drop twice-a-day for three months 
• UNR844 13.3 mg/mL eye drops, one drop twice-a-day for three months 
• UNR844 23 mg/mL eye drops, one drop twice-a-day for three months 
• UNR844 30 mg/mL eye drops, one drop twice-a-day for three months 
2.1.1.2 
Baseline and post-Baseline 
Baseline (Day 1) is the first study treatment in the study. The baseline value for efficacy and 
safety variables is the last available value (scheduled or unscheduled) collected prior to or at 
the date of first study treatment. 
All data collected after the date of first study 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 first study treatment) + 1; 
The study day for a scheduled or unscheduled visit before baseline is defined as: 
Study day = (Date of visit) – (Date of first study treatment).  
2.1.1.3 
End of study/end of treatment 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 when a subject completes or discontinues the treatment.  


Novartis 
For business use only 
Page 16 of 46 
SAP 
 
CUNR844A2202 
 
To report data by visit in the outputs, the end of study with early discontinuation will be 
allocated to Month 12 /End of Study (Month 12/EOS) visit. To be more specific, any visit name 
equal to "Early Exit Visit" will be allocated to "Month 12/EOS" and analyzed as "Month 
12/EOS". 
2.1.1.4 
Unscheduled visits 
Data collected at unscheduled visits will only be used in ‘by-visit’ tabulations, graphs or 
analyses when it can be mapped to a missed scheduled visit by the 1/3 – 2/3 rule mentioned 
above. If multiple unscheduled visits are allocated to the same missed scheduled visit: 
• The unscheduled visit closest to the missed scheduled visit will be used; 
• If there are multiple unscheduled visits with the same distance/interval to the missed 
scheduled visit, the latest one will be used; 
To be more specific, suppose such a visit falls between two adjacent scheduled visits (e.g. visits 
A and B) corresponding to visit days 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, otherwise, it will 
allocated to visit B. 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 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 - 4, 7, 10 and 12. 
All data collected at unscheduled visits will be listed. 
Figure 2-1 
Graphical illustration of visit allocation using the 1/3 – 2/3 rule 
 
Table 2-1 
Allocation of 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 – 40 
  
M2 
60 
41 – 70 
  


Novartis 
For business use only 
Page 17 of 46 
SAP 
 
CUNR844A2202 
 
M3 
90 
71 – 100 
  
M4 
120 
101 – 130 
  
M5 
150 
131 – 160 
  
M6 
180 
161 – 190 
  
M7 
210 
191 – 220 
  
M8 
240 
221 – 250 
  
M9 
270 
251 – 280 
  
M10 
300 
281 – 310 
 
M11 
330 
311 – 340 
 
M12 
360 
>=341 
 
Table 2-2 
Allocation of unscheduled visit for an assessment to be done at 
Baseline, Month 1-4, 7, 10, and 12 
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 – 100 
  
M4 
120 
101 – 150 
  
M7 
210 
151 – 240 
  
M10 
300 
241 – 320 
  
M12 
360 
>= 321 
  
 
2.1.1.5 
Analysis periods 
The on-treatment period of this study lasts from date of the first administration of study 
treatment to the date of the last administration of study treatment. If dates are incomplete in a 
way that clear assignment to pre-, on-, post-treatment period cannot be made, then the respective 
data will be assigned to the on-treatment period. 
The post-treatment period is after the on-treatment period, which starts from 1 day after the date 
of the last actual administration of any study treatment until end of study (EOS).  
2.1.1.6 
Missing baseline and post-baseline data  
Missing baseline data will not be imputed. 
Observations with values ‘not done’, ‘not evaluable’, ‘not applicable’ will be treated as missing 
values. 
2.1.1.7 
Worse-seeing and better-seeing eyes 
The worse-seeing eye (WSE) is defined as the eye that has the higher monocular logMAR value 
at baseline and the better-seeing eye (BSE) is defined as the eye that has the lower logMAR 


Novartis 
For business use only 
Page 18 of 46 
SAP 
 
CUNR844A2202 
 
value at baseline. For subjects with identical logMAR value of monocular DCNVA for both 
eyes at baseline, the right eye is defined as the worse-seeing eye. 
2.1.1.8 
Rule applicable to VA data collected with the digital device (M&S) 
Physiologically non-plausible records 
Any score of “100” for DCNVA in ETDRS letter will be considered not physiologically 
plausible and the value will be excluded before the analyses. 
Multiple entries  
If multiple entries for the same assessment are observed within one visit, the latest assessment 
will be used. 
2.2 
Analysis sets 
Full Analysis Set (FAS) comprises all participants to whom study treatment has been assigned 
by randomization and received at least one dose of the study treatment. According to the intent 
to treat principle, participants will be analyzed according to the treatment and strata (if 
applicable) they have been assigned to during the randomization procedure. FAS will be used 
for all efficacy variables, unless otherwise stated. 
Safety Set (SAF) includes all participants who received at least one dose of study treatment. 
Participants will be analyzed according to the study treatment received, where treatment 
received is defined as the randomized/assigned treatment, if the patient took at least one dose 
of that treatment, or the first treatment received if the randomized/assigned treatment was never 
received. 
Rules of exclusion criteria of analysis sets with protocol deviations and subject classification 
are specified in Section 5.5. 
The number and percentage of subjects within each of the above analysis sets will be 
summarized. 
2.2.1 
Subgroups of interest 
Subgroup analysis will be done by classifying the population according to stratification factors 
at randomization (See Section 2.13). In addition, analyses based on the following subgroups 
will be performed to assess any potential impact of the COVID-19 pandemic on key study 
endpoints, if there is a sufficient number of subjects in each subgroup: 
• According to the internal guidance (http://go/covid19info), the start and end dates of the 
COVID-19 pandemic for different geographical regions/countries participating in Study 
CUNR844A2202 are defined below: 
Region/Country 
Start Date 
End Date 
Japan 
21-Feb-2020 
End date has not yet been defined 
Rest of the World (including 
US, Canada, and Australia) 01-Mar-2020 
End dates have not yet been defined 


Novartis 
For business use only 
Page 19 of 46 
SAP 
 
CUNR844A2202 
 
The following subgroups will be defined once the end dates of the regions are available: 
o Exposed subjects to COVID-19 pandemic: subjects who are recruited prior to 
the end date; 
o Non-exposed subjects to COVID-19 pandemic: subjects who are recruited on or 
after the end date. 
• Subgroups of subjects who are infected and non-infected will be defined and identified 
through data in the following way: 
o Subjects infected by COVID-19: subjects who discontinue study treatment due 
to COVID-19 infection, or are infected by COVID-19 as identified from 
COVID-19 infection and health related PD term; 
o Subjects not infected by COVID-19: subjects who don’t meet any of the above 
conditions. 
2.3 
Patient 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 baseline 
characteristics (DCNVA, 
 
cycloplegic refraction) will be listed and summarized descriptively by treatment group for the 
FAS. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
primary system organ class (SOC) and preferred term (PT), by treatment group separately for 
ocular and non-ocular histories/conditions. This includes any abnormalities noted during 
baseline evaluation of anterior and posterior eye segment health.  
2.4 
Treatments 
(study 
treatment, 
concomitant 
therapies, 
compliance) 
The SAF will be used for the analyses below.  
The duration of exposure in days to UNR844, placebo will be summarized by means of 
descriptive statistics using the SAF. The duration of exposure in days to UNR844 or placebo is 
defined as the date of the last administration of different doses of UNR844 or placebo (from 


