Conditions: Dry Eye Disease
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 328
Healthy volunteers: no

Brief summary:
The objective of this study is to assess the efficacy, safety, and tolerability of CyclASol Ophthalmic Solution in comparison to vehicle for the treatment of the signs and symptoms of DED.

Detailed description:
This Phase 2b/3 study will assess the efficacy, safety and and tolerability of CyclASol Ophthalmic Solution as one drop twice daily versus vehicle.

Arms:
arm 1: Cylclosporine A solution in vehicle arm 2: Vehicle only

Interventions: intervention 1: CyclASol topical ocular, eye drops intervention 2: Vehicle topical ocular, eye drops
Intervention descriptions: intervention 1: Cyclosporine A solution in vehicle intervention 2: Vehicle

Protocol document:
Prot_SAP_000.pdf: 
CyclASol® 0.1% Ophthalmic Solution 
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Clinical Trial Protocol: CYS-003 / 17-110-0009 
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Clinical Trial Protocol: CYS-003 
Protocol Title: 
A Phase 2b/3, multicenter, randomized, double-masked, 
vehicle-controlled clinical study to assess the efficacy and 
safety of topical CyclASol® for the treatment of signs and 
symptoms of Dry Eye Disease 
Protocol Number: 
CYS-003 / 17-110-0009 
Study Phase: 
2b / 3 
Investigational Product Name: 
CyclASol® 0.1 % Ophthalmic Solution (Cyclosporine A 
0.1%) 
IND/IDE/PMA Number: 
128163 
Indication: 
Dry Eye Disease (keratoconjunctivitis sicca) 
Investigators: 
Multicenter 
Sponsor: 
Novaliq GmbH 
Im Neuenheimer Feld 515 
69120 Heidelberg 
Germany 
Contract Research Organization: 
 
 
IRB/IEC: 
Alpha IRB 
1001 Avenida Pico 
Suite C, #497 
San Clemente, CA 92673 
USA 
 
 
Date 
Original Protocol: 
14 September 2017 
Amendment 1: 
20 December 2017 
Amendment 2: 
29 January 2018 
 
Confidentiality Statement 
This protocol contains confidential, proprietary information of 
 and Novaliq GmbH. 
Further dissemination, distribution, or copying of this protocol or its contents is strictly 
prohibited. 
 


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SPONSOR PERSONNEL 
Vice President of Preclinical 
and Clinical Development: 
 
 
 
 
 
 
Chief Medical Officer: 
 
 
 
 
MEDICAL MONITOR 
Medical Monitor 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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SYNOPSIS 
Protocol Title: 
A Phase 2b/3, multicenter, randomized, double-masked, 
vehicle-controlled clinical study to assess the efficacy and 
safety of topical CyclASol® for the treatment of signs and 
symptoms of Dry Eye Disease  
Protocol Number: 
CYS-003 / 17-110-0009 
Investigational Product: 
1) CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 
0.1% solution) 
2) Vehicle Ophthalmic Solution (F4H5) 
Study Phase: 
2b / 3 
Study Objective 
The objective of this study is to assess the efficacy, safety, 
and tolerability of CyclASol 0.1% Ophthalmic Solution in 
comparison to the vehicle for the treatment of the signs 
and symptoms of Dry Eye Disease (DED). 
Overall Study Design: 
Structure: 
This clinical study is multicenter, randomized, double-
masked, and vehicle-controlled with a run-in period with 
artificial tears. 
Duration: 
An individual subject’s participation is estimated to be 
approximately 14 weeks (approx. 2 weeks screening and 
12 weeks treatment period) 
Controls: 
Vehicle Ophthalmic Solution (F4H5) 
Dosage/Dose Regimen: 
Subjects eligible to be randomized will receive one of the 
following treatments to dose with bilaterally BID for 
approximately 85 days (from Visit 1 to Visit 5). 
 
1) CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 
0.1% solution) 
 
2) Vehicle Ophthalmic Solution (F4H5) 
 
A 14-day study-run-in period will be used for subject 
selection before randomization. During this period, all 
subjects will receive Systane® Balance to dose with 
bilaterally BID. 


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Summary of Visit Schedule: 
This clinical study involves 6 visits over the course of 
approximately 14 weeks: 
• Visit 0, Day -14 ± 2 days, Screening; 
• Visit 1, Day 1, Baseline/Randomization; 
• Visit 2, Day 15 ± 1 days, 2-Week Follow-Up; 
• Visit 3, Day 29 ± 2 days, 4-Week Follow-Up; 
• Visit 4, Day 57 ± 2 days, 8-Week Follow-Up; and 
• Visit 5, Day 85 ± 2 days, 12-Week Follow-Up and 
Study Exit. 
Measures Taken to Reduce Bias: 
This trial is a multi-center, randomized, double-masked 
and vehicle-controlled clinical study. 
Study Population Characteristics: 
Number of Subjects: 
Approximately 
 subjects will be screened to enroll at 
least 316 (158 per treatment arm) subjects at 
approximately 10 sites. 
Condition/Disease: 
Dry Eye Disease (keratoconjunctivitis sicca) 
Inclusion Criteria: 
Each subject must: 
a. Be at least 18 years of age; 
b. Provide written informed consent; 
c. Have a subject reported history of Dry Eye Disease  
; 
d. Be currently using (within 30 days before Visit 0) 
over-the-counter (OTC) eye drops, lubricating gels 
and/or artificial tears for dry eye symptoms at Visit 0; 
e. Have an OSDI® score of  
 at Visit 0 and Visit 1; 
f. Have a total corneal fluorescein staining score of 
 
 
 
g. Have a total lissamine green conjunctival score (sum 
of temporal and nasal regions) 
 
h. Have an unanesthetized Schirmer’s Test score 
 
i. 
 
 
j. Be able and willing to follow instructions and 


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participate in all study assessments and visits. 
Exclusion Criteria: 
Each subject must not: 
a. Have any clinically significant slit-lamp findings at 
Visit 0 that require prescriptive medical treatment 
and/or in the opinion of the investigator may interfere 
with study parameters including trauma, Steven 
Johnson Syndrome, advanced epithelial basement 
membrane disease; 
 
 
 
 
 
 
 
 
 
 
 
c. Have abnormal lid anatomy (e.g. incomplete eyelid 
closure, entropion, or ectropion) or abnormal 
blinking; 
 
 
 
 
e. Have an ocular or periocular malignancy; 
 
 
 
g. Have a history of herpetic keratitis; 
h. Have active ocular allergies or ocular allergies that 
may become active during the study period; 
i. Be diagnosed with an ongoing ocular or systemic 
infection (bacterial, viral, or fungal), including a 
fever, or be undergoing treatment with antibiotics at 
Visit 0 or Visit 1; 
j. Have worn contact lenses within 90 days before Visit 
0 or anticipate using contact lenses during the study; 
 
 


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l. Have used topical CsA or Lifitegrast within 60 days 
before Visit 0; 
 
 
n. Have had intraocular surgery or ocular laser surgery 
within 180 days before Visit 0, or have any planned 
ocular or eyelid surgeries during the study period; 
o. Be a woman who is pregnant, nursing, or planning a 
pregnancy; 
p. Be unwilling to submit a urine pregnancy test at Visit 
0 and Visit 5 (or early termination visit) if of 
childbearing potential. Non-childbearing potential is 
defined as a woman who is permanently sterilized (i.e. 
has had a hysterectomy, bilateral tubal ligation, or 
bilateral oophorectomy), or is post-menopausal (i.e. 
without menses for 12 consecutive months); 
q. Be a woman of childbearing potential who is not 
using an acceptable means of contraception. 
Acceptable methods of contraception include 
hormonal contraceptives (i.e. oral, implantable, 
injectable, or transdermal contraceptives), mechanical 
contraceptives (i.e. spermicide in conjunction with a 
barrier such as a diaphragm or a condom), intrauterine 
devices (IUD), or the surgical sterilization of the 
partner. For non-sexually active females, abstinence 
may be regarded as an adequate method of birth 
control; however, if the subject becomes sexually 
active during the study, she must agree to use 
adequate birth control as defined above for the 
remainder of the study; 
r. Have an uncontrolled systemic disease; 
 
 
 
 
 
