Conditions: Postoperative Ocular Pain After PRK Surgery
Keywords: ocular pain photorefractive keratectomy (PRK) SAF312 corneal epithelial defect
Allocation: NA | Intervention model: CROSSOVER
Enrollment: 40
Healthy volunteers: no

Brief summary:
The purpose of this study is to determine if SAF312 eye drops have an adequate safety and efficacy profile to justify further clinical development for the treatment of ocular pain associated with corneal epithelial defect such as after photorefractive keratectomy (PRK) surgery

Detailed description:

Arms:
arm 1: None arm 2: None

Interventions: intervention 1: SAF312 intervention 2: Placebo
Intervention descriptions: intervention 1: None intervention 2: None

Protocol document:
Prot_000.pdf: 
Novartis Institutes for BioMedical Research
SAF312
Clinical Trial Protocol CSAF312X2201
A randomized, vehicle-controlled, subject and investigator-
masked, proof-of-concept study to evaluate the use of 
topical ocular SAF312 in the treatment of postoperative 
ocular pain in patients undergoing photorefractive 
keratectomy (PRK) surgery
Document type:
Amended Protocol Version
EUDRACT number:
N/A
Version number:
v02 (Clean)
Clinical Trial Phase:
Phase II
Release date:
11-Apr-2017
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Site Operations Manual (SOM)
A Site Operations Manual (SOM) accompanies this protocol, providing the operational details 
for study conduct. Note: The SOM will not be part of the Clinical Study Report.
Notification of serious adverse events
Dear Investigator,
You must report a serious adverse event (SAE) (initial or follow-up) to Novartis as 
summarized below.  Refer to Section 9.2 of the protocol for SAE criteria and additional 
requirements.  See also page 2 of the Site Operations Manual for further details on the method 
of reporting a SAE.

Complete SAE report

Submit SAE report to Novartis Drug Safety and Epidemiology (DS&E) within 24 hours 
after awareness of the SAE

Notify the Novartis Medical Lead

The fax number(s) and email address(es) are located in the Site Operations Manual.


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Table of contents
Notification of serious adverse events.................................................................................2
Table of contents .................................................................................................................3
List of tables ........................................................................................................................6
List of figures ......................................................................................................................6
List of abbreviations............................................................................................................7
Pharmacokinetic definitions and symbols...........................................................................9
Glossary of terms...............................................................................................................10
Protocol synopsis...............................................................................................................18
1
Introduction .......................................................................................................................21
1.1
Background............................................................................................................21
1.2
Nonclinical data.....................................................................................................21
1.2.1
Teratogenicity and reproductive toxicity data.......................................23
1.3
Clinical data...........................................................................................................23
1.3.1
Human safety and tolerability data .......................................................23
1.3.2
Human pharmacokinetic data................................................................25
1.3.3
Human pharmacodynamic data.............................................................25
1.4
Study purpose ........................................................................................................26
2
Study objectives and endpoints .........................................................................................26
2.1
Primary objective(s)...............................................................................................26
2.2
Secondary objective(s)...........................................................................................26
3
Investigational plan ...........................................................................................................27
3.1
Study design...........................................................................................................27
3.2
Rationale of study design.......................................................................................29
3.3
Rationale for dose/regimen, route of administration and duration of treatment....30
3.4
Rationale for choice of comparator .......................................................................32
3.5
Rationale for choice of background therapy..........................................................32
3.7
Risks and benefits..................................................................................................32
3.7.1
Blood sample volumes ..........................................................................34
4
Population..........................................................................................................................35
4.1
Inclusion criteria ....................................................................................................35
4.2
Exclusion criteria...................................................................................................35
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5
Restrictions for Study Subjects .........................................................................................37
5.1
Contraception requirements...................................................................................37
5.2
Prohibited treatment...............................................................................................38
5.3
Dietary restrictions and smoking...........................................................................38
5.4
Other restrictions ...................................................................................................38
6
Treatment...........................................................................................................................39
6.1
Study treatment......................................................................................................39
6.1.1
Investigational treatment and control drugs..........................................39
6.1.2
Additional study treatment....................................................................39
6.2
Treatment arms ......................................................................................................40
6.3
Treatment assignment and randomization.............................................................40
6.4
Treatment blinding.................................................................................................40
6.5
Treating the subject................................................................................................41
6.6
Permitted dose adjustments and interruptions of study treatment.........................41
6.7
Emergency breaking of assigned treatment code ..................................................42
6.8
Treatment exposure and compliance .....................................................................42
6.9
Recommended treatment of adverse events ..........................................................43
6.10
Rescue medication.................................................................................................43
6.11
Concomitant treatment...........................................................................................43
7
Study completion and discontinuation ..............................................................................44
7.1
Study completion and post-study treatment ..........................................................44
7.2
Discontinuation of study treatment........................................................................44
7.3
Withdrawal of informed consent ...........................................................................45
7.4
Lost to follow-up ...................................................................................................46
7.5
Study Stopping rules..............................................................................................46
7.6
Early study termination by the sponsor .................................................................46
8
Procedures and assessments ..............................................................................................47
8.1
Assessment schedule .............................................................................................47
8.2
Informed consent procedures.................................................................................53
8.3
Subject screening...................................................................................................53
8.4
Subject demographics/other baseline characteristics.............................................53
8.4.1
Drug screen ...........................................................................................54
8.5
Efficacy / Pharmacodynamics ...............................................................................54
8.5.1
VAS (Visual Analog Scale) pain assessment........................................54
8.5.2
Oral analgesics use................................................................................54
8.5.3
Patient diary ..........................................................................................54


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8.6
Safety.....................................................................................................................54
8.6.1
Body temperature..................................................................................54
8.6.2
Blood Pressure and Pulse Rate..............................................................54
8.6.3
Blink Rate..............................................................................................54
8.6.4
Visual acuity..........................................................................................54
8.6.5
Slit lamp biomicroscopy .......................................................................55
8.6.6
Intraocular Pressure (IOP).....................................................................55
8.6.7
Dilated fundus exam .............................................................................55
8.6.8
Ocular hyperemia..................................................................................55
8.7
Pharmacokinetics...................................................................................................55
8.8
Other assessments..................................................................................................56
8.8.1
Ocular assessments................................................................................56
8.8.2
Corneal Staining....................................................................................56
9
Safety monitoring ..............................................................................................................57
9.1
Adverse events.......................................................................................................57
9.2
Serious adverse event reporting.............................................................................59
9.2.1
Definition of SAE .................................................................................59
9.2.2
SAE reporting........................................................................................60
9.3
Reporting Medication errors including misuse/abuse ...........................................60
9.4
Pregnancy reporting...............................................................................................61
9.5
Early phase safety monitoring ...............................................................................62
10 Data review and database management.............................................................................62
10.1
Site monitoring ......................................................................................................62
10.2
Data collection.......................................................................................................63
10.3
Database management and quality control............................................................63
10.4
Data Monitoring Committee..................................................................................64
10.5
Adjudication Committee........................................................................................64
11 Data analysis......................................................................................................................64
11.1
Analysis sets ..........................................................................................................64
11.2
Subject demographics and other baseline characteristics......................................64
11.3
Treatments .............................................................................................................64
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11.4
Analysis of the primary variable(s) .......................................................................65
11.4.1
Variable(s).............................................................................................65
11.4.2
Statistical model, hypothesis, and method of analysis..........................65
11.4.3
Handling of missing values/censoring/discontinuations.......................65
11.4.4
Sensitivity analyses ...............................................................................66
11.5
Analysis of secondary variable(s)..........................................................................66
11.5.1
Efficacy / Pharmacodynamics...............................................................66
11.5.2
Safety.....................................................................................................66
11.5.3
Pharmacokinetics ..................................................................................67
11.5.4
Pharmacokinetic / pharmacodynamic interactions................................67
11.5.5
Other assessments .................................................................................67
11.7
Sample size calculation..........................................................................................68
11.8
Power for analysis of key secondary variables......................................................69
12 Ethical considerations........................................................................................................70
12.1
Regulatory and ethical compliance........................................................................70
12.2
Responsibilities of the investigator and IRB/IEC..................................................70
12.3
Publication of study protocol and results...............................................................70
13 Protocol adherence ............................................................................................................70
13.1
Protocol Amendments ...........................................................................................71
14 References .........................................................................................................................72
List of tables
Table 6-1
Overview of study medication ..............................................................39
Table 6-2
Definition of treatment sequences.........................................................40
Table 6-3
Blinding levels ......................................................................................41
Table 8-1
Details for highly repetitive assessments ..............................................52
Table 9-1
Summary of reporting requirements for medication errors...................61
List of figures
Figure 3-1
Study schedule ......................................................................................29
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List of abbreviations
AE
adverse event
AK
anterior keratectomy
b.i.d.
twice a day
BMI
Body Mass Index
CD-ROM
compact disc – read only memory
CFR
Code of Federal Regulation
COAR
Clinical Operations, Analytics & Regions
CRF
Case Report/Record Form (paper or electronic)
CRO
Contract Research Organization
CV
coefficient of variation
EC
Ethics committee
ECG
Electrocardiogram
EDC
Electronic Data Capture
ePRO
electronic Patient Reported Outcomes
FDA
Food and Drug Administration
GCP
Good Clinical Practice
h
hour
IB
Investigator's Brochure
ICH
International Conference on Harmonization of Technical Requirements for 
Registration of Pharmaceuticals for Human Use
IEC
Independent Ethics Committee
IOP
Intraocular pressure 
IRB
Institutional Review Board
IRT
Interactive Response Technology
LLQ
lower limit of quantification
MedDRA
Medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
OPAS
Ocular Pain Assessment Survey
OU
Both eyes (study eye and fellow eye)
PD
pharmacodynamic(s)


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PK
pharmacokinetic(s)
PRK
photorefractive keratectomy
SAE
serious adverse event
SAP
Statistical analysis plan
SD
standard deviation
SE
Study eye
SOM
Site Operations Manual
SUSAR
Suspected Unexpected Serious Adverse Reactions
t.i.d.
three times a day
VAS
Visual analog scale 
WHO
World Health Organization


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Pharmacokinetic definitions and symbols
AUC0-t
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to time 't' where t is a defined time point after administration [mass 
x time / volume]
AUCinf
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to infinity [mass x time / volume]
AUClast
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the time of the last quantifiable concentration [mass x time / 
volume]
AUCtau
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau [mass x time / volume]
AUCtau,ss
The area under the plasma (or serum or blood) concentration-time curve from 
time zero to the end of the dosing interval tau at steady state [mass x time / 
volume]
Clast 
The last observed quantifiable concentration [mass / volume]
Cmax
The observed maximum plasma (or serum or blood) concentration following 
drug administration [mass / volume]
Cmin 
The lowest concentration observed during a dosing interval.  Cmin can occur 
at 0 hours (pre-dose) or at the end of a lag-phase or at the end of the dosing 
interval if no lag-phase exists. [mass / volume]
Cmin,ss
The lowest plasma (or serum or blood) concentration observed during a 
dosing interval at steady state [mass / volume]
Racc
The accumulation ratio
T1/2
The terminal elimination half-life [time]
Tlast 
The time point that corresponds to the last measurable concentration [time]
Tmax
The time to reach the maximum concentration after drug administration [time]


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
Any drug (an active drug or an inactive drug, such as a placebo) 
which is used as a comparator to the investigational drug being tested 
in the trial
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 
100 mg once a day, 75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent 
must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Epoch
Interval of time in the planned conduct of a study. An epoch is 
associated with a purpose (e.g. screening, randomization, treatment, 
follow-up), which applies across all arms of a study.
Healthy volunteer
A person with no known significant health problems who volunteers 
to be a study participant 
Investigational drug
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and Directive 
2001/20/EC and is synonymous with “investigational new drug” or 
“test substance”
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the 
study as well as their associated treatment controls. This includes any 
placebos, any active controls, as well as approved drugs used outside 
of their indication/approved dosage or tested in a fixed combination. 
Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed 
by the protocol when used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies 
that dispense study drug using an IRT system.
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any 
background therapy administered to each of the clinical trial subjects, 
regardless of randomization group, rescue medication, active drug 
run-ins etc.)
Part
A single component of a study which contains different objectives or 
populations within that single study. Common parts within a study 
are: a single dose part and a multiple dose part, or a part in patients 
with established disease and in those with newly-diagnosed disease.
Patient
An individual with the condition of interest


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Period
A minor subdivision of the study timeline; divides phases into 
smaller functional segments such as screening, baseline, titration, 
washout, etc.
Premature subject 
withdrawal
Point/time when the subject exits from the study prior to the planned 
completion of all study drug administration and assessments; at this 
time all study drug administration is discontinued and no further 
assessments are planned.
Randomization 
number
A unique identifier assigned to each randomized subject, 
corresponding to a specific treatment arm assignment
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with 
major study milestones such as enrollment, randomization, 
completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or 
when study drug was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any 
reason; may or may not also be the point/time of premature subject 
withdrawal.
Study drug/treatment
Any drug (or combination of drugs) administered to the subject as 
part of the required study procedures; includes investigational drug, 
active drug run-ins or background therapy.
Study treatment
Any drug administered to the study participants as part of the 
required study procedures; includes investigational drug (s), 
control(s) or non-investigational medicinal product(s)
Study treatment 
discontinuation
When the subject permanently stops taking study treatment prior to 
the defined study treatment completion date
Subject
A trial participant (can be a healthy volunteer or a patient)
Subject number
A unique number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the 
subject and should be used to identify the subject throughout the 
study for all data collected, sample labels, etc.
Treatment number
A unique identifier assigned in non-randomized studies to each dosed 
subject, corresponding to a specific treatment arm 
Variable
A measured value or assessed response that is determined in specific 
assessments and used in data analysis to evaluate the drug being 
tested in the study


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Withdrawal of 
consent (WoC)
Withdrawal of consent from the study is defined as when a subject 
does not want to participate in the study any longer, and does not 
want any further visits or assessments, and does not want any further 
study related contact, and does not allow analysis of already obtained 
biologic material


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Protocol synopsis
Protocol 
number
CSAF312X2201
Title
A randomized, vehicle-controlled, subject and investigator-masked, proof-of-
concept study to evaluate the use of topical ocular SAF312 in the treatment of 
postoperative ocular pain in patients undergoing photorefractive keratectomy 
(PRK) surgery
Brief title
Study of SAF312 as an eye drop for treatment of eye pain following 
photorefractive keratectomy (PRK) surgery
Sponsor and 
Clinical Trial 
Phase
Novartis
Phase II
Intervention 
type
Drug
Study type
Interventional 
Purpose and 
rationale
The purpose of this study is to determine if SAF312 
 eye drops four times 
daily has an adequate safety and efficacy profile to justify further clinical 
development for the treatment of ocular pain associated with corneal epithelial 
defect such as after PRK surgery
Primary 
Objective(s)
To evaluate pain control in the immediate post-operative period.
Secondary 
Objectives
To evaluate the efficacy of SAF312 eye drops for reducing use of oral analgesics 
following PRK procedure.  To assess safety and tolerability of SAF312 eye drops 
four times daily. 
To evaluate pain severity post-operatively.
To assess the systemic exposure after ocular dosing of SAF312 
 eye drops 
four times daily at various time points in PRK patients.
Study design
This is a proof-of-concept, subject and investigator-masked, randomized, vehicle 
controlled study of SAF312 administered as eye drops in add ition to standard of 
care treatment in patients after photorefractive keratectomy (PRK) surgery. 
Patients will be randomized to two sequences: 1) SAF312, followed by placebo, or 
2) placebo, followed by SAF312. Each patient will receive the assigned dose fo ur 
times daily for 72 hours following PRK surgery on their study eye (Day 1, 
Periods 1 and 2).  The initial study eye will be the non -dominant eye as 
established at screening and in agreement of the patient and the PI. Each patient will 
return for follow-up visits on Days 2, 3, 4 and 8 after surgery of Periods 1 and 2.
Population
Approximately 40 male and female patients who are eligible for PRK surgery and 
between 18 and 75 years old (inclusive). 
Key Inclusion 
criteria

Male and female patients age 18 to 75 who are eligible for bilateral PRK 
surgery.