Novartis 
For business use only 
Page 20 of 46 
SAP 
 
CUNR844A2202 
 
‘Study treatment’ CRF), and date of the first administration of different doses of UNR844 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. 
Compliance will be presented by summarizing the total number of days with the use of study 
treatment twice, once, or none, and the total number of times of using study treatment by 
treatment group and by eye. This information will be obtained from the CRF by counting the 
number of days with the use of study treatment twice, once, or none in each eye. The total 
number of times of using study treatment will be to count all the recorded use of study treatment 
at the subject level for each eye during the treatment phase.  
The reason for premature discontinuation of study treatment will also be summarized. 
In addition, to assess any potential impact of the COVID-19 pandemic on study treatment 
compliance, summary tables on the duration of exposure, and the total number of days with the 
use of study treatment twice, once, or none, will be provided for the subgroups of exposed/non-
exposed, and infected/not infected subjects, as defined in Section 2.2.1, if there is a sufficient 
number of subjects in each subgroup. 
2.4.1 
Prior, concomitant and post therapies 
Prior medications are defined as drugs taken and stopped prior to the first administration 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 will be summarized by treatment group (separately for 
ocular and non-ocular medications/therapies), and presented in alphabetical order by ATC 
classification codes and preferred term. The tables will be presented with the 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, prior and concomitant medications, and significant non-
drug therapies and procedures will be listed including the reported name, laterality if applicable, 
and treatment start/end date, etc.  
2.5 
Analysis of the primary objective 
The primary objective of the study is to characterize the dose response relationship among 
UNR844 doses 0 (placebo), 5 mg/mL, 13.3 mg/mL, 23 mg/mL and 30 mg/mL dosed twice-
daily at Month 3. This will be evaluated by measuring the DCNVA (letters) in logMAR using 
the electronic visual acuity system. 
2.5.1 
Primary endpoint 
The primary efficacy variable is defined as the change from baseline in binocular DCNVA 
assessed using letters at Month 3. 


Novartis 
For business use only 
Page 21 of 46 
SAP 
 
CUNR844A2202 
 
2.5.2 
Statistical hypothesis, model, and method of analysis  
MCP-Mod methodology is utilized to test for a dose-response signal and estimate the dose-
response relationship. 
Testing an overall dose-response signal 
The null hypothesis of flat dose-response relationship for change from baseline in binocular 
DCNVA at Month 3 as compared to placebo will be tested at a one-sided significance level of 
2.5% against the alternative hypothesis of a monotonic decreasing dose response relationship. 
Five candidate models to describe the potential dose-response shape (defined in terms of change 
from baseline in binocular DCNVA at Month 3 as compared to placebo, the placebo effect is 
set to -0.08 logMAR and the maximum treatment effect is assumed to be -0.08 logMAR), were 
selected (see Figure 2-2. of the plot of the candidate models) 
1. Emax model 1 (with ED50 = 0.079%) 
2. Emax model 2 (with ED50 = 0.375%) 
3. Sigmoid-Emax model 1 (with ED50 = 1.500% and Hill coefficient= 4.301) 
4. Sigmoid-Emax model 2 (with ED50 = 1.089% and Hill coefficient= 2.643) 
5. Exponential model (with delta=1.770) 
For each of the underlying candidate models an optimal contrast will be derived. Then for each 
contrast (m, m=1, …, 5), a t-statistic Tm based on multiplying mean responses per dose group 
with model-derived contrast vectors will be derived. For the purpose of derivation of the 
contrasts, the dose is used to allow calculation of optimal contrasts. 
Response estimates at the dose will be based on the least square means per dose based on an 
MMRM model. 
The model will include the change from baseline in binocular DCNVA (mean of the two 
assessments) as the dependent variable, binocular DCNVA at the baseline as the covariate, 
region, dose, age group, assessment visit, interaction of dose and assessment visit as the fixed 
effect and participant 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. 
Under a normality assumption on the primary endpoint based on the least-squared estimates 
across the doses, a critical value q for testing each individual candidate model contrast is 
determined under the null hypothesis and under the constraint that the family-wise error rate is 
controlled at the desired one-sided 2.5% level. If Tmax = maxm Tm > q, the overall null hypothesis 
of a flat dose-response curve is rejected and the procedure will move on to the next step of dose-
response curve estimation as well as estimation of the dose that achieves a decrease of 0.08 
logMAR correct as compared to placebo (if there are multiple such doses, the smallest is 
chosen). 


Novartis 
For business use only 
Page 22 of 46 
SAP 
 
CUNR844A2202 
 
Figure 2-2 
Dose-response shapes of the candidate models 
 
Otherwise, if no contrast test is statistically significant, then no overall dose response signal can 
be detected from the observed data and the procedure stops without proceeding to dose 
estimation. 
Bootstrap model averaging will be used to estimate the dose-response curve, the target dose and 
to derive confidence intervals. Parametric bootstrap simulation will be performed using the 
least-squares dose group estimates based on their multivariate normal distribution. 
Each simulated vector of dose estimates will be fitted by generalized least-squares fitting of the 
resulting simulated values (Pinheiro, Bornkamp et al. 2014) with the Emax model, the sigmoid 
Emax model and the exponential model. The best model for each simulated bootstrap 
sample (based on generalized Akaike information criterion, AIC) will be recorded and used for 
prediction of the dose-response curve and the target dose. The final reported estimates will be 
based on the median of the obtained predictions. Approximate confidence intervals for the dose-
response curve and the target dose will be calculated based on the bootstrap quantiles. 
2.5.3 
Handling of missing values/censoring/discontinuations 
2.5.3.1 
Missing data related to intercurrent event 
Primary estimand: 
The underlying question for the primary estimand is: what is the efficacy attributable to different 
doses of UNR844 received after 3 months of treatment, taking into account any unfavorable 
effect of the drug such as discontinuation due to unsatisfactory therapeutic effect or Adverse 
Events (AE). The estimand definition that addresses this question is the dose-specific difference 