 
 
 
 
 
 


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aa. Have a condition or be in a situation (e.g. language 
barrier) which the investigator feels may put the 
subject at significant risk, may confound the study 
results, or may interfere with the subject’s 
participation in the study significantly; or 
 
 
Study Formulations and 
Formulation Numbers: 
1) Systane Balance (run-in) 
2) CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 
0.1% solution) 
3) Vehicle Ophthalmic Solution (F4H5) 
Evaluation Criteria: 
Efficacy Measures: 
Primary Efficacy Measures: 
The following primary endpoints will be tested in order 
using hierarchical fixed sequence testing: 
1. Change from baseline in total Corneal fluorescein 
staining (NEI scale) at Day 29 
2. Change from baseline in Ocular Surface Disease 
Index (OSDI) at Day 29 
  
 
 
 
 
 


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Safety Measures: 
• Visual acuity (VA) 
• Slit-lamp biomicroscopy 
• Intraocular pressure (IOP) 
• Dilated fundoscopy 
• Systemic and ocular adverse events 
 
 
 


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General Statistical Methods and Types of Analyses 
Hypotheses and Sample Size: 
The primary endpoints will be tested in a hierarchical fixed sequence in the following order. 
The statistical hypotheses for the primary endpoint of change from baseline corneal fluorescein 
staining (NEI scale) total score at Day 29 are as follows: 
 
H01: 
The difference, between study eyes treated with CyclASol and study eyes treated 
with vehicle, in the mean change from baseline corneal fluorescein staining (NEI 
scale) total score at Day 29 = 0.  
 
HA1:  The difference, between study eyes treated with CyclASol and study eyes treated 
with vehicle, in the mean change from baseline corneal fluorescein staining (NEI 
scale) total score at Day 29 ≠ 0, with superiority claimed if the difference is less 
than 0 (CyclASol minus vehicle). 
The statistical hypotheses for the primary endpoint of the change from baseline total OSDI score 
at Day 29 are as follows: 
 
H02:  
The difference, between subjects treated with CyclASol and subjects treated with 
vehicle, in the mean change from baseline total OSDI score at Day 29 = 0. 
 
HA2:  The difference, between subjects treated with CyclASol and subjects treated with 
vehicle, in the mean change from baseline total OSDI score at Day 29 ≠ 0, with 
superiority claimed if the difference is less than 0 (CyclASol minus vehicle) 
One-hundred forty-two (142) intent to treat (ITT) subjects (study eyes) per treatment group 
yields 90% power to reject H01 in favor of HA1 and conclude superiority of CyclASol over 
vehicle in the mean change from baseline corneal fluorescein staining (NEI scale) total score at 
Day 29 assuming a true difference (CyclASol minus vehicle) of -0.85, a common standard 
deviation of 2.2, and a two-sided alpha = 0.05. Additionally, 142 ITT subjects per treatment 
group yields 82% power to reject H02 in favor of HA2 and conclude superiority of CyclASol over 
vehicle in the mean change from baseline total OSDI score at Day 29 assuming a true difference 
(CyclASol minus vehicle) of - 5.0, a common standard deviation of 14.5, and a two-sided alpha 
= 0.05. Accounting for subject discontinuations, 316 total subjects will be enrolled assuming a 
dropout rate of 10%. 
Hierarchical fixed sequence testing will be employed to maintain the type I error rate. The 
primary analyses will first test the difference in the mean change from baseline corneal 
fluorescein staining (NEI scale) total score between treatments at Day 29. If the test of the 
difference is statistically significant at the two-sided alpha = 0.05 level in favor of CyclASol , 
then the study will be considered a success; CyclASol will be declared to be superior to vehicle 
in the mean change from baseline corneal fluorescein staining (NEI scale) total score at Day 29; 
and the difference in the mean change from baseline total OSDI score between treatments at Day 


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29 will be tested at the two-sided alpha = 0.05 level. 
If in addition to a statistically significant test of the difference in the mean change from baseline 
corneal fluorescein staining (NEI scale) total score at Day 29 in favor of CyclASol, the test of the 
difference in the mean change from baseline total OSDI score at Day 29 is also statistically 
significant in favor of CyclASol, then CyclASol will be declared to be superior to vehicle in both 
the mean change from baseline corneal fluorescein staining (NEI scale) total score and the mean 
change from baseline total OSDI score at Day 29. 
Primary Efficacy Analyses: 
The primary comparisons in this study will be between CyclASol versus vehicle at Day 29. The 
primary efficacy endpoints (e.g. change from baseline in corneal fluorescein staining [total NEI] 
and OSDI) will be analyzed separately using an ANCOVA model with terms for baseline value, 
treatment, and the interaction of treatment by baseline value (the interaction term will be 
maintained in the model only if the p-value for the term is <0.10). 
Least squares mean for each treatment group and for the difference between treatment groups 
will be presented from the model together with two-sided p-values and 95% confidence intervals. 
In the event that the interaction of treatment by baseline value is significant, estimate and 
contrast statements will be used to determine the treatment group means and differences at the 
25th, 50th, and 75th percentile of the baseline score over treatment groups. 
Two-sample t-tests, Wilcoxon rank sum tests and mixed-effect repeated measures analysis 
comparing treatment groups will be performed as sensitivity analyses.   
The primary analysis will use the Full Analysis Set (FAS) with available data per subject. 
Additional robustness analyses will include repeating the primary analysis on the per protocol set 
(PPS); the FAS imputing missing data using last observation carried forward (LOCF); the FAS 
imputing missing data using Markov Chain Monte Carlo (MCMC) multiple imputation 
methodology under different assumptions of missingness (at random and not at random); and an 
analysis of trimmed means (Permutt et al., 2017). 
  
 
 
 
 
  
 
 
 
  


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Safety Variables 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies and percentages 
of subjects with treatment-emergent adverse events (TEAEs), serious TEAEs, and TEAEs 
causing premature discontinuation will be provided by treatment group. An AE is treatment 
emergent if it occurs or worsens after the first dose of study treatment. Furthermore, frequencies 
will be given of subjects with TEAEs by system organ class, by system organ class and preferred 
term, by system organ class, preferred term and maximal severity, by system organ class, 
preferred term and strongest relationship, and by system organ class, preferred term, maximal 
severity, and strongest relationship. Separate summaries will be performed for ocular and non-
ocular AEs. Other safety endpoints including visual acuity, slit-lamp biomicroscopy, dilated 
fundoscopy, and intraocular pressure will be summarized by treatment group and visit using 
descriptive statistics. Changes or shifts from baseline will also be summarized where appropriate. 
For assessments performed by eye, study eye and fellow eye will be summarized separately. In 
addition, shifts from baseline to worst on-treatment value for ocular safety assessments will be 
summarized. 


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TABLE OF CONTENTS 
SYNOPSIS ......................................................................................................................................3 
TABLE OF CONTENTS ............................................................................................................12 
List of Abbreviations ...................................................................................................................15 
1 
INTRODUCTION...............................................................................................................17 
1.1 
Dry Eye Disease (DED) ........................................................................................... 17 
1.2 
Product Rational ...................................................................................................... 17 
1.3 
Trial Rational ........................................................................................................... 18 
1.4 
Summary of Known and Potential Risks and Benefits to Human Subjects ...... 19 
2 
STUDY OBJECTIVES .......................................................................................................20 
3 
CLINICAL HYPOTHESES ..............................................................................................20 
4 
STUDY DESIGN .................................................................................................................20 
4.1 
Overall Study Design ............................................................................................... 20 
4.2 
Participant and Study Completion ........................................................................ 22 
4.3 
End of Study Definition .......................................................................................... 22 
4.4 
Justification of Study Design .................................................................................. 23 
4.5 
Justification for Dose ............................................................................................... 23 
5 
STUDY POPULATION .....................................................................................................23 
5.1 
Number of Subjects (approximate) ........................................................................ 23 
5.2 
Study Population Characteristics .......................................................................... 24 
5.3 
Inclusion Criteria .................................................................................................... 24 
5.4 
Exclusion Criteria .................................................................................................... 24 
5.5 
Withdrawal Criteria (if applicable) ....................................................................... 27 
6 
STUDY PARAMETERS ....................................................................................................27 
6.1 
Efficacy Measures .................................................................................................... 27 
6.1.1 
Primary Efficacy Variable(s) ........................................................................27 
 