Normal eye exam except for refractive error at baseline.

Planned myopia correction should not exceed -4.00 Diopters (sphere) and 
3.00 diopters of astigmatism, with spherical equivalent not higher than -4.50, 
confirmed by manifest refraction at baseline. Monovision treatment is allowed.


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Key Exclusion 
criteria

Monocular patient (including amblyopia) or best corrected visual acuity score 
worse than 20/80 (Snellen), or 55 letters (EDTRS), at baseline.

Any systemic or ocular disease that might affect wound healing (such as 
severe rheumatoid arthritis or diabetes or history of keloid formation) or a 
history of ocular trauma, uveitis, infection, or inflammation in the 6 months 
prior to baseline.  Patients with mild, well controlled diabetes with no evidence 
of ocular or systemic complications of diabetes can be included.

Patients with active inflammatory or infectious ocular conditions, severe or 
progressive retinal disease, and use of topical or systemic steroids, or use of 
coumadin or similar drugs within the last 6 months prior to baseline.

Patients with any corneal dystrophy (epithelial, stromal or endothelial) or any 
cornea disease (including significant scarring, ocular herpes or pterygium).

Previous refractive or corneal surgery (such as LASIK, PRK, radial 
keratotomy, pterygium removal, corneal transplantation).

History of allergic or hypersensitivity reaction or significant adverse events to 
any of the drugs to be used in this study including: 

tetracaine or similar topical ocular anesthetic

NSAIDs and aspirin

oral analgesic (including acetaminophen and codeine)

antibiotics

steroids

inability to tolerate or wear bandage contact lens

Chronic pain of any etiology or any significant illness which has not resolved 
within two (2) weeks prior to initial dosing.

Concurrent therapy or history of chronic therapy or abuse of systemic or 
ocular NSAIDs, analgesics, pain medication (including gabapentin or 
pregabalin and similar), opiates or cannabis. Patients with use of any topical 
eye medication except for lubricating eye drops within two weeks prior to 
surgery, in the study eye will be excluded. Patients with any use of topical or 
systemic NSAIDs during the 30 days before the study, or use of Restasis®
within the 3 months prior to surgery will also be excluded.

History of drug abuse or unhealthy alcohol use within the 12 months prior to 
dosing. Unhealthy alcohol use is defined as a history of, or current alcohol 
misuse/abuse, defined as “Five or more drinks on the same occasion on each 
of 5 or more days in the past 30 days."

Subjects using CPAP or other sleep apnea devices.

Subjects who do not weigh at least 50 kg, or who do not have a body mass 
index (BMI) within the range of 18 - 35 kg/m2. BMI = Body weight (kg) / 
[Height (m)]2

Pregnant or nursing (lactating) women.
Study treatment
SAF312 and placebo, multiple topically delivered doses
Efficacy/PD 
assessments
Visual Analog Scale (VAS) for pain

Incidence of and amount (mg/kg of body weight) of rescue oral analgesics 
needed in each treatment period


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Key safety 
assessments

Adverse event monitoring - AEs and SAEs

Vital sign monitoring (blood pressure, pulse rate, and body temperature)

Ocular exam and assessment results

Epithelial defects

Tear production

Blink rate

Size of epithelial defect by slit lamp exam

Ocular hyperemia

Dilated fundus exam

Intraocular pressure (IOP)

Visual acuity
Other 
assessments
Data analysis
The primary efficacy analysis will assess the effect of SAF312 eye drops on the 
pain visual analog scale (VAS) pain assessment prior to the 6 hour dose 
post-operatively compared to vehicle, and the average ocular pain VAS 
assessments from the first post-operative assessment up to the pre-dose 12 hour 
post-operative assessment compared to vehicle. The secondary efficacy analysis 
will assess the effect of SAF312 
 eye drops on whether patients need oral 
analgesics in 24 hours, 2 days, and 3 days post-operatively compared to vehicle, 
as well as the amount of oral analgesics needed in 12 hours, 24 hours, 2 days, 
and 3 days post-operatively compared to vehicle.
Key words
SAF312, proof-of-concept, efficacy, ocular pain, photorefractive keratectomy, PRK
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1
Introduction
1.1
Background
SAF312, a potent inhibitor of the transient receptor potential cation channel subfamily V 
member 1 (TRPV1), is currently in development as topical ocular eye drops for the treatment 
of post-operative pain after photorefractive keratectomy (PRK).
In the oral administration program, SAF312 was evaluated in a total of four clinical studies 
(SAD, MAD, PoC for post-operative dental pain and PoC for neurogenic detrusor overactivity 
due to spinal cord lesions). The development of oral SAF312 did not progress because of 
dose-dependent inhibition of noxious heat pain perception.
In the Proof of Concept study of SAF312 for postoperative pain after PRK the dose of 1 drop 
of SAF312 
 4 times daily for 3 days will be used, as this was estimated as the therapeutic 
dose and provides a margin of safety from the MTD that was at the same drug concentration 
but at 8 times daily for 7 days. Pain after PRK is currently partially treated with Non-Steroid-
Anti-Inflammatory (NSAID) or diluted anesthetic ocular drops; both groups of drugs have the 
side effect of delaying wound healing. 
 
 
There is an unmet medical need for pain control using a topical ocular drug that does 
not delay wound healing.
The most relevant data for the present study are summarized in the sections below. 
For detailed information, please refer to the IB.
1.2
Nonclinical data
SAF312 is a selective, non-competitive, reversible inhibitor of TRPV1 channels. SAF312 
inhibited capsaicin, low pH and anandamide stimulation of human TRPV1 with IC50 values of 
12, 5, and 10 nM, respectively. Characterization of the selectivity of SAF312 resulted in no 
activity of >50% inhibition at 10 μM being observed for a total of 278 GPCRs, transporters, 
ion channels, nuclear receptors and enzymes. SAF312 was highly selective versus other TRP 
channel family members and had no activity against estrogen receptors. SAF312 exhibits 
pharmacodynamic activity in acute and long lasting inflammatory hyperalgesia nonclinical 
models. SAF312 showed sustained analgesic properties upon repeated oral dosing. 
Recent evidence has indicated a link between TRPV1 inhibition and hyperthermia, and this 
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was confirmed for SAF312 in clinical studies. However, topical dosing in the eye will limit 
systemic effects of SAF312 while achieving inhibition of corneal TRPV1.
Accumulating data indicates a primary role for TRPV1 in ocular pain. TRPV1 is expressed in 
several corneal cell types in humans including the corneal epithelium, stroma and 
endothelium (Zhang et al 2007, Yang et al 2013a, Mergler et al 2010) and also has been 
localized to the ophthalmic branch of trigeminal nerve endings in the mouse cornea 
(Bates et al 2010). A role for TRPV1 in neurogenic pain in the cornea may be assumed given 
the co-localization of TRPV1 with substance P and calcitonin-gene-related peptide (CGRP) 
receptor in rat corneal neurons (Murata and Masuko 2006) and by the fact that TRPV1 
agonists can trigger release of tachykinins (reviewed in Yang et al 2013b).
The role of TRPV1 in wound healing in the eye is complex. TRPV1 knockout mice were 
reported to have reduced corneal epithelial migration and proliferation following epithelial 
debridement (Sumioka et al 2014). However, homozygous TRPV1 knockout mice were 
reported to have reduced inflammation and fibrosis in a mouse corneal wound healing model 
(Okada et al 2011). Additionally, treatment with a TRPV1 agonist topically on the cornea, 
which ablated TRPV1-expressing corneal neurons, had an analgesic effect without damaging 
the cornea or impairing corneal wound healing in mice (Bates et al 2010), suggesting that loss 
of TRPV1 activity reduces pain sensation and does not affect wound healing. 
Moreover, TRPV1 activation by hypertonic stress in human corneal epithelial cells induced 
the release of inflammatory cytokines (Pan et al 2011). These studies clearly show a role for 
TRPV1 in corneal nociception and inflammatory responses in the cornea. Expression of 
TRPV1 has been confirmed in the human cornea epithelium and stroma and in corneal nerves.
Overall, there is a well-validated role for TRPV1 in corneal nociception. SAF312 is a potent 
antagonist of TRPV1 that achieves therapeutic levels in the cornea following topical 
administration. Unlike steroids or NSAIDS, topical treatment of SAF312 did not affect the 
rate of corneal wound healing. It is expected that topical ocular dosing of SAF312 will result 
in minimal systemic exposure, below that associated with heat perception and hyperthermia, 
while preferentially targeting TRPV1 in the corneal nerve to reduce postoperative pain 
associated with PRK.
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1.3
Clinical data
1.3.1
Human safety and tolerability data
 The most frequent ocular adverse events in the SAF312 treated 
patients were corneal staining, hyperemia and mild anterior chamber inflammation, in levels 
similar to placebo (refer to Investigator's Brochure for details).
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For oral SAF312, 
 
 A total of 379 subjects 
 
have been exposed to study medication (271 of those to SAF312). 
 
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1.4
Study purpose
To determine if SAF312 
 eye drops four times daily has an adequate safety and efficacy 
profile to justify further clinical development for the treatment of ocular pain associated with 
corneal epithelial defect such as after PRK surgery.
2
Study objectives and endpoints
2.1
Primary objective(s)
Primary objective(s)
Endpoints related to primary objective(s)

To evaluate pain control in the 
immediate post-operative 
period.

Visual analog scale (VAS) pre-dose pain assessment 
at 6 hours post-operatively

Average ocular pain VAS assessments from the first 
post-operative assessment up to the pre-dose 12 hour 
assessment
2.2
Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To evaluate the efficacy of 
SAF312 
 eye drops four 
times daily for reducing use of 
oral analgesics following PRK 
procedure 

Incidence of and amount of rescue oral analgesics 
needed in 12 hours, 24 hours, 2 days, and 3 days 
post-operatively after each PRK surgery.

To assess safety and 
tolerability of SAF312 
 
eye drops four times daily

AEs and SAEs

Visual acuity, intraocular pressure (IOP), dilated 
fundus exam, ocular hyperemia

Size of epithelial defect by slit lamp exam

Blink rate, tear production, 

Vital signs (blood pressure, pulse rate, and body 
temperature)

To evaluate pain severity post-
operatively

All VAS measurements during the first 3 days after 
surgery

To assess the systemic 
exposure after ocular dosing of 
SAF312 
 eye drops four 
times daily at various time 
points in PRK patients

Plasma concentration of SAF312


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3
Investigational plan
3.1
Study design
This is a proof-of-concept, subject and investigator-masked, randomized, vehicle controlled 
study of SAF312 administered as eye drops in addition to standard of care treatment in 
patients after photorefractive keratectomy (PRK) surgery. PRK surgery is performed as an 
outpatient procedure under topical anesthesia with removal of the corneal epithelium to 
expose the stroma for the laser ablation, as described in the SOM. SAF312 dosing will be as 
single eye drop of 
 suspension 
, administered four times daily (every six 
hours) in one eye from immediate post-op (time 0) to last dose at 72 hours.
Each patient, if eligible, will participate in this 2 treatment period, cross over study. 
Patients will undergo PRK surgery on 2 separate occasions (periods), one eye at a time. 
Patients will be randomized to receive SAF312 or vehicle following procedure 1 and the 
alternate following procedure 2 (Figure 3-1).  Patients and investigator site staff will remain 
masked to treatment.  Sponsor staff will be unmasked for evaluation of adverse events and for 
interim analysis, as detailed in Section 6.4. 
SAF312 has been shown to be safe in humans with intact corneas (CSAF312X2101 study). 
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Approximately 40 patients will be randomized to two sequences to achieve about 
30 evaluable patients: 1) SAF312, followed by placebo (n=20, or 2) placebo, followed by 
SAF312 (n=20. Each patient will receive the assigned dose, one drop four times daily for 72 
hours following PRK surgery on their study eye (Day 1, Periods 1 and 2).  The initial study 
eye will be the non-dominant eye as established at screening and in agreement of the patient 
and the PI. Each patient will return for follow-up visits on Days 2, 3, 4 and 8 of Period 1 after 
surgery in the first eye, with optional daily visits to follow the patient until wound healing is 
complete. If there is any complication or any reason to not have surgery in the second eye, the 
patient will not have the second eye surgery performed.
Patients will have PRK surgery on their second study eye (dominant eye) on Period 2, Day 1.  
The PRK surgery of the second eye should be performed after the epithelial defect of the first 
eye is resolved and at the discretion of the PI.  After the second PRK, patients will receive the 
opposing treatment four times daily for 72 hours following the PRK surgery.  Patients will 
return daily for the first 3 postoperative days (Period 2, Days 2-4) and at 1 week after the 
second surgery (Period 2, Day 8), with optional daily visits to follow the patient until wound 
healing is complete. An end of study (EOS) visit will take place 30 days after the second eye 
surgery (or after final dose of investigational product if the patient ends treatment early in 
period 1).  To allow flexibility for scheduling the day of the second surgery, the day of the 
second PRK procedure (start of Period 2) may be as soon as Day 8 assessments are complete, 
or as long as six weeks after the first surgery.
All patients will receive standard of care treatment following PRK surgery, including 
application of a bandage contact lens (Air Optix® Night and Day® Aqua or equivalent) 
following the procedure and before receiving study drops for pain. A course of topical ocular 
antibiotic (Moxifloxacin or equivalent 1 eye drop four times daily) will be started after 
application of first dose of study drops and will be continued for 4-7 days. Prednisolone 
acetate ophthalmic 1 eye drop four times daily will be given for 1 week after PRK, followed 
by taper. Preservative-free unit-dose artificial tears may be used as needed.  The first dose of 
study drops after each PRK procedure will be administered by site staff. Subsequent doses 
will be self-administered. Whenever drops are administered in sequence, at least 5 minutes 
must pass between eye drop administrations. To summarize, patients will undergo PRK 
procedure, bandage lens is placed on the cornea, SAF312 or placebo is given, after 
approximately 5 minutes antibiotic is given, and after another 5 minutes, prednisolone is 
administered. Detailed administration and assessment timing will be included in a table in the 
SOM.
Rescue medication will consist of oral analgesic (acetaminophen 300 mg + codeine 30 mg) as 
needed up to a total of 10 tabs/day or 1-2 tabs every 4 hours.
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Figure 3-1
Study schedule
After at least 10 patients have had PRK surgery and study treatment for 72 hours in both eyes 
(completing Period 2, Day 4 visit), enrollment may be paused for an interim analysis (IA).  
Please see Section 11.9 for details.
3.2
Rationale of study design
The rationale for the key elements of the study design are as follows:

Bilateral cross-over design with interim analysis: Cross-over design may be helpful in 
decreasing inter-patient variability because of different pain tolerance in different 
individuals. Capturing data from both eyes, in conjunction with an interim analysis after at 
least 10 evaluable patients (20 eyes) allows for an adjustment in the number of patients 
required to enable the decision to complete the study. There are no prior PRK pain studies 
with bilateral design, only with unilateral surgery, since unilateral PRK was the standard 
of care several decades ago when these studies were performed (in contrast to today's 
standard of bilateral simultaneous PRK). So, the interim analysis will estimate the inter-
subject and intra-subject variability to confirm the power calculations for the whole study, 
and the sample size may be adjusted accordingly.