Novartis 
For business use only 
Page 23 of 46 
SAP 
 
CUNR844A2202 
 
in mean change from baseline in DCNVA at Month 3 attributable to the initially randomized 
medication accounting for beneficial and detrimental effect of the drug. 
Three types of intercurrent events (ICEs) listed below will be addressed for this estimand: 
• ICE 1: treatment discontinuation due to unsatisfactory therapeutic effect or AE; 
• ICE 2: treatment discontinuation due to other reasons; 
• ICE 3: use of prohibited medication or therapy, or changes in prohibited medication, 
which would potentially affect efficacy (as captured by ‘Protocol Deviations’ CRF). 
For this estimand, data following the above three types of intercurrent events will be dealt with 
in three specific ways: 
• For ICE 1, include data collected post discontinuation if available. If not available, 
impute assuming no further benefit, i.e. Copy Increment from Reference (CIR) method 
will be used for imputation; 
• For ICE 2, exclude data collected post discontinuation, treat them as missing and impute 
assuming Missing at Random (MAR); 
• For ICE 3, exclude data collected post-use of prohibited medication, treat them as 
missing and impute assuming MAR. 
If a subject has multiple intercurrent events, treatment discontinuation due to unsatisfactory 
therapeutic effect or AE will be considered as the priority intercurrent event, and data handling 
following this intercurrent event will be according to what is specified above, by ignoring the 
other intercurrent event(s) of the same subject. If only the other two intercurrent events (non-
priority) happen to the same subject, consider the event which occurs earliest. Data handling 
following this earliest intercurrent event will be according to what is specified above. 
Supportive estimand 1: 
The underlying question for the supportive estimand 1 is: what is the true efficacy of different 
doses of UNR844, when administered as planned for 3 months, in participants who had no 
relevant intercurrent events such as discontinuation or use of prohibited medications? The 
estimand definition that addresses this question is: dose-specific difference in mean change 
from baseline in DCNVA at Month 3 attributable to the study treatment received, excluding the 
effect of intercurrent events such as discontinuation or use of prohibited medications. 
For this estimand, data following the three types of intercurrent events will be dealt with in 
three specific ways: 
• For ICE 1, exclude data collected post discontinuation, treat them as missing and impute 
assuming MAR; 
• For ICE 2, exclude data collected post discontinuation, treat them as missing and impute 
assuming MAR; 
• For ICE 3, exclude data collected post-use of prohibited medication, treat them as 
missing and impute assuming MAR. 


Novartis 
For business use only 
Page 24 of 46 
SAP 
 
CUNR844A2202 
 
If a subject has multiple intercurrent events, consider the event which occurs earliest. Data 
handling following this earliest intercurrent event will be according to what’s specified above. 
Supportive estimand 2: 
The underlying question for the supportive estimand 2 is: what is the efficacy attributable to the 
randomly assigned doses of UNR844 after 3 months of treatment, considering the impact of 
any intercurrent events as inherent part of the assigned treatment? The estimand definition that 
addresses this question is: dose-specific difference in mean change from baseline in DCNVA 
at Month 3 attributable to the randomized treatment. 
For this estimand, data following the three types of intercurrent events will be dealt with in 
three specific ways: 
• For ICE 1, include data collected post discontinuation, if available. If not available, 
impute assuming no further benefit, i.e. CIR method will be used for imputation; 
• For ICE 2, include data collected post discontinuation, if available. If not available, 
impute assuming no further benefit, i.e. CIR method will be used for imputation; 
• For ICE 3, include data collected post-use of prohibited medication, if available. If not 
available, impute assuming no further benefit, i.e. CIR method will be used for 
imputation. 
If a subject has multiple intercurrent events, consider the event which occurs earliest. Data 
handling following this earliest intercurrent event will be according to what’s specified above. 
Supportive estimand 3: 
The underlying question for the supportive estimand 3 is: what is the efficacy attributable to 
each UNR844 arm/dose group, after 3 months of BID treatment, taking into account any 
unfavorable effect of the drug such as discontinuation due to unsatisfactory therapeutic effect 
or Adverse Events (AE), as based on the primary estimand, assuming the subjects had no 
relevant intercurrent events due to COVID-19 infection. The estimand definition that addresses 
this question is: dose-specific difference in mean change from baseline in DCNVA at Month 3 
attributable to the initially randomized medication accounting for beneficial and detrimental 
effect of the drug, by excluding the effect of COVID-19 infection related intercurrent events. 
For this estimand, in addition to the data handling for the three types of intercurrent events, as 
described for the primary estimand, data following the below types of COVID-19 infection 
related intercurrent events will be dealt with in the following ways: 
• Treatment discontinuation due to COVID-19 infection: exclude data collected post 
discontinuation, treat them as missing and impute assuming MAR; 
• Infected by COVID-19 (identified from COVID-19 infection and health related PD 
term): exclude data collected post infection, treat them as missing and impute assuming 
MAR. 
The priority rule for the primary estimand is still applicable for the supportive estimand. In 
addition to the priority rule for the primary estimand, if a subject has multiple intercurrent events, 
consider the event which occurs earliest. Data handling following this earliest intercurrent event 
will be according to the specifications stated above. An exception to apply only the rule of the 


Novartis 
For business use only 
Page 25 of 46 
SAP 
 
CUNR844A2202 
 
first intercurrent event, is when treatment discontinuation due to lack of efficacy or AEs other 
than COVID-19 infection (as defined by the above intercurrent events) occurs first, and 
infection by COVID-19 infection occurs later. In such a case, in order to rule out the effect due 
to COVID-19, while still being consistent with the primary estimand definition, both of these 
events need to be accounted for by applying the corresponding data handling rule following 
each event. 
2.5.3.2 
Missing data not related to intercurrent event 
In the case of missing data occurring in other scenarios, i.e. independent of intercurrent events 
related to response to study treatment, the estimand based on MAR approach will be considered 
specifically for each treatment arm the participants are assigned. This will result in a reasonable 
estimate of the true outcome based on the treatment effect observed for up to 7 months after 
study treatment discontinuation in prior completed clinical study with UNR844. 
2.5.4 
Sensitivity analyses for primary endpoint/estimand 
There will be two sensitivity analyses corresponding to the primary estimand, refer to Section 
2.5.3.1 for more details. 
Sensitivity analysis #1: 
The efficacy endpoint is the same as the primary efficacy analysis, with the only change to 
exclude data collected post treatment discontinuation due to unsatisfactory therapeutic effect or 
AE, and impute assuming no further benefit, i.e. the CIR method. 
Sensitivity analysis #2: 
In this study, a subject with unexpected fluctuations is defined as a subject who has a change in 
DCNVA equal to or more than 15 letters between two consecutive scheduled visits. In cases 
that data records showing a difference of 0.30 logMAR or larger between two consecutive 
scheduled visits, data collected on or after the second visit will be excluded from primary and 
secondary analyses to remove the impact of unexpected fluctuations.  
• If any intercurrent event happened before the first visit of the two consecutive scheduled 
visits, missing data imputation will follow the data handling rule specified in the primary 
estimand. For example, CIR method will be used for missing data post treatment 
discontinuation due to unsatisfactory therapeutic effect or AE. The priority rule for the 
primary estimand is still applicable for this analysis. 
• Otherwise, intercurrent events happening on or after the first visit of the two consecutive 
scheduled visits will be ignored, and all missing data will be imputed as missing at 
random (MAR). 
2.5.5 
Supportive analyses 
There will be three supportive analyses corresponding to the three supportive estimands, refer 
to Section 2.5.3.1 for more details. 
2.6 
Analysis of the key secondary objective 
There is no key secondary objective for the study.  


