Clinical trial NCT03150160
Conditions: Glaucoma
Keywords: travoprost brinzolamide 1%/brimonidine 0.2% normal tension glaucoma intraocular pressure efficacy safety
Sponsor: Novartis Pharmaceuticals
Start date: 2017-09-21; Completion date: 2017-12-04
Enrollment: 1 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study was to determine the incremental intraocular pressure (IOP) lowering that is achieved when Simbrinza is used adjunctively to Travatan in patients with normal tension glaucoma that may benefit from further IOP lowering.

Detailed description:
This study was prematurely terminated due to administrative reasons and not due to any safety or efficacy concerns.

Arms: arm 1: Brinzolamide 1%/brimonidine 0.2% fixed combination + travoprost 0.004% ophthalmic solution arm 2: Placebo + travoprost 0.004% ophthalmic solution
Interventions: intervention 1: brinzolamide 1%/brimonidine 0.2% fixed combination intervention 2: Placebo intervention 3: travoprost 0.004% ophthalmic solution
Intervention descriptions: intervention 1: One drop applied topically to the affected eye(s) in the morning and evening intervention 2: One drop applied topically to the affected eye(s) in the morning and evening intervention 3: One drop applied topically to the affected eye(s) in the evening

Protocol documents:
Prot_000.pdf: 
Clinical Development
QVJ499
CQVJ499A2404 / NCT03150160
A 6-week, Double Masked, Placebo-Controlled Study to 
Evaluate the Efficacy and Safety of Twice-daily 
Brinzolamide 1% / Brimonidine 0.2% Fixed Dose 
Combination as an Adjunctive Therapy to Travoprost 
0.004% in Reducing Intraocular Pressure in Patients With 
Normal Tension Glaucoma
Document type:
Abbreviated Clinical Study Report 
Development phase:
IV 
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 6.1 Jan 20, 2014


1
Study information
Study title: A 6-week, Double Masked, Placebo-Controlled Study to Evaluate the Efficacy and 
Safety of Twice-daily Brinzolamide 1% / Brimonidine 0.2% Fixed Dose Combination as an 
Adjunctive Therapy to Travoprost 0.004% in Reducing Intraocular Pressure in Patients With 
Normal Tension Glaucoma 
Test drug/investigational product: Brinzolamide 1%/Brimonidine 0.2% / QVJ499
Indication studied: Normal tension glaucoma 
Study design: See study title
Sponsor: Novartis
Protocol identification: Protocol no. CQVJ499A2404
Development phase of study: IV
Study initiation date: 21-Sep-2017 (first patient first visit)
Early termination date: 09-Nov-2017
Study completion date: 04-Dec-2017 (last patient last visit)
Principal Investigator: Professor 
Company/Sponsor signatory: 
, M.Sc, Novartis Pharmaceuticals Corporation, 
Statement: This study was conducted in compliance with Good Clinical Practice (GCP), 
including the archiving of essential documents. 
Report date(s): 09-Apr-2018 (content final)
Earlier reports from the same study: None


2
Synopsis


3
Table of contents
1
Study information................................................................................................................2
2
Synopsis...............................................................................................................................3
3
Table of contents .................................................................................................................4
List of tables ........................................................................................................................7
List of figures ......................................................................................................................7
4
List of abbreviations and definition of terms ......................................................................8
5
Ethics ...................................................................................................................................9
5.1
Independent ethics committee or institutional review board...................................9
5.2
Ethical conduct of the study ....................................................................................9
5.3
Patient information and consent ..............................................................................9
6
Investigators and study administrative structure .................................................................9
7
Introduction .........................................................................................................................9
7.1
Background..............................................................................................................9
7.2
Purpose ..................................................................................................................10
8
Study objectives.................................................................................................................10
8.1
Primary objective and related endpoint .................................................................10
8.2
Secondary objectives and related endpoint............................................................10
8.3
Exploratory objectives and related endpoints........................................................11
9
Investigational plan ...........................................................................................................11
9.1
Study design...........................................................................................................11
9.2
Discussion of study design, including the choice of control groups .....................11
9.3
Population..............................................................................................................12
9.3.1
Inclusion criteria....................................................................................12
9.3.2
Exclusion criteria ..................................................................................12
9.4
Treatment...............................................................................................................13
9.4.1
Investigational and control treatment....................................................13
9.4.2
Treatment arms......................................................................................13
9.4.3
Treatment assignment ...........................................................................13
9.4.4
Treatment masking................................................................................13
9.4.5
Treating the patient ...............................................................................14
9.4.6
Concomitant treatment..........................................................................15
9.4.7
Discontinuation of study treatment and premature patient 
withdrawal.............................................................................................15
9.4.8
Emergency unmasking of treatment assignment...................................15
9.4.9
Early study termination.........................................................................15
9.4.10
Treatment exposure and compliance.....................................................16


9.5
Efficacy and safety assessments ............................................................................16
9.5.1
Visit schedule........................................................................................16
9.5.2
Efficacy assessments.............................................................................16
9.5.3
Safety assessments ................................................................................17
9.5.4
Other assessments .................................................................................17
9.6
Data quality assurance ...........................................................................................17
9.6.1
Monitoring.............................................................................................17
9.6.2
Data collection ......................................................................................17
9.6.3
Database management and quality control ...........................................17
9.6.4
Quality assurance and auditing .............................................................18
9.7
Statistical methods.................................................................................................18
9.7.1
Data analysis .........................................................................................18
9.7.2
Analysis sets..........................................................................................18
9.7.3
Patient disposition, demographics and other baseline characteristics...18
9.7.4
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)...........................................................................19
9.7.5
Analysis of the primary variable...........................................................19
9.7.6
Analysis of secondary efficacy variables..............................................19
9.7.7
Safety analyses......................................................................................19
9.7.8
Handling of missing values/censoring/discontinuations.......................20
9.7.9
Sample size calculation.........................................................................20
9.7.10
Power for analysis of key secondary variables .....................................20
9.7.11
Interim analysis .....................................................................................20
9.8
Changes in the conduct of the study or planned analyses .....................................20
9.8.1
Protocol amendments............................................................................20
9.8.2
Other changes in study conduct ............................................................20
9.8.3
Changes in planned analysis .................................................................20
10 Study patients ....................................................................................................................21
10.1
Disposition of patients...........................................................................................21
10.2
Protocol deviations ................................................................................................21
11 Efficacy evaluation............................................................................................................21
11.1
Data sets analyzed..................................................................................................21
21
11.3
Measurements of treatment compliance ................................................................22
11.4
Efficacy results and tabulations of individual patient data....................................22
11.4.1
Analysis of efficacy...............................................................................22
11.4.2
Statistical and analytical issues.............................................................23


11.4.3
Tabulation of individual response data .................................................23
11.4.4
Drug dose, drug concentration and relationships to response...............23
11.4.5
Drug-drug and drug-disease interactions ..............................................23
11.4.6
By-patient displays................................................................................23
11.4.7
Summary of efficacy results..................................................................23
12 Safety evaluation ...............................................................................................................23
12.1
Extent of exposure.................................................................................................23
12.1.1
Dosage...................................................................................................23
12.1.2
Patient exposure ....................................................................................24
12.1.3
Concomitant medication .......................................................................24
12.2
Adverse events.......................................................................................................24
12.2.1
Display of adverse events......................................................................24
12.2.2
Analysis of adverse events....................................................................24
12.2.3
Listing of adverse events by patient......................................................24
12.3
Deaths, other serious adverse events and other significant adverse events...........24
12.4
Clinical laboratory evaluation................................................................................24
12.5
Vital signs, physical findings and other observations related to safety.................25
12.5.1
Vital signs..............................................................................................25
12.5.2
Electrocardiogram.................................................................................25
12.5.3
Best corrected visual acuity (BCVA)....................................................25
12.5.4
Special safety topics..............................................................................25
12.6
Summary of safety results .....................................................................................25
13 Discussion and overall conclusions...................................................................................26


List of tables
Table 9-1
Study medication formulation and batch numbers................................13
22
Table 11-2
IOP measurements at each visit for patient 
..........22
Table 12-1
Vital signs measurements at each visit for patient 
.....................................................................................................25
Table 12-2
BCVA measurements at each visit for patient 
......25
List of figures
Figure 9-1
Study design..........................................................................................11


4
List of abbreviations and definition of terms
AE
Adverse Event
BCVA
Best Corrected Visual Acuity
BID
bis in die (twice a day)
CFB
Change from baseline
CRF
Case Report Form (paper or electronic)
DSM
Drug Supply Management
EDC
Electronic Data Capture
ETDRS
Early Treated of Diabetic Retinopathy Study
FAS
Full Analysis Set
GCP
Good Clinical Practice
ICF
Informed Consent Form
IEC
Independent Ethics Committee
IOP
Intraocular Pressure
IRB
Institutional Review Board
IRT
Interactive Response Technology
MedDRA
Medical Dictionary for Regulatory Activities 
OAG
Open Angle Glaucoma
PGA
Prostaglandin Analogue
PPS
Per Protocol analysis set
QD
quaque die (once a day)
RDC
Remote Data Capture
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
WHO
World Health Organization 


5
Ethics
5.1
Independent ethics committee or institutional review board
The study protocol and all amendments were reviewed by the Independent Ethics Committee 
(IEC) or Institutional Review Board (IRB) for each center, as listed in Appendix 16.1.3.
5.2
Ethical conduct of the study
The study was conducted according to the ethical principles of the Declaration of Helsinki.
5.3
Patient information and consent
Informed consent was obtained from each patient in writing at the screening visit. The study 
was described by the Investigator or designee, who answered any questions, and written 
information was also provided. 
Samples of the written information given to each patient and the consent form are presented in 
Appendix 16.1.3.
6
Investigators and study administrative structure
The administrative structure of the study, including internal and external participants, is 
described in Appendix 16.1.4-Section 1.
A list of Investigators, their affiliations and their qualifications, plus that of other important staff 
is provided in Appendix 16.1.4-Section 2.
Novartis staff analyzed this study and authored this report. The signatures of the Principal or 
Coordinating Investigator, the Sponsor’s Responsible Medical Officer, and the report authors 
are provided in Appendix 16.1.5.
7
Introduction
7.1
Background 
Glaucoma is a group of progressive optic neuropathies, caused by the degeneration and death 
of retinal ganglion cells and the axons that form the optic nerve, which may lead to visual field 
deterioration if left untreated (Weinreb and Khaw 2004).
Prostaglandin analogues (PGAs) are often preferred as initial monotherapy because of their 
intraocular pressure (IOP)–lowering efficacy, low frequency of systemic side effects, and lower 
frequency of instillation compared with older therapies such as beta-blockers 
(Nasser and Stewart 2006, Stewart et al 2005, Stewart et al 2008). One of the commonly used 
topical IOP lowering PGAs used to treat elevated IOP is travoprost. Travoprost 0.004% solution 
is marketed by Novartis under trade names Travatan® and Travatan Z®. 
Despite the efficacy of the PGAs, a significant proportion of patients require more than one 
medication to reach target IOPs. Clinicians must often add medications or switch to more 
powerful fixed dose combination drops in order to reach target pressures and manage the disease, 
after initiation of a prostaglandin analogue (PGA).