Primary Endpoint (Electronic Patient Reported Outcome (ePRO) Visual Analog 
Scale (VAS) pain scale): A validated electronic tool was selected to enable collection of 
sequential data.  Previous studies of pain in PRK have shown that the most intense pain is 
experienced within the first 12 hours after surgery with the peak around 4-6 hours after 
surgery (Sher et al 1993), and these are the timepoints selected for primary endpoint 
analysis. Since we cannot be sure exactly when pain will be experienced by our patients in 
this study, and also it is important clinically to both try to decrease the maximum pain as 
well as the overall pain that the patient experiences during the immediate postoperative 
period, we decided to evaluate both 6 hours and the period up to 12 hours postoperatively, 
as primary endpoints.


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
Rescue oral analgesics: It is not ethical to refuse pain control medication to patients 
postoperatively as part of a clinical trial, and all prior clinical trials of NSAIDs in 
postoperative pain after PRK used rescue oral analgesics, similar to the Standard of care 
after PRK. This can be a potential confounder of the pain VAS evaluation. We plan to use 
three approaches when analyzing pain VAS scores to account for the influence of pain 
meds (assuming 4 hours of rescue medication effect): (1) any recorded VAS score within 
4 hours after use of rescue medication will be considered missing; (2) all the recorded 
VAS scores will be used; and (3) any recorded VAS scores within 4 hours after rescue 
medication use will be imputed by the record taken prior to the rescue medication. 
We will use the first approach as the primary analysis, and the other two for help with 
decision making.

Randomization and Masking (Patient and investigator masked): Minimizes bias of 
investigators or subjects in assessing subjective readouts, such as adverse events or 
perception of pain (primary endpoint).

Patient population: PRK is a common procedure with approximately 37,000 surgeries 
performed in the US in 2014 (http://www.statista.com/statistics/271478/number-of-lasik-
surgeries-in-the-us/). The patient population is relatively homogeneous (usually under 
45 years of age), with healthy corneas and eyes.  The procedure results in a controlled, 
large, epithelial defect of 8mm with a consistent healing time of 3 to 4 days.  
Resultant pain is moderate to severe (especially the first day), often requiring oral 
narcotics or other pain killers.  Pain after PRK is currently partially treated with 
Non-Steroid-Anti-Inflammatory (NSAID) or diluted anesthetic ocular drops; both groups 
of drugs have a side effect of delaying wound healing. There is no animal model for ocular 
pain control; however SAF312 when tested in an animal model of PRK in rabbits did not 
delay wound healing.  Further, TRPV1 antagonists in mice and TRPV1 knock out mice 
showed no delayed corneal epithelial healing after injury (Okada et al 2011; 
Bates et al 2010).  There is an unmet medical need for pain control using a topical ocular 
drug that does not delay wound healing.
3.3
Rationale for dose/regimen, route of administration and duration 
of treatment
SAF312 is a potent inhibitor of the transient receptor potential cation channel subfamily V 
member 1 (TRPV1). Oral SAF312 was effective in dental pain, but the development of oral 
SAF312 did not progress because of dose-dependent inhibition of noxious heat pain 
perception. SAF312 was developed as a topical ocular formulation for the treatment of ocular 
pain from corneal epithelial defect such as after PRK surgery. After PRK surgery the pain is 
the most intense during the first day after surgery and after the 3rd day (72 hours) it is much 
less, and at a level were topical ocular NSAIDs have no beneficial effect compared to placebo 
(Sher et al 1993). So, the duration of treatment with SAF312 after PRK surgery in the PoC 
study, is planned for 3 days (72 hours) after surgery.
C
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In this PoC study we plan to use the topical ocular dose of a single eye drop of 
 
suspension, administered four times daily to a single 
eye 
 
 
 
 
 
 
The proposed total daily dose of 3.7 mg of SAF312 from topical ocular 4 -times daily 
administration of a single eye drop of 
 suspension 
 dose is 13.5 -fold 
lower than the total daily oral dose of 50 mg (from 25 mg twice daily dose regimen) which is 
the lowest dose at which impaired heat perception was reported in humans.  
Preliminary assessment of exposure data in humans indicates relative bioavailability of 
 suspension topical ocular dose compared to 25 mg oral dose, 
therefore, lower systemic exposures are anticipated from the proposed ocular dose than the 
oral dose.
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3.4
Rationale for choice of comparator
Vehicle eye drops will be used as a placebo to mask and compare efficacy and enable better 
determination of the relation of any observed ocular adverse events to SAF312.
3.5
Rationale for choice of background therapy
Current standard of care treatment after PRK include bandage contact lens, antibiotic, steroid 
anti-inflammatory, preservative-free artificial tears as well as oral and topical pain control 
medication, as per each surgeons preferences (Woreta et al 2013). In the current study, we 
keep all the parts of the standard of care treatment after PRK, with the exception of replacing 
topical ocular pain control medication with either SAF312 or placebo, but keeping oral pain 
control rescue medication in place to allow pain control and relief for the patient.
3.7
Risks and benefits
There is no benefit expected for subjects participating in this study. If SAF312 is shown in the 
future to provide superior analgesic effect compared to current standard of care (NSAIDs or 
diluted topical anesthetic), the patient may experience better analgesia postoperatively during 
the period treated with SAF312 (but not during the vehicle-treated period), but at present there 
is no information available on analgesic effect of SAF312.
The risk to subjects in this trial will be minimized by adherence to the eligibility criteria, close 
clinical monitoring, continuous monitoring of masked emerging safety and tolerability data 
and stopping rules.
Potential risks associated with SAF312 (please note different risk profile for topical ocular 
versus oral systemic administration)
Topical Ocular SAF312
 
 

Ocular safety and tolerability was excellent without dose limiting adverse events. 
All dose cohorts in the single and multiple ascending parts of the study, 
 
 showed no dose limiting adverse events and the
maximum feasible concentration 
 is accepted in the maximum tolerated dose 
 
 All adverse events of suspected causality to SAF312 were 
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of mild severity, except for moderate severity eye irritation that lead to discontinuation of 
treatment in one patient of the
 cohort. The most frequent ocular 
adverse events in the SAF312 treated patients were corneal staining, hyperemia and mild 
anterior chamber inflammation, in levels similar to placebo (more details in the 
Investigators Brochure).

Systemic safety and tolerability of ocular SAF312 was excellent without dose limiting 
adverse events, including no evidence of risks identified with oral SAF312. 
 
Oral systemic SAF312 compound specific risks based on clinical safety and tolerability are:

Impaired temperature perception/sensation neurologic risk. The most commonly 
reported AEs in subjects dosed with SAF312 were transient sensation of cold and chills. 
At the highest tested single doses (800 and 1050 mg) some prolonged sensory neurologic 
changes with intact sensory and motor nerve conduction were observed. However, this 
risk is negligible as the dose used in this study is much lower. Dose-dependent changes in 
thermal perception (noxious heat) were noted as assessed by the “hand immersion test”
(water at 49°C) as part of the multiple dose study and in the dental pain study. 
Altered thermal perception was dose-dependent and a dose of 12.5 mg or 15 mg lacked 
relevant effects on heat pain perception.  Based on the data it is concluded that doses of
15 mg SAF312 or less allow for outpatient studies. In order to prevent potential injuries 
resulting from altered thermal perception a series of precautionary measures are 
implemented in all future clinical studies of oral SAF312.

Autonomic dysreflexia in patients with spinal cord injury. One of the two patients 
treated with oral SAF312 for neurogenic detrusor overactivity due to spinal cord lesions 
developed circulatory collapse, headache, nausea, vomiting, and temperature regulation 
disorder as part of autonomic dysreflexia. Patients with an impaired autonomous nerve system 
(e.g. as consequence of spinal cord injury) may have a higher risk for developing autonomic 
dysreflexia and should not be treated with SAF312 or other TRPV1 receptor inhibitors.
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
Hyperthermia. Transient increases in body temperature were observed in subjects dosed 
with SAF312 and these were generally not associated with clinically relevant changes in 
blood pressure or pulse. At repeat doses of 25 mg a mild transient elevation in body 
temperature was observed and at 12.5 mg SAF312 all reported body temperatures were 
within the normal range.

QT interval shortening. The clinical studies performed with SAF312 demonstrated 
transient shortening of the QT interval; none of the QT interval changes was symptomatic 
or associated with clinically relevant arrhythmias (ventricular or supraventricular). 
The lowest QTcF value noted during the single oral dose study was 342 milliseconds (ms) 
and was observed on day 1 at 1-2 hours post-dosing in one subject in each of the three 
different dosing groups (i.e., 7.5, 125 and 1050 mg). The lowest QTcF values observed in 
the multiple dosing study were between 355 ms and 364 ms, except one subject (Part B) 
who was discontinued from the study due to a shortened QTcF of 333 ms compared to 
351 ms at baseline, with no associated arrhythmia after a single dose of 125 mg SAF312. 
The minimum QTcF value measured in patients with post-operative pain treated with 
SAF312 was 347 ms (one subject). The clinical relevance of drug - induced short QTcF 
intervals of this magnitude is presently unknown. Recently, (Anttonen et al 2007) reported 
that a short QTcF interval (<340 ms) was not associated with a higher mortality in a 
population of non-referral middle-aged subjects.
Women of child bearing potential should be informed that taking the investigational drug may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
There may be unknown risks of SAF312 which may be serious.
3.7.1
Blood sample volumes
A maximum of approximately 72 mL of blood is planned to be collected from each subject as 
part of the study. Additional samples for serum pregnancy test and monitoring of any safety 
findings would be in addition to this. This is not considered to be a risk for this population.
Timings of blood sample collection are outlined in the Assessment schedule, Section 8.1.
A summary blood log is provided in the Site Operations Manual, together with instructions 
for all sample collection, processing, storage, and shipment information.
See Section 8.9 regarding the potential use of residual samples. 


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4
Population
Male and female patients who are eligible for PRK surgery and between 18 and 75 years old 
(inclusive). The study plans to enroll approximately 40 patients to achieve about 30 evaluable 
completers. Sample size may be adjusted based on the interim analysis.  
Subject selection is to be established by checking through all eligibility criteria at screening, 
with confirmation of select eligibility criteria at baseline. A relevant record (e.g. checklist) of 
the eligibility criteria must be stored with the source documentation at the study site. 
Deviation from any entry criterion excludes a subject from enrollment into the study. 
Additional subjects may be enrolled when subjects discontinue the study for reasons other 
than safety. All patients exposed to investigational product will be included in some analyses 
such as patients who discontinued or who only had surgery in one eye will be included in 
safety analysis (details in the analysis plan).
4.1
Inclusion criteria
Population eligible for inclusion in this study must fulfill all of the following criteria:
1. Male and female patients age 18 to 75 who are eligible for bilateral PRK surgery.
2. Normal eye exam except for refractive error at baseline.
3. Planned myopia correction should not exceed -4.00 Diopters (sphere) and 3.00 diopters of 
astigmatism, with spherical equivalent not higher than -4.50, confirmed by manifest 
refraction at baseline.  Monovision treatment is allowed.
4. Written informed consent must be obtained before any assessment is performed.
4.2
Exclusion criteria
Population fulfilling any of the following criteria are not eligible for inclusion in this study:
1. Monocular patient (including amblyopia) or best corrected visual acuity score worse than 
20/80 (Snellen) or 55 letters (EDTRS), at baseline.
2. Any systemic or ocular disease that might affect wound healing (such as severe 
rheumatoid arthritis or diabetes or history of keloid formation) or a history of ocular 
trauma, uveitis, infection, or inflammation in the 6 months prior to baseline.  
Especially for diabetes: Patients with severe diabetes, uncontrolled diabetes, diabetic 
keratopathy, diabetic retinopathy, diabetic macular edema, diabetic nephropathy, diabetic 
foot ulcers or other systemic complications of diabetes are excluded. Patients with mild,
well controlled diabetes with no evidence of ocular or systemic complications of diabetes 
can be included.
3. Patients with active inflammatory or infectious ocular conditions, severe or progressive 
retinal disease, and use of topical or systemic steroids, or use of coumadin or similar drugs 
within the last 6 months prior to baseline.
4. Patients with any corneal dystrophy (epithelial, stromal or endothelial) or any cornea 
disease (including significant scarring (at the discretion of the PI), ocular herpes or 
pterygium).
5. Previous refractive or corneal surgery (such as LASIK, PRK, radial keratotomy, 
pterygium removal, corneal transplantation). 


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6. History of allergic or hypersensitivity reaction or significant adverse events to any of the 
drugs to be used in this study including:

tetracaine or similar topical ocular anesthetic

NSAIDs and aspirin

oral analgesic (including acetaminophen and codeine)

antibiotics 

steroids

inability to tolerate or wear bandage contact lens
7. Chronic pain of any etiology or any significant illness which has not resolved within 
two (2) weeks prior to initial dosing.
8. Concurrent therapy or history of chronic therapy or abuse of systemic or ocular NSAIDs, 
analgesics, pain medication (including gabapentin or pregabalin and similar), opiates or 
cannabis. 
Patients with use of any topical eye medication except for lubricating eye drops within 
two weeks prior to surgery, in the study eye will be excluded. 
Patients meeting any of the following will also be excluded:
(a) any use of topical NSAIDs during 30 days before baseline, OR
(b) systematic/chronic use of systemic NSAIDS within 30 days prior to baseline, OR
(c) occasional use of systemic NSAIDS within 3 days prior to baseline, OR 
(d) use of ocular cyclosporine (or similar medication) within the 3 months prior to surgery.
9. Use of other investigational drugs at the time of enrollment, or within 5 half-lives of 
enrollment, or within 30 days of baseline, whichever is longer; or longer if required by 
local regulations.
10. History of drug abuse or unhealthy alcohol use within the 12 months prior to dosing. 
Unhealthy alcohol use is defined as a history of, or current alcohol misuse/abuse, defined as 
“Five or more drinks on the same occasion on each of 5 or more days in the past 30 days."
11. Subjects using CPAP or other sleep apnea devices.
12. Subjects who do not weigh at least 50 kg, or who do not have a body mass index (BMI) 
within the range of 18 - 35 kg/m2. BMI = Body weight (kg) / [Height (m)]2
13. Pregnant or nursing (lactating) women.
14. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using basic methods of contraception during dosing of 
investigational drug. Basic contraception methods include:

Total abstinence from heterosexual intercourse (when this is in line with the preferred 
and usual lifestyle of the subject). Periodic abstinence (e.g. calendar, ovulation, 
symptothermal, post-ovulation methods) and withdrawal are not acceptable methods 
of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least six weeks before taking 
investigational drug.  In case of oophorectomy alone, only when the reproductive 
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
Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject.

Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps). For UK: with spermicidal foam/gel/film/cream/vaginal 
suppository

Use of oral, injected or implanted hormonal methods of contraception or other forms 
of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS)
In case of use of oral contraception women should be stable on the same pill for a 
minimum of 3 months before taking study drug.
Women are considered post-menopausal and not of child bearing potential if they have 
had 12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile 
(e.g. age appropriate, history of vasomotor symptoms) or have had surgical bilateral 
oophorectomy (with or without hysterectomy), total hysterectomy or tubal ligation at least 
six weeks ago. In the case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment is she considered 
not of child bearing potential.
15. Unable to communicate well with the investigator, to understand and comply with the 
requirements of the study including use of ePRO device at home and adherence to the 
dosing and visit schedule.
No additional exclusions may be applied by the investigator, in order to ensure that the 
study population will be representative of all eligible patients.
5
Restrictions for Study Subjects
A corneal and eye examination consistent with eligibility for PRK surgery is needed at 
baseline. 
During recruitment, screening/informed consent review, and baseline visit, the subjects must 
be informed and reminded of the restrictions outlined in this section.
5.1
Contraception requirements
Women of child bearing potential must be informed that taking the study treatment may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered or continue in the study.
Please refer to exclusion criteria (Section 4.2) for details of contraception requirements for the 
study.


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5.2
Prohibited treatment
No ocular medication other than study drugs (study drugs include standard of care drugs such 
as antibiotic and steroid, as well as preservative free artificial tears) will be allowed from the 
first dosing until all of the Study Completion evaluations have been conducted. All drugs, 
including artificial tears are stored and administered at room temperature only 
(refrigerated/cold eye drops are not allowed with the exception of use during PRK surgery 
inside the operating room if desired by surgeon).
Mitomycin C must not be used as an intraoperative medication for patients on this study.
No pain medication may be used within 24 hours prior to surgery. No pain medication 
other than rescue analgesics may be used from surgery until 4 days post-surgery for 
ocular or periocular pain.  If a patient requires analgesics at the time scheduled for the 
second surgery, the PI and patient must decide whether the patient will discontinue use of pain 
medication 24 hours prior to the scheduled surgery (if medically feasible) or postpone the 
surgery until analgesic use is discontinued.
Should a subject have an incidental and limited need for a medication to be taken at any point 
during the study (e.g. antibiotic prophylaxis prior to dental surgery or for pain relief of pain in 
any other part of the body or fever, limited use of acetaminophen [e.g., up to 2 tablets of 
325mg, or ibuprofen up to 2 tablets of 200mg etc.]), the sponsor should be advised, as 
administration of any concomitant medication may require the subject to be withdrawn.  Total 
acetaminophen dose must be less than 3g/day, including rescue analgesics and any incidental 
need for medication unrelated to ocular pain.
5.3
Dietary restrictions and smoking

No cannabis use for 4 weeks before screening until after Study Completion evaluation.

No cigarettes/use of nicotine products and no alcohol use for 24 hours before dosing and 
until after completion of study treatment (Day 4 in each period).
5.4
Other restrictions

No strenuous physical exercise, particularly contact sports or other activities with a risk of 
contact to the eyes (e.g.basketball) until the later of: complete healing of epithelial defect 
following each surgery, OR at least one week after each surgery.


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6
Treatment
6.1
Study treatment
Details on the requirements for storage and management of study treatment, and instructions 
to be followed for subject numbering, prescribing/dispensing and taking study treatment are 
outlined in the Site Operations Manual.
6.1.1
Investigational treatment and control drugs
Table 6-1
Overview of study medication
Drug
Formulation
Appearance 
Unit dose
Packaging
Provided 
by
SAF312 
Topical 
ocular drops
Colorless to off-
white clear liquid OR 
white to off-white 
uniform suspension 
 
SAF312 
per 37 µL 
drop size
Single use 
droppers 
(preservative 
free)
Alcon
SAF312 
vehicle/Placebo
Topical 
ocular drops
Colorless to off-
white clear liquid OR 
white to off-white 
uniform suspension 
NA
Single use 
droppers 
(preservative 
free)
Alcon
6.1.2
Additional study treatment
Ancillary treatments will be provided by participating sites with funding provided by Sponsor. 
All patients will receive standard of care ancillary treatment following PRK surgery, 
including:

A course of topical ocular antibiotic (Moxifloxacin or equivalent 1 eye drop four times 
daily): start right after PRK surgery, and after application of first dose of study eye drop 
and continued for 4-7 days, per managing physician.

Prednisolone acetate ophthalmic: 1 eye drop four times daily will be started right after 
PRK surgery and after instillation of antibiotic eye drop and will be given for 1 week after 
PRK, followed by taper per local procedures.

Preservative-free unit-dose artificial tears may be used as needed. Artificial tears may not
be chilled for analgesic effect.  
Whenever drops are administered in sequence, at least 5 minutes must pass between eye drop 
administrations.
To summarize, patients will undergo PRK procedure, bandage lens is placed on the cornea, 
SAF312 or placebo is given, after approximately 5 minutes antibiotic is administered, and 
after another 5 minutes, prednisolone is administered. Detailed administration and assessment
timing are included in Table 1-1 of the SOM.
Ancillary medication must be recorded on the Concomitant medications/Significant non-drug 
therapies CRF.
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6.2
Treatment arms
Subjects will be assigned to one of the following 2 treatment sequences in a ratio of 1:1 
lasting 3 days per period.
Table 6-2
Definition of treatment sequences
Sequence
Period 1
Period 2
1
SAF312 
4 times daily (every 6 hours) for 72 hours
(inclusive)
Vehicle control to SAF312
4 times daily (every 6 hours) for 72 hours
(inclusive)
2
Vehicle control to SAF312 
4 times daily (every 6 hours) for 72 hours
(inclusive)
SAF312 
4 times daily (every 6 hours) for 72 hours
(inclusive)
6.3
Treatment assignment and randomization
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. 
A randomization list will be produced by or under the responsibility of the Sponsor 
Biostatistics & Clinical Data Operations (Statistical Programming) Groups using a validated 
system that automates the random assignment of treatment arms to randomization numbers in 
the specified ratio.
Follow the details outlined in the Site Operations Manual regarding the process and timing of 
treatment assignment and randomization of subjects.
6.4
Treatment blinding
This is a subject and investigator-masked study. Subjects and investigators will remain 
masked to study treatment throughout the study, except where indicated below.
The identity of the treatments will be concealed by the use of study drugs that are all identical 
in packaging, labeling, and schedule of administration, and similar in appearance.
Site staff
With the exception of any unmasked site staff identified below, all site staff (including study 
investigator and study nurse) will be masked to study treatment throughout the study.
Unmasking a single subject at site for safety reasons (necessary for subject management) will 
occur via an emergency system in place at the site (see Section 6.7).
Sponsor staff
The following unmasked sponsor roles are required for this study:

Unmasked sample analyst(s) (PK)
The sample analysts will receive a copy of the randomization schedule, to facilitate analysis 
of the samples. The sample analysts will provide the sample data to the study team under 
masked conditions unless otherwise allowed.


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The study statistician will be able to access the randomization list for interim analyses and is 
allowed to share unmasked information with the rest of the clinical team as appropriate for 
internal decision purposes, as outlined in Table 6-3. For example, unmasked summaries and 
unmasked individual data can be shared with the team for interim analyses.
Study programmers and other personnel involved in study data analysis (e.g. biomarker expert) 
are allowed to access treatment assignment information for the purpose of conducting interim 
analyses.
The clinical trial team is allowed to share unmasked results with other sponsor staff 
(e.g. decision boards) as required for internal decision making on the study or the project at 
the time of interim analyses while the study is ongoing.
All unmasked personnel will otherwise keep randomization lists and data or information that 
could unmask other study team members confidential and secure except as described above.
Following final database lock all roles may be considered unmasked.
Table 6-3
Blinding levels
Role
Time or Event
Randomization 
list generated
Treatment 
allocation & 
dosing
Safety event 
(single subject 
unblinded)
Interim 
Analysis
Subjects/Patients
B
B
B
B
Site staff
B
B
UI
B
Drug Supply and Randomization 
Office
UI
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
UI
UI
All other sponsor staff not 
identified above
B
B
UI
UI
B Remains blinded
UI Allowed to be unblinded on individual patient level
6.5
Treating the subject
SAF312 will be administered to the subject via the following route of administration: ocular 
drops.  Drops will be administered at the study site by the study personnel during the day of 
surgery. During the daily follow up postoperative visits, if the patient is at the site during the 
expected time for eye drop administration, the study personnel may administer the eye d rops. 
The remainder of drops will be home administered by the patient.  See the Site Operations 
Manual for further details.
Sponsor qualified medical personnel will be readily available to advise on trial related 
medical questions or problems.
6.6
Permitted dose adjustments and interruptions of study treatment
Study treatment dose adjustments and/or interruptions are not permitted.


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6.7
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Most often, study treatment discontinuation and knowledge of the possible 
treatment assignments are sufficient to treat a study subject who presents with an emergency 
condition. Emergency treatment code breaks are performed using the IRT. When the 
investigator contacts the system to break a treatment code for a subject, he/she must provide 
the requested subject identifying information and confirm the necessity to break the treatment 
code for the subject. The investigator will then receive details of the investigational drug 
treatment for the specified subject and a fax or email confirming this information. The system 
will automatically inform the study monitor for the site and the Study Team that the code has 
been broken.
It is the investigator’s responsibility to ensure that there is a dependable procedure in place to 
allow access to the IRT at any time in case of emergency.   The investigator will need to 
provide: 

protocol number

study drug name (if available)

subject number.
In addition, the investigator must provide oral and written information to inform the subject 
how to contact his/her backup in cases of emergency when he/she is unavailable to ensure that 
un-masking can be performed at any time.
An assessment will be done by the appropriate site personnel and sponsor after an emergency 
unblinding to assess whether or not study treatment should be discontinued for a given subject.
6.8
Treatment exposure and compliance
PK parameters (measures of treatment exposure) will be determined in all subjects treated 
with SAF312, as detailed in Section 8.7.
The investigator must promote compliance by instructing the subject to take the study 
treatment and rescue medication exactly as prescribed and by stating that compliance is 
necessary for the subject’s safety and the validity of the study. Subjects will be instructed that 
failing to comply with study procedures, such as repeatedly missing doses of study medication 
or repeatedly entering incorrect rescue medication use information in the electronic 
Patient Reported Outcomes (ePRO) device may be removed from the study at the discretion 
of the investigator in coordination with the Sponsor. The subject must also be instructed to 
contact the investigator if he/she is unable for any reason to take the study treatment as 
prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit using 
rescue medication counts and ePRO information provided by the subject. This information 
should be captured in the source document at each visit. All study treatment dispensed and 
returned must be recorded in the Drug Accountability Log. 
Compliance must be reconciled against patient-reported use in the electronic diary at each 
applicable visit.


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6.9
Recommended treatment of adverse events
AEs will be treated at the discretion of the Investigator and in accordance with current 
medical practice.
 
 
The most common drug suspected adverse events in 
this study were: corneal staining, hyperemia and mild anterior chamber inflammation 
(more details in the IB). 
 
 
Ocular AEs should be treated according to the type of the AE.
Subjects should remain in the study even after receiving treatments for AEs until the 
Investigator feels that subject discharge is warranted.
Medication used to treat AEs must be recorded on the Concomitant medications/Significant 
non-drug therapies eCRF.
6.10
Rescue medication
Rescue medication is provided by the Sponsor, and will consist of oral analgesic 
(acetaminophen 300 mg + codeine 30 mg). Patients will be instructed to take as needed for 
pain relief up to a total of 10 tabs/day or 1-2 tabs every 4 hours during the treatment period 
(Visits 2-5 and 7-10).  Patients must be instructed to complete a VAS for pain assessment 
prior to taking rescue medication.
Use of pain medication after the treatment period (after visits 5 and 10) is per PI discretion, 
and must be recorded on the Concomitant medications/Significant non-drug therapies CRF.
6.11
Concomitant treatment
All prescription medications, over-the-counter drugs and significant non-drug therapies 
(including physical therapy and blood transfusions) administered or taken within the timeframe 
defined in the entry criteria prior to the start of the study and during the study, must be recorded on 
the Concomitant medications/ Significant non-drug therapies section of the CRF.
Both temporary and permanent punctal plugs are allowed at the discretion of the PI, but must 
be recorded on the Concomitant Medication or Medical History form, respectively.
Benzodiazepines and similar medication are allowed in moderation and if absolutely 
necessary for a specific patient on a case by case basis, on day of surgery only.
Medication entries should be specific to trade name, the single dose and unit, the frequency 
and route of administration, the start and discontinuation date and the reason for therapy.
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7
Study completion and discontinuation
7.1
Study completion and post-study treatment
Each subject will be required to complete the study in its entirety and thereafter no further 
study treatment will be made available to them.
Study completion is defined as when the last subject completes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the 
date of that decision.
The final study visit is conducted at least 30 days after final treatment (study medication) and 
will serve as safety follow-up.  Any subjects who discontinue the study after receiving 
treatment or are otherwise not seen at the final visit should, at a minimum, have a safety 
follow-up call conducted at least 30 days after the last study treatment. The information 
collected is kept as source documentation.  All SAEs reported during this time period must be 
reported as described in Section 9.2 and the Site Operations Manual.  Documentation of 
attempts to contact the subject should be recorded in the source documentation.
7.2
Discontinuation of study treatment
Subjects may voluntarily discontinue study treatment for any reason at any time.
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continuation would be detrimental to the subject’s well-being.
Study treatment must be discontinued under the following circumstances:

Subject withdraws consent

Pregnancy

Any adverse event graded severe or higher (see severity grading in Section 9.1) related to 
study drug

Emergence of the following adverse events: 

Severe or persistent moderate ocular discomfort as reported by the subject that is 
outside the expected discomfort from PRK surgery

Cornea or ocular surface epithelial defects (extensive and non-healing) that are 
outside the expected extent and rate of healing after PRK surgery

Any condition requiring additional or new intraocular surgery (concurrent or after the 
PRK surgery) in the study eye

Any severe intraoperative complication occurred during the PRK surgery. In this case 
the patient will be withdrawn from the study and will not be dosed with any dose of 
the investigational drug.