Novartis 
For business use only 
Page 26 of 46 
SAP 
 
CUNR844A2202 
 
2.7 
Analysis of secondary efficacy objective(s) 
There are three secondary objectives: 
1. Characterize dose response of UNR844 as measured by change from baseline in 
monocular DCNVA assessed using letters at Month 3; 
2. Assess the duration of effect using change in DCNVA after Month 3 with various dose 
concentrations of UNR844; 
3. Evaluate the efficacy of improving DCNVA in presbyopic participants, as measured by 
the proportion of participants gaining at least 0.30 logMAR DCNVA at Month 3. 
2.7.1 
Secondary endpoints 
The corresponding secondary endpoints are: 
1. Change from baseline in monocular DCNVA assessed using letters (i.e. worse-seeing 
eye and better-seeing eye) at Month 3; 
2. Binocular and monocular (worse-seeing eye and better-seeing eye) DCNVA assessed 
using letters over time after Month 3 (i.e. Month 4 to Month 12); 
3.  Proportion of participants gaining at least 0.30 logMAR in binocular and monocular 
(worse-seeing eye and better-seeing eye) DCNVA assessed using letters (without near 
correction) from baseline at Month 3. 
2.7.2 
Statistical hypothesis, model, and method of analysis 
1. Change from baseline in monocular DCNVA assessed using letters (i.e. worse-seeing 
eye and better-seeing eye) at Month 3: 
• MCP-Mod as described in Section 2.5.2 will be applied to the worse-seeing eye and 
better-seeing eye , with intercurrent events and missing data handled in the same way 
as the for the primary estimand and supportive estimand 2 (Section 2.5.2 and Section 
2.5.3). 
2. Gain of 3 lines (change from baseline of ≤ - 0.30 logMAR and < + 0.10 logMAR in 
BCDVA) in binocular, worse-seeing eye and better-seeing eye, respectively at Month 
3: 
• For the endpoints of gaining of 3 lines in binocular, worse-seeing eye and better-
seeing eye, respectively at Month 3. Missing data imputation will be done in the same 
way as the primary endpoint (Section 2.5.3), defined for the primary estimand, based 
on their corresponding continuous endpoints, i.e. binocular and monocular DCNVA. 
After imputation, these endpoints will be dichotomized to generate the endpoints of 
gaining of 3 lines in both eyes, worse-seeing eye and better-seeing eye, respectively, 
at Month 3. Then a logistic regression model, by adjusting for baseline DCNVA and 
age (grouped as 45 to 50 years and 51 to 55 years), will be fitted to each imputed data 
set for each of the three endpoints. By applying Rubin’s rule to combine results of 
these individual data sets, pairwise comparison of each dose versus placebo will be 
obtained for each of the three endpoints.  
3. Change from Month 3 in binocular and monocular (worse-seeing eye and better-seeing 
eye) DCNVA over time after Month 3 (i.e. Month 4 to Month 12): 


Novartis 
For business use only 
Page 27 of 46 
SAP 
 
CUNR844A2202 
 
• Only observed data for these endpoints will be analyzed with no imputation for 
missing data.  
• For binocular, worse-seeing eye and better-seeing eye, DCNVA over time after 
Month 3 will be summarized by treatment group and scheduled visits, and the mean 
line plots for the change from Month 3 over time will also be presented. In addition, 
the binocular and monocular DCNVA will be listed. 
2.7.3 
Handling of missing values/censoring/discontinuations 
Missing data handling of secondary analyses for different endpoints are specified in Section 
2.7.2.  
2.8 
Safety analyses 
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
treatment group. 
 
 
. The on-treatment period lasts from the date of first administration of study 
treatment to the date of the last administration of study treatment. Where appropriate, baseline 
data or change from baseline data will also be summarized.  
Note: 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period. 
2.8.1 
Adverse events (AEs) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 28 of 46 
SAP 
 
CUNR844A2202 
 
A subject with multiple adverse events within a primary SOC is only counted once towards the 
total of the SOC. 
  
In addition, all AEs (from the first date of treatment to the end of study) will be summarized 
separately for ocular and non-ocular AEs by treatment in the following ways: 
• AEs by primary SOC and PT; 
• Study treatment related AEs, by primary SOC and PT; 
• SAEs by primary SOC and PT; 
• Study treatment related SAEs, by primary SOC and PT.  
All AEs, deaths and serious adverse events (including those from the pre-treatment period and 
from the first date of treatment to the end of study) will be listed. 
In addition, in order to assess the impact of the COVID-19 pandemic, summary tables will be 
provided for the subgroups of exposed/non-exposed, infected/not-infected subjects (as defined 
in Section 2.2.1) by treatment, for the following safety endpoints, if there is a sufficient number 
of subjects in each subgroup: 
 
 
For the ClinicalTrials.gov and EudraCT requirements, two tables are mandatory: 
• all adverse events which are not serious adverse events with an incidence greater than 
X% will be provided by PT on the safety set population. Detailed threshold (X%) will 
be determined by safety disclosure; 
• and all serious adverse events and SAE suspected to be related to study treatment will 
be provided by primary SOC and PT on the safety set population. 
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is less than or equal to 1 day gap between 
the end date of the preceding AE and the start date of the consecutive AE; 
• more than one occurrence will be counted if there is more than 1 day gap between the 
end date of the preceding AE and the start date of the consecutive AE. 
If at least one SAE is occurring in a less than or equal 1 day gap, then one occurrence is 
calculated for that SAE. 
The number of deaths resulting from SAEs, irrespective of study treatment relationship, will be 
provided by primary SOC and PT. 
2.8.1.1 Adverse events of special interest / grouping of AEs 
Not applicable. 
2.8.2 
Deaths 
All deaths will be listed. 


Novartis 
For business use only 
Page 29 of 46 
SAP 
 
CUNR844A2202 
 
2.8.3 
Laboratory data 
All laboratory data for hematology, chemistry and urinalysis will be listed by treatment group, 
subject, and visit/time. 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
Not applicable. 
2.8.4.2 Vital signs 
All vital signs data (including systolic/diastolic blood pressure, and heart rate measurements) 
will be listed by treatment group, subject, and visit/time.  
 
 
 
 
2.9 
Pharmacokinetic endpoints   
Not applicable. 
2.10 
PD and PK/PD analyses 
Not applicable. 


Novartis 
For business use only 
Page 30 of 46 
SAP 
 
CUNR844A2202 
2.12 
Biomarkers 
Not applicable. 