The fixed dose combination of brinzolamide 1% and brimonidine 0.2% is marketed under the 
trade name Simbrinza®. In two pivotal studies, Simbrinza, dosed twice daily (BID), has been 
shown to lower IOP ~ 27-38% from untreated baselines (Aung et al 2014, Gandolfi et al 2014). 
The mechanisms by which brinzolamide 1% and brimonidine 0.2% lowers IOP differs from 
PGAs and thus Simbrinza may be a suitable adjunctive therapy for patients on a PGA that 
require further IOP lowering. Hence, the combination of PGA + Simbrinza should be evaluated 
to understand the IOP lowering effect further.
7.2
Purpose
The purpose of this study was to determine the incremental IOP lowering that is achieved when 
Simbrinza, BID, is used adjunctively to Travatan in patients with normal tension glaucoma that 
may benefit from further IOP lowering. Data from this study was intended for publications and 
to provide health care practitioners with important treatment guidance on the use of Simbrinza 
in this clinical setting.
The study was prematurely terminated on 09-Nov-2017 due to administrative reasons, and not 
based on any safety or efficacy concerns (see further details in Section 9.4.9). All participating 
sites were promptly notified to stop enrollment and to discontinue ongoing patients. 
8
Study objectives
8.1
Primary objective and related endpoint
Primary Objective
Endpoint for primary objective
To demonstrate that Simbrinza is superior to 
placebo in lowering diurnal IOP when added to 
baseline Travatan therapy
Change from baseline (on Travatan) in diurnal 
IOP in the study eye at Week 6
8.2
Secondary objectives and related endpoint
Secondary Objectives
Endpoints for secondary objectives
To evaluate the differences between Simbrinza 
and placebo in diurnal IOP percentage change 
from a Travatan baseline therapy
Percentage IOP change from baseline (on 
Travatan) in diurnal IOP at Week 6
To evaluate the differences between Simbrinza 
and placebo in diurnal IOP, from a Travatan 
baseline therapy
Diurnal IOP at Week 6
To evaluate the differences between Simbrinza 
and placebo in IOP change at each time point, 
from a Travatan baseline therapy
Change from baseline in IOP for each time 
point at Week 6
To evaluate the differences between Simbrinza 
and placebo in IOP percentage change at each 
time point, from a Travatan baseline therapy
Percentage change from baseline in IOP for 
each time point at Week 6


8.3
Exploratory objectives and related endpoints
Refer to Appendix 16.1.1-Protocol-Section 2.1 for exploratory objectives and related endpoints.
9
Investigational plan
9.1
Study design
Figure 9-1
Study design
BID: twice a day, QD: once a day.
This was a multicenter, randomized, double-masked, two-arm, placebo-controlled, parallel-
group study in patients with normal tension glaucoma who were insufficiently controlled on 
travoprost 0.004% (Travatan) monotherapy. Approximately 200 patients were planned to be 
randomized and treated for up to 11 weeks, whilst they were to receive double-masked study 
medication for 6 weeks.
The study was divided into 2 sequential phases for a total of 5 visits:

Phase I: a Screening/Eligibility phase

Phase II: the Masked Treatment Phase
For full details of study design refer to Appendix 16.1.1-Protocol-Section 3.1
9.2
Discussion of study design, including the choice of control 
groups
Normal tension glaucoma patients are a difficult to manage sub-group of open angle glaucoma 
(OAG) patients that have lower baseline pressures than OAG patients with elevated IOP. This 
study was designed to investigate the incremental IOP lowering that is achieved when 
Visit 5
(Day 42)
Travatan (QD)
Simbrinza (BID)
Travatan (QD)
Placebo (BID)
Visit 4
(Day 14)
First Dose
Randomization
Last Dose
Primary Endpoint
Visit 3
Eligibility 2
Visit 2
Eligibility 1
3-8 Days
Travatan (QD)
Visit 1
Screening
42 Days
Up to 29 Days
Washout/Run-in
Phase I:
Screening/Eligibility
Phase II:
Masked Treatment


Simbrinza is added to Travatan (a PGA) which is often used as initial therapy to lower IOP. 
Understanding the magnitude of further IOP lowering that could be achieved by the addition of 
Simbrinza to Travatan in a low baseline setting, could only be achieved with a placebo 
comparator and could provide essential data to health care practitioners.
The study was designed to minimize the study length and assessments, while ensuring scientific 
validity: the two eligibility visits were to minimize regression to the mean and increase the 
likelihood of stable IOP entry data; the Day 14 visit allowed patient safety to be monitored 
during the masked treatment phase; the primary assessments were at 42 days to minimize patient 
time in the trial. IOP assessments at 09:00 and 11:00 allowed collection of a trough IOP 
(12 hours post dose) and a peak IOP (2 hours post dose), respectively.
Selection bias was reduced by randomization and ascertainment bias by masking of the patient 
and the Investigator / study staff who made the study assessments.
The placebo control allowed for assessment of the additive effects of Simbrinza, adjunctive to 
Travatan, with a minimization of bias through masking the patients and the study personnel 
who conducted the assessments. 
9.3
Population
The study population consisted of adult and elderly patients 18 years of age or older, with 
previously documented normal tension glaucoma (IOP < 22 mmHg and glaucomatous damage) 
and had inadequately controlled IOP while on a Travatan monotherapy (IOP ≥ 16 and < 22 
mmHg in the study eye).
9.3.1
Inclusion criteria
Key inclusion criteria

Mean IOP measurements in at least 1 eye ≥ 16 and < 22 mmHg at 09:00 while on a 
Travatan monotherapy at two consecutive visits (same eye at Visits 2 & 3 to be eligible 
for the study).  

Mean IOP must be < 25 mmHg in the other eye at any time point up to randomization. 
Inclusion criteria are described in details in Appendix 16.1.1-Protocol-Section 4.1
9.3.2
Exclusion criteria
Key exclusion criteria

Patients with a central cornea thickness < 500 µm and > 600 µm as measured by 
pachymetry in either eye.

Patients with Schaffer angle Grade < 2 in either eye, as measured by gonioscopy (extreme 
narrow angle with complete or partial closure).

Patients with a cup/disc ratio greater than 0.80 in either eye. 

Patients with severe central visual field loss in either eye or field loss threatening fixation 
in either eye. Severe central visual field loss is defined as a sensitivity of less than or equal 
to 10 dB in at least 2 of the 4 visual field test points closest to the point of fixation. 

Chronic, recurrent or severe inflammatory eye disease in either eye (from screening).  



Clinically significant or progressive retinal disease such as retinal degeneration, diabetic 
retinopathy, or retinal detachment in either eye. 
Exclusion criteria are described in details in Appendix 16.1.1-Protocol-Section 4.2
9.4
Treatment
9.4.1
Investigational and control treatment
Simbrinza (brinzolamide 1%/brimonidine 0.2%) eye-drops suspension was supplied in opaque 
DROP-TAINER® bottle with a masked label indicating that the product is for investigational 
use only. Placebo eye-drops solution (identical to Simbrinza but did not have active ingredients) 
was supplied in opaque DROP-TAINER® bottle with a masked label indicating that the product 
is for investigational use only. Travatan (travoprost 0.004%) eye-drops solution was supplied 
in a DROP-TAINER® bottle and was unmasked (open label) product.
All test materials were supplied by Novartis Drug Supply Management (DSM). The batch and 
formulation numbers of Simbrinza, Travatan and placebo are provided in Table 9-1.
A listing of patients receiving each batch of test material is provided in Appendix 16.1.6.
Table 9-1
Study medication formulation and batch numbers
Study drug and strength
Formulation control 
number
Batch number
Simbrinza (brinzolamide 1%/brimonidine 0.2%)
Placebo
Travatan (travoprost 0.004%)
9.4.2
Treatment arms
Patients were assigned at Visit 3 (Eligibility 2) to one of the following two treatment arms in a 
ratio of 1:1:

Arm 1: Simbrinza (eye drops dosed in the morning and in the evening) + Travatan (eye 
drops dosed in the evening)

Arm 2: Placebo (eye drops dosed in the morning and in the evening) + Travatan (eye 
drops dosed in the evening) 
9.4.3
Treatment assignment
Refer to Appendix 16.1.1-Protocol-Section 5.3 for details of randomization procedures.
The randomization scheme for patients was reviewed and approved by a member of the Novartis 
Randomization Office. The randomization list is provided in Appendix 16.1.7.
9.4.4
Treatment masking
Patients, investigator staff, persons performing the assessments, and data analysts remained 
masked to the identity of the treatment from the time of randomization until database lock, using 
the following methods: (1) Randomization data were kept strictly confidential until the time of 
unmasking, and were not accessible by anyone else involved in the study. (2) The identity of 


the treatments was concealed by the use of masked study drugs that were identical in packaging, 
labeling, and schedule of administration.
Unmasking 
was 
only 
permitted 
in 
the 
case 
of 
patient 
emergencies
(see
Appendix 16.1.1-Protocol-Section 5.5.9) and at the conclusion of the study.
Refer to Appendix 16.1.1-Protocol-Section 5.4 for further details on treatment masking.
9.4.5
Treating the patient
9.4.5.1
Patient numbering
Each patient was uniquely identified in the study by a combination of his/her center number 
and a 5-digit Patient Number. Refer to Appendix 16.1.1-Protocol-Section 5.5.1 for full details 
on patient numbering.
9.4.5.2
Dispensing the study treatment
Each study site was supplied with masked study drug (Simbrinza or placebo) in packaging of 
identical appearance labeled with the protocol and kit numbers. Travatan was provided open 
label containing the protocol and unique kit number. 
The 
masked 
study 
drug 
and 
Travatan 
were 
dispensed 
as 
described 
in 
Appendix 16.1.1-Protocol-Section 5.5.2.
9.4.5.3
Supply, storage and tracking of study treatment
For details on handling of study treatment, refer to Appendix 16.1.1-Protocol-Section 5.5.3.1.
9.4.5.4
Instructions for prescribing and taking study treatment
General instructions:

Patients wearing contact lenses had to remove the lenses before instillation of either 
medication. Following instillation of the study medications, the patient had to wait 
approximately 15 minutes after the last dose before re-inserting lenses.