Any protocol deviation that results in a significant risk to the subject’s safety


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Discontinuation of Study/investigational treatment will be at the discretion of the Investigator, 
under the following circumstances:

Emergence of the following adverse events: 

Any need for eye surgery (outside the planned bilateral PRK)

A serious adverse event that, in the opinion of the investigator, is not related to the 
study drug

Temperature increase to > 39.0oC measured orally which is sustained for >15 minutes 
at any time

Hyperthermia (> 38.0oC)-related changes in vital signs which are judged as clinically 
significant by the investigator (an increase in heart rate to > 120 BPM and/or a drop in 
blood pressure to <80/40 mmHg)

≥ Grade 2 hypertension (≥ 24 hour or symptomatic increase in BP by > 20 mmHg 
(diastolic) or to > 160/100)

≥ Grade 2 intraocular inflammation

Corneal edema/corneal opacity ≥ Grade 1
The appropriate personnel from the site and the sponsor will assess whether study and 
investigational treatment should be discontinued for any subject whose treatment code has 
been broken inadvertently for any reason.
Subjects who discontinue study treatment or who decide they do not wish to participate in the 
study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see protocol Section 7.3). Where possible, they should return for the 
assessments indicated at EOS visit in the Assessment schedule. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, e-mail, and/or letter) should be 
made to contact them as specified in protocol Section 7.4.
7.3
Withdrawal of informed consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time.
Withdrawal of consent from the study is defined as when a subject:

Does not want to participate in the study anymore and

Does not want any further visits or assessments and

Does not want any further study related contacts and

Does not allow analysis of already obtained biologic material.
In this situation, the investigator must make every effort (e.g. telephone, e-mail, letter) to 
determine the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up.


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7.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator should show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject cannot be formally considered lost to follow-
up until his/her scheduled end of study visit would have occurred.
7.5
Study Stopping rules
Under any of the following conditions, the current study/part will be placed on temporary 
hold and potentially halted, pending full review of the clinical data by the investigator and 
Sponsor:

Two or more incidents of a similar serious adverse event that, in the opinion of the 
investigator, are related to the study drug

The principal investigator and the sponsor consider that the number and/or severity of 
adverse events justify discontinuation of the study.

Any severe or higher adverse event (see severity grading in Section 9.1) related to study 
drug

The Sponsor requests it. 
7.6
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. Should this be necessary, subjects 
must be seen as soon as possible and treated as a prematurely withdrawn subject. 
The investigator may be informed of additional procedures to be followed in order to ensure 
that adequate consideration is given to the protection of the subject’s interests. 
The investigator will be responsible for informing IRBs/IECs of the early termination of the 
trial.


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8
Procedures and assessments
8.1
Assessment schedule
Study Phase Screening Baselin
e
Treatment 12
Treatment 22
End of 
Study
or 
Early 
Exit
Visit Numbers1
Screen
1
2
3
4
5
Opt*
62
Opt*
72
8
9
10
Opt*
11
Opt*
12
Study Day(s)
-29 to -2
-1
-14 +0
1
2
3
4
5-7 
8
9 or 
later
1
2
3
4
5-7
8
9 or 
later
30 days 
post-last 
dose 
(study 
med)
Time (post-initial 
dose of treatment 
cycle)
-
-
0h
1h
24h
48h
72h
74h
-
-
0h
1h 24h
48h
72h
74h
-
-
Informed consent
X
Inclusion / 
Exclusion criteria
X
X
Medical 
history/current 
medical conditions
X
X
Ocular history
X
X
Demography
X
Pregnancy test3
X
X
X
Drug screen
X
X
X
Blood Pressure 
and Pulse Rate
X
X
X4
X4
X4
X4
X
X4,2
X4
X4
X4
X
X
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Study Phase Screening Baselin
e
Treatment 12
Treatment 22
End of 
Study
or 
Early 
Exit
Visit Numbers1
Screen
1
2
3
4
5
Opt*
62
Opt*
72
8
9
10
Opt*
11
Opt*
12
Study Day(s)
-29 to -2
-1
-14 +0
1
2
3
4
5-7 
8
9 or 
later
1
2
3
4
5-7
8
9 or 
later
30 days 
post-last 
dose 
(study 
med)
Time (post-initial 
dose of treatment 
cycle)
-
-
0h
1h
24h
48h
72h
74h
-
-
0h
1h 24h
48h
72h
74h
-
-
Body temperature
X
X
X4
X4
X4
X4
X
X4,2
X4
X4
X4
X
X
Body weight
X
X
Body height
X
Concomitant 
therapies
As required
X
Adverse events
As required
X
Serious adverse 
events
As required
X5
PK blood 
collection6
See table below
PRK Procedure7
SE
SE4
X
X4
X4
X
X4
X4
X
VAS (Visual 
Analog Scale) 
pain assessment8
X
X 
X 
Patient diary8
X
X
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Protocol No. CSAF312X2201
Study Phase Screening Baselin
e
Treatment 12
Treatment 22
End of 
Study
or 
Early 
Exit
Visit Numbers1
Screen
1
2
3
4
5
Opt*
62
Opt*
72
8
9
10
Opt*
11
Opt*
12
Study Day(s)
-29 to -2
-1
-14 +0
1
2
3
4
5-7 
8
9 or 
later
1
2
3
4
5-7
8
9 or 
later
30 days 
post-last 
dose 
(study 
med)
Time (post-initial 
dose of treatment 
cycle)
-
-
0h
1h
24h
48h
72h
74h
-
-
0h
1h 24h
48h
72h
74h
-
-
Oral analgesics 
use9
X
X
X
X
X
X
Blink Rate
OU10
OU
OU4
OU4 OU4 OU4
OU
OU4,2
OU4
OU4
OU4
OU
OU 
See table below
Visual acuity
OU10
OU
SE4
SE4
SE4
OU
SE4
SE4
SE4
SE
OU
Dominant eye test
X7,12,10
Ocular hyperemia
OU10
OU
SE4
SE4
SE4
SE4
OU
SE4,2
SE4
SE4
SE4
SE
OU
Slit lamp 
biomicroscopy
OU10
OU
SE4
SE
SE4
SE4
SE4
OU
SE4,2
SE SE4
SE4
SE4
SE
OU 
Corneal Staining
OU10
OU
OU13
OU13
OU
SE SE4
SE4
SE4
SE*
SE*
SE*
SE SE4 SE4
SE4
SE*
SE*
SE*
OU
SE
14
SE4
SE4
SE*
SE*
SE*
SE
SE4
SE4
SE*
SE*
SE*
Tear Production
OU10
SE
SE
OU
SE
SE
OU
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Study Phase Screening Baselin
e
Treatment 12
Treatment 22
End of 
Study
or 
Early 
Exit
Visit Numbers1
Screen
1
2
3
4
5
Opt*
62
Opt*
72
8
9
10
Opt*
11
Opt*
12
Study Day(s)
-29 to -2
-1
-14 +0
1
2
3
4
5-7 
8
9 or 
later
1
2
3
4
5-7
8
9 or 
later
30 days 
post-last 
dose 
(study 
med)
Time (post-initial 
dose of treatment 
cycle)
-
-
0h
1h
24h
48h
72h
74h
-
-
0h
1h 24h
48h
72h
74h
-
-
Intraocular 
Pressure (IOP)
OU10
OU
SE
SE 
OU
Dilated fundus 
exam
OU10
OU
OU
SE15
SE15,*
SE15
SE15,*
SE15
SE15,*
SE15
SE15,*
Study completion 
information
X
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1 Visit structure given for internal programming purpose only
2 Treatment Period 2 may begin any time after wound closure from Period 1 surgery and Day 8 assessments completed (including on Day 8), and up to 6 weeks post first 
surgery.  If Day 1 of Treatment Period 2 is less than 1 week from Day 8 of Treatment Period 1, pre-dose ocular and vital sign assessments (e.g., Blink rate, Body 
temperature) do not need to be repeated.
3 Serum test at baseline with urine pregnancy test by local standards for other timepoints
4 Pre-dose (prior to PRK, as applicable)
5 PG sample may be drawn at any timepoint if missed at designated timepoint
6 Patient may decline any PK blood draw and remain in the study with the agreement of the PI and sponsor
7 First and second study eye (SE) will be established based on results of the dominant eye test.  SE will preferably be the non-dominant eye in the first treatment period, 
subject to investigator treatment decision. 
8 ePRO VAS pain scores, study and rescue medication dose diary, and related questions will be collected at pre-specified time points (pre-dose, 1 hour, 3 hours, 6 hours, 
9 hours, 12 hours and prior to every dose until day 5 post-operatively) as instructed by the ePRO and described in the SOM.   VAS pain scores will also be collected for up 
to 24 hours following the final dose in each period, as detailed in the ePRO. In addition, for both periods 1 and 2, the following timepoints will include VAS pain scores at 
pre-dose (as stated above) AND 30 minutes after dose:  hours 6 (+30 minutes), 18 (+30 minutes), 24 (+30 minutes), and 30 (+30 minutes). ePRO devices will be collected 
when all assessments are complete.
9 As collected by the site staff at each post-surgery visit (Days 1-4 in each period)
10
e used as screening values rather than repeating assessments.
Study eye for current period = SE, assessments on both eyes = OU
13 If bandage contact lens is still in place at Visit 6 or 11 (Study Day 8 for either period), corneal staining will not be performed.
ge contact 
lens needs to replaced prior to day 4, attempt to retrieve and store all used lenses.  
16 Optional per Sponsor
* Patients may be followed for wound closure, at PI discretion, on study Days 5-7 or after Day 8, until wound is completely healed.  On those visits, wound size estimation 
by slit lamp should be performed, preferably by the same examiner, along with anterior segment OCT, if available, at Sponsor’s option.  Other assessments are at PI 
discretion.  These additional visits and assessments will be optional for both sites and patients.
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Table 8-1
Details for highly repetitive assessments
Study Phase
Visit
Day
Time 
(post-
dose)
PK blood
collection
Screening
Screen
-29 to -2
-
Baseline
1
-1
-14 +0
-
Treatment 13
2
1
Prior to 
dose
Prior to 
dose4
0.25h
X
0.5h
X
1h
X
2h
X
3
2
24h
Prior to 
dose
4
3
48h
5
4
72h
Prior to 
dose
72.25h
X
72.5h
X
73h
X
74h
X
63
8
-
Treatment 23
73
1
Prior to 
dose
Prior to 
dose4
0.25h
X
0.5h
X
1h
X
2h
X
8
2
24h
Prior to 
dose
9
3
48h
10
4
72h
Prior to 
dose
72.25h
X
72.5h
X
73h
X
74h
X
11
8
-
End of Study or Early Exit 
12
30 days post-last dose (study med)
-
1 Patient may decline any PK blood draw and remain in the study with the agreement of the PI and sponsor
2 Participating sites only, testing is at the Sponsor’s option
3 Treatment Period 2 may begin any time after Day 8 assessments completed (including on Day 8), and up to 6 
weeks post first surgery.  If Day 1 of Treatment Period 2 is less than 1 week from Day 8 of Treatment Period 1, 
pre-dose ocular and vital sign assessments (e.g., Blink rate, Body temperature) do not need to be repeated.
4 Prior to PRK
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8.2
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent.
Novartis will provide to investigators a proposed informed consent form that complies with 
the ICHE6 GCP guideline and regulatory requirements and is considered appropriate for this 
study. The informed consent form will also include a section related to optional future 
research which will require a separate signature if the subject agrees to future research.  
Any changes to the proposed consent form suggested by the investigator must be agreed to by 
Novartis before submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. 
Any new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an Investigator 
Notification or an Aggregate Safety Finding. New information might require an update to the 
informed consent and then must be discussed with the subject.
Ensure subjects are informed of the contraception requirements outlined in the Section 4.2
(Exclusion criteria) and in Section 5.1 (Contraception requirements).
A copy of the approved version of all consent forms must be provided to the Novartis monitor 
after IRB/IEC approval.
8.3
Subject screening
Re-screening will be allowed in communication with the Sponsor, on a case-by-case basis. 
Re-screened subjects will keep their original screening numbers.
Information on what data should be collected for screening failures is outlined in the 
Site Operations Manual.
8.4
Subject demographics/other baseline characteristics
Subject demographic and baseline characteristic data will be collected on all subjects.  
Relevant medical history/current medical conditions data will also be collected until signature 
of informed consent.  Details are outlined in the SOM.
Investigators have the discretion to record abnormal test findings on the medical history CRF, 
if in their judgment, the test abnormality occurred prior to the informed consent signature.
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8.4.1
Drug screen
Drug test for drugs of abuse will be conducted at screening.   Testing to assess use of rescue 
medication will be conducted during treatment.  Samples will be sent to a central lab.  Results 
will be kept as source documentation.  Central lab details are included in central laboratory 
manual.
8.5
Efficacy / Pharmacodynamics
8.5.1
VAS (Visual Analog Scale) pain assessment
VAS pain scores, study and rescue medication dose diary, and related questions will be 
entered in a provided device.  See SOM for details.
8.5.2
Oral analgesics use
Rescue medication use will be recorded in the eCRF and reconciled with patient entries in the 
provided electronic device.  See SOM for details.
8.5.3
Patient diary
VAS pain scores, study and rescue medication dose diary, and related questions will be 
entered in a provided device.  See SOM for details.
8.6
Safety
Safety assessments are specified below; methods for assessment and recording are specified in 
the SOM, with the Assessment schedule (Section 8.1) detailing when each assessment is to be 
performed.
8.6.1
Body temperature
See SOM for details.
8.6.2
Blood Pressure and Pulse Rate
See SOM for details.
The CRF should contain the blood pressure and pulse rate measurements. 
8.6.3
Blink Rate
Blink rate will be assessed as blinks per 1 minute, as per SOM and Assessment schedule. 
This data will be included in the clinical study report.
8.6.4
Visual acuity
Best-corrected visual acuity and uncorrected visual acuity, together with the refractive 
correction (if checked) will be obtained in each eye separately. This assessment is to be 
performed prior to pupil dilation. The results will be recorded in the appropriate eCRF page.