 
 
 
 
 
6.2 
Safety Measures ....................................................................................................... 29 
6.3 
Other Measures ....................................................................................................... 29 


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7 
STUDY MATERIALS ........................................................................................................29 
7.1 
Study Treatment(s) .................................................................................................. 29 
7.1.1 
Study Treatment(s)/ Formulation(s)/ Medical Device Composition or Design29 
7.1.2 
Description of for the Route of Administration, Dosage, Dosage Regimen, 
and Treatment Period(s). ........................................................................................30 
7.1.3 
Instructions for Use and Administration .......................................................31 
7.2 
Other Study Supplies .............................................................................................. 31 
8 
STUDY METHODS AND PROCEDURES .....................................................................31 
8.1 
Subject Entry Procedures ....................................................................................... 31 
8.1.1 
Overview .......................................................................................................31 
8.1.2 
Informed Consent..........................................................................................31 
8.1.3 
Washout Intervals .........................................................................................32 
8.1.4 
Procedures for Final Study Entry ..................................................................32 
8.1.5 
Methods for Assignment to Treatment Groups: ...........................................32 
8.2 
Concurrent Therapies ............................................................................................. 32 
8.2.1 
Prohibited Medications/Treatments ..............................................................32 
8.2.2 
Escape Medications ......................................................................................33 
8.2.3 
Special Diet or Activities ..............................................................................33 
8.3 
Examination Procedures ......................................................................................... 33 
8.3.1 
Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) ............................................................................................................33 
8.3.2 
Early Termination/Discontinuations .............................................................37 
8.4 
Schedule of Visits, Measurements and Dosing ..................................................... 37 
8.4.1 
Scheduled Visits............................................................................................37 
8.4.2 
Unscheduled Visits .......................................................................................37 
8.5 
Compliance with Protocol ....................................................................................... 38 
8.6 
Subject Disposition .................................................................................................. 38 
8.6.1 
Completed Subjects ......................................................................................38 
8.6.2 
Discontinued Subjects ...................................................................................38 
8.7 
Study Termination .................................................................................................. 39 
8.8 
Study Duration ........................................................................................................ 39 
8.9 
Monitoring and Quality Assurance ....................................................................... 39 
9 
ADVERSE EVENTS ..........................................................................................................40 
9.1 
Adverse Event .......................................................................................................... 40 
9.1.1 
Severity .........................................................................................................40 
9.1.2 
Relationship to Investigational Product ........................................................41 


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9.1.3 
Expectedness .................................................................................................41 
9.2 
Serious Adverse Events ........................................................................................... 42 
9.3 
Procedures for Reporting Adverse Events ............................................................ 42 
9.3.1 
Reporting a Suspected Unexpected Adverse Reaction .................................43 
9.3.2 
Reporting a Serious Adverse Event ..............................................................43 
9.4 
Procedures for Unmasking (if applicable) ............................................................ 44 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ............. 44 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES............................45 
10.5 Additional Analyses ................................................................................................. 50 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES ............................................50 
11.1 Protection of Human Subjects................................................................................ 50 
11.1.1 Subject Informed Consent.............................................................................50 
11.1.2 Institutional Review Board (IRB) Approval .................................................51 
11.2 Ethical Conduct of the Study ................................................................................. 51 
11.3 Subject Confidentiality ........................................................................................... 51 
11.4 Documentation ......................................................................................................... 51 
11.4.1 Retention of Documentation .........................................................................51 
11.5 Labeling, Packaging, Storage, Accountability, and Return or Disposal of 
Investigational Product ........................................................................................... 52 
11.5.1 Labeling/Packaging.......................................................................................52 
11.5.2 Storage of Study Drug ..................................................................................52 
11.5.3 Accountability of Study Drug .......................................................................52 
11.5.4 Return or Disposal of Study Drug ................................................................53 
11.6 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) ..................................................................................................................... 53 
11.7 Handling of Biological Specimens .......................................................................... 53 
11.8 Publications .............................................................................................................. 53 
12 
REFERENCES ....................................................................................................................54 
Appendix 1:  Schedule of Visits and Measurements .................................................................55 
Appendix 2:  Examination Procedures, Tests, Equipment, and Techniques .........................57 
Appendix 3:  Protocol Amendment 2 Summary .......................................................................77 
Appendix 4:  Sponsor and 
 Approvals ................................................................................80 
Appendix 5:  Investigator’s Signature .......................................................................................81 


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List of Abbreviations 
AE 
Adverse Event 
AIC 
Akaike Information Criterion 
ANCOVA 
Analysis of Covariance 
BCVA 
Best-Corrected Visual Acuity 
BID 
Twice Daily 
BLQ 
Below the Limit of Quantification 
CD 
Compact Disc 
CFR 
Code of Federal Regulations 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CS 
Compound Symmetry 
CsA 
Cyclosporine A 
CV 
Curriculum Vitae 
DED 
Dry Eye Disease 
DEWS 
(International) Dry Eye Workshop 
DHHS 
Department of Health and Human Services 
EKG 
Electrocardiography, Electrocardiogram 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
g 
Gram 
GCP 
Good Clinical Practice 
GMP 
Good Manufacturing Practice 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigators’ Brochure 
IBI 
Inter Blink Interval  
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug Application 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Independent Review Board 
 
 
ITT 
Intent to Treat 
IUD 
Intrauterine Device 
IWRS 
Interactive Web Response System 
KCS 
Keratoconjunctivitis Sicca 
kg 
Kilogram 
LASIK 
Laser-assisted in Situ Keratomileusis 
LOCF 
Last Observation Carried Forward 


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logMAR 
Logarithm of the Minimum Angle of Resolution 
MCMC 
Markov Chain Monte Carlo 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
Milligram 
mL 
Milliliter 
µL  
Microliter  
mm 
Millimeter 
mmHg 
Millimeters of Mercury 
 
 
NCS 
Not Clinically Significant 
nd  
Not Done  
NDA 
New Drug Application 
NEI 
National Eye Institute 
NOAEL 
No Observed Adverse Effect Level 
NSAID  
Nonsteroidal Anti-inflammatory Drug 
OD 
Right Eye 
OS 
Left Eye 
OSDI 
Ocular Surface Disease Index 
OU 
Both Eyes 
 
 
OTC 
Over the Counter 
PHI 
Protected Health Information 
PK 
Pharmacokinetic 
PPS 
Per Protocol Set 
PRN 
As Needed 
QD 
Once Daily 
SAE 
Serious Adverse Event 
SAF 
Safety Set  
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
 
 
SFA 
Semifluorinated Alkane 
SOP 
Standard Operating Procedures 
TEAE 
Treatment-emergent Adverse Event 
TFBUT 
Tear Film Break-up Time 
TMF 
Trial Master File  
US 
United States 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WHO 
World Health Organization  
 
 


