Clinical trial NCT04630158
Conditions: Chronic Ocular Pain
Keywords: Eye pain Dry eye like symptoms Ocular surface pain Corneal induced chronic pain neuropathic eye pain post-operative corneal induced chronic pain CICP corneal corneal pain
Sponsor: Novartis Pharmaceuticals
Start date: 2021-04-21; Completion date: 2023-06-08
Enrollment: 153 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The study was designed to demonstrate the safety and efficacy of two dose concentrations of SAF312 eye drops (5 mg/mL and 15 mg/mL) in subjects with CICP persisting at least for 4 months after refractive or cataract surgery and chronicity confirmed during the observational period. The study also determined the optimal dose to carry forward for further development.

Detailed description:
This was a Phase II randomized, double-masked, multi-center, parallel group, placebo-controlled study to evaluate the safety and efficacy of SAF312, 5 mg/mL and 15 mg/mL eye drops versus Placebo used twice-daily in both eyes for 12 weeks. The study consisted of a 12-week observation period starting from Screening Visit (Visit 1) until the Baseline/Randomization Visit (Visit 2). Subjects who met eligibility criteria at Visit 2 were randomized to one of the three treatment arms (SAF312 5 mg/mL, SAF312 15 mg/mL, Placebo) in a 1:1:1 ratio. Subjects who qualified for randomization had visits every 2 weeks for the first 4 weeks, and then monthly visits for the remainder of the 12-week treatment period.

Arms: arm 1: Randomized to a 1:1:1 topical eye drops, twice daily arm 2: Randomized to a 1:1:1 topical eye drops, twice daily arm 3: Randomized to a 1:1:1 topical eye drops, twice daily
Interventions: intervention 1: SAF312 Placebo intervention 2: SAF312
Intervention descriptions: intervention 1: Topical ocular, suspension eye drops intervention 2: Topical ocular, suspension eye drops

Protocol documents:
Prot_000.pdf: 
Novartis Research and Development 
SAF312 
Clinical Trial Protocol CSAF312B12201 / NCT04630158  
A 12-week parallel group, randomized, placebo-controlled, 
double-blinded, multi-center study to evaluate efficacy and 
safety of 2 concentrations of SAF312 eye drops (5 mg/ml 
and 15 mg/ml) used twice-daily in the treatment of post-
operative corneal induced chronic pain (CICP) following 
Photorefractive Keratectomy (PRK) or Laser-assisted in 
Situ Keratomileusis (LASIK) surgeries 
Document type: 
Clinical Trial Protocol 
EUDRACT number: 
Not applicable 
Version number: 
03 
Clinical Trial Phase: 
II 
Release date: 
06-Oct-2021
Property of Novartis  
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018 


Novartis 
Confidential 
Page 2 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 6 
Glossary of terms ................................................................................................................. 8 
Amendment rationale (Version No.3, 06-Oct-2021) ......................................................... 10 
Amendment rationale (Version No.2, 25-Mar-2021) ........................................................ 11 
Amendment rationale (Version No.1, 22-Sep-2020) ........................................................ 12 
Protocol summary .............................................................................................................. 15 
1 
Introduction ....................................................................................................................... 18 
1.1 
Background ............................................................................................................ 18 
1.2 
Purpose .................................................................................................................. 19 
2 
Objectives and endpoints ................................................................................................... 20 
2.1 
Primary Estimands ................................................................................................. 21 
2.2 
Secondary Estimands ............................................................................................. 22 
3 
Study design ...................................................................................................................... 22 
4 
Rationale ............................................................................................................................ 23 
4.1 
Rationale for study design ..................................................................................... 23 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 24 
4.3 
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ...................................................................................................................... 25 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 25 
4.5 
Risks and benefits .................................................................................................. 25 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 26 
5 
Population .......................................................................................................................... 26 
5.1 
Inclusion criteria .................................................................................................... 26 
5.2 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 29 
6.1 
Study treatment ...................................................................................................... 29 
6.1.1 
Investigational and control drugs .......................................................... 29 
6.1.2 
Additional study treatments .................................................................. 29 
6.1.3 
Treatment arms/group ........................................................................... 29 
6.1.4 
Treatment duration ................................................................................ 30 
6.2 
Other treatment(s) .................................................................................................. 30 
6.2.1 
Concomitant therapy ............................................................................. 30 
6.2.2 
Prohibited medication ........................................................................... 30 


Novartis 
Confidential 
Page 3 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
6.2.3 
Rescue medication ................................................................................ 30 
6.3 
Subject numbering, treatment assignment, randomization .................................... 31 
6.3.1 
Subject numbering ................................................................................ 31 
6.3.2 
Treatment assignment, randomization .................................................. 31 
6.4 
Treatment blinding ................................................................................................. 31 
6.5 
Dose escalation and dose modification .................................................................. 32 
6.5.1 
Dose modifications ................................................................................ 32 
6.5.2 
Follow-up for toxicities ......................................................................... 32 
6.6 
Additional treatment guidance ............................................................................... 32 
6.6.1 
Treatment compliance ........................................................................... 32 
6.6.2 
Recommended treatment of adverse events .......................................... 32 
6.6.3 
Emergency breaking of assigned treatment code .................................. 32 
6.7 
Preparation and dispensation ................................................................................. 33 
6.7.1 
Handling of study treatment and additional treatment .......................... 33 
7 
Informed consent procedures ............................................................................................ 34 
8 
Visit schedule and assessments ......................................................................................... 35 
8.1 
Screening ............................................................................................................... 40 
8.1.1 
Information to be collected on screening failures ................................. 40 
8.2 
Subject demographics/other baseline characteristics ............................................. 41 
8.3 
Efficacy .................................................................................................................. 41 
8.3.1 
Pain Severity and Frequency Visual Analog Scales ............................. 41 
8.3.2 
OPAS questionnaire .............................................................................. 42 
 
 42 
8.3.4 
Appropriateness of efficacy assessments .............................................. 42 
8.4 
Safety ..................................................................................................................... 42 
8.4.1 
Laboratory evaluations .......................................................................... 42 
8.4.2 
Pregnancy .............................................................................................. 43 
8.4.3 
Visual Acuity ........................................................................................ 43 
8.4.4 
Slit Lamp Examination ......................................................................... 43 
8.4.5 
Intraocular Pressure ............................................................................... 43 
8.4.6 
Dilated Fundus Exam ............................................................................ 43 
8.4.7 
Corneal Endothelial Cell Microscopy ................................................... 43 
8.4.8 
Appropriateness of safety measurements .............................................. 44 
8.5 
Additional assessments .......................................................................................... 44 
8.5.1 
Other Assessments ................................................................................ 44 
9 
Discontinuation and completion ........................................................................................ 48 


Novartis 
Confidential 
Page 4 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
9.1 
Discontinuation ...................................................................................................... 48 
9.1.1 
Discontinuation of study treatment ....................................................... 48 
9.1.2 
Discontinuation from study ................................................................... 49 
9.1.3 
Lost to follow-up ................................................................................... 49 
9.2 
Withdrawal of informed consent/Opposition to use data/biological samples ....... 49 
9.3 
Study completion and post-study treatment .......................................................... 50 
9.4 
Early study termination by the sponsor ................................................................. 50 
10 Safety monitoring and reporting ........................................................................................ 51 
10.1 
Definition of adverse events and reporting requirements ...................................... 51 
10.1.1 
Adverse events ...................................................................................... 51 
10.1.2 
Serious adverse events .......................................................................... 52 
10.1.3 
SAE reporting........................................................................................ 53 
10.1.4 
Pregnancy reporting .............................................................................. 53 
10.1.5 
Reporting of study treatment errors including misuse/abuse ................ 54 
10.2 
Additional Safety Monitoring ................................................................................ 55 
11 Data Collection and Database management ...................................................................... 55 
11.1 
Data collection ....................................................................................................... 55 
11.2 
Database management and quality control ............................................................ 55 
11.3 
Site monitoring ...................................................................................................... 56 
12 Data analysis and statistical methods ................................................................................ 56 
12.1 
Analysis sets .......................................................................................................... 56 
12.2 
Subject demographics and other baseline characteristics ...................................... 57 
12.3 
Treatments ............................................................................................................. 57 
12.4 
Analysis of supporting primary objectives ............................................................ 57 
12.4.1 
Definition of primary endpoint(s) ......................................................... 57 
12.4.2 
Statistical model, hypothesis, and method of analysis .......................... 57 
12.4.3 
Handling of intercurrent events of primary estimand ........................... 58 
12.4.4 
Handling of missing values not related to intercurrent event ............... 58 
12.4.5 
Sensitivity analyses for primary endpoint/estimand ............................. 58 
12.4.6 
Supplementary analysis ......................................................................... 59 
12.5 
Analysis supporting secondary objectives ............................................................. 59 
12.5.1 
Safety endpoints .................................................................................... 60 
12.5.2 
Patient reported outcomes ..................................................................... 61 
 
 61 
12.7 
Interim analyses ..................................................................................................... 61 
12.8 
Sample size calculation .......................................................................................... 62 


Novartis 
Confidential 
Page 5 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
12.8.1 
Primary endpoint(s) ............................................................................... 62 
13 Ethical considerations and administrative procedures ...................................................... 62 
13.1 
Regulatory and ethical compliance ........................................................................ 62 
13.2 
Responsibilities of the investigator and IRB/IEC .................................................. 62 
13.3 
Publication of study protocol and results............................................................... 63 
13.4 
Quality Control and Quality Assurance ................................................................. 63 
14 Protocol adherence ............................................................................................................ 63 
14.1 
Protocol amendments ............................................................................................. 64 
15 References ......................................................................................................................... 65 
16 Appendices ........................................................................................................................ 66 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 20 
Table 6-1 
Investigational and control drug ............................................................ 29 
Table 6-2 
Prohibited medication ........................................................................... 30 
Table 8-1 
Assessment Schedule ............................................................................ 36 
Table 8-2 
Proposed in-office Assessment Sequence ............................................. 39 
Table 8-3 
Grading of Conjunctival Staining ......................................................... 46 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ......................................................................................... 54 
Table 12-1 
Power to detect a significant difference from placebo under 
different assumed treatment effects and SD with N = 50 pts/arm ........ 62 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 22 
Figure 8-1 
McMonnies Redness Photographic Scale ............................................. 44 
Figure 8-2 
Corneal Fluorescein Modified NEI Scale ............................................. 45 
 


Novartis 
Confidential 
Page 6 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
List of abbreviations 
AE 
adverse event 
AESI 
adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical 
AUC 
Area under the curve 
B-hCG 
Beta-human chorionic gonadotropin 
b.i.d. 
twice a day 
CFR 
Code of Federal Regulation 
CICP 
Corneal Induced Chronic Pain 
Cmax 
Maximum of serum concentration 
CMO&PS 
Chief Medical Office and Patient Safety  
CO 
Clinical Operation 
COVID-19 
Coronavirus disease 2019 
CRA 
Clinical Research Associate 
CRC 
Central Reading Center 
CRF 
Case Report/Record Form (paper or electronic) 
CTT 
Clinical Trial Team 
D 
Death 
EC 
Ethics committee 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EMA 
European Medicines Agency 
EOS 
End of Study 
EOT 
End of Treatment 
ePRO 
Electronic Patient Reported Outcome 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FIH 
First in human 
GCP 
Good Clinical Practice 
GCS 
Global Clinical Supply 
ICH 
International Council for Harmonization 
IE 
Intercurrent Events 
IEC 
Independent Ethics Committee 
IMP 
Investigational medicinal product 
IN 
Investigator Notification 
IOP 
Intraocular Pressure 
IRB 
Institutional Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine device 
IUS 
Intrauterine system 
IVCM 
In Vivo Confocal Microscopy 


Novartis 
Confidential 
Page 7 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
LASEK 
Laser Assisted Sub-Epithelial Keratectomy 
LASIK 
Laser-assisted in Situ Keratomileusis 
LSM 
Least square mean 
MAR 
Missing at Random 
MedDRA 
Medical dictionary for regulatory activities 
MFD 
Maximum feasible dose 
mg 
milligram(s) 
mL 
milliliter(s) 
ml 
milliliter(s) 
MMRM 
Mixed model repeated measure 
NGF 
Nerve growth factor 
OPAS 
Ocular Pain Assessment Scale 
PK 
pharmacokinetic(s) 
PRK 
Photorefractive Keratectomy 
RDO 
Retrieved Dropped Out 
RK 
Radial Keratotomy 
QMS 
Quality Management System 
REML 
Residual/restricted maximum likelihood 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SMILE 
Small Incision Lenticule Extraction 
SMQ 
Standardized MedDRA Query 
SUSAR 
Suspected Unexpected Serious Adverse Reactions 
TRPV1 
Transient Receptor Potential Vanilloid 1  
UTE 
Unsatisfactory therapeutic effect 
VA 
Visual acuity 
VAS 
Visual Analogue Scale 
WoC 
Withdrawal of consent 
WHO 
World Health Organization 


Novartis 
Confidential 
Page 8 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
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)  
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of 
care 
Enrollment 
Point/time of subject entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol). 
Estimand  
A precise description of the treatment effect reflecting the clinical question 
posed by the trial objective. It summarizes at a population-level what the 
outcomes would be in the same patients under different treatment 
conditions being compared. Attributes of an estimand include the 
population, variable (or endpoint) and treatment of interest, as well as the 
specification of how the remaining intercurrent events are addressed and a 
population-level summary for the variable. 
Investigational drug 
The study drug whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug” or “investigational medicinal product”. 
Medication number 
A unique identifier on the label of each study drug package in studies that 
dispense study drug using an IRT system. 
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 
Period 
A minor subdivision of the study timeline; divides phases into smaller 
functional segments such as screening, baseline, titration, washout, etc. 
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 
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/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. 
Discontinuation from 
study 
Point/time when the participant permanently stops receiving the study 
treatment and further protocol required assessments or follow-up, for any 
reason. No specific request is made to stop the use of their samples or 
data. 
Discontinuation from 
study treatment 
Point/time when the participant permanently stops receiving the study 
treatment for any reason (prior to the planned completion of study drug 


Novartis 
Confidential 
Page 9 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
administration, if any). Participant agrees to the other protocol required 
assessments including follow-up. No specific request is made to stop the 
use of their samples or data. 
Subject 
An individual who has consented to participate in this study. The term 
Subject may be used to describe either a healthy volunteer or a patient. 
Subject number 
A number assigned to each subject who enrolls in the study. When 
combined with the center number, a unique identifier is created for each 
subject in the study. 
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 
Vehicle 
A vehicle refers to the inactive version of the investigational medicinal 
product (IMP) i.e., it contains all the components of the IMP with the 
exception of the drug (active ingredient).  In this protocol, the term placebo 
may be used interchangeably with vehicle as the placebo also does not 
contain any drug (active ingredient). 
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 
 
 
 


Novartis 
Confidential 
Page 10 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Amendment rationale (Version No.3, 06-Oct-2021) 
The main purpose of this amendment is to modify the types of refractive surgery to be included, 
as well as revise some of the inclusion criteria so that the patients recruited for the study will 
be more representative of the true population of patients experiencing post-operative corneal 
induced chronic pain. This amendment also makes specific allowance for optometrists to serve 
as a primary care provider for the purposes of the study. 
 
• Section 5 “Population” and throughout the document : To modify the types of 
refractive surgery in the study population so that it is inclusive of subjects with various 
types of corneal refractive surgery or cataract surgery in both eyes (including LASEK, 
RK, SMILE and Cataract surgeries) with resulting CICP.  
• Section 5.1 Revised Inclusion Criteria #2 to #2a: Revision of the criterion to include 
optometrist since in some US states, optometrists may be the primary eye care 
professional managing patients with post-surgical CICP.  
• Section 5.1 Revised Inclusion Criteria #3 to #3a: Revision of Visit 1 pain severity 
question to “worst pain over the last 7 days”. Since chronic pain fluctuates, this single 
screening question may be more representative of their overall experience with CICP. 
The ocular pain severity VAS cutoff is revised from ≥ 50 mm to ≥ 30 mm.  
• Section 5.1 Revised Inclusion Criteria #5 to #5a: The last 7 days average pain severity 
VAS prior to the Baseline visit (Visit 2) is revised from ≥ 50 mm to ≥ 30 mm to align 
with threshold value outlined in Inclusion Criteria #3a at screening visit. 
• Section 5.2 Revised Exclusion Criteria #1 to #1a: Since many CICP are using bandage 
and scleral lenses as non-pharmacological treatment for CICP, this patient group is now 
included. 
• Section 5.2 Revised Exclusion Criteria #20 to #20a: Remove the duplicative text similar 
to Exclusion Criteria #14. The criteria is also updated to exclude the subject who is 
unable or willing to comply with the protocol requirements.  
• Section 8.1 “Screening”: Addition of clarification under what circumstance re-screening 
is permitted under the current protocol version. 
• Tablet 8-1 and Table 8-2: To include “Contact IRT” as a mandatory task in the 
assessment schedule and the proposed sequence to perform the task   
• Section 8.5.1.8 “Post-Anesthetic Severity of Eye Pain: Anesthetic procedure is updated 
to align with other modifications in this amendment 
• Section 12.4.6 Revised the supplementary estimand based on treatment policy strategy.  
 


Novartis 
Confidential 
Page 11 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Amendment rationale (Version No.2, 25-Mar-2021)  
The main purpose of this amendment is to provide clarifications and updates on various aspects 
of the protocol, as well as update required elements as per the new OneCTP Protocol template 
Version 4.0. 
• Revision per the updated protocol template of “Treatment discontinuation” 
to “Discontinuation of study treatment” in the protocol where applicable  
• Section 2 “Primary Estimands”: Update to primary estimand 
• Addition of Section 4.6 “Rationale for Public Health Emergency mitigation 
procedures” per the updated protocol template 
• Section 5.1 “Inclusion Criteria”: Revision and clarification for select criteria  
• Section 5.2 “Exclusion Criteria”: Revision and clarification for select criteria  
• Section 6.1.1 “Investigational and control drugs”: Revised “unblinded study personnel” 
to “unblinded site personnel” for clarification  
 
 
 
• Table 6-2 “Prohibited medication”: Clarification to prohibited medication table 
• Section 6.4 “Treatment blinding”: Removal of unblinded study role since the updated 
study medication packaging design does not reveal the appearance of the study 
medication while performing the study medication accountability check. 
• Section 6.7 “Preparation and dispensation”: Revised “unblinded study personnel” to 
“unblinded site personnel” for clarification  
• Section 7 “Informed consent procedures”: Revision with the text in alignment with 
addition of Section 4.6 “Rationale for Public Health Emergency mitigation procedures” 
per the updated protocol template 
• Section 8 “Visit schedule and assessments”: Revision and clarification for the schedule 
of assessment  
• Section 8.2 “Subject demographics/other baseline characteristics” Addition of baseline 
characteristics to align wit with the information to be captured in the CRF 
• Section 8.3 “Efficacy” Revision and clarification for selected parameters in efficacy 
section 
• Section 8.4 “Safety” Revision and clarification for selected parameters in safety section 
• Section 8.5 “Additional assessments” Clarification and addition of description for 
assessments under this section 
• Section 9  “Discontinuation and completion”: Addition, revision and re-numbering of 
the section according to the new protocol template 


Novartis 
Confidential 
Page 12 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
x Section 10 “Safety monitoring and reporting”: Minor revision of the wording according 
to new protocol template 
x Section 12 “Data analysis and statistical methods”  Statistical analysis and methods were 
revised with the following: 
x 12.4.2: Randomization strata removed from the MMRM model 
x 12.4.3: Update to primary estimand 
x 12.4.6: update to supplementary estimand 
Amendment rationale (Version No.1, 22-Sep-2020)  
The main purpose of this amendment is the change of the indication term and study design 
based on FDA recommendations. 
In addition, this amendment includes modifications to account for the COVID-19 pandemic, or 
any similar scenario that may occur during the course of the study.   
Major changes to the protocol 
x Protocol summary: Updated based on the changes within the protocol. 
x Section 1.1 Background: The indication term chronic ocular surface pain (COSP) was 
updated to corneal induced chronic pain (CICP) 
x Section 3 “Study design”: 12-week observation period was added to confirm chronicity 
of eye pain. During the observation period subjects will be contacted by the site via 
phone call for confirmation of pain reporting compliance and safety check-in 
x Section 5 “Population”: Adjustments to inclusion/exclusion criteria to be aligned with 
FDA and clinical site feedback 
o Inclusion criteria 2 – Subjects who have undergone PRK or LASIK surgery in 
both eyes PRQWKVSULRUWRVFUHHQLQJ 
o Inclusion criteria 4 - 6XEMHFWVZKRGHPRQVWUDWHDUHGXFWLRQLQRFXODUSDLQ 
o New inclusion criteria 5 and 6 were added at Baseline visit 
o Exclusion criteria 1 – Clarification of contact lenses use during the study 
o Exclusion criteria 3 – Use of nerve growth factor eye drops within 14 days of 
the Screening Visit was added as a new exclusion criteria 
o Exclusion criteria 8 – Subjects with amniotic membrane transplantation on 
ocular surface within 30 days prior to the Screening Visit was added as a new 
exclusion criteria 
x 
Section 8 “Visit Schedule and Assessments” in Table 8-1 “Assessment schedule” 
additional assessments of the cornea 
 were added or 
updated as follows: Corneal Endothelial Cell Microscopy new examination, 
 
, 
 
 updated and removed ActiGraph. 
The following new sections to evaluate efficacy and safety were added:  
PI