Novartis 
For business use only 
Page 31 of 46 
SAP 
 
CUNR844A2202 
2.14 
Interim analysis 
2.14.1 
Planned Interim analysis 
The interim analysis will be performed when all subjects complete (or discontinue prior to) the 
Month 3 visit as described in Section 2.5. The major objective of this interim analysis is to 
determine if the overall null hypothesis of a flat dose-response curve can be rejected. For this 
interim analysis, the following analyses will be presented: 
• Key information of subject disposition, demographics and other baseline 
characteristics; 
• Duration of exposure, on-treatment period, and compliance; 
• Analysis corresponding to the primary objective, as described in Section 2.5; 
• Analysis corresponding to the secondary objective: to characterize dose response of 
UNR844 as measured by change from baseline in monocular DCNVA at Month 3, as 
described in Section 2.7; 
• Analysis corresponding to the secondary objective: to evaluate the efficacy of 
improving DCNVA in presbyopic participants, as measured by the proportion of 
participants gaining at least 0.30 logMAR DCNVA at Month 3, as described in Section 
2.7; 
 
 
 
 
 
 
 
 
 
 
 
 


Novartis 
For business use only 
Page 32 of 46 
SAP 
 
CUNR844A2202 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
2.14.2 
Interim Analysis Team 
Interim Analysis Team (IAT) is an independent group of individuals who have experience and 
expertise in the management of patients within this disease area, experience in statistical 
methods, experience in efficacy and safety monitoring and experience in the monitoring of 
randomized clinical trials. The members of the IAT for this study are appointed by Novartis.  
Table 2-3 
Interim Analysis Team Members 
Expert (Specialty) 
Institution, City, Country 
Phone, Fax and email address 
 MD 
 
Novartis Pharmaceuticals,  
Basel, Switzerland 
 
 
 PhD 
 
Novartis Pharmaceuticals, 
Dallas, TX USA  
 
 MD 
Novartis Pharmaceuticals,  
New Jersey, USA  
 PhD 
Statistician 
(
) 
Novartis Pharmaceuticals, 
Shanghai, China  
 
 
 PhD  
Statistician 
(
) 
Novartis Pharmaceuticals, 
Dallas, TX, USA 
 
 MPH 
(
  
Novartis Pharmaceuticals, 
Shanghai, China 
      
 
 ,  
)  
Novartis Pharmaceuticals,  
Paris, France 
 
* UNR844A2202 Team members, will be involved in the daily activities of the trial until the start the 
process at the beginning of the first IA and cease the involvement of daily activities thereafter. 


Novartis 
For business use only 
Page 33 of 46 
SAP 
 
CUNR844A2202 
 
Further appointments to the IAT may be made if there are resignations from the initial 
membership, or if the IAT members believe that additional expertise is required. Any such 
appointments would be formally made by Novartis after consultation with the members of the 
IAT. 
2.14.3 
Conflict of interest  
IAT members must abide by the Novartis Conflict of Interest Policy. 
2.14.4 
Insider Trading 
It is prohibited for any IAT member to use any material non-public information received in 
connection with their role as IAT member to make decisions about buying or selling shares or 
other securities in Novartis Pharma AG or any other company of the Novartis group or with 
which Novartis does business and to which the information pertains. It is also prohibited to 
disclose to any person such material non-public information, whether or not the disclosing 
person has actual knowledge of the use of the information by the recipient. An IAT member 
using or disclosing “insider” information may commit a severe criminal offence, the penalty of 
which may be fines and imprisonment. 
IAT members must abide by the Novartis Global Corporate Policy and Procedure on Insider 
Trading. 
2.14.5 
Responsibilities 
2.14.5.1 The IAT 
The IAT will function independently of all other individuals associated with the conduct of this 
trial, including investigators, and Novartis personnel involved in the project. 
The IAT is responsible for monitoring the efficacy and safety of the trial participants, ensuring 
that the trial is being conducted with the highest scientific and ethical standards, and making 
appropriate recommendations based on the data seen. The IAT will be responsible for: 
• reviewing the planned contents of the interim analysis report i.e. table/figure/listing shells, 
and making recommendations regarding changes or adjustments that may be required to 
ensure the IAT has the information it requires for fulfilling its obligations; 
• reviewing reports relevant to trial conduct and assumptions, efficacy and safety variables, 
and outcomes leading to discontinuation of the trial treatment, and making 
recommendations regarding changes or adjustments that may be required to ensure patient 
safety and preserve trial integrity; 
• suggesting modifications to the trial protocol, which may include, but are not limited to: 
changes in inclusion/exclusion criteria, frequency of visits or safety monitoring, alterations 
in trial procedures or trial conduct, or discontinuation of one or more trial treatment groups 
if applicable; 
• recommending continuation of the trial according to the protocol and any relevant 
amendments OR to discontinue the trial (with provisions for orderly discontinuation in 
accordance with good clinical practice). 


Novartis 
For business use only 
Page 34 of 46 
SAP 
 
CUNR844A2202 
 
2.14.5.2 Clinical Trial Team (CTT) 
The Novartis Clinical Trial Team (CTT) is responsible for the following activities related to the 
operation of the IAT: 
• Designating the Novartis leadership team who are involved in the review of IAT 
recommendation(s) (see Section 2.14.5.4 for details). 
• Designating the Independent Statisticians and Independent Programmers from within 
Novartis Analytics.   
• Ensuring the proper secure handling of the treatment codes from the Interactive Response 
Technology (IRT) provider (who is responsible for generating the randomization list). 
• Writing the analysis plan and programs that produce the interim analysis report. Note: trial 
statistician and trial programmer will have no access to treatment decodes  
• Requesting from the Novartis Randomization Office (RO) the release of the randomization 
codes in accordance with Novartis SOPs in time for production of the interim analysis 
• Implementing agreed-upon recommendation(s) and/or trial modifications received from the 
IAT.  
• Monitoring trial conduct, and the collection and quality control of trial data. 
• Communicating all pertinent regulatory information to the national regulatory bodies of the 
countries in which the trial is conducted. 
• Informing the IAT of any amendments to the trial protocol, changes to the design or 
endpoints, or any new clinically relevant information on the trial medication.  
2.14.5.3 Randomization Office (RO) 
Upon receipt and approval of the randomization release request form for the first IA (or if 
randomization list was extended since previous release), the RO will: 
• Request DI-C&S to upload the randomization list including the treatment group description 
into the restricted area in Global Programming and Statistical Environment (GPS II), which 
will only be accessible to the Novartis Independent Statistician and Independent 
Programmer after the data is available. The data can be uploaded any time before the interim 
analysis database lock. 
The personnel at the RO and DI-C&S will have no access to the non-randomization trial data, 
nor play any other role in the trial or project. 
2.14.5.4 Independent Statistician and Independent Programmer  
The Independent Statistician (IS) and Independent Programmer (IP) will not be involved in 
daily activities of the trial CUNR844A2202 or project UNR844 other than those involved in 
preparing and providing information to the IAT. They will be situated in a separate location 
from the rest of the CTT, or if this cannot be achieved, a firewall will be in place to avoid 
disclosure of confidential information. They will be responsible for generating data analyses 
for the IAT, including tables, figures and listings produced according to the pre-specified 
interim analysis plan.  
In this study, the IS responsible for Biostatistics, will be designated within Novartis. The IS 
responsible for the Biostatistics, will be involved in the daily activities of the trial until the start 


