Conditions: Dry Eye
Keywords: Dry Eye Sjogrens dry eye syndrome (DES) Keratoconjunctivitis sicca (KCS) keratitis Xerophthalmia Sjögren's Syndrome Sjogren's Syndrome
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 718
Healthy volunteers: no

Brief summary:
The study was planned to be conducted in 2 parts: Part 1 to determine the efficacy and safety of ECF843 vs vehicle, followed by Part 2 with additional exploratory assessments of ECF843 vs Vehicle. Both parts of the study included a double-masked study design, with randomization stratified for subjects with Sjogren's Syndrome.

Detailed description:
Part 1 of the study was a double-masked, randomized, parallel design in which participants were assigned to one of the following five treatment arms/groups in a ratio of 1:1:1:1:1.

* ECF843 0.45 mg/mL three times daily (TID) or vehicle
* ECF843 0.15 mg/mL TID or vehicle
* ECF843 vehicle TID
* ECF843 0.15 mg/mL twice daily (BID) or vehicle
* ECF843 vehicle BID The planned duration of double-masked treatment during Part 1 was 56 days. For subjects randomized to ECF843, the maximum drug exposure was up to 28 days. At some point during Part 1, all participants received vehicle.

The study was terminated after completion of Part 1 and Part 2 of the study was not therefore initiated.

Arms:
arm 1: ECF843 0.45 mg/mL TID or vehicle (Part 1) arm 2: ECF843 0.15 mg/mL TID or vehicle (Part 1) arm 3: ECF843 vehicle TID (Part 1) arm 4: ECF843 0.15 mg/mL BID or vehicle (Part 1) arm 5: ECF843 vehicle BID (Part 1)

Interventions: intervention 1: ECF843 intervention 2: ECF843 vehicle
Intervention descriptions: intervention 1: Topical ocular eye drop intervention 2: Topical ocular eye drop

Protocol document:
Prot_000.pdf: 
Novartis Research and Development
ECF843 / NCT04391894
Clinical Trial Protocol 
A randomized, double-masked, multicenter study to 
evaluate the safety and efficacy of ECF843 vs Vehicle in 
subjects with dry eye disease
Document type:
Amended Protocol Version
EUDRACT number:
NA
Version number:
V01 (Clean)
Clinical Trial Phase:
IIb
Release date:
20-Apr-2021
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis/Sponsor
Clinical Trial Protocol Template Version 2.0 dated 01-Aug-2018


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Table of contents
Table of contents .................................................................................................................2
List of tables ........................................................................................................................5
List of figures ......................................................................................................................5
Glossary of terms.................................................................................................................8
Amendment 1 dated 20-Apr-2021.....................................................................................10
Protocol summary..............................................................................................................14
1
Introduction .......................................................................................................................17
1.1
Background............................................................................................................17
1.2
Purpose ..................................................................................................................18
2
Objectives, endpoints and estimands.................................................................................18
2.1
Primary Estimands.................................................................................................19
2.2
Secondary Estimands.............................................................................................19
3
Study design ......................................................................................................................20
4
Rationale............................................................................................................................21
4.1
Rationale for study design .....................................................................................21
4.2
Rationale for dose/regimen and duration of treatment ..........................................22
4.3
Rationale for choice of control drugs (comparator/placebo) or combination 
drugs ......................................................................................................................23
4.4
Purpose and timing of interim analyses/design adaptations..................................23
4.5
Risks and benefits..................................................................................................24
4.6
Rationale for Public Health Emergency mitigation procedures ............................25
5
Population..........................................................................................................................25
5.1
Inclusion criteria ....................................................................................................25
5.2
Exclusion criteria...................................................................................................26
6
Treatment...........................................................................................................................28
6.1
Study treatment......................................................................................................28
6.1.1
Investigational and control drugs..........................................................28
6.1.2
Additional study treatments ..................................................................29
6.1.3
Treatment arms/group ...........................................................................29
6.1.4
Treatment duration................................................................................29
6.2
Other treatment(s)..................................................................................................29
6.2.1
Concomitant therapy.............................................................................29
6.2.2
Prohibited medication ...........................................................................30
6.3
Subject numbering, treatment assignment, randomization....................................30
6.3.1
Subject numbering ................................................................................30
6.3.2
Treatment assignment, randomization ..................................................31


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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..................................33
6.7
Preparation and dispensation.................................................................................33
6.7.1
Handling of study treatment and additional treatment..........................34
6.7.2
Handling of study treatment..................................................................34
6.7.3
Handling of additional treatment ..........................................................34
6.7.4
Instruction for prescribing and taking study treatment .........................34
7
Informed consent procedures ............................................................................................35
8
Visit schedule and assessments .........................................................................................36
8.1
Screening ...............................................................................................................43
8.1.1
Information to be collected on screening failures.................................43
8.2
Subject demographics/other baseline characteristics.............................................43
8.3
Efficacy..................................................................................................................44
8.3.1
Ocular Hyperemia .................................................................................44
8.3.2
Tear Break-Up Time .............................................................................44
8.3.3
Corneal Fluorescein Staining................................................................45
8.3.4
Conjunctival Lissamine Staining ..........................................................46
8.3.5
Appropriateness of efficacy assessments..............................................47
8.4
Safety.....................................................................................................................47
8.4.1
Laboratory evaluations..........................................................................47
8.4.2
Pregnancy..............................................................................................47
8.4.3
Appropriateness of safety measurements..............................................47
8.5
Additional assessments..........................................................................................47
8.5.1
Clinical Outcome Assessments (COAs) ...............................................47
8.5.2
Patient Reported Outcomes (PRO) .......................................................48
50
50
51
52
9
Study discontinuation and completion ..............................................................................53
9.1
Discontinuation......................................................................................................53


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9.1.1
Discontinuation of study treatment .......................................................53
9.1.2
Discontinuation from study...................................................................54
9.1.3
Withdrawal of informed consent...........................................................54
9.1.4
Lost to follow-up...................................................................................55
9.1.5
Early study termination by the sponsor.................................................55
9.2
Study completion and post-study treatment ..........................................................55
10 Safety monitoring and reporting........................................................................................56
10.1
Definition of adverse events and reporting requirements......................................56
10.1.1
Adverse events ......................................................................................56
10.1.2
Serious adverse events ..........................................................................57
10.1.3
SAE reporting........................................................................................58
10.1.4
Pregnancy reporting ..............................................................................59
10.1.5
Reporting of study treatment errors including misuse/abuse................59
10.2
Additional Safety Monitoring................................................................................60
11 Data Collection and Database management......................................................................60
11.1
Data collection.......................................................................................................60
11.2
Database management and quality control............................................................60
11.3
Site monitoring ......................................................................................................61
12 Data analysis and statistical methods ................................................................................62
12.1
Analysis sets ..........................................................................................................62
12.2
Subject demographics and other baseline characteristics......................................62
12.3
Treatments .............................................................................................................63
12.4
Analysis supporting primary objectives ................................................................63
12.4.1
Definition of primary endpoint(s).........................................................63
12.4.2
Statistical model, hypothesis, and method of analysis..........................63
12.4.3
Handling of intercurrent events of primary estimand ...........................64
12.4.4
Handling of missing values not related to intercurrent event ...............64
12.4.5
Sensitivity analyses for primary estimand ............................................64
12.4.6
Supplementary analysis.........................................................................65
12.5
Analysis supporting secondary objectives.............................................................65
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)....................................65
12.5.2
Safety endpoints....................................................................................66
66
67
67
67
12.7
Interim analyses.....................................................................................................68


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12.8
Sample size calculation..........................................................................................68
12.8.1
Primary endpoint(s)...............................................................................68
12.8.2
Secondary endpoint(s)...........................................................................69
69
13 Ethical considerations and administrative procedures ......................................................69
13.1
Regulatory and ethical compliance........................................................................69
13.2
Responsibilities of the investigator and IRB/IEC..................................................70
13.3
Publication of study protocol and results...............................................................70
13.4
Quality Control and Quality Assurance.................................................................70
14 Protocol adherence ............................................................................................................70
14.1
Protocol amendments.............................................................................................71
15 References .........................................................................................................................72
16 Appendices ........................................................................................................................73
List of tables
Table 2-1
Objectives and related endpoints ..........................................................18
Table 6-1
Investigational and control drug............................................................28
Table 6-2
Prohibited medication ...........................................................................30
Table 6-3
Blinding levels ......................................................................................32
Table 6-4
Dose and treatment schedule.................................................................34
Table 8-1
Assessment Schedule, Part 1.................................................................38
Table 8-2
Assessment Schedule, Part 2.................................................................39
Table 8-3
Assessments & Specifications...............................................................47
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse .........................................................................................60
Table 12-1
Power to Detect a Significant Difference from Vehicle .......................68
69
69
List of figures
Figure 3-1
Study Design .........................................................................................20
Figure 8-1
McMonnies Redness Photographic Scale .............................................44
Figure 8-2
Corneal Fluorescein Modified NEI Scale .............................................45
Figure 8-3
Lissamine Conjunctival Oxford Staining Scale....................................46


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List of abbreviations
µg
microgram
ADR
adverse drug reaction
AE
adverse event
ATC
Anatomical Therapeutic Chemical
BFS
blow-fill-seal
BID
bis in die (twice daily)
CFR
Code of Federal Regulation
CMO
Chief Medical Office
CO
Country Office
CRF
case report/record form (paper or electronic)
CRO
contract research organization
CSR 
clinical study report
CTT 
clinical trial team
DED
dry eye disease
 
DRF
dose range finding
EC
ethics committee
eCRF
electronic case report form
EDC
electronic data capture
ELISA
enzyme-linked immunosorbent assay
EMA
European Medicines Agency
EOS
end of study
EOT
end of treatment
EU
European Union
FAS
Full Analysis Set
FDA
Food and Drug Administration
FITC
fluorescein isothiocyanate
F/U
Follow up
GCP
Good Clinical Practice
GCS
Global Clinical Supply
HA
Hyaluronic Acid
hr
hour
IB 
Investigator's Brochure
IBI
Inter Blink Interval
ICF
Informed Consent Form
ICH
International Council for Harmonization
IE
Intercurrent event
IEC
Independent Ethics Committee
IL-1
interleukin-1
IMP 
investigational medicinal product
IN
Investigator Notification
IOP
intraocular pressure
IRB
Institutional Review Board


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IRT
interactive response technology
IUD
intrauterine device
IUS
intrauterine system
IVT
intravitreal injections
J2R
jump to reference
kDa
kilodaltons
LASIK
laser-assisted in situ keratomileusis
LLOQ
lower limit of quantification
LSM
least square mean
MAR
missing at random
MedDRA
medical dictionary for regulatory activities
mg
milligram(s)
mL
milliliter(s)
mm
millimeter
MMRM
mixed model repeated measures
NEI
National Eye Institute
PK
pharmacokinetic(s)
PRG4
proteoglycan-4
PRK
photorefractive keratectomy
PRN
pro re nata (as needed)
PRO 
patient reported outcomes
QID
quarter in die (four times daily)
QMS
Quality Management System
RDO
Retrieved drop-out
REML
residual/restricted maximum likelihood
RNA 
ribonucleic acid
SAE
serious adverse event
SANDE
Symptom Assessment in Dry Eye
SAP
statistical analysis plan
SMQ
standardized MedDRA query
SUSAR
suspected unexpected serious adverse reactions
TBUT
tear breakup time
TFOS DEWS II
Tear Film and Ocular Surface Society Dry Eye Workshop II
TID
ter in die (three times daily)
TNF
tumor necrosis factor
UI 
International Unit
US
United States
WHO
World Health Organization


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Clinical Outcome 
Assessment (COA)
A measure that describes or reflects how a subject feels, functions, or survives
Cohort
A specific group of subjects fulfilling certain criteria
Control drug
A study drug used as a comparator to reduce assessment bias, preserve blinding of 
investigational drug, assess internal study validity, and/or evaluate comparative effects 
of the investigational drug.
Discontinuation from 
study
Point/time when the subject 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 subject permanently stops receiving the study treatment for any 
reason (prior to the planned completion of study drug administration, if any). Subject
agrees to the other protocol required assessments including follow-up. No specific 
request is made to stop the use of their samples or data.
Dosage
Dose of the study treatment given to the subject in a time unit (e.g. 100 mg once a day, 
75 mg twice a day)
Enrollment
Point/time of subject entry into the study at which informed consent must be obtained 
(i.e. prior to starting any of the procedures described in the protocol). The action of 
enrolling one or more subjects.
Estimand
As defined in the ICH E9(R1) addendum, estimand is 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 subjects 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”.
Investigational 
treatment
All investigational drug(s) whose properties are being tested in the study as well as 
their associated treatment controls. This includes any placebos, any active controls, as 
well as approved drugs used outside of their indication/approved dosage or tested in a 
fixed combination. Investigational treatment generally does not include other treatments 
administered as concomitant background therapy required or allowed by the protocol 
when used within approved indication/dosage.
Medication number
A unique identifier on the label of each study drug package in studies that dispense 
study drug using an IRT system.
Non-investigational 
medicinal Product 
(NIMP)
Products which are not the object of investigation (e.g. any background therapy 
administered to each of the clinical trial subjects, regardless of randomization group, 
rescue medication, active drug run-ins etc.)
Part
A single component of a study which contains different objectives or populations within 
that single study. Common parts within a study are: a single dose part and a multiple 
dose part, or a part in subjects with established disease and in those with newly-
diagnosed disease.
Patient
An individual with the condition of interest
Patient-Reported 
Outcome (PRO)
A measurement based on a report that comes directly from the patient about the status 
of a subject's health condition without amendment or interpretation of the patient's 
report by a clinician or anyone else
Period
A minor subdivision of the study timeline; divides phases into smaller functional 
segments such as screening, baseline, titration, washout, etc.
Randomization
The process of assigning trial subjects to investigational drug or control/comparator 
drug using an element of chance to determine the assignments in order to reduce bias.
Randomization 
number
A unique identifier assigned to each randomized subject, corresponding to a specific 
treatment arm assignment


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Re-screening
If a subject fails the initial screening and is considered as a Screen Failure, he/she can 
be invited once for a new Screening visit after medical judgment and as specified by 
the protocol
Screen Failure
A subject who is screened but is not treated or randomized
Stage
A major subdivision of the study timeline; begins and ends with major study milestones 
such as enrollment, randomization, completion of treatment, etc.
Study completion
Point/time at which the subject came in for a final evaluation visit or when study drug 
was discontinued whichever is later.
Study drug 
discontinuation
Point/time when subject permanently stops taking study drug for any reason; may or 
may not also be the point/time of premature subject withdrawal.
Study treatment
Any drug administered to the study subjects as part of the required study procedures; 
includes investigational drug (s), control(s) or non-investigational medicinal product(s)
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 unique number assigned to each subject upon signing the informed consent. This 
number is the definitive, unique identifier for the subject and is used to identify the 
subject throughout the study for all data collected, sample labels, etc.
Variable
Information used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints.
Withdrawal of 
consent (WoC)
Withdrawal of consent from the study occurs when the Subject explicitly requests to 
stop use of their data and biological samples (opposition to use data and biological 
samples) AND no longer wishes to receive study treatment, AND does not agree to 
further protocol required assessments. This request should be in writing (depending on 
local regulations) and recorded in the source documentation.


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Amended Protocol Version 01 (Clean)
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Amendment 1 dated 20-Apr-2021
Amendment rationale
The main purpose of this amendment is to update the design of Part 2 of the study in order to 
remain focused on continued evaluation and development of ECF843.
 
This amendment also includes clarifications and updates to various aspects of the study.
Changes to the protocol
All changes in Amendment 1 are provided in summary below. However, minor changes such 
as administrative edits or repetition of a word or concept for consistency, are not listed for every 
section. These changes are shown in track changes version of the protocol using strike through 
red font for deletions and red underline for insertions. 
Major changes are made to the protocol in the following sections: 

List of abbreviations: updated to include new abbreviations in the amendment

Glossary of terms: added new terms used in the Amendment 1; updated as per new OneCTP 
Protocol template Version 4 15-Feb-2021. 

Protocol summary: updated for Purpose and Rationale, Study Design, Study treatment, and 
Other assessments. Details on the specific changes are described in each individual section 
below. 

1.2 Purpose: updated the purpose of Part 2 to reflect an intention to keep the focus on further 
exploration of the safety and efficacy of ECF843. 

2.1 Primary Estimands: clarified subject attributes for primary estimands with regards to 
prohibited/rescue medications and treatment duration. 

3 Study design: 
 
 updated to a double-masked design for Part 2; clarified that no protocol 
assessments or solicitation of AEs will be collected between Part 1 and Part 2 which 
includes specific parameters when an SAE would be captured; clarified that a list of subjects 
eligible for Part 2 will be discussed between the Investigator and Sponsor; added possibility 
that if a study site was initiated close to the end of enrollment without sufficient time to 
recruit subjects, the site may enroll new subjects into Part 2 if approved by Sponsor; 
amended randomization ratio of ECF843 to Vehicle to 3:1; 
 
 

4.1 Rationale for study design: specified that criteria for selection of subjects for primary 
efficacy analysis are documented in the statistical analysis plan (SAP); 
 
 

4.2 Rationale for dose/regimen and duration of treatment: updated to state that no safety 
concerns have been identified with BID/TID dosing; clarified treatment duration in Part 2.
 
 


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
4.4 Purpose and timing of interim analyses/design adaptations: Primary analysis for Part 2 
added.

4.6 Rationale for Public Health Emergency mitigation procedures: new section added

5 Population: clarified that subjects who discontinue the study in Part 1, will not be eligible 
for Part 2; expanded on eligibility for Part 2 based on subjects who discontinue treatment 
only or experience treatment related AE/SAEs. 

5.1 Inclusion criteria: clarified scoring for corneal staining and using an average of 3 
consecutive readings for Tear Break-up Time (TBUT). 

5.2 Exclusion criteria: clarified exclusion #6 regarding corneal scars; 
 
 updated exclusion #22 defining female sterilization to include “bilateral” tubal 
ligation; clarified that woman are considered not of child bearing potential if they are post-
menopausal. 

6.1 Study treatment: amended for double masked treatment for Part 2. 

6.1.3 Supply of Study Treatment: section fully deleted.

6.1.3 Treatment arms/groups:Treatment arms/groups: 
 specified that 
ECF843 vehicle dosing frequency will be determined from Part 1.

Table 6-2 Prohibited medication :added Intravitreal injections and Punctal plugs. 

Table 6-3 Blinding levels: added blinding levels for Bioanalytical Team

6.4 Treatment blinding: clarified that CTT members/site staff will be unmasked again at the 
end of Part 2; removed language of open label to subjects and site staff. 