Novartis 
Confidential 
Page 13 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
x Section 8.3.1 Pain Severity and Frequency will be collected separately using VAS  
x Section 8.4.6 Dilated Fundus Exam 
x Section 8.4.7 Corneal Endothelial Cell Microscopy  
The following new assessments were added under Section 8.5: 
x Section 8.5.1.1 In Vivo Confocal Microscopy only at selected sites for exploratory 
analysis  
x Section 8.5.1.3 Corneal Fluorescein Staining the degree of staining is based on 
Modified NEI Scale. Figure 8-2 was added. 
x Section 8.5.1.4 Conjunctival Lissamine Staining will be assessed based on the 
proportion of the staining area. Oxford grading scale was removed. Table 8-3 was 
added 
 
 
 
 
Modifications were made to include revised Estimands per ICH E9 (R1) guidance in the 
following:  
x Section 2 “Objectives and endpoints” in Table 2-1 multiple updates to reflect study 
design changes 
o Primary endpoint was changed from mean global pain Visual Analog Scale 
(VAS) to mean pain severity VAS  
o Updates to the secondary 
 objectives and endpoints 
o Section 2.1 - Addition of Primary Estimands 
Modifications were made to the statistical analysis and methods in the following sections:  
x Section 12 “Data analysis and statistical methods”  Statistical analysis and methods were 
revised with the following  
o Section 12.4 Updated strategy in primary endpoint(s)/estimand(s) 
o Section 12.5 Addition of secondary endpoints  
 
 
o Section 12.8 Possible sample size increase due to the pandemic  
Changes were incorporated to address the COVID-19 pandemic in the following sections: 
x Section 7 Informed Consent Procedures 
x Section 8 Visit Schedule and Assessments 
x Section 8.4 Safety 
Other changes incorporated in this amendment are:  
x List of Abbreviations: Updated with new relevant abbreviations  
x Glossary of terms: Updated with new relevant terms  
Other minor clarifications were made where applicable, including Section 6 “Treatment”, 
Section 8.1 “Screening”, and Section 8.2 Subject demographics” 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
P
I


Novartis 
Confidential 
Page 14 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
 
IRBs/IECs 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 


Novartis 
Confidential 
Page 15 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Protocol summary 
 
Protocol 
number 
CSAF312B12201 
Full Title 
A 12-week parallel group, randomized, placebo-controlled, double-blinded, multi-
center study to evaluate efficacy and safety of 2 concentrations of SAF312 eye 
drops (5 mg/ml and 15 mg/ml) used twice-dailyin the treatment of post-operative 
corneal induced chronic pain (CICP) following Photorefractive Keratectomy 
(PRK) or Laser-assisted in Situ Keratomileusis (LASIK) surgeries. 
Brief title 
Study of efficacy and safety of SAF312 eye drops in subjects with post-operative 
corneal induced chronic pain (CICP) 
Sponsor and 
Clinical Phase 
Novartis Phase II 
Investigation 
type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The study is designed to demonstrate the safety and efficacy of two dose 
concentrations of SAF312 eye drops (5 mg/ml and 15 mg/ml) in subjects with 
CICP persisting at least for 4 months after refractive or cataract surgery and 
chronicity confirmed during the observational period. The study will also 
determine the optimal dose to carry forward for further development. 
Primary 
Objective  
To demonstrate the efficacy of at least 1 of 2 concentrations of SAF312 (5 mg/ml 
or 15 mg/ml) with superiority to placebo in reducing ocular pain severity.  
Secondary 
Objectives 
1. To evaluate additional efficacy of 2 concentrations of SAF312 vs placebo 
(e.g., time to pain improvement, quality of life) 
2. To demonstrate SAF312 does not induce negative effects to the ocular 
surface after prolonged TRPV1 inhibition 
3. To evaluate the safety of 2 concentrations of SAF312 (5 mg/ml and 15 
mg/ml) 
Exploratory 
objectives 
 
 
2. To monitor a subject's behavior regarding use of artificial tear/gel/lubricant 
and rescue medication  
3. To evaluate corneal nerve density and morphology 
Study design 
This study is a Phase 2 randomized, double-blinded, multi-center, parallel group, 
placebo-controlled evaluation of the safety and efficacy of SAF312, 5 mg/ml and 
15 mg/ml eye drops versus placebo used twice-daily in both eyes for 12 weeks. 
Eligible subjects will have undergone refractive surgery (i.e., PRK, LASIK, 
LASEK, RK, or SMILE) or cataract surgery in both eyes with or without refractive 
enhancement in one or both eyes at least 4 months prior to Screening, and have 
been suffering from chronic ocular pain as a result of the their surgery. Eligible 
patients must also demonstrate chronicity of the pain at Baseline Visit as 
described in inclusion criteria. Overall approximately 150 subjects will be enrolled 
in the study and randomized to one of 3 study arms in 1:1:1 ratio 
Population 
7KHVWXG\SRSXODWLRQZLOOFRQVLVWRIVXEMHFWV\HDUVROGZLWKpersistent 
ocular surface pain for at least 4 months after refractive or cataract surgery 
PI


Novartis 
Confidential 
Page 16 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
(including clear lensectomy). The goal is to randomize a total of approximately 
150 subjects. 
Key Inclusion 
criteria 
• 
Subjects who have undergone refractive surgery (i.e., PRK, LASIK, LASEK, 
RK, or SMILE) or cataract surgery in both eyes, with or without refractive 
enhancement in one or both eyes, ≥4 months prior to Screening Visit and 
experiencing persistent ocular surface pain since the surgery, and have been 
seen by an ophthalmologist or optometrist at least once with complaint of 
continued ocular pain since surgery. 
NOTE: The 4 month requirement must be based on the date of the last surgery. 
• 
Subjects who demonstrate a ≥ 60% reduction in ocular pain within 5 minutes 
after instillation of a single topical ocular anesthetic drop at Screening Visit. 
At Baseline 
• 
Subjects with  an average pain severity VAS score of ≥ 30 mm based on Daily 
eDiary for the last 7 days prior to Baseline Visit (Visit 2). 
• 
Subjects who have reported pain severity >10 mm based on Daily eDiary for > 
50% of the days of the observational period (Screening). 
Key Exclusion 
criteria 
• 
Use of nerve growth factor eye drops within 14 days of the Screening Visit 
• 
Seasonal allergic conjunctivitis, or other acute or seasonal ocular diagnosis 
that are active at the time of Screening or would be active during the course of 
the study. 
• 
Any history of ocular herpes simplex virus or herpes zoster virus infection, or 
other severe ocular conditions such as graft versus host disease, Stevens-
Johnson syndrome or sarcoidosis. 
• 
Presence of any ocular infection (bacterial, viral, or fungal) within 30 days prior 
to Screening. 
• 
Chronic topical ocular medications (i.e., cyclosporine, lifitegrast) initiated <6 
months prior to Screening Visit, or any anticipated change during the study. 
• 
Use of ocular or nasal corticosteroids within 30 days of Screening Visit. 
• 
Use of neuromodulatory medications (e.g., gabapentin, pregabalin) or opioid 
use for non-ocular pain within 30 days of Screening Visit. 
• 
Chronic medications (both over the counter and prescription) that have not 
been stable for at least 30 days prior to Screening Visit, or any anticipated 
change in the chronic medication regimen. 
• 
Subjects requiring hospitalization within 6 months prior to screening for severe 
psychiatric 
disorders 
or 
major 
psychiatric 
illness 
(e.g., 
psychosis, 
schizophrenia, mania, depression). 
Study treatment 
Subjects will be assigned one of the following 3 treatments - SAF312 5 mg/ml 
(0.5%), SAF312 15 mg/ml (1.5%) or SAF312 placebo eye drops, administered as 
one drop in each eye twice-daily for three months 
Efficacy 
assessments 
• 
Pain Severity Visual Analog Scale (VAS) 
• 
Pain Frequency VAS 
• 
OPAS questionnaire 
 
 
Key safety 
assessments 
• 
Visual Acuity 
• 
Slit Lamp Examination 
• 
Intraocular Pressure 
• 
Dilated Fundus Exam 


Novartis 
Confidential 
Page 17 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
x 
Corneal Endothelial Cell Microscopy  
Other 
assessments  
x 
In Vivo Confocal Microscopy  
x 
Conjunctival Redness 
x 
Corneal Fluorescein Staining 
x 
Conjunctival Lissamine Staining 
x 
Schirmer's Test 
x 
Pain Characterization Questionnaire 
 
 
 
 
 
Data analysis 
The primary objective of the study is to show that at least one SAF312 arm will 
improve weekly mean pain severity VAS score in comparison with its placebo by 
rejecting the null hypothesis below at a significDQFHOHYHOĮ -sided). Mixed 
model repeated measure (MMRM) analysis will be used with change from baseline 
at each week on treatment as response variable, and treatment, week,  and 
baseline score as covariates. Two interaction term (treatment*week and 
baseline*week) will also be included in the model. The two-sided p value for the 
least square mean (LSM) difference between the SAF312 and the placebo group 
at each week will be reported for the difference.  
Key words 
Eye pain, corneal induced chronic pain (CICP), photorefractive keratectomy 
(PRK), laser-assisted in situ keratomileusis (LASIK), Laser Assisted Sub-
Epithelial Keratectomy (LASEK), Radial Keratotomy (RK), Small Incision 
Lenticule Extraction (SMILE), Cataract, adults, randomized study, placebo 
P
I


Novartis 
Confidential 
Page 18 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
1 
Introduction 
1.1 
Background 
Transient Receptor Potential Vanilloid 1 (TRPV1) receptors belong to the superfamily of TRP 
Ca2+-permeable non-selective cation channels (Clapham et al 2001). These channels are 
expressed primarily on a subset of somatic and visceral primary afferent sensory neurons 
(Holzer 2004; Gunthorpe et al 2002; Hayes et al 2000). TRPV1 can be activated by capsaicin, 
noxious heat, acidic solutions, mechanical distortion, hyperosmolarity and inflammatory 
mediators such as bradykinin, prostaglandins and nerve growth factor (NGF), which are likely 
to be released or upregulated by tissue damage or in specific disease conditions 
(Caterina and Julius 2001; Geppetti and Trevisani 2004). The activation of TRPV1 results in 
nociceptive stimuli interpreted by the brain as pain. Importantly, chronic peripheral nociceptor 
activity can further increase the release of the inflammatory mediators which regulate TRPV1 
activity, and results in a sensitization of the channel and a lowering of its thresholds for 
activation causing hyperalgesia and allodynia. Taken together, these findings indicate that 
TRPV1 is a key integrator of nociceptive and inflammatory response information. 
Accumulating data indicates a primary role for TRPV1 receptors in ocular pain 
(Zhang et al 2007; Yang et al 2013; Mergler et al 2010). Furthermore, the chronic stimulation 
of corneal and conjunctival nerves in many ocular conditions, creates a cycle of stimulus 
amplifications due to damage on the ocular surface, inflammation, and constant exposure of 
inflammatory cytokines in the tears. This is of particular importance in regards to the highly 
innervated cornea. 
SAF312 is a highly selective and potent antagonist of TRPV1. Topical ocular administration of 
SAF312 in nonclinical studies has resulted in high ocular exposure with relatively low systemic 
exposure, which could enable ocular pain management while avoiding known systemic side 
effects associated with TRPV1 antagonism (eg, heat insensitivity, transient hyperthermia, 
autonomic dysreflexia in patients with spinal cord injury). Plasma exposure of SAF312 after 4-
times daily ocular administration of 15 mg/ml (1.5%) eye drops (the highest dose to be used in 
this study) was very low (Day 8 Cmax (maximum of serum concentration), 0.941 ng/mL and 
AUC0-24h, 15.1 ng*h/ml) and at least 100-fold and 37-fold lower than corresponding exposure 
values (Cmax, 93.9 ng/ml and AUCtau, 554 ng*h/ml) after repeated oral dosing of 12.5 mg 
b.i.d. where tolerability risks were not observed, yet noted at higher oral doses.   
Two clinical studies with topical ocular SAF312 eye drops, suspension (eye drops) have been 
conducted to date. One study was the first in human (FIH) study assessing the safety of SAF312 
eye drops, followed by a proof of concept study for acute pain relief after PRK surgery 
compared to vehicle. The safety of topical ocular SAF312 eye drops has been demonstrated in 
both studies for all tested dose concentrations of 1.5 mg/ml to 25 mg/ml (0.15% up to 2.5%), 
no indication of delayed wound healing, and esthesiometry measurements demonstrated no 
anesthetic effect when compared to tetracaine 0.5% (marketed topical ocular anesthetic as 
positive control) or vehicle (as negative control). These findings are of importance to provide 
reassurance that the drug is not simply anesthetizing the ocular surface and leaving the patient 
at risk due to inhibition of the natural ocular defensive mechanisms or inhibition of corneal 
epithelial cell migration (e.g., response to injury). Proof of concept for the efficacy of SAF312 
eye drops was demonstrated with the study meeting both primary endpoints of a statistically 


Novartis 
Confidential 
Page 19 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
significant difference in Visual Analogue Scale (VAS) pain severity score at 6 hours post-
operatively, and the average of 0-12 hour VAS between SAF312-treated eyes and Vehicle-
treated eyes. For detailed information, please refer to the IB. 
Although many patients suffer from acute ocular pain due to various causes, the treatment of 
corneal induced chronic pain remains an unmet need since there are currently no topical ocular 
treatments available that are safe to be used chronically. CICP may be considered as neuropathic 
in nature, but is perpetuated by continuous nociceptive stimuli from the peripheral neurons. It 
is also known that many patients with chronic pain do not necessarily describe their symptom 
as “pain”, and that the description can change from day to day or even within a day. Therefore, 
the term “pain” is used as an umbrella term which can include other symptoms the patient may 
describe as painful like burning, stinging, foreign body sensation, stabbing, pressure, grittiness 
or sandiness.  
Due to the fact that CICP is driven by malfunctioning peripheral nerve impulses, treatment with 
a topical ocular drop could provide significant relief for patients who have a need for chronic 
treatment. 
SAF312 is currently under development as a topical ocular eye drop suspension for the 
treatment of corneal induced chronic pain (CICP). Chronic ocular pain has been reported with 
the most common types of elective ocular refractive vision correction surgical procedures, 
Photorefractive Keratectomy (PRK) and Laser-assisted in situ Keratomileusis (LASIK). It has 
been reported that approximately 95% of patients experience pain immediately following 
LASIK or PRK surgery. Many patients have resolution of their pain within 1 month after 
surgery. However, up to 60% of patients continue to have chronic pain beyond 1 month, and up 
to 44% after 6 months; in some cases the pain will continue for many years or even permanently 
(Shtein 2011; Levitt et al 2015; Benatti and Afshari 2016). Therefore, the pain experienced by 
these patients can be considered as a form of peripheral neuropathy. Similarly chronic pain may 
occur following other surgeries such as laser-assisted sub epithelial keratectomy (LASEK), 
radial keratectomy (RK), and small incision lenticule extraction (SMILE) and following 
cataract surgery.  
Patients who experience CICP regardless of the cause, may have concurrent (i.e., coexisting or 
underlying) ocular conditions which require the use of other ocular medications to treat the 
concurrent condition(s) as deemed appropriate by the patient’s physician. Because SAF312 is 
intended to perform as an analgesic, current treatments the patient may be using for concurrent 
ocular conditions will be allowed to continue, and SAF312 eye drops will be administered in 
addition to those current treatments. 
1.2 
Purpose 
The study is designed to demonstrate the safety and efficacy of two dose concentrations of 
SAF312 eye drops (5 mg/ml and 15 mg/ml) in subjects with CICP persisting at least for 4 
months after refractive or cataract surgery, and chronicity of pain confirmed during the 3 month 
observation period. The study will also determine the optimal dose to carry forward for further 
development. 


Novartis 
Confidential 
Page 20 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
2 
Objectives and endpoints 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
x 
To demonstrate the efficacy of at least 1 of 
2 concentrations of SAF312 (5 mg/ml or 15 
mg/ml) with superiority to placebo in 
reducing ocular pain severity 
x 
Change from baseline to Week 12 in weekly 
mean pain severity Visual Analog Scale 
(VAS) 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
x 
To evaluate additional efficacy of 2 
concentrations of SAF312 vs placebo 
x 
Change from baseline to Day 7 and Day 14 
using the pain severity VAS 
x 
Change from baseline to Week 12 in pain 
frequency VAS 
x 
Change from Baseline to Week 12 in Ocular 
Pain Assessment Scale (OPAS) sub-scale 
Quality of Life 
 
x 
To demonstrate SAF312 does not induce 
negative effects to the ocular surface after 
prolonged TRPV1 inhibition 
x 
Change from baseline to Week 12 in ocular 
surface parameters (eg, corneal and 
conjunctival staining score, Schirmer score, 
conjunctival redness score) 
x 
To evaluate the safety of 2 concentrations of 
6$)DQG 
x 
Comparison of adverse events rates 
between active and placebo 
Exploratory objective(s) 
Endpoint(s) for exploratory objective(s) 
x 
To monitor a subject's behavior regarding 
artificial tear/gel/lubricant use 
 
x 
To monitor a subject's behavior regarding 
rescue medication use 
 
x 
To evaluate corneal nerve density and 
morphology 
x 
Frequency of artificial tear/gel/lubricant use 
over the 12 week treatment period 
 
x 
Frequency of rescue medication use over 
the 12 week treatment period 
 
x 
Change from Baseline to Week 12 in total 
corneal nerve fiber length  
x 
Presence of microneuromas  
PI


Novartis 
Confidential 
Page 21 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Objective(s) 
Endpoint(s) 
• 
Density of corneal dendritiform cells   
 
2.1 
Primary Estimands 
The estimand is the precise description of the treatment effect and reflects strategies to 
address events occurring during trial conduct which could impact the interpretation of the trial 
results (e.g premature discontinuation of treatment). 
The primary clinical question of interest is: What is the effect of SAF312 versus placebo on 
change from baseline in pain severity after treatment in subjects with CICP, had they not taken 
rescue or prohibited medications and had they not discontinued treatment? 
 
The justification for the primary estimands is that they will capture the effect of the study drug 
for the full duration when administered without confounding effects from prohibited 
medications or rescue medications. Further details can be found in Section 12. 
 
The primary estimands are described by the following attributes: 
1. Population: subjects with CICP persisting at least 4 months after refractive surgery, and 
chronicity of pain confirmed during the 3-month observation period. Further details 
about the population are provided in Section 5. 
2. Endpoint: change from baseline in ocular pain severity VAS. The score is derived by 
averaging the seven daily measurements of each week. 
3. Treatment of interest: the randomized treatment (SAF312 or placebo) with or without 
treatment for any underlying ocular conditions. Further details about the investigational 
treatment and control treatment are provided in Section 6. 
Handling of remaining intercurrent events (IE): 
1. Rescue medications: had subjects not taken rescue medication and behaved like other 
subjects who did not take them (hypothetical strategy) 
2. Prohibited medications: had subjects not taken prohibited medication and behaved like 
other subjects who did not take them (hypothetical strategy) 
3. Treatment discontinuation for any reasons: had patients taken the assigned treatment for 
the entire study duration and behaved like other subjects who did not discontinue 
treatment (hypothetical strategy) 
 
The summary measure: difference in variable means between SAF312 and placebo. 
Supplementary estimands to the primary estimand are defined in Section 12. 
 
 


Novartis 
Confidential 
Page 22 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
2.2 
Secondary Estimands 
Not applicable. 
3 
Study design 
Figure 3-1 
Study Design 
 
This study is a Phase 2 randomized, double-blinded, multi-center, parallel group, placebo-
controlled evaluation of the safety and efficacy of SAF312, 5 mg/ml and 15 mg/ml eye drops 
versus placebo used twice-daily in both eyes for 12 weeks. Eligible subjects will have 
undergone refractive surgery (i.e., PRK, LASIK, LASEK, RK, or SMILE) in both eyes or 
cataract surgery in both eyes, with or without refractive enhancement in one or both eyes at 
least 4 months prior to Screening, and have been suffering from chronic ocular pain as a result 
of the their surgery. Both eyes do not necessarily need to have undergone surgery on the same 
day. If the second eye underwent surgery on a different day than the first, eligibility for time 
since surgery would be based on the date of the most recent surgery. In cases where more than 
one procedure was performed on an eye (eg, refractive surgery with CICP followed some time 
later by cataract surgery, or cataract surgery followed some time later by refractive 
enhancement), the Screening visit must be ≥ 4 months after the most recent procedure. Eligible 
patients must also demonstrate chronicity of the pain as described in inclusion criteria. Overall 
approximately 150 subjects will be enrolled in the study (i.e. approximately 50 subjects will be 
enrolled in each treatment arm in 1:1:1 ratio). 
The study will consist of a 12 week observation period starting from Screening Visit (Visit 1) 
until the Baseline/Randomization Visit (Visit 2). Subjects who qualify for randomization will 
then be asked to attend visits every two weeks for the first 4 weeks, and then monthly for the 
remainder of the 12 week treatment period. End of Treatment (EOT) will occur at Visit 6 when 
the subject receives the last study treatment. End of Study (EOS) will occur 4 days after EOT. 