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1 INTRODUCTION 
1.1 Dry Eye Disease (DED) 
Dry Eye Disease (DED) is defined by the International Dry Eye Workshop (DEWS) as a 
multifactorial disease of the ocular surface characterized by a loss of homeostasis of the tear 
film, and accompanied by ocular symptoms, in which tear film instability and hyperosmolarity, 
ocular surface inflammation and damage, and neurosensory abnormalities play etiological roles 
(DEWS II Definition and Classification 2017). As many as 5 - 35% of patients visiting 
ophthalmic clinics report dry eye symptoms, making it one of the most common conditions seen 
by ophthalmic specialists (McCarty CA, et al. 1998; Lin PY, et al. 2003). Estimates range from 
20 million people in the United States (US) being affected with mild to moderate dry eye, to a 
high of as many as one out of every five Americans. Prevalence is greater in females and the 
elderly. Schaumberg et al. reported prevalence rates ranging from 3.9% in men aged 50–54 years 
to 7.7% in those 80 years or older, while an increased rate from 5.7% in women younger than 50 
years to 9.8% in women >75 years was observed (Schaumberg DA, et al. 2003). Prevalence is 
affected by geographical parameters and appears to be higher in Asian populations. Dry eye can 
be related to external factors, such as the low humidity of air conditioned offices, winter heating, 
a dusty or windy outdoor environment, prolonged computer use, or wearing contact lenses, as 
well as to internal factors, such as hormonal imbalance, autoimmune disease, the presence of 
many widely prescribed systemic medications, anatomical changes or trauma, and aging. 
Symptoms result in mildly decreased quality of life at a minimum, and with increasing severity, 
loss of function and productivity, pain, light sensitivity, and the misery that accompanies 
significantly impaired vision and decreased quality of life. With the aging population in the 
United States and other countries of the developed world, and with increasing computer use, 
DED is expected to continue to become more prevalent and finding a treatment is becoming 
more important (Schaumberg DA, et al. 2009).  
1.2 Product Rational 
Cyclosporine A (CsA), a potent and selective immunosuppressive drug, acts as a regulator of T-
cells via inhibition of calcineurin. Due to this mode of action it has been widely studied as 
topical treatment for T-cell mediated disease of the ocular surface such as DED. In the US, CsA 
eye drops formulated as an emulsion are approved and marketed as Restasis 0.05% for this 
indication since 2002. In Europe - Ikervis®, a 0.1% CsA emulsion formulation, received a 
marketing authorization by the European Commission for the treatment of DED in early 2015. 
CyclASol is a clear ophthalmic solution of CsA developed with the goal of avoiding the use of 
oils, surfactants and preservatives. Potential benefits from the CyclASol formulation include 
improved tolerability and efficacy, early onset of efficacy and decreased visual disturbances 
associated with oily eye drops, emulsions or ointments. Moreover, the multiple dose containers 
allow for a convenient handling. 
For 
the 
solubilization 
of 
CsA 
in 
CyclASol 
the 
semifluorinated 
alkane 
(SFA) 
 F4H5
 
is used as the 
vehicle. 
 F4H5 is 


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colorless, it has a high vapor pressure and is immiscible with water but has nearly the same 
refractory index as water. F4H5’s physical properties make it an optimal vehicle for topical 
ocular use. As a result of its high vapor pressure (Krafft MP 2009), F4H5 dissipates quickly from 
the ocular surface and consequently does not interact physically with the tear film, as shown in 
rabbits, where F4H5 had no effect on tear film break-up time (TFBUT). Due to the low surface 
tension of F4H5, CyclASol eye drops are of small size, 
 
 potentially reducing pre-corneal clearance. Importantly, the low surface tension of 
the CyclASol formulation facilitates dissemination of the applied eye drop on the conjunctiva. 
These dissemination and spreading properties are further thought to improve the local 
bioavailability. 
 
1.3 Trial Rational 
The preclinical profile of CyclASol and of F4H5, the new excipient, has been well characterized. 
The chronic toxicity studies with F4H5 in rats (oral route) and rabbits (ocular route) estimated 
NOAELs of 1000 mg/kg/day and 342 mg/kg/day, respectively. These values were 1000-fold and 
342-fold above the anticipated clinical dose.  
 
Nonclinical and clinical data suggest that the CyclASol formulation may deliver CsA more 
rapidly to the target tissues than Restasis. In a murine dry eye model CsA in F4H5 and Restasis 
were equally effective in reducing corneal staining and, F4H5/CsA was associated with a more 
rapid therapeutic response and the only treatment that maintained conjunctival goblet cells 
(Gehlsen 2015).  
 
After successful completion of a Phase 1 safety, tolerability and PK study, a second, multicenter, 
randomized, double-masked (with an open label comparator - Restasis) phase 2 study 
investigating the efficacy and safety of CyclASol Ophthalmic Solution (0.05% and 0.1%) in 
comparison to vehicle in patients with DED was conducted. This was an exploratory Phase 2 
study without formal power calculations and no adjustments for multiple comparisons. In this 
study both CyclASol groups showed consistent improvements in corneal and conjunctival 
staining compared to the vehicle over the 4-month treatment period. These improvements were 
already visible after 2 weeks of treatment (Visit 2) and became statistically significant over 
Restasis at Visit 3 (1 month), which indicates an earlier onset of effect compared to Restasis. The 
most pronounced effect was seen in the central and inferior area of the cornea, which is 
particularly important from a patient perspective as it positively influences proper visual function 
in dry eye patients. 
  
 
All treatment groups demonstrated improvement in symptoms. In the Ocular Surface Disease 
Index (OSDI), the vision-related subscale (questions 6 through 9), particularly the question 
regarding impact on reading, demonstrated a numerically more pronounced effect in CyclASol 
groups when compared to vehicle. 
 
The CyclASol effect became statistically significant over vehicle (total corneal staining p<0.1, 
central corneal staining p<0.001, conjunctival staining p <0.01) when using a model-based 


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analysis. This analysis also suggests a significant CyclASol effect for OSDI as a symptom 
parameter (p <0.01). 
 
 
 
 
Moreover, both CyclASol concentrations showed excellent safety, tolerability, and comfort 
profiles. Due to the comparable safety profile but slightly better efficacy of CyclASol 0.1% over 
CyclASol 0.05%, the higher concentration (CyclASol 0.1%) was chosen for the present study. 
 
Based on these encouraging results the present Phase 2b/3 study was designed to confirm 
efficacy and safety of CyclASol. Furthermore, additional symptoms shall be explored to learn for 
further studies. 
1.4 Summary of Known and Potential Risks and Benefits to Human 
Subjects  
The investigational product (IP) CyclASol 0.1% Ophthalmic Solution contains CsA as active 
ingredient and its vehicle, which consists of F4H5. CsA is a potent and selective 
immunosuppressive drug, used routinely for decades as an oral immunomodulator in various 
indications. CsA containing eye drops have been proven safe over the last 15 years. The 
excipient F4H5 used in CyclASol is physically, chemically and physiologically inert. However, 
it is not part of any pharmaceutical product approved so far. Therefore, it has been subjected to 
the same pivotal non-clinical studies as a new active substance with favorable results. 
 
The Phase 2 study showed that CyclASol eye drops are effective in the treatment of signs and 
symptoms of DED in particular in the sub-population selected for the present study.  
 
In the Phase 1 clinical study with CyclASol the most frequently reported treatment-emergent 
adverse event TEAE was headache (1 subject [5.6%] after CyclASol and 3 subjects [16.7%] after 
placebo) and in the Phase 2 clinical study the most frequently reported ocular TEAE (11 subjects 
[5.3%]) was visual acuity (VA) reduced. 
All TEAEs were of mild to moderate intensity. In Phase 1 no subject discontinued the study due 
to AEs and in Phase 2 three (3) subjects (1.4%) withdrew from study treatment due to an ocular 
TEAE, two of which were considered at least possibly related to study drug. No deaths were 
observed in either study. Three (3) treatment-emergent serious adverse events (SAEs) were 
reported during the Phase 2 study. All SAEs were non-ocular, were considered not-related to 
study treatment, and had recovered by the end of the study. 
Adverse effects resulting from systemic absorption of CsA appear unlikely, because no systemic 
exposure of CsA could be detected after application of 1 or 2 drops of CyclASol twice daily in 
neither of the two clinical CyclASol trials, since all plasma concentrations were below the 
quantification limit (BLQ) (i.e. <0.100 ng/mL).  
Adverse effects due to systemic absorption of F4H5 appear very unlikely, as this excipient is 
very poorly absorbed and did not indicate any potential for toxicity in animal studies. In the two 


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clinical studies, most samples showed concentrations BLQ, the sporadic samples with 
measurable F4H5 concentrations were hardly above the BLQ. 
 
In summary, based on the preclinical and clinical data obtained to date, risks to subjects in the 
planned CYS-003 study are considered very low. Furthermore, the patients randomized in the 
study will be closely monitored, and current standard ophthalmological safety assessments will 
be performed during the entire treatment period. The efficacy demonstrated to date supports that 
CyclASol improves signs and symptoms of DED. In particular corneal and conjunctival staining 
signs were reduced and symptoms related to visual function showed improvement. CyclASol 
therefore provides a favorable risk-benefit treatment profile to patients with DED and the CYS-
003 study plans to further assess this positive profile.  
2 STUDY OBJECTIVES 
The objective of this study is to assess the efficacy, safety, and tolerability of CyclASol in 
comparison to the vehicle for the treatment of the signs and symptoms of (DED). 
3 CLINICAL HYPOTHESES 
The clinical hypotheses for this study are that CyclASol is superior to vehicle in improving the 
primary sign and symptom endpoints of DED, as follows: 
• Corneal fluorescein staining (NEI Scale) total score at day 29 is more reduced compared 
to baseline in patients receiving CyclASol than in patients receiving vehicle; 
• OSDI total score at day 29 is more reduced compared to baseline in patients receiving 
CyclASol than in patients receiving vehicle. 
 