6.7 Preparation and dispensation: 
; added new paragraph 
regarding section 4.6 and public health emergency instructional text for IMP delivery to 
subject

7 Informed consent procedures: clarified that subjects will sign the ICF for Part 1 and again 
for Part 2; added statement about unknown risks to the fetus for women of child bearing 
potential; listed all informed consents applicable to this study. 

8 Visit schedule and assessments: re-emphasized that only subjects assigned exclusively to 
vehicle in Part 1 will be eligible for Part 2; restated that a list of subjects eligible for Part 2 
will be discussed between the Investigator and Sponsor; added possibility that if a study site
was initiated close to the end of enrollment without sufficient time to recruit subjects, the 
site may enroll new subjects into Part 2 if approved by Sponsor; clarified that no visits can 
be skipped; 
. 

Table 8-1 Assessment Schedule, Part 1: updated “Patient diary” to be “At home SANDE”
and 
. 
Footnotes updated accordingly. 
 
 
 
 
 


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
8.1 Screening: expanded on criteria for ability to re-screen with regards to time frames to 
stabilize chronic medications or use of contact lenses. 
 
 
 
 
 
 
 
 
 

9 Study discontinuation and completion: clarified that subjects should not be discontinued
after completion of Part 1 unless subject withdraws informed consent or deemed not eligible 
for Part 2; subjects who discontinue study in Part 1 will not be eligible for Part 2; subjects 
who discontinue treatment but do not discontinue the study in Part 1, decision for 
participation in Part 2 will be at discretion of Investigator, with guidance from Sponsor, as 
needed. 

9.1.1 Discontinuation of study treatment: added definition and updated to be consistent with
Glossary of terms. 

9.1.2 Discontinuation from study: new section added

9.1.3 Withdrawal of informed consent: updated definition of withdrawing informed consent 
as per new OneCTP Protocol Version 4. 

10.1.1 Adverse events: updated Eye Drop Comfort Scale to be assessed according to new 
applicable visits;
 

10.1.4 Pregnancy reporting: minor edits to clarify process for pregnancy reporting 

12.3 Treatments: 
.

12.4.2 Statistical model, hypothesis, and method of analysis: type I error control changed 
from 10% to 5%.

12.4.3 Handling of intercurrent events of primary estimand: updated primary estimand 
strategy.

12.4.5 Sensitivity analyses for primary estimand: sensitivity analysis dropped.

12.4.6 Supplementary analysis: updated supplementary estimand strategy
 

12.7 Interim Analysis: primary analysis for Part 2 added.

12.8 Sample size calculation: sample size adjusted based on updated overall type I error 
5%; 95% confidence level provided for updated study design in Part 2. 


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IRB/ IECs
A copy of this amended protocol will be sent to the Institutional Review Board (IRBs) and 
Health Authorities. 
The changes described in this amended protocol require IRB and Health Authority approval,
according to local regulations, prior to implementation.
The changes herein affect the trial specific global model consent form.


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Protocol summary
Protocol 
number
CECF843A2201
Full Title
A randomized, double-masked, multicenter study to evaluate the safety and efficacy of 
ECF843 vs Vehicle in subjects with dry eye disease
Brief title
A study to assess the safety and efficacy of ECF843 vs Vehicle in subjects with dry eye 
disease
Sponsor and 
Clinical Phase
Novartis Phase IIB
Investigation 
type
Drug; Biological
Study type
Interventional
Purpose and 
rationale
The purpose of Part 1 of the study is to determine the safety and efficacy of topical ocular 
ECF843 compared to topical ocular vehicle for the relief of the signs and symptoms 
associated with moderate to severe dry eye disease (DED).
Part 2 of the study is intended to explore additional endpoints and potential areas of 
differentiation as a treatment for patients with DED.
Primary 
Objective(s) 
The primary objective of the study is to demonstrate superiority of ECF843 versus vehicle 
for improvement in dry eye related ocular symptoms and ocular surface damage as
assessed by change from baseline in Symptom Assessment in Dry Eye (SANDE) score 
and change from baseline in composite corneal fluorescein staining score
Secondary 
Objectives
To evaluate the improvement of ECF843 vs vehicle in corneal damage by quadrant as 
assessed by change from baseline in inferior and central corneal fluorescein staining
To evaluate the safety of ECF843 vs Vehicle as assessed by incidence and severity of 
ocular and non-ocular adverse events
Study design
The study will be conducted in 2 parts: Part 1 – efficacy and safety of ECF843 vs vehicle, 
followed by Part 2 – exploratory assessments of ECF843 vs vehicle.
Part 1 uses a double-masked design where subjects will be randomized to receive BID or 
TID treatment with either ECF843 or vehicle for 56 days. For subjects randomized to 
ECF843, the maximum drug exposure will be up to 28 days. 
Part 2 will be initiated only if safety and efficacy of ECF843 during Part 1 is demonstrated. 
Part 2 also uses a double-masked design of ECF843 versus Vehicle for 84 days after a 2-
week vehicle run-in phase.
Population
This study will enroll adult subjects, 18 years of age or older with at least 6 months history 
of physician diagnosed moderate to severe dry eye disease in both eyes as defined by 
entry criteria.
It is estimated that approximately 800 subjects will need to be screened in Part 1 to have 
approximately 680 subjects randomized into the 56-day treatment period.
For Part 2, it is estimated that up to 200 subjects will need to be screened to randomize up 
to 160 subjects into the 2 treatment arms.
Key Inclusion 
criteria
1
Written informed consent must be obtained before any assessment is performed
2
Adult male or female subjects 18 years of age or older
3
Subjects must be able and willing to follow the protocol and required assessments
4
At least 6 months history of physician diagnosed dry eye disease in both eyes
5
Must use, or feel the need to use, artificial tears/gels/lubricants on a regular basis
6
Tear Break-up Time (TBUT) ≤ 5 seconds in at least one eye (average of 3 consecutive 
TBUT readings)
7
Composite corneal fluorescein staining score ≥ 4 (modified National Eye Institue (NEI) 
scale) in at least one eye (composite score is the sum score of the 5 regions within a 
single cornea)
8
PART 1 ONLY: In-office SANDE global ocular discomfort score ≥ 60 (as measured by 
100 mm visual analog scale (VAS)


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9
PART 2 ONLY: In office Eye Dryness Score ≥ 40mm (as measured by 100mm VAS 
scale)
Key Exclusion 
criteria
1
Ocular infection (bacterial, viral, or fungal) in either eye within 30 days prior to 
Screening
2
Use of artificial tears, gels, lubricants within 4 hours of conducting assessments at the 
Screening Visit
3
Use of contact lenses in either eye within 14 days of Screening, and any use of contact 
lenses for the duration of the study
4
Subjects with uncontrolled ocular rosacea (affecting the eye adnexa), posterior 
blepharitis or Meibomian gland dysfunction
5
Clinically significant conjunctivochalasis in either eye defined as an excessive 
redundancy of the conjunctiva that obliterates the inferior tear meniscus and/or rolls 
over the lower lid margin seen upon routine ocular exam or apparent with normal lid 
closure
6
Corneal conditions, other than dry eye related corneal epitheliopathies, affecting the 
corneal structure of either eye
7
Use of Restasis® , Cequa® , or Xiidra® within 30 days of Screening
8
Use of ocular, nasal, inhaled, or systemic corticosteroids within 30 days of Screening 
(low dose over-the-counter steroid creams applied to the skin are acceptable)
Study treatment
In Part 1, subjects will be screened and assigned to one of the following five masked 
treatment arms in a ratio of 1:1:1:1:1.
ECF843 0.45 mg/mL TID
ECF843 0.15 mg/mL TID
ECF843 vehicle TID
ECF843 0.15 mg/mL BID
ECF843 vehicle BID
In Part 2, following a 2-week run-in phase with vehicle, subjects will be assigned at Visit 2 
to one of the following two treatment groups in a ratio of 3:1.
ECF843 (concentration and dosing frequency to be determined from Part 1)
Vehicle (dosing frequency to be determined from Part 1)
Efficacy 
assessments
The following assessments are included to evaluate the efficacy of ECF843:
Ocular discomfort
Ocular hyperemia
Tear film break-up time
Corneal fluorescein staining
Conjunctival lissamine staining
Key safety 
assessments
The following assessments are included to evaluate the safety of ECF843:
Corrected Visual Acuity
Slit-Lamp Exam
Intraocular pressure
Fundus exam
Adverse events
Other 
assessments
The following patient reported outcomes (PRO) will be evaluated:
SANDE (Symptom Assessment in Dry Eye)


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Data analysis
The primary objective of Part 1 of the study is to show that at least one ECF843 arm will 
improve SANDE symptom score and/or composite corneal fluorescein staining score in
comparison with its corresponding vehicle (BID or TID) by rejecting the null hypothesis 
below at a significance level α=0.05 (2-sided).
For each of the primary endpoints, mixed model repeated measures (MMRM) will be used 
with change from baseline at all post-baseline visits on treatment as response variable, 
and treatment, visit, randomization strata and baseline score as covariate.
For secondary endpoints, change from baseline in inferior and central corneal fluorescein 
staining, 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. A 95% confidence interval will be 
provided for the difference between the ECF843 arm vs its corresponding vehicle at each 
post-baseline visit.
Key words
Dry Eye Disease, lubricin, proteoglycan 4, PRG4


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1
Introduction
1.1
Background
Dry Eye Disease (DED, also known as keratoconjunctivitis sicca) is defined as a multifactorial 
disease characterized by a loss of homeostasis of the tear film and ocular surface, and 
accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, ocular 
surface inflammation and damage, and neurosensory abnormalities play etiological roles. This 
updated, evidence-based definition based on the collective current understanding of DED was 
published in 2017 as a key outcome from the Tear Film and Ocular Surface Society Dry Eye 
Workshop II (TFOS DEWS II) (Craig et al 2017b). DED is a highly prevalent condition with 
an estimated 344M people affected globally (Craig et al 2017a). Through visual disturbances 
and chronic ocular pain or discomfort, DED can have a significant impact on a subject's quality 
of life and economic impact (including treatment costs, absenteeism, and reduced work 
productivity) (Yu et al 2011, McDonald et al 2016). Despite the many years of research in this 
area, understanding of DED remains in its infancy highlighting challenges in diagnosis, etiology, 
and treatment choices.
To date, very few prescription treatments are available for subjects suffering from chronic DED. 
In the United States (US), Restasis® (cyclosporine 0.05%) was approved in 2003 to increase 
tear production in patients whose tear production is presumed to be suppressed due to ocular 
inflammation associated with keratoconjunctivitis sicca (dry eye) (Rhee and Mah 2017). No 
other prescription treatments were approved in the US until 2016 when Xiidra® (lifitegrast 5%) 
received approval for the treatment of both signs and symptoms of DED (Keating 2017). In 
2018, another cyclosporin formulation called Cequa® (cyclosporin 0.09%) was approved in the 
US for increasing tear production in patients with keratoconjunctivitis sicca (Mandal et al 2019). 
Ocular adverse events coupled with delayed onset of action with each of these therapies means 
there remains potential to improve subject satisfaction and address an unmet medical need for 
new treatments that are safe, effective, and have a more rapid onset of action 
(O'Neil et al 2019).
Lubricin, also known as Proteoglycan 4 (PRG4), is a mucin-like glycoprotein expressed in areas 
of high shear stress and friction including the tear film where it binds to and protects tissues of 
the ocular surface (Samsom et al 2014). Lubricin has been found to be endogenously 
transcribed, translated, expressed and secreted by the ocular surface epithelia from various 
species (Schmidt et al 2013, Samsom et al 2014), and lubricin messenger RNA has been 
detected in lacrimal and Meibomian glands of rabbits (Cheriyan etal2011)
Preliminary unpublished data suggest a deficiency of functional lubricin on the ocular surface 
of subjects with dry eye disease and those with Sjögren’s Syndrome related dry eye compared 
to normals. Importantly, decreased expression of lubricin has been shown to occur in the 
presence of inflammatory mediators including some pro-inflammatory cytokines that have been 
associated with DED such as interleukin-1 (IL-1) and tumor necrosis factor-alpha (TNFα) 
(Jones and Flannery 2007). In addition to pro-inflammatory mediators, Cathepsin-S is 
hypothesized to be involved in the degradation of lubricin. Interestingly, Cathepsin-S activity 
in human tears was found to be 2-fold higher in subjects with Sjögren’s Syndrome compared to 
subjects with non-Sjögren’s DED, and 41-fold higher than in normal controls 
(Hamm-Alvarez et al 2014). Degradation of lubricin by Cathepsin also resulted in increased 


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friction in an in vitro ocular surface friction model (Regmi et al 2017). Furthermore, in vitro 
models also suggest a potential anti-inflammatory effect even though the actual mechanism by 
which this occurs is not yet understood. Together, these data suggest that lubricin may play a 
key role in the health of the ocular surface.
rhLubricin is a recombinant human form of endogenously expressed lubricin, and ECF843 
refers to the Novartis formulation of rhLubricin. ECF843 is hypothesized to restore the 
homeostasis on the ocular surface in subjects suffering from DED. The hypothesis that ECF843 
will be an effective treatment for the signs and symptoms of DED is based on the results of two 
small controlled clinical studies comparing the effects of rhLubricin to marketed artificial tear 
products containing hyaluronic acid (HA) with dosing as frequently as four times per day for 
up to 28 days. An improvement from baseline in ocular signs and symptoms was observed in 
both studies, and the effect of rhLubricin within a short time frame could suggest a rapid onset 
of benefit to subjects.
1.2
Purpose
The purpose of the study is to determine the safety and efficacy of topical ocular ECF843 
compared to topical ocular vehicle (Part 1) for the relief of the signs and symptoms associated 
with moderate to severe DED. The study design includes a component for dose-regimen 
selection. Part 2 of the study is intended to explore additional endpoints and potential areas of 
differentiation as a treatment for patients with DED.
This Phase II study will establish the foundation for further development and registration of 
ECF843.
2
Objectives, endpoints and estimands
Table 2-1
Objectives and related endpoints
Objective(s)
Endpoint(s)
Primary objective(s)
Endpoint(s) for primary objective(s)

Part 1: To demonstrate superiority of ECF843 versus vehicle 
for improvement in dry eye related ocular symptoms and ocular 
surface damage

Change from baseline in Symptom 
Assessment in Dry Eye (SANDE) 
score;

Change from baseline in composite 
corneal fluorescein staining score
Secondary objective(s)
Endpoint(s) for secondary objective(s)

Part 1: To evaluate the improvement of ECF843 vs vehicle in 
corneal damage by quadrant

Change from baseline in inferior and 
central corneal fluorescein staining

Part 1: To evaluate the safety of ECF843 vs Vehicle

Incidence and severity of ocular and 
non-ocular adverse events


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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 treatment effect of ECF843 versus 
vehicle on change from baseline in signs and symptoms in subjects with moderate to severe 
DED, if artificial tears/gels/lubricants and prohibited medications were not used, and treatment 
was received for the entire study duration?
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 artificial tears/gels/lubricants. Further details can be found in Section 12.
The primary estimands are described by the following attributes:
1. Population: subjects with moderate to severe DED. Further details about the population 
are provided in Section 5.
2. Endpoint: change from baseline in SANDE score and change from baseline in composite 
corneal fluorescein staining score.
3. Treatment of interest: the randomized treatment (ECF843 or vehicle) if artificial 
tears/gels/lubricants and prohibitive medications were not used and treatment was 
received for the entire study duration. Further details about the investigational treatment 
and control treatment are provided in Section 6.
Handling of remaining intercurrent events:
1. Artificial tears/gels/lubricants: Had subjects never used artificial tears/gels/lubricants for 
occasional rescue and behaved like other subjects who did not take them (hypothetical 
strategy)
2. Prohibited medications: Had subjects never used prohibited medications and behaved like 
other subjects who did not take them (hypothetical strategy)
3. Discontinuations from treatment for any reason: had subjects 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 ECF843 and vehicle.
Supplementary estimands to the primary estimand are defined in Section 12.
2.2
Secondary Estimands
Not applicable.


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3
Study design
Figure 3-1
Study Design
The study will be conducted in 2 parts: Part 1 – efficacy and safety of ECF843 vs vehicle, 
followed by Part 2 – additional exploratory assessments of ECF843 vs Vehicle. Both parts of 
the study include a double-masked study design, with randomization stratified for subjects 
with Sjogren's Syndrome.
In Part 1 subjects will be randomized to receive twice daily (BID) or three times daily (TID) 
treatment with either ECF843 or vehicle for 56 days. For subjects randomized to ECF843, the 
maximum drug exposure will be up to 28 days. At some point during Part 1, all subjects will 
receive vehicle. The study will be conducted in a way that neither the Investigator nor the 
subject are aware of the criteria for qualification into the primary efficacy analysis, nor the 
period(s) during which vehicle treatment is assigned. There will be a database lock after all 
subjects have completed their participation in Part 1 of the study. The data will be analyzed to 
determine the efficacy and safety of ECF843 vs vehicle and selection of the optimal 
concentration and posology. Part 1 must be fully completed prior to initiating Part 2. Part 2 
will be initiated only if safety and efficacy of ECF843 during Part 1 is demonstrated.
Between the end of the subject's participation in Part 1 and the beginning of participation in 
Part 2, subjects will be treated as needed and according to Investigator judgement, and no 
protocol assessments or proactive solicitation of adverse events will be collected. If a subject
spontaneously reports a serious adverse event (SAE) within 30 days of completing Part 1, 
those events will be captured as stated in Section 10.1.3.
Only subjects assigned exclusively to vehicle treatment in Part 1 may be eligible to participate 
in Part 2 of the study. A list of subjects eligible for screening in Part 2 of the study will be 
discussed between the Investigator and the Sponsor prior to initiating screening visits. In the 


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event a study site was initiated close to the end of enrollment and did not have sufficient time 
to begin recruiting subjects, the site may enroll subjects into Part 2 of the study if approved by 
the Sponsor.
Subjects will again be asked to sign the informed consent form (ICF) in order to participate in 
Part 2, and will be re-screened to determine continued eligibility. If the subject meets all entry 
criteria, the subject may be randomized to receive either ECF843, at the concentration and 
posology selected from Part 1, or Vehicle at the same selected posology at a 3:1 ratio for 84 
days of treatment. Enrollment for Part 2 of the study will be discussed between the Investigator 
and the Sponsor prior to initiating screening visits.
4
Rationale
4.1
Rationale for study design
Part 1 of the study is a double-masked, randomized, parallel design which includes 
two concentrations and two posologies in order to evaluate the difference in efficacy based on 
concentration and frequency of dosing. Because administration of vehicle does provide benefit 
to subjects and shows some efficacy in many dry eye clinical studies, there is not a true placebo 
(e.g., a treatment that has no effect on the disease being studied). Therefore, it is important to 
compare active to vehicle at the same frequency of dosing. To address this, there are two vehicle 
arms: one for comparison of BID active vs vehicle and one for TID active vs vehicle.
The primary objectives for Part 1 of the study are based on the assessment of ocular symptoms 
(via an at home daily electronic diary using the SANDE VAS symptom scores) and ocular 
surface damage assessed by the degree of corneal fluorescein staining. These are well 
established endpoints that are recognized as key parameters to define severity of the dry eye 
disease state, as well as improvement in the disease severity after treatment.
The active and vehicle test articles are presented in identical packaging to ensure no bias to the 
study results due to knowledge of the treatment assignment. There is an additional level of 
masking which includes the selection of subjects that will be included in the primary efficacy 
analysis of the study. The criteria for selection of these subjects is pre-defined and documented 
in the statistical analysis plan (SAP) but is not disclosed to the Investigator nor the subject to 
avoid the selection bias and regression effects that have been observed in many historical dry 
eye studies. The criteria for selection of subjects into the primary analysis are within the 
guidelines of the stated entry criteria for the study in order to protect against any unintended 
risk to the subject. In order to preserve this level of masking, and to allow for exploration of 
differences in treatment outcomes between the population of subjects who are selected vs those 
that are not, all subjects will remain in the study for the full treatment period.