Patients had to shake masked study medication before use.

Patients were not allowed to discard any unused or empty bottles and bring all Travatan 
and masked study medication bottles to the study visit.
Appendix 16.1.1-Protocol-Section 5.5.4 describes the detailed instructions for Travatan 
administration during screening/eligibility phase, and Travatan and masked study medication 
administration during masked treatment phase.
All kits of investigational treatment assigned by the Interactive Response Technology (IRT)
were recorded in the IRT system.
The investigator promoted compliance by instructing the patient to apply the study drug exactly 
as prescribed and by stating that compliance is necessary for the patient’s safety and the validity 
of the study. The patient was instructed to contact the investigator if he/she was unable for any 
reason to apply the study drug as prescribed.


9.4.5.5
Permitted dose adjustments and interruptions of study treatment
Study drug dose adjustments and/or interruptions were not permitted.
9.4.5.6
Rescue medication
Rescue medication was not permitted in this study. If an Investigator felt a patient was not 
adequately controlled on study medications, they were discontinued from receiving the study 
treatment and were managed accordingly to usual care.
9.4.6
Concomitant treatment
The Investigator instructed the patient to notify the study site about any new medications he/she 
took after the start of the study drug.
All medications and significant non-drug therapies (including physical therapy and blood 
transfusions) administered after the patient was enrolled into the study were required to be 
recorded on the Concomitant medications/Significant non-drug therapies after start of study 
drug Case Report Form (CRF). All anti-IOP medications administered at the time of the 
Screening Visit were recorded on the Ocular Anti-Hypertensive Medications CRF.
Use of the treatments displayed in Appendix 16.1.1-Protocol-Section 5.5.8-Table 5-1 were not 
allowed after screening.
9.4.7
Discontinuation of study treatment and premature patient withdrawal
Patients could voluntarily withdraw from the study for any reason at any time. A patient could 
be considered withdrawn if he or she stated an intention to withdraw, failed to return for visits, 
or became lost to follow-up for any other reason.
The Investigator was obliged to discontinue study drug for a given patient or withdraw the 
patient from the study if, on balance, he/she believed that continuation would be detrimental to 
the patient’s well-being.
Refer to Appendix 16.1.1-Protocol-Section 5.6.2 for details on discontinuation of study 
treatment, Appendix 16.1.1-Protocol-Section 5.6.3 for details on withdrawal of informed 
consent and Appendix 16.1.1-Protocol-Section 5.6.4 for details on patients lost to follow-up.
9.4.8
Emergency unmasking of treatment assignment
Refer to Appendix 16.1.1-Protocol-Section 5.5.9 for emergency code breaking details.
9.4.9
Early study termination
According to Appendix 16.1.1-Protocol-Section 5.6.5, the study could be terminated by 
Novartis at any time for any reason. This could include reasons related to the benefit risk 
assessment of participating in the study, practical reasons, or for regulatory or medical reasons 
(including slow enrollment). If this was necessary, the patient was to be seen as soon as possible 
and treated as a prematurely withdrawn patient. The Investigator could be informed of 
additional procedures to be followed in order to ensure that adequate consideration was given 
to the protection of the patient’s interests. The Investigator was responsible for informing the 


Institutional Review Board/Independent Ethics Committee (IRBs/IECs) of the early termination 
of the study.
This study was terminated early due to administrative reasons, and not based on any safety or 
efficacy concerns. Investigators were instructed to bring the ongoing patients for an Exit Visit 
as soon as possible. Study medications were stopped at the time of the Exit Visits. The 
Investigators informed the IECs of the early termination of the trial.
9.4.10
Treatment exposure and compliance
All Travatan and masked study treatment dispensed and returned were recorded in the Drug 
Accountability Log.
Refer to Appendix 16.1.1-Protocol-Section 6.3 for further details.
9.5
Efficacy and safety assessments
9.5.1
Visit schedule
The study visits and procedures are presented in Appendix 16.1.1-Protocol Section 6-Table 6-1
which lists all of the assessments and indicates with an “X” the visits at which they were 
performed.
All activities performed during eligibility visits E1 (Visit 2) and E2 (Visit 3) are listed in 
Appendix 16.1.1-Protocol Section 6-Table 6-2.
All activities performed during week 2 (Visit 4) and week 6 (Visit 5, exit) are listed in 
Appendix 16.1.1-Protocol Section 6-Table 6-3.
Refer to Appendix 16.1.1-Protocol-Section 6 for additional details of visit schedule and 
assessment.
9.5.2
Efficacy assessments
9.5.2.1
Assessment of efficacy
Intraocular pressure (IOP) measurement
All IOP measurements were to be performed in both eyes at each visit with a Goldmann 
applanation tonometer as described in Appendix 16.1.1-Protocol-Section 6.4.1.
Two consecutive IOP measurements were taken for each eye. The applanation probe was 
withdrawn from the eye between the two measurements.
Time of first IOP measurement was recorded in the source document and in Electronic Data 
Capture (EDC). The same procedure was repeated on the contralateral eye.
9.5.2.2
Appropriateness of efficacy assessments
Assessments described in the protocol are standard ophthalmic assessments for this indication 
and patient population.


9.5.3
Safety assessments
9.5.3.1
Assessment of safety
Safety assessments consisted of collecting all adverse events (AEs), serious adverse events 
(SAEs), with their severity and relationship to study drug. Safety evaluation included vital signs 
(blood pressure and pulse rate), ophthalmic examinations (automated perimetry, slit-lamp exam, 
dilated fundus examination, and best corrected visual acuity) and pregnancy test (for women of 
childbearing potential). 
Full information about the definition of AEs and SAEs, the procedures for reporting them is 
given in the Appendix 16.1.1-Protocol-Section 7.
Refer to Appendix 16.1.1-Protocol-Section 6.5 for details of all safety assessments.
9.5.3.2
Appropriateness of safety assessments
The safety assessments selected are standard for this indication/patient population.
9.5.4
Other assessments
Gonioscopy and Pachymetry were not part of safety assessments, and were only performed at 
Screening Visit. Refer to Appendix 16.1.1-Protocol-Section 6.6 for details of these assessments.
9.6
Data quality assurance
9.6.1
Monitoring
The responsibility for site monitoring resided with the Novartis field monitors. Details of the 
monitoring procedures are described in Appendix 16.1.1-Protocol-Section 8.1
9.6.2
Data collection
Designated Investigator staff entered the data required by the protocol into iMedidata Remote 
Data Capture (RDC) system. They were not given access to the system until adequately trained. 
Documented training on RDC system was completed by the designated Investigator site staff 
before their access was granted. 
9.6.3
Database management and quality control
Novartis staff reviewed the data entered into the CRFs by investigational staff for completeness 
and accuracy and instructed the site personnel to make any required corrections or additions. 
Queries were sent to the investigational site using an electronic data query. Designated 
Investigator site staff were required to respond to each query and confirm or correct the data.
Concomitant medications entered into the database were coded using the World Health 
Organization (WHO) Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Concomitant procedures, non-drug therapies and adverse 
events were coded using Medical Dictionary for Regulatory Activities (MedDRA) version 19.0 
terminology.
Randomization codes and data about all study treatment dispensed to the patient and all IRT 
recorded dosage changes were tracked using an IRT. 


9.6.4
Quality assurance and auditing
There were no audits or Health Authority inspections conducted at sites participating in this 
study.
9.7
Statistical methods
This section describes the statistical analyses that were planned as per the protocol and statistical 
analysis plan (SAP). See Section 9.8.3 where the changes in planned analyses and the reason 
for them are detailed.
9.7.1
Data analysis
9.7.2
Analysis sets
The analysis sets defined as per the protocol and SAP were:
All enrolled analysis set included all patients who signed an Informed Consent Form (ICF) 
and were assigned patient numbers. This analysis set was used to summarize patient disposition 
and pre-treatment AEs.
All randomized analysis set included all enrolled patients who were randomized to treatment.
Safety analysis set: included all patients exposed to at least one dose of any study therapy. 
Patients in the safety analysis set were analyzed according to the treatment received.
Full Analysis Set (FAS) included all randomized patients with IOP measurement at baseline 
who had at least one on-treatment assessment. This analysis set was primary analysis set for 
IOP endpoints. Patients in the FAS were analyzed according to randomized treatment.
Per protocol analysis set (PPS) a subset of all patients in the FAS and excluded all data which 
met any of the critical deviation criteria identified in the SAP. In addition, individual patient 
visits and data points that did not satisfy protocol criteria could be excluded from the PPS.
The final patient evaluability was determined prior to breaking the code for masked treatment 
assignment and locking the database.
9.7.3
Patient disposition, demographics and other baseline characteristics
All patients who signed informed consent were accounted in patient disposition.
Patient disposition table were to present the number and percentage of patients for the following:

Screened/Run in 

Screen/ Run in Failure

Entered the double-masked phase 

Completed the double-masked phase

Discontinued the double-masked phase 

Reason for discontinuation
Details of the planned data analysis for patient demographics and other baseline characteristics 
are presented in Appendix 16.1.1-Protocol-Section 9.2.