Novartis 
Confidential 
Page 23 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Potential participants will be required to provide written informed consent prior to any study-
specific Screening procedures being performed. Once informed consent is obtained subjects 
will be evaluated for eligibility based on the inclusion and exclusion criteria (Section 5). Final 
eligibility will be based on an assessment of the subject’s pain severity VAS prior to 
randomization, as well as their response to a single drop of topical ocular anesthetic (eg, 
tetracaine, proparacaine eye drops per clinical practice). Response to anesthetic is defined as a 
UHGXFWLRQLQRFXODUSDLQZLWKLQPLQXWHVDIWHULQVWLOODWLRQRIWKHDQHVWKHWLFGURS7KH
use of the anesthetic test is necessary for the selection of subjects with a primarily peripheral 
neuropathic type pain (i.e., primarily resulting from stimulation of the peripheral nerves) versus 
a purely central neuropathic pain. Subjects with a primarily central neuropathic pain are unlikely 
to experience significant improvement with a topical ocular treatment targeting the peripheral 
nerves. Subjects who meet eligibility criteria at Visit 2, will be randomized to one of the three 
treatment groups (SAF312 5 mg/ml, SAF312 15 mg/ml, placebo) in a 1:1:1 ratio. Subjects will 
visit the study site for assessments as outlined in the visit assessment schedule (see Table 8-1). 
All subjects will be allowed to continue their current treatment regimen for any underlying or 
unrelated ocular condition if applicable (eg, treatment for glaucoma, dry eye) as long as 
eligibility criteria are met. No new treatments can be initiated once the subject has begun 
participation in the study unless additional treatments are needed for proper management of an 
adverse event. Whenever topical ocular eye drops other than the investigational medicinal 
product (IMP) are administered, the subject should first dose with their concomitant 
medication(s) and wait approximately 10 minutes prior to instillation of the assigned IMP. 
4 
Rationale 
4.1 
Rationale for study design 
This study will evaluate the safety and efficacy of two concentrations of SAF312 twice daily 
for 12 weeks in the treatment of CICP following refractive or cataract surgery. The aim is to 
evaluate the treatment effect of SAF312 compared to placebo, and to determine the appropriate 
concentration to carry forward for further development. 
The active and placebo IMPs will be presented in identical packaging to ensure no bias to the 
study results due to knowledge of the treatment assignment. Due to the difference in appearance 
of SAF312 eye drops vs placebo eye drops (milky white vs clear, respectively), sites will be 
required to have an unblinded staff member to manage drug dispensation, drug accountability, 
as well as collection of adverse events or subject reports of product comments/complaints. All 
other site staff and Sponsor staff will be blinded to treatment assignments. To ensure masking 
of subjects to their treatment assignment, no subject will receive both placebo and active 
treatment so no change in appearance of the test article will be noticeable by a particular subject. 
Subjects may be informed that their study treatment may appear cloudy or white, but must not 
be informed about the specific identity of the treatments based on differences in appearance. 
A 12-week observation period prior to randomization is included as a method to confirm the 
chronicity of their ocular pain, observe trends in the subject’s pain occurrences (
 
), and to observe behaviors with artificial tears and rescue medications 
prior to receiving randomized treatment. This observation period confirms the selection of 
PI


Novartis 
Confidential 
Page 24 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
appropriate subjects with chronic pain, as well as provides meaningful data 
 
 regarding changes induced by study treatment. During this observational period, 
subjects will be observed in their real-world setting with no changes to their medications or 
actions. The only requirement will be completion of eDiary data, and pain assessments. 
4.2 
Rationale for dose/regimen and duration of treatment 
Topical ocular administration of SAF312 eye drops in non-clinical studies has resulted in high 
ocular exposure with minimal systemic exposure, which is expected to enable ocular pain 
management while avoiding systemic side effects. In the FIH study CSAF312X2101, dose 
concentrations of 5 mg/ml, 15 mg/ml and 25 mg/ml (0.5%, 1.5% and 2.5%, respectively) were 
administered as a single drop 4 times daily in one eye of a subject for 7 days. A supra-therapeutic 
dose concentration of SAF312 eye drops was tested using the maximum feasible dose (MFD) 
of 25 mg/ml (2.5%) and administered 8 times daily for 7 days. In each evaluation, SAF312 was 
safe and well tolerated at single and multiple ocular doses, even up to supra-therapeutic dose 
concentration levels. Esthesiometry assessments also demonstrated the lack of any anesthetic 
effect of SAF312 eye drops when compared to Tetracaine topical ocular anesthetic drops. 
In the proof-of-concept study for the treatment of acute ocular pain after PRK (photorefractive 
keratectomy) surgery, SAF312 at 25 mg/ml (2.5%) was administered 4 times daily (every 6 
hours) for 72 hours. SAF312 was safe and well tolerated with no notable systemic or ocular 
adverse events, and no delay in wound healing. Systemic exposure of SAF312 was confirmed 
to be minimal (Cmax 2.40 ng/mL on Day 4) which is consistent with the lack of observed 
systemic adverse events. 
An ocular PK study in rabbits was conducted to determine the tissue concentrations of SAF312 
eye drop in selected ocular tissues and plasma following a single topical ocular administration 
in both eyes, at four different dose concentrations of SAF312 at 5 mg/ml, 10 mg/ml, 15 mg/ml 
and 25 mg/ml (0.5%, 1.0%, 1.5% and 2.5%, respectively). Concentrations of SAF312 in the 
cornea and conjunctiva were greater than ten times the IC50 (estimate of the IC90) for up to 12 
hours post-instillation (12 hours was the end of the evaluation period). There was an 
approximate dose-proportionality for increase in SAF312 area under the curve (AUC) and 
Cmax in the cornea and conjunctiva, and Cmax between 5 mg/ml and 10 mg/ml, but less than 
dose-proportional above 10 mg/ml. There was also differentiation in exposure observed 
between 5 mg/ml and 10 mg/ml but no clear differentiation between 10 mg/ml and 15 mg/ml 
or 25 mg/ml.   
In toxicology studies completed to date, no notable adverse events were identified after 2 weeks 
of topical ocular dosing. Likewise, no notable adverse in-life events were observed when 
SAF312 was administered up to a dose concentration of 25 mg/ml (2.5%) four times daily for 
13 weeks.  
Based on these data, the Phase 2 study includes dosing of SAF312 at concentrations of 5 mg/ml 
(0.5%, lowest feasible dose) and 15 mg/ml (1.5%, highest feasible dose) to ensure evaluation 
of the full range of possible concentrations, and evaluation of concentrations that have potential 
to reveal a dose response based on differentiated tissue exposure. With target tissue exposure 
concentrations remaining well above the estimated IC90 for at least 12 hours, b.i.d. dosing has 
been selected as the dosing frequency. 


Novartis 
Confidential 
Page 25 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Twelve weeks of exposure will allow for proper assessment of: 1) the efficacy of treatment 
response, 2) the safety of prolonged TRPV1 inhibition in the eye, and 3) the sustainability of 
the effect of the treatment (eg, no loss of effect over time). Both eyes will be treated with the 
IMP. Because it is difficult for subjects to clearly delineate pain from one eye or the other, 
treating both eyes will avoid confounding the data with pain that may not be addressed in the 
eye that does not receive treatment. There have been no safety concerns identified with the use 
of SAF312 eye drops, and the systemic exposure via topical ocular administration is very low, 
therefore dosing both eyes is not expected to pose additional safety risks to the subject. 
Because PK has already been evaluated in both the FIH and the Phase 2a PRK (PoC) studies, 
PK is not planned as part of this Phase 2 study in patients with CICP. Plasma samples may, 
however, be collected ad hoc in cases of SAEs. 
4.3 
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs 
Currently, there is no standard of care for CICP. If pharmacological treatments are needed, 
treatments may include short-term off-label use of topical ocular steroids, or non-steroidal anti-
inflammatory medications, or oral pain medications. 
Subjects will be allowed to continue using medications needed to treat concurrent ocular 
conditions. The use of placebo (vehicle) as a comparator is therefore not considered to be an 
undue risk to the subjects enrolled in the trial. Moreover, since there is no standard of care for 
the treatment of CICP, the use of placebo as a comparator will allow for the establishment of 
the magnitude of change in the clinical endpoints that may be seen spontaneously during 
treatment, and therefore provide a better estimate of the true treatment effect of SAF312. 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4.5 
Risks and benefits 
As of yet there is no known benefit to receiving topical ocular SAF312 treatment for the Corneal 
Induced Chronic Pain (CICP) indication. The safety, tolerability and pharmacokinetics of 
SAF312 eye drops has been evaluated in two studies. A FIH Phase 1 study established the safety 
and tolerability of SAF312 eye drops when used at concentrations as high as 25 mg/mL (2.5%) 
up to 8 times per day, for 7 days, established the lack of an anesthetic effect, and revealed low 
systemic exposure of the drug. The PoC study in acute pain after PRK surgery confirmed the 
low systemic exposure and demonstrated efficacy of SAF312 eye drops in reducing post-
operative pain compared to placebo when dosed 4 times per day for 3 days. In both studies, the 
adverse effects observed with oral dosing of SAF312 (eg, heat insensitivity, transient 
hyperthermia, autonomic dysreflexia in patients with spinal cord injury) were not observed. 
Together, these data support the anticipated safety and efficacy of SAF312 eye drops for the 
treatment of CICP. Because there is no standard of care for CICP, and treatment options for 
chronic pain are limited, SAF312 may provide a novel approach to address the current unmet 
need for patients in need of a chronic treatment for CICP. 


Novartis 
Confidential 
Page 26 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Any risks to subjects in this current study may be minimized by compliance with the eligibility 
criteria and study procedures, as well as close monitoring by the study staff. 
When dosed orally, SAF312 resulted in autonomic dysreflexia in one subject with spinal cord 
injury. Even though systemic exposure with SAF312 is very low with topical ocular 
administration, due to the severity of this potential event, patients with spinal cord injury will 
be excluded from the study. 
Patients will undergo certain ophthalmological procedures which are standard in clinical 
practice and ophthalmic clinical studies. The assessment of the ocular surface requires the use 
of fluorescein and lissamine vital dyes. As with any application of a substance to the ocular 
surface, the patient may have unknown hypersensitivities to the dyes. Any subject 
demonstrating a potential hypersensitivity reaction will receive appropriate medical care. To 
minimize any risks, the study and associated procedures will be carried out by experienced 
study staff under the supervision of the Principal Investigator. 
Subjects enrolled in the study will be allowed to continue any current medications they may be 
prescribed to treat a concurrent or underlying ocular condition which avoids any risk of 
worsening of those conditions due to study requirements. Although subjects may receive 
placebo instead of active drug, the use of placebo is not considered a risk since it is the same 
formulation as the IMP but without the active ingredient. If patients receive inadequate 
treatment of CICP due to the use of placebo, patients will be allowed to use rescue medication 
to avoid any undue risk or suffering as a result of study requirements. 
Given the minimal systemic exposure after topical ocular administration, and the lack of safety 
findings in non-clinical or clinical studies conducted to date, the foreseeable risks associated 
with SAF312 eye drops are considered low compared to the anticipated benefit for patients with 
CICP. There may be risks associated with the use of SAF312 which are unknown at this time. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities i.e. pandemic, 
epidemic or natural disaster, mitigation procedures to ensure subject safety and trial integrity 
are listed in relevant sections. Notification of the Public health emergency should be discussed 
with Novartis prior to implementation of mitigation procedures, and permitted/approved by 
Local or Regional Health Authorities and Ethics Committees as appropriate. 
 
5 
Population 
The study population will consist of subjects (≥ 18 years old) with chronic ocular pain persisting 
for at least 4 months after refractive (i.e. PRK, LASIK, LASEK, RK, or SMILE) or cataract 
surgery (including clear lensectomy). The goal is to randomize a total of approximately 150 
subjects in approximately 30 centers. Assuming a screening failure rate of approximately 50%, 
approximately 300 subjects are planned to be screened.  
5.1 
Inclusion criteria 
Subjects eligible for inclusion in this study must meet all of the following criteria: 


Novartis 
Confidential 
Page 27 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
1. Subjects ≥ 18 years old who have given written informed consent. 
2a. Subjects who have undergone refractive surgery (PRK, LASIK, LASEK, RK, or SMILE) 
or cataract surgery in both eyes, with or without refractive enhancement in one or both 
eyes, ≥4 months prior to Screening Visit and experiencing persistent ocular surface pain 
since the surgery, and have been seen by an ophthalmologist or optometrist at least once 
with complaint of continued ocular pain since surgery. 
NOTE: The 4 month requirement must be based on the date of the last surgery. 
3a. Subjects with worst ocular pain severity (VAS) of ≥ 30 mm) over the last 7 days prior to 
screening . 
4. Subjects who demonstrate a ≥ 60% reduction in ocular pain within 5 minutes after 
instillation of a single topical ocular anesthetic drop at Screening Visit (as calculated by 
the electronic Patient Reported Outcome (ePRO) device). 
 
At Baseline Visit 
5a.  Subjects with  an average pain severity VAS score of ≥ 30 mm based on Daily eDiary for 
the last 7 days prior to Baseline Visit (Visit 2). 
6. Subject who have reported pain severity VAS score >10 mm based on Daily eDiary for >50% 
of the days of the 12-week observational period (as calculated in the ePRO portal). 
5.2 
 Exclusion criteria 
Subjects meeting any of the following criteria are not eligible for inclusion in this study. 
1a. Use of corrective contact lenses  within 14 days of the Screening Visit and any use of 
corrective contact lenses for the duration of the study (bandage or scleral lenses are 
permitted). 
2. Use of artificial tears, gels, lubricants or pain medication within 4 hours of conducting 
assessments at the Screening Visit. 
3. Use of nerve growth factor eye drops within 14 days of the Screening Visit. 
4. Seasonal allergic conjunctivitis, or other acute or seasonal ocular diagnosis that are active 
at the time of Screening or Baseline visits or would be active during the course of the 
study. 
5. Any history of ocular herpes simplex virus or herpes zoster virus infection, or other severe 
ocular conditions such as graft versus host disease, Stevens-Johnson syndrome, 
sarcoidosis. 
6. Presence of any ocular infection (bacterial, viral, or fungal) within 30 days prior to 
Screening Visit. 
7. Chronic topical ocular medications (ie, cyclosporine, lifitegrast) initiated <6 months prior 
to Screening Visit, or any anticipated change during the study. 
8. Subjects with amniotic membrane transplantation on ocular surface within 30 days prior to 
Screening Visit. 
9. Use of ocular or nasal corticosteroids within 30 days of Screening Visit 
10. Use of neuromodulatory medications (eg, gabapentin, pregabalin) or opioid use for non-
ocular pain within 30 days of Screening Visit. 


Novartis 
Confidential 
Page 28 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
11. Chronic medications (both over the counter and prescription) that have not been stable for 
at least 30 days prior to Screening Visit, or any anticipated change in the chronic 
medication regimen. 
NOTE: chronic refers to medications taken on a specific regimen which includes 
medications that may not be taken daily (e.g., bisphosphonates given once per month, 
sliding scale medications such as insulin or coumadin). 
12. History of hypersensitivity to any of the study drugs or its inactive ingredients or to active 
ingredients of similar chemical classes. 
13. Subjects requiring hospitalization within 6 months prior to screening for severe psychiatric 
disorders (e.g. psychosis, schizophrenia, mania, depression) or major psychiatric illness. 
14. Past history of a chronic or recurring ocular or systemic condition that could interfere with 
efficacy assessments, or preclude safe administration of study medication, according to the 
investigator's judgement. 
15. Have uncontrolled systemic (e.g. hypertension, cardiac failure, severe kidney or liver 
disease) or ocular diseases (e.g. proliferative retinal diseases) which could affect trial 
parameters. 
16. Subjects with spinal cord injuries who are at risk of autonomic dysfunction. 
17. Participation in an interventional clinical trial within 3 months prior to Screening Visit 
18. Pregnant or breastfeeding females or those with a positive pregnancy test at Baseline. 
19. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using effective methods of contraception during 
dosing of study treatment. Effective contraception methods include: 
• Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception 
• Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or bilateral tubal ligation at least six weeks before 
taking investigational drug. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment 
• Male sterilization (at least 6 months prior to screening). For female subjects on the 
study, the vasectomized male partner should be the sole partner for that subject 
• Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) 
• Use of oral, (estrogen and progesterone), injected or implanted hormonal methods of 
contraception or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example, hormone vaginal ring or transdermal hormone 
contraception or placement of an intrauterine device (IUD) or intrauterine system 
(IUS). 
In case of use of oral contraception, women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 


Novartis 
Confidential 
Page 29 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
20a. Subjects who for any reasons are unable or unwilling to comply with the specific 
requirements of the protocol. 
6 
Treatment 
6.1 
Study treatment 
6.1.1 
Investigational and control drugs 
SAF312 will be supplied to the subject as ocular eye drops to be administered into the 
conjunctival sac. Subjects will self-administer their first dose at the clinical study site in the 
presence of an unblinded site personnel prior to completion of Visit 2. Subsequent drops will 
be administered at home by subjects. 
Sponsor-qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. Any questions related to the identity of the IMP must be addressed by 
an unblinded site personnel.  
Table 6-1 
Investigational and control drug 
Investigational/ 
Control Drug 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Presentation 
Sponsor (global 
or local) 
SAF312 15 mg/ml 
eye drops, 
suspension 
topical ocular 
double blind 
opaque 
droptainer 
Novartis Global 
SAF312 5 mg/ml 
eye drops, 
suspension 
topical ocular 
double blind 
opaque 
droptainer 
Novartis Global 
SAF312 Placebo 
eye drops, 
suspension 
topical ocular 
double blind 
opaque 
droptainer 
Novartis Global 
6.1.2 
Additional study treatments 
There are no additional study treatments included in this study. Subjects will be allowed to 
continue any current treatment regimen for concurrent or underlying ocular conditions. No new 
treatments can be initiated once the subject has begun participation in the study Screening Visit 
(Visit 1) unless additional treatments are needed for proper management of an adverse event. If 
used, any new medication must be recorded on the Concomitant medications therapies page of 
the CRF.   
6.1.3 
Treatment arms/group 
At Baseline (Visit 2), all eligible subjects will be randomized (ratio 1:1:1) via Interactive 
Response Technology (IRT) to one of the treatment arms in the double-blinded treatment. 
• SAF312 Placebo eye drops, suspension, b.i.d. 
• SAF312 5 mg/ml (0.5%) eye drops, suspension, b.i.d. 
• SAF312 15 mg/ml (1.5%) eye drops, suspension, b.i.d. 


Novartis 
Confidential 
Page 30 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
6.1.4 
Treatment duration 
Subjects will dose both eyes with their assigned treatment for 12 weeks (84 days). 
6.2 
Other treatment(s) 
6.2.1 
Concomitant therapy 
All medications (systemic or ocular), procedures, and significant non-drug therapies 
administered after the subject is enrolled into the study must be recorded on the appropriate 
Case Report Forms (CRF). 
Artificial tears and rescue medications should only be used when needed, and should NOT be 
used prophylactically.  
If a subject is using other topical ocular medications for the treatment of concurrent ocular 
conditions, the subject should first dose with their concomitant medication(s) and wait 
approximately 10 minutes prior to instillation of the study medication. 
6.2.2 
Prohibited medication 
Use of the treatments displayed in the below table are not allowed starting from Screening Visit 
(Visit 1). 
 
Table 6-2 
Prohibited medication 
Medication 
Prohibition period 
Action taken 
Use of topical ocular 
medications (prescription or 
over the counter) within 4 hours 
prior to a study visit 
Study duration 
Reschedule study visit outside 
of the 4 hour window 
Use of ocular or oral pain 
medication within 4 hours of a 
study visit 
Study duration 
Reschedule the study visit 
outside of the 4 hour window 
Ocular, nasal, inhaled, or 
systemic corticosteroids 
Study duration 
No action 
Use of oral or topical ocular 
antihistamines, mast cell 
stabilizers (e.g. Ketotifen) 
Study duration 
No action 
New use or change in dosing of 
neuromodulators for any 
reason, and any use of topical 
ocular NGF 
Study duration 
Discontinue study treatment 
All medications administered after the subject enrolls in the study must be listed on the 
Concomitant medications/Significant non-drug eCRF page. 
6.2.3 
Rescue medication 
There is no rescue medication that will be proactively provided to study sites or subjects. 
However, on the discretion of the investigator, medication (local or systemic, over the counter 


Novartis 
Confidential 
Page 31 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
or prescription) used for pain relief will be allowed and will be specified if used for ocular or 
non-ocular pain. The data will be entered by the subject in the electronic daily diary (eDiary). 
 
6.3 
Subject numbering, treatment assignment, randomization 
6.3.1 
Subject numbering 
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned when 
the subject is first enrolled for screening and is retained as the primary identifier for the subject 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (assigned by Novartis to the investigative site) with a sequential subject 
number suffixed to it, so that each subject is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential Subject 
No. available. 
6.3.2 
Treatment assignment, randomization 
At visit 2 after completion of the observation period, all eligible subjects will be randomized 
via Interactive Response Technology (IRT) to one of the treatment arms. The investigator or 
his/her delegate will contact the IRT after confirming that the subject fulfills all the 
inclusion/exclusion criteria. The IRT will assign a randomization number to the subject, which 
will be used to link the subject to a treatment arm and will specify a unique medication number 
for each package of study treatment to be dispensed to the subject. 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased and concealed from subjects and investigator staff. A subject 
randomization list will be produced by the IRT provider using a validated system that automates 
the random assignment of subject numbers to randomization numbers. These randomization 
numbers are linked to the different treatment arms, which in turn are linked to medication 
numbers. A separate medication list will be produced under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment. The randomization scheme for 
subjects will be reviewed and approved by a member of the Randomization Office. 
Randomization will be stratified according to baseline mean pain severity over the 7 days prior 
to Baseline Visit (≥75mm or <75mm).  
6.4 
Treatment blinding 
Subjects, investigator staff, persons performing the assessments, study monitors and Clinical 
Trial Team (CTT) will remain blind to the identity of the treatment from the time of 
randomization until database lock, using the following methods: (1) Randomization data are 
kept strictly confidential until the time of unblinding and will not be accessible by anyone else 
involved in the study with the following exceptions: unblinded site personnel will be required 
for initial dose administration, and discussions with subjects that may contain unblinding 
information (2) the identity of the treatments will be concealed by the use of study treatment 
that are all identical in packaging, labeling, and schedule of administration. 