Novartis 
For business use only 
Page 35 of 46 
SAP 
 
CUNR844A2202 
 
of the process at the beginning of the IA when another statistician within Novartis will assume 
the role of Trial Statistician until the end of the study. 
The IP will be designated within Novartis and will not be involved in the daily activities of the 
trial or program other than those involved in preparing and providing information to the IAT. 
The IS and IP will have access to clinical data in the GPS restricted area and the randomization 
list including the treatment group description directly from the RO via WDCS II.  
The Independent Statistician and Independent Programmer will receive unmasked treatment 
codes according to the applicable and documented Novartis procedures. Thus, all analyses 
outputs sent to the IAT will be unmasked. Independent Statistician will provide paper/electronic 
reports to the IAT, and then communicate with the IAT as needed. 
The Independent Statistician will function independently of the investigators and CTT members, 
and will be responsible to the IAT for the conduct of all interim analyses of efficacy and safety 
data.  
2.14.5.5 IRT Provider 
The IRT provider Novartis IRT will release the randomization list to the Randomization Office 
and DI-C&S as soon as complete. No further approval by the RO is necessary.   
2.14.6 
Confidentiality Agreement 
Confidentiality agreements will be signed by all participants in the IAT who will see unmasked 
interim results. For IAT members this confidentiality agreement is part of their employee 
contract with the Global Program Head (GPH). For this trial, these agreements will have been 
signed by GPH, Global Clinical Program Head (GCPH), Clinical Development Director (CDD), 
Independent Statistician (IS), Independent Programmer (IP), and filed according to Novartis’ 
SOPs. The confidentiality agreement is designed to ensure that the interim analysis results will 
not be shared with others inappropriately or without proper documentation before the final trial 
clinical database is locked and the final analysis is completed. 
2.14.7 
Organizational diagram  
The organization diagram shown below shows the inter-relationship between the IAT and other 
functional areas involved in the trial.  
 


 
 
 
 
 
 
Figure 2-3 
Organization diagram 
 
 
 
 
1. Before the interim analysis database lock: 
Novartis RO 
IRT vendor 
Novartis RO 
Novartis DI-C&S 
Novartis Trial 
Statistician 
Novartis EDM 
Novartis Independent 
Statistician/programmer 
Global Program 
Head or designee 
Internal IAT 
Authorization to send treatment information for IA 
Novartis implement recommendations 
Forwards recommendations  
Data 
without 
treatment codes 
Data 
without 
treatment codes 
Semi-blinded 
randomization 
list (electronic) 
unmasked 
randomization 
list 
for 
QC 
Download 
randomization list 
into restricted GPS 
II folder 
Request treatment 
information for IA 
Provides approved   
unmasked interim 
analysis 
 


Novartis 
For business use only 
Page 37 of 46 
SAP 
 
CUNR844A2202 
 
• The Novartis Trial Statistician will request the Novartis Randomization Office (RO) to 
authorize DI-C&S to download the randomization list including the treatment group 
description into the restricted area in the Global Programming and Statistical 
Environment (GPS II). Only the Independent Statistician and Programmer will have 
access to the restricted area in GPS II. 
2. The RO will release a copy of the randomization list including the treatment group 
description to the Independent Statistician for QC purposes. After each interim analysis 
database lock: 
• The Independent Statistician and Programmer will produce an interim analysis report 
according to plan using the randomization list; 
• The Independent Statistician will send the interim analysis report to the IAT members. 
3. After each IAT meeting where interim analysis are reviewed: 
• The IAT recommendation(s) will be provided in writing by the IAT Chair to the GPH 
or designee.  
Novartis will review the IAT recommendations and take appropriate actions. 
2.14.8 
Data Review Meetings  
Meetings are planned to take place two times in this study. At each meeting, the IAT will review 
cumulative patient safety data. The meeting will be limited to members of the IAT. 
The first interim analysis meeting is planned for the IAT to review comparative data relating to 
treatment efficacy and patient safety.  
The second interim meeting is planned for the IAT to review the data from FPFV up to 60% of 
the participants complete 6 months (i.e. Month 9) of treatment holiday period. The major 
objective of this interim analysis is to assess the retention of the treatment effect over the 9 
months treatment holiday period. 
2.14.9 
Recommendations from the IAT  
A summary (e.g. FIR slide deck) from the IAT Chair will be provided in writing to the GPH or 
designee. This summary may or may not provide any comparative information (e.g. if the IAT 
recommendation is to continue the trial without modification). The GPH or designee will 
communicate the IAT conclusions to Novartis management, investigators, and the Novartis 
clinical team as appropriate, depending upon the type of recommendation. 
Any recommendations of the IAT involving an issue that poses a possible safety risk to patients 
will be handled by all parties in an expedited manner. In the event that there is a safety concern 
about trial continuation, or other recommendation to modify the trial, the IAT Chair should 
communicate this immediately to the GPH or designee, who will then inform the Global Head 
of Development at Novartis. Communication of concerns expressed by the IAT shall be 
restricted to the fewest number of individuals possible associated with the trial, or within 
Novartis. This will generally include the Global Head of Analytics (or designee) and the Head 
of DS&E. Other individuals will be brought into the discussions only as needed, i.e. if their 
input is needed to assist in reaching a final decision. Further communication by this small group 
with the IAT will take place as necessary. However, individuals directly involved in decision 