9.7.4
Treatments (study drug, rescue medication, other concomitant 
therapies, compliance)
Data for study drug administration and concomitant therapies were to be listed by treatment 
group and patient. Extent of exposure, as a continuous variable and categorically, was to be 
analyzed with summary statistics, using the Safety Analysis Set.
9.7.5
Analysis of the primary variable
9.7.5.1
Variable
The primary efficacy endpoint in this study was the change from baseline (CFB) to week 6 in 
diurnal IOP.
CFB Diurnal IOP = average of change from baseline at 9:00 and 11:00 time points, with 
baseline being the average of the E1 and E2 IOP by time point.
The primary analysis set for the efficacy analysis was the FAS.
9.7.5.2
Statistical hypothesis, model, and method of analysis
Refer to Appendix 16.1.1-Protocol Section 9.4.2.
9.7.5.3
Supportive analyses
The primary analysis was planned to be repeated using the per protocol set in order to assess its 
robustness in regard to deviations.
9.7.6
Analysis of secondary efficacy variables
9.7.6.1
Efficacy
Analyses of treatment differences of secondary endpoints was planned to use the same methods 
as those for the primary endpoint. Hypothesis tests were to use the same null and alternative 
hypotheses as in Appendix 16.1.1-Protocol Section 9.4.2, with µ representing the mean for the 
variable being tested.
See Appendix 16.1.1-Protocol-Section 9.5.1 for details of the planned statistical analysis of 
secondary efficacy endpoints.
9.7.7
Safety analyses
The planned safety analyses consisted of descriptive summaries of the data as relevant to the 
scale of data, e.g., frequency and percent for adverse events, and mean changes from baseline 
as appropriate.
Frequency and percentage of patients were to be provided for each categorical variable by 
treatment group.


9.7.8
Handling of missing values/censoring/discontinuations
Missing observations were not to be imputed. The statistical models that were employed and 
the associated analyses were robust under the missing completely at random and the missing at 
random assumptions.
9.7.9
Sample size calculation
With 90 evaluable patients per treatment group in the primary efficacy analysis, there was 
approximately 80% power to detect a difference in mean change from baseline in diurnal IOP 
at Week 6 of 1.5 mmHg between the treatment groups. This calculation was based on the 
assumption of a common standard deviation for mean IOP of 3.5 mmHg and the use of a two-
sample two-sided t-test performed at the α = 0.05 level of significance. 
Assuming a drop-out rate of 10%, approximately 100 patients per treatment group were to be 
randomized to ensure the required number of evaluable patients in the final efficacy analysis.
9.7.10
Power for analysis of key secondary variables
Not applicable
9.7.11
Interim analysis
No formal interim analysis was planned for this study.
9.8
Changes in the conduct of the study or planned analyses
9.8.1
Protocol amendments
The study protocol was amended once. The original protocol and amendment are provided in 
Appendix 16.1.1. Previous sections of this report describe the study conduct as amended. The 
key features of Amendment 1 (12-Apr-2017) are given below:
Amendment 1 introduced the following changes:

Section 4.2 Exclusion criteria: to clarify that it is not clinically relevant to measure both 
horizontal and vertical cup/disc ratio to exclude patients (exclusion criteria)

Section 9.5.2 Safety variables: Data for fundus parameters and slit-lamp exam will no 
longer be collected

Other editorial changes
9.8.2
Other changes in study conduct
See Section 9.4.9.
9.8.3
Changes in planned analysis
At the time of the premature termination of this study, only one patient was randomized. 
Therefore, the planned efficacy and safety analyses could not be performed. 
The patient data reports generated from the clinical databasereporting efficacy measure and key 
safety data are the only results presented in this report.


10
Study patients
10.1
Disposition of patients
At the time of the premature termination of this study, four patients at three participating centers 
in Republic of Korea had signed the Informed Consent Form. Of these four patients:

One patient (
) did not complete the screening visit and did not receive 
any study medication. (Appendix 16.3)

Two patients (
) completed screening and were 
in the run-in phase, taking open-label Travatan run-in medication. (Appendix 16.3)

One patient (
) was randomized, taking open-label Travatan medication 
plus masked Placebo. (Appendix 16.3)
10.2
Protocol deviations
No protocol deviations were reported (Appendix 16.3).
11
Efficacy evaluation
11.1
Data sets analyzed
Not applicable.


11.3
Measurements of treatment compliance
Not applicable.
11.4
Efficacy results and tabulations of individual patient data
11.4.1
Analysis of efficacy 
The IOP measurements at each visit for the one patient who was randomized to placebo (
) are provided in Table 11-2 below.
Table 11-2
IOP measurements at each visit for patient 
Eye
Visit 2 IOP (mmHg)
Visit 3 IOP (mmHg)
Visit 4 IOP (mmHg)
Exit Visit
IOP (mmHg)
09:00
11:00
09:00
11:00
09:00
11:00
Right 
FR: 20 
SR: 19 
FR: 19 
SR: 19 
FR: 19 
SR: 19 
FR: 16 
SR: 16 
FR: 16 
SR: 14 
FR: 16 
SR: 15 
FR: 18 
SR: 19 
Left 
FR: 16 
SR: 17 
FR: 20 
SR: 20 
FR: 18 
SR: 19 
FR: 16 
SR: 16 
FR: 15 
SR: 14 
FR: 15 
SR: 15 
FR: 17 
SR: 18 
FR: First Reading; SR: Second Reading.
Source: Appendix 16.3


11.4.1.1 Primary efficacy results
Not applicable.
11.4.1.2 Secondary efficacy results
Not applicable.
11.4.1.3 Exploratory efficacy results
Not applicable.
11.4.2
Statistical and analytical issues
Not applicable.
11.4.3
Tabulation of individual response data
Not applicable
11.4.4
Drug dose, drug concentration and relationships to response
Not applicable
11.4.5
Drug-drug and drug-disease interactions
Not applicable
11.4.6
By-patient displays
Individual patient data generated from clinical database for all patients are provided in 
Appendix 16.3.
11.4.7
Summary of efficacy results
The IOP measurements at each study visit for the one patient who was randomized to placebo,
can be found in Table 11-2.
12
Safety evaluation
12.1
Extent of exposure
12.1.1
Dosage
The planned doses in the study were:
Phase I (Run-in period): One drop of Travatan applied topically to the affected eye(s) once 
daily (evening).
Phase II (Masked Treatment Phase): Eligible patients were assigned to one of the following 
two treatment arms in a ratio of 1:1

Arm 1: One drop of Simbrinza applied topically to the affected eye(s) in the morning and 
evening + one drop of Travatan applied topically to the affected eye(s) in the evening. 



Arm 2: One drop of Placebo applied topically to the affected eye(s) in the morning and 
evening + one drop of Travatan applied topically to the affected eye(s) in the evening.  
12.1.2
Patient exposure

Patient 
 did not receive any study medication (Appendix 16.3).

Patient 
 received open label Travatan from 
 to 
 (Appendix 16.3).

Patient 
 received open label Travatan from 
 to 
 (Appendix 16.3).

Patient
 received open label Travatan from 
 to 
 (the date of last dose of open label Travatan was inadvertently captured as 
 on the ‘Exposure’ page of eCRF; however, the actual date was 
) 
and masked placebo from 
 to 
 (Appendix 16.3).
12.1.3
Concomitant medication
Concomitant medications taken by the one patient who was randomized to placebo (
) included diltiazem HCL 90 mg, losartan potassium 100 mg and apixaban 10 mg 
for hypertension (Appendix 16.3).
No concomitant medications data were reported for the other patients (Appendix 16.3).
12.2
Adverse events
12.2.1
Display of adverse events
One non-serious AE (common cold) was reported by the one patient who was randomized to 
placebo (
) (Appendix 16.3). 
12.2.2
Analysis of adverse events
The reported AE of common cold was mild in severity and was not related to the study 
medication (Appendix 16.3).
12.2.3
Listing of adverse events by patient
No AE listing was generated as there was only one AE reported.
12.3
Deaths, other serious adverse events and other significant 
adverse events
There were no deaths, serious adverse events and other significant adverse events reported in 
the study. Therefore no listings were generated, and no narratives were required.
12.4
Clinical laboratory evaluation
No laboratory evaluations (hematology, clinical chemistry and urinalysis) were performed in 
this study.


12.5
Vital signs, physical findings and other observations related to 
safety
12.5.1
Vital signs
The vital signs measurements at visit for the one patient who was randomized to placebo
(
) are provided in Table 12-1 below.
Table 12-1
Vital signs measurements at each visit for patient 
Vital 
Sign
Visit 2 
Visit 3 
Visit 4
Early Exit 
Visit
09:00
11:00
09:00
11:00
09:00
11:00
PR 
72 bpm
74 bpm
94 bpm
84 bpm
84 bpm
76 bpm
94 bpm
SBP 
135 mmHg
132 mmHg
138 mmHg
135 mmHg
132 mmHg
124 mmHg
140 mmHg
DBP
83 mmHg
81 mmHg
82 mmHg
83 mmHg
82 mmHg
79 mmHg
93 mmHg
PR: pulse rate; SBP: systolic blood pressure; DBP: diastolic blood pressure
Source: Appendix 16.3
12.5.2
Electrocardiogram
Not applicable
12.5.3
Best corrected visual acuity (BCVA)
The Early Treated of Diabetic Retinopathy Study (ETDRS) visual acuity score at each visit for 
the one patient who was randomized to placebo (
) are provided in 
Table 12-2 below.
Table 12-2
BCVA measurements at each visit for patient 
Eye
Visit 2
09:00
Visit 3
09:00
Visit 4
09:00
Early Exit 
Visit
Right eye
69
74
73
72
Left eye
75
69
72
65
Source: Appendix 16.3
12.5.4
Special safety topics
None.
12.6
Summary of safety results
There were no deaths or SAEs reported during the study.
One non-serious AE (common cold) was reported by the one patient who was randomized to 
placebo (
). The AE of common cold was mild in severity and was not related 
to the study medication.
There were no AEs leading to discontinuation reported during the study.