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8.6.5
Slit lamp biomicroscopy
Slit lamp exam of the adnexae, conjunctiva/sclera, cornea, anterior chamber, iris, lens and 
undilated fundus exam will be obtained for each subject according to the Assessment schedule. 
Results from the slit lamp biomicroscopy exam will be recorded in the appropriate eCRF page.
8.6.6
Intraocular Pressure (IOP)
See SOM for details.
8.6.7
Dilated fundus exam
Dilated fundus exam will be obtained for each subject according to the Assessment schedule.
8.6.8
Ocular hyperemia
Ocular hyperemia will be assessed by simple live scoring at the timepoints shown in the 
Assessment schedule. For more details refer to the SOM. This data will be included in the 
clinical study report.
8.7
Pharmacokinetics
PK samples will be collected at the timepoints defined in the Assessment schedule, 
Section 8.1. Follow instructions outlined in the central laboratory manual regarding sample 
collection, numbering, processing and shipment. See Section 8.9 regarding the potential use of 
residual samples.
In order to better define the PK profile, the timing of the PK sample collection may be altered 
based on emergent data. The number of samples/blood draws and total blood volume 
collected will not exceed those stated in the protocol. 
SAF312 will be determined by a validated LC-MS/MS method; the anticipated Lower Limit 
of Quantification (LLQ) in plasma is 0.05 ng/mL. Concentrations will be expressed as ng/mL.  
If feasible, bandage contact lenses (BCL) exposed to study drug may be analyzed for residual 
drug exposure after treatment.  The bioanalysis of SAF312 in BCL will be exploratory, and 
the LC/MS/MS method used for the purpose may not be validated.  Concentrations below the 
LLQ will be reported as “zero” and missing data will be labeled as such in the Bioanalytical 
Data Report.
For standard PK abbreviations and definitions see the list provided at the beginning of this protocol.
The following PK parameters may be determined as relevant using the actual recorded 
sampling times using non-compartmental method(s) with Phoenix™
WinNonlin®
(Version 6.4 or higher): Cmax, Cmin (pre-dose), Tmax, AUClast, AUC0-t, Clast and Tlast 
from the plasma concentration-time data. Other PK parameters maybe calculated if deemed 
necessary. The linear trapezoidal rule will be used for AUC calculation.


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8.8
Other assessments
8.8.1
Ocular assessments
8.8.1.1
Dominant eye test
The dominant eye and the non-dominant eye of each subject will be identified with the 
dominant eye test. In each study period, one eye (the subject of the PRK surgery) will be 
selected as the study eye (SE).  SE will preferably be the non-dominant eye in the first 
treatment period, subject to investigator treatment decision. 
8.8.1.2
Wound size estimation by slit lamp exam
Adjust slit beam and angle of illumination to allow visualization of the corneal wound 
boundary.  Adjust beam height to approximate maximum horizontal (wound width) and 
vertical (wound height) of the surgical epithelial wound in millimeters. 
8.8.1.3
Tear Production
Tear production will be evaluated by Shirmer’s test, as per SOM and Assessment schedule. 
This data will be included in the clinical study report.
8.8.2
Corneal Staining
Corneal staining will be determined on a scale of 0-3 as the average from each of 5 zones 
(central plus 4 quadrants). Results will be recorded for each zone. This test will be performed 
using a slit lamp after instilling fluorescein into the lower palpebral conjunctiva of both eyes.
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9
Safety monitoring
9.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (i.e., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a subject or 
clinical investigation subject after providing written informed consent for participation in the 
study until the end of study visit. Therefore, an AE may or may not be temporally or causally 
associated with the use of a medicinal (investigational) product.
In addition, all reports of intentional misuse and abuse of the study treatment are also 
considered an adverse event irrespective if a clinical event has occurred. See Section 9.5 for 
an overview of the reporting requirements.
The occurrence of adverse events must be sought by non-directive questioning of the subject 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the subject during or between visits or through physical examination finding, laboratory 
test finding, or other assessments.
Instructions for reporting of adverse events commonly associated with PRK surgery have 
been added to the SOM.
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Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria:

they induce clinical signs or symptoms,

they are considered clinically significant,

they require therapy.
Clinically significant abnormal laboratory values or test results should be identified through a 
review of values outside of normal ranges/clinically notable ranges, significant changes from 
baseline or the previous visit, or values which are considered to be non-typical in patients with 
underlying disease. Investigators have the responsibility for managing the safety of individual 
subject and identifying adverse events.
Adverse events must be recorded on the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, and accompanied by the following information:
1. the severity grade 

mild: usually transient in nature and generally not interfering with normal activities

moderate: sufficiently discomforting to interfere with normal activities

severe: prevents normal activities
2. its relationship to the study treatment 

Yes or

No
3. its duration (start and end dates) or if the event is ongoing an outcome of not 
recovered/not resolved must be reported.
4. whether it constitutes a SAE (see Section 9.2 for definition of SAE) and which seriousness 
criteria have been met  
5. Action taken regarding investigational treatment.
All adverse events must be treated appropriately. Treatment may include one or more of 
the following: 

no action taken (e.g. further observation only)

investigational treatment dosage increased/reduced

investigational treatment interrupted/withdrawn

concomitant medication or non-drug therapy given

hospitalization/prolonged hospitalization (see Section 9.2 for definition of SAE)
6. its outcome (not recovered/not resolved; recovered/resolved; recovering/resolving, 
recovered/resolved with sequelae; fatal; or unknown). 
Information about common side effects already known about the investigational drug can be 
found in the IB.  Once an adverse event is detected, it must be followed until its resolution or 
until it is judged to be permanent, and assessment should be made at each visit (or more 
frequently, if necessary) of any changes in severity, the suspected relationship to the 
investigational drug, the interventions required to treat it, and the outcome.


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The investigator must also instruct each subject to report any new adverse event (beyond the 
protocol observation period) that the subject, or the subject’s personal physician, believes 
might reasonably be related to study treatment. This information must be recorded in the 
investigator’s source documents; however, if the AE meets the criteria of an SAE, it must be 
reported to Novartis.
9.2
Serious adverse event reporting
9.2.1
Definition of SAE
An SAE is defined as any adverse event (appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the 
following criteria:

is fatal or life-threatening

results in persistent or significant disability/incapacity

constitutes a congenital anomaly/birth defect

requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 

routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

elective or pre-planned treatment for a pre-existing condition (that is unrelated to the 
indication under study) and has not worsened since the start of study drug

treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission

social reasons and respite care in the absence of any deterioration in the subject’s 
general condition

is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention.
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met.
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (see Annex IV, ICH-E2D Guideline).
Medical and scientific judgment should be exercised in deciding whether other situations 
should be considered serious reactions, such as important medical events that might not be 
immediately life threatening or result in death or hospitalization but might jeopardize the 
subject or might require intervention to prevent one of the other outcomes listed above. 
Examples of such events are intensive treatment in an emergency room or at home for allergic 
bronchospasm, blood dyscrasias or convulsions that do not result in hospitalization or 
development of dependency or abuse (see Annex IV, ICH-E2D Guideline).
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
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All AEs (serious and non-serious) are captured on the CRF; SAEs also require individual 
reporting to Novartis Drug Safety & Epidemiology (DS&E) as per Section 9.2.2.
9.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days following the last study treatment must be 
reported to Novartis within 24 hours of learning of its occurrence as described below. 
Any SAEs experienced after this period should only be reported to Novartis if the investigator 
suspects a causal relationship to study treatment.
Note: SAEs reported by subjects deemed to be screen failures must be reported to Novartis as 
outlined here with appropriate information also captured in the CRFs as specified in the Site 
Operations Manual.
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at 
a different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event.
Follow- up information provided must describe whether the event has resolved or continues, if 
and how it was treated, whether the blind was broken or not (if applicable) and whether the 
subject continued or withdrew from study participation. Each re-occurrence, complication, or 
progression of the original event must be reported as a follow-up to that event regardless of 
when it occurs.
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment a Drug Safety and 
Epidemiology Department associate may urgently require further information from the 
investigator for Health Authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study 
treatment that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with EU Guidance 2011/C 172/01 or as per national regulatory 
requirements in participating countries.
Follow the detailed instructions outlined in the SOM regarding the submission process for 
reporting SAEs to Novartis.   Note:  SAEs must be reported to Novartis within 24 hours of 
the investigator learning of its occurrence/receiving follow-up information.
9.3
Reporting Medication errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, patient/subject 
or consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately 
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Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects.
All study treatment errors and uses outside of what is foreseen in the protocol will be 
collected in the dose administration record (DAR) CRF.  Study treatment errors are only to be 
reported to Novartis Drug Safety and Epidemiology department if the treatment error is 
associated with an SAE.
All instances of misuse or abuse must be documented in the adverse event (AE) CRF 
irrespective of the misuse/abuse being associated with an AE/SAE. In addition, all instances 
of misuse or abuse must be reported to Novartis Drug Safety and Epidemiology. As such, 
instances of misuse or abuse are also to be reported using the SAE form/CRF. Table 9-1
summarizes the reporting requirements.
Table 9-1
Summary of reporting requirements for medication errors 
Treatment error type
Document in Dose 
Administration (DAR) 
CRF
Document in AE 
CRF
Complete SAE 
form/CRF
Unintentional study 
treatment error
Yes
Only if associated 
with an AE
Only if associated with 
an SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 9.1 and Section 9.2, respectively.
9.4
Pregnancy reporting
To ensure subject safety, each pregnancy occurring after signing the informed consent must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should 
be followed up to determine outcome, including spontaneous or voluntary termination, details 
of the birth, and the presence or absence of any birth defects, congenital abnormalities, or 
maternal and/or newborn complications.
Pregnancy must be recorded on the Pharmacovigilance Pregnancy Form and reported by the 
investigator to the local Novartis Drug Safety and Epidemiology Department. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the study treatment.
Any SAE experienced during the pregnancy and unrelated to the pregnancy must be reported 
on a SAE form.
The study drug must be discontinued, though the subject may stay in the study, if she wishes 
to do so. All assessments that are considered as a risk during pregnancy must not be 
performed. The subject may continue all other protocol assessments.


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9.5
Early phase safety monitoring
The Investigator will monitor adverse events in an ongoing manner and inform the Sponsor of 
any clinically relevant observations. Any required safety reviews will be made jointly 
between medically qualified personnel representing the
Sponsor and Investigator. 
Such evaluations may occur verbally, but the outcome and key discussion points will be 
summarized in writing (e-mail) and made available to both Sponsor and all Investigator(s). 
Criteria pertaining to stopping the study/treatment or adapting the study design are presented 
above.
When two or more clinical site(s) are participating in the clinical study, the Sponsor will 
advise the Investigator(s) at all sites in writing (e-mail) (and by telephone if possible) of any 
new, clinically relevant safety information reported from another site during the conduct of 
the study in a timely manner.
10
Data review and database management
10.1
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and CRFs with the investigators and their staff. 
During the study Novartis employs several methods of ensuring protocol and GCP 
compliance and the quality/integrity of the sites’ data. The monitor will visit the site to check 
the completeness of subject records, the accuracy of entries on the CRFs, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and ensure that study drug 
is being stored, dispensed, and accounted for according to specifications. Key study personnel 
must be available to assist the monitor during these visits.
The investigator must maintain source documents for each subject in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information on CRFs must be traceable to these source documents in the 
subject's file. The investigator must also keep the original informed consent form signed by 
the subject (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the CRF entries. Novartis monitoring standards require full verification 
for the presence of informed consent, adherence to the eligibility criteria, documentation of 
SAEs, and the recording of data that will be used for all primary and safety variables. 
Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.


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10.2
Data collection
Designated investigator staff will enter the data required by the protocol into the Electronic 
Case Report Forms using fully validated software that conforms to 21 CFR Part 11 
requirements. Designated investigator site staff will not be given access to the EDC system 
until they have been trained. Automatic validation programs check for data discrepancies and, 
by generating appropriate error messages, allow the data to be confirmed or corrected before 
transfer of the data to the Sponsor. The Investigator must certify that the data entered into the 
Electronic Case Report Forms are complete and accurate. After database lock, the investigator 
will receive copies of the subject data for archiving at the investigational site.
Data not requiring a separate written record will be defined in the Site Operations Manual and 
Assessment schedule and can be recorded directly on the CRFs. All other data captured for 
this study will have an external originating source (either written or electronic) with the CRF 
not being considered as source.
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
10.3
Database management and quality control
Novartis staff or CRO staff working on behalf of Novartis review the data entered into the 
CRFs by investigational staff for completeness and accuracy and instruct the site personnel to 
make any required corrections or additions. Queries are sent to the investigational site using 
an electronic data query. Designated investigator site staff is required to respond to the query 
and confirm or correct the data.
Concomitant medications entered into the database will be coded using the WHO Drug 
Reference List, which employs the Anatomical Therapeutic Chemical classification system. 
Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
Laboratory samples will be processed centrally and the results will be sent electronically to 
Novartis.
Diary and PRO data will be entered into an electronic diary by the subject. The system will be 
supplied by a vendor(s), who will also manage the database. The database will be sent 
electronically to Novartis.
Randomization codes and data about all study drug(s) dispensed to the subject and all dosage 
changes will be tracked using an Interactive Response Technology (IRT). 
Each occurrence of a code break via IRT will be reported to the clinical team and monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis.
The occurrence of any protocol deviations will be determined. After these actions have been 
completed and the database has been declared to be complete and accurate, it will be locked 
and the treatment codes will be unmasked and made available for data analysis. Any changes 
to the database after that time can only be made by joint written agreement between the 
COAR Analytics NIBR Franchise Head and the relevant NIBR TA Head.


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10.4
Data Monitoring Committee
Not required
10.5
Adjudication Committee
Not required
11
Data analysis
Any data analysis carried out independently by the investigator should be submitted to 
Novartis before publication or presentation.
11.1
Analysis sets
For all analysis sets, subjects will be analyzed according to the study treatment(s) received.
The safety analysis set will include all subjects that received any study drug.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and with no 
protocol deviations that impact on PK data.
The primary PD analysis set will include all subjects who completed treatment through Day 4 
in both eyes/treatment periods with available PD data, and with no protocol deviations that 
impact PD data. The secondary PD analysis set will include all subjects (completers and non-
completers) with available PD data, and with no protocol deviations that impact PD data.
11.2
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
11.3
Treatments
Data for study drug administration (rescue medication) and concomitant therapies will be 
listed by treatment sequence and subject.
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11.4
Analysis of the primary variable(s)
The primary aim of this study is to evaluate the efficacy of SAF312
 eye drops on the 
pain in the immediate post-operative period.
11.4.1
Variable(s)
The primary variables are visual analog scale (VAS) pre-dose pain assessment at 6 hours post-
operatively, and the average ocular pain VAS assessments from the first post-operative 
assessment up to the pre-dose 12 hour post-operative assessment.
11.4.2
Statistical model, hypothesis, and method of analysis
The primary efficacy analysis will assess the effect of SAF312
 eye drops on the visual 
analog scale (VAS) pain assessment prior to the 6 hour dose post-operatively compared to 
vehicle, and the average ocular pain VAS assessments from the first post-operative 
assessment up to the pre-dose 12 hour post-operative assessment compared to vehicle.
A longitudinal mixed effect model accounting for the cross-over effect with repeated 
measurement for VAS will be used.  The model will include fixed effects of treatment, hour 
post-operatively, period, sequence, the treatment-by-hour post-operatively interaction, the 
hour post-operatively-by-period interaction, and the hour post-operatively-by-sequence 
interaction.  Repeated measurement over hour post-operatively-by-period for each subject will 
be accounted for using the unstructured covariance matrix.  Kenward-Roger method will be 
used for approximating the denominator degrees of freedom.  Least square means will be 
estimated for each treatment-by-hour post-operatively combination and the corresponding 
90% confidence intervals will be obtained.  The difference between SAF312 and vehicle, the 
p-value, and the corresponding 90% confidence interval will be obtained from the model at 
each time point.
A mixed effect model accounting for the cross-over effect for natural logarithmic transformed 
average (0-12hr) will be used.  The model will include fixed effects of treatment, period, and 
sequence and a random effect of subject.  Kenward-Roger method will be used for 
approximating the denominator degrees of freedom.  Least square geometric means will be 
estimated for each treatment and the corresponding 90% confidence intervals will be obtained.  
The difference between SAF312 and vehicle, the p-value, and the corresponding 90% 
confidence interval will be obtained from the model.
Efficacy analyses will be performed on both of the primary PD dataset (completers only) and 
the secondary PD dataset (completers and non-completers). Completers are defined as patients 
who completed treatment through Day 4 in both eyes / treatment periods.  The primary 
efficacy analysis will be the one based on the primary PD dataset.
11.4.3
Handling of missing values/censoring/discontinuations
An additional equal number of subjects may be enrolled for subjects who withdraw from the 
study for reasons other than safety. Decisions regarding enrollment of these additional 
subjects will be discussed with the sponsor on a case-by-case basis.