4 STUDY DESIGN 
4.1 Overall Study Design 
This is a Phase 2b/3 multicenter, randomized, double-masked, and vehicle-controlled clinical 
study to evaluate the efficacy, safety and tolerability of CyclASol 0.1% Ophthalmic Solution in 
subjects with DED. Approximately 316 subjects of either sex and of any race who are at least 18 
years of age with a subject-reported history of dry eye in both eyes and meeting all other study 
eligibility criteria will be randomized at approximately 10 sites in the US to receive treatment 
with CyclASol or vehicle in a 1:1 ratio (approx. 158 subjects per treatment arm). This study is 
composed of two distinct parts: a 14-day run-in period and an 85-day treatment period. During 
the run-in period, subjects will dose Systane Balance bilaterally BID for approximately two 
weeks. Eligible patients will thereafter dose the study treatment (CyclASol or vehicle) bilaterally 
BID for approximately 3 month. A chart illustrating the study’s structure is below. 
 


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Visit 0 
Day -14 ± 2 days 
Screening 
Informed consent (incl. HIPAA) 
Demographics, medical/medication history & 
ocular history 
Review of qualification criteria 
Urine pregnancy test (as needed) 
Symptom questionnaires, 
 
Eye evaluations (Efficacy /Safety) 
AE query 
In-office dose of run-in 
Dispensation of subject diary and run-in to 
qualified subjects 
↓ 
Approximate 14-Day Run-In Period with Systane Balance 
↓ 
Visit 1 
Day 1 
Baseline / Randomization 
Collection and review of run-in/diary 
AE query, medical/medication update 
Review of qualification criteria 
Symptom questionnaires, 
 
Eye evaluations (Efficacy /Safety) 
Randomization 
In-office dose and drop comfort scale and 
questionnaire 
Dispensation of study drug and subject diary 
↓ 
Visit 2 
Day 15 ± 1 day 
2-Week Follow-Up 
Collection and review of  study drug/diary 
AE query, medical/medication update 
Symptom questionnaires 
Eye evaluations (Efficacy /Safety) 
Redispensation of study drug and dispensation of 
subject diary 
↓ 
Visit 3 
Day 29 ± 2 days 
Collection and review of study drug/diary 
AE query, medical/medication update 


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4-Week Follow-Up 
Symptom questionnaires, 
 
Eye evaluations (Efficacy /Safety) 
Dispensation of study drug and subject diary 
↓ 
Visit 4 
Day 57 ± 2 days 
8-Week Follow-Up 
Collection and review of study drug/diary 
AE query, medical/medication update 
Symptom questionnaires 
Eye evaluations (Efficacy /Safety) 
Dispensation of study drug and subject diary 
↓ 
Visit 5 
Day 85 ± 2 days 
12-Week Follow-Up and 
Study Exit 
Collection and review of study drug/diary 
AE query 
medical/medication update and further 
demographic data 
Urine pregnancy test (as needed) 
Symptom questionnaires, reading assessments 
Eye evaluations (Efficacy /Safety) 
Study exit 
 
Subjects who terminate early during the treatment period will be asked, if possible, to complete 
safety assessments before commencing any alternate dry eye therapy. Subjects who are 
terminated early from the study will not be replaced. 
 
4.2 Participant and Study Completion 
An estimated 
 subjects will be screened to enroll and randomize at least 316 subjects at 
approximately 10 sites with 158 subjects per each of the two treatment arms.  
The study is planned to start with first patient first visit in October 2017 and is estimated be 
completed with last subject last visit occurring in June 2018. 
4.3 End of Study Definition 
The end of the study for an individual patient is defined as that patient’s last clinic visit. 
 
The end of the study for the overall trial is defined as the finalization of the Clinical Study 
Report. 


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4.4 Justification of Study Design 
Based on CYS-002 results Novaliq plans a confirmatory study in DED patients having 
 
 (NEI grading) at baseline. This population responded best in signs and 
symptoms. 
The study will be a randomized, double-masked, vehicle controlled study to demonstrate efficacy 
and safety of CyclASol after 1-month treatment duration. Vehicle controlled studies are currently 
the standard for DED studies. Randomization and double masking are state of the art measures to 
reduce bias. Fast onset of efficacy is important for patients and their compliance to therapies, 
thus early demonstration of efficacy (e.g. at 1 month) is desired and highly clinically relevant. 
Moreover, DED is a fluctuating condition with phase-like recurring dry eye complaints that may 
be linked to seasonal and / or environmental changes (van Setten, et al. 2016), thus a primary 
endpoint assessment at a shorter treatment duration is considered clinically relevant and has a 
greater potential to capture the true drug effect. 
Total corneal fluorescein staining (NEI grading) and total OSDI have been selected as the 
primary sign endpoint and primary symptom endpoint, respectively. The two primary endpoints 
will be tested in a sequential order with total corneal fluorescein staining being tested first. Both 
primary endpoints are well accepted by regulators and clinicians. The hierarchical testing has 
been selected to protect the α – error. Corneal staining is being tested first as the CYS-002 data 
for this endpoint is stronger. 
4.5 Justification for Dose 
The dose for this trial has been selected based on the previous CYS-002 study, which 
investigated two concentrations of CyclASol (0.05% and 0.1%). Neither the statistical analysis 
on the total population nor the modelling & simulation analysis identified a clear dose-response 
for sign or symptoms between the two CyclASol groups.  However, there were some trends 
favoring CyclASol 0.1% over CyclASol 0.05% in symptoms in all subjects and in the target 
population for the current study (patients having total corneal staining of ≥10 at baseline). 
Moreover, the CsA amount applied with the CyclASol 0.1% is still lower than that of Restasis 
 
 
 Novaliq intends to pursue the 
concentration of CyclASol 0.1% for the current pivotal study CYS-003. 
5 STUDY POPULATION 
5.1 Number of Subjects (approximate) 
An estimated 
subjects will be screened to enroll and randomize at least 316 
subjects at approximately 10 sites with 158 subjects per each of the two treatment 
arms. Subjects meeting all of the inclusion criteria and none of the exclusion criteria 
will be enrolled into the study and randomized in a 1:1 ratio of CyclASol to vehicle. 


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5.2 Study Population Characteristics 
All subjects must be at least 18 years of age, of either sex, and of any race. 
Furthermore, subjects must have a subject-reported history of dry eye in both eyes 
and meet all inclusion criteria and none of the exclusion criteria. 
5.3 Inclusion Criteria 
Each subject must: 
a. Be at least 18 years of age; 
b. Provide written informed consent; 
c. Have a subject reported history of Dry Eye Disease
 
 
d. Be currently using (within 30 days before Visit 0) over-the-counter (OTC) eye 
drops, lubricating gels and/or artificial tears for dry eye symptoms at Visit 0; 
e. Have an OSDI score of 
 at Visit 0 and Visit 1; 
f. Have a total corneal fluorescein staining score of 
 
 
 
g. Have a total lissamine green conjunctival score (sum of temporal and nasal 
regions) of 
 
h. Have an unanesthetized Schirmer’s Test score 
 
 
 
 
j. Be able and willing to follow instructions and participate in all study 
assessments and visits. 
5.4 Exclusion Criteria 
Each subject must not: 
a. Have any clinically significant slit-lamp findings at Visit 0 that require 
prescriptive medical treatment and/or in the opinion of the investigator may 
interfere with study parameters including trauma, Steven Johnson Syndrome, 
advanced epithelial basement membrane disease; 
 
 