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Part 2
Part 2 of the study is an exploratory, double-masked, randomized parallel assessment of 
ECF843 vs Vehicle. 
 
 
 
 
Due to different medications being approved in various countries, the comparison is being done 
to vehicle rather than an active comparator in order to help inform hypotheses for areas where 
ECF843 may be differentiated from other currently available treatments, and that warrant 
further evaluation in future studies.
4.2
Rationale for dose/regimen and duration of treatment
The planned doses and posologies of ECF843 eye drops are 
 BID or TID, 
and 
 TID, based on an estimated maximum average drop size of 
 
 and solution concentration of 0.15 mg/mL and 0.45 mg/mL, respectively. Previous 
clinical studies LUB0114MD and LUB0115MD, evaluating 0.15 mg/mL rhLubricin eye drops 
QID and BID/PRN, respectively, demonstrated the efficacy and tolerability/safety of rhLubricin 
in subjects with DED. The additional dose level of 0.45 mg/mL is included to further assess the 
dose/response relationship. Test concentrations included in this study are based on the lowest 
and highest feasible doses that can be reproducibly manufactured while adhering to formulation 
specifications.
There are no animal models and limited in vitro models to justify the selection of dose. In in 
vitro testing using a cartilage-glass friction assay with 14 different concentrations of rhLubricin 
ranging from 0-300 µg/mL, maximum lubrication was observed at concentrations of 50 µg/mL 
or higher (Gleghorn et al 2009). Lubrication is a surrogate for potency of formulated ECF843, 
and the potential effect that may be observed in the clinical assessments.
Supportive nonclinical ocular pharmacokinetic (PK) data are limited to studies in rats and dogs. 
Compared to rats, dogs have a blink rate and eye size closer to humans. In the rat studies, 
fluorescein isothiocyanate (FITC)-labeled lubricin was administered topically and tear and 
ocular surface fluorescence measured for 10 minutes (Dompe Study MIR 027/15 in vivo, 
PR&DS 090/14 in vivo). ECF843 was rapidly cleared from the ocular surface with 
 
). In the dog study, animals received a single bilateral topical ocular dose 
of 0.15 mg/mL or 0.45 mg/mL unlabeled ECF843 followed by collection of tear and ocular 
tissues at time points up to 6 hours for PK. The tear results confirmed the rapid clearance of 
ECF843 observed in the rat study, although there were quantifiable levels at 
 
 
Half-life could not be determined due to the limited quantifiable data available. ECF843 was 
not detected in ocular tissues, indicating negligible absorption, although these data do not 
discount the possible presence of ECF843 on the ocular surface below the sensitivity of the 
ECF843 assay.
The previously observed efficacy in humans with 0.15 mg/mL BID implies that the effect 
persists beyond the detectable presence of ECF843 on the eye, and despite the rapid ocular 


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clearance observed in rat and dogs. The target ocular ECF843 concentration is unknown; 
however, studies are in progress to obtain definitive concentrations of endogenous lubricin in 
human tears and conjunctiva (via impression cytology), which could possibly be used as target 
concentrations in modeling.
Clinical Study CECF843A2201 will evaluate and compare ECF843 dosed BID and TID, and is 
based on BID previously demonstrating a positive effect in humans. TID could further enhance 
residence time of ECF843 and result in better efficacy. No safety concerns have been identified 
which would preclude BID or TID dosing in this study.
ECF843 eye drops at doses of 0.15 mg/mL and 0.45 mg/mL BID/TID is expected to be safe 
and well tolerated, based on previous human studies and ocular toxicology assessments in 
monkeys, administered ECF843 eye drops for 3 months at up to 0.45 mg/mL 4 times per day 
 With regard to systemic 
exposure and safety, the molecular size of ECF843 at approximately 450 kilodaltons (kDa) 
makes it unlikely that ECF843 will be systemically bioavailable. This has so far been confirmed 
in the dose range finding (DRF) toxicology study in which monkeys were administered ECF843 
eye drops up to 0.45 mg/mL 6 times per day for 7 days, and where ECF843 was non-quantifiable 
(< LLOQ of 100 ng/mL) in the serum at 0.5, 1, 3 and 6 hrs post-dose on Day 7.
Due to the mechanism of action of ECF843 and consistent with other DED studies, the duration 
of dosing in Parts 1 and 2 should be sufficient to detect if any pharmacological effect can be 
observed. To date there have been two clinical studies conducted with a rhLubricin formulation 
which included up to 28 days of QID dosing. Additionally, the 84 day assessment period in Part 
2 is consistent with other currently approved pharmacological treatments for patients with DED. 
The lengths of treatment in Part 1 and Part 2 are both supported by toxicology testing since only 
subjects who had received vehicle during Part 1 of the study may enter Part 2.
4.3
Rationale for choice of control drugs (comparator/placebo) or 
combination drugs
Part 1 and Part 2 of the study are vehicle-controlled in order to assess whether ECF843 
demonstrates a pharmacological effect that is superior to administering the same formulation 
without the active ingredient (rhLubricin). A vehicle control is standard in dry eye studies for 
product registration by the US Food and Drug Administration (FDA), and has been confirmed 
through the FDA Pre-Investigational New Drug (pre-IND) Application meeting as being an 
appropriate control.
4.4
Purpose and timing of interim analyses/design adaptations
For Part 1, the primary analysis will be performed after all subjects in Part 1 have completed or 
discontinued from randomized treatment. The data will be analyzed to determine the efficacy 
and safety of ECF843 vs vehicle and to select the concentration and posology for Part 2. Part 2 
will be initiated only if efficacy and safety of ECF843 vs vehicle from Part 1 are demonstrated.
For Part 2, the primary analysis will be performed after all subjects in Part 2 have completed or 
discontinued from 12 weeks of treatment. The data will be used to explore the efficacy and 
safety of ECF843 vs vehicle after 12 weeks of treatment.
Refer to Section 12 (Data Analysis and Statistical Methods) for further details.


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4.5
Risks and benefits
ECF843  is a formulation of a recombinant human lubricin. Lubricin is transcribed, translated, 
and expressed by ocular surface tissues to reduce friction and protect the ocular surface. 
Additional evidence suggests lubricin may confer a potential anti-inflammatory effect. Lubricin 
is hypothesized to play a key role in ocular surface health and may restore homeostasis on the 
ocular surface in subjects suffering from DED. Because current choices for prescription 
treatments are limited and generally are associated with ocular adverse events and/or delayed 
onset of action, ECF843 may provide a novel treatment option and address a significant unmet 
medical need for subjects with moderate to severe DED.
Limited clinical experience exists with the investigational treatment in this study. Two clinical 
studies (LUB0114MD and LUB0115MD) have been conducted using a different formulation 
of rhLubricin, with one of the studies including up to 28 days of exposure with four times a day 
(QID) dosing. Both studies demonstrated clinical efficacy based on improvements in ocular 
signs and symptoms of dry eye disease. No serious adverse events (SAEs) or deaths reported in 
either study, and no adverse drug reactions (ADRs) were identified based on the safety data 
from these two studies.
The risk to subjects in this current study may be minimized by compliance with the eligibility 
criteria and study procedures, as well as close clinical monitoring.
Because lubricin is an endogenous protein expressed on the ocular surface, the likelihood of 
hypersensitivity reactions is low. Evaluation of subject serum samples for detection of anti-
ECF843 antibody formation will be performed in Part 2 of the study.
Subjects will undergo certain ophthalmological procedures which are common in dry eye 
practice (e.g., corneal fluorescein staining, slit-lamp biomicroscopy, fundus examination) 
during this study. Any subject demonstrating a potential hypersensitivity reaction to the 
investigational medicinal product (IMP) will cease use of the IMP and receive appropriate 
care. To minimize any discomfort and risks, the study and associated procedures will be carried 
out by experienced study staff under the supervision of a Principal Investigator who is 
experienced in managing subjects with dry eye. Although subjects may receive vehicle instead 
of active drug for part or all of the study, the inclusion of a vehicle control is not considered a 
major risk in a dry eye study since vehicle itself can provide some benefit to subjects.
Women of child bearing potential should be informed that taking the investigational drug may 
involve unknown risks to the fetus if pregnancy were to occur during the study, and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the subject will not reliably comply, they 
should not be entered in the study.
Given the minimal systemic exposure after topical ocular administration, and the lack of safety 
findings in clinical studies conducted to date, the foreseeable risks associated with ECF843 are 
considered very low compared to the anticipated benefit to subjects with DED. There may be 
risks associated with the use of ECF843 which are unknown at this time.


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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 subjectsafety 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
This study will enroll adult subjects, 18 years of age or older with at least 6 months history of 
physician diagnosed moderate to severe dry eye disease in both eyes as defined by entry criteria.
It is estimated that approximately 800 subjects will need to be screened in Part 1 to have 
approximately 680 subjects randomized into the 56-day treatment period. Enrollment in the 
study will remain open until a sufficient number of evaluable subjects is achieved in Part 1.
For Part 2, it is estimated that up to 200 subjects will need to be screened to randomize up to 
160 subjects into the 2 treatment arms.
Subjects discontinuing the study after randomization in either Part 1 or Part 2 will not be 
replaced, and subjects who discontinue the study in Part 1 will no longer be eligible for Part 2.
For subjects who discontinue treatment but do not discontinue the study during Part 1, or for 
subjects who experience a treatment related adverse event (AE) or serious adverse event (SAE), 
eligibility for Part 2 will be dependent on the reasons for treatment discontinuation or nature of 
the AE/SAE. The decision for participation in Part 2 will be at the discretion of the Investigator, 
with guidance from the Sponsor as needed.
The following inclusion/exclusion criteria apply to screening of subjects in Part 1, as well as 
screening and baseline in Part 2.
5.1
Inclusion criteria
Subjects eligible for inclusion in Part 1 must meet all of the following criteria at the Screening 
Visit (i.e., Visit 1).
Subjects eligible for inclusion in Part 2 must meet all of the following criteria at the Screening 
Visits (i.e., Visit 1) and Baseline Visit (i.e., Visit 2).
1. Written informed consent must be obtained before any assessment is performed
2. Adult male or female subjects 18 years of age or older
3.
Subjects must be able and willing to follow the protocol and required assessments
4. At least 6 months history of physician diagnosed dry eye disease in both eyes
5. Must use, or feel the need to use, artificial tears/gels/lubricants on a regular basis
6. Tear Break-up Time (TBUT) ≤ 5 seconds in at least one eye (average of 3 consecutive 
TBUT readings)
7. Composite corneal fluorescein staining score ≥ 4 (modified National Eye Institute 
(NEI) scale) in at least one eye (composite score is the sum score of the 5 regions within a 
single cornea)


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8. PART 1 ONLY: In office SANDE global ocular discomfort score ≥ 60 (as measured by 
100 mm Visual Analog Scale (VAS)
9. PART 2 ONLY: In office Eye Dryness Score ≥ 40mm (as measured by 100mm VAS 
scale)
10. Schirmer score ≥ 1 and ≤ 10 mm after 5 minutes in at least one eye
11. Subjects with Sjögren's Syndrome must have dry eye (same inclusion criteria as above) 
associated with a confirmed diagnosis of primary or secondary Sjögren's Syndrome (e.g., 
diagnosis supported by lab results, positive biopsy, etc., which may be obtained by any 
qualified physician including rheumatologist, etc).
5.2
Exclusion criteria
Subjects meeting any of the following exclusion criteria at the Screening Visit in Part 1 are not 
eligible for participation in the study.
Subjects meeting any of the following exclusion criteria at the Screening and Baseline Visits in 
Part 2 are not eligible for participation in Part 2 of the study.
1. Ocular infection (bacterial, viral, or fungal) in either eye within 30 days prior to Screening
2. Use of artificial tears, gels, lubricants within 4 hours of conducting assessments at the 
Screening Visit
3. Use of contact lenses in either eye within 14 days of Screening, and any use of contact lenses 
for the duration of the study
4. Subjects with uncontrolled ocular rosacea (affecting the eye adnexa), posterior blepharitis 
or Meibomian gland dysfunction
NOTE: Controlled is defined as a stable condition, not as an asymptomatic condition. If the 
subject is doing lid scrubs and/or warm compresses to control these conditions, they must 
continue with their normal regimen. However, subjects must have been utilizing these 
therapies for at least 30 days prior to Screening, no new regimens added during the course 
of the study, and no current regimens discontinued during the study.
5. Clinically significant conjunctivochalasis in either eye defined as an excessive redundancy
of the conjunctiva that obliterates the inferior tear meniscus and/or rolls over the lower lid 
margin seen upon routine ocular exam or apparent with normal lid closure
6. Corneal conditions, other than dry eye related corneal epitheliopathies, affecting the corneal 
structure of either eye including but not limited to:

Clinically significant corneal dystrophies defined as affecting the structure of the 
corneal surface, affecting best-corrected visual acuity, or is an actively changing or 
unstable condition

Corneal scars with residual corneal surface irregularity

Pterygia that extend > 2mm onto the corneal surface, or are elevated rather than flat, or 
show concentrated staining

Keratoconus
7. Any history of ocular herpes simplex virus or herpes zoster virus infection, or other severe 
ocular conditions such as graft versus host disease, Stephen's Johnson Syndrome, 
sarcoidosis


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8. Currently active, or history of ocular allergies during the time of year the subject will be
participating in the study
9. History of hypersensitivity to ECF843, staining reagents (fluorescein sodium or lissamine),
or their excipients.
10. Subjects with current punctal plugs or punctal cauterization or occlusion
11. Chronic medications (both over the counter and prescription) that have not been stable for
at least 30 days prior to Screening. Subjects who have any anticipated change in their
chronic medication regimen are excluded until the new regimen has been stable for at least
30 days.
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). Pro
re nata (PRN) medications such as low dose acetaminophen (e.g., Tylenol) and over the
counter Non Steroidal Anti Inflammatory Drugs (NSAIDs) are not excluded.
12. Use of Restasis®, Cequa®, or Xiidra® within 30 days prior to Screening
13. Medical device use to treat meibomian gland dysfunction (e.g., LipiFlow, Intense Pulse
Light Therapy, or similar) within 3 months prior to Screening
14. Use of ocular, nasal, inhaled, or systemic corticosteroids within 30 days of Screening (low
dose over-the-counter steroid creams applied to the skin are acceptable), or any use during
the duration of study participation
15. Any history of corneal refractive surgery (e.g., laser-assisted in situ keratomileusis [LASIK],
photorefractive keratectomy [PRK], etc)
16. Any intraocular surgery including cataract surgery within 6 months prior to Screening
17. Chronic systemic disease that was diagnosed within the last 30 days or that has not been
stable for at least 30 days prior to the Screening
18. Use of other investigational drugs within 5 half-lives of enrollment, or within 30 days, or
until the expected pharmacodynamic effect has returned to baseline, whichever is longer
19. History of malignancy of any organ system (other than localized basal cell carcinoma of the
skin or in situ cervical cancer), treated or untreated, within the past 5 years, regardless of
whether there is evidence of local recurrence or metastases
20. Subjects demonstrating any medical condition (systemic or ophthalmic) that may, in the
opinion of the Investigator, preclude the safe administration of test article or safe
participation in this study, or potentially impact the outcome of the study
21. Pregnant or nursing (lactating) women
22. 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 investigational drug. 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.


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
Male sterilization (at least 6 m 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 contraceptive 
for a minimum of 3 months before taking investigational drug. Women are considered post-
menopausal and not of child-bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g., age appropriate, history of 
vasomotor symptoms Women are considered not of child bearing potential if they are post-
menopausal or have had surgical bilateral oophorectomy (with or without hysterectomy), total 
hysterectomy or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow-up hormone level 
assessment is she considered not of child-bearing potential.
6
Treatment
6.1
Study treatment
Part 1
Subjects will receive double-masked treatment for 56 days.
Part 2
Subjects will receive double-masked treatment for 84 days after a 14-day ECF843 vehicle run-
in period.
6.1.1
Investigational and control drugs
Table 6-1
Investigational and control drug
Investigational/ 
Control Drug
(Name and 
Strength)
Pharmaceutical 
Dosage Form
Route of 
Administration
Presentation 
Sponsor (global 
or local)
ECF843 0.15 
mg/ml
Liquid as drops 
single-dose 
ophthalmic
Topical ocular
Double masked
Global
ECF843 0.45 
mg/ml
Liquid as drops 
single-dose 
ophthalmic
Topical ocular
Double masked
Global
ECF843 Vehicle
Liquid as drops 
single-dose 
ophthalmic
Topical ocular
Double masked 
Global


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ECF843 active and vehicle will be packed as double masked kits. Each kit will consist of a 
carton containing 6 aluminum foil pouches to protect the product from light, and each pouch 
will contain 3 blow-fill-seal (BFS) containers for single use. IRT will instruct on the number of 
kits to be dispensed. A sufficient number of kits will be dispensed per visit to cover the required 
treatment period between visits.
6.1.2
Additional study treatments
No other treatment beyond investigational drug and control drug are included in this trial.
6.1.3
Treatment arms/group
In Part 1, subjects will be screened and assigned to one of the following five masked treatment 
arms/groups in a ratio of 1:1:1:1:1.

ECF843 0.45 mg/mL TID or vehicle

ECF843 0.15 mg/mL TID or vehicle

ECF843 vehicle TID

ECF843 0.15 mg/mL BID or vehicle

ECF843 vehicle BID
In Part 2, following a 2-week run-in phase with vehicle, subjects will be assigned at Visit 2 to 
one of the following two masked treatment arms/groups in a ratio of 3:1.