Novartis 
Confidential 
Page 32 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Unblinding of the investigator may occur in the case of subject emergencies and at the 
conclusion of the study. 
6.5 
Dose escalation and dose modification 
Investigational study treatment dose adjustments and/or interruptions are not permitted. 
6.5.1 
Dose modifications 
Dose modification, adjustment and/or interruptions are not allowed in this study. For subjects 
who do not tolerate the protocol-specified dosing schedule, rescue medication should be used. 
If the subject is still unable to tolerate the protocol-specified dosing schedule, the subject should 
be discontinued from the study treatment. 
6.5.2 
Follow-up for toxicities 
Not applicable 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
The investigator should promote compliance by instructing the subject to take the study 
treatment exactly as described in the protocol by stating that compliance is necessary for the 
subject’s safety and the validity of the study. The subject should inform the investigator if he/she 
was unable for any reason to use the study treatment as required. This information should be 
captured in the source document at each visit. 
Study treatment will be packaged in droptainers for b.i.d. dosing of both eyes each day. A new 
droptainer will be opened daily for use during a single day. In addition to subject reported 
compliance, site staff will record used versus unused bottles as support for assessment of 
treatment compliance. All study treatment dispensed and returned must be recorded in the Drug 
Accountability Log and returned to the Sponsor. 
6.6.2 
Recommended treatment of adverse events 
There are no adverse events of special interest (AESI) that require specific treatment 
instructions. Investigators must treat adverse events as needed and according to investigator 
judgement. Medication used to treat adverse events (AEs) must be recorded on the appropriate 
CRF. 
6.6.3 
Emergency breaking of assigned treatment code 
Emergency code breaks must only be undertaken when it is required in order to treat the subject 
safely. Most often, discontinuation from study treatment 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 


Novartis 
Confidential 
Page 33 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
for the specified subject and a fax or email confirming this information. The system will 
automatically inform the Novartis 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 ensure 
appropriate site personnel are available as his/her backup if needed. Investigators will also 
ensure subjects are provided the appropriate contact information in case of emergency. 
Once the treatment code has been broken for a particular subject, that subject must be 
discontinued from study treatment, while adverse event (AE) treatment and follow-up continue 
as appropriate. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs (Section 6.1.1). 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the subject by contacting 
the IRT and obtaining the medication number(s). The study medication has a 2-part label (base 
plus tear-off label), immediately before dispensing the medication kit to the subject, site 
personnel will detach the outer part of the label from the packaging and affix it to the source 
document. 
An unblinded site personnel will instruct the subject on proper drug storage and use, and will 
dispense the assigned medication to the subject, prior to instillation of the first dose of study 
medication at the site. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e. pandemic, epidemic or natural disaster, that limits or prevents on-site study visits, 
delivery of IMP directly to a subject's home may be permitted (if allowed by Local or Regional 
Health Authorities and Ethics Committees as appropriate) in the event the Investigator has 
decided that an on-site visit by the subject is no longer appropriate or possible, and that it is in 
the interest of the subject's health to administer the study treatment even without performing an 
on-site visit. The dispatch of IMP from the site to the subject’s home remains under the 
accountability of the Investigator. Each shipment/provisioning will be for a maximum of 1 
month supply. In this case, regular phone calls or virtual contacts (e.g., every 2 weeks or more 
frequently if needed) will occur between the site and the subject for instructional purposes, 
safety monitoring, investigation of any adverse events, ensuring subjects continue to benefit 
from treatment, and discussion of the subject's health status until the subjects can resume visits 
at the study site. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 


Novartis 
Confidential 
Page 34 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the labels and in the Investigator’s Brochure. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the subject except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
study monitors during site visits or remotely and at the completion of the trial. Subjects will be 
asked to return all used and unused study treatment and packaging at each returning visit and at 
the end of the study or at the time of discontinuation of study treatment. 
At the conclusion of the study, and as appropriate, during the course of the study, the 
investigator will return all used and unused study treatment, packaging, drug labels, and a copy 
of the completed drug accountability log to the Novartis study monitor or to the Novartis 
address provided in the investigator folder at each site. 
6.7.1.2 
Handling of additional treatment 
Not applicable 
7 
Informed consent procedures 
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the subject's representative(s) gives consent (if allowed according 
to local requirements), the subject must be informed about the study to the extent possible given 
his/her understanding. If the subject is capable of doing so, he/she must indicate agreement by 
personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the subject source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the International Council for Harmonization (ICH) Good Clinical Practice 
(GCP) guidelines and regulatory requirements and is considered appropriate for this study. Any 
changes to the proposed consent form suggested by the investigator must be agreed by Novartis 
before submission to the IRB/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 (IN) 


Novartis 
Confidential 
Page 35 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
or an aggregate safety finding. New information might require an update to the informed 
consent and then must be discussed with the subject. 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 
As per Section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities i.e., pandemic, epidemic or natural disaster, that may challenge the ability to obtain 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g., telephone, videoconference) if 
allowable by a local Health Authority. 
Guidance issued by local regulatory bodies on this aspect, prevail and must be implemented 
and appropriately documented (e.g., the presence of an impartial witness, sign/dating separate 
ICFs by trial subject and person obtaining informed consent, etc.). 
8 
Visit schedule and assessments 
Assessment schedule (Table 8-1) lists all the assessments and when they are performed. All 
data obtained from these assessments must be supported in the subject’s source documentation. 
Subjects should be seen for all visits/assessments as outlined in the assessment schedule 
(Table 8-1) or as close to the designated day/time as possible, and follow the proposed in-
office assessment sequence as outline in (Table 8-2) . Missed or rescheduled visits should not 
lead to automatic discontinuation. Visits that occur after the rescheduling of a previous visit 
should be done based on the initial protocol visit timing, and not based on the previous visit. 
If the EOS follow-up contact cannot be done on time (EOT+4 days), the contact should be 
made later, but should not be made earlier (i.e., at least 4 days should elapse prior to the 
follow-up contact).  
Subjects who prematurely discontinue the study, for any reason, should be scheduled for a visit 
as soon as possible, at which time all of the assessments listed for the final visit will be 
performed. At this final visit, all dispensed investigational product should be reconciled, and 
the AE and concomitant medications recorded on the CRF. 
Subjects should avoid dosing with any topical ocular medications or any pain medications 
within 4 hours of a scheduled visit. 
If the COVID-19 pandemic limits or prevents on-site study visits, in which IMP could not be 
dispensed and other study assessments may not be performed, alternative methods of IMP 
dispensing and safety monitoring may be implemented. Depending on local regulations, site 
capabilities and patient’s visit status in the study, phone calls or virtual contacts (e.g. teleconsult) 
can be performed for safety follow-up for the duration of the pandemic, until it is safe for the 
subject to visit the site again. 
 


Novartis 
 
Confidential 
 
Page 36 
Clinical Trial Protocol (Version No. 03) 
 
 
 
Protocol No. CSAF312B12201 
 
Table 8-1 
Assessment Schedule 
 
Period 
Screening      
 
Treatment 
Post Treatment 
Follow-up  
Visit Name 
Visit 1  
Screening 
Phone 
Check-in 
Visit 2   
Baseline 
Visit 2   
Randomization 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOT Follow-up Contact 
/ EOS 
Days 
-84 
-42 ± 7 
1  
1 
14 ± 2 
28 ± 2 
56 ± 2 
84 ± 2 
EOT + 4 
Informed consent 
X 
 
 
 
  
  
  
  
 
Demography 
X 
 
 
 
  
  
  
  
 
Medical history / current 
medical conditions 
X 
 
 
 
  
  
  
  
 
Previous /Con Meds 
X 
X 
X 
 
X 
X 
X 
X 
X 
Inclusion / Exclusion criteria 
X 
 
X 
 
  
  
  
  
 
Pregnancy test 
(dipstick/strip) 
 
 
S 
 
  
  
  
S 
 
Adverse Events 
X 
X 
X 
 
X 
X 
X 
X 
X 
Anesthetic test 
X 
 
 
 
 
 
 
 
 
Placebo response 
mitigation training video and 
knowledge check 
S 
 
 
S1 
 
 
 
 
 
Dispense electronic diary 
S 
 
 
 
  
  
  
  
 
Pain Severity VAS  
X2 
R 
R3 
R4 
R4 
R4 
R4 
 
 
Pain Frequency VAS 
X2 
R 
 
R4 
R4 
R4 
R4 
 
 
Artificial tears use  
X2 
R 
 
R4 
R4 
R4 
R4 
 
 
Rescue medications 
X2 
R 
 
R4 
R4 
R4 
R4 
 
 
OPAS Questionnaire 
X 
 
X6 
 
X6 
X6 
X6 
X6 
 
Pain Characterization 
Questionnaire  
X 
 
 
 
  
  
  
  
 
PI
PI


Novartis 
 
Confidential 
 
Page 37 
Clinical Trial Protocol (Version No. 03) 
 
 
 
Protocol No. CSAF312B12201 
 
Period 
Screening      
 
Treatment 
Post Treatment 
Follow-up  
Visit Name 
Visit 1  
Screening 
Phone 
Check-in 
Visit 2   
Baseline 
Visit 2   
Randomization 
Visit 3 
Visit 4 
Visit 5 
Visit 6 / EOT Follow-up Contact 
/ EOS 
Days 
-84 
-42 ± 7 
1  
1 
14 ± 2 
28 ± 2 
56 ± 2 
84 ± 2 
EOT + 4 
Visual Acuity  
X 
 
X 
 
  
  
  
X 
 
Slit lamp examination  
X 
 
X 
 
X 
X 
X 
X 
 
Signs evaluation: (Corneal 
fluorescein staining; 
Conjunctival lissamine 
staining. Conjunctival 
redness; Schirmer score)  
X 
 
X 
 
X 
X 
X 
X 
 
Contact IRT 
X 
 
 
X 
X 
X 
X 
X 
 
Intraocular Pressure (IOP)  
 
 
X 
 
  
  
  
X 
 
Ophthalmoscopy dilated 
fundus exam  
 
 
X 
 
  
  
  
X 
 
Corneal endothelial cell 
microscopy  
 
 
X 
 
 
 
 
X 
 
In vivo confocal 
microscopy7  
 
 
X 
 
 
 
 
X 
 
Dispense study medication 
 
 
 
S8 
S 
S 
S 
  
 
Collect electronic diary 
 
  
 
 
 
 
 
 
 
S 
 
Collect study medication  
  
 
 
 
S 
S 
S 
S 
 
Electronic diary compliance 
check9 
 
 
S 
 
S 
S 
S 
 S 
 
X Assessment to be recorded in the clinical database or received electronically from a vendor 
S Assessment to be recorded in the source documentation only 
R Reminder for the tasks to be completed by the subject outside of the clinical site 
1 The Pain Assessment Knowledge Check can be optional for any subject who had completed the Knowledge Check already during Screening Visit (Visit 1). 
2 Two entries to be completed on the same day of screening. The first entry is to be made at the time of the on-site screening visit, the second entry and all subsequent 
entries are to be completed at home before their evening dose of study medication. 
3 Confirm eligibility based on the eDiary data.  
4 Remind the subject to complete the once daily eDiary recording prior to the evening dose of study medication every day until the evening prior to the EOT visit. 
 
  
PI


Novartis 
 
Confidential 
 
Page 38 
Clinical Trial Protocol (Version No. 03) 
 
 
 
Protocol No. CSAF312B12201 
 
6 Enter the PIN code and select the scheduled visit on the Visit Selection menu to allow the study subject to complete the questionnaire on the tablet device 
7 To be conducted at selected sites only 
8 Study medication is only dispensed after the subject is randomized 
9 Review subject daily eDiary entry compliance and subject reported outcome of Pain Severity VAS, Pain Frequency, Frequency of Artificial Tear use and rescue 
medication use. If pain rescue medication were reported in eDiary, request further detailed medication information and make entry into eCRF concomitant medication 
page. 
 
 
 


Novartis 
 
Confidential 
 
Page 39 
Clinical Trial Protocol (Version No. 03) 
 
 
 
Protocol No. CSAF312B12201 
 
Table 8-2 
Proposed in-office Assessment Sequence 
 
 
Visit 1 (Screening) 
Visit 2 (Baseline/ Randomization) 
Visits 3 / 4 / 5 
Visit 6 (EOT) 
ICF / Demographics / MH / Incl + Excl 
Con meds / AE / MH / Incl + Excl 
Con meds / AE 
Con meds / AE 
Concomitant medications / adverse events 
Pregnancy test 
OPAS questionnaire 
Pregnancy test 
Placebo response mitigation training video
1 
Confirm eligibility on pain severity 
VAS 
 
eDiary compliance check 
Dispense eDiary 
eDiary compliance check 
Slit-lamp exam 
OPAS questionnaire 
Pain severity and frequency VAS 
OPAS questionnaire 
Conjunctival redness 
Use of artificial tears / rescue medications 
Corneal fluorescein staining 
Visual acuity 
Pain Characterization questionnaire 
Visual acuity 
Lissamine conjunctival staining 
Slit-lamp exam 
OPAS questionnaire 
Slit-lamp exam 
Schirmer test 
Conjunctival redness 
Conjunctival redness 
eDiary compliance check 
Corneal fluorescein staining 
Visual acuity 
Corneal fluorescein staining 
Contact IRT 
Lissamine conjunctival 
staining 
Slit-lamp exam 
Lissamine conjunctival staining 
Collect/dispense IMP 
Schirmer test 
Conjunctival redness 
Schirmer test 
eDiary
 reminders 
IOP 
Corneal fluorescein staining 
IOP 
 
Dilated fundus exam 
Lissamine conjunctival staining 
Dilated fundus exam 
Specular Microscopy / 
*Confocal microscopy 
Schirmer test 
Specular Microscopy / Confocal 
microscopy
2 
Collect meds / devices 
Anesthetic test 
Contact IRT 
Contact IRT 
Contact IRT 
Randomize/dispense IMP 
 
 
 
 
 
Dose in clinic (unblinded site 
personnel  only) 
eDiary 
 reminders 
eDiary 
 reminders 
 
Placebo response mitigation training 
video
3 
NOTE:  
 
1 Includes Pain Assessment Knowledge Check  
 2 Confocal microscopy is performed only at select sites after specular microscopy  
 3 Pain Assessment Knowledge Check can be performed optionally at Visit 2, but should be performed if not completed previously 
PI
PI
PI
PI


Novartis 
Confidential 
Page 40 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
8.1 
Screening 
Subjects will be screened at the Screening Visit (Visit 1), and eligible subjects will be enrolled 
into the observational period of the study. 
Re-screening of subjects who fail entry criteria for any reason is permitted only under select 
circumstances as outlined below.  
• Screen failure due to stabilization timeframes: If it is determined prior to the completion of 
Screening Visit that the subject did not meet eligibility pertaining to any of the following: 
o < 4 months since the surgical procedure (Inclusion #2a), 
o Timeframe required for stabilization of chronic medications or medical history 
(Exclusion #1a, 2, 3, 4, 6, 7, 8, 9, 10, 11, 17, 20a), or 
o Time window required for ocular medication or pain medication use prior to the 
screening visit (Exclusion #2), 
the subject will be screen failed and may be brought back at a later date after the proper 
timeframes have been achieved to re-attempt the screening process.  
• Screen failure under protocol version 02 due to ocular pain severity eligibility criteria that 
would have been met under protocol version 03: If a subject was screen failed under 
protocol version 02 due to the following pain severity inclusion criteria: 
o Ocular pain severity VAS < 50 mm at Screening Visit (per Inclusion #3) 
the subject may be brought back at a later date to re-attempt the screening process. 
• 
Screen failure due to insufficient reduction in ocular pain during the anesthetic test caused 
by technologic or procedural issues: If a subject was screen failed due to an insufficient 
ocular pain reduction during the anesthetic test, the subject may be allowed to re-screen in 
specific circumstances (including device malfunction, procedural errors). In all cases, the 
site must receive Sponsor approval prior to re-screening. 
In the case of re-screening, the subject will receive a new subject number and all screening 
assessments required at Screening Visit must be completed, regardless whether the assessments 
were conducted at the previous screening visit.  
Re-screening is only allowed one time for each subject, with the exception of subjects who 
screen failed due to pain severity eligibility criteria under protocol version 02. A subject who 
screen failed under this criterion potentially could be re-screened a second time based on the 
additional re-screening criteria stated above. Re-screening must not be used as a method to force 
subject eligibility into the study.  
 
8.1.1 
Information to be collected on screening failures 
Subjects who sign an informed consent form and are subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate eCRF. The informed consent, demographic information, and 
Inclusion/Exclusion pages must also be completed for screen failure subjects. No other data 


Novartis 
Confidential 
Page 41 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
will be entered into the clinical database for subjects who are screen failures, unless the subject 
experienced a serious adverse event (SAE) during the screening phase (see 10.1.2 SAE section 
for reporting details). If the subject fails to be randomized, the IRT must be notified within 2 
days of the screen fail that the subject was not randomized. 
Subjects who are randomized and fail to start treatment, e.g. subjects randomized in error, will 
be considered an early terminator. The reason for early termination should be recorded on the 
appropriate eCRF. 
8.2 
Subject demographics/other baseline characteristics 
The following information will be collected/documented at Screening/Baseline Visits for each 
randomized subject: 
• Age 
• Sex 
• Race/Ethnicity 
• Ancestry (applicable for Japanese and Chinese only) 
• Iris color  
Ocular baseline characteristic will include:  
• Time since date of the last surgery 
• Surgery type (PRK,LASIK, LASEK, RK, SMILE or Cataract) 
• Pain Characterization Questionnaire 
• Frequency of artificial tear use  
• Frequency of rescue medication use 
• Corneal fluorescein staining 
• Conjunctival lissamine staining 
• Conjunctival redness score 
• Schirmer score 
Baseline values of efficacy parameters: 
• Pain Severity VAS 
• Pain frequency VAS 
• OPAS 
 
 
8.3 
Efficacy 
8.3.1 
Pain Severity and Frequency Visual Analog Scales 
The pain severity Visual Analogue Scale (VAS) is to be completed through an electronic diary 
by the subject at the Screening Visit, and thereafter every evening (before bed during the 
observational period, and before their evening dose of study medication during the study 
treatment period). The subject will provide a score for severity of their ocular pain over the past 


Novartis 
Confidential 
Page 42 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
24 hours by putting a vertical mark on the horizontal scoring line. The severity scoring line 
utilizes the anchors of 'No Pain' to 'Very Severe' pain.  
The Pain Frequency Visual Analogue Scale (VAS) is to be completed through an electronic 
diary by the subject at the Screening Visit, and thereafter every evening (before bed during the 
observational period, and before their evening dose of study medication during the study 
treatment period). The subject will provide a score for frequency of their ocular pain over the 
past 24 hours by putting a vertical mark on the horizontal scoring line. The frequency scoring 
line utilizes the anchors of 'Rarely' to 'All the Time'. 
8.3.2 
OPAS questionnaire 
The Ocular Pain Assessment Survey (OPAS) questionnaire is completed electronically by the 
subject at each office visit as indicated in the Schedule of Assessments. The OPAS will be used 
to assess the subject's ocular pain, aggravating factors, quality of life, and perception of overall 
improvement of ocular and non-ocular pain. The OPAS is a multidimensional tool specifically 
designed to assess ocular pain in subjects with eye pain of any origin. 
8.3.4 
Appropriateness of efficacy assessments 
The efficacy assessments included in this study for the evaluation of ocular pain are commonly 
used in clinical research.  
8.4 
Safety 
Safety assessments are specified below and the assessment schedule details when each 
assessment is to be performed. If the COVID-19 pandemic limits or prevents on-site study visits, 
phone calls or virtual contacts should be conducted for safety monitoring and discussion of the 
subject´s health status, until the subject can again visit the site. 
Clinically significant abnormalities, per the opinion of the Investigator, for any of the safety 
parameters will be recorded on the ocular medical history page of the eCRF if present at the 
time of informed consent, and on the AE page if occurring on or after the time of consent. 
For details on AE collection and reporting, refer to Section 10.1 - Definition of adverse events 
and reporting requirements 
8.4.1 
Laboratory evaluations 
Not Applicable 


Novartis 
Confidential 
Page 43 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
8.4.2 
Pregnancy 
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 must agree that in 
order to participate in the study they must adhere to the contraception requirements outlined in 
the exclusion criteria. 
All women of childbearing potential who are not surgically sterile will have a urine pregnancy 
test. These assessment results must be captured in the source documentation. Additional urine 
pregnancy tests may be performed at the discretion of the investigator and/or according to local 
requirements and the test results will be recorded in the source document. A positive urine 
pregnancy test requires immediate interruption of study drug until serum beta-human chorionic 
gonadotropin (B-hCG) is performed and found to be negative. If positive, the subject must be 
discontinued from the trial. 
8.4.3 
Visual Acuity 
Visual acuity (VA) will be performed using a Snellen chart. VA testing should precede IOP 
measurement, the administration of eye drops to dilate or anesthetize the eye, or any 
examination requiring contact with the eye. 
8.4.4 
Slit Lamp Examination 
At every scheduled visit, the anterior segment’s structures of the study eye will be carefully 
examined according to clinical practice. The slit lamp results will be recorded in the source 
documents.  
8.4.5 
Intraocular Pressure 
Intraocular pressure (IOP) will be measured according to the standard clinical practice and 
expressed in mmHg. Every effort should be made to use the same method/instrument 
throughout the study.  
If using Goldmann applination tonometry, the IOP measurement should be performed after 
the corneal fluorescein staining and lissamine conjunctival staining at Visit 2 and Visit 6, to 
avoid the staining outcomes are confounded by the anesthetic. 
8.4.6 
Dilated Fundus Exam 
 For the fundus exam pupil must be dilated. Fundus results will be recorded in the source 
documents 
8.4.7 
Corneal Endothelial Cell Microscopy 
Each site must use the specified brand of equipment for use on all subjects at the site. 
Certification of the equipment and examiners at each investigative site will occur prior to 
evaluation of study subjects. At the Baseline and End of Treatment Visits Specular microscopy 
of the corneal endothelial cell images will be obtained by the Investigator and submitted to the 
Central Reading Center (CRC) to determine the changes in endothelial cell count, density, and 
shape from the initial baseline to the end of treatment. A standardized procedure for the 
collection of the Specular microscopy images will be provided by the CRC in a separate manual. 