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c. Have abnormal lid anatomy (e.g. incomplete eyelid closure, entropion, or 
ectropion) or abnormal blinking; 
 
 
e. Have an ocular or periocular malignancy; 
 
g. Have a history of herpetic keratitis; 
h. Have active ocular allergies or ocular allergies that may become active during 
the study period; 
i. Be diagnosed with an ongoing ocular or systemic infection (bacterial, viral, or 
fungal), including a fever, or be undergoing treatment with antibiotics at Visit 
0 or Visit 1; 
j. Have worn contact lenses within 90 days before Visit 0 or anticipate using 
contact lenses during the study; 
 
l. Have used topical CsA or Lifitegrast within 60 days before Visit 0; 
 
 
n. Have had intraocular surgery or ocular laser surgery within 180 days before 
Visit 0, or have any planned ocular or eyelid surgeries during the study period; 
o. Be a woman who is pregnant, nursing, or planning a pregnancy; 
p. Be unwilling to submit a urine pregnancy test at Visit 0 and Visit 5 (or early 
termination visit) if of childbearing potential. Non-childbearing potential is 
defined as a woman who is permanently sterilized (i.e. has had a 
hysterectomy, bilateral tubal ligation, or bilateral oophorectomy), or is post-
menopausal (i.e. without menses for 12 consecutive months); 


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q. Be a woman of childbearing potential who is not using an acceptable means of 
contraception. Acceptable methods of contraception include hormonal 
contraceptives (i.e. oral, implantable, injectable, or transdermal 
contraceptives), mechanical contraceptives (i.e. spermicide in conjunction 
with a barrier such as a diaphragm or a condom), intrauterine devices (IUD), 
or the surgical sterilization of the partner. For non-sexually active females, 
abstinence may be regarded as an adequate method of birth control; however, 
if the subject becomes sexually active during the study, she must agree to use 
adequate birth control as defined above for the remainder of the study; 
r. Have an uncontrolled systemic disease; 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
aa. Have a condition or be in a situation (e.g. language barrier) which the 
investigator feels may put the subject at significant risk, may confound the 
study results, or may interfere with the subject’s participation in the study 
significantly; or 
 


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5.5 Withdrawal Criteria (if applicable) 
If at any time during the study the investigator determines that a subject’s safety has 
been compromised, the subject may be withdrawn from the study in particular: 
• the occurrence of an exclusion criterion which is clinically relevant and 
affects the subject’s safety, if discontinuation is considered necessary by 
the investigator and/or sponsor. 
• the occurrence of an AE if discontinuation of trial drug is desired or 
considered necessary by the investigator and/or the subject. 
• the occurrence of pregnancy. 
Subjects may withdraw consent from the study at any time without reason. 
The sponsor and/or the investigator may discontinue any subject for non-compliance 
or any valid medical reason (see Section 8.6). 
6 STUDY PARAMETERS 
6.1 Efficacy Measures 
6.1.1 Primary Efficacy Variable(s) 
Two primary endpoints will be tested in the following order using hierarchical 
fixed sequence testing: 
1. Change from baseline in total corneal fluorescein staining (NEI scale) 
at Day 29 
2. Change from baseline in Ocular Surface Disease Index (OSDI) at Day 
29 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
  
 
 


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6.1.4 Criteria for Effectiveness 
Hierarchical fixed sequence testing will be employed to maintain the type I 
error rate. The primary analyses will first test the difference in the mean 
change from baseline corneal fluorescein staining (NEI scale) total score 
between treatments at Day 29. If the test of the difference is statistically 
significant at the two-sided alpha = 0.05 level in favor of CyclASol, then the 
study will be considered a success; CyclASol will be declared to be superior 
to vehicle in the mean change from baseline corneal fluorescein staining (NEI 
scale) total score at Day 29; and the difference in the mean change from 
baseline total OSDI score between treatments at Day 29 will be tested at the 
two-sided alpha = 0.05 level. 
If in addition to a statistically significant test of the difference in the mean 
change from baseline corneal fluorescein staining (NEI scale) total score at 
Day 29 in favor of CyclASol, the test of the difference in the mean change 
from baseline total OSDI score at Day 29 is also statistically significant in 
favor of CyclASol, then CyclASol will be declared to be superior to vehicle in 
both the mean change from baseline corneal fluorescein staining (NEI scale) 
total score and the mean change from baseline total OSDI score at Day 29.  
 
 
 
 


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6.2 Safety Measures 
These evaluations will be performed in an effort to ensure subject safety throughout 
the trial: 
• Change in visual acuity from baseline at Visit 1 to Visits 2, 3, 4, and 5; 
• Change in slit-lamp biomicroscopy findings from Visit 1 to Visits 2, 3, 4, and 
5; 
• Change in intraocular pressure from Visit 0 to Visit 3 and 5;  
• Change in dilated fundoscopy findings from Visit 0 to Visit 5. 
• Systemic and ocular AEs 
 
 
 
 
7 STUDY MATERIALS 
7.1 Study Treatment(s) 
7.1.1 Study Treatment(s)/ Formulation(s)/ Medical Device Composition or Design 
Run-In 
• Systane Balance Lubricant Eye Drops  
 
Randomized Study Treatments 
• CyclASol 0.1% Ophthalmic Solution 
• Vehicle Ophthalmic Solution (F4H5) 
 


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7.1.2 Description of for the Route of Administration, Dosage, Dosage Regimen, and 
Treatment Period(s). 
• At the end of Visit 0, qualified subjects will receive the run-in medication 
(Systane Balance). Their first dose of run-in will be in-office. They will then 
be instructed to dose at home BID up to and including the morning of Visit 1. 
Subjects will be instructed to dose in the morning and in the evening at 
bedtime. Subjects will record in the subject’s diary that their doses were taken. 
 
• Study drug will be provided to sites as subject kits containing 3 bottles of 
CyclASol 0.1% Ophthalmic Solution or Vehicle Ophthalmic Solution. 
 
• At Visit 1, used/unused run-in will be collected from subjects. At the end of 
Visit 1, qualified subjects will be randomized and the first dose of study drug 
will be administered in the study center. The subject will receive the first 
bottle out of the assigned subject kit for dosing BID. Subjects will record in 
their diary that their doses were taken. A bottle should not be used after 30 
days after opening; based on the use of visit windows for a subject this may be 
prolonged at the discretion of the Investigator.  
 
• At Visit 2, used/unused study drug will be collected from subjects for drug 
accountability. If the bottle is still intact and contains sufficient liquid it will 
be returned to the subject with instructions to continue to dose BID. If the 
bottle is not intact or there is insufficient liquid in the bottle, the subject will 
be dispensed a new bottle to continue BID dosing. Subjects will record in their 
diary that their doses were taken. A bottle should not be used after 30 days 
after opening; based on the use of visit windows for a subject this may be 
prolonged at the discretion of the Investigator. 
 
• At Visit 3 used/unused study drug will be collected from subjects for drug 
accountability. Subjects will receive their bottle from the same subject kit with 
instructions to continue to dose BID. The site must ensure that the study drug 
supply given to the subject is taken from the correct kit that was previously 
assigned to that subject. Subjects will record in their diary that their doses 
were taken. A bottle should not be used after 30 days after opening; based on 
the use of visit windows for a subject this may be prolonged at the discretion 
of the Investigator. 
 
• At Visit 4 used/unused study drug will be collected from subjects for drug 
accountability. Subjects will be dispensed the third bottle from the same 
subject kit with instructions to continue to dose BID. The site must ensure that 
the study drug supply given to the subject is taken from the correct kit that 
was previously assigned to that subject. Subjects will record in their diary that 
their doses were taken. A bottle should not be used after 30 days after 
opening; based on the use of visit windows for a subject this may be 
prolonged at the discretion of the Investigator. 


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• At Visit 5 used/unused study drug will be collected from subjects for drug 
accountability.  
 
• Subjects will be instructed to use run-in (at Visit 1) or study drug on the day 
of visits (Visit 2, 3, 4, and 5) at least 2 hours prior to the start of the visit. 
 
• Subjects will be instructed to immediately contact the site if there is any 
problem with the study drug (e.g. if the bottle was dropped or lost). In case the 
subject needs a replacement, the next bottle from the kit will be dispensed. If 
no bottle remains in the kit, a new kit will be assigned to the subject using the 
IWRS. 
7.1.3 Instructions for Use and Administration 
Subjects will be instructed to instill one drop in each lower eyelid two times daily 
(in the morning and in the evening before bed). Subjects will be instructed to use 
a second drop only if the first drop misses the eye. Subjects will receive detailed 
written instructions how to dose and complete their diary.  
 