ECF843 (concentration and dosing frequency to be determined from Part 1)

ECF843 vehicle (dosing frequency to be determined from Part 1)
6.1.4
Treatment duration
The planned duration of double-masked treatment during Part 1 is 56 days. In Part 2, a 14-day 
open label vehicle run-in will be followed by 84 days of masked treatment. Subjects may be 
discontinued from treatment earlier due to unacceptable toxicity, disease progression and/or 
treatment is discontinued at the discretion of the investigator, Sponsor, or the subject. Refer to 
Section 9.1 on discontinuation from the study for additional details.
6.2
Other treatment(s)
6.2.1
Concomitant therapy
All prescription and over-the-counter medications, procedures, and significant non-drug 
therapies (including physical therapy and blood transfusions) administered after the subject was 
enrolled into the study must be recorded on the appropriate electronic Case Report Forms 
(eCRFs). Concomitant topical ocular medications for reduction of intraocular pressure are 
permitted.
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt, the investigator should contact the Novartis medical monitor before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, contact Novartis to determine if the subject should continue participation in the study.


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6.2.2
Prohibited medication
Use of the treatments displayed in the below table are not allowed after Screening (Visit 1).
Table 6-2
Prohibited medication
Medication
Prohibition period
Action taken
Ocular, nasal, inhaled, or systemic 
corticosteroids
During the course of the study
Do not discontinue study treatment 
but document use of the product in 
the eCRF
Any topical ocular medications 
(prescription or over-the-counter; 
excluding IOP-lowering 
medication)
During the course of the study
Do not discontinue study treatment 
but document use of the product in 
the eCRF
If the addition of a medication is 
needed for treatment of an 
adverse event, the decision to 
discontinue study treatment will be 
made by the Investigator and 
Sponsor based on the relevance 
and duration of the prohibited 
treatment
Intravitreal injections of any kind
During the course of the study
Do not discontinue study 
treatment, but document use of the 
product in the eCRF
If the addition of a medication is 
needed for treatment of an 
adverse event, the decision to 
discontinue study treatment will be 
made by the Investigator and 
Sponsor based on the relevance 
and duration of the prohibited 
treatment
Medical device treatments such as 
those used to treat Meibomian 
gland dysfunction (eg, LipiFlow, 
pulse light therapy, etc)
During the course of the study
Discontinue study treatment
Punctal plugs or punctal 
cauterization
Placement of new occlusion during 
the course of the study
Discontinue study treatment
Subjects should be discouraged from using artificial tears, gels, lubricants during the study. 
However, if a subject is in need of occasional rescue and must use these products, the subject 
can remain in the study but the use of the products must be documented in the eCRF. If a subject 
is unable to refrain from use of these products and is unable to continue with the requirements 
of the study, the subject should be discontinued.
Topical ocular prescription medications should be administered at least 10 minutes before 
dosing with the study medication.
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 enrolled for screening and is retained for the subject throughout his/her 
participation in the trial. A new subject No. will be assigned at every subsequent enrollment if 


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the subject is re-screened. The subject No. consists of the Site Number (Site No.) (as assigned 
by Novartis/Sponsor to the investigative site) with a sequential subject number suffixed to it, so 
that each subject’s participation is numbered uniquely across the entire database. Upon signing 
the ICF, the subject is assigned to the next sequential subject No. available
6.3.2
Treatment assignment, randomization
Separate randomization lists will be generated for the two parts of the study.
For Part 1, all eligible subjects will be randomized via 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 the first 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 by or under the responsibility of Novartis 
Global Clinical Supply (GCS) using a validated system that automates the random assignment 
of medication numbers to packs containing the study treatment.
The same process applies to the subjects eligible to participate in Part 2.
Randomization in both Part 1 and Part 2 will be stratified by subjects with a documented 
diagnosis of Sjogren's Syndrome. Stratification of subjects with Sjogren's Syndrome is intended 
to ensure these subjects are evenly distributed across the treatment arms.
The randomization scheme for subjects will be reviewed and approved by a member of the 
Randomization Office.
6.4
Treatment blinding
Subjects, investigator staff, persons performing the assessments, and Clinical Trial Team (CTT) 
will remain masked to the identity of the treatment from the time of randomization until 
database lock, using the following methods: (1) Randomization data are kept strictly 
confidential until the time of unblinding and will not be accessible by anyone involved in the 
study. (2) the identity of the treatments will be concealed by the use of study treatment that are 
all identical in packaging, labeling, schedule of administration, appearance, taste, and odor.
Unmasking of the CTT members/site staff will occur at the end of Part 1 and again at the end 
of Part 2.


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Table 6-3
Blinding levels
Role
Time and Event
Randomization list 
generated
Treatment 
allocation & 
dosing
Safety event (single 
subject unblinded)
Subjects/Patients
B
B
B
Site staff
B
B
B
Drug Supply and Randomization 
Office
UI
UI
UI
Bioanalytical Team
UI
UI
UI
Statistician/statistical 
programmer/data analysts
B
B
B
All other sponsor staff not 
identified above
B
B
B
B Remains blinded
UI Allowed to be unblinded on individual patient level
6.5
Dose escalation and dose modification
Investigational or other study treatment dose adjustments and/or interruptions are not permitted.
6.5.1
Dose modifications
Dose interruptions and/or reductions are not allowed.
6.5.2
Follow-up for toxicities
Not applicable 
6.6
Additional treatment guidance
6.6.1
Treatment compliance
The Investigator must promote compliance by instructing the subject to dose the study treatment 
exactly as prescribed and by stating that compliance is necessary for the subject’s safety and 
the validity of the study. The subject must also be instructed to contact the Investigator if he/she 
is unable for any reason to dose the study treatment as prescribed.
Compliance will be assessed by the Investigator and/or study personnel at each visit by 
questioning the subject and verifying drug accountability including the number of used and 
unused BFS containers. This information should be captured in the source document at each 
visit.
All study treatment dispensed and returned must be recorded in the Drug Accountability Log.
6.6.2
Recommended treatment of adverse events
At present, there is insufficient information to provide specific recommendations regarding 
treatment of adverse events (AEs). Due to the expected lack of systemic exposure of the drug, 
the nature of ECF843 as an endogenous protein, and the fact that to date there have been no
significant adverse events (ocular or non-ocular), an abundance of caution is not warranted at 
this time point.


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If the subject were to experience significant discomfort upon instillation of the investigational 
product, the eye should be flushed with sterile saline (or equivalent). Should the subject 
experience blurred vision for a time just after instillation of the investigational product, he/she 
should not drive or use machines until the effect has worn off. The Investigator must treat the 
subject as needed and appropriate for their condition.
Medication used to treat AEs must be recorded on the appropriate eCRF.
6.6.3
Emergency breaking of assigned treatment code
Emergency code breaks must only be undertaken when it is required to in order to treat the 
subject safely. Blinding codes may also be broken after a subject discontinues treatment due to 
disease progression if deemed essential to allow the investigator to select the subject’s next 
treatment regimen, and after discussion and agreement with the sponsor. Most often, study 
treatment discontinuation and knowledge of the possible treatment assignments are sufficient 
to treat a study subject who presents with an emergency condition. Emergency treatment code 
breaks are performed using the IRT. When the investigator contacts the system to break a 
treatment code for a subject, he/she must provide the requested subject identifying information 
and confirm the necessity to break the treatment code for the subject. The investigator will then 
receive details of the investigational drug treatment for the specified subject and a fax or email 
confirming this information. The system will automatically inform the Novartis/sponsor 
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 provide:

protocol number

subject name (if available)

subject number
In addition, oral and written information to the subject must be provided on how to contact 
his/her backup in cases of emergency, or when he/she is unavailable, to ensure that un-blinding 
can be performed at any time.
Subjects will be discontinued from the study once the treatment code has been broken.
6.7
Preparation and dispensation
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section.
A unique medication number is printed on the study medication label.
For both Part 1 and Part 2, 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 secondary packaging 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.
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 


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Health Authorities and IRBs/IECs 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 2 week 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
6.7.2
Handling of study treatment
Study treatment must be received by a designated person at the study site, handled and stored 
safely and properly and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, all study treatment must be stored according to the 
instructions specified on the 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 
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 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 monitor or to the Novartis address provided 
in the investigator folder at each site.
6.7.3
Handling of additional treatment
Not applicable
6.7.4
Instruction for prescribing and taking study treatment
Table 6-4
Dose and treatment schedule
Investigational / Control Drug
Dose
Frequency and/or Regimen
ECF843 0.15 mg/mL
one drop in each eye
BID
ECF843 0.15 mg/mL
one drop in each eye
TID
ECF843 0.45 mg/mL
one drop in each eye
TID
Vehicle
one drop in each eye
BID or TID as per study design


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Part 1
Each single use BFS container contains enough drug for instillation of one drop per eye at each 
dosing time point. There will be additional drug remaining in the container after dosing. 
However, subjects must NOT continue dosing beyond the single time point with any container.
Drug must be stored as indicated on the container label.
Subjects will dose according to their randomized dosing frequency (BID or TID). If dosing BID, 
subjects will dose in the morning upon wakening and in the evening prior to bed time. If dosing 
TID, subjects will dose morning upon wakening, mid-day, and evening prior to bed time. 
Subjects should avoid touching the tip of the container to any surface, including the eye or 
surrounding skin, to avoid contamination.
Part 2
ECF843 and Vehicle will be handled as described above; the dose frequency will be derived 
from the Part 1 results. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system.
7
Informed consent procedures
Eligible subjects may only be included in the study after providing (witnessed, where required 
by law or regulation) Institutional Review Board/Independent Ethics Committee (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 ICF.
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). For this study, the subject must sign informed consent 
prior to participation in Part 1, and again confirm and sign the informed consent prior to 
participation in Part 2 (the main informed consent form for a single subject contains both 
signatures). In the case of subjects who are enrolled only in Part 2, only 1 signature is required.
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 ICF that complies with 
the International Council for Harmonisation Good Clinical Practice (ICH GCP) guidelines and 
regulatory requirements and is considered appropriate for this study. Any changes to the 
proposed consent form suggested by the investigator must be agreed by Novartis before 
submission to the IRB/IEC.
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the subject 
informed consent and should be discussed with the subject during the study as needed. Any new 
information regarding the safety profile of the investigational drug that is identified between IB 
updates will be communicated as appropriate, for example, via an investigator notification or 


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an aggregate safety finding. New information might require an update to the informed consent 
and then must be discussed with the subject.
The following informed consents are included in this study:

Main study informed consent, which also includes:

A subsection that requires a separate signature for the ‘Optional Consent for Additional 
Research’ to allow future research on data/samples collected during this study

As applicable, Pregnancy Outcomes Reporting Consent for female subjects or the
female partners of any male subjects who took study treatment
Women of child bearing potential must be informed that taking the study treatment may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order 
to participate in the study, they must adhere to the contraception requirements.
 
 
 
 
 
 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval.
8
Visit schedule and assessments
Assessment schedules (Table 8-1 and Table 8-2) list when all of the assessments are to be 
performed. All data obtained from these assessments must be supported in the subject’s source 
documentation.
Only subjects assigned exclusively to vehicle treatment in Part 1 may be eligible to participate 
in Part 2 of the study. A list of subjects eligible for screening in Part 2 of the study will be 
discussed between the Investigator and the Sponsor prior to initiating screening visits. In the 
event a study site was initiated close to the end of enrollment and did not have sufficient time 
to begin recruiting subjects in Part 1, the site may enroll subjects into Part 2 of the study if 
approved by the Sponsor. 
Subjects are encouraged to stick to the scheduled visits as much as possible. If a subject is 
unable to return to the site as per the visit schedule, no visits should be missed, and efforts 
should be made to resupply the subject with sufficient drug (as needed). Subjects should be seen 
for all visits/assessments as outlined in the assessment schedule (Table 8-1 and Table 8-2) as 
close as possible to the target visit day and as close to the same time of day for each visit as 
possible. If a subject returns to the site for a visit earlier or later than planned, the next sequential 
visit should take place. The remaining subsequent visits should then be scheduled in a way that


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brings the subject back to their original target dates for each visit as determined at 
Screening/Baseline. 
Subjects must not have dosed with study medication within 4 hours of the visit assessments 
being conducted. 
 
 
Missed or rescheduled visits should not lead to automatic discontinuation.
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 must be reconciled, and the 
adverse event and concomitant medications recorded on the eCRF.


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Table 8-1
Assessment Schedule, Part 1
Period
Screening
Treatment
Visit Name
Visit 1-Screening
Visit 1-Randomization
Visit 2
Visit 3
Visit 4
Visit 5/EOS
Days
1
1
14
28
42
56
Informed consent
X
Inclusion / Exclusion criteria
X
Demography
X
Medical history/current medical conditions X
Concomitant medications
X
X
X
X
X
Pregnancy Test (urine)
X
X
In office SANDE score 
X
Corrected visual acuity
X
X
X
X
X
Slit lamp biomicroscopy
X
X
X
X
X
Ocular hyperemia
X
X
X
X
X
Tear break-up time (TBUT)
X
X
X
X
X
Corneal fluorescein staining2
X
X
X
X
X
Conjunctival lissamine staining
X
X
X
X
X
Schirmer Tear Test
X
Intraocular Pressure (IOP)
X
X
X
X
X
Fundus Exam
X
X
Contact IRT3
X
X
X
X
Randomization
X
Dispense study medication
X
X
X
X
In-office study drug administration
X


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Period
Screening
Treatment
Visit Name
Visit 1-Screening
Visit 1-Randomization
Visit 2
Visit 3
Visit 4
Visit 5/EOS
Days
1
1
14
28
42
56
Adverse Events
X
X
X
X
X
X
At home SANDE questionnaire (eDiary)4
X
X
X
X
Study completion information
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
 
3 Sites will enter average SANDE score (obtained from the electronic diary) and the corneal fluorescein staining score from the eye with the highest composite score 
(sum of the 5 regions)
4 Subjects will complete an electronic diary once daily (in the evening before bed time and prior to the evening dose of study medication) from Visit 1-Screening through 
to the end of the study (at home SANDE questionnaire)
 
Table 8-2
Assessment Schedule, Part 2
Period
Screening
Treatment
Post Treatment Follow-up 
Visit Name
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7/
EOT
Visit 8/ 
EOS8 
Safety F/U EOS8
+4. +8, +12 Weeks
Days
-14
1
7
14
28
42
84
126
154, 182, 210
Informed consent
X
Inclusion / Exclusion 
criteria
X
X
Demography
X
Medical history/current 
medical conditions
X
Concomitant 
medications
X
X
X
X
X
X
X
X
X
Pregnancy Test (urine)
X
X


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Period
Screening
Treatment
Post Treatment Follow-up 
Visit Name
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7/
EOT
Visit 8/ 
EOS8 
Safety F/U EOS8
+4. +8, +12 Weeks
Days
-14
1
7
14
28
42
84
126
154, 182, 210
In office SANDE score 
X
X
Corrected visual acuity
X
X
Slit lamp biomicroscopy X
X
X
X
X
X
X
Ocular hyperemia
X
X
X
X
X
X
Tear break-up time 
(TBUT)
X
X
X
X
Corneal fluorescein 
staining3
X
X
X
X
X
X
X
Conjunctival lissamine 
staining
X
X
X
X
X
X
X
Schirmer Tear Test
X
X
Intraocular Pressure 
(IOP)
X
X
X


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Period
Screening
Treatment
Post Treatment Follow-up 
Visit Name
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7/
EOT
Visit 8/ 
EOS8 
Safety F/U EOS8
+4. +8, +12 Weeks
Days
-14
1
7
14
28
42
84
126
154, 182, 210
Fundus exam
X
X
Randomization
X
Dispense study drug
X
X
X
X
X
In-office study drug 
administration
X
X
X
X
Adverse Events6
X
X
X
X
X
X
X
X
X
At home SANDE 
questionnaire (eDiary)7
X
X
X
X
X
X
Study completion 
information
X
X Assessment to be recorded in the clinical database or received electronically from a vendor
 
6 Adverse events will not be collected from the time the subject completes Part 1 until the subject confirms/signs consent for participation in Part 2


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Period
Screening
Treatment
Post Treatment Follow-up 
Visit Name
Visit 1
Visit 2
Visit 3
Visit 4
Visit 5
Visit 6
Visit 7/
EOT
Visit 8/ 
EOS8 
Safety F/U EOS8
+4. +8, +12 Weeks
Days
-14
1
7
14
28
42
84
126
154, 182, 210
7 Subjects will complete an electronic diary (at home SANDE questionnaire) once daily (in the evening before bed time and prior to the evening dose of study 
medication) from Visit 1 (Screening) through to the end of the treatment 
8 Post treatment follow up visits begin at Visit 8/EOS for ALL subjects.
 
 


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8.1
Screening
No subjects may be re-screened if they fail entry criteria for any reason other than required 
stabilization time frames for medications and/or medical history.
If a subject is enrolled and it is determined prior to the completion of Visit 1 that the subject did 
not meet criteria pertaining to:

duration of DED diagnosis;

time frame required for stabilization of chronic medications or therapies, time frames 
related to medical history or use of contact lenses
the subject will be screen failed and brought back at a later date to re-attempt the screening 
process once the proper time frames have been achieved.
In the case of re-screening, the subject will receive a new subject number and all screening 
assessments required at Visit 1 must be completed on the day of randomization, regardless if 
the assessments were conducted at the previous screening visit.
Re-screening is only allowed one time for a particular subject and per part of the study. Re-
screening must not be used as a method to force subject eligibility into the study.
For subjects requiring washout of prior medications or contact lenses, informed consent must 
be obtained prior to washout. Subject will be enrolled into the study and brought back for 
screening assessments (Visit 1) after the washout is completed.
8.1.1
Information to be collected on screening failures
Subjects who sign an ICF and 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 demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for screen failure subjects. No other data will be entered into the 
clinical database for subjects who are screen failures, unless the subject experienced a serious 
adverse event during the screening phase (see Section 10.1.3 for SAE reporting details). If the 
subject fails to be randomized, the IRT must be notified within 2 days of the screen fail and 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
Country specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF.
The following information will be collected/documented at screening visit for each subject:

Date of birth, age

Gender

Race/Ethnicity

Concomitant medications


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
Past relevant medical history and current medical conditions

Completed clinical assessments

Ocular assessment
8.3
Efficacy
The following assessments are included to evaluate the efficacy of ECF843:

Ocular hyperemia

Tear break-up time (TBUT)

Corneal fluorescein staining

Conjunctival lissamine staining
8.3.1
Ocular Hyperemia
The investigator will grade conjunctival bulbar redness. Both nasal and temporal inter-palpebral 
bulbar conjunctival regions will be graded according to the McMonnies redness photographic 
scale.
Figure 8-1
McMonnies Redness Photographic Scale
8.3.2
Tear Break-Up Time
For individual subjects, TBUT should be assessed by the same examiner at all time points, and 
must be measured immediately after instillation of the fluorescein dye if performed at that visit.
Fluorescein impregnated strips supplied by the sponsor will be used according to package 
instructions. One drop of sterile saline, or equivalent, will be applied to the tip of the strip. 
DO NOT use anesthetic drops to wet the strips. Immediately after application of the wetting 
drop to the strip, gently flick the excess drop off the end of the strip prior instilling the dye. A 
new strip should be used for each eye.
Immediately after instillation of the fluorescein, position the subject’s head in the headrest of 
the slit-lamp instrument and instruct the subject not to wipe or dab their eyes, and to gently 
blink 3 times (avoid forceful blinks), then stare and NOT BLINK. The Investigator will monitor 
the integrity of the tear film and, using a stopwatch, measure the time from the last blink until 
the first black (dry) spot appears in the precorneal tear film (record values to 2 decimal points).