Novartis 
Confidential 
Page 44 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
8.4.8 
Appropriateness of safety measurements 
The safety assessments selected are standard for this indication/subject population. 
8.5 
Additional assessments 
8.5.1 
Other Assessments 
In vivo confocal microscopy is included as an exploratory assessment at select sites to evaluate 
corneal nerve morphology in patients with CICP. 
The following ocular surface assessments (corneal and conjunctival staining, conjunctival 
redness, Schirmer’s test) are included to evaluate whether long term inhibition of TRPV1 
receptors with SAF312 eye drops has an adverse effect on ocular surface parameters.  
 
  
Finally, the Pain Characterization questionnaire will be used to gain greater detail regarding the 
subject's ocular pain. 
Frequency of artificial tear/gel/lubricant use and rescue medication use will be captured in the 
eDiary on a daily basis to gain insights to subject behavior with these products. 
8.5.1.1 
 In Vivo Confocal Microscopy 
In Vivo Confocal Microscopy (IVCM) will be performed by the Investigators only at selected 
sites for exploratory analysis. The images will be sent to an independent reader for objective 
and subjective evaluation to quantify and evaluate the distribution and morphology of corneal 
nerves. A standardized procedure for the collection of the images will be provided in a separate 
manual. 
8.5.1.2 
Conjunctival Redness  
Redness of the interpalpebral conjunctiva will be evaluated by the investigator using the 
McMonnies scale (Figure 8-1). The inter-palpebral region of the temporal and nasal regions 
will each be graded using the 0-5 scale. 
Figure 8-1 
McMonnies Redness Photographic Scale 
 


Novartis 
Confidential 
Page 45 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
8.5.1.3 
Corneal Fluorescein Staining 
Corneal fluorescein staining will be conducted by the Investigator. For individual subjects, 
corneal fluorescein staining should be assessed by the same examiner at all visits using the same 
slit lamp and the same settings. 
Fluorescein impregnated strips (to be provided by Novartis) will be used to deliver dye to the 
ocular surface. To wet the strip, a single drop of sterile saline solution (or similar) is placed on 
the tip of the strip. Anesthetic drops must NOT be used as a wetting agent.  
Immediately after application of the wetting drop, the strip should be gently flicked to remove 
excess fluid. Immediately after flicking the strip, the wet tip of the strip is allowed to gently 
touch the inner edge of the inferior cul-de-sac of the eye to draw the fluorescein onto the ocular 
surface. The subject should be instructed to not rub their eyes and gently blink several times to 
distribute the dye across the ocular surface. 
The degree of staining is based on the Corneal Fluorescein Modified NEI Scale. Each of the 
five regions (as depicted in the diagram, and defined as central (C), superior (S), inferior (I), 
temporal (T), and nasal (N)) will be graded based on a scale of 0 to 4, with higher scores 
suggestive of higher degrees of corneal staining (Figure 8-2). The examiner will indicate the 
appropriate score for each region. If the assessment falls between grades, round up to the higher 
score. After entry of the scores per region, the total or composite (sum) score for each eye will 
be automatically calculated (maximum score = 20/eye). 
Figure 8-2 
Corneal Fluorescein Modified NEI Scale 
 
 
8.5.1.4 
Conjunctival Lissamine Staining 
Conjunctival lissamine staining will be conducted by the Investigator and after corneal 
fluorescein staining. For individual subjects, conjunctival lissamine staining should be assessed 
by the same examiner at all visits using the same slit lamp and the same settings. 


Novartis 
Confidential 
Page 46 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
Lissamine impregnated strips (to be provided by Novartis) will be used to deliver the dye to the 
ocular surface. To wet the strip, a single drop of sterile saline solution (or similar) is placed on 
the tip of the strip. Anesthetic drops must NOT be used as a wetting agent. 
Immediately after application of the wetting drop, the strip should be gently flicked to remove 
excess fluid. Immediately after flicking the strip, the wet tip of the strip is allowed to gently 
touch the inner edge of the inferior cul-de-sac of the eye to draw the lissamine onto the ocular 
surface. The subject should be instructed to not rub their eyes and gently blink several times to 
distribute the dye across the ocular surface.  
The degree of lissamine staining in the temporal and nasal inter-palpebral conjunctiva will be 
assessed based on the proportion of the area that is covered by staining. The proportion of 
staining area will be assessed based on the table provided in Table 8-3: 
Table 8-3 
Grading of Conjunctival Staining  
 
Grading scale  Percentage of the staining area 
0 
0% 
1 
1%–15% 
2 
16%–30% 
 3 
31%–45% 
4 
>45% 
The score for nasal and temporal regions will be captured separately and the total conjunctival 
lissamine staining will be the sum of the nasal and temporal scores (total score of 0-8). 
8.5.1.5 
Schirmer's Test (without anesthesia) 
The Schirmer’s test will be performed without anesthetic in both eyes simultaneously, and after 
completion of ocular surface stainings. 
The subject should be seated in the examining chair with the room lights dimmed and their head 
against a headrest for comfort. Prepare the sterile strips (Tear Flo™ or similar) while they are 
still in the package by folding the rounded end at the indentation (approximately 5 mm from 
the tip). The strip will be bent and inserted between the bulbar and palpebral conjunctiva over 
the inferior lid margin in the lateral third of the eyelid towards the lateral canthus, and left in 
place for 5 minutes with the eyes closed. Tear secretion is measured in millimeters of the length 
of strip wetted by tears. The measurement (score) will be made to the nearest whole number. 
8.5.1.6 
Mitigation of Placebo Response Training Video and Pain Assessment 
Knowledge Check 
At Screening Visit (Visit 1):  Upon completion of ICF but before starting the use of ePRO 
device, the subject will use the study tablet device, personal mobile device, laptop, or tablet to 
watch a video regarding placebo response mitigation.  
After completing the video, a printed copy of the Pain Assessment Knowledge Check will be 
given to the subject to have him/her complete the questions in order to check their level of 


Novartis 
Confidential 
Page 47 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
understanding of the video content. Site staff should review the responses with the subject and 
answer any questions they may have regarding incorrect responses or the information as a whole. 
At Baseline/Randomization Visit (Visit 2): if the subject meets criteria for randomization, the 
study subject is expected to watch the Video once more BEFORE they leave the clinic. The 
Pain Assessment Knowledge Check can be optional for any subject who had completed the 
Knowledge Check already during Visit 1 (Screening). 
8.5.1.7 
Pain Characterization Questionnaire 
The Pain Characterization questionnaire is a series of questions asking about the specific details 
of the subject's ocular pain (e.g., pain descriptors, timing throughout the day) that is not already 
captured in the other questionnaires included in the efficacy assessments. The pain 
characterization questionnaire will be collected electronically at Screening Visit only and 
therefore not intended for any safety or efficacy assessments. 
8.5.1.8 
Post-Anesthetic Severity of Eye Pain 
The anesthetic test will be administered to identify subjects with primarily peripheral 
neuropathic pain.  
The subject will be asked to complete the pre-anesthetic pain severity VAS question in the 
ePRO. After the subject records the pain severity score, one drop of topical ocular anesthetic 
will be administered in each eye per the study site standard practice (e.g., Tetracaine, 
proparacaine). Once the anesthetic has taken effect, within 5 min of drop instillation, the subject 
will complete the post-anesthetic severity eye pain VAS question in the ePRO. For both the pre- 
and post-anesthetic pain severity, the subject will complete the pain severity VAS considering 
the pain at the time when each question is completed. The question is the same pain severity 
question as described in Section 8.3.1., with the severity scoring line anchors of 'No Pain' to 
'Very Severe' pain.  
The ePRO will calculate the difference between the pre-anesthetic pain severity score and the 
post-DQHVWKHWLFVFRUHPXVWEHIRUVXEMHFWWRTXDOLI\IRUWKHVWXG\ 
 
 
 
 
 
 
 
 
 
 
 
PI


Novartis 
Confidential 
Page 48 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
9 
Discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Discontinuation of study treatment for a subject occurs when study treatment is permanently 
stopped for any reason (prior to the planned completion of study drug administration, if any) 
and can be initiated by either the subject or the investigator. 
The investigator must discontinue study treatment for a given subject if, he/she believes that 
continuation would negatively impact the subject's well-being. 
Discontinuation from study treatment is required under the following circumstances: 
• Subject decision 
• Pregnancy 
• Use of prohibited treatment as per recommendations in the prohibited treatment (Section 
6.2.2) 
• Any situation in which continued study participation might result in a safety risk to the 
subject 
• Following emergency unblinding 
• Adverse events 
• Unsatisfactory therapeutic effect 
If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s discontinuation from study treatment and 
record this information. 
Subjects who discontinue from study treatment agree to return for the end of treatment and 
follow-up visits indicated in the Assessment Schedule (refer to Section 8). 
If the subject cannot or is unwilling to attend any visit(s), the site staff should maintain regular 
telephone contact with the subject, or with a person pre-designated by the subject. This 
telephone contact should preferably be done according to the study visit schedule. 
After discontinuation from study treatment, at a minimum, in abbreviated visits, the following 
data should be collected at clinic visits or via telephone/email contact: 
• New / concomitant treatments 
• AE / SAE 


Novartis 
Confidential 
Page 49 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
The investigator must also contact the IRT to register the subject’s discontinuation from study 
treatment. 
If discontinuation occurs because treatment code has been broken, please refer to Emergency 
breaking of treatment code in Section 6.6.3. 
9.1.2 
Discontinuation from study 
Discontinuation from study is when the subject permanently stops receiving the study treatment, 
and further protocol-required assessments or follow-up, for any reason. 
If the subject agrees, a final evaluation at the time of the subject’s study discontinuation should 
be made as detailed in the assessment table (refer to Section 8). 
9.1.3 
Lost to follow-up 
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the subject, e.g. dates of telephone 
calls, registered letters, etc. A subject should not be considered as lost to follow-up until due 
diligence has been completed or until the end of the study. 
9.2 
Withdrawal of informed consent/Opposition to use 
data/biological samples  
Withdrawal of consent/opposition to use data/biological samples occurs when a subject: 
• Explicitly requests to stop use of their biological samples and/or data (opposition to use 
subject’s data and biological samples) 
and 
• No longer wishes to receive study treatment 
and 
• Does not want any further visits or assessments (including further study-related contacts) 
This request should be in writing (depending on local regulations) and recorded in the source 
documentation. 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw their consent/opposition 
to use data/biological samples and record this information. 
Where consent to the use of Personal and Coded Data is not required in a certain country's legal 
framework, the subject therefore cannot withdraw consent. However, they still retain the right 
to object to the further collection or use of their Personal Data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the subject are not allowed unless safety findings require 
communicating or follow-up. 


Novartis 
Confidential 
Page 50 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
If the subject agrees, a final evaluation at the time of the subject’s withdrawal of 
consent/opposition to use data/biological samples should be made as detailed in the assessment 
table (refer to Section 8). 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation, including processing of biological samples that has already 
started at time of consent withdrawal/opposition. No new Personal Data (including biological 
samples) will be collected following withdrawal of consent/opposition. 
9.3 
Study completion and post-study treatment 
Study completion is defined as when the last subject finishes their Study Completion visit and 
any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator or, in the event of an early study termination decision, the date 
of that decision. 
Sites will contact the subjects by telephone 4 days after EOT visit (Visit 6) to inquire about any 
adverse events that began after the last treatment with IMP.  The investigator must show "due 
diligence" by documenting in the source documents steps taken to contact the subject, e.g. dates 
of telephone calls. 
9.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time. 
Reasons for early termination:  
• Unexpected, significant, or unacceptable safety risk to subjects enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider subject welfare and safety. 
Should early termination be necessary, subjects must be seen as soon as possible and treated as 
a subject who discontinued from study treatment: The investigator should contact such 
information to the subject, when the subject should stop taking drug, when the subject should 
come in for a final visit(s) that the safety follow up period must be completed if applicable and 
which visits to be performed. . The investigator may be informed of additional procedures to be 
followed in order to ensure that adequate consideration is given to the protection of the subject’s 
interests. The investigator or sponsor depending on local regulation will be responsible for 
informing IRBs/IECs of the early termination of the trial. 


Novartis 
Confidential 
Page 51 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An AE is any untoward medical occurrence (e.g. any unfavorable and unintended sign 
[including abnormal laboratory findings], symptom or disease) in a subject or clinical 
investigation subject after providing written informed consent for participation in the study. 
Therefore, an AE may or may not be temporally or causally associated with the use of a 
medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual subject and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the subject at 
each visit during the study. Adverse events also may be detected when they are volunteered by 
the subject during or between visits or through physical examination findings, laboratory test 
findings, or other assessments. 
Adverse events must be recorded under the signs, symptoms, or diagnosis associated with them, 
accompanied by the following information (as far as possible) (if the event is serious refer to 
Section 10.1.2): 
1. The severity grade 
mild: usually transient in nature and generally not interfering with normal activities 
moderate: sufficiently discomforting to interfere with normal activities 
severe: prevents normal activities 
2. Its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 
will usually be ‘Not suspected.’ The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single subject 
3. Its duration (start and end dates or ongoing) and the outcome must be reported 
4. Whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met 
5. Action taken with study treatment 
All adverse events must be treated appropriately. Treatment may include one or more of the 
following: 
• Dose not changed 
• Dose Reduced/increased 


Novartis 
Confidential 
Page 52 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
• Drug interrupted/permanently discontinued 
6. its outcome 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the subject. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
 
Adverse event monitoring should be continued until the end of study visit. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent (e.g. continuing at the end of the study), and assessment must be made at each visit 
(or more frequently, if necessary) of any changes in severity, the suspected relationship to the 
interventions required to treat it, and the outcome. 
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator's Brochure (IB). 
10.1.2 
Serious adverse events 
An SAE is defined as any AE [appearance of (or worsening of any pre-existing)] undesirable 
sign(s), symptom(s), or medical conditions(s) which meets any one of the following criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of a SAE refers to a reaction in which the subject was at risk of 
death at the time of the reaction; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the subject or might 


Novartis 
Confidential 
Page 53 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant.” Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias, or convulsions that 
do not result in hospitalization or development of dependency or abuse (please refer to the ICH-
E2D Guidelines). 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
10.1.3 
SAE reporting 
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until 30 days after the last study visit must be reported to 
Novartis safety immediately, without undue delay, under no circumstances later than within 24 
hours of learning of its occurrence. Detailed instructions regarding the submission process and 
requirements are to be found in the investigator folder provided to each site. Information about 
all SAEs is collected and recorded on the eSAE with paper back. Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. 
All follow-up information for the SAE including information on complications, progression of 
the initial SAE and recurrent episodes must be reported as follow-up to the original episode 
within 24 hours of the investigator receiving the follow-up information. An SAE occurring at a 
different time interval or otherwise considered completely unrelated to a previously reported 
one must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, a CMO & PS Department 
associate may urgently require further information from the investigator for health authority 
reporting. Novartis may need to issue an Investigator Notification to inform all investigators 
involved in any study with the same study treatment that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with European Union 
(EU) Guidance 2011/C 172/01 or as per national regulatory requirements in participating 
countries. 
Any SAEs experienced after the 30 day period after the last study visit should only be reported 
to Novartis Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial subject becomes pregnant, the study treatment should be stopped, and the 
pregnancy consent form should be presented to the trial subject. The subject must be given 
adequate time to read, review and sign the pregnancy consent form. This consent form is 


Novartis 
Confidential 
Page 54 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
necessary to allow the investigator to collect and report information regarding the pregnancy. 
To ensure subject safety, each pregnancy occurring after signing the informed consent must be 
reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship between the use of SAF312 
eye drops and any pregnancy outcome. Any SAE experienced during pregnancy must be 
reported. 
If a female partner of a male trial subject who took study treatment in this study becomes 
pregnant, pregnancy outcomes should be collected. Consent to report information regarding 
these pregnancy outcomes should be obtained from the mother. 
After consent is provided, the pregnancy reporting will occur up to one year after the estimated 
date of delivery. 
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (European Medicines Agency (EMA) definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate CRF irrespective of whether or not associated with an AE/SAE and reported to 
Safety only if associated with an SAE (see Table 10-1). Misuse or abuse will be collected and 
reported in the safety database within 24 hours of Investigator’s awareness only if it is 
associated with an SAE. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse 
Treatment error type 
Document as a 
protocol deviation 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE form 
Unintentional study 
treatment error 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
Misuse/Abuse 
Yes 
Only if associated with 
an AE 
Only if associated with 
an SAE 
For more information on AE and SAE definition and reporting requirements, please see the 
respective sections. 


Novartis 
Confidential 
Page 55 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
10.2 
Additional Safety Monitoring 
Not applicable 
11 
Data Collection and Database management 
11.1 
Data collection 
Designated investigator staff will enter the data required by the protocol into the Electronic 
CRF (eCRF). The eCRFs have been built using fully validated secure web-enabled software 
that conforms to 21 Code of Federal Regulation (CFR) Part 11 requirements, Investigator site 
staff will not be given access to the EDC system until they have been trained. Automatic 
validation programs check for data discrepancies in the eCRFs, allow modification and/or 
verification of the entered data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the subject data for archiving 
at the investigational site. 
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification. 
11.2 
Database management and quality control 
Novartis personnel will review the data entered by investigational staff for completeness and 
accuracy. Electronic data queries stating the nature of the problem and requesting clarification 
will be created for discrepancies and missing values and sent to the investigational site via the 
EDC system. Designated investigator site staff are required to respond promptly to queries and 
to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
terminology. 
Randomization codes and data about all study treatment (s) dispensed to the subject and all 
dosage changes will be tracked using an Interactive Response Technology (IRT). The system 
will be supplied by a vendor, who will also manage the database. The data will be sent 
electronically to Novartis at specific timelines. 
Each occurrence of a code break via IRT will be reported to the clinical team and study monitor. 
The code break functionality will remain available until study shut down or upon request of 
Novartis. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unblinded and made 


Novartis 
Confidential 
Page 56 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
available for data analysis. Any changes to the database after that time can only be made after 
written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis 
representative will review the protocol and data capture requirements (i.e. eCRFs) with the 
investigators and their staff. During the study, Novartis employs several methods of ensuring 
protocol and GCP compliance and the quality/integrity of the sites’ data. The study  monitor 
will visit the site to check the completeness of subject records, the accuracy of data capture / 
data entry, the adherence to the protocol and to Good Clinical Practice (GCP), the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted for 
according to specifications. Key study personnel must be available to assist the study  monitor 
during these visits. Continuous remote monitoring of each site’s data may be performed by a 
centralized Novartis/Clinical Research Associate (CRA) organization. Additionally, a central 
analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each 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 study monitor access to all relevant source documents to confirm 
their consistency with the data capture and/or data entry. Novartis monitoring standards require 
full verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAEs, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the CRFs are performed according 
to the study-specific monitoring plan. No information in source documents about the identity 
of the subjects will be disclosed. 
12 
Data analysis and statistical methods 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
The Safety Set includes all subjects who received at least one dose of study treatment. Subjects 
will be analyzed according to the study treatment received, where treatment received is defined 
as the randomized treatment if the subject took at least one dose of that treatment or the first 
treatment received if the randomized treatment was never received. 