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11.4.4
Sensitivity analyses
To account for the potential influence of the rescue medication on the primary endpoints, we 
plan to use three different approaches of analyzing the VAS pain scores and calculating the 
average (0-12hr) (assuming that the influence window of rescue medication is 4 hours): 
(1) any recorded VAS pain score at time points within 4 hours of the use of rescue medication 
will be considered missing; (2) all the recorded VAS pain scores will be used; (3) any 
recorded VAS pain score at time points within 4 hours of the use of rescue medication will be 
imputed by the record taken prior to the use of rescue medication. We will use the first 
approach as the primary analysis, and the other two for help with the decision making.
11.5
Analysis of secondary variable(s)
11.5.1
Efficacy / Pharmacodynamics
The secondary efficacy analysis will assess the effect of SAF312 
eye drops on whether 
patients need oral analgesics in 12 hours, 24 hours, 2 days, and 3 days post-operatively 
compared to vehicle, as well as the amount of oral analgesics needed in 12 hours, 24 hours, 2 
days, and 3 days post-operatively compared to vehicle.  Number of patients who do not use 
oral analgesics from each treatment group will be reported by each assessment time post-
operatively. McNemar’s test will be used to analyze the difference of the numbers of patients 
who take or do not take oral analgesics between SAF312 and vehicle.  The amount of oral 
analgesics needed will be analyzed
at each assessment time post-operatively.
Efficacy analyses will be performed on both of the primary PD completer-only dataset 
(completers only) and the secondary PD all-subject dataset (completers and non-completers). 
Completers are defined as patients who completed treatment through Day 4 in both eyes / 
treatment periods.
11.5.2
Safety
The following safety assessments will be descriptively analyzed:

AEs and SAEs

Vital signs (blood pressure, pulse rate, and body temperature)

Ocular assessments 

Visual acuity

Intraocular pressure (IOP)

Dilated fundus exam

Ocular hyperemia

Size of epithelial defect by slit lamp exam

Blink rate

Tear production

Epithelial defects


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Vital signs
All vital signs data will be listed by treatment group, subject, and visit/time, and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment group and subject.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment. An adverse event starting in one 
period/epoch and continuing into the next period/epoch is counted only in the onset period. 
A subject with multiple adverse events within a body system and treatment period/epoch is 
only counted once towards the total of this body system and treatment.
Ocular assessments
All ocular assessments will be listed by treatment, subject, visit/time and eye. 
Summary statistics will be provided descriptively by treatment, visit/time and eye.
11.5.3
Pharmacokinetics
SAF312 plasma concentration data will be listed by treatment, subject, and visit/sampling 
time point. Descriptive summary statistics will be provided by treatment and visit/sampling 
time point including the frequency (n) of concentrations.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum and maximum. An exception to this is Tmax where median, 
minimum and maximum will be presented. Concentrations below LLQ will be treated as zero 
in summary statistics and for PK parameter calculations. A geometric mean will not be 
reported if the dataset includes zero values. PK parameters will be calculated as described in 
Section 8.5 and will be listed by treatment and subject.
11.5.4
Pharmacokinetic / pharmacodynamic interactions
There are no known PD markers to be evaluated in the study. However, ocular surface 
temperature is being explored as a potential biomarker.
11.5.5
Other assessments
Not applicable
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11.7
Sample size calculation
The study will be considered positive if:

ocular pain VAS at 6 hours post-operatively for SAF312 is statistically significantly lower 
compared to vehicle, OR

average of ocular pain VAS up to 12 hours post-surgery (average 0-12 hrs) for SAF312 is 
statistically significantly lower compared to vehicle.
This study will randomize approximately 40 patients in a 1:1 ratio between two sequences, to 
provide approximately 30 patients (60 eyes) evaluable for the primary endpoints.  A total of 
60 eyes will provide approximately 83% power to reject the null hypothesis of equality of 
mean VAS at the 0.1 level of significance (two-sided) in unilateral parallel design, assuming a 
treatment difference of 20 mm and standard deviation of 30 mm. The basis for the treatment 
difference assumption is Sher et al 1993, which is a study comparing Diclofenac to vehicle on 
pain severity in PRK subjects wherein a treatment difference ranging from 15 mm to 30 mm 
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(adjusted for a 100 mm scale) was reported between 6-hour and 12-hour post PRK with 
maximum difference observed at about 6-hour post PRK time point.  With bilateral cross-over 
design, the power is expected to be higher than that estimated from the unilateral parallel 
design as we expect high correlation between the two eyes from the same subject.  
While there is no adequate data to inform exact sample size calculation for the average (0-12 
hrs) endpoint, we assume that the sample size based on the mean VAS will also be adequate 
for the comparison based on the average (0-12 hrs) endpoint. 
11.8
Power for analysis of key secondary variables
Not applicable
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12
Ethical considerations
12.1
Regulatory and ethical compliance
This clinical study was designed and shall be implemented, executed and reported in 
accordance with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with 
applicable local regulations (including European Directive 2001/20/EC, US Code of Federal 
Regulations Title 21, and Japanese Ministry of Health, Labor, and Welfare), and with the 
ethical principles laid down in the Declaration of Helsinki.
12.2
Responsibilities of the investigator and IRB/IEC
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion 
from the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial 
protocol, written informed consent form, consent form updates, subject recruitment 
procedures (e.g. advertisements) and any other written information to be provided to subjects. 
Prior to study start, the investigator is required to sign a protocol signature page confirming 
his/her agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data and 
records to Novartis monitors, auditors, Novartis Quality Assurance representatives, designated 
agents of Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the 
clinical site is requested by a regulatory authority, the investigator must inform Novartis 
immediately that this request has been made.
For multi-center trials, a Coordinating Investigator will be selected by Novartis around the 
time of Last Patient Last Visit to be a reviewer and signatory for the clinical study report. 
12.3
Publication of study protocol and results
The key design elements of this protocol will be posted in a publicly accessible database such 
as clinicaltrials.gov. In addition, upon study completion and finalization of the study report 
the results of this trial will be either submitted for publication and/or posted in a publicly 
accessible database of clinical trial results.
13
Protocol adherence
This protocol defines the study objectives, the study procedures and the data to be collected 
on study participants. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances is an 
investigator allowed to collect additional data or conduct any additional procedures for any 
research related purpose involving any investigational drugs under the protocol.
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC and health authorities, where required, it cannot be 
implemented.


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13.1
Protocol Amendments
Any change to the protocol can only be made in a written protocol amendment that must be 
approved by Novartis, Health Authorities where required, and the IRB/IEC prior to 
implementation.
Amendments that are intended to eliminate an apparent immediate hazard to subjects may be 
implemented immediately, provided the Health Authorities are subsequently notified by 
protocol amendment and the reviewing IRB/IEC is notified.
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any subject included in this 
study, even if this action represents a deviation from the protocol. In such cases, the reporting 
requirements identified in Section 9 (Safety Monitoring) must be followed and the Study Lead 
informed.


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14
References
Anttonen O, Junttila MJ, Rissanen H, et al (2007) Prevalence and prognostic significance of 
short QT interval in a middle-aged Finnish population. Circulation p. 714-20.
Bates BD, Mitchell K, Keller JM, et al (2010) Prolonged analgesic response of cornea to 
topical resiniferatoxin, a potent TRPV1 agonist. Pain p. 522-8.
Mergler S, Valtink M, Coulson-Thomas VJ, et al (2010) TRPV channels mediate 
temperature-sensing in human corneal endothelial cells. Exp. Eye Res. p. 758-70.
Murata Y, Masuko S (2006) Peripheral and central distribution of TRPV1, substance P and 
CGRP of rat corneal neurons. Brain Res. p. 87-94.
Okada Y, Reinach PS, Shirai K, et al (2011) TRPV1 involvement in inflammatory tissue 
fibrosis in mice. Am. J. Pathol. p. 2654-64.
Pan Z, Wang Z, Yang H, et al (2011) TRPV1 activation is required for hypertonicity-
stimulated inflammatory cytokine release in human corneal epithelial cells. Invest. 
Ophthalmol. Vis. Sci. p. 485-93.
Qazi Y, Hurwitz S, Khan S, et al (2016) Validity and Reliability of a Novel Ocular Pain 
Assessment Survey (OPAS) in Quantifying and Monitoring Corneal and Ocular Surface Pain. 
Ophthalmology p. 1458-68.
Sher NA, Frantz JM, Talley A, et al (1993) Topical diclofenac in the treatment of ocular pain 
after excimer photorefractive keratectomy. Refract Corneal Surg p. 425-36.
Sumioka T, Okada Y, Reinach PS, et al (2014) Impairment of corneal epithelial wound 
healing in a TRPV1-deficient mouse. Invest. Ophthalmol. Vis. Sci. p. 3295-302.
Woreta FA, Gupta A, Hochstetler B, et al (2013) management of post-photorefractive 
keratectomy pain. Survey Ophthalmology 58(6):529-35.
Yang Y, Yang H, Wang Z, et al (2013a) Functional TRPV1 expression in human corneal 
fibroblasts. Exp. Eye Res. p. 121-9.
Yang Y, Yang H, Wang Z, et al (2013b) Wakayama symposium: dependence of corneal 
epithelial homeostasis on transient receptor potential function. Ocul Surf p. 8-11.
Zhang F, Yang H, Wang Z, et al (2007) Transient receptor potential vanilloid 1 activation 
induces inflammatory cytokine release in corneal epithelium through MAPK signaling. J. Cell. 
Physiol. p. 730-9.

SAP_001.pdf: 
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SAP
CSAF312X2201
Biostatistics & Statistical Programming / 
Novartis Institutes for BioMedical Research
SAF312
CSAF312X2201
A randomized, vehicle-controlled, subject and investigator-
masked, proof-of-concept study to evaluate the use of 
topical ocular SAF312 in the treatment of postoperative 
ocular pain in patients undergoing photorefractive 
keratectomy (PRK) surgery
Statistical Analysis Plan (SAP)
Document type:
SAP Documentation – NIBR 
Document status:
Final/Amendment 2
Release date:
22-Mar-2018
Number of pages:
14
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Personal Data


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................3
1
Introduction .........................................................................................................................4
1.1
Scope of document ..................................................................................................4
1.2
Study reference documentation ...............................................................................4
1.3
Study objectives.......................................................................................................4
1.3.1. Primary objective(s).......................................................................................4
1.3.2. Secondary objective(s)...................................................................................4
1.4
Study design and treatment......................................................................................5
2
First interpretable results (FIR) ...........................................................................................6
4
Statistical methods: Analysis sets........................................................................................8
5
Statistical methods for Pharmacokinetic (PK) parameters..................................................9
5.1
Variables..................................................................................................................9
5.2
Descriptive analyses ................................................................................................9
6
Statistical methods for Pharmacodynamic (PD) parameters.............................................10
6.1
Primary objective...................................................................................................10
6.1.1
Variables ...............................................................................................10
6.1.2
Descriptive analyses..............................................................................10
6.1.3
Statistical model, assumptions and hypotheses.....................................10
6.2
Secondary objective...............................................................................................11
6.2.1
Variables ...............................................................................................11
6.2.2
Descriptive analyses..............................................................................12
6.2.3
Statistical model, assumptions and hypotheses.....................................12
7
Statistical methods for safety and tolerability data............................................................12
7.1.1
Variables ...............................................................................................13
7.1.2
Descriptive analyses..............................................................................13
7.1.3
Graphical presentation ..........................................................................13
List of tables
Table 4-1
Protocol deviation codes and analysis sets..............................................8
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1
Introduction 
1.1
Scope of document
The RAP documents contain detailed information to aid the production of Statistics & 
Programming input into the Clinical Study Report (CSR) for trial “CSAF312X2201”.
The Statistical analysis plan (SAP) describes the implementation of the statistical analysis 
planned in the protocol.
1.2
Study reference documentation
Final study protocol (V02) is available at the time of finalization of Statistical Analysis Plan.
1.3
Study objectives
1.3.1. Primary objective(s)
Primary objective(s)
Endpoints related to primary objectives

To evaluate pain control in the 
immediate post-operative period.

Visual analog scale (VAS) pre-dose pain 
assessment at 6 hours post-operatively.

Average ocular pain VAS assessments 
from the first post-operative assessment 
up to the pre-dose 12 hour assessment.
1.3.2. Secondary objective(s)
Secondary objective(s)
Endpoints related to secondary objective(s)

To evaluate the efficacy of SAF312 
 eye drops four times daily for 
reducing use of oral analgesics 
following PRK procedure.

Incidence of and amount of rescue 
oral analgesics needed in 6 hours, 12 
hours, 24 hours, 2 days, and 3 days 
post-operatively after each PRK 
surgery.

To assess the safety and tolerability 
of SAF312 
 eye drops four 
times daily.

AEs and SAEs.

Visual acuity, intraocular pressure 
(IOP), dilated fundus exam, ocular 
hyperemia.

Size of epithelial defect by slit lamp 
exam.

Blink rate, tear production

Vital signs (blood pressure, pulse 
rate, and body temperature).


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1.4
Study design and treatment
This is a proof-of-concept, subject and investigator-masked, randomized, vehicle controlled 
study of SAF312 administered as eye drops in addition to standard of care treatments in patients 
after photorefractive keratectomy (PRK) surgery. Patients will be randomized to two sequences: 
1) SAF312, followed by vehicle, or 2) vehicle, followed by SAF312. Each patient will receive 
the assigned dose four times daily for 72 hours following PRK surgery on their study eye (Day 
1, Periods 1 and 2). The initial study eye will be the non-dominant eye as established at 
screening and in agreement of the patient and the PI. Each patient will return for follow-up 
visits on Days 2, 3, 4 and 8 after surgery of Periods 1 and 2.