The vital signs measurements and ETDRS visual acuity scores at each study visit for the one 
patient who was randomized to placebo (
), can be found in Table 12-1 and 
Table 12-2, respectively.
13
Discussion and overall conclusions
This was a phase IV study with the objective of evaluating the efficacy (incremental IOP 
lowering that could be achieved) and safety of Simbrinza (brinzolamide 1% / brimonidine 0.2% 
fixed dose combination) BID when used as an adjunctive therapy to Travatan (travoprost 
0.004%) in patients with normal tension glaucoma, that may benefit from further IOP lowering. 
The study was terminated prematurely with only one patient randomized at that time. The 
reason for premature termination was administrative, and not based on any safety or efficacy 
concerns.
Conclusions:
Due to the early study termination and limited data, efficacy and overall safety profile of 
Simbrinza as an adjunctive therapy to Travatan could not be analyzed; therefore, this study 
could not report any conclusion.

SAP_001.pdf: 
Global Medical Affairs 
Brinzolamide 1% / Brimonidine 0.2% “Simbrinza” 
CQVJ499A2404 / NCT03150160
Additive effect of twice-daily Brinzolamide 1% / 
Brimonidine 0.2% fixed dose combination as an adjunctive 
therapy to travoprost 0.004% patients with normal tension 
glaucoma
Statistical Analysis Plan (SAP)
Author:
 TS
Document type:
SAP Documentation
Document status:
Final V1.0
Release date:
28-Aug-17
Number of pages:
26
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


Novartis
For business use only
Page 2
SAP Final V 1.0
CQVJ499A2404
Document History – Changes compared to previous final version of SAP
Date
Time point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
28-Aug-2017
Prior to DB 
lock
Creation of final 
version
N/A - First version
NA


Novartis
For business use only
Page 3
SAP Final V 1.0
CQVJ499A2404
Table of contents
Table of contents................................................................................................................. 3
List of abbreviations............................................................................................................ 5
1
Introduction......................................................................................................................... 7
1.1
Study design ............................................................................................................ 7
1.2
Study objectives and endpoints ............................................................................... 8
2
Statistical methods............................................................................................................... 9
2.1
Data analysis general information........................................................................... 9
2.1.1
General definitions................................................................................ 10
2.2
Analysis sets .......................................................................................................... 10
2.2.1
Subgroup of interest.............................................................................. 11
2.3
Patient disposition, demographics and other baseline characteristics................... 11
2.3.1
Patient disposition................................................................................. 12
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ........................................................................................................... 12
2.4.1
Study treatment / compliance ............................................................... 12
2.4.2
Prior, concomitant and post therapies................................................... 12
2.5
Analysis of the primary objective ......................................................................... 13
2.5.1
Primary endpoint................................................................................... 13
2.5.2
Statistical hypothesis, model, and method of analysis.......................... 13
2.5.3
Handling of missing values/censoring/discontinuations....................... 14
2.5.4
Supportive analyses .............................................................................. 14
2.6
Analysis of the key secondary objective ............................................................... 14
2.6.1
Key secondary endpoint........................................................................ 14
2.6.2
Statistical hypothesis, model, and method of analysis.......................... 14
2.6.3
Handling of missing values/censoring/discontinuations....................... 14
2.7
Analysis of secondary efficacy objective(s).......................................................... 14
2.7.1
Secondary endpoints............................................................................. 14
2.7.2
Statistical hypothesis, model, and method of analysis.......................... 15
2.7.3
Handling of missing values/censoring/discontinuations....................... 15
2.8
Safety analyses ...................................................................................................... 15
2.8.1
Adverse events (AEs) ........................................................................... 16
2.8.2
Deaths ................................................................................................... 16
2.8.3
Laboratory data..................................................................................... 16
2.8.4
Other safety data ................................................................................... 16
2.9
Pharmacokinetic endpoints.................................................................................... 18
2.10
PD and PK/PD analyses ........................................................................................ 18
2.11
Patient-reported outcomes..................................................................................... 18
2.12
Biomarkers ............................................................................................................ 18


Novartis
For business use only
Page 4
SAP Final V 1.0
CQVJ499A2404
18
2.14
Interim analysis ..................................................................................................... 19
No formal interim analysis is planned for this study. .............................................................. 19
3
Sample size calculation..................................................................................................... 19
4
Change to protocol specified analyses .............................................................................. 19
5
Appendix........................................................................................................................... 20
5.1
Imputation rules..................................................................................................... 20
5.1.1
Study drug............................................................................................. 20
5.1.2
AE date imputation ............................................................................... 20
5.1.3
Concomitant medication date imputation............................................. 21
5.2
AEs coding/grading............................................................................................... 22
5.3
Laboratory parameters derivations........................................................................ 22
5.4
Statistical models................................................................................................... 22
5.4.1
Primary analysis.................................................................................... 22
5.5
Rule of exclusion criteria of analysis sets ............................................................. 23
6
Reference........................................................................................................................... 26


Novartis
For business use only
Page 5
SAP Final V 1.0
CQVJ499A2404
List of abbreviations
ADR
Adverse Drug Reaction
AE
Adverse Event
BCVA
Best Corrected Visual Acuity
BID
bis in die (twice a day)
CAI
Carbonic Anhydrase Inhibitor
CCT
Central Corneal Thickness
CFR
US Code of Federal Regulations 
CLV
Corrected Loss Variance
CRF
Case Report/Record Form (paper or electronic)
CPO
Country Pharma Organization
CPSD
Corrected Patterns Standard Deviation
CRO
Contract Research Organization
DS&E
Drug Safety & Epidemiology
ECG
Electrocardiogram
EDC
Electronic Data Capture
ETDRS
Early Treated of Diabetic Retinopathy Study
FAS
Full Analysis Set
GAT
Goldman Applanation Tonometer
GCP
Good Clinical Practice
IB
Investigator’s Brochure
ICF
Informed Consent Form
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IN
Investigator Notification
IOP
Intraocular Pressure
IRB
Institutional Review Board
IRT
Interactive Response Technology
MAOI
Monoamine Oxidase Inhibitors
MedDRA
Medical Dictionary for Regulatory Activities 
MMRM
Mixed Model Repeated Measures
OAG
Open Angle Glaucoma
OCT
Optical Coherence Tomography
OD
Oculus Dexter (right eye)
OS
Oculus Sinister (left eye)
OU
Oculus Uterque (both eyes)
PGA
Prostaglandin Analogue
p.o.
oral(ly)
PPS
Per Protocol analysis set
PSD
Patterns Standard Deviation
QD
quaque die (once a day)
SAE
Serious Adverse Event


Novartis
For business use only
Page 6
SAP Final V 1.0
CQVJ499A2404
SAP
Statistical Analysis Plan
SCR
Screening
SOC
System Organ Class
SUSAR
Suspected Unexpected Serious Adverse Reactions
TD
Study Treatment Discontinuation
TID
three times a day
UNSC
Unscheduled
VA
Visual Acuity
WHO
World Health Organization 


Novartis
For business use only
Page 7
SAP Final V 1.0
CQVJ499A2404
1
Introduction
The purpose of this Statistical Analysis Plan (SAP), is to describe the implementation of the 
statistical analyses planned in the study protocol for the production of the clinical study report 
(CSR). This document is aligned with Version 00 of the original clinical study protocol dated 
11-Feb-2017.
1.1
Study design
Figure 1-1
Study design
This study is a multicenter, randomized, double-blind, 2-arm, parallel-group study in patients 
with normal tension glaucoma who are insufficiently controlled on Travatan 0.004% 
monotherapy. About 200 patients will be randomized in a 1:1 ratio to either Simbrinza + 
Travatan or vehicle + Travatan and treated for up to 10 weeks whilst they will receive double-
masked study medication for 6 weeks. The randomization will be stratified by study site. This
study is divided into 2 sequential periods for a total of 5 visits. 
Phase I of the study is a Screening/Eligibility Phase which includes Screening Visit and 2 
Eligibility Visits (E1 and E2). The intent of the Screening/Eligibility Phase is to identify eligible 
patients for this study, including a determination of baseline IOP measurements at E1 and E2 
Visits while on Travatan monotherapy. 
Period II is the randomized, masked Treatment Phase which includes 2 on-therapy visits at 
Week 2 and Week 6 (Exit Visit). The primary analysis time point is at Week 6. A patient will 
be considered to have completed the study when the patient has completed the last visit planned 
in the protocol (Visit 5/ Day 42).
The analysis will be performed after DBL following the end of study, defined as 30 days after 
last patient last visit. (LPLV). No interim analysis is planned for this study.


Novartis
For business use only
Page 8
SAP Final V 1.0
CQVJ499A2404
1.2
Study objectives and endpoints
Objectives and related endpoints
Objectives
Endpoints
      Analysis
Primary 
Refer to Section 2.5

To demonstrate that 
Simbrinza is superior to 
vehicle in lowering diurnal 
IOP when added to 
baseline Travatan therapy

Change from baseline in diurnal IOP 
in the study eye at Week 6
Secondary 
Refer to Section 2.7

To evaluate the 
differences between 
Simbrinza and vehicle in 
diurnal IOP percentage 
change from baseline

Percentage IOP change from 
baseline in diurnal IOP at Week 6

To evaluate the 
differences between 
Simbrinza and vehicle in 
diurnal IOP

Diurnal IOP at Week 6

To evaluate the 
differences between 
Simbrinza and vehicle in 
IOP change at each time 
point from baseline

Change from baseline in IOP for 
each time point at Week 6

To evaluate the 
differences between 
Simbrinza and vehicle in 
IOP percentage change at 
each time point from 
baseline

Percentage change from baseline in 
IOP for each time point at Week 6


Novartis
For business use only
Page 9
SAP Final V 1.0
CQVJ499A2404
2
Statistical methods
2.1
Data analysis general information
The final analysis will be performed by Novartis and/or a designated CRO. SAS version 9.4 or 
later software will be used to perform all data analyses and to generate tables, figures and 
listings.
One eye from each patient will be chosen as the study eye and only the study eye will be used 
for efficacy analysis. If only 1 of a patient’s eyes is dosed, or if both are dosed but only one eye 
is diagnosed with normal tension glaucoma, the dosed normal tension glaucoma eye will be 
selected as the study eye. If both eyes are dosed, and are both diagnosed with normal tension 
glaucoma, the worse evaluable eye will be selected as the study eye. Worse eye is defined as 
the eye with the higher IOP at 09:00 averaged across the 2 eligibility visits . If both eyes are 
equal at 09:00 IOP, then the worse eye will be defined as the eye with the higher IOP at 11:00 
averaged across the 2 eligibility visits. If both eyes are equal at 09:00 and 11:00 IOP then the 
right eye will be selected for analysis.