7.2 Other Study Supplies 
Schirmer’s test strips, sodium fluorescein, lissamine green, lissamine strips, Fluress, 
Tropicamide, InflammaDry. 
8 STUDY METHODS AND PROCEDURES 
8.1 Subject Entry Procedures 
8.1.1 Overview 
Subjects as defined by the criteria in sections 5.2, 5.3, and 5.4 will be 
considered for entry into this study. 
8.1.2 Informed Consent 
Before a subject’s participation in the trial (i.e., changes in a subject’s medical 
treatment and/or study-related procedures), the study will be discussed with 
each subject, and subjects wishing to participate must give written informed 
consent (and/or assent) using an informed consent form. The informed 
consent form must be the most recent version that has received 
approval/favorable review by a properly constituted Institutional Review 
Board (IRB). 


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8.1.3 Washout Intervals 
Prohibiteed medications and treatments are listed in the Exclusion Criteria 
(Section 5.4) with their respective washout intervals.  
8.1.4 Procedures for Final Study Entry 
To qualify for Final Study Entry, each subject must meet all of the Inclusion 
Criteria (Section 5.3) and none of the Exclusion Criteria (Section 5.4). 
8.1.5 Methods for Assignment to Treatment Groups: 
Before the initiation of study run-in at Visit 0, each subject who provides 
written and informed consent will be assigned to a screening number. All 
screening numbers will be assingned in strict numerical sequence at a site and 
no numbers will be skipped or omitted. Each subject who meets all the 
inclusion and none of the exclusion criteria at Visit 0 and Visit 1 will be 
assigned a randomization number at the end of Visit 1. The IWRS will be 
used to assign all randomization numbers. 
Randomization and kit numbers will be assigned automatically to each subject 
by strata as they are entered into the IWRS.
 
  
 
 
 
 
The site staff will dispense from this kit medication required until the next 
visit. Both the randomization number and the dispensed study drug kit number 
will be recorded on the subject’s source document and electronic Case Report 
Form (eCRF). The rest of the kit will remain at the site and the site ensures 
that the same subject will receive study medication from the respective kit at 
his/her next visit. The sponsor, investigators, and study staff will be masked 
during the randomization process and throughout the study. 
8.2 Concurrent Therapies 
The use of any concurrent medication, prescription or OTC, is to be recorded on the 
subject’s source document and corresponding eCRF along with the reason the 
medication was taken. 
Concurrent enrollment in another investigational drug or medical device study is not 
permitted. 
8.2.1 Prohibited Medications/Treatments 
Disallowed medications and treatments are listed in the Exclusion Criteria 
(Section 5.4). All medications and treatments that were not allowed prior to 


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study are also not allowed during the study, in particular no other dry eye 
treatment shall be used during the course of the study such as artificial tears 
(other than run-in medication), gels, ointments shall be used during the course 
of the study. Physical treatments such as lid scrubs, lid wipes, warm 
compresses must be kept stable. Hypochlorous acid wipes are not allowed. 
8.2.2 Escape Medications 
Not applicable. 
 
 
 
 
 
8.3 Examination Procedures 
8.3.1 Procedures to be Performed at Each Study Visit with Regard to Study 
Objective(s) 
The procedures outlined in this section will performed as described in 
Appendix 2. 
Visit 0 (Day -14 ± 2 days): Screening 
• Informed consent / HIPAA 
• Medical/medication history and demographic data 
• Urine pregnancy test for females of childbearing potential 
• Ocular Surface Disease Index (OSDI) 
 
 
 
 
• Visual acuity (ETDRS) 
• Slit-lamp biomicroscopy 
 
 
• Fluorescein staining (NEI scale) 
 
 
 
 
 
 
• Intraocular pressure 
• Dilated fundoscopy 
• Review of qualification criteria 
• In-office instillation of run-in drops to qualified subjects 
• Dispensation of subject diary and run-in for bilateral, BID dosing until 
Visit 1 as described in Section 7.1.3 
• Adverse event query 


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• Qualified subjects are scheduled for Visit 1 
Visit 1 (Day 1): Baseline / Randomization 
• Collection and review of run-in and diary 
o Calculate subject compliance as described in Section 8.5 
o Ask subject if he/she dosed with run-in the morning of Visit 1 
and, if applicable, record the time of the dose 
• Medical/medication history update 
• Adverse event query 
• OSDI 
• 
 
 
 
 
 
 
 
 
 
 
• Visual acuity 
• Slit-lamp biomicroscopy 
 
 
 
 
• Fluorescein staining (NEI scale) 
 
 
 
 
 
 
• Review of qualification criteria 
• Randomization 
• In-office instillation of randomized study drug 
 
 
• Dispensation of subject diary and randomized study drug for bilateral, 
BID dosing until Visit 2 as described in Section 7.1.3 
• Adverse event query 
• Randomized subjects are scheduled for Visit 2 
Visit 2 (Day 15 ± 1): 2-Week Follow-Up 
• Collection and review of study drug and subject diary 
 
 
 
 
 
 
 
• Medical/medication history update 
• Adverse event query 


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• OSDI 
 
 
 
 
 
  
• Visual acuity 
• Slit-lamp biomicroscopy 
• Fluorescein staining (NEI scale) 
 
 
 
 
• Dispensation of subject diary and randomized study drug for bilateral, 
BID dosing until Visit 3 as described in Section 7.1.3 
• Adverse event query 
• Schedule for Visit 3 
Visit 3 (Day 29 ± 2): 4-Week Follow-Up 
• Collection and review of study drug and subject diary; 
 
 
 
 
 
 
 
• Medical/medication history update 
• Adverse event query 
• OSDI 
 
 
 
 
 
 
 
• Visual acuity 
• Slit-lamp biomicroscopy 
 
 
 
 
• Fluorescein staining (NEI scale) 
 
 
 
 
 
 
• Intraocular pressure 
• Dispensation of subject diary and randomized study drug for bilateral, 
BID dosing until Visit 4 as described in Section 7.1.3 
• Adverse event query 
• Schedule for Visit 4 


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Visit 4 (Day 57 ± 2): 8-Week Follow-Up 
• Collection and review of study drug and subject diary 
 
 
 
 
 
 
 
• Medical/medication history update 
• Adverse event query 
• OSDI 
 
 
 
 
 
 
• Visual acuity 
• Slit-lamp biomicroscopy 
• Fluorescein staining (NEI scale) 
 
 
 
 
• Dispensation of subject diary and randomized study drug for bilateral, 
BID dosing until Visit 5 as described in Section 7.1.3 
• Adverse event query 
• Schedule for Visit 5 
Visit 5 (Day 85 ± 2): 12-Week Follow-Up and Study Exit 
• Collection and review of study drug and subject diary 
 
 
 
 
 
 
 
• Medical/medication history update, and further demographic data 
 
• Urine pregnancy test for females of childbearing potential 
• Adverse event query 
• OSDI 
 
 
 
 
 
 
 
• Visual acuity 
• Slit-lamp biomicroscopy 


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• Fluorescein staining (NEI scale) 
 
 
 
 
 
 
• Intraocular pressure 
• Dilated fundoscopy 
• Adverse event query 
• Study exit 
8.3.2 Early Termination/Discontinuations 
If a subject is discontinued from the study before Visit 5 (Day 85 ± 2 days), 
then all safety evaluations that are to be performed at Visit 5 should be 
performed and the demographic data 
 should be obtained on 
the day of early termination/discontinuation or at the discretion of the 
investigator.  
Adverse events (both elicited and observed) will be monitored throughout the 
study. All AEs will be promptly reviewed by the investigator for accuracy and 
completeness. All AEs will be documented on the appropriate eCRF. 
If a female has a positive pregnancy test during the study, then the investigator 
will notify 
 immediately. The investigator shall request from the subject 
and/or the subject’s physician copies of all related medical reports during the 
pregnancy and shall document the outcome of the pregnancy. The investigator 
will retain these reports together with the subject’s source documents and will 
provide a copy of all documentation to 
. 
8.4 Schedule of Visits, Measurements and Dosing 
8.4.1 Scheduled Visits 
Refer to Appendix 1 for a schedule of visits and measurements. 
8.4.2 Unscheduled Visits 
An unscheduled visit may be performed during the course of the study to 
ensure subject safety. All procedures performed at an unscheduled visit will 
be recorded in the source documents and on the Unscheduled Visit eCRF 
pages. Any unscheduled visit procedure listed in the eCRF that is not 
performed should be indicated as “not done.” 
Evaluations that may be conducted at an Unscheduled Visit include 
• Slit-lamp biomicroscopy; 


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• VA; 
• IOP; 
• Urine pregnancy test (for women of childbearing potential); 
• Dilated fundoscopy; 
• Assessment of AEs; 
• Assessment of concomitant medications and/or treatments; and 
• Any other assessments needed in the judgement of the investigator. 
8.5 Compliance with Protocol 
Subjects will be instructed on the proper use and storage of the study drug at Visits 0, 
1, 2, 3, and 4, and provided with written instructions. Subject diaries and study drug 
will be collected at each visit from Visit 1 up to and including Visit 5 to assess 
subject compliance with the protocol. 
 