Novartis 
For business use only 
Page 38 of 46 
SAP 
 
CUNR844A2202 
 
making or conduct of the trial will not have access to this information until a final decision has 
been made.  
3 
Sample size calculation 
3.1 
Primary endpoint(s) 
A total sample size of 210 randomized participants (in 1:1:1:1:1 allocation ratios corresponding 
to five UNR844 dosing regimens [placebo, 5 mg/mL, 13.3 mg/mL, 23 mg/mL, 30 mg/mL, 
respectively, treated twice-daily for 3 months]) is required to ensure an average power of 86% 
to detect the presence of dose response under the set of candidate models considered in MCP-
Mod, assuming a maximum effect for mean binocular change from baseline in logMAR over 
placebo of -0.08 (SD = 0.14) for a UNR844 arm. To allow for a ~5% drop-out rate during the 
treatment period (i.e. 3 months), 225 participants (45 in each of the 5 treatment groups) will be 
randomized. The power calculations leading to the sample size determination were based on 
simulations using all five candidate models considered in MCP-Mod. The maximum t-statistic 
contrast test was applied to each of the simulated data sets to assess the presence of a dose 
response signal. It is the average power of this test that is ensured to be 86% under two of the 
candidate models (the most likely and the worst case) considered for the sample size of 225 
participants. 
If participants dropping out due to COVID-19 leads to power reduction to be below 82% based 
on the above assumptions, additional participants will be recruited to ensure adequate power. 
4 
Change to protocol specified analyses 
In protocol Section 12.5.1, it is stated: gain of 3 lines (change from baseline of ≤ - 0.3 logMAR) 
in binocular, worse-seeing eye and better-seeing eye, respectively at Month 3. Now the team 
has updated the success criteria to: gain of 3 lines (change from baseline of ≤ - 0.30 logMAR 
and < + 0.10 logMAR in BCDVA) in binocular and monocular DCNVA at Month 3.  
In protocol Section 12.6.1, it is stated: summary tables for adverse events (AEs) will include 
only AEs that started or worsened during the on-treatment period, the treatment-emergent AEs. 
In order to get summary level information also on the post-treatment AEs, it is decided to show 
the t AEs and SAEs from the first date of treatment to the end of study in the summary tables. 
In addition, summary tables for AEs related to study treatment will also be provided, as stated 
in the corresponding section of the SAP. 
Due to the early termination of the study, all analysis has been simplified and some of them 
have been limited to descriptive statistics. 
The analysis of exploratory variables will be performed for variables which will provide 
information for future trials within the UNR844 program, hence the following exploratory 
endpoints for final analysis are removed: 
 
 


Novartis 
For business use only 
Page 39 of 46 
SAP 
 
CUNR844A2202 
 
 
 
 
 
 
. 
The second planned interim analysis is removed.  
 
 
  
 
Concomitant medications as well as significant non-drug therapies that are prohibited will not 
be provided. The start, stop or change in dosing after the screening visit will not be provided 
either.  
5 
Appendix 
Statistical methods are described in the main part of the clinical study report. This appendix 
provides further details on missing data imputation, statistical methods and the statistical 
derivation. 
5.1 
 Imputation rules of missing dates 
The general approach to handling partial 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 partial 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. 


Novartis 
For business use only 
Page 40 of 46 
SAP 
 
CUNR844A2202 
 
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. 
  
  
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.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
YYYY = TRTY 
  
( 4.a ) 
Uncertain 
( 4.b ) 
Before Treatment 
Start 
( 4.c ) 
Uncertain 
( 4.c ) 
After Treatment Start 
YYYY > TRTY 
  
( 3.a ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
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: 


Novartis 
For business use only 
Page 41 of 46 
SAP 
 
CUNR844A2202 
 
a. And the AE day and month are missing the imputed AE start date is set to the 
AE reference start date + 1 day. 
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 partial 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 last visit 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 last visit date and the end of the year (31DECYYYY). 
3. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date. 
4. 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.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
( 2.b ) 
Before Treatment 
Start 
YYYY = TRTY 
  
( 4.a ) 
Uncertain 
( 4.b ) 
Before Treatment 
Start 
( 4.a ) 
Uncertain 
( 4.c ) 
After Treatment Start 
YYYY > TRTY 
  
( 3.a ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
( 3.b ) 
After Treatment Start 
  


Novartis 
For business use only 
Page 42 of 46 
SAP 
 
CUNR844A2202 
 
  
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). 
5. 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. 
5.1.2.3 
Medical history partial date of diagnosis imputation 
No applicable.  
5.2 
AEs coding/grading 
Adverse events are coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
The below severity grade will be used in this study: 
• Mild: usually transient in nature and generally not interfering with normal activities 
• Moderate: sufficiently discomforting to interfere with normal activities 
• Severe: prevents normal activities 


Novartis 
For business use only 
Page 43 of 46 
SAP 
 
CUNR844A2202 
 
5.3 
Laboratory parameters derivations 
Not applicable. 
5.4 
Statistical models  
5.4.1 
Primary analysis 
Multiple comparison procedures-modeling approach (MCP-Mod) was qualified by CHMP as 
“an efficient statistical methodology for model-based design and analysis of Phase II dose-
finding studies under model uncertainty” (EMA 2014). This methodology allows both the 
statistical testing of evidence of dose response (PoC), as well as the estimation of target doses 
to be used in confirmatory studies.  
Generalized MCP-Mod (Pinheiro, Bornkamp et al. 2014) will be applied based on the output 
from a Multilevel Modelling for Repeated Measurements (MMRM). The model will include 
the change from baseline in binocular DCNVA (mean of the two assessments) as the dependent 
variable, binocular DCNVA at the baseline as the covariate, region, dose, age group, assessment 
visit, interaction of dose and assessment visit as the fixed effect and participant 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.  
To perform generalized MCP-Mod the least square mean per dose and associated covariance 
matrix will be obtained from the MMRM. 
Five candidate models to describe the potential dose-response shape (defined in terms of change 
from baseline in binocular DCNVA at Month 3 as compared to placebo) were selected  
1. Emax model: f(d, θ) = 𝐸𝐸0 + 𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚× 𝑑𝑑(𝑑𝑑+ 𝐸𝐸𝐸𝐸50)
⁄
 
• Emax model 1: ED50 = 0.079%  
• Emax model 2: ED50 = 0.375%  
2. Sigmoid Emax model: f(d, θ) = 𝐸𝐸0 + 𝐸𝐸𝑚𝑚𝑚𝑚𝑚𝑚× 𝑑𝑑ℎ(𝑑𝑑ℎ+ 𝐸𝐸𝐸𝐸50
ℎ)
⁄
 with fixed hill 
parameter 
• Sigmoid-Emax model 1 : ED50 = 1.500% and ℎ = 4.301 
• Sigmoid-Emax model 2 : ED50 = 1.089% and ℎ = 2.643  
3. Exponential model: f(d, θ) = 𝐸𝐸0 + 𝐸𝐸1 × 𝑒𝑒𝑒𝑒𝑒𝑒(𝑑𝑑𝛿𝛿
⁄
−1) 
• Exponential model 1 : 𝛿𝛿 =1.770 
where E0 is the expected placebo effect, Emax is the maximum change in effect over placebo, 
ED50 is the dose at with which 50% of Emax is achieved, h is Hill parameter, 𝐸𝐸1 is the slope 
parameter, 𝛿𝛿 is controlling the convexity of the model, d is total daily dose and θ refers to the 
vector of model parameters.  
Bootstrap model averaging will be used to estimate the dose-response curve, the target dose and 
to derive confidence intervals. Parametric bootstrap simulation will be performed using the 
least-squares dose group estimates based on their multivariate normal distribution.  
The main steps for the parametric bootstrap are showed below: 