Novartis
For business use only
Page 10
SAP Final V 1.0
CQVJ499A2404
2.1.1
General definitions
Investigational drug, will refer to Simbrinza only. Whereas, study treatment will refer to the 
combination drugs Simbrinza (bid), Travatan (qd), Vehicle (bid).
The term investigational treatment may also be referred to as study treatment which is used 
throughout this document.
The term study drug can be used to refer to investigational and components of study treatment.
Date of first administration of study treatment 
The date of first administration of study treatment is defined as the date patient receives the first 
dose of study treatment after being randomized to one study arm.
Date of last administration of study treatment 
The date of last administration of study treatment is defined as the date patient receives the last 
dose of study treatment.
Baseline
Baseline IOP assessment is defined as the average of the non-missing IOP measurements at 
visits 2 and 3. For all other assessment baseline is the non-missing measurements at visit 3.
Study Periods or Phases
There are two periods in this study: Period 1 for screening and Eligibility, and Period 2 for the 
blinded treatment.
Study day
The study day, describes the day of the event or assessment date in Period 1 or 2 after enrollment, 
relative to the reference start date.  
Last contact 
The last time the investigator or a designated study personal contacted the patient to collect 
some information or complete some study procedures.
2.2
Analysis sets
Enrolled and Randomized 
All enrolled analysis set includes all patients who signed an ICF and are assigned patient
numbers. This analysis set will be used to summarize patient disposition and pre-treatment AEs.
All randomized analysis set includes all patients who are randomly assigned to receive a study
treatment.


Novartis
For business use only
Page 11
SAP Final V 1.0
CQVJ499A2404
Full Analysis Set
Full analysis set (FAS) includes all randomized patients with IOP measurement at baseline who 
had at least one on-treatment assessment. This analysis set will be the primary analysis set for
IOP endpoints. Patients in the FAS will be analyzed according to randomized treatment.
Per protocol set (PPS) 
Per protocol analysis set (PPS) consists of a subset of all patients in the FAS and excludes all 
data which have met any of the critical deviation criteria identified in Section 5.5. In addition, 
individual patient visits and data points that do not satisfy protocol criteria may be excluded 
from the PPS.
The final patient evaluability will be determined prior to breaking the code for masked treatment 
assignment and locking the database.
The number and percentage of patients in each analysis set will be summarized based on all 
randomized patients. In addition, a listing will be produced to show the patient 
inclusion/exclusion into each of the analysis sets with the corresponding reason(s) for exclusion.  
If protocol deviations do occur, then the data from specific patients, visits, or evaluations may 
be excluded from analysis. The criteria and determination of clinically significant protocol 
deviations will be data based and finalized prior to the database lock. 
Safety
The Safety analysis set includes all patients exposed to at least one dose of any study therapy. 
Patients in the safety analysis set will be analyzed according to the treatment received.
2.2.1
Subgroup of interest
To determine whether the treatment effect is consistent, the estimate of the between-group 
treatment effect (with a nominal 95% CI) for the primary endpoint will be provided for the 
following subgroups:

age categories (<65, ≥65 years) and (< 50, 50 – 64, ≥ 65); 

sex (female, male); 

baseline IOP categories (16-<19 mmHg, ≥19-21 mmHg).
The subgroup analyses will be based on the FAS.
2.3
Patient disposition, demographics and other baseline 
characteristics
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Patient characteristics summaries include tables and listings such as 
demographics [(age (continuous and categorically as <65, ≥ 65 and also as < 50, 50 – 64, ≥ 65), 
gender, race, ethnicity, iris color, and region]) and baseline characteristics (baseline IOP by 
time point, baseline diurnal IOP, baseline IOP category (16-<19 mmHg, ≥19-21 mmHg), 
corneal thickness, and diagnosis for the FAS. All descriptive summary statistics will be 


Novartis
For business use only
Page 12
SAP Final V 1.0
CQVJ499A2404
displayed with n and % for categorical data, and with mean, standard deviation, median, 
minimum, and maximum for continuous data.
2.3.1
Patient disposition
All patients who signed informed consent will be accounted for in Patient disposition. The 
number and percentage of patients who entered the run-in period and the number and percentage 
of screen failures will be based on all enrolled (signed informed consent) patients.
The number and percentage of patients who either discontinued treatment, died or experienced 
an AE during the run-in period as well as the number and percentage of randomized patients 
will be based on all patients who entered the run-in period. 
The number and percentage of patients in the FAS, in the safety analysis set, in the PPS will be 
based on all randomized patients. In addition, the number and percentage of patients  and 
number and percentage of patients who completed the study and those who discontinued the 
study will be based on all randomized patients. The reasons for discontinuation and the deaths 
that occurred during the double-blind phase will be summarized based on all randomized 
patients.
Patient disposition table will present the followings:

Screened/Run in 

Screen/ Run in Failure

Entered the double-blind phase 

Completed the double-blind phase

Discontinued the double-blind phase 

Reason for discontinuation 
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.4.1
Study treatment / compliance
The extent of drug exposure will be analyzed by phase both as continuous and categorical 
variable with summary statistics, using the Safety Set. The categories are: (1 - 14 Days); (15 -
28 Days); (29 - 45 Days) and > 45 Days.  
No summaries of treatment compliance are planned.
2.4.2
Prior, concomitant and post therapies
All prior and concomitant medications will be coded using WHO Drug Dictionary and will be 
summarized by ATC (Anatomical Therapeutic Chemical) class coding Level 3 and preferred 
name using counts and percentages.  Within each summary, events will be sorted 
alphabetically. Details regarding WHO-DD version will be included in the footnote in the 
tables/listings. 
Prior medications are medications, which started and stopped prior to the patient’s study 
treatment start date. 
Concomitant medications are medications which:


Novartis
For business use only
Page 13
SAP Final V 1.0
CQVJ499A2404

started prior to, on, or after the patient’s study treatment start date; 

AND ended on or after the patient’s study treatment start date, or were ongoing at the 
end of the study.
A summary of concomitant medication use will be presented overall and by visit.
Note: If medication start dates are partial, the start date will be imputed as the earliest possible 
date, and stop date as the latest possible date. In the case where it is not possible to define a 
medication as prior or concomitant, the medication will be classified as concomitant.
2.5
Analysis of the primary objective
The primary objective of this study is to demonstrate that Simbrinza is superior to vehicle in 
lowering diurnal IOP when added to baseline Travatan therapy. 
2.5.1
Primary endpoint
The primary efficacy endpoint in this study is the change from baseline (CFB) to week 6 in 
diurnal IOP.
CFB Diurnal IOP = average of change from baseline at 9:00 and 11:00 time points, with 
baseline being the average of the E1 and E2 IOP by time point.
The primary analysis set for the efficacy analysis will be the FAS.
2.5.2
Statistical hypothesis, model, and method of analysis
The primary efficacy analysis will be an assessment of differences between treatments in 
mean change from baseline in diurnal IOP (average of change from baseline at 9:00 and 11:00 
time points, with baseline being the average of the E1 and E2 IOP by time point) at Week 6.  
The null and alternative hypotheses for the primary analysis are:
H0:  μSimbrinza+Travatan  = μVehicle+ Travatan  
  H1:  μSimbrinza+Travatan  ≠μVehicle+ Travatan  
where μSimbrinza+Travatan  refers to actual mean diurnal IOP change from baseline for patients 
randomized to receive brinzolamide / brimonidine plus Travatan, and μVehicle+Travatan  refers to 
actual mean diurnal IOP change from baseline for patients randomized to receive Vehicle plus 
Travatan. 
The treatment difference (Simbrinza – Vehicle) in mean diurnal IOP change from baseline 
will be analyzed using a mixed model for repeated measures (MMRM) with terms for 
treatment, visit, visit by treatment interaction and baseline IOP as covariate. Covariance 
structures such as unstructured (UN) will be used. Least squares mean estimates within 
treatment and for the difference of the treatments along with their associated 2-sided 95% 
confidence intervals will be provided. 
A greater reduction from baseline in diurnal IOP at Week 6 on the adjunctive therapy 
(Simbrinza plus Travatan) relative to Vehicle plus Travatan, i.e. negative treatment difference 
in mean diurnal IOP change from baseline to Week 6, will indicate IOP-lowering advantage for 
the adjunctive therapy (Simbrinza plus Travatan) over Vehicle plus Travatan.
To address multiplicity associated with testing one primary endpoint and several secondary 
endpoints, a fixed testing procedure will be used for hypothesis testing of primary and 
secondary endpoints, and is further described in Section 2.7.2.


Novartis
For business use only
Page 14
SAP Final V 1.0
CQVJ499A2404
2.5.3
Handling of missing values/censoring/discontinuations
The analysis of change from baseline in diurnal IOP will be a likelihood-based approach via
MMRM, without explicit data imputation. The MMRM analyses are robust to data that are
missing at random.
2.5.4
Supportive analyses
The primary analysis will be repeated using the per protocol set in order to assess its robustness 
in regard to deviations.
2.6
Analysis of the key secondary objective
2.6.1
Key secondary endpoint
Not applicable.
2.6.2
Statistical hypothesis, model, and method of analysis
Not applicable.
2.6.3
Handling of missing values/censoring/discontinuations
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
The secondary objectives for this study are:

To evaluate the differences between Simbrinza and vehicle in diurnal IOP percentage 
change from a Travatan baseline therapy.

To evaluate the differences between Simbrinza and vehicle in diurnal IOP (on Travatan 
baseline therapy).

To evaluate the differences between Simbrinza and vehicle in IOP change at each time 
point from a Travatan baseline therapy.

To evaluate the differences between Simbrinza and vehicle in IOP percentage change 
at each time point from a Travatan baseline therapy.
2.7.1
Secondary endpoints
The secondary endpoints for this study corresponding to the above objectives are:

Percentage IOP change from baseline (PCFB) in diurnal IOP at Week 6.