 
 
 
 
 
 
8.6 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the study. 
8.6.2 Discontinued Subjects 
Subjects may be discontinued prior to their completion of the study due to: 
• AEs; 
• Protocol violations; 
• Lack of efficacy; 
• Administrative reasons (e.g., inability to continue, lost to follow up); 
• Sponsor termination of study; 
• Pregnancy; 
• Other 
Note: In addition, any subject may be discontinued for any sound medical 
reason at the discretion of the investigator. 
Notification of a subject discontinuation and the reason for discontinuation 
will be made to 
and/or study sponsor and will be clearly documented on 
the eCRF. 
Discontinued subjects will not be replaced. 


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8.7 Study Termination 
The study may be stopped at any time by the investigator, the sponsor, and/or 
 
with appropriate notification. 
The whole trial may be discontinued prematurely in the event of any of new 
information leading to unfavorable risk-benefit judgment of the IP, e.g. due to: 
• 
Occurrence of significant previously unknown adverse reactions or unexpectedly 
high intensity or incidence of known adverse reactions, or 
• 
Other unfavorable safety findings. 
• 
Sponsor’s decision that continuation of the trial is unjustifiable for medical or 
ethical reasons. 
• 
Poor enrollment of subjects making completion of the trial within an acceptable 
time frame unlikely. 
• 
Discontinuation of development of the sponsor’s IP. 
• 
Health Authorities and IECs/ IRBs will be informed about the discontinuation of 
the trial in accordance with applicable regulations. 
The whole trial may be terminated or suspended upon request of Health Authorities. 
8.8 Study Duration 
An individual subject’s participation will involve 6 visits over approximately a 14-
week period. If applicable and as needed, after the study, subjects will be treated 
according to the standard of care by the discretion of the investigator / treating 
physician. 
8.9 Monitoring and Quality Assurance 
During the course of the study a monitor, or designee, will make routine site visits to 
review protocol compliance, assess study drug/device accountability, and ensure the 
study is being conducted according to the pertinent regulatory requirements.  The 
review of the subjects’ medical records will be performed in a manner that adequately 
maintains subject confidentiality.  Further details of the study monitoring will be 
outlined in a monitoring plan. 
Regulatory authorities of domestic and foreign agencies, sponsor quality assurance 
and or its designees may carry out on-site inspections and/or audits which may 
include source data checks.  Therefore, direct access to the original source data will 
be required for inspections and/or audits.  All inspections and audits will be carried 
out giving consideration to data protection as well as subject confidentiality to the 
extent that local, state, and federal laws apply. 


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9 ADVERSE EVENTS 
9.1 Adverse Event 
An adverse event (AE) is defined as any untoward medical occurrence associated 
with the use of a drug in humans, whether or not the event is considered drug-related. 
An AE can therefore be any unfavorable and unintended sign (e.g., an abnormal 
laboratory finding), symptom, or disease occurring after the subject started dosing 
with the study drug or the run-in medication, without any judgment about causality. 
If there is a worsening of a medical condition that was present prior to the 
administration of the study drug, this should also be considered a new AE and 
reported. Any medical condition present prior to the administration of the study drug 
that remains unchanged or improved should not be recorded as an AE at subsequent 
visits. 
Worsening of DED will be considered an AE only if the dry eye status of the subject 
exceeds their previous experiences with the condition. This will be determined by the 
subject and the investigator.  
A clinically significant visual acuity decrease 
 
 from baseline (Visit 0) will be considered an AE. 
Study drug includes the investigational drug under evaluation and any comparator 
drug, vehicle, or any other medications required by the protocol given during any 
stage of the study. 
Documentation regarding the AE should be made as to the nature, date of onset, end 
date, severity, relationship to study drug, action(s) taken, seriousness, and outcome of 
any sign or symptom observed by the physician or reported by the subject upon 
indirect questioning.  
9.1.1 Severity 
Severity of an AE is defined as a qualitative assessment of the degree of 
intensity of an AE as determined by the investigator or reported to him/her by 
the patient/subject.  The assessment of severity is made irrespective of 
relationship to investigational product or seriousness of the event and should 
be evaluated according to the following scale: 
• Mild: Event is noticeable to the subject, but is easily tolerated and does 
not interfere with the subject’s daily activities. 
• Moderate:  Event is bothersome, possibly requiring additional therapy, and 
may interfere with the subject’s daily activities. 
• Severe:  Event is intolerable, necessitates additional therapy or alteration 
of therapy, and interferes with the subject’s daily activities. 


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9.1.2 Relationship to Investigational Product 
The relationship of each AE to the investigational product should be 
determined by the investigator using these explanations: 
• Suspected:  A reasonable possibility exists that the investigational product 
caused the AE. 
• Not Suspected: A reasonable possibility does not exist that the 
investigational product caused the AE. 
 
Suspected adverse reaction means any AE for which there is a reasonable 
possibility that the investigational product caused the AE.  “Reasonable 
possibility” means there is evidence to suggest a causal relationship 
between the investigational product and the AE.  Types of evidence that 
would suggest a causal relationship between the investigational product 
and the AE include:  a single occurrence of an event that is uncommon and 
known to be strongly associated with IP exposure (e.g., angioedema, 
hepatic injury, Stevens-Johnson Syndrome); one or more occurrences of 
an event that is not commonly associated with IP exposure, but is 
otherwise uncommon in the population exposed to the IP (e.g., tendon 
rupture); an aggregate analysis of specific events observed in a clinical 
trial (such as known consequences of the underlying disease or condition 
under investigation or other events that commonly occur in the study 
population independent of drug therapy) that indicates those events occur 
more frequently in the IP-treatment group than in a concurrent or 
historical control group. 
9.1.3 Expectedness 
The expectedness of an AE should be determined based upon existing safety 
information about the study drug. CyclASol contains the active ingredient 
CsA and the vehicle F4H5 and has been tested in two clinical studies up to 
now, AEs of those have been listed in the investigator’s brochure. Therefore, 
the following definition will be used: 
• Unexpected: An AE that is not listed in the investigator’s brochure (IB) in 
the Adverse Reaction Section at the specificity or severity that has been 
observed. 
• Expected: An AE that is listed in the investigator’s brochure (IB) in the 
Adverse Reaction Section at the specificity and severity that has been 
observed. 
• Not Applicable: Any AE that is unrelated to the study drug. 
The investigator should initially classify the expectedness of an AE, but the 
final classification is subject to the Medical Monitor’s determination. 


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9.2 Serious Adverse Events 
An AE is considered serious if, in the view of either the investigator or sponsor, it 
results in any of the following outcomes: 
• Death; 
• A life-threatening AE; 
o Note:  An AE is considered “life-threatening” if, in the view of either the 
investigator or sponsor, its occurrence places the patient or subject at 
immediate risk of death.  It does not include an AE that, had it occurred in a 
more severe form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization; 
o Note:  The term “inpatient hospitalization” refers to any inpatient admission 
(even if less than 24 hours).  For chronic or long-term inpatients, inpatient 
admission includes transfer within the hospital to an acute