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Repeat this procedure to obtain three consecutive TBUT measurements.
8.3.3
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. The right eye should be completed first, followed by the left 
eye.
At visits where TBUT is also done, instillation of the sodium fluorescein dye will have already 
occurred. As long as the corneal staining assessment is done within the specified time frame, 
no additional instillation of fluorescein dye is required. At visits where TBUT is not done, 
follow the same procedure as described above for instillation of fluorescein dye to each eye.
Staining will be assessed a minimum of 2.5 minutes and preferably less than 5 minutes after 
instillation of the dye. Evaluation of the cornea will be done through a slit lamp with use of a 
cobalt blue filter.
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).
A (+1) will be added to the sum score for any eye with the presence of filaments.
Figure 8-2
Corneal Fluorescein Modified NEI Scale


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8.3.4
Conjunctival Lissamine Staining
Conjunctival lissamine staining will be conducted by the Investigator and assessed after corneal 
fluorescein staining. For individual subjects, lissamine staining should be assessed by the same 
examiner at all visits using the same slit lamp and the same settings. The right eye should be 
completed first, followed by the left eye.
Lissamine impregnated strips supplied by the sponsor will be used according to package 
instructions. One drop of sterile saline, or equivalent, will be applied to the tip of the strip. 
DO NOT use anesthetic drops to wet the strips. Immediately after application of the wetting 
drop to the strip, gently flick the excess drop off the end of the strip prior instilling the dye. A 
new strip should be used for each eye.
The degree of staining is based on the Lissamine Conjunctival Oxford Staining Scale. The nasal 
and temporal conjunctival regions are assessed for interpalpebral lissamine conjunctival 
staining (the corneal region must not be assessed). Each of the two regions (as depicted in the 
diagram) will be graded on a scale of 0 to 5 (Figure 8-3). 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 = 10/eye).
Figure 8-3
Lissamine Conjunctival Oxford Staining Scale


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8.3.5
Appropriateness of efficacy assessments
The efficacy assessments included in this study for the evaluation of ocular signs and symptoms 
are commonly used in clinical research for DED and are accepted methods for evaluation of 
drugs for market authorization by the US FDA.
8.4
Safety
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed.
For details on AE collection and reporting, refer to Section 10 (Safety monitoring and reporting).
Table 8-3
Assessments & Specifications
Assessment
Specification
Corrected Visual 
Acuity
Qualified site personnel will conduct Snellen visual acuity testing in each eye separately 
per standard clinical practice and should precede any examination requiring 
administration of eye drops to dilate the eye or any examination requiring contact with the 
eye.
Subjects must use their standard prescribed correction or pin hole. No refraction will be 
conducted at the visit to determine best correction.
Slit Lamp Exam
The Investigator will perform a slit-lamp assessment of the anterior portion of the eye of 
both eyes before instillation of any diagnostic eye drops, including evaluation of the lids, 
cornea, conjunctiva, iris, anterior chamber, and lens.
Intraocular 
Pressure
Intraocular pressures will be measured in both eyes by a qualified technician and 
according to the study site’s regular practice. The same method must be used throughout 
the study for both eyes in each subject.
Fundus Exam
The Investigator will perform an ophthalmoscopic examination of the posterior segment of 
both eyes including the vitreous, retina, macula, choroid and optic nerve. Dilation can be 
performed at the Investigator's discretion.
8.4.1
Laboratory evaluations
Not Applicable.
8.4.2
Pregnancy
A urine pregnancy test will be conducted for all women of childbearing potential to assess 
pregnancy as indicated in the Schedule of Assessments.
Additional pregnancy testing might be performed if requested by local requirements.
8.4.3
Appropriateness of safety measurements
The safety assessments selected are standard for this indication/subject population.
8.5
Additional assessments
8.5.1
Clinical Outcome Assessments (COAs)


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Subject questionnaires should be completed in the language most familiar to the subject, and 
given sufficient time to complete the questionnaires truthfully and accurately.
For questionnaires completed by the subject in the clinic, the site personnel should check PRO 
measures for completeness and ask the subject to complete any missing responses. The 
responses that are stored electronically in the database will be considered the source file.
Completed measures and any unsolicited comments written by the subject should be reviewed 
and assessed by the investigator for responses which may indicate potential AEs or SAEs before 
any clinical study examinations. This assessment should be documented in study source records. 
If AEs or SAEs are confirmed, study investigators should not encourage the subject to change 
responses reported in the completed questionnaires. Study investigators must follow reporting 
instructions outlined in Section 10 (e.g. reference “Adverse Events” section) of the study 
protocol.
Site personnel should monitor a subject's compliance with completion of the daily diary. If the 
subject is not compliant with diary entries, the reason for the non-compliance should be 
determined and corrective efforts should be made. If the subject is repeatedly unable to comply 
with the daily diary requirements, the subject should be considered not appropriate for the study 
due to inability to follow protocol requirements, and should be discontinued.
8.5.2
Patient Reported Outcomes (PRO)
8.5.2.1.1 Symptom Assessment in Dry Eye (SANDE) Questionnaire
The SANDE questionnaire is completed through an electronic diary by the subject at the 
Screening Visit(s) of Part 1 and Part 2, and thereafter every evening before bedtime during the 
study. The SANDE uses a 100 mm visual analog sacle (VAS) and asks the subject to score 
frequency and severity of their ocular discomfort over the past 24 hours by putting a vertical
mark on two separate horizontal scoring lines. The frequency scoring line utilizes the anchors 
of 'Rarely' to 'All the Time', while the severity scoring line utilizes the anchors of 'Very Mildly' 
to 'Very Severely' uncomfortable. The overall SANDE score is calculated by taking the square 
root of the product of the frequency and severity scores.


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8.5.5.2
Unanesthetized Schirmer Test
 
 
Qualified site personnel will conduct the test with the subject seated in the examining chair with 
the room lights dimmed and their head against a headrest for comfort. Both eyes will be assessed 
simultaneously.

Prepare the strips while they are still in the package by folding the rounded end at the 
indentation.

Position the strips into the inferior cul-de-sac at the lateral third of the eyelid.

After inserting the strip into each eye, instruct the subject to gently close their eyes. The 
subject should avoid forceful lid closure.

Leave the strips in place for 5 minutes.

After 5 minutes, ask the subject to gently open their eyes. The study staff will remove the 
strip from the eye and immediately record the length of the strip that is wetted by the tears. 
The measurement should be made to the nearest whole number.


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9
Study discontinuation and completion
The investigator should discontinue study treatment for a given subject and/or withdraw the 
subject from the study if he/she believes that continuation would be detrimental to the subject's 
well-being, or that the subject is unable or unwilling to comply with protocol requirements.
A subject will be considered to have completed Part 1 of the study when the subject has 
completed the last visit planned for Part 1. The subject should NOT be discontinued from the 
study after Part 1 unless the subject withdraws informed consent, or is deemed not eligible for 
participation in Part 2 of the study. Subjects who discontinue the study in Part 1 will no longer 
be eligible for Part 2. 
For subjects who discontinue treatment but do not discontinue the study during Part 1, or for 
subjects who experience a treatment related AE or SAE, eligibility for Part 2 will be dependent 
on the reasons for treatment discontinuation or nature of the AE/SAE. The decision for 
participation in Part 2 will be at the discretion of the Investigator, with guidance from the 
Sponsor as needed.
The investigator and/or referring physician will recommend the appropriate follow-up medical 
care, if needed, for all subjects who are prematurely withdrawn from the study.
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 subjector the investigator
Discontinuation from study treatment is required under the following circumstances:

Subject/guardian decision

Pregnancy

Use of prohibited treatment as per recommendations in the prohibited treatment section (see 
Section 6.2.2)

Any situation in which continued study participation might result in a safety risk to the 
subject

Inability or unwillingness of the subject to follow the protocol requirements

Following emergency unblinding (see Section 6.6.3)

Adverse events that indicate a safety risk to the subject

Unsatisfactory therapeutic effect


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If discontinuation from study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the subject’s premature discontinuation of 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 study treatment discontinuation, at a minimum, in abbreviated visits, the following data 
should be collected at clinic visits or via telephone/email contact:

New / concomitant treatments

Adverse Events / Serious Adverse Events
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 section.
9.1.2
Discontinuation from study
Discontinuation from study is when the subjectpermanently 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
Withdrawal of informed consent
Subjects may voluntarily withdraw informed consent to participate in the study for any reason 
at any time. Withdrawal of informed 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 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 informed 
consent/opposition to use data/biological samples and record this information.
Where consent to the use of personal and coded data is not requiredin a certain country's legal 
framework, the subject therefore cannot withdraw informed consent. However, they still retain 
the right to object to the further collection or use of their personal data.


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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.
All efforts should be made to complete the assessments prior to study discontinuation. 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/Sponsor 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 informed consent withdrawal/opposition. No new Personal Data 
(including biological samples) will be collected following withdrawal of consent/opposition.
9.1.4
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without stating 
an intention to discontinue or withdraw, the investigator 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.
9.1.5
Early study termination by the sponsor
The study can be terminated by Novartis at any time for any reason. This may include reasons 
related to the benefit/ risk assessment of participating in the study, practical reasons (including 
slow enrollment), or for regulatory or medical reasons. 
In taking the decision to terminate, Novartis will always consider the 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 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 the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial.
9.2
Study completion and post-study treatment
Study completion is defined as when the last subject finishes the 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.
Once a subject completes the study in its entirety, no further study treatment will be made 
available to the subject.


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10
Safety monitoring and reporting
10.1
Definition of adverse events and reporting requirements
10.1.1
Adverse events
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a 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.


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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. 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 (i.e., blinded study medication [ECF843 vs Vehicle],as 
applicable). 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 if the event is ongoing, an outcome of not recovered/not 
resolved must be reported
4. whether it constitutes a SAE (see Section 10.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. action taken regarding with study treatment (i.e., blinded study medication [ECF843 vs 
Vehicle], as applicable)
6. its outcome
All adverse events must be treated appropriately. Treatment may include one or more of the 
following:

Dose not changed

Drug withdrawn
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 collection will be performed through the End of Study (EOS) visit.
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
the interventions required to treat it, and the outcome.
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 adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s), or medical conditions(s) which meets any one of the following 
criteria:


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
fatal

life-threatening
Life-threatening in the context of a SAE refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to a reaction that hypothetically might have 
caused death if it were more severe (ICH-E2D).

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 
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 (ICH-E2D).
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.
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred.
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 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.
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 


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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 Chief Medical Office and 
Patient Safety (CMO&PS) Department associate may urgently require further information from 
the investigator for health authority reporting. Novartis may need to issue an Investigator 
Notification (IN) to inform all investigators involved in any study with the same study treatment 
that this SAE has been reported.
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with 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 should only be reported to Novartis Safety if the 
investigator suspects a causal relationship to study treatment.
10.1.4
Pregnancy reporting
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 
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 to the ECF843 treatment to 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported.
10.1.5
Reporting of study treatment errors including misuse/abuse
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, subject or 
consumer (EMA definition).
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol.
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal product, 
which is accompanied by harmful physical or psychological effects.
Study treatment errors and uses outside of what is foreseen in the protocol will be recorded on 
the appropriate eCRF irrespective of whether or not associated with an AE/SAE and reported 
to Safety only if associated with an SAE. Misuse or abuse will be collected and reported in the 


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safety database irrespective of it being associated with an AE/SAE within 24 hours of 
Investigator’s awareness.
Table 10-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
CRF (Yes/No)
Document in AE eCRF
Complete SAE form
Unintentional study 
treatment error
Yes
Only if associated with an 
AE
Only if associated with an 
SAE
Misuse/Abuse
Yes
Yes
Yes, even if not 
associated with a SAE
For more information on AE and SAE definition and reporting requirements, please see 
Section 10.
10.2
Additional Safety Monitoring
Not Applicable
11
Data Collection and Database management
11.1
Data collection
All data should be recorded, handled, and stored in a way that allows its accurate reporting, 
interpretation, and verification.
Designated investigator staff will enter the data required by the protocol into the eCRFs. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
Code of Federal Regulations (CFR) Part 11 requirements, Investigator site staff will not be 
given access to the Electronic Data Capture (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 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 (or designated Contract Research Organization (CRO)) will review the data 
entered by investigational staff for completeness and accuracy. Electronic data queries stating 
the nature of the problem and requesting clarification will be created for discrepancies and 
missing values and sent to the investigational site via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes to the 
data.


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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 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 monitor. The 
code break functionality will remain available until study shut down or upon request of Novartis.
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked and the treatment codes will be unmasked and made 
available for data analysis/moved to restricted area to be accessed by independent programmer 
and statistician. 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 as detailed in the study-specific monitoring plan to check the 
completeness of subject records, the accuracy of data capture / data entry, the adherence to the 
protocol and to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the study monitor during these visits. Continuous remote 
monitoring of each site’s data may be performed by a centralized Novartis Trial Monitoring 
organization. Additionally, a central analytics organization may analyze data and identify risks 
and 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 eCRFs must be traceable to these source documents in the 
subject’s file. The investigator must also keep the original ICF signed by the subject (a signed 
copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the 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 eCRFs are performed according to the 


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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.
All the efficacy endpoints will be based on the study eye. Study eye is defined as the eye with 
the highest composite corneal staining score at baseline. If both eyes have equal composite 
corneal staining scores, then the right eye will be selected as the study eye. The safety analysis 
will be presented for both eyes.
12.1
Analysis sets
The analysis sets will be defined for Part 1 and Part 2, respectively.
Part 1:
The Full Analysis Set (FAS) 1 comprises all subjects to whom study treatment has been 
assigned by randomization in Part 1. 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 1 includes all subjects who received at least one dose of study treatment in Part 
1. 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.
Part 2:
The Full Analysis Set (FAS) 2 comprises all subjects to whom study treatment has been 
assigned by re- randomization in Part 2. 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 2 includes all subjects who received at least one dose of study treatment in Part 
2. Subjects will be analyzed according to the study treatment received, where treatment received 
is defined as the re-randomized treatment if the subject took at least one dose of that treatment 
or the first treatment received if the re-randomized treatment was never received.
12.2
Subject demographics and other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively by treatment group for FAS 1 and FAS 2, respectively.
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class and preferred term, by study part and treatment group.


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12.3
Treatments
The Safety set 1 and Safety Set 2 will be used for the analyses below, respectively. Categorical 
data will be summarized as frequencies and percentages. For continuous data, mean, standard 
deviation, median, 25th and 75th percentiles, minimum, and maximum will be presented.
The duration of exposure in days to ECF843 and vehiclewill be summarized by means of 
descriptive statistics.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized according to the Anatomical Therapeutic Chemical (ATC) 
classification system, by treatment group.
12.4
Analysis supporting primary objectives
The primary aim of the study is to demonstrate improvement in moderate to severe DED with 
ECF843. This will be evaluated by measuring signs and symptoms as primary estimands. The 
analysis of the primary estimands will be based on FAS 1.
12.4.1
Definition of primary endpoint(s)
The two primary endpoints are the change from baseline in SANDE symptom score and the 
change from baseline in composite corneal fluorescein staining score in Part 1.
12.4.2
Statistical model, hypothesis, and method of analysis
The primary objective of Part 1 of the study is to show that at least one ECF843 arm will 
improve SANDE symptom score and/or composite corneal fluorescein staining score in 
comparison with its corresponding vehicle (BID or TID) 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 SANDE symptom score in ECF843 arm and 
the corresponding vehicle arm.
H3: θT=θv vs. H4: θT≠θv
where θT and θv are mean change from baseline of composite corneal fluorescein staining score 
in ECF843 arm and the corresponding vehicle arm.
Hochberg method will be used to adjust overall type I error (0.05) among the comparisons 
between each ECF843 arm and its corresponding vehicle for each primary endpoint.
For SANDE symptom score, mixed model repeated measures (MMRM) will be used with 
change from baseline at all post-baseline score on treatment as response variable, and treatment,
day, randomization strata and baseline score as covariates. Two interaction term (treatment*day 
and baseline*day) will also be included in the model.
For composite corneal fluorescein staining score, MMRM will be used with change from 
baseline at all post-baseline visits on treatment as response variable, and treatment, visit, 
randomization strata and baseline score as covariate. Two interaction term (treatment*visit and 
baseline*visit) will also be included in the model.


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For both endpoints, 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. Residual/restricted maximum likelihood (REML) method will be used to 
estimate parameters.
The two-sided p value for the least square mean (LSM) difference between the ECF843 and the 
vehicle group at each post-baseline day/visit will be reported for the difference.
12.4.3
Handling of intercurrent events of primary estimand
The primary estimands will be the treatment effect of ECF843 against its corresponding vehicle, 
had subjects not taken artificial tears/gels/lubricants or prohibited medications as described in 
Section 6.2.2, and had they stayed on 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. The 
primary analysis will account for different IEs as following:
1. Use of artificial tears/gels/lubricants: For subjects who use artificial tears/gels/lubricants 
occasionally for rescue, the data on the day(s) will be excluded and treated as missing.
2. Use of prohibited medications:

For subjects who took ocular, nasal, inhaled, or systemic corticosteroids, intravitreal 
injections of any kind, the data on the day(s) + 3 days following the last day of prohibited 
medications will be excluded and treated as missing.

For subjects who took the following prohibited medications, 

Any topical ocular medications (prescription or over the counter; excluding IOP-
lowering medication)

Medical device treatments such as those used to treat Meibomian gland dysfunction 
(eg, LipiFlow, pulse light therapy, etc)

Punctal plugs or punctal cauterization

The data on the day(s) of prohibited medications will be excluded and treated as missing.
3. Discontinuation of study treatment for any reason: For subjects who discontinue study 
treatment, the data collected following the discontinuation will be excluded and treated as 
missing.
Missing data will be implicitly imputed under Missing at Random (MAR) assumption for 
MMRM analysis, that is missing data are imputed based on the treatment-specific information 
for the repeated measurements at baseline and post-baseline days/visits.
12.4.4
Handling of missing values not related to intercurrent event
For all analyses, imputation of intermittent missing observations before discontinuation from 
study treatment will be carried out following a MAR mechanism for all treatment arms.
12.4.5
Sensitivity analyses for primary estimand
Not applicable.