Diurnal IOP at Week 6 in each treatment arm.

Change from baseline in IOP for each time point at Week 6.

Percentage change from baseline in IOP for each time point at Week 6.


Novartis
For business use only
Page 15
SAP Final V 1.0
CQVJ499A2404
2.7.2
Statistical hypothesis, model, and method of analysis
The null and alternative hypotheses for each secondary endpoint are:
H0:  μSimbrinza+Travatan  = μVehicle+Travatan
H1:  μSimbrinza+Travatan  ≠μVehicle+Travatan
where μSimbrinza+Travatan refers to the mean for patients randomized to receive brinzolamide / 
brimonidine plus Travatan, and μVehicle+Travatan refers to the mean for patients randomized to 
receive Vehicle plus Travatan for each respective secondary endpoint.
At the subject level, diurnal IOP percentage change from baseline is constructed as follows:
Obtain percentage differences from baseline for each of the time point-matched IOPs at 
Week 6 (e.g. [(IOP Week 6 09:00 minus baseline IOP 09:00) / baseline IOP)]*100 and 
similarly for the 11:00 time point)
Obtain mean of the percentage changes from baseline at Week 6
The analysis of the difference between the treatment groups with respect to the secondary 
endpoints will be based on the same approach described above for the primary endpoint.
A fixed testing procedure will be used for hypothesis testing of primary and secondary 
endpoints. The secondary efficacy hypotheses will be relevant only if the primary efficacy null 
hypothesis is first rejected at the 5% level (two-sided). The testing order for the secondary 
hypotheses (all based on IOP at Week 6) will be:
Difference between treatments in percentage diurnal IOP change from baseline 
Difference between treatments in diurnal IOP
Difference between treatments in IOP change from baseline at 11:00
Difference between treatments in percentage IOP change from baseline at 11:00
Difference between treatments in IOP change from baseline at 09:00
Difference between treatments in percentage IOP change from baseline at 09:00
Significance for a comparison will be claimed only if the null hypothesis is rejected for the 
previous endpoint in this series.
The primary dataset for the analyses of the secondary endpoints is the Full Analysis Set.
However, the analyses will be repeated using the per protocol set.
2.7.3
Handling of missing values/censoring/discontinuations
For these analyses, missing observations will not be imputed. The statistical models that will 
be employed and the associated analyses are robust under the missing completely at random 
and the missing at random assumptions.
2.8
Safety analyses
The safety assessments in this study are automated perimetry, fundus parameters, best-corrected 
visual acuity (BCVA), slit-lamp exam, blood pressure, pulse rate and adverse events. The safety 
analyses will consist of descriptive summaries of the data as relevant to the scale of data, e.g., 
frequency and percent for adverse events, and mean changes from baseline as appropriate.


Novartis
For business use only
Page 16
SAP Final V 1.0
CQVJ499A2404
Observed values for each continuous variable will be presented descriptively (N, mean, 
standard deviation, median, minimum and maximum) at each visit by treatment group. Change 
from baseline will be summarized similarly. Frequency and percentage of patients will be 
provided for each categorical variable by treatment group.
2.8.1
Adverse events (AEs)
The number of patients reporting any adverse event (AE) and the incidence of each AE will 
be summarized by treatment group. Incidence (frequency and percentages) of all the AEs will 
be presented by: Preferred Term (PT), System Organ Class (SOC) and PT. The adverse events 
will also be presented by severity (Mild; Moderate; Severe) and by relationship (Related; Not 
related) to study treatments.
Adverse events leading to study discontinuation, AEs leading to death and AEs that occurred 
in at least 5% of the patients will be summarized by treatment group and presented by SOC 
and PT, as well as by PT alone. 
Any AE starting after the first dose of study treatments with a missing severity will be 
classified as severe. If a subject reports an AE more than once within that SOC/PT, the AE 
with the worst case severity will be used in the corresponding severity summaries.
Serious adverse events will be summarized by treatment group and presented by SOC and PT, 
as well as by PT alone. Treatement related SAEs will also be reported by SOC and PT.
All the adverse events (SAEs) will be summarized for the following subgroups: Age 
categories (<65, ≥65 years) and (< 50, 50 – 64, ≥ 65); Sex (female, male).
Note: All AEs and SAEs will be summarized by study periods and corresponding listings will 
be provided. Furthermore, listings will be provided for all post-treatment adverse events or 
serious adverse events. A post-treatment event will be defined as any adverse event that 
occurs 30 days post treatment, having been absent during treatment, or worsens relative to 
the treatment state.
2.8.1.1
Adverse events of special interest / grouping of AEs
There are no adverse events of special interest in this study.
2.8.2
Deaths
All on study reported deaths will be summarized by treatment group and a listing will be 
provided.
2.8.3
Laboratory data
No laboratory evaluations will be performed during this study, except urine pregnancy test for 
women of childbearing potential therefore, no laboratory data will be summarized.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Not applicable.
2.8.4.2
Vital signs
Assessment of vital signs will include sitting blood pressure (systolic, diastolic measurement 


Novartis
For business use only
Page 17
SAP Final V 1.0
CQVJ499A2404
in mm Hg) and pulse rate (in beats per minute). These parameters will be measured at 
Screening, Visit 1 (Eligibility 1), Visit 2 (Eligibility 2), Visit 3 (Baseline), Visit 4 (Day 14), 
and Visit 5 (Day 42) / Exit visit.
For the blood pressure (systolic and diastolic blood pressure), two measurements, separated 
by two minutes, will be obtained. If either of the systolic or diastolic readings differ by more 
than 5 mmHg, then a third blood pressure reading should be taken and recorded.
Pulse rate and both mean systolic and mean diastolic blood pressure measurements (sites must
calculate the mean values) will be collected at each visit.
Each value will be categorized as low, normal or high using the normal ranges as in the table 
below. A shift table reporting baseline and post-baseline values at visit will be reported. For 
each vital sign parameter, counts and percentages of subjects who experience any abnormal 
findings during the study will be also presented.
Vital Sign Normal Ranges
Age Range
Vital sign Parameters
Heart Rate
(BPM)
Systolic Blood
Pressure
(mmHg)
Diastolic Blood
Pressure
(mmHg)
All
60 to 100 
100 to 140
60 to 90
BPM = Beats per minute
mmHg = millimeters of mercury
Vital signs summaries will be reported also by age (<65, ≥65 years) and (< 50, 50 – 64, ≥ 65); 
Sex (female, male).
A subject listing will be provided which contains data for each abnormal finding for each 
vital sign parameter. The variables listed will include treatment, investigator number, patient 
number, age, sex, race, ethnicity, visit number for abnormal finding, the actual value, and 
normal range (low/high).
2.8.4.3 Automated Perimetry
Automated perimetry assessment will be conducted at Screening, Visit 1 (Eligibility 1) and 
at and Visit 5 (Day 42) / Exit visit. All visual fields must be reliable at Screening before study 
drug dispensation at Visit 3 (E2).
The counts and percentages of patients with unreliable visual fields at Week 6 will be 
presented overall and by subgroups, such as: age (< 65, ≥ 65, and < 50, 50 - 64, ≥ 65), sex 
(female, male).
A listing will be provided which presents all patients with unreliable visual fields with the 
following variables: treatment, investigator, patient, age, sex, race and ethnicity.
2.8.4.4 Best Corrected Visual Acuity (BCVA)
Visual acuity assessment will be conducted at Screening, Visit 1 (Eligibility 1), Visit 2


Novartis
For business use only
Page 18
SAP Final V 1.0
CQVJ499A2404
(Eligibility 2), Visit 3 (Baseline), Visit 4 (Day 14), and Visit 5 (Day 42) / Exit visit.
Observed values and change from baseline values for the study eye will be presented
descriptively (N, mean, median, standard deviation, standard error, minimum, and maximum)
at each study visit for each treatment. A plot of mean change in BCVA by study visit and by
treatment with error bars representing +/- 1 standard error will be presented using the study 
eye. The x-axis will be study visit and the y-axis will be the change in BCVA from baseline. 
Counts and percentages of subjects who experience pre-specified category of worst change 
from baseline across all post-baseline assessments and category of change from baseline to 
last on-treatment BCVA assessment will be presented according to the following categories: 
≤4 letter decrease or improvement, 5-9 letter decrease, 10-14 letter decrease, ≥15 letter 
decrease. 
For change to any visit, a patient will be counted only in the category that represents their 
worst change from baseline across all post-baseline assessments. A listing will be provided 
which presents all subjects with a ≥10 letter decrease in BCVA from baseline to any visit. 
The listing will include the following variables: treatment, investigator, subject, age, sex, race, 
ethnicity, visit, baseline value, value at the visit and a change from baseline value. All 
summaries will also be reported by age (<65, ≥65 years) and (< 50, 50 – 64, ≥ 65); sex (female, 
male).
2.9
Pharmacokinetic endpoints
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
Not applicable.
2.12
Biomarkers
Not applicable.


Novartis
For business use only
Page 19
SAP Final V 1.0
CQVJ499A2404
 
 
2.14
Interim analysis
No formal interim analysis is planned for this study. 
3
Sample size calculation
With 90 evaluable patients per treatment group in the primary efficacy analysis, there is 
approximately 80% power to detect a difference in mean change from baseline in diurnal IOP 
at Week 6 of 1.5 mmHg between the treatment groups. This calculation is based on the 
assumption of a common standard deviation for mean IOP of 3.5 mmHg and the use of a two-
sample two-sided t-test performed at the α = 0.05 level of significance. 
Assuming a drop-out rate of 10%, approximately 100 patients per treatment group will be 
randomized to ensure the required number of evaluable patients in the final efficacy analysis.
4
Change to protocol specified analyses
The analyses stated above are consistent with the study protocol.


Novartis
For business use only
Page 20
SAP Final V 1.0
CQVJ499A2404
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
In order to impute the missing/partial start or end dates of the study drug, we will first set two  
reference dates: the date of randomization and the end of study visit date. Using these dates, 
the algorithm will be applied as follows:

When the whole study drug start date is missing, the imputed date is the randomization 
date.

When the study drug start day and month are missing, the imputed day and month are 
the randomization day and month.

When the study drug start month is missing, the imputed month is the randomization 
month.