Novartis 
Confidential 
Page 57 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
12.2 
Subject demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation (SD), median, minimum, and maximum will be presented. For selected 
parameters, 25th and 75th percentiles will also be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by treatment group. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, SD, median, 25th and 75th percentiles, 
minimum, and maximum will be presented. 
The duration of exposure in days to SAF312 and placebo will be summarized by means of 
descriptive statistics using the safety set. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group. 
12.4 
Analysis of supporting primary objectives 
The analysis of the primary endpoints will be based on FAS.  
12.4.1 
Definition of primary endpoint(s) 
The primary endpoint is the change from baseline in weekly mean pain severity VAS at Week 
12. The weekly mean pain severity VAS will be calculated as the mean of the daily pain severity 
VAS from the 7 days of the week.  Baseline value will be calculated as the mean of the daily 
pain severity VAS from the 7 days prior to the first dose.  
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary objective of the study is to show that at least one SAF312 arm will improve weekly 
mean pain severity VAS in comparison with its placebo by rejecting the null hypothesis below 
at a significance level α=0.05 (2-sided).  
H1: uT=uv  vs. H2: uT≠uv 
where uT and uv are mean change from baseline of weekly mean pain severity VAS at Week 12 
in SAF312 arm and the placebo arm.  
Dunnett procedure will be used to adjust overall type I error (0.05) among the comparisons 
between each SAF312 arm and the placebo arm.  
Mixed model repeated measure (MMRM) analysis will be used with change from baseline at 
each week on treatment as response variable, and treatment, week, and baseline score as 
covariates. Two interaction term (treatment*week and baseline*week) will also be included in 


Novartis 
Confidential 
Page 58 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
the model. An unstructured within subject correlation structure will be used for covariance 
matrix. The Kenward-Roger approximation will be used to estimate denominator degree of 
freedom. REML (residual/restricted maximum likelihood) method will be used to estimate 
parameters.  
The two-sided p value for the least square mean (LSM) difference between the SAF312 and the 
placebo group at each week will be reported for the difference.  
12.4.3 
Handling of intercurrent events of primary estimand 
In the primary analysis, the estimand will be the treatment effect of SAF312 against placebo, 
had subjects not taken prohibited or rescue medications as described below, and had they stayed 
on the study treatment for the whole study duration. The hypothetical strategy assumes the 
subjects with Intercurrent events (IEs) will behave like other subjects who did not take 
rescue/prohibited medications and stayed on study treatment.  
For subjects who use rescue medications for pain relief due to any reason, the data on the day(s) 
will be excluded and treated as missing.   
For subjects who take the following prohibited medications: 
• Ocular, nasal, inhaled, or systemic corticosteroids  
• Use of oral or topical ocular antihistamines, mast cell stabilizers 
The data on the day(s) + 3 days following the last day of these prohibited medications will be 
excluded and treated as missing.  
For subjects with new use or changes in dosing of neuromodulators for any reason or topical 
ocular NGF, the data starting from the day will be excluded and treated as missing.  
For subjects who discontinue study treatment for any reason, the data collected following the 
treatment discontinuation will be excluded and treated as missing.  Missing data after study 
treatment discontinuation will be based on the Missing at Random (MAR) assumption. 
The multiple imputations will be carried out on the weekly mean pain severity VAS.  
12.4.4 
Handling of missing values not related to intercurrent event 
The primary MMRM model implicitly imputes missing data under a MAR assumption. 
Handling of missing daily pain severity values within a week (within-week imputation) 
The weekly mean of the seven 24-hour average pain severity assessments will be calculated 
based on the available assessments. If only one measurement is available, the mean will be 
based on that value. 
Handling of missing weekly mean pain score values (weekly mean imputation) 
For all analyses, imputation of intermittent missing observations before treatment 
discontinuation will be carried out following a MAR mechanism for all treatment arms. 
12.4.5 
Sensitivity analyses for primary endpoint/estimand 
Not applicable. 


Novartis 
Confidential 
Page 59 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
12.4.6 
Supplementary analysis 
A supplementary clinical question of interest is: What is the effect of SAF312 versus placebo 
on change from baseline in weekly mean pain severity VAS score, regardless of 
discontinuation from study treatment discontinuations for any reason, and regardless of 
occasional use of rescue medication or prohibited medications?  
The supplementary analyses to the primary analysis will be performed on the FAS population. 
The supplementary analysis will be performed using all observed data regardless of intercurrent 
events (a treatment policy strategy). The target population, the primary variable and the 
summary measure of the supplementary estimand for the supplementary estimand are the same 
as for the primary estimand. Differently from the primary estimand, this analysis considers all 
intercurrent events are inherent in the treatment regimen and will not exclude any observed data 
even when subjects take rescue/prohibited medications or discontinue treatment.  
For subjects who use rescue medications for pain relief due to any reason, all observed data will 
be used for analysis. If not available, missing data will be under the MAR assumption for both 
SAF312 and placebo arms.  
For subjects who take the following prohibited medications: 
• Ocular, nasal, inhaled, or systemic corticosteroids  
• Use of oral or topical ocular antihistamines, mast cell stabilizers 
All observed data will be used for analysis. If not available, missing data on the day(s) +3 
days of the IEs will be under the MAR assumption for both SAF312 arms and  placebo arm.  
 
For subjects with new use or change in dosing of neuromodulators for any reason or topical 
ocular NGF, all observed data will be used for analysis.  If not available, missing data on the 
days of IEs will be under the MAR assumption for both SAF312 and placebo arms. 
 
For subjects who discontinue from study treatment due to any reason, retrieved drop-out 
(RDO) data collected after study treatment discontinuation will be used for analysis. If not 
available, missing data after treatment discontinuation will be multiply imputed based on 
Jump to Reference assumption for SAF312 arms and under the MAR assumption for  placebo 
arm.  
The supplementary analysis will be performed using MMRM but includes all the observed 
data and imputed data if appropriate. 
Subgroup analysis 
Subgroup analyses of the primary endpoints will be outlined in the statistical analysis plan 
(SAP). 
12.5 
Analysis supporting secondary objectives 
For secondary endpoints: 
• Change from baseline in pain severity Visual Analog Scale (VAS) at Day 7 and Day 14 
• Change from baseline to Week 12 in pain frequency VAS 


Novartis 
Confidential 
Page 60 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
• Change from baseline in OPAS subscale Quality of Life at Week 12 
• Change from baseline to Week 12 in ocular surface parameters (corneal staining score, 
conjunctival staining score, Schirmer score, conjunctival redness score) 
Summary statistics (mean, median, 25th percentile, 75th percentile, standard deviation, 
minimum and maximum, the number of non-missing observations, and 95% confidence interval) 
by treatment arm will be provided. 95% confidence interval will be provided for the difference 
between the SAF312 arm vs. placebo for pain severity VAS, pain frequency VAS, and OPAS 
subscale Quality of Life. 
12.5.1 
Safety endpoints 
For all safety analyses, the safety set will be used. The safety assessments are adverse events 
(ocular and non-ocular), slit lamp biomicroscopy, IOP, visual acuity, ophthalmoscopy, and  
corneal endothelial cells evaluations. All listings and tables will be presented by treatment group. 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period starts from the date of the first administration of study treatment to 4 
days after the date of the last administration of study treatment. 
The safety analysis will consist of descriptive summaries. Continuous variables will be 
presented with n, mean, SD, median, minimum and maximum. Categorical data will be 
displayed with frequency and percentage.  
Adverse events 
All information obtained on adverse events will be displayed by treatment group and subject. 
The number (and percentage) of subjects with treatment emergent adverse events (events started 
after the first dose of study medication or events present prior to start of double-blind treatment 
but increased in severity based on preferred term) will be summarized in the following ways: 
• by treatment, primary system organ class and preferred term. 
• by treatment, primary system organ class, preferred term and maximum severity. 
• by treatment, Standardized MedDRA Query (SMQ) and preferred term. 
Ocular and non-ocular adverse events will be summarized separately. Separate summaries will 
be provided for study treatment related adverse events, death, SAE, other significant adverse 
events leading to discontinuation. 
Subject listings of all adverse events will be provided. Deaths and other serious or clinically 
significant non-fatal adverse events will be listed separately. A subject with multiple adverse 
events within a primary system organ class is only counted once towards the total of the primary 
system organ class. 


Novartis 
Confidential 
Page 61 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
12.5.2 
Patient reported outcomes 
Patient-reported outcomes include the following: 
x OPAS questionnaire subscales 
 
 
Summary of change from baseline will be provided by treatment group. No test will be 
performed on the PRO endpoints. 
12.6 
Analysis of exploratory endpoints 
Exploratory endpoints include: 
 
 
 
 
 
 
 
 
x Frequency of artificial tears/gel/lubricant use over the 12-week treatment period 
x Frequency of rescue medication use over the 12-week treatment period 
x Change from Baseline to Week 12 in total corneal nerve fiber length  
x Presence of microneuromas  
x Density of corneal dendritiform cells 
The analysis will be based on FAS.  
 
  
For continuous endpoints, summary statistics (mean, median, 25th percentile, 75th percentile, 
SD, minimum and maximum, the number of non-PLVVLQJREVHUYDWLRQVDQGFRQILGHQFH
interval) will be provided by treatment arm at each time point. Differences of change from 
baseline endpoints between each SAF312 arm vs. placebo will be summarized at each post-
EDVHOLQHYLVLWZLWKFRQILGHQFHLQWHUYDO 
For frequency of pain events, artificial tears/gel/lubricant, rescue medications, and 
microneuromas, percentage of subjects by treatment group over time will be presented. The 
GLIIHUHQFHLQSHUFHQWDJHEHWZHHQHDFK6$)DQGSODFHERZLOOEHVXPPDUL]HGZLWK
confidence interval.  
12.7 
Interim analyses 
No interim analysis is planned for this trial. A final analysis will be performed after all subjects 
have completed Week 12 or discontinued prior to Week 12.  
P
I
PI


Novartis 
Confidential 
Page 62 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
Assuming a true treatment difference in change from baseline in weekly mean pain severity 
VAS of 15 mm and a SD of 23 mm, a sample size of 50 subjects per arm provides approximately 
83% power that the primary analysis will be statistically significant at the two-sided 5% 
significance level adjusted by 2 comparisons.  
See Table 12-1 for power to detect a significant difference from placebo under various assumed 
treatment effect of weekly mean pain severity VAS and SD.  
nQuery Advisor 7.0 is used for the estimate. 
Table 12-1 
Power to detect a significant difference from placebo under different 
assumed treatment effects and SD with N = 50 pts/arm 
  
Treatment effect: difference from placebo in change from 
baseline in weekly mean pain severity VAS  
SD of change from baseline in 
weekly mean l pain severity 
VAS  
15 
20 
17 
98% 
>99% 
20 
92% 
>99% 
23 
83% 
97% 
The sample size may increase by up to 20% (i.e., 60 pts/arm) in order to maintain power in 
case dropout increases during the pandemic. 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for GCP, with applicable local regulations 
(including European Directive 2001/20/EC, US CFR 21), and with the ethical principles laid 
down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the 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 
study monitors, auditors, Novartis Quality Assurance representatives, designated agents of 
Novartis, IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site 


Novartis 
Confidential 
Page 63 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
is requested by a regulatory authority, the investigator must inform Novartis immediately that 
this request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion (defined as last patient last visit) 
and finalization of the study report the results of this trial will be submitted for publication and 
posted in a publicly accessible database of clinical trial results, such as the Novartis clinical trial 
results website and all required Health Authority websites (e.g. Clinicaltrials.gov, EudraCT 
etc.). 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings. 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study subjects. Additional assessments required to ensure safety of subjects should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study subjects. 
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. 


Novartis 
Confidential 
Page 64 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
14.1 
Protocol amendments 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, health authorities where required, and the IRB/IEC prior to 
implementation. 
Only amendments that are required for subject safety 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, Novartis should 
be notified of this action and the IRB/IEC at the study site should be informed according to 
local regulations. 


Novartis 
Confidential 
Page 65 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
15 
References 
References are available upon request 
Benatti CA, Afshari NA (2016) Postoperative Pain After Laser Refractive Surgery. Int 
Ophthalmol Clin; 56(2):83-100. 
Caterina MJ, Julius D (2001) The vanilloid receptor: a molecular gateway to the pain 
pathway. Annu. Rev. Neurosci; 24(1):487-517. 
Clapham DE, Runnels LW, Strübing C (2001) The TRP ion channel family. Nat. Rev. 
Neurosci; 2(6):387-96. 
Geppetti P, Trevisani M (2004) Activation and sensitisation of the vanilloid receptor: role in 
gastrointestinal inflammation and function. Br. J. Pharmacol; 141(8):1313-20. 
Gunthorpe MJ, Benham CD, Randall A, et al (2002) The diversity in the vanilloid (TRPV) 
receptor family of ion channels. Trends Pharmacol. Sci; 23(4):183-91. 
Hayes P, Meadows HJ, Gunthorpe MJ, et al (2000) Cloning and functional expression of a 
human orthologue of rat vanilloid receptor-1. Pain; 88(2):205-15. 
Holzer P (2004) Gastrointestinal pain in functional bowel disorders: sensory neurons as novel 
drug targets. Expert Opin. Ther. Targets; 8(2):107-23. 
Levitt AE, Galor A, Weiss JS, et al (2015) Chronic dry eye symptoms after LASIK: parallels 
and lessons to be learned from other persistent post-operative pain disorders. Mol Pain; 
11(21):1-12. 
Mergler S, Valtink M, Coulson-Thomas VJ, et al (2010) TRPV channels mediate 
temperature-sensing in human corneal endothelial cells. Exp. Eye Res; 90(6):758-70. 
Shtein RM (2011) Post-LASIK dry eye. Expert Rev Ophthalmol; 6(5):575-82. 
Yang Y, Yang H, Wang Z, et al (2013) Functional TRPV1 expression in human corneal 
fibroblasts. Exp. Eye Res; 107(1):121-9. 
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; 213(3):730-9. 


Novartis 
Confidential 
Page 66 
Clinical Trial Protocol (Version No. 03) 
 
Protocol No. CSAF312B12201 
 
16 
Appendices 
Not applicable 

SAP_001.pdf: 
Clinical Development 
SAF312 
CSAF312B12201 / NCT04630158
A 12-week parallel group, randomized, placebo-controlled, double-
blinded, multi-center study to evaluate efficacy and safety of 2 
concentrations of SAF312 eye drops (5 mg/ml and 15 mg/ml) used 
twice-daily in the treatment of post-operative corneal induced 
chronic pain (CICP) following Photorefractive Keratectomy (PRK) or 
Laser-assisted in Situ Keratomileusis (LASIK) surgeries
Statistical Analysis Plan (SAP) 
Document type:
SAP Documentation
Document status:
Final V3.0
Release date:
16-June-2023
Number of pages:
33
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template Version 3.0, Effective from 01-Jul-2020


Novartis
For business use only
Page 2 of 33
SAP
CSAF312B12201
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and title 
impacted 
(Current)
08-
Mar-
2021
Prior
to 
DB
lock
Creation of final 
version
NA
First version
(V1.0) approved in
Documentum
system.
NA
04-
May-
2022
Prior
to 
DB
lock
Creation of 
amendment -1
Aligned with 
protocol amendment 
version 3
Updated to
version V2.0
Section 1.1,
Section 2.1 2.2, 
and 2.5
Section 4 and 5
16-
Jun-
2023
Prior
to 
DB
lock
Creation of 
amendment -2
Update to version V3.0
Section 2.2, 
Section 2.3.2, 
Section 2.4.3, 
Section 2.4.4, 
Section 2.5, 
Section 2.8.1.3, 
Section 2.8.4, 
Section 2.13, 
Section 5.2.2 and 
Section 5.4


Novartis
For business use only
Page 3 of 33
SAP
CSAF312B12201
Table of contents
Table of contents..................................................................................................................3
List of tables.........................................................................................................................5
List of figures.......................................................................................................................5
List of abbreviations ............................................................................................................6
1
Introduction..........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints................................................................................8
2
Statistical methods ...............................................................................................................9
2.1
Data analysis general information............................................................................9
2.1.1
General definitions ..................................................................................9
2.2
Analysis sets...........................................................................................................11
2.2.1
Subgroup of interest ..............................................................................12
2.3
Subject disposition, demographics and other baseline characteristics...................12
2.3.1
Subject disposition.................................................................................12
2.3.2
Demographics and baseline characteristics...........................................13
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................13
2.4.1
Study treatment / compliance................................................................13
2.4.2
Prior, concomitant and post therapies ...................................................13
2.4.3
Rescue medication.................................................................................14
2.4.4
Prohibited medication............................................................................14
2.5
Analysis of the primary objective..........................................................................15
2.5.1
Primary endpoint ...................................................................................15
2.5.2
Statistical hypothesis, model, and method of analysis ..........................16
2.5.3
Handling of missing values not related to intercurrent event................17
2.5.4
Supportive analyses...............................................................................17
2.6
Analysis of the key secondary objective................................................................18
2.7
Analysis of secondary efficacy objective(s) ..........................................................18
2.7.1
Secondary endpoints..............................................................................18
2.7.2
Statistical hypothesis, model, and method of analysis ..........................19
2.7.3
Handling of missing values/censoring/discontinuations .......................19
2.8
Safety analyses.......................................................................................................19
2.8.1
Adverse events (AEs)............................................................................19
2.8.2
Deaths....................................................................................................20
2.8.3
Laboratory data......................................................................................20


Novartis
For business use only
Page 4 of 33
SAP
CSAF312B12201
2.8.4
Other safety data....................................................................................20
2.9
Pharmacokinetic endpoints ....................................................................................21
2.10
PD and PK/PD analyses.........................................................................................21
2.11
Patient-reported outcomes......................................................................................21
2.12
Biomarkers.............................................................................................................22
22
2.14
Interim analysis......................................................................................................22
3
Sample size calculation......................................................................................................22
4
Change to protocol specified analyses...............................................................................23
5
Appendix............................................................................................................................23
5.1
Imputation rules .....................................................................................................23
5.1.1
AE date imputation................................................................................23
5.1.2
Concomitant medication date imputation..............................................25
5.2
Statistical models ...................................................................................................26
5.2.1
Primary Analysis ...................................................................................26
5.2.2
Supplementary Analysis........................................................................27
5.3
Rule of exclusion criteria of analysis sets..............................................................29
5.4
Data issue of conjunctival lissamine staining & conjunctival redness from 
Site 
................................................................................................................33
6
Reference ...........................................................................................................................33


Novartis
For business use only
Page 5 of 33
SAP
CSAF312B12201
List of tables
Table 1-1
Objectives and related endpoints.............................................................8
Table 2-1
Allocation of assessments to analysis visit window..............................11
Table 2-2
Prohibited medication............................................................................14
Table 2-3
The handling of intercurrent events strategy for primary estimands.....15
Table 2-4
The handling of intercurrent events strategy for supplementary 
estimands ...............................................................................................18
Table 2-5
Converting Snellen Fraction to Approximate ETDRS Letters Score....20
Table 3-1
Power to detect a significant difference from placebo under 
different assumed treatment effects and SD with N = 50 pts/arm.........23
Table 5-1
Protocol deviations................................................................................29
List of figures
Figure 1-1
Study Design ...........................................................................................7


Novartis
For business use only
Page 6 of 33
SAP
CSAF312B12201
List of abbreviations
AE
Adverse Event
ATC
Anatomical Therapeutic Classification
b.i.d.
bis in diem/Twice a day
CICP
Corneal Induced Chronic Pain
COVID-19
Coronavirus Disease 2019
CRC
Central Reading Center
CSR
Clinical Study Report
eCRF
Electronic Case Report Form
EOS
End of Study
EOT
End of Treatment
FAS
Full Analysis Set
IE
Intercurrent Events
IOP
Intraocular Pressure
LASEK
Laser Assisted Sub-Epithelial Keratectomy
LASIK
Laser-assisted in Situ Keratomileusis
LSM
Least Square Mean
MAR
Missing at Random
MedDRA
Medical Dictionary for Drug Regulatory Affairs
mg
milligram(s)
mL
milliliter(s)
ml
milliliter(s)
MMRM
Mixed Model Repeated Measure
NGF
Nerve Growth Factor
OPAS
Ocular Pain Assessment Scale
PK
Pharmacokinetics
PRK
Photorefractive Keratectomy
PRO
Patient-reported Outcomes
REML
Residual/Restricted Maximum Likelihood
RK
Radial Keratotomy
QoL
Quality of Life
SAE
Serious Adverse Event
SAF
Safety Analysis Set
SAP
Statistical Analysis Plan
SD
Standard Deviation
SMILE
Small Incision Lenticule Extraction
SMQ
Standardized MedDRA Query
SOC
System Organ Class
TRPV1
Transient Receptor Potential Vanilloid 1
VA
Visual Acuity
VAS
Visual Analogue Scale
WHO
World Health Organization


Novartis
For business use only
Page 7 of 33
SAP
CSAF312B12201
1
Introduction
The purpose of the Statistical Analysis Plan (SAP) is to describe the implementation of 
statistical analysis planned in the study protocol, and to provide detailed statistical methods that 
will be used for the Clinical Study Report (CSR) of study CSAF312B12201.
Data will be analyzed according to the data analysis plan described in this document that will 
be incorporated into the [CSAF312B12201 CSR-Section 9.7] and [CSAF312B12201 CSR-
Appendix 16.1.9].
1.1
Study design
Figure 1-1
Study Design
This study is a Phase 2 randomized, double-blinded, multi-center, parallel group, placebo-
controlled evaluation of the safety and efficacy of SAF312, 5 mg/ml and 15 mg/ml eye drops 
versus placebo used twice-daily in both eyes for 12 weeks. Eligible subjects will have 
undergone refractive surgery (i.e., PRK, LASIK, LASEK, RK, or SMILE) or cataract surgery 
in both eyes, with or without refractive enhancement in one or both eyes at least 4 months prior 
to Screening, and have been suffering from chronic ocular pain as a result of the surgery. Both 
eyes do not necessarily need to have undergone surgery on the same day. If the second eye 
underwent surgery on a different day than the first eligibility for time since surgery would be 
based on the date of the second surgery. In cases where more than one procedure was performed 
on an eye (e.g. refractive surgery with CICP followed some time later by cataract surgery, or 
cataract surgery followed some time later by refractive enhancement), the Screening visit must 
be 
 4 months after the most recent procedure. Eligible patients must also demonstrate 
chronicity of the pain as described in the inclusion criteria.
The study will consist of a 12-week observation period starting from Screening Visit (Visit 1) 
until the Baseline/Randomization Visit (Visit 2). Subjects who qualify for randomization will 
then be asked to attend visits every 2 weeks for the first 4 weeks, and then monthly for the 