Novartis 
For business use only 
Page 44 of 46 
SAP 
 
CUNR844A2202 
 
1. Simulate a set of dose response according to the least square mean per dose obtained 
from MMRM. 
2. For each set of simulated dose response fit Emax, Sigmoid Emax, and Exponential model 
by minimizing the generalized least-squares. 
3. Select the best dose-response model (e.g. model with the lowest least squares). 
4. Save inferences based on the selected model (e.g. dose-response predictions or dose 
predictions). 
The multiple imputation for different estimand frameworks will be done using the “Five 
Macros”, which fit a Bayesian Normal RM model and then impute post withdrawal data under 
a series of possible post-withdrawal profiles including J2R, CIR, and CR as described by 
Carpenter et al (Carpenter et al. 2013).  
In “Five Macros”, all intermediate missing values will be imputed assuming MAR and the 
MNAR part of the model is restricted to patterns that are monotone. That means control-based 
imputations method is only applicable to monotone missing pattern, therefore we need to 
prepare the data in several tweaks in order to use “Five Macros”.  
1. Prepare the data <in_data>: <in_data> stores the change from baseline in DCNVA 
where the structure is one record per subject per analysis visit.  If a subject experiences IEs 
stated in SAP. Define a new variable <Method_var> and assign value according to 
different estimand framework.  
2. Part1A declares the parameter estimation model and checks consistency with the dataset.  
%part1A(Jobname=UNR,Data=<in_data>,Subject=<SUBJID>, 
        Response=<CHG_DCNVA>,Time=<VISIT>,Treat=<Treatment>, 
        Catcov=<Region> <Age group>,Cov=<Baseline DCNVA>, 
        Covgroup=<Treatment>); 
3. Part1B fits the parameter estimation model using the MCMC procedure and draws a pseudo-
independent sample from the joint posterior distribution for the linear predictor parameters 
and the covariance parameters. 
%part1B(Jobname=UNR,Ndraws=1000,thin=100,seed=20220810); 
4. Part2A calculates the predicted mean under MAR, and under MNAR for each subject based 
on their withdrawal pattern once for each draw of the linear predictor parameter estimates. 
The choice of MNAR is controlled by the method used, which may vary from subject to 
subject. 
%part2A(Jobname=UNR,methodV=<Method_var>,ref=<PLACEBO>); 
<PLACEBO>is the treatment level used as the reference arm for every record 
5. Part2B imputes the intermediate missing values using MAR and the trailing missing values 
using MNAR, by deriving the conditional distribution for the missing values conditional on 
the observed values and covariates, using the appropriate sampled covariance parameter 
estimates. 
%part2B(Jobname=UNR,seed=20220824); 


Novartis 
For business use only 
Page 45 of 46 
SAP 
 
CUNR844A2202 
 
6. Carry out MMRM analysis as stated in Section 5.4.1 per imputation for <Dataset>.  
Then combine the least-squares means, and treatment differences using the PROC 
MIANALYZE procedure to provide the final results. 
In Five Macros, the imputation method per subject should be unique for monotone missing 
pattern, which means it cannot handle the scenario when one subject has different imputation 
methods for the monotone missing records. In supportive estimand 3, when the treatment 
discontinuation due to lack of efficacy or AEs happens first, and infection by COVID-19 
infection occurs later, the imputation methods could be different in such case (e.g. CIR first and 
then MAR). In order to deal with this scenario with Five Macros, we will first impute the 
missing data with CIR and manually set the records that are supposed to be imputed as MAR 
to missing in all imputed data sets. Then use Five Macros again to impute the missing data as 
MAR for each of the imputed data sets.   
5.4.2 
Secondary analysis 
Logistic regression 
The change of DCNVA from baseline will be dichotomized to generate the endpoints of gaining 
of 3 lines in both eyes, worse-seeing eye and better-seeing eye, respectively at Month 3. Then 
a logistic regression model, by adjusting for baseline DCNVA and age.  
Odds ratios will be computed for comparisons of UNR844 versus placebo utilizing the logistic 
regression model fitted.  
If the proportions of 3-lines gain are 0% or 100% in one of the treatment groups odds ratio 
estimate and p-values will not be displayed in outputs, but “-” will be shown. 
The odds ratio will be calculated such that an odds ratio >1 is favorable for UNR844. Using 
PROC GENMOD to calculate the confidence interval for the odds ratios assumes asymptotic 
normality of the Wald estimate for the regression coefficient. The 95% confidence interval for 
the regression parameter of the active treatment effect relative to control(s) will be calculated 
using an exponential transformation to create the confidence interval for the odds ratio.  
All p-values reported on linear hypotheses about regression coefficients will be based on the 
Wald tests, and converted to one-sided, based on the formula below: 
• If the point estimate of the odds ratio is ≥ 1, the one-sided p-value = two-sided p-value/2; 
• If the point estimate of the odds ratio is < 1, the one-sided p-value = 1 – two-sided p-
value/2. 
The SAS procedure PROC GENMOD will be used for logistic regression model by adding the 
model options: DIST=BIN, and LINK=LOGIT. The following SAS code will be used to fit the 
logistic regression model to each of the multiply imputed data set, and combine the results: 
PROC GENMOD DATA = <Dataset>; 
 
CLASS <Treatment> <Age group> 
MODEL <CAT_DCNVA> = <Baseline DCNVA> <Age group> 
  <Treatment>/DIST = BIN LINK = LOGIT; 
      LSMEAN <Treatment> / DIFF cl; 
 
BY _IMPUTATION_; 
 
OUTPUT DIFFS = diff; 


Novartis 
For business use only 
Page 46 of 46 
SAP 
 
CUNR844A2202 
 
RUN; 
 
PROC MIANALYZE parms= diff; 
 
CLASS <Treatment>; 
 
modeleffects <Treatment>; 
 
ods output PARAMETERESTIMATES=outDIFF; 
RUN; 
5.5 
Rule of exclusion criteria of analysis sets  
The below classification of non-PDs will be used for the analysis sets.  
Table 5-1 
Subject Classification 
Analysis Set 
Non-PD criteria that cause participants to be excluded 
Full Analysis Set 
Not randomized, or mistakenly randomized.  
Safety Set 
Did not receive any dose of the study treatment 
 
6 
Reference 
EMA (2014). "Qualification Opinion on MCP-Mod as an efficient statistical methodology for 
model-based design and analysis of Phase II dose finding studies under model uncertainty." 
Pinheiro, J., B. Bornkamp, E. Glimm and F. Bretz (2014). "Model-based dose finding under 
model uncertainty using general parametric models." Statistics in Medicine 33(10): 1646-1661. 
 Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol 
deviation: a framework for relevant, accessible assumptions, and inference via multiple 
imputation. J Biopharm Stat; 23(6):1352-71.