When the study drug start day is missing, the imputed day is the randomization day.

When the whole study drug end date is missing, the imputed the date is the end of 
study visit date.

When the study drug end day and month are missing, the imputed day and month are 
the end of study visit day and month.

When the study drug end month is missing, the imputed month is the end of study visit 
month.

When the study drug end day is missing, the imputed day is the end of study visit day.
5.1.2
AE date imputation
Adverse event end date imputation
When the end date of an adverse event is partial or missing the following algorithm will be 
applied

If the AE end date year is missing or AE is ongoing, the end date will not be imputed

If the AE end date month is missing, the imputed end date should be set to the earliest 
of 31DECYYY or date of death

If the AE end date day is missing, the imputed end date should be set to the earliest of 
the last day of the month or the date of death

If the imputed AE end date is less than the existing AE start date then use AE start 
date as AE
Adverse event start date imputation
When the start date of an adverse event is partial or missing the following algorithm will be 
applied:
Before imputing AE start date, find the AE start reference date.

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).

Else AE start reference date = treatment start date
Impute AE start date -


Novartis
For business use only
Page 21
SAP Final V 1.0
CQVJ499A2404

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.

If the AE start date year value is less than the treatment start date year value, the AE 
started before treatment. Therefore:
o
If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).
o
Else if AE month is not missing, the imputed AE start date is set to the mid-
month point (15MONYYYY).

If the AE start date year value is greater than the treatment start date year value, the 
AE started after treatment. Therefore:
o
If the AE month is missing, the imputed AE start date is set to the year start 
point (01JanYYYY).
o
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).

If the AE start date year value is equal to the treatment start date year value
o
And the AE month is missing the imputed AE start date is set to the AE 
reference start date + 1 day.
o
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).
o
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.
5.1.3
Concomitant medication date imputation
Concomitant medication (CM) end date imputation

If the CM end date year value is missing, the date uncertainty is too high to impute a
rational date. Therefore, if the CM end year value is missing or ongoing, the imputed 
CM end date is set to NULL.

Else, if the CM 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).

If the CM end date day is missing, the imputed end date should be set to the earliest 
of the (treatment follow up period date, last day of the month, date of death).

If the imputed CM end date is less than the existing CM start date, use the CM start 
date as the imputed CM end date.
When the start date of a concomitant medication is partial or missing the following 
algorithm will be applied:

If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date.


Novartis
For business use only
Page 22
SAP Final V 1.0
CQVJ499A2404

If the CM start date year value is less than the treatment start date year value, the CM
started before treatment. Therefore:
o
If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY).
o
Else if the CM month is not missing, the imputed CM start date is set to the 
midmonth point (15MONYYYY).

If the CM start date year value is greater than the treatment start date year value, the 
CM started after treatment. Therefore:
o
If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY).
o
Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY).

If the CM start date year value is equal to the treatment start date year value:
o
And the CM month is missing or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior to treatment 
start date.
o
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). 
o
Else if the CM month is greater than the treatment start date month, the 
imputed CM start date is set to the month start point (01MONYYYY).

If complete (imputed) CM end date is available and the imputed CM start date is 
greater than the (imputed) CM end date, then imputed CM start date should be set to 
the (imputed) CM end date.
5.2
AEs coding/grading
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology . Details regarding MedDRA version will be included in the footnote in the 
tables/listings.
5.3
Laboratory parameters derivations
Not applicable.
5.4
Statistical models
5.4.1
Primary analysis
The methodology is described in Section 2.5
A mixed model repeated measures (MMRM) model
The MMRM model (implemented via SAS procedure MIXED) is used for the analysis of 
change from baseline, in which treatment, visit, and treatment-by-visit interaction will be 
included as fixed-effect factors and baseline sub-scale score as a covariate, with a common 
unstructured covariance matrix (UN). The least squares mean and associated standard error 
for each treatment at each time point will be presented by using LSMEANS statement. Other 


Novartis
For business use only
Page 23
SAP Final V 1.0
CQVJ499A2404
covariance structures such as variance components (VC), compound symmetry (CS), 
autoregressive [AR(1)], and Toeplitz (Toep) will be considered.
Moreover, least squares means, associated two-sided 95% confidence interval and two-sided 
p-value of treatment difference at each time point will be presented as well by using 
ESTIMATE statement.
The SAS syntax is specified as follows:
PROC MIXED DATA  = <input_dataset> ORDER = data;
  CLASS <treat_var> <time_point>;
  MODEL <change> = <treat_var> <time_point> <base_var>
<treat_var>*<time_point>/DDFM =kr SOLUTION;
  REPEATED <time_point>/SUB=<patient>(<treat_var>) TYPE=un;
  LSMEANS <treat_var> <treat_var>*<time_point>/OM;
  ESTIMATE 'Week 2'  <treat_var> 1 -1
                     <treat_var>*<time_point>
1
0
                                                -1
0
/cl;
  ESTIMATE 'Week 6'
<treat_var> 1 -1
                     <treat_var>*<time_point>
0
1
                                                0 -1
/cl;
RUN;
where change
= change from baseline 
treat_var
= treatment group
            base_var   
= baseline sub-scale score
            time_point
= scheduled post-baseline visits (Week 2,6 )            
patient             = patient’s ID
5.5
Rule of exclusion criteria of analysis sets 
Table 1
Protocol deviations that cause subjects to be excluded
Deviation 
ID
Description of Deviation
Exclusion in Analyses
INCL01
Written 
informed 
consent 
not 
obtained prior to study assessments
Excluded from PP analysis
INCL03
Ability to simultaneously wash out 
the effects of non-study IOP lowering 
medications 
according 
to 
the 
following minimum time schedule 
AND 
establish 
a 
Travatan 
monotherapy baseline (Phase I, 
screening/washout period)
Excluded from PP analysis


Novartis
For business use only
Page 24
SAP Final V 1.0
CQVJ499A2404
Deviation 
ID
Description of Deviation
Exclusion in Analyses
INCL04
Mean IOP measurements in at least 1 
eye ≥ 16 and < 22 mmHg at 09:00 
while on a Travatan monotherapy at 
two consecutive visits
Excluded from PP analysis
INCL06
Documented diagnosis of normal 
tension 
glaucoma 
(defined 
as 
glaucomatous optic neuropathy in the 
presence of normal IOP < 22 mmHg).  
Documented optic disk changes, 
visual field deterioration or optical 
coherence 
tomography 
(OCT) 
changes can serve as objective 
markers of damage
Excluded from PP analysis
EXCL01
Use of other investigational drugs 
within 5 half-lives of screening, or 
within 30 days until the expected 
pharmacodynamic effect has returned 
to baseline, whichever is longer
Excluded from PP analysis
EXCL03
Patients 
taking 
medications 
prohibited by the protocol
Excluded from PP analysis
EXCL05
Pregnant 
or 
nursing 
(lactating) 
women
Excluded from PP analysis
EXCL07
Patients with any form of glaucoma 
other than open angle glaucoma in 
either eye.
Excluded from PP analysis
EXCL08
Patients with a central cornea 
thickness < 500 µm and > 600 µm as 
measured by pachymetry in either 
eye.
Excluded from PP analysis
EXCL09
Patients with Schaffer angle Grade < 
2 in either eye, as measured by 
gonioscopy.
Excluded from PP analysis
EXCL12
Chronic, 
recurrent 
or 
severe 
inflammatory eye disease  in either 
eye.
Excluded from PP analysis
EXCL13
Ocular trauma or surgery within the 
past 6 months in either eye; ocular 
infection or laser surgery within the 
past 3 months in either eye
Excluded from PP analysis
EXCL14
Clinically significant or progressive 
retinal 
disease 
such 
as 
retinal 
Excluded from PP analysis


Novartis
For business use only
Page 25
SAP Final V 1.0
CQVJ499A2404
Deviation 
ID
Description of Deviation
Exclusion in Analyses
degeneration, diabetic retinopathy, or 
retinal detachment in either eye
EXCL17
Current or anticipated treatment with 
any psychotropic drugs that augment 
an adrenergic response
Excluded from PP analysis
EXCL18
Concurrent use of a monoamine 
oxidase inhibitor
Excluded from PP analysis
COMD01
Use of prohibited medication during 
the study
Excluded from PP analysis
TRT01
OL Travatan treatment deviation (>3 
consecutive doses missed)
Excluded from PP analysis
TRT01
Masked treatment deviation (>3
consecutive doses missed)
Excluded from PP analysis
Table 2
Subject Classification
Analysis Set
PD ID that
   
cause subjects to be excluded
Non-PD criteria that cause 
subjects to be excluded
ENR
NA
Not having informed consent;
Not having passed the screening phase 
( screening failure) 
RAN
NA
Not randomized
FAS
NA
Not in RAN;
Mistakenly randomized and no double-blind 
study drug taken
PPS
INCL01, INCL03, INCL04,
INCL06, EXCL01, EXCL03,
EXCL05, EXCL07, EXCL08,
EXCL09, EXCL12, EXCL13,
EXCL14, EXCL17, EXCL18, 
EXCL19, COMD01
TRT01
Not in FAS;
Discontinued the study early
SAF
NA
No double-blind study drug taken


Novartis
For business use only
Page 26
SAP Final V 1.0
CQVJ499A2404
6
Reference
1. Armitage P, McPherson CK and Rowe BC (1969). Repeated significance tests on 
accumulating data. J .R. Statist. Soc. A, 132, 232-244. 
2. Clopper CJ and Pearson ES (1934).  The use of confidence or fiducial limits illustrated in 
the case of the binomial.  Biometrical, 26, 404-413.
3. Greenland S, Lanes S and  Jara M (2008). Estimating effects from randomized trials with 
discontinuations: the need for intent-to-treat design and G-estimation. Clinical Trials, 5, 
5–13.
4. Lan KKG, DeMets DL (1983). Discrete sequential boundaries for clinical trials. 
Biometrika, 70, 649-53.
5. Smith B, Vandenhende FR, DeSante KA, Farid NA, Welch PA, Callaghan JT and Forgue 
ST (2000). Confidence Interval Criteria for Assessment of Dose Proportionality. 
Pharmaceutical Research, 17(10), 1278-83.