To evaluate pain severity post-
operatively

All VAS measurements during the 
first 3 days after surgery.

To assess the systemic exposure after 
ocular dosing of SAF312 
 eye 
drops four times daily at various time 
points in PRK patients.

Plasma concentration of SAF312.
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Figure 1-1: Study design
2
First interpretable results (FIR)
The template shows the analysis / results to be presented in the FIR. Study outputs required to 
be created at the time of the FIR will be highlighted in TFL shells document and marked as 
“Key” in the Programming Deliverables Tracker (PDT) output list. 
FIR will focus on the following analyses:

Analysis populations (if needed)

Subject disposition

Demographics and baseline characteristics.

Safety results
o
Number and percentage of subjects with adverse events by body system – Ocular
o
Number and percentage of subjects with adverse events by body system – Non-
ocular
o
Overall incidence of AEs—number of events and number of subjects, to include 
AEs of mild, moderate and severe intensity, SAEs, AEs leading to 
discontinuation of study and Study-drug related AEs leading to discontinuation 
of study.

Pharmacokinetic results for plasma:
o
Total SAF312 plasma concentration-time profiles: Overlaying mean (SD) plot.

Pharmacodynamic analyses will be provided for the completers population 
Pharmacodynamic analyses will include, but are not limited to: 
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o
Table of model estimated treatment comparison of VAS pain assessment at 6 
hours post-operatively
o
Plot of model estimated means with SE of VAS pain assessment over time by 
treatment (overlaid).
o
Table of model estimated treatment comparison of average VAS pain 
assessment (0-12hr) 
o
Proportion of oral analgesics use incidence
o
McNemar’s test of oral analgesics use incidence
o
Summary of the amount of oral analgesics use by treatment during the four time 
intervals
o
Wilcoxon signed rank test of the amount of oral analgesics tablets during the 
four time intervals: 0-6 hours post-operatively, 0-12 hours post-operatively, 0-
24 hours post-operatively, 0-2 days post-operatively and 0-3 days post-
operatively
o
Histogram of patients taking 0, 1, 2, 3, or 4 rescue oral analgesic tablets during 
the first 24 hours after surgery (0-24 hours post-operatively) by treatment.
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4
Statistical methods: Analysis sets
For subjects for which the actual treatment received does not match the randomized treatment,
the treatment actually received will be used for the analysis.
For subjects for which the actual sequence of treatments received does not match the 
randomized sequence of treatments, the actual sequence will be used for analysis involving a 
sequence component (e.g. ANOVAs with a sequence effect) if the actual sequence is one of the 
sequences planned in the study design. If the actual sequence is not one of the sequences 
planned in the study design, the actual randomized sequence will be used for analysis involving 
a sequence component but data points from periods in which the subject has not received the 
randomized treatment will be excluded from the analysis. 
All subjects that received study drug and with no protocol deviations with relevant impact on 
safety will be included in the safety analysis set.
The PK analysis set will include all subjects with at least one available valid (i.e. not flagged 
for exclusion) PK concentration measurement, who received any study drug and experienced
no protocol deviations with relevant impact on PK data.
The primary PD analysis set for primary efficacy analysis will contain all patients who 
experienced no protocol deviations with relevant impact on VAS data.
The secondary PD analysis set will contain all patients who experienced no protocol deviations 
with relevant impact on PD data.
The analysis sets and protocol deviation codes are related as follows:
Table 4-1
Protocol deviation codes and analysis sets
Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from all (safety) analysis in case of these 
PDs: 
Exclude subject completely 
from all (safety) analysis 
sets
Subjects are excluded from PK analysis in case of these PDs: 
Exclude subject from PK 
analysis set 
Subjects are excluded from primary PD analysis in case of these 
PDs:
Exclude subject from
primary PD analysis set
OTH13
VAS data entry mechanism issue affecting all 
visits


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Category
Deviation code
Text description of deviation
Data exclusion
Subjects are excluded from secondary PD analysis in case of 
these PDs:
Exclude subject from 
secondary PD analysis sets
If updates to this table are needed, an amendment to the SAP needs to be implemented prior to 
DBL.
5
Statistical methods for Pharmacokinetic (PK) parameters
All subjects within the PK analysis set will be included in the PK data analysis.
5.1
Variables 
The following pharmacokinetic parameters will be determined as feasible, assuming sufficient 
data exists, using the actual recorded sampling times and non-compartmental method(s) with 
Phoenix WinNonlin (Version 6.4 or higher): Cmax, Cmin (pre-dose), Tmax, AUClast, AUC0-
t, Clast and Tlast from the plasma concentration-time data. Other PK parameters may be 
calculated if deemed necessary.
5.2
Descriptive analyses
SAF312 plasma concentrations will be listed by treatment, subject, and visit/sampling time 
point. Descriptive summary statistics will be provided by treatment and visit/sampling time 
point including the frequency and percentage of concentrations below LLOQ. 
Pharmacokinetic parameters will be calculated as described in Section 5.1 and will be listed by 
treatment and subject. Descriptive summary statistics will be provided by treatment and visit.
Summary statistics will include mean (arithmetic and geometric), SD, CV (arithmetic and 
geometric), median, minimum, maximum, and the frequency (n, %) of concentrations below 
the LLOQ. An exception to this is Tmax where only median, minimum and maximum will be 
presented. Concentrations below LLOQ will be treated as zero in summary statistics and for PK 
parameter calculations. A geometric mean will not be reported if the dataset includes zero 
values.
Graphical methods will be employed to show mean and individual concentration-time profiles:

Arithmetic mean (SD) of SAF312 plasma concentration data will be plotted across time 
in both linear view and semi-logarithm view. 

Overlaying individual SAF312 plasma concentration-time profiles by day as applicable 
will be generated. 

Individual SAF312 plasma concentration-time profiles will be generated. 
Graphical methods will be employed to show mean Cmin time profiles.


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6
Statistical methods for Pharmacodynamic (PD) parameters
The primary and secondary analyses will be performed on the PD dataset.
6.1
Primary objective
The primary objective of this trial is to evaluate pain control in the immediate post-operative 
period.
6.1.1
Variables 
The primary variables are visual analog scale (VAS) pre-dose pain assessment at 6 hours post-
operatively, and the average ocular pain VAS assessments from the first post-operative 
assessment up to the pre-dose 12 hour post-operative assessment.
6.1.2
Descriptive analyses
The VAS individual assessments will be listed by treatment sequence, subject and visit/time.  
Descriptive statistics will be provided by treatment and visit/time. Summary statistics will 
include mean (arithmetic), SD, CV, median, minimum, maximum. Graphical methods will be 
employed to show arithmetic mean plots with SD over time by treatment.
The average ocular pain VAS assessments from the first post-operative assessment up to the 
pre-dose 12 hour post-operative assessment will also be listed by treatment sequence and 
subject. Descriptive statistics will be provided by treatment. Summary statistics will include 
mean (arithmetic and geometric), SD, CV (arithmetic and geometric), median, minimum, 
maximum. Boxplots will be employed to visualize the data by treatment.
6.1.3
Statistical model, assumptions and hypotheses
VAS pain assessment at 6 hours post-operatively
A longitudinal mixed effect model accounting for the cross-over effect with repeated 
measurement for VAS will be used, with all assessments post-operatively for each period 
included in the analysis up to 3 days post-operatively. The model will include fixed effects of 
treatment, hour post-operatively, period, sequence, the treatment-by-hour post-operatively 
interaction, the hour post-operatively-by-period interaction, and the hour post-operatively-by-
sequence interaction. Repeated measurement over hour post-operatively-by-period for each 
subject will be accounted for using random effects for subjects, for subject-treatment 
combinations within a sequence, and for subject-timepoint combinations within a sequence. 
Kenward-Roger method will be used for approximating the denominator degrees of freedom.
Should model convergence issues occur, the team will choose an appropriate statistical model 
which converges adequately for treatment effect estimation. Least square means will be 
estimated for each treatment-by-hour post-operatively combination for each treatment and the 
corresponding 90% confidence intervals will be obtained. The difference between SAF312 and 
vehicle, the two-sided p-value, and the corresponding 90% confidence interval will be obtained 
from the model at each time point. The outcome of interest will be the comparison of SAF312 
versus vehicle at the assessment occurring prior to the 6-hour dose post-operatively.
VAS pain assessment average up to 12 hours post-operatively


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The analysis will assess the average ocular pain VAS assessments from the first post-operative 
assessment up to the pre-dose 12 hour post-operative assessment compared to vehicle.
A mixed effect model accounting for the cross-over effect for natural logarithmic transformed 
average (0-12hr) will be used. The model will include fixed effects of treatment, period, and 
sequence and a random effect of subject. Should model convergence issues occur, the team will 
choose an appropriate statistical model which converges adequately for treatment effect 
estimation. Kenward-Roger method will be used for approximating the denominator degrees of 
freedom. Least square geometric means will be estimated for each treatment and the 
corresponding 90% confidence intervals will be obtained by back transforming the estimates to 
the original scale. The geometric mean ratio between SAF312 and vehicle, the two-sided p-
value, and the corresponding 90% confidence interval will be obtained from the model.
6.1.3.1
Handling of missing values/censoring/discontinuations
An additional equal number of subjects may be enrolled for subjects who withdraw from the 
study for reasons other than safety. Decisions regarding enrollment of these additional subjects 
will be discussed with the sponsor on a case-by-case basis.
6.1.3.2
Graphical presentation of results
Model estimated means of the VAS assessments with SE over time by treatment (overlaid) will 
be used to present the model results.
6.1.3.3
Sensitivity analyses
To account for the potential influence of the rescue medication on the primary endpoints, three 
different approaches of analyzing the VAS pain scores and calculating the average (0-12hr) 
(assuming that the influence window of rescue medication is 4 hours) will be used: 
1. any recorded VAS pain score at time points within 4 hours after the use of rescue oral 
analgesics will be considered missing; 
2. all the recorded VAS pain scores will be used; 
3. any recorded VAS pain score at time points within 4 hours after the use of rescue 
medication will be imputed by the record taken prior to the use of rescue medication.
All three approaches will be used as sensitivity for help with the decision making.
An analysis on the log odds of VAS may be added to address the concern that the vehicle 
population may present differently from the literature, which could affect the hypothesized 
effect size.
6.2
Secondary objective
The secondary objective is to evaluate the efficacy of SAF312 
 eye drops four times daily 
for reducing use of oral analgesics following PRK procedure.
6.2.1
Variables 
The secondary variables are:


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1. Incidence of rescue oral analgesics: Number of patients who do not use oral analgesics
in the four time intervals: 0-6 hours post-operatively, 0-12 hours post-operatively, 0-24 
hours post-operatively, 0-2 days post-operatively and 0-3 days post-operatively. 
2. Amount (mg/kg of body weight) of rescue oral analgesics needed during the four time 
intervals: 0-6 hours post-operatively, 0-12 hours post-operatively, 0-24 hours post-
operatively, 0-2 days post-operatively and 0-3 days post-operatively. 
3.
Amount (number of pills) of rescue oral analgesics needed during the four time 
intervals: 0-6 hours post-operatively, 0-12 hours post-operatively, 0-24 hours post-
operatively, 0-2 days post-operatively and 0-3 days post-operatively.
6.2.2
Descriptive analyses
The variables will be listed by treatment sequence, subject and visit/time interval and 
descriptive statistics will be provided by treatment and visit/time interval. For continuous 
variables summary statistics will include mean (arithmetic), SD, CV, median, minimum, 
maximum. Categorical variables will be summarized in frequency tables by treatment and 
visit/time.
Graphical methods will be employed to show group summary plots by time interval and by 
treatment as required. Histograms of patients taking 0, 1, 2, 3, or 4 rescue oral analgesic tablets 
during the first 24 hours after surgery (0-24 hours post-operatively) will be provided by 
treatment.
6.2.3
Statistical model, assumptions and hypotheses
Incidence of rescue oral analgesics
The McNemar’s test will be used to analyze the difference of the numbers of patients who take 
or do not take oral analgesics between SAF312 and vehicle during the five time intervals of 
interest. The associated p-values will be reported.
Amount of oral analgesics needed
The amount (mg/kg body weight, and number of pills) of oral analgesics needed during the five
time intervals of interest will be analyzed by Wilcoxon signed rank test. The associated p-values 
will be reported.
6.2.3.1
Supportive analyses
The amount (mg/kg body weight, and number of pills) of oral analgesics during each of the five
time intervals will be analyzed using a generalized linear mixed effect model. The distribution 
of the amount will be assumed to be Beta-Binomial. The model will include fixed effects of 
treatment, period, and sequence and a random effect of subject. The estimated mean and the 
difference of the two groups, with the associated p-values and the 90% confidence intervals will 
be reported.
7
Statistical methods for safety and tolerability data
All subjects within the Safety analysis set will be included in the safety data analysis.


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7.1.1
Variables 
Adverse events, vital signs (blood pressure, pulse rate, body temperature), and ocular 
assessments (Visual acuity, Intraocular pressure, Dilated fundus exam, Ocular hyperemia, Size 
of epithelial defect by slit lamp exam, blink rate, tear production), as well as subject 
demographics, baseline characteristics, and treatment information.
7.1.2
Descriptive analyses
Subject demographics and other baseline characteristics
All data for background and demographic variables will be listed by treatment sequence and 
subject. Summary statistics will be provided for all subjects, as well as for each treatment 
sequence.
Relevant medical history, current medical conditions, results of laboratory screens, drug tests 
and any other relevant information will be listed by treatment sequence and subject.
Treatment
Data for study drug administration (rescue medication) and concomitant therapies will be listed 
by treatment sequence and subject.
Vital signs
All vital signs data will be listed by treatment sequence, subject, and visit/time and if ranges are 
available abnormalities (and relevant orthostatic changes) will be flagged. Summary statistics 
will be provided by treatment and visit/time.
Adverse events
All information obtained on adverse events will be displayed by treatment and subject. Ocular 
and non-ocular adverse events will be listed and summarized separately.
The number and percentage of subjects with adverse events will be tabulated by body system 
and preferred term with a breakdown by treatment within the following time windows: overall, 
acute (AE’s occurring within 8 days post-operatively in each period and extended period (AE’s 
occurring beyond 8 days post-operatively in each period if applicable). An adverse event 
starting in one period and continuing into the next period is counted only in the onset period. A 
subject with multiple adverse events within a body system and treatment period is only counted 
once towards the total of this body system and treatment.
Ocular assessments
All ocular assessments will be listed by subject and visit/time. Summary statistics will be 
provided descriptively by treatment, visit/time and eye.
7.1.3
Graphical presentation 
Boxplots to visualize trends in longitudinal safety data (vitals) will be created.
Mean and boxplot figures will be presented for selected ocular parameters as needed.


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