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12.4.6
Supplementary analysis
A supplementary clinical question of interest is: what is the effect of ECF843 versus vehicle on 
change from baseline in signs and symptoms after treatment in subjects with moderate to severe 
DED, regardless of discontinuation from study treatment for any reason,and regardless of use 
of artificial tears/gel/lubricants, or prohibited medications?
The supplementary estimands will be the difference between change from baseline in each 
primary endpoint for ECF843 vs corresponding vehicle, regardless of intercurrent events
(treatment policy).

Use of artificial tears/gels/lubricants: For subjects who use artificial tears/gels/lubricants 
occasionally for rescue, all observed data will be used for analysis. If not available, missing 
data on the days of the IEs will be multiple imputed under MAR assumption for both 
ECF843 and vehicle arms.

Use of prohibited medications: For subjects who take ocular, nasal, inhaled, or systemic 
corticosteroids, intravitreal injections of any kind, all observed data will be used for analysis. 
Missing data on the day(s) + 3 days following the last day of prohibited medications, if any,
will be multiple imputed under MAR assumption for both ECF843 arms and vehicle arms.

For subjects who take the following prohibited medications, 

Any topical ocular medications (prescription or over the counter; excluding IOP-lowering 
medication)

Medical device treatments such as those used to treat Meibomian gland dysfunction (eg, 
LipiFlow, pulse light therapy, etc)

IVT injections, punctal plugs or punctal cauterization

all observed data will be used for analysis. If not available, missing data on the days of the 
IEs will be multiple imputed under MAR assumption for both ECF843 arms and vehicle 
arms.

Discontinuation of study treatment 

For subjects who discontinue 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 multiple imputed based on J2R 
assumption for ECF843 arms and under MAR assumption for vehicle arms.

The supplementary analysis will be performed using MMRM but includes all the observed 
data and imputed data if appropriate.
Subgroup analyses
Subgroup analyses of the primary endpoints will be outlined in the statistical analysis plan 
(SAP). 
12.5
Analysis supporting secondary objectives
12.5.1
Efficacy and/or Pharmacodynamic endpoint(s)
For secondary endpoints, change from baseline in inferior and central corneal fluorescein 
staining, summary statistics (mean, median, 25th percentile, 75th percentile, standard deviation, 
minimum and maximum, the number of non-missing observations, and 95% confidence 


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interval) by treatment arm will be provided. A 95% confidence interval will be provided for the 
difference between the ECF843 arm vs. its corresponding vehicle at each post-baseline visit.
12.5.2
Safety endpoints
Safety analysis for Part 1 and Part 2 will be performed separately, based on respective safety 
set. All listings and tables will be presented by treatment group.
The safety analysis will consist of descriptive summaries. Continuous variables will be 
presented with n, mean, standard deviation, median, minimum and maximum. Categorical data 
will be displayed with frequency and percentage.
Adverse events
All information obtained on adverse events (ocular and non-ocular), 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.
Separate summaries will be provided for study medication related adverse events, death, serious 
adverse events, other significant adverse events leading to discontinuation.
The number (and proportion) of subjects with adverse events of special interest/related to 
identified and potential risks will be summarized by treatment.
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.
Adverse events which will be counted for a specific treatment period are those which are 
treatment-emergent. These events are those with an onset after the start of the treatment period, 
or which were present prior to the start of the treatment period but increased in severity, changed 
from being not suspected to being suspected of study drug relationship, or developed into SAEs 
after the start of the treatment period.


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12.7
Interim analyses
For Part 1, the primary analysis will be performed after all subjects in Part 1 have completed 
randomized treatment or discontinued prior to that. The analysis will be used to evaluate 
efficacy and safety of ECF843 vs. Vehicle. For Part 2, the primary analysis will be performed 
when all subjects in Part 2 have completed 12 weeks of treatment or discontinued treatment. 
The analysis will be used to explore efficacy and safety of ECF843 vs. vehicle after 12 weeks 
of treatment.
12.8
Sample size calculation
12.8.1
Primary endpoint(s)
Part 1 of the study is powered on 2 primary endpoints, change from baseline in SANDE 
symptom score and composite corneal fluorescein staining score.
In one previous rhLubricin clinical study (LUB0114MD) there was an observed standard 
deviation of 20 mm in change from baseline of SANDE score at Day 28. A second rhLubricin 
clinical study (LUB0115MD) showed a standard deviation of 23 mm in change from baseline 
in SANDE symptom score at Day 14.
Assuming a true treatment difference in change from baseline in SANDE symptom score of 10 
mm and a standard deviation of 23 mm, a sample size of 112 subjects per arm provides 
approximately 80% power that the primary analysis will be statistically significant at the two-
sided 5% significance level adjusted by 3 comparisons.
See the table below for power to detect a significant difference from vehicle under various 
assumed treatment effect of SANDE Symptom score and standard deviation.
Table 12-1
Power to Detect a Significant Difference from Vehicle
Treatment effect: difference from vehicle in change from baseline in SANDE 
Symptom Score
Standard 
deviation of 
change from 
baseline in 
SANDE 
symptom score
10
11
12
13
14
23
80%
88%
93%
97%
98%
25
72%
81%
88%
93%
96%
27
64%
74%
82%
88%
93%


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Assuming a true treatment difference in change from baseline in composite corneal fluorescein 
staining of 1 and a standard deviation of 1, a sample size of 112 subjects per arm provides more 
than 99% power that the primary analysis will be statistically significant at the two-sided 5% 
significance level adjusted by 3 comparisons.
nQuery Advisor 8.4 is used for the estimate.
12.8.2
Secondary endpoint(s)
There are no power considerations for secondary endpoints.
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 International Council for Harmonisation (ICH) Harmonized Tripartite Guidelines for 
Good Clinical Practice, with applicable local regulations (including European Directive 
2001/20/EC, US CFR 21), and with the ethical principles laid down in the Declaration of 
Helsinki.


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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 ICF, consent form updates, subject recruitment procedures (e.g. advertisements) and 
any other written information to be provided to subjects. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Quality Assurance representatives, designated agents of Novartis, IRBs/IECs, and 
regulatory authorities as required. If an inspection of the clinical site is requested by a regulatory 
authority, the investigator must inform Novartis immediately that this request has been made.
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 


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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.
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.


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15
References
References are available upon request
Cheriyan T, Schmid TM, Spector M (2011) Presence and distribution of the lubricating 
protein, lubricin, in the meibomian gland in rabbits. Mol. Vis.; 17:3055-61.
Craig JP, Nelson JD, Azar DT, et al (2017a) TFOS DEWS II Report Executive Summary. 
Ocul Surf; 15:802-812.
Craig JP, Nichols KK, Akpek EK, et al (2017b) TFOS DEWS II Definition and Classification 
Report. Ocul Surf; 15:276-283.
Gleghorn JP, Jones AR, Flannery CR, et al (2009) Boundary mode lubrication of articular 
cartilage by recombinant human lubricin. J. Orthop. Res.; 27:771-7.
Hamm-Alvarez SF, Janga SR, Edman MC, et al (2014) Tear cathepsin S as a candidate 
biomarker for Sjögren's syndrome. Arthritis & Rheumatology; 66:1872-81.
ICH E2D (2004) Clinical Safety Data Management: Definitions and Standards for Expedited 
Reporting. London, UK.
Jones AR, Flannery CR (2007) Bioregulation of lubricin expression by growth factors and 
cytokines. Eur Cell Mater; 13:40-5; discussion 45.
Keating GM (2017) Lifitegrast Ophthalmic Solution 5%: A Review in Dry Eye Disease. 
Drugs; 77:201-8.
Mandal A, Gote V, Pal D, et al (2019) Ocular Pharmacokinetics of a Topical Ophthalmic 
Nanomicellar Solution of Cyclosporine (Cequa®) for Dry Eye Disease. Pharm. Res.; 36:36.
McDonald M, Patel DA, Keith MS, et al (2016) Economic and Humanistic Burden of Dry 
Eye Disease in Europe, North America, and Asia: A Systematic Literature Review. Ocul Surf; 
14:144-67.
O'Neil EC, Henderson M, Massaro-Giordano M, et al (2019) Advances in dry eye disease 
treatment. Curr Opin Ophthalmol; 30:166-78.
Regmi SC, Samsom ML, Heynen ML, et al (2017) Degradation of proteoglycan 4/lubricin by 
cathepsin S: Potential mechanism for diminished ocular surface lubrication in Sjögren's 
syndrome. Exp. Eye Res.; 161:1-9.
Rhee MK, Mah FS (2017) Clinical utility of cyclosporine (CsA) ophthalmic emulsion 0.05% 
for symptomatic relief in people with chronic dry eye: a review of the literature. Clin 
Ophthalmol; 11:1157-1166.
Samsom ML, Morrison S, Masala N, et al (2014) Characterization of full-length recombinant 
human Proteoglycan 4 as an ocular surface boundary lubricant. Exp. Eye Res.; 127:14-9.
Schmidt TA, Sullivan DA, Knop E, et al (2013) Transcription, translation, and function of 
lubricin, a boundary lubricant, at the ocular surface. JAMA Ophthalmol; 131:766-76.
Yu J, Asche CV, Fairchild CJ (2011) The economic burden of dry eye disease in the United 
States: a decision tree analysis. Cornea; 30:379-87.


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16
Appendices
None

SAP_001.pdf: 
Clinical Development 
ECF843 
CECF843A2201 / NCT04391894
A randomized, double-masked, multicenter study to 
evaluate the safety and efficacy of ECF843 vs Vehicle in 
subjects with dry eye disease 
Statistical Analysis Plan (SAP) 
Author: 
 
Document type: 
SAP Documentation 
Document status: 
Final V2.0 
Release date: 
09-Jun-2021
Number of pages: 
37 
Property of Novartis 
For business use only 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
For business use only 
Page 2 
SAP 
 
CECF843A2201 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for update 
Outcome for 
update 
Section and title 
impacted (Current) 
28-
Sep-
2020 
Prior 
to DB 
lock 
Creation of final version 
NA  
First version 
(V1.0) approved in 
Documentum 
system. 
NA 
09-
Jun-
2021 
Prior 
to DB 
lock 
Creation of amendment -1 
• Aligned with protocol 
amendment dated on 31-Mar-
2021 
Updated to 
version V2.0 
Section 1.1,  
Section 2.1, 2.4, 2.5, 
2.6, 2.7, 2.8, 2.11, 
2.13, 2.14 
Section 3 and 5 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 6 
1.1 
Study design ............................................................................................................ 6 
1.1.1 
Part 1 ....................................................................................................... 6 
1.1.2 
Part 2 ....................................................................................................... 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 10 
2.2 
Analysis sets .......................................................................................................... 13 
2.2.1 
Subgroup of interest .............................................................................. 14 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 14 
2.3.1 
Subject disposition ................................................................................ 14 
2.3.2 
Demographics and baseline characteristics ........................................... 14 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 15 
2.4.1 
Study treatment / compliance ................................................................ 15 
2.4.2 
Prior, concomitant and post therapies ................................................... 15 
2.5 
Analysis of the primary objective .......................................................................... 17 
2.5.1 
Primary endpoints ................................................................................. 17 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 19 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 20 
2.5.4 
Supportive analyses ............................................................................... 20 
2.6 
Analysis of the key secondary objective ............................................................... 21 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 21 
2.7.1 
Secondary endpoints ............................................................................. 21 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 21 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 22 
2.8 
Safety analyses....................................................................................................... 22 
2.8.1 
Adverse events (AEs) ............................................................................ 22 
2.8.2 
Deaths .................................................................................................... 23 
2.8.3 
Laboratory data ..................................................................................... 23 
2.8.4 
Other safety data ................................................................................... 23 
2.9 
Pharmacokinetic endpoints .................................................................................... 24 
2.10 
PD and PK/PD analyses ........................................................................................ 24 


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2.11 
Patient-reported outcomes ..................................................................................... 24 
 
 24 
 
 24 
2.13 
Other Exploratory analyses.................................................................................... 25 
 
 25 
2.14 
Interim analysis ...................................................................................................... 25 
3 
Sample size calculation ..................................................................................................... 26 
3.1 
Primary endpoints(s) .............................................................................................. 26 
3.1.1 
SANDE symptom scores....................................................................... 26 
3.1.2 
Composite corneal fluorescein staining score ....................................... 26 
3.2 
Secondary endpoint(s) ........................................................................................... 27 
 
 27 
4 
Change to protocol specified analyses .............................................................................. 27 
5 
Appendix ........................................................................................................................... 28 
5.1 
Imputation rules of missing dates .......................................................................... 28 
5.1.1 
AE date imputation ............................................................................... 28 
5.1.2 
Concomitant medication date imputation ............................................. 29 
5.2 
Statistical models ................................................................................................... 31 
5.2.1 
Primary analysis .................................................................................... 31 
5.2.2 
Supplementary Analysis ........................................................................ 32 
5.3 
Rule of exclusion criteria of analysis sets.............................................................. 33 
5.4 
Exclusion of subjects with data issue of conjunctival lissamine staining from 
analysis .................................................................................................................. 36 
5.5 
Handling of subject with incorrect randomization stratum ................................... 37 
6 
Reference ........................................................................................................................... 37 


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List of abbreviations 
AE 
 
Adverse event 
 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BID 
bis in diem/twice a day 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DMC 
DED 
Data Monitoring Committee 
Dry Eye Disease  
FAS 
Full Analysis Set 
Ecrf 
IE 
Electronic Case Report Form 
Intercurrent event 
IVR 
Interactive Voice Response 
IWR 
J2R 
MAR 
Interactive Web Response 
Jump to Reference 
Missing at Random 
MedDRA 
MMRM 
Medical Dictionary for Drug Regulatory Affairs 
Mixed Model Repeated Measurement 
NCI 
National Cancer Institute 
o.d. 
Once Daily 
OS 
Overall Survival 
PFS 
Progression-Free Survival 
PK 
Pharmacokinetics 
PPS 
Per-Protocol Set 
PRO 
Patient-reported Outcomes 
qd 
Qua’que di’e / once a day 
QoL 
Quality of Life 
RAP 
RDO 
Report and Analysis Process 
Retrieved drop-out 
SAP 
SANDE 
Statistical Analysis Plan 
Symptom Assessment in Dry Eye  
SOC 
System Organ Class 
TFLs 
TID 
Tables, Figures, Listings 
ter in die/three times a day 
WHO 
World Health Organization 
 
 
 


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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 CECF843A2201. 
Data will be analyzed according to the data analysis plan described in this document that will 
be incorporated into Section 9.7 and Appendix 16.1.9 of the CSR.   
1.1 
Study design 
The study will be conducted in 2 parts: Part 1 – efficacy and safety of ECF843 vs vehicle, 
followed by Part 2 – additional exploratory assessments of ECF843 vs Vehicle (Figure 1-1). 
Figure 1-1 
Study design in protocol 
 
1.1.1 
Part 1 
Part 1 uses a double-masked design where subjects will be randomized to receive twice a day 
(BID) or three times a day (TID) treatment with either ECF843 or vehicle for 56 days. For 
subjects randomized to active ECF843, the maximum drug exposure will be up to 28 days. 
Approximately 800 subjects will be enrolled into the Part 1 of the study. 
There is an additional level of masking which includes the selection of subjects that will be 
included in the primary efficacy analysis of the study. The criteria for selection of these subjects 
is pre-defined but is not disclosed to the Investigator nor the subject to avoid the selection bias 
and regression effects that have been observed in many historical dry eye studies. The criteria 
for selection of subjects into the primary analysis are within the guidelines of the stated entry 
criteria for the study in order to protect against any unintended risk to the subject. In order to 
preserve this level of masking, and to allow for exploration of differences in treatment outcomes 


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between the population of subjects who are selected vs those that are not, all subjects will 
remain in the study for the full treatment period. 


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No interim analyses will be performed in Part 1. 
1.1.2 
Part 2 
There will be a database lock after all subjects have completed their participation in Part 1 of 
the study. The data will be analyzed to determine the efficacy and safety of ECF843 vs vehicle 
and selection of the optimal concentration and posology. Part 2 will be initiated only if safety 
and efficacy of at least one concentration and dosing frequency of ECF843 during Part 1 is 
demonstrated. Only subjects assigned to vehicle treatment in Part 1 may be eligible to 
participate in Part 2 of the study.  
Between the end of the subject's participation in Part 1 and the beginning of participation in 
Part 2, subjects will be treated as needed and according to Investigator judgement.  
Subjects will again be asked to sign the informed consent form in order to participate in Part 2 
and will be re-screened to determine continued eligibility. If the subject meets all entry criteria, 
the subject may be randomized to receive either ECF843, at the concentration and posology 
selected from Part 1, or Vehicle at the same selected posology at a 3:1 ratio for 84 days of 
treatment. Enrollment for Part 2 of the study will be discussed between the Investigator and the 
Sponsor prior to initiating screening visits.  
Screening: Subjects will be screened for eligibility at Part 2 Visit 1. 
Run-in period:  Screened subjects will enter a 14-day vehicle run-in period after screening.  
Randomization: At Part 2 Visit 2 (baseline), subjects must screen for eligibility criteria at Visit 
2 again. Only eligible subjects will be randomized into the study treatment. The randomization 
will be stratified by subjects with a documented diagnosis of Sjogren's syndrome (yes/no).  
Subjects will be equally randomized to study treatment.  


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Treatment period: The randomized subjects will begin 12 weeks study treatment after 
randomization.  They will attend the following study visits after baseline for treatment: at Day 
7, Day 14, Day 28, Day 42 and Day 84. Day 84 is the time point for primary analysis. 
Part 2 is double-masked and exploratory. No interim analyses will be performed in Part 2. 
 