Novartis
For business use only
Page 8 of 33
SAP
CSAF312B12201
remainder of the 12-Week treatment period. End of Treatment (EOT) will occur at Visit 6 when 
the subject receives the last study treatment. End of Study (EOS) will occur 4 days after EOT. 
Visit 6/EOT is the time point for primary analysis.
Potential participants will be required to provide written informed consent prior to any study-
specific Screening procedures being performed. Once informed consent is obtained subjects 
will be evaluated for eligibility based on the inclusion and exclusion criteria. Final eligibility 
will be based on an assessment of the subject’s pain severity VAS prior to randomization, as 
well as their response to a single drop of topical ocular anesthetic (e.g. tetracaine, proparacaine 
eye drops per clinical practice). Response to anesthetic is defined as a  60% reduction in ocular 
pain within 5 minutes after instillation of the anesthetic drop. The use of the anesthetic test is 
necessary for the selection of subjects with a primarily peripheral neuropathic type pain (i.e. 
primarily resulting from stimulation of the peripheral nerves) versus a purely central 
neuropathic pain. Subjects with a primarily central neuropathic pain are unlikely to experience 
significant improvement with a topical ocular treatment targeting the peripheral nerves. 
Overall, approximately 150 subjects will be enrolled in the study. Subjects who meet eligibility 
criteria at Visit 2 will be randomized to one of the 3 treatment groups (SAF312 5 mg/mL, 
SAF312 15 mg/mL, or placebo) in a 1:1:1 ratio. Randomization will be stratified according to 
No interim analysis planned.
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)
To demonstrate the efficacy of at least 1 of 
2 concentrations of SAF312 (5 mg/ml or 15 
mg/ml) with superiority to placebo in 
reducing ocular pain severity
Change from baseline to Week 12 in weekly 
mean pain severity Visual Analog Scale 
(VAS)
Secondary objective(s)
Endpoint(s) for secondary objective(s)
To evaluate additional efficacy of 2 
concentrations of SAF312 vs placebo
Change from baseline to Day 7 and Day 14 
using the pain severity VAS
Change from baseline to Week 12 in pain 
frequency VAS
Change from Baseline to Week 12 in Ocular 
Pain Assessment Scale (OPAS) sub-scale 
Quality of Life
To demonstrate SAF312 does not induce 
negative effects to the ocular surface after 
prolonged TRPV1 inhibition
Change from baseline to Week 12 in ocular 
surface parameters (e.g. corneal and 
conjunctival staining score, Schirmer score, 
conjunctival redness score)


Novartis
For business use only
Page 9 of 33
SAP
CSAF312B12201
Objective(s)
Endpoint(s)
To evaluate the safety of 2 concentrations of 
SAF312 (0.5 and 1.5%)
Comparison of adverse events rates 
between active and placebo
Exploratory objective(s)
Endpoint(s) for exploratory objective(s)
To monitor a subject's behavior regarding 
artificial tear/gel/lubricant use
To monitor a subject's behavior regarding 
rescue medication use
To evaluate corneal nerve density and 
morphology
Frequency of artificial tear/gel/lubricant use 
over the 12-week treatment period
Frequency of rescue medication use over 
the 12-week treatment period
Change from Baseline to Week-12 in total 
corneal nerve fiber length 
Presence of microneuromas 
Density of corneal dendritiform cells 
2
Statistical methods
2.1
Data analysis general information
The analysis will be performed by the Biostatistics and statistical programming groups of 
Novartis, using SAS 9.4 or above.
For categorical variables, frequencies and percentages will be computed. For continuous 
variables, descriptive statistics, including number of non-missing observations, mean, standard 
deviation, median, minimum, and maximum will be presented. For selected parameters, 25th 
and 75th percentiles will also be presented. Where appropriate, point estimates and two-sided 
95% confidence intervals of treatment group differences will be provided.
These summary statistics will be presented by treatment group unless otherwise specified.
2.1.1
General definitions 
2.1.1.1
Study Treatment
Any drug administered to the study participants as part of the required study procedures; 
includes investigational drug (s), and control(s), which includes:
PI


Novartis
For business use only
Page 10 of 33
SAP
CSAF312B12201
SAF312 15 mg/mL (1.5%) eye drops, suspension, b.i.d.
SAF312 5 mg/mL (0.5%) eye drops, suspension, b.i.d.
SAF312 Placebo eye drops, suspension, b.i.d.
All dosage strengths of SAF312 and placebo will be identical in appearance (in Drop-tainers 
for b.i.d. dosing of both eyes each day). The following abbreviated treatment groups will be 
used as the headers in the tables:
SAF312 15 mg/ml 
SAF312 5 mg/ml 
SAF312 Placebo
2.1.1.2
Baseline and post-Baseline
Baseline (Day 1) is the date of first dose of study treatment. The baseline value for 
efficacy and safety variables is the last available value collected prior to or at the first 
date of study treatment. Missing baseline data will not be imputed.
All data collected after the first date of treatment are defined as post-baseline. The study 
day for a baseline or post-baseline scheduled or unscheduled visit is defined as: 
Study day = (Date of visit) – (Date of first dose of study treatment) + 1;
The study day for a scheduled or unscheduled visit before baseline is defined as 
Study day = (Date of visit) – (Date of first dose of study treatment).
2.1.1.3
End of study/end of treatment/unscheduled visit day mapping:
The end of treatment date (date of last exposure from ‘Study Treatment’ CRF form) is the date 
of the last study treatment prior to/on the end of study date. The end of study date (from ‘Study 
disposition’ CRF) is the date when a subject completes or discontinues the study. For reporting 
data by visit in outputs, visit window (Section 2.1.1.5) rules will be applied based on study day 
to allocate assessments to the actual (reported) visit number.
2.1.1.4
Unscheduled visits
Unscheduled visit measurements will be included in the following:
1. derivations of measurements at scheduled visits per specified visit windowing rules 
below.
2. derivations of baseline/last on-treatment measurements.
3. derivations of the maximum/minimum on-treatment values and maximum/minimum 
changes from baseline values for safety analyses.
4. subject data listings where appropriate.
2.1.1.5
Visit Windows
Visit windows will be applied for all measurements except data from e-diary daily. Weekly 
mean will be calculated every 7 days starting from study day 1.


Novartis
For business use only
Page 11 of 33
SAP
CSAF312B12201
Table 2-1
Allocation of assessments to analysis visit window
Scheduled main visit 
name/label
Target study
day
Analysis visit window 
in study days
Visit Label
Visit 1 Screening
-84
Screening
Visit 2 Baseline
1
1
Baseline
Visit 3
14
2 - 21
Visit 3 (week 2)
Visit 4
28
22 - 42
Visit 4 (week 4)
Visit 5
56
43 - 70
Visit 5 (week 8)
Visit 6 EOT
84
Visit 6 / EOT (week 
12)
To allocate assessments to each scheduled visit
If no measurement is available within a visit window, the assessment will be considered 
missing for the visit.
If there is more than one measurement available within the same visit window, use the 
following rules:
1. The record closest to the target day will be used. 
2. If there are multiple records with the same distance to the target day, the latest record 
will be used.
3. If there are multiple records with the same distance on the same day, the average will 
be used.
2.1.1.6
7-day average of assessments
The Pain Severity Visual Analog Scale (VAS) score is captured in the e-diary daily by the 
patient for the entire 6 months of the study (observational period and treatment period), and 
weekly mean of the scores is calculated by averaging the available Pain Severity VAS scores 
during the 7 days of that week. Pain frequency will be analyzed in the same manner.
To calculate the frequency of artificial tear/gel/lubricant use, the information is captured daily 
as mentioned above, and the daily frequency collected by the patient in e-diary during the 7 
days of that week will be averaged.
2.1.1.7
Change from baseline for continuous parameters
Change from baseline will be calculated as:
change from baseline = post-baseline value – baseline value
For summary statistics the raw values (and not imputed values) will be used.
2.2
Analysis sets
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 


Novartis
For business use only
Page 12 of 33
SAP
CSAF312B12201
to the treatment and strata they have been assigned to during the randomization procedure. Mis-
randomized subjects who do not take study medication will be excluded from FAS.
The Safety Set (SAF) includes all subjects who received at least one dose of study treatment. 
Subjects will be analyzed according to the study treatment received, where treatment received 
is defined as the randomized treatment if the subject took at least one dose of that treatment or 
the first treatment received if the randomized treatment was never received.
The number and percentage of subjects within each of the above analysis sets will be 
summarized. 
Rules of exclusion criteria of analysis sets with protocol deviations and subject classification 
are specified in Appendix.
2.2.1
Subgroup of interest
The subgroups of interest are specified below:
Baseline age group: < 65 years, and >= 65 years
Sex: male, female
Race: Caucasian, Asian and Others
Eye color: 
1. If the two irises of a subject are the same color as Black, Brown, Hazel, Green, 
Blue or Gray, the subject will be classified as one of the categories:  
“Black/Brown”, “Hazel/Green”, or “Blue/Gray”.
2. If the two irises of a subject are of the same color but different from the colors 
listed above, or if the two irises have a different color, the subject will be 
classified as “Other”. 
Baseline pain severity: 7-day average pain severity VAS >= 75, 7-day average pain 
severity VAS < 75
Region: Japan, Non-Japan
2.3
Subject disposition, demographics and other baseline 
characteristics
Subject characteristics and study conduct summaries include tables and listings such as
subject disposition table, demographics and baseline characteristics tables, summary of screen 
failures by reason and listing of subjects excluded from analysis sets.
2.3.1
Subject disposition
Subject disposition will be summarized separately by treatment group and total for the FAS. 
Specifically, the number and proportion of subjects who discontinued the study will be 
summarized by treatment and total. The primary reason for premature study discontinuation 
will be summarized in the table.


Novartis
For business use only
Page 13 of 33
SAP
CSAF312B12201
2.3.2
Demographics and baseline characteristics
Demographics table will include age, sex, race, ethnicity, ancestry, and eye color. 
Baseline characteristics table will include: type of prior surgery(PRK,LASIK, LASEK, RK, 
SMILE or Cataract), time (days) since last surgery, corneal fluorescein staining(sum score), 
conjunctival lissamine staining(sum score), conjunctival redness score ( Temporal and Nasal), 
schirmer score, Pain Characterization Questionnaire (question 2 only), 7-day average of pain 
severity VAS score, 7-day average of pain frequency VAS score, 7-day average of artificial 
tear/gel/lubricant use frequency and 7-day frequency of rescue medication use .
Demographic and baseline characteristics will be summarized for FAS populations by treatment 
group using frequencies and percentages (for categorical variables) and descriptive statistics of 
mean, standard deviation, minimum, median and maximum (for continuous variables). 
Relevant medical histories and current medical conditions at baseline will be summarized by
system organ class, preferred term and treatment group, for ocular and non-ocular 
histories/conditions, respectively.
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The SAF will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented.
2.4.1
Study treatment / compliance
The duration of exposure in days to study treatment will be summarized by means of descriptive 
statistics by treatment group. The duration of exposure is defined as: date of the last 
administration of study treatment (date of last exposure in CRF ‘Study Treatment’ form) – date 
of first administration of study treatment (date of first exposure in CRF ‘Study Treatment’ form) 
+ 4 + 1.
Compliance will be presented by summarizing the total number of days without missing a dose 
or dose interrupted within the treatment period by treatment group. Reason for premature 
discontinuation from the study treatment will also be summarized.
2.4.2
Prior, concomitant and post therapies
Prior medications are defined as drugs taken and stopped prior to the first administration of 
study treatment. Any medication given at least once between the day of the first dose of the 
study treatment and the end of study visit will be a concomitant medication. Prior or 
concomitant medication will be identified based on recorded or imputed start and end dates of 
taking the medication.
Prior and concomitant medication will be summarized by treatment group (separately for ocular 
and non-ocular medications/therapies), presented in alphabetical order by ATC classification 
codes and preferred term. The tables will be presented with overall number and percentage of 
subjects receiving at least one drug of a particular ATC code and at least one drug in a particular 


Novartis
For business use only
Page 14 of 33
SAP
CSAF312B12201
preferred term. Medications will be coded according to the WHO Drug Reference List 
dictionary. 
In addition, all information will be listed including the reported name, laterality, and treatment 
start/end date, etc.
2.4.3
Rescue medication
There is no rescue medication that will be proactively provided to study sites or subjects. 
However, at the discretion of the investigator, medication (local or systemic, over the counter 
or prescription) used for pain relief will be allowed and will be specified if used for ocular or 
non-ocular pain. Rescue medication will be the newly assigned medication for pain (ocular or 
non-ocular) during treatment period. Pain medication used as background therapy will not be 
counted as rescue medication. 
The number and percentage of subjects who received any rescue medication will be summarized 
by treatment group. The 7-day frequency of rescue medication use will be summarized by week 
and treatment group.
2.4.4
Prohibited medication
Moreover, concomitant medications that are prohibited as per protocol (Table 2-2) and given 
during the conduct of the study will be provided. The number and percentage of subjects taking 
concomitant medications will be summarized by treatment group. 
Table 2-2
Prohibited medication
Medication
Prohibition period
Action taken
Artificial tears/gels/lubricant 
eye drops other than those 
started before enrollment
Study duration
No action
Use of topical ocular 
medications (prescription or 
over the counter) within 4 hours 
prior to a study visit
Study duration
Reschedule study visit outside 
of the 4 hour window
Use of ocular or oral pain 
medication within 4 hours of a 
study visit
Study duration
Reschedule the study visit 
outside of the 4 hour window
Ocular, nasal, inhaled, or 
systemic corticosteroids
Study duration
No action
Use of oral or topical ocular 
antihistamines, mast cell 
stabilizers (e.g. Ketotifen)
Study duration
No action
Neuromodulators and NGF for 
any reason
Study duration
Discontinue study treatment


Novartis
For business use only
Page 15 of 33
SAP
CSAF312B12201
2.5
Analysis of the primary objective
The primary objective of the study is to demonstrate the efficacy of at least 1 of 2 concentrations 
of SAF312 (5 mg/ml or 15 mg/ml) with superiority to placebo in reducing ocular pain severity.
For the purpose of the statistical analyses presented in this document, the following terminology 
is used:
Intercurrent events (IE) - Events that occur after treatment initiation and either preclude 
observation of the variable or affect its interpretation (e.g. rescue medications, 
discontinuation of treatment, switching treatment, terminal events such as death, etc.)
Missing at Random (MAR) – the multiple imputation model will be built based on similar 
patients (i.e. with the same covariates and observed measurement history) in the same 
treatment arm.
Jump to Reference (J2R) – the multiple imputation model will be built based on the 
available placebo data (including partial information from patients that discontinued 
prematurely). The imputation model will include important background characteristics and 
observed data. 
2.5.1
Primary endpoint
The primary clinical question of interest is: What is the effect of SAF312 versus placebo on 
change from baseline in pain severity after treatment in subjects with CICP, had they not taken 
rescue or prohibited medications, and had they not discontinued treatment?
The justification for the primary estimands is that they will capture the effect of the study drug 
for the full duration when administered without confounding effects from prohibited 
medications or rescue medications. They also account for discontinuation from treatment due 
to AEs, lack of efficacy, and use of prohibited medications. The hypothetical strategy assumes 
the subjects with Intercurrent events (IEs) will behave like other subjects who did not take 
rescue/prohibited medications and stayed on study treatment.
The analysis of the primary endpoints will be based on FAS. 
The primary estimand is defined as follows for signs and symptoms:
The target population is subjects with CICP persisting at least 4 months after refractive 
surgery or cataract surgery, and chronicity of pain confirmed during the 3-month 
observation period who meet the inclusion and exclusion criteria. 
The primary endpoint is the change from baseline in ocular pain severity VAS at Week 12. 
The score is derived by averaging the seven daily measurements of each week.
The treatment of interest is SAF312 arms versus placebo, had they not needed rescue or 
prohibited medications and behaved like other patients who did not take them, had they not 
discontinued treatment and behaved like other patients who did not discontinue treatment.  
Table 2-3
The handling of intercurrent events strategy for primary estimands
Intercurrent Events
Strategy


Novartis
For business use only
Page 16 of 33
SAP
CSAF312B12201
Rescue medications for pain relief due to any 
reason
The data on the days will be excluded 
and treated as missing.
Missing weekly mean pain score values 
will be handled under MAR assumption 
in MMRM
Prohibited medications that could confound the 
primary endpoint (See Table 2-2)
Ocular, nasal, inhaled, or systemic 
corticosteroids
Use of oral or topical ocular 
antihistamines, mast cell stabilizers
The data on the day(s) + 3 days 
following the last day of these 
prohibited medications will be excluded 
and treated as missing.
Missing weekly mean pain score values 
will be handled under MAR assumption 
in MMRM
Any new use or change in dosing of 
neuromodulators for any reason, or any 
use of topical ocular NGF 
The data starting from the day will be 
excluded and treated as missing 
Missing weekly mean pain score values 
will be handled based on the MAR 
assumption in MMRM
Discontinuation of study treatment due to any 
reasons (e.g. AEs, pandemic)
The data after study treatment 
discontinuation will be treated as 
missing.
Weekly mean pain score values at or 
after the week of study treatment 
discontinuation will be handled under 
MAR assumption in MMRM
The summary measure is the treatment difference of the variable means between 
SAF312 arms and placebo respectively.
o
SAF312 15 mg/ml vs SAF312 placebo
o
SAF312 5 mg/ml vs SAF312 placebo
2.5.2
Statistical hypothesis, model, and method of analysis
The primary objective of the study is to show that at least one SAF312 arm will improve weekly 
mean pain severity VAS score in comparison with its placebo by rejecting the null hypothesis 
1: 
=
 vs. 
2: 
where 
and 
 are mean change from baseline of weekly mean pain severity VAS score in 
SAF312 arm and the placebo arm. 
Dunnett procedure will be used to adjust overall type I error (0.05) among the comparisons 
between each SAF312 arm and the placebo arm. 
Mixed model repeated measure (MMRM) analysis will be used with change from baseline at 
each week on treatment as response variable, and treatment, week and baseline score as 
covariates. Two interaction term (treatment*week and baseline*week) will also be included in 
the model. 


Novartis
For business use only
Page 17 of 33
SAP
CSAF312B12201
An unstructured within subject correlation structure will be used for covariance matrix. If the 
unstructured covariance matrix results in a lack of convergence, then other covariance structures 
will be investigated. Toeplitz, First Order Autoregressive AR(1) and Compound Symmetry will 
be applied, in the specified order, until the model converges. 
The Kenward-Roger approximation will be used to estimate denominator degree of freedom. 
REML (residual/restricted maximum likelihood) method will be used to estimate parameters. 
The two-sided p value for the least square mean (LSM) difference between the SAF312 and the 
placebo group at each week will be reported for the difference. The primary inference will be 
based on LSM difference at Week 12 (Visit 6).
Line plots (LSM ± 1 SE) will be presented by treatment groups and post-baseline day/visit. The 
x-axis will be study visit and the y-axis will be the change from baseline value.
2.5.3
Handling of missing values not related to intercurrent event
The primary MMRM model implicitly imputes missing data under MAR assumption.
2.5.3.1
Handling of missing daily pain severity values within a week
The weekly mean of the seven 24-hour average pain severity assessments will be calculated 
based on the available assessments. If only one measurement is available, the mean will be 
based on that value. If no measurement is available, the weekly mean VAS score will be missing. 
The data collected beyond 12 weeks will not be analyzed.
2.5.3.2
Handling of missing weekly mean pain score values
For all analyses, imputation of intermittent missing value of pain severity VAS score before 
treatment discontinuation will be carried out following a MAR mechanism for all treatment 
arms. 
2.5.4
Supportive analyses
The subgroup analyses will be conducted to assess the consistency of treatment effect across 
various subgroups described in Section 2.2.1. Subgroup analyses will be conducted using the 
same model and analysis strategies described in the primary analyses but fitted by category of 
each of the subgroups. Subgroup variables that are used as fixed effects in the model will be 
removed from the model statement in the subgroup analysis if applicable. Subgroups will be 
presented graphically using forest plots. If a subgroup has limited number of subjects, the
analyses on this subgroup may fail to converge and not be implemented. Instead, summary
statistics for subgroup will be provided.
2.5.4.1
Supplementary estimand
The target population, the primary variable and the summary measure of this estimand are the 
same as for the primary estimand. The supplementary estimand is defined to estimate the 
treatment effect of SAF312 versus placebo, regardless of occasional rescue medication, 
prohibited medications and treatment discontinuations due to any reason. 


