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
Phase: PHASE4
Conditions: Glaucoma
Sponsor: Novartis Pharmaceuticals

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.