1.2 
Study objectives and endpoints 
Table 1-2 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary 
objective(s) 
Part 1: To demonstrate superiority of ECF843 versus 
vehicle for improvement in dry eye related ocular symptoms 
and ocular surface damage 
• Change from baseline in 
Symptom Assessment in Dry Eye 
(SANDE) score 
• Change from baseline in 
composite corneal fluorescein 
staining score  
Secondary objective(s) 
Endpoint(s) for secondary 
objective(s) 
Part 1: To evaluate the improvement of ECF843 vs vehicle 
in corneal damage by quadrant  
• Change from baseline in inferior 
and central corneal fluorescein 
staining  
Part 1: To evaluate the safety of ECF843 vs Vehicle 
• Incidence and severity of ocular 
and non-ocular adverse events  


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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  
The general definitions list below apply to both Part 1 and Part 2 unless otherwise specified. 
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: 
Part 1:  
• ECF843 0.45mg/ml, TID 
• ECF843 0.15mg/ml, TID 
• Vehicle, TID 
• ECF843 0.15mg/ml, BID 
• Vehicle, BID 
Part 2: 
• ECF843 (concentration and dosing posology to be determined from Part 1) 
• Vehicle (the same selected posology as ECF843) 
2.1.1.2 
Date of the first administration of randomized study treatment 
 
The date of the first administration of randomized study treatment refers to:  
• In Part 1, it is the date subjects receive the first dose of actually randomized study 
treatment 
  
• In Part 2, it is the date subjects receive the first dose of of randomized treatment at Visit 
2 (first exposure date from ‘study treatment’ eCRF). 
 
 


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2.1.1.3 
Baseline and post-Baseline 
The baseline value for efficacy and safety variables is the last available value collected prior to 
or on the first administration of randomized study treatment 
. Missing 
baseline data will not be imputed. 
All data collected after the first administration of randomized study treatment are 
defined as post-baseline assessments.  
2.1.1.4 
Study day 
The study day for a baseline or post-baseline scheduled or unscheduled visit is defined as 
Study day = (Date of visit) – (Date of the first administration of randomized study treatment) + 
1. 
The study day for a scheduled or unscheduled visit before baseline is defined as  
Study day = (Date of visit) – (Date of the first administration of randomized study treatment).
 
 
2.1.1.5 
End of study/end of randomized treatment 
The end of study date (from ‘Study disposition’ CRF) is the date when a subject completes or 
discontinues the study.  
 
 
 
In Part 2, the end of treatment date (from ‘Treatment disposition’ CRF) is the date of the last 
study treatment prior to/on the end of study date. This value must be compared to the "last 
exposure date"(“Study treatment” eCRF). In case of different dates, the earlier will be used as 
treatment end date. 
For reporting data by visit in outputs, visit window rules will be applied based on study day to 
allocate assessments to the actual (reported) visit number (Section 2.1.1.7). 
2.1.1.6 
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. 
 


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2.1.1.7 
Visit Windows 
Visit windows will be applied for all measurements except SANDE scores. Only one SANDE 
per day within a programmed window (5:00pm -11:59pm) can be entered into eDiary. If the 
subject does not complete the assessment within this window, the SANDE score will be missing 
for that day. 
Table 2-1 
Part 1: Allocation of assessments to analysis visit window 
Scheduled 
main visit 
name 
Target study 
day 
Analysis visit 
window in study  
days 
Visit Label 
Visit 1(D1) 
Visit 2(D14) 
Visit 3(D28) 
Visit 4(D42) 
Visit 5(D56) 
Table 2-2 
Part 2: Allocation of assessments to analysis visit window 
Scheduled 
main visit 
name 
Target study 
day 
Analysis visit 
window in study  
days 
Visit Label 
Visit 1(D-14) 
-14 
≤ -1 
Screening 
Visit 2(D1) 
1 
1 
Baseline 
Visit 3(D7) 
7 
2 − 11 
Day 7 
Visit 4(D14) 
14 
12 − 21 
Day 14 
Visit 5(D28) 
28 
22 − 35 
Day 28 
Visit 6(D42) 
42 
36 − 63 
Day 42 
Visit 7(D84) 
84 
≥ 63 
Day 84 
For both Part 1 and Part 2: 
• 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. 


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2.1.1.8 
Change from baseline for continuous parameters 
Change from baseline will only be summarized for subjects with both baseline and post-
baseline values and 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. 
2.1.1.9 
Study eye 
Study eye is defined as the eye with the highest composite corneal staining score at baseline. If 
both eyes have equal composite corneal staining scores, then the right eye will be selected as 
the study eye. The other eye will be fellow eye. All the efficacy endpoints will be based on the 
study eye if laterality applies. The safety analysis will be presented for both eyes.   
 
2.2 
Analysis sets 
Part 1 
• The All Enrolled Set 1 (ENS1) includes all subjects who signed informed consent for Part 
1. This analysis set will be used to summarize patient disposition. 
• The Full Analysis Set 1 (FAS1) comprises all subjects
 
 
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.  
FAS1 will be used for all efficacy analyses, unless otherwise stated. 
• The Safety Set 1(SAF1) includes 
 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 actual 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. 
 
 
 
Part 2 
• The All Enrolled Set 2 (ENS2) includes all subjects who signed informed consent for Part 
2. This analysis set will be used to summarize patient disposition. 
• The Full Analysis Set 2 (FAS2) comprises all subjects to whom study treatment has been 
assigned by re-randomization in Part 2. 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 2 (SAF2) includes all subjects who received at least one dose of study 
treatment in Part 2. Subjects will be analyzed according to the study treatment received, 


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where treatment received is defined as the re-randomized treatment if the subject took at 
least one dose of that treatment or the first treatment received if the re-randomized treatment 
was never received. 
 
Rules of exclusion criteria of analysis sets with protocol deviations and subject classification 
are specified in Appendix 5.3. Rule of exclusion of subjects for analysis are specified in 
Appendix 5.4. 
2.2.1 
Subgroup of interest 
The subgroups of interest are specified below: 
• Baseline age group: < 65 years, and >=65 years 
• Sex: male, female 
• Documented diagnosis of Sjogren's syndrome: yes, no 
• Race: asian, non-asian 
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 table will be reported for ENS1 and ENS2.
 
 
 
In addition, the number and percentage of subjects who completed the study, discontinued from 
the randomized treatment/study by the reason of discontinuation, will be summarized by 
treatment and total.  Percentages will be based on the number of subjects in FAS1 and FAS2. 
 
Subjects who prematurely discontinue the randomized study treatment (treatment period) will 
be listed along with the reason for discontinuation.  
 
In addition, protocol deviations (PDs) will be summarized through presenting the number and 
percentage of subjects with each deviation for FAS1 and FAS2. 
2.3.2 
Demographics and baseline characteristics 
 
Demographic table will include age, sex, race, ethnicity, ancestry, eye color, Sjögren's 
Syndrome status.  
 
Baseline characteristics table will include:  
• SANDE score 


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• conjunctival lissamine staining score 
• corneal fluorescein staining score 
• intraocular pressure (IOP) 
• tear break-up time (TBUT) average score 
• schirmer score 
• conjunctival redness 
 
Demographic and baseline characteristics will be summarized for FAS1 and FAS2 populations 
by treatment group for study eye.  
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented.  
Relevant medical histories and current medical conditions at baseline will be summarized by 
system organ class, preferred term and treatment group separately for ocular and non-ocular 
histories/conditions. 
2.4 
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance) 
 
The SAF 1 and SAF 2 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 randomized 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 randomized study treatment (end of treatment date) – date of first 
administration of randomized study treatment +1 (Section 2.1.1.1). 
 
Compliance will be presented by summarizing the total number of days with missing dose or 
dose interrupted within the randomized treatment period by treatment group. Reason of 
premature discontinuation from the randomized 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 
randomized study treatment (Section 2.1.1.2). Any medication given at least once between the 
day of the first administration of the study treatment and the EORT Visit will be a concomitant 
medication, including those that were started pre-baseline visit and continued into the treatment 
period. Post therapies are defined as drugs taken after EORT Visit, including those taken prior 
to EORT Visit and continued until the end of study. Prior, concomitant medication and post 
therapies will be identified based on recorded or imputed start and end dates of taking the 
medication. 


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Prior, concomitant medication or post therapies 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 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. 
2.4.2.1 
Rescue medication 
The number and percentage of subjects who received artificial tears/gels/lubricants for 
occasional rescue use during treatment period will also be summarized by treatment group.  
2.4.2.2 
Prohibited medication  
Moreover, concomitant medications that are prohibited as per protocol (Table 2-3) during the 
conduct of the study will be summarized specifically. The number and percentage of subjects 
who used prohibited medications during treatment period will be summarized by treatment 
group.  
Table 2-3 
 
Prohibited medication  
Medication 
Prohibition period 
Action taken 
Ocular, nasal, inhaled, or 
systemic corticosteroids 
During the study 
Do not discontinue study 
treatment but document use of 
the product in the eCRF 
Any topical ocular medications 
(prescription or over-the-
counter; excluding IOP-
lowering medication) 
During the study 
Do not discontinue study 
treatment but document use of 
the product in the eCRF 
If the addition of a medication 
is needed for treatment of an 
adverse event, the decision to 
discontinue study treatment will 
be made by the Investigator 
and Sponsor based on the 
relevance and duration of the 
prohibited treatment 
Intravitreal injections of any 
kind 
During the course of the study 
Do not discontinue study 
treatment, but document use of 
the product in the eCRF 
If the addition of a medication 
is needed for treatment of an 
adverse event, the decision to 
discontinue study treatment will 
be made by the Investigator 
and Sponsor based on the 
relevance and duration of the 
prohibited treatment 


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Medication 
Prohibition period 
Action taken 
Medical device treatments such 
as those used to treat 
Meibomian gland dysfunction 
(e.g., LipiFlow, pulse light 
therapy, etc.) 
During the study 
Discontinue study treatment 
Punctal plugs or punctal 
cauterization 
Placement of new occlusion 
during the course of the study 
Discontinue study treatment 
 
2.5 
Analysis of the primary objective 
The primary aim of the study is to demonstrate improvement in moderate to severe DED with 
ECF843. This will be evaluated by measuring signs and symptoms as primary estimands.  
The symptoms measure of SANDE questionnaire is completed through an electronic diary 
every evening before bedtime during the study. The signs measure of corneal fluorescein 
staining will be conducted by the Investigator during site visits based on the Corneal Fluorescein 
Modified NEI Scale.  
 
For the purpose of the statistical analyses presented in this document, the following 
terminology is used: 
• Jump to Reference (J2R) – the multiple imputation model will be build based on the 
available vehicle data (including partial information from patients that discontinued 
prematurely). The imputation model will include important background characteristics 
and observed data.  
• Missing at Random (MAR) – the multiple imputation model will be build based on 
similar patients (i.e. with the same covariates and observed measurement history) in the 
same treatment arm. 
• Retrieved drop-out (RDO) patients - Patients who discontinue study treatment and 
decide to remain in the study by following an abbreviated schedule of assessments. 
• 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.) 
2.5.1 
Primary endpoints 
The primary clinical question of interest is: What is the effect of ECF843 versus its 
corresponding vehicle on change from baseline in signs and symptoms after treatment in 
subjects with moderate to severe DED, had they not taken occasional rescue use of artificial 
tears/gels/lubricants, prohibited medications and behaved like other subject who did not take 
them, had they not dicontinued treatment and behaved like other subjects who did not 
discontinue treatment? 
The justification for the primary estimands is that they will capture the effect of the study drug 
when administered without confounding effects from prohibited medications ，occasional 


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rescue use of artificial tears/gels/lubricants, and adjusting for  unfavorable outcome treatment 
discontinuation  
The analysis of the primary estimands will be based on FAS 1.   
The primary estimand is defined as follows for signs and symptoms: 
• The target population is subjects with moderate to severe DED  who meet the inclusion 
and exclusion criteria 
.  
• The primary endpoints are the change from baseline in SANDE score and change from 
baseline in composite corneal fluorescein staining score 
 
• The treatment of interest is ECF843 versus vehicle had they not needed occasional rescue 
use of artificial tears/gels/lubricants, prohibited medications and behaved like other subjects 
who did not take them, and had they not dicontinued treatment and behaved like other 
subjects who did not discontinue treatment.    
Table 2-4 
The handling of intercurrent events strategy for primary estimands 
Intercurrent Events 
Strategy 
Artificial tears/gels/lubricants for occasional 
rescue use 
• 
The data on the days will be excluded 
and treated as missing. 
• 
Missing data will be  under MAR 
assumption in MMRM 
Prohibited medications that could confound the 
primary endpoint (See Table 2-3) 
• 
Ocular, nasal, inhaled, or systemic 
corticosteroids 
• 
Intravitreal injections of any kind 
• 
The data on the day(s) + 3 days 
following the last day of these 
prohibited medications will be excluded 
and treated as missing. 
• 
Missing data will be  under MAR 
assumption in MMRM 
• 
Any topical ocular medications 
(prescription or over the counter; 
excluding IOP-lowering medication) 
• 
Medical device treatments such as 
those used to treat Meibomian gland 
dysfunction (eg, LipiFlow, pulse light 
therapy, etc) 
• 
Punctal plugs or punctal cauterization 
• 
The data on the days of prohibited 
medications will be excluded and 
treated as missing. 
• 
Missing data will be under MAR 
assumption in MMRM 
Discontinuation of study treatment  
• 
The data after study treatment 
discontinuation will be treated as 
missing. 
• 
Missing data after study treatment 
discontinuation will be based on the 
MAR assumption in MMRM 
 
• The summary measure is the treatment difference of the variable means between 
ECF843 and vehicle within each dose regimen (BID or TID) respectively. 
• 
ECF843 0.45mg/ml, TID vs ECF843 vehicle, TID 
• 
ECF843 0.15mg/ml, TID vs ECF843 vehicle, TID 


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• 
ECF843 0.15mg/ml, BID vs ECF843 vehicle, BID 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary objective of Part 1 of the study is to show that at least one ECF843 arm will 
improve SANDE symptom score and/or composite corneal fluorescein staining score in 
comparison with its corresponding vehicle (BID or TID) 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 SANDE symptom score in ECF843 arm and 
the corresponding vehicle arm.  
H3: θT = θv  vs. H4: θT ≠ θv 
where θT and θv are mean change from baseline of composite corneal fluorescein staining score 
in ECF843 arm and the corresponding vehicle arm.  
Hochberg method will be used to adjust overall type I error (α = 0.05) among the comparisons 
between each ECF843 arm and its corresponding vehicle for each primary endpoint.  
• 
For SANDE symptom score, mixed model repeated measures (MMRM) will be used with 
change from baseline at all post-baseline scores 
 on randomized study 
treatment as response variable, and treatment, day, randomization strata and baseline score 
as covariates. Two interaction term (treatment*day and baseline*day) will also be included 
in the model.  
• 
For composite corneal fluorescein staining score, MMRM will be used with change from 
baseline at all post-baseline visits 
 on randomized study treatment as response 
variable, and treatment, visit, randomization strata and baseline score as covariate. Two 
interaction term (treatment*visit and baseline*visit) will also be included in the model.  
For composite corneal fluorescein staining score, 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 (AR1)  and Compound symmetry will be applied, in the specified order, until 
the model converges.  
For SANDE symptom score, Toeplitz within subject correlation structure will be used for 
covariance matrix.  If the Toeplitz covariance matrix results in a lack of convergence then other 
covariance structures will be investigated: First-order autoregressive (AR1)  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. 
Residual/restricted maximum likelihood (REML) method will be used to estimate parameters.  
The two-sided p values for the least square mean (LSM) difference between the ECF843 and 
corresponding vehicle group 
 will be reported for primary inference.Line 
plots (LSM ± 1 SE) will be presented by treatment groups and post-baseline day/visit. The x-
axis will be study day/visit and the y-axis will be the change from baseline value. 


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2.5.3 
Handling of missing values/censoring/discontinuations 
 
For other missing values not related to intercurrent event, the primary MMRM model 
implicitly imputes missing data under a MAR assumption.  
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. 
The summary statistics (mean, median, 25th percentile, 75th percentile, standard deviation, 
minimum and maximum, the number of non-missing observations, and 95% confidence interval) 
for change from baseline in SANDE symptom score and composite  corneal fluorescein staining 
will be provided by treatment group for each post-baseline visit 
 
.  
Line plots with error bar (mean ± 1 SE) will be presented by treatment groups and all post-
baseline visits 
. Subgroup summary and plot will also be presented. 
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 ECF843, regardless of occasional rescue use of artificial 
tears/gels/lubricants , prohibited medications and treatment discontinuations.  
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 2-5 
The handling of intercurrent events strategy for supplementary 
estimand 
Intercurrent Events 
Strategy 
Artificial tears/gels/lubricants for occasional 
rescue use 
• 
All observed data will be used for 
analysis 
• 
Missing data on the days of IEs, if any, 
will be multiple imputed under MAR 
assumption 
Prohibited medications that could confound the 
primary endpoint (See Table 2-3) 
• 
Ocular, nasal, inhaled, or systemic 
corticosteroids 
• 
All observed data will be used for 
analysis 


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Intercurrent Events 
Strategy 
• 
Intravitreal injections of any kind 
• 
Missing data on the days of IEs + 3 
days, if any, will be multiple imputed 
under MAR assumption 
• 
Any topical ocular medications 
(prescription or over the counter; 
excluding IOP-lowering medication) 
• 
Medical device treatments such as 
those used to treat Meibomian gland 
dysfunction (eg, LipiFlow, pulse light 
therapy, etc) 
• 
Punctal plugs or punctal cauterization 
• 
All observed data will be used for 
analysis 
• 
Missing data on the days of IEs, if any, 
will be multiple imputed under MAR 
assumption 
Discontinuation of study treatment 
• 
RDO data collected after study 
treatment discontinuation will be used 
for analysis. 
• 
Missing data after the treatment 
discontinuation, if any, will be multiple 
imputed based on J2R assumption for 
the ECF843 arms and under MAR 
assumption for vehicle arms 
 
2.5.4.2 
Sensitivity Analysis 
 
Not applicable.  
2.6 
Analysis of the key secondary objective 
There is no key secondary objective in either Part 1 or Part 2 of the study. 
2.7 
Analysis of secondary efficacy objective(s) 
2.7.1 
Secondary endpoints 
The second efficacy objective is to evaluate the improvement of ECF843 vs vehicle in corneal 
damage by quadrant. The analysis of the secondary endpoints will be based on FAS 1.   
• Change from baseline in central corneal fluorescein staining 
 
• Change from baseline in inferior corneal fluorescein staining 
 
• Change from baseline in tear breakup time (TBUT) 
 
• Change from baseline in conjunctival lissamine staining score 
 
2.7.2 
Statistical hypothesis, model, and method of analysis 
No statistical hypothesis test will be performed. The summary statistics (mean, median, 25th 
percentile, 75th percentile, standard deviation, minimum and maximum, the number of non-
missing observations, and 95% confidence interval) for change from baseline in inferior and 


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central corneal fluorescein staining will be provided by treatment group for each post-baseline 
visit.  
A 95% confidence interval will be provided for the difference between the ECF843 arm and its 
corresponding vehicle at each post-baseline visit. 
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 
 
Safety analyses for Part 1 and Part 2 will be based on SAF1 and SAF2, respectively.  All 
listings and tables will be presented by treatment group.   
 