Novartis
For business use only
Page 18 of 33
SAP
CSAF312B12201
The justification for the supplementary estimand is that they will capture the effect of the study 
drug when administered in the real world with intercurrent events considered as inherent in the 
treatment regimen.
Table 2-4
The handling of intercurrent events strategy for supplementary 
estimands
Intercurrent Events
Strategy
Rescue medications for pain relief due to any 
reason
All observed data will be used for 
analysis
Missing weekly mean pain score values 
will be multiple imputed under MAR 
assumption
Prohibited medications that could confound the 
primary endpoint (See Table 2-2)
Ocular, nasal, inhaled, or systemic 
corticosteroids
Use of oral or topical ocular 
antihistamines, mast cell stabilizers
All observed data will be used for 
analysis
Missing weekly mean pain score values 
will be multiple imputed under MAR 
assumption 
Any new use or change in dosing of 
neuromodulators for any reason, or any 
use of topical ocular NGF
All observed data will be used for 
analysis
Missing weekly mean pain score values 
will be multiple imputed under MAR 
assumption
Discontinuation of study treatment due to any 
reason 
Weekly mean pain score values at or 
after the week of study treatment 
discontinuation will be multiple imputed 
based on J2R assumption for the 
SAF312 arms and under MAR 
assumption for the placebo arm
Mixed model covariance matrix will be handled in the same manner as primary estimand.
2.6
Analysis of the key secondary objective
There is no key secondary objective in the study.
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
For secondary endpoints:
Change from baseline in pain severity Visual Analog Scale (VAS) at Day 7 and Day 14
Change from baseline to Week 12 in pain frequency VAS
Change from baseline in OPAS subscale Quality of Life at Week 12
Change from baseline to Week 12 in ocular surface parameters (corneal staining score, 
conjunctival staining score, Schirmer score, conjunctival redness score)


Novartis
For business use only
Page 19 of 33
SAP
CSAF312B12201
2.7.2
Statistical hypothesis, model, and method of analysis
No statistical hypothesis test will be performed on the secondary endpoints. Summary 
statistics (mean, median, 25th percentile, 75th percentile, standard deviation, minimum and 
maximum, the number of non-missing observations, and 95% confidence interval) by treatment 
arm will be provided.95% confidence interval will be provided for the difference between the 
SAF312 arm vs. placebo for pain severity VAS, pain frequency VAS, OPAS subscale Quality 
of Life and ocular surface parameters. 
Where laterality applies, each eye will be summarized separately.
2.7.3
Handling of missing values/censoring/discontinuations
All observed data will be used for analysis and missing data will not be imputed.
2.8
Safety analyses
For all safety analyses, the SAF will be used. All listings and tables will be presented by 
treatment group. 
Adverse Events will be reported at subject level and other safety endpoints will be reported at 
eye level (Left and Right) where appropriate.
2.8.1
Adverse events (AEs)
Summary tables for AEs will summarize for pre-treatment AEs and treatment emergent AEs 
(TEAEs) separately:
Pre-treatment AEs are adverse events started between ICF signature and prior to the first 
administration of study treatment.
TEAEs are adverse events started after the first administration of study treatment or events 
present prior to start of the treatment but increased in severity based on preferred term.
The number and percentage of subjects with AEs will be summarized for ocular and non-ocular 
respectively, by treatment, in the following ways:
Primary system organ class and preferred term.
Primary system organ class, preferred term and maximum severity.
Standardized MedDRA Query (SMQ) and preferred term.
Separate summaries for TEAEs will be provided for study medication related AEs, death, 
serious adverse events (SAE), other significant AEs leading to discontinuation.
A subject with multiple adverse events within a primary system organ class is only counted 
once towards the total of the primary system organ class. All of these analyses will be based on 
the most updated MedDRA version available prior to the database lock.
All adverse events reporting will be included in the subject listings respectively.
2.8.1.1
Adverse events of special interest / grouping of AEs
Not applicable.


Novartis
For business use only
Page 20 of 33
SAP
CSAF312B12201
2.8.1.2
Adverse event reporting for clinical trial safety disclosure
For the legal requirements of ClinicalTrials.gov, two required tables on TEAEs which are not 
serious adverse events with an incidence greater than 5% and on TEAEs and SAEs suspected 
to be related to study treatment will be provided by system organ class and preferred term on 
the safety set population.
If for the same subject, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:
a single occurrence will be counted if there is 
 day gap between the end date of the 
preceding AE and the start date of the consecutive AE
more than one occurrence will be counted if there is >1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE (respectively non-SAE) has to be checked in 
a block e.g., among AEs in a 
 day gap block, if at least one SAE is occurring, then one 
occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment, and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2
Deaths
Deaths will be listed separately.
2.8.3
Laboratory data
Not applicable.
2.8.4
Other safety data
Where laterality applies, each eye will be summarized separately.
Corrected Visual Acuity
Snellen visual acuity (VA) testing in each eye will be conducted. The Snellen numerator and 
denominator will be entered in the eCRF. ETDRS will be derived from the Snellen visual acuity 
for summary (Table 2-5).
Table 2-5
Converting Snellen Fraction to Approximate ETDRS Letters Score
Snellen Fraction/ decimal
Approximate ETDRS Letters Score
0
> 0.005 to 0.015
1
> 0.015 to 0.020
3
> 0.020 to 0.025
5
> 0.025
85 + (50*log10[Snellen fraction]) rounded to the 
nearest integer


Novartis
For business use only
Page 21 of 33
SAP
CSAF312B12201
If numerator Snellen = 0 and denominator Snellen = 0, then ETDRS letters score is taken as 
missing.
Descriptive summaries (mean, median, 25th percentile, 75th percentile, standard deviation, 
minimum and maximum, the number of non-missing observations, and 95% confidence interval) 
of change from baseline VA values will be presented at each study visit by treatment group.
Intraocular Pressure
Intraocular pressure (IOP) measurements will be recorded in mmHg and rounded to the nearest 
whole number for summary. 
Descriptive summaries (mean, median, 25th percentile, 75th percentile, standard deviation, 
minimum and maximum, the number of non-missing observations, and 95% confidence interval) 
of change from baseline IOP values will be presented at each study visit by treatment group. 
Slit Lamp Exam and Fundus Exam/Ophthalmoscopy
Slit lamp and Fundus exams will be performed, and results will be captured in the source 
document at each visit. The eCRF will record only if those assessments were indeed performed 
or not for compliance perspective.
Subject listing will be provided.
Corneal Endothelial Cell Microscopy
At the Baseline and End of Treatment Visits, Specular microscopy of the corneal endothelial 
cell images will be obtained by the Investigator and submitted to the Central Reading Center 
(CRC) to determine the changes in endothelial cell count, density, and shape from the initial 
baseline to the end of treatment.
Listing of the parameters will be provided by subject by visit.
2.9
Pharmacokinetic endpoints  
Not applicable.
2.10
PD and PK/PD analyses
Not applicable.
2.11
Patient-reported outcomes
In addition to the VAS, patient-reported outcomes include the following:
OPAS questionnaire subscales
No test will be performed on the PRO endpoints that are not pertaining to the primary endpoint. 
Please refer to Section 2.7 and Section 2.13 for detail.


Novartis
For business use only
Page 22 of 33
SAP
CSAF312B12201
2.12
Biomarkers
Not applicable.
2.13
Other Exploratory analyses
Exploratory endpoints include:
Frequency of artificial tears/gel/lubricant use over the 12-week treatment period
Frequency of rescue medication use over the 12-week treatment period
Change from Baseline to Week 12 in total corneal nerve fiber length 
Presence of microneuromas 
Density of corneal dendritiform cells
The analysis will be based on FAS. Descriptive summaries (mean, median, 25th percentile, 
75th percentile, standard deviation, minimum and maximum, the number of non-missing 
observations, and 95% confidence interval) of frequency of artificial tears/gel/lubricant use 
and frequency of rescue medication use will be presented by week and treatment group.
The details of the rest exploratory analysis will be documented in Data Exploration Strategy 
separately. If any of the exploratory analysis is considered of clinical or regulatory relevance, 
it will be included in an SAP/CSR via amendment or addendum process as appropriate. 
2.14
Interim analysis
Not applicable.
3
Sample size calculation
Assuming a true treatment difference in change from baseline in weekly mean pain severity 
VAS of 15 mm and a SD of 23 mm, a sample size of 50 subjects per arm provides approximately 
83% power that the primary analysis will be statistically significant at the two-sided 5% 
significance level adjusted by 2 comparisons. 
See Table 3-1 for power to detect a significant difference from placebo under various assumed 
treatment-effect of weekly mean pain severity VAS and SD. 
Query Advisor 7.0 is used for the estimate.
PI


Novartis
For business use only
Page 23 of 33
SAP
CSAF312B12201
Table 3-1
Power to detect a significant difference from placebo under different 
assumed treatment effects and SD with N = 50 pts/arm
Treatment effect: difference from placebo in change from 
baseline in weekly mean pain severity VAS 
SD of change from baseline in 
weekly mean l pain severity 
VAS 
15
20
17
98%
>99%
20
92%
>99%
23
83%
97%
The sample size may increase by up to 20% (i.e. 60 pts/arm) in order to maintain power in 
case dropout increases during the pandemic.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
5.1.1
AE date imputation
5.1.1.1
Adverse event end date imputation
1. If the AE end date month is missing, the imputed end date should be set to the earliest of 
the (treatment follow-up period date, 31DECYYYY, and/or date of death). 
2. If the AE end date day is missing, the imputed end date should be set to the earliest of the 
(treatment follow-up period date, last day of the month, and/or date of death). 
3. If AE year is missing or AE is ongoing, the end date will not be imputed. 
5.1.1.2
Adverse event start date imputation
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial Adverse Event Start Date
Not used
MON
YYYY
Treatment Start Date 
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.


Novartis
For business use only
Page 24 of 33
SAP
CSAF312B12201
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
( 1 )
No convention
YYYY < TRTY
( 2.a )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
( 2.b )
Before Treatment 
Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment 
Start
( 4.c )
Uncertain
( 4.c )
After Treatment Start
YYYY > TRTY
( 3.a )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
Before imputing AE start date, find the AE start reference date. 
1. If the (imputed) AE end date is complete and the (imputed) AE end date < treatment start 
date then AE start reference date = min (informed consent date, earliest visit date).
2. Else AE start reference date = treatment start date
Impute AE start date
1. If the AE start date year value is missing, the date uncertainty is too high to impute a rational 
date. Therefore, if the AE year value is missing, the imputed AE start date is set to NULL.
2. If the AE start date year value is less than the treatment start date year value, the AE started 
before treatment. Therefore:
a.
If AE month is missing, the imputed AE start date is set to the mid-year point 
(01JulYYYY).
b. Else if AE month is not missing, the imputed AE start date is set to the mid-month 
point (15MONYYYY).
3. If the AE start date year value is greater than the treatment start date year value, the AE 
started after treatment. Therefore:
a.
If the AE month is missing, the imputed AE start date is set to the year start point 
(01JanYYYY).
b. Else if the AE month is not missing, the imputed AE start date is set to the later of 
(month start point (01MONYYYY), AE start reference date + 1 day).
4. If the AE start date year value is equal to the treatment start date year value:
a.
And the AE month is missing the imputed AE start date is set to the AE reference 
start date + 1 day.
b. Else if the AE month is less than the treatment start month, the imputed AE start 
date is set to the mid-month point (15MONYYYY).


Novartis
For business use only
Page 25 of 33
SAP
CSAF312B12201
c.
Else if the AE month is equal to the treatment start date month or greater than the 
treatment start date month, the imputed AE start date is set to the later of (month 
start point (01MONYYYY), AE start reference date + 1 day).
If complete (imputed) AE end date is available and the imputed AE start date is greater than the 
(imputed) AE end date, then imputed AE start date should be set to the (imputed) AE end date.
5.1.2
Concomitant medication date imputation
5.1.2.1
Concomitant treatment end date imputation
1. If CM end day is missing and CM month/year are non-missing, then impute CM day as 
the minimum of treatment follow-up period date, date of death and the last day of the 
month.
2. If CM end month are missing and CM year is non-missing, then impute CM day as the 
minimum of treatment follow- up period date, date of death and the end of the year 
(31DECYYYY).
3. If CM end year value is missing, the date uncertainty is too high to impute a reliable 
date. Therefore, if the CM end year value is missing or ongoing, the imputed CM end 
date is set to NULL. 
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date.
5.1.2.2
Concomitant treatment start date imputation 
The following table explains the notation used in the logic matrix. Please note that missing 
start dates will not be imputed.
Day
Month
Year
Partial CMD Start Date
Not used
MON
YYYY
Treatment Start Date
Not used
TRTM
TRTY
The following matrix explains the logic behind the imputation.
MON
MISSING
MON < TRTM
MON = TRTM
MON > TRTM
YYYY
MISSING
 ( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
( 1 )
Uncertain
YYYY < TRTY
( 2.a ) 
Before Treatment Start
( 2.b )
Before Treatment Start
( 2.b )
Before Treatment Start
( 2.b )
Before Treatment Start
YYYY = TRTY
( 4.a )
Uncertain
( 4.b )
Before Treatment Start
( 4.a )
Uncertain
( 4.c )
After Treatment Start
YYYY > TRTY
( 3.a )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
( 3.b )
After Treatment Start
1. If the CM start date year value is missing, the imputed CM start date is set to one day 
prior to treatment start date. 


Novartis
For business use only
Page 26 of 33
SAP
CSAF312B12201
2. If the CM start date year value is less than the treatment start date year value, the CM 
started before treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the mid-year 
point (01JulYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the mid-
month point (15MONYYYY).
3. If the CM start date year value is greater than the treatment start date year value, the CM 
started after treatment. Therefore:
a.
If the CM month is missing, the imputed CM start date is set to the year start 
point (01JanYYYY).
b. Else if the CM month is not missing, the imputed CM start date is set to the 
month start point (01MONYYYY).
4. If the CM start date year value is equal to the treatment start date year value:
a.
And the CM month is missing, or the CM month is equal to the treatment start 
date month, then the imputed CM start date is set to one day prior treatment start 
date.
b. Else if the CM month is less than the treatment start date month, the imputed 
CM start date is set to the mid-month point (15MONYYYY).
c.
Else if the CM month is greater than the treatment start date month, the imputed 
CM start date is set to the month start point (01MONYYYY).
If complete (imputed) CM end date is available and the imputed CM start date is greater than 
the (imputed) CM end date, then imputed CM start date should be set to the (imputed) CM end 
date.
5.2
Statistical models
5.2.1
Primary Analysis
The following MMRM model will be used for the primary estimand and supplementary 
estimand:
change from baseline in weekly mean pain severity VAS score = intercept + baseline weekly 
mean pain severity VAS score + treatment + week + treatment*week + baseline weekly mean 
pain severity VAS score * week + error
   
   
 
PI


Novartis
For business use only
Page 27 of 33
SAP
CSAF312B12201
5.2.2
Supplementary Analysis
PI
PI


Novartis
For business use only
Page 28 of 33
SAP
CSAF312B12201
PI


Novartis
For business use only
Page 29 of 33
SAP
CSAF312B12201
5.3
Rule of exclusion criteria of analysis sets 
Table 5-1
Protocol deviations
PD ID
Deviation Text
Data exclusion
INCL01
written informed consent not 
obtained
Exclude from all analysis sets
INCL02a
refractive or cataract surgery  
<4 months in either eye prior to 
screening, and/or ocular pain is 
not persistent since surgery, 
and/or not seen for ocular pain 
since surgery by an 
ophthalmologist
Include in all analysis sets 
INCL03a
pain severity VAS <30 mm at 
screening visit
Include in all analysis sets
INCL04
<60% reduction in ocular pain 
within 5 min after instillation of 
single topical ocular anesthetic 
drop at screening visit
Include in all analysis sets
INCL05a
average pain severity VAS <30 
mm based on daily eDiary for 
last 7 days prior to baseline 
visit
Include in all analysis sets
INCL06
pain severity >10 mm based on 
during the 12-week 
observational period
INCL07
subject <18 years of age at 
screening
Include in all analysis sets
EXCL01a
corrective contact lenses within 
14 days of screening visit, and 
any use of contact lenses for 
the duration of the study
Include in all analysis sets
EXCL02
use of artificial tears, gels, 
lubricants, or pain medication 
within 4 hrs of conducting 
assessments at screening visit
Include in all analysis sets
PI


Novartis
For business use only
Page 30 of 33
SAP
CSAF312B12201
PD ID
Deviation Text
Data exclusion
EXCL03
use of nerve growth factor eye 
drops within 14 days of the 
screening visit
Include in all analysis sets
EXCL04
seasonal allergic conjunctivitis, 
or other acute or seasonal 
ocular diagnosis that is active 
at the time of screening or 
baseline visits or would be 
active during the study
Include in all analysis sets
EXCL05
any history ocular HSV or HZV 
infection, or other severe ocular 
conditions such as GvHD, 
Stephen's Johnson Syndrome, 
sarcoidosis
Include in all analysis sets
EXCL06
presence of any ocular 
infection (bacterial, viral, or 
fungal) within 30 days prior to 
screening visit
Include in all analysis sets
EXCL07
chronic topical ocular 
medications (i.e. cyclosporine, 
lifitegast) initiated <6 months 
prior to screening visit, or any 
anticipated changes during the 
study
Include in all analysis sets
EXCL08
amniotic membrane 
transplantation on ocular 
surface within 30 days prior to 
screening visit
Include in all analysis sets
EXCL09
use of ocular or nasal 
corticosteroids within 30 days 
of screening visit
Include in all analysis sets
EXCL10
use of neuromodulatory 
medications (e.g. gabapentin, 
pregabalin) or opioid use for 
non-ocular pain within 30 days 
of screening visit
Include in all analysis sets
EXCL11
chronic medications (both over 
the counter and prescription) 
that have not been stable for at 
least 30 days prior to screening 
visit, or any anticipated change 
in the chronic medication 
regimen
Include in all analysis sets
EXCL12
history of hypersensitivity to 
any of the study drugs or its 
inactive ingredients or to active 
ingredients of similar chemical 
classes
Include in all analysis sets


Novartis
For business use only
Page 31 of 33
SAP
CSAF312B12201
PD ID
Deviation Text
Data exclusion
EXCL13
severe psychiatric disorders or 
major psychiatric illness 
requiring hospitalization in the 
last 6 months or requiring 
treatment with more than one 
psychiatric medication 
Include in all analysis sets
EXCL14
past history of a chronic or 
recurring ocular or systemic 
condition that could interfere 
with efficacy assessments, or 
preclude safe administration of 
study medication per 
investigator's judgement
Include in all analysis sets
EXCL15
uncontrolled systemic or ocular 
diseases which could affect 
trial parameters
Include in all analysis sets
EXCL16
subjects with spinal cord 
injuries who are at risk of 
autonomic dysfunction
Include in all analysis sets
EXCL17
participation in a clinical trial 
within 3 months prior to 
screening visit
Include in all analysis sets
EXCL18
pregnant or breastfeeding 
females, or those with a 
positive pregnancy test
Include in all analysis sets
EXCL19
women of childbearing 
potential unless using basic 
methods of contraception 
during dosing of study 
treatment
Include in all analysis sets
EXCL20a
Subjects who for any reasons 
are unable or unwilling to 
comply with the specific 
requirements of the protocol
Include in all analysis sets
WITH01
Subject withdrew consent but 
continued to receive study 
treatment
Include in all analysis sets
WITH02
subject received prohibited 
medication requiring treatment 
discontinuation (i.e. 
neuromodulators or nerve 
growth factors) but continued to 
receive study treatment
Include in all analysis sets


Novartis
For business use only
Page 32 of 33
SAP
CSAF312B12201
PD ID
Deviation Text
Data exclusion
WITH03
subject unable to tolerate the 
protocol-specified dosing 
schedule despite use of rescue 
medication; treatment 
discontinuation required but 
continued to receive study 
treatment
Include in all analysis sets
TRT01
randomized subject 
administered incorrect 
treatment and/or dose
Include in all analysis sets
TRT02
study treatment dose 
adjustments and/or 
interruptions made
Include in all analysis sets
TRT03
compliance with study 
treatment <80% or >120% per 
eDiary entries
Include in all analysis sets
TRT04
Treatment not given due to 
COVID-19
Include in all analysis sets
TRT05
Drug supply method changed 
due to COVID-19
Include in all analysis sets
COMD01
Prohibited concomitant 
medication (e.g. 
corticosteroids, antihistamines) 
and/or procedure as per 
protocol
Include in all analysis sets
COMD02
Prohibited changes in 
concomitant medication 
regimen as per protocol
Include in all analysis sets
OTH01
Any other protocol deviation 
with impact on patient rights or 
safety 
Include in all analysis sets
OTH02
Any other protocol deviation 
with impact on trial's scientific 
value/data integrity
Include in all analysis sets
OTH03
Any other PD without impact on 
patient safety/rights or trials's 
scientific value/data integrity
Include in all analysis sets
OTH04
Subject missed a visit or 
assessment not allowed in the 
study
Include in all analysis sets
OTH05
Missed visit due to COVID-19
Include in all analysis sets
OTH06
Visit not done at study site due 
to COVID-19
Include in all analysis sets
OTH07
Assessment / procedure 
changed due to COVID-19
Include in all analysis sets
OTH08
Discontinuation due to COVID-
19
Include in all analysis sets


Novartis
For business use only
Page 33 of 33
SAP
CSAF312B12201
PD ID
Deviation Text
Data exclusion
OTH09
Unblinding for non-emergent 
situation, or masking process 
not followed with impact on 
data integrity (e.g. treatment 
identity revealed based on 
description of appearance)
Include in all analysis sets
OTH10
staining strips moistened with 
anesthetic
Include in all analysis sets
OTH11
electronic diary compliance 
<50%
Include in all analysis sets
5.4
Data issue of conjunctival lissamine staining & conjunctival 
redness from Site 
Site 
 used a different grading scale to evaluate conjunctival lissamine staining and 
conjunctival redness from what were specified in the protocol.  
All data for conjunctival lissamine staining and conjunctival redness for Site 
 will be 
flagged in listings and excluded in the summary for these assessments.
6
Reference
1. Carpenter JR, Roger JH, Kenward MG (2013) Analysis of longitudinal trials with protocol
deviation: a framework for relevant, accessible assumptions, and inference via multiple
imputation. J Biopharm Stat; 23(6):1352-71.
2. DIA missing data: https://www.lshtm.ac.uk/research/centres-projects-groups/missing-data
 
PI
PI
PI