 
 
Safety analyses 
 will be based on ESS1 and will be presented by dosing 
posology (TID and BID). The reporting will include all the data from 
 
 until the end of the study.  The baseline value for all safety endpoints in ESS1 is the 
last available value collected prior to or on the first administration 
. 
The safety analysis will consist of descriptive summaries. Continuous variables will be 
presented with n, mean, standard deviation, median, minimum and maximum. Categorical data 
will be displayed with frequency and percentage.  
Adeverse Events will be reported at subject level and other safety endpoints will be reported 
for each eye. 
2.8.1 
Adverse events (AEs) 
 
In Part 1, AEs  will be summarized for TEAE, pre-treatment AE and post-treatment AE 
separately. 
1. Pre-treatment AEs are adverse events started between ICF signature and prior to the first 
administration of randomized study treatment. 
2. Treatment emergent adverse events (TEAEs) are adverse events started after the first 
administration of randomized study treatment or events present prior to start of the 
randomized treatment but increased in severity based on preferred term. 
3.  Post-treatment AEs are adverse events started after the last administration of randomized 
study treatment to the end of the study. 
 
For Part 1 and Part 2, 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. 
 


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Separate summaries for TEAEs will be provided for study medication related AEs, death, 
serious adverse events (SAE), other significant AEs leading to discontinuation. 
 
For ESS1, the number (and percentage) of subjects with AEs will be summarized for ocular 
and non-ocular respectively, by dosing posology (TID and BID) 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. 
 
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 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. 
2.8.2 
Deaths 
All deaths that occurred during the study will be summarized by system organ class, preferred 
term and treatment group. A subject listing will be presented for all deaths including date and 
cause of death. 
2.8.3 
Laboratory data 
Not applicable. 
2.8.4 
Other safety data 
2.8.4.1 
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. 
 
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 in SAF1 and SAF2, by dosing posology (TID and BID) in ESS1.  
 
2.8.4.2 
Intraocular Pressure 
 
Intraocular pressure (IOP) measurements will be recorded in mmHg and rounded to the 
nearest whole number for summary. 


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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 in SAF1 and SAF2, by dosing posology (TID and BID) in ESS1.  
2.8.4.3 
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. 
 
A subject listing will be presented by visit. 
 
2.9 
Pharmacokinetic endpoints   
Not Applicable. 
 
2.10 
PD and PK/PD analyses 
Not Applicable. 
 
2.11 
Patient-reported outcomes 
The site personnel should check PRO measures for completeness and ask the subject to 
complete any missing responses. The responses that are stored electronically in the database 
will be considered the source file. 
All observed data will be used for analysis and missing data will not be imputed. And the 
analysis for Part 1 and Part 2 will be  based on FAS 1 and FAS 2, respectively 


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2.13 
Other Exploratory analyses 
The analysis of exploratory endpoints for Part 1 and Part 2 will be based on FAS 1 and FAS 2, 
respectively. Only observed data will be used for analysis and no missing data will be imputed.  
2.14 
Interim analysis 
Two interim analyses are planned for the study. The first interim analysis will be perfromed 
when after all subjects have completed their participation in Part 1. The data will be analyzed 
to determine the efficacy and safety of ECF843 vs vehicle and selection of the optimal 
concentration and posology.  
Part 2 will be initiated only if safety and efficacy of ECF843 during Part 1 is demonstrated. The 
second interim analysis will be performed when all subjects in Part 2 have completed 12 weeks 
of treatment or discontinued treatment. The analysis will be used to explore efficacy and safety 
of ECF843 vs. vehicle after 12 weeks of treatment. The final analysis will be performed at the 
end of Part 2.  


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3 
Sample size calculation 
3.1 
Primary endpoints(s) 
Part 1 of the study is powered on 2 primary endpoints, change from baseline in SANDE 
symptom score and composite corneal fluorescein staining score. 
3.1.1 
SANDE symptom scores 
In one previous rhLubricin clinical study (LUB0114MD) there was an observed standard 
deviation of 20 mm in change from baseline of SANDE score (measured with a visual analog 
scale (VAS)100mm)at Day 28. A second rhLubricin clinical study (LUB0115MD) showed a 
standard deviation of 23 mm in change from baseline in SANDE symptom score at Day 14.  
Assuming a true treatment difference in change from baseline in SANDE symptom score of 10 
mm and a standard deviation of 23 mm, a sample size of 112 subjects per arm provides 
approximately 80% power that the primary analysis will be statistically significant at the two-
sided 5% significance level adjusted by 3 comparisons.  
See Table 3-1 for power to detect a significant difference from vehicle under various assumed 
treatment effect of SANDE Symptom score and standard deviation.  
Table 3-1 
Power to Detect a Significant Difference from Vehicle 
  
Treatment effect: difference from vehicle in change from baseline in SANDE 
Symptom Score 
Standard 
deviation of 
change from 
baseline in 
SANDE 
symptom 
score 
10 
11 
12 
13 
14 
23 
80% 
88% 
93% 
97% 
98% 
25 
72% 
81% 
88% 
93% 
96% 
27 
64% 
74% 
82% 
88% 
93% 
3.1.2 
Composite corneal fluorescein staining score 
Assuming a true treatment difference in change from baseline in composite corneal fluorescein 
staining of 1 and a standard deviation of 1, a sample size of 112 subjects per arm provides more 
than 99% power that the primary analysis will be statistically significant at the two-sided 5% 
significance level adjusted by 3 comparisons. 
nQuery Advisor 8.4 is used for the estimate.  


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3.2 
Secondary endpoint(s) 
There are no power considerations for secondary endpoints. 
4 
Change to protocol specified analyses 
The following analyses are updated and changed from protocol amendment version 1 dated 20 
Apr 2021. 
1. Section 2.5.2 Statistical hypothesis, model, and method of analysis: The initial within 
subject correlation structure used for SANDE symptom score in MMRM is updated 
from “Unstructured” to “Toeplitz”. This also applies to the supportive analysis for 
SANDE symptom score stated in 2.5.4 Supportive analyses. 


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5 
Appendix 
5.1 
Imputation rules of missing dates 
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, 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, 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. 
  
 
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 


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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). 
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 end date 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 end date and the end of the year (31DECYYYY). 
3. Only include if ongoing records will have an imputed CM end date. If CM 
day/month/year is missing, then use the treatment end date + 1 day as the imputed CM 
end date.  
4. If imputed CM end date is less than the CM start date, use the CM start date as the 
imputed CM end date. 


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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.  
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). 


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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 primay estimand and supplementary 
estimand. 
 
change from baseline in SANDE = intercept + baseline SANDE  + treatment + day +  
Sjogren's Syndrome (yes/no) + treatment*day + baseline SANDE * day + error 
 
change from baseline in corneal fluorescein staining score = intercept + baseline corneal 
fluorescein staining score + treatment + visit +  Sjogren's Syndrome (yes/no) + treatment*visit 
+ baseline corneal fluorescein staining score * visit + error 
 
The SAS Proc MIXED will be used to perform the MMRM analyses. The data structure is 
one record per subject per analysis visit.  SAS codes for all statistical methodology described 
in this section, including the imputation implementation,  will be included as programming 
note in TFL Shells. 
The following SAS code can be used to perform the primary analyses: 
 
PROC MIXED DATA=<Dataset> order=Internal; 
   CLASS USUBJID <Treatment> <Visit> < Sjogren's Syndrome>; 
   MODEL <Chg> = <Treatment> <Visit> <Baseline> < Sjogren's Syndrome> 
 
 
<Visit>*<Treatment>  
 
 
<Visit>*<Baseline>/ DDFM=KENWARDROGER; 
   REPEATED <Visit>/TYPE=UN SUBJECT=USUBJID; 
   LSMEANS  <Visit>*<Treatment> /DIFF CL ALPHA = 0.05; 
   ODS OUTPUT LSMEANS=outLsm DIFFS=Diffs; 
RUN; 
 
Where 
<Dataset> = dataset to store SANDE score or  corneal fluorescein staining score where the structure is 
one record per FAS subject per day/visit. 
<Chg> = change from baseline in SANDE score or corneal fluorescein staining score 
<Treatment> = randomized treatment assignment  
< Sjogren's Syndrome> = diagnosis of Sjogren's Syndrome at baseline 
<Visit> = ordered day or visit  


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<Baseline> = baseline value for SANDE score or corneal fluorescein staining score 
The terms in the brackets are to be adjusted according to the real data set and variable names. 
If an MMRM model (for corneal fluorescein staining score) with unstructured covariance 
matrix does not converge, choose the covariance structures in the following order until 
convergence is reached: 
• Toeplitz: change to TYPE = TOEP in the ‘Repeated’ statement; 
• First-order autoregressive: change to TYPE = AR(1) in the ‘Repeated’ statement; 
• Compound symmetry: change to TYPE = CS in the ‘Repeated’ statement. 
If an MMRM model (for SANDE score) with Toeplitz covariance matrix does not converge, 
choose the covariance structures in the following order until convergence is reached: 
• First-order autoregressive: change to TYPE = AR(1) in the ‘Repeated’ statement; 
• Compound symmetry: change to TYPE = CS in the ‘Repeated’ statement. 
 
P-values from three comparisons requested in Section 2.5.1 will be extracted from <Diffs> 
and adjusted p-values will be calculated using following code:  
 
PROC multtest inpvalues= <rawPvalues> hoc; Run; 
5.2.2 
Supplementary Analysis 
The multiple imputation for the Supplementary estimand will be done using the “five macros”, 
which fit a Bayesian Normal RM model and then impute post withdrawal data under a series of 
possible post-withdrawal profiles including J2R, CIR and CR as described by Carpenter et al 
(Carpenter et al. 2013).  
In “five macro”, all intermediate missing values will be imputed assuming MAR and the MNAR 
part of the model is restricted to patterns that are monotone. That means control-based 
imputations method is only applicable to monotone missing pattern, therefore we need prepare 
the data in several tweaks in order to use “five macro”.  
0. Prepare the data <in_data>: <in_data> stores SANDE score or corneal fluorescein 
staining score where the structure is one record per FAS subject per day/visit 
a. For subjects in treatment arms, if a subject experience IEs stated in Section 2.5.4.1, 
where J2R method is proposed for imputation. Define a new variable 
<Method_var> = “J2R” for the subject. Otherwise <Method_var> = 
“MAR”. 
b. For subjects in vehicle arm, <Method_var> = “MAR”  
1. Part1A declares the parameter estimation model and checks consistency with the dataset 
%part1A(Jobname=ECF,Data=<in_data>,Subject=USUBJID,Response=<Chg>,Time=<
Visit>,Treat=<Treatment>,Covbytime=<Baseline>); 


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2. Part1B fits the parameter estimation model using the MCMC procedure and draws a pseudo-
independent sample from the joint posterior distribution for the linear predictor parameters 
and the covariance parameters. 
%part1B(Jobname=ECF,Ndraws=1000,thin=250,seed=20210301); 
3. Part2A calculates the predicted mean under MAR, and under MNAR for each subject based 
on their withdrawal pattern once for each draw of the linear predictor parameter estimates. 
The choice of MNAR is controlled by the method used, which may vary from subject to 
subject. 
%part2A(Jobname=ECF,methodV=<Method_var>,refV=<Ref_var>); 
<Ref_var> is the variable indicating the reference group for all subjects in the study 
4. Part2B imputes the intermediate missing values using MAR and the trailing missing values 
using MNAR, by deriving the conditional distribution for the missing values conditional on 
the observed values and covariates, using the appropriate sampled covariance parameter 
estimates. 
%part2B(Jobname=ECF,seed=20210302); 
5. Instead of running Part3 from ‘five macros’, we will carry out MMRM analysis as stated in 
Section 5.2.1 per imputation for <Dataset>.  It then combines the least-squares means, 
their differences and p-values using the MIANALYZE procedure to provide final results. 
 
PROC MIXED DATA=<Dataset> order=Internal; 
 
BY _imputation_; 
   CLASS USUBJID <Treatment> <Visit> < Sjogren's Syndrome>; 
   MODEL <Chg> = <Treatment> <Visit> <Baseline> < Sjogren's Syndrome> 
 
 
<Visit>*<Treatment>  
 
 
<Visit>*<Baseline>/ DDFM=KENWARDROGER; 
   REPEATED <Visit>/TYPE=UN SUBJECT=USUBJID; 
   LSMEANS  <Visit>*<Treatment> /DIFF; 
   ODS OUTPUT LSMEANS=outLsm DIFFS=Diffs; 
RUN; 
P-values from three comparisons requested in Section 2.5.1 in PROC MIANALYZE will 
be extracted from <Diffs> and adjusted p-values will be calculated using following code:  
 
PROC multtest inpvalues= <rawPvalues> hoc; Run; 
 
5.3 
Rule of exclusion criteria of analysis sets  
 
The following table provides the definitions of the protocol deviations of the study, together 
with the exclusion rules.  
Table 5-1 
Protocol deviations 
PD ID 
Deviation Text 
Data exclusion 
INCL01 
written informed consent not 
obtained 
Exclude from all analysis sets 


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PD ID 
Deviation Text 
Data exclusion 
INCL02 
Patient < 18 years of age at 
Screening 
Include in all analysis sets  
INCL03 
patient not able or willing to 
follow protocol or assessments 
Include in all analysis sets 
INCL04 
< 6 months dry eye diagnosis 
in both eyes 
Include in all analysis sets 
INCL05 
not use or need AT, gels or 
lubricants 
Include in all analysis sets 
INCL06 
Tear Break-up Time (TBUT) > 
5 seconds in both eyes 
Include in all analysis sets 
INCL07 
Composite corneal fluorescein 
staining score < 4 (modified 
NEI scale) in both eyes 
Include in all analysis sets 
INCL08 
In office SANDE global ocular 
discomfort score < 60mm 
Include in all analysis sets 
INCL09 
Eye Dryness Score < 40mm 
Include in all analysis sets 
INCL10 
Schirmer score 0 or > 10 mm 
after 5 min both eyes 
Include in all analysis sets 
INCL11 
Sjogrens Syndrome patient 
lacks confirmed diagnosis 
Include in all analysis sets 
EXCL01 
Ocular infection (bacterial, viral, 
or fungal) in either eye within 
30 days prior to Screening 
Include in all analysis sets 
EXCL02 
Use of artificial tears, gels, 
lubricants within 4 hrs of 
conducting assessments at 
Screening 
Include in all analysis sets 
EXCL03 
contact lens use in either eye 
within 14 days of Screening, 
and any use during study 
Include in all analysis sets 
EXCL04 
uncontrolled ocular rosacea, 
posterior blepharitis, or MGD 
Include in all analysis sets 
EXCL05 
Clinically significant 
conjunctivochalasis in either 
eye 
Include in all analysis sets 
EXCL06 
Corneal conditions, 
dystrophies, scar, pterygia, 
keratoconus in either eye 
Include in all analysis sets 
EXCL07 
history ocular HSV or infection, 
GvHD, Stephen's Johnson 
Syndrome, 
sarcoidosis 
Include in all analysis sets 
EXCL08 
active or history of ocular 
allergies during time patient will 
be in study 
Include in all analysis sets 
EXCL09 
hypersensitivity to ECF843, 
stains, Xiidra, or other 
Include in all analysis sets 


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PD ID 
Deviation Text 
Data exclusion 
EXCL10 
current punctal plugs or punctal 
cauterization or occlusion 
Include in all analysis sets 
EXCL11 
unstable chronic meds 30 days 
prior to Screen 
Include in all analysis sets 
EXCL12 
Use of Restasis, Cequa, or 
Xiidra within 30 days prior to 
Screening 
Include in all analysis sets 
EXCL13 
Medical device use to treat 
MGD within 3 months prior to 
Screen 
Include in all analysis sets 
EXCL14 
Use of ocular, nasal, inhaled, 
or systemic corticosteroids 
within 30 days of Screen or 
during the study 
Include in all analysis sets 
EXCL15 
history of corneal refractive 
surgery 
Include in all analysis sets 
EXCL16 
any intraocular surgery 
including cataract surgery 
within 6 months prior to 
Screening 
Include in all analysis sets 
EXCL17 
Chronic systemic disease 
diagnosed within the last 30 
days or not stable 30 days prior 
to Screen 
Include in all analysis sets 
EXCL18 
Use of other investigational 
drugs within 5 half-lives of 
enrollment, 30 days, or return 
to baseline 
Include in all analysis sets 
EXCL19 
History of malignancy of any 
organ system treated or 
untreated within 5 yrs 
Include in all analysis sets 
EXCL20 
any systemic or ophthalmic 
condition that precludes study 
participation per Investigator 
opinion  
Include in all analysis sets 
EXCL21 
Pregnant or nursing (lactating) 
women 
Include in all analysis sets 
EXCL22 
women of child bearing 
potential unless using basic 
methods of contraception 
during study 
Include in all analysis sets 
WITH01 
Subject withdrew consent but 
continued to receive study 
medication 
Include in all analysis sets 
TRT01 
randomized subject 
administered incorrect 
treatment and/or dose 
Include in all analysis sets 


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PD ID 
Deviation Text 
Data exclusion 
TRT02 
Investigational or other study 
treatment dose adjustments 
and/or interruptions made 
Include in all analysis sets 
COMD01 
Prohibited concomitant 
medication and/or procedure 
as per protocol 
Include in all analysis sets 
COMD02 
Prohibited concomitant 
medication change 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 
TRT03 
Drug supply method changed 
due to COVID-19 
Include in all analysis sets 
TRT04 
Treatment not given due to 
COVID-19 
Include in all analysis sets 
OTH08 
Discontinuation due to COVID-
19 
Include in all analysis sets 
OTH09 
Unblinding for non-emergent 
situation 
Include in all analysis sets 
OTH10 
staining strips moistened with 
anesthetic 
Include in all analysis sets 
TRT05 
patient noncompliance with 
study drug 
Include in all analysis sets 
OTH11 
SANDE compliance <50% 
Include in all analysis sets 
5.4 
Exclusion of subjects with data issue of conjunctival 
lissamine staining from analysis 
Site 
 used a conjunctival lissamine green grading scale different from the Oxford scale in 
the protocol. The reported scores could not be adjusted or correlated retrospectively.  
The impacted subjects 
 will be 
flagged in listings but excluded in the summary for conjunctival lissamine staining. 


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5.5 
Handling of subject with incorrect randomization 
stratum 
If randomization stratum (Sjogren's status) collected from diagnosis in RAVE is different from 
that in Cenduit IRT, the actual stratum in RAVE will be used for all analyses. 
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 
3. Five marcos: 
https://lshtm.sharepoint.com/:u:/s/MissingDataPublicFiles/EZzccbzMWopLndHoj-
gzBNoBzYx-GVYqQSvwDf-lUJhPsQ?e=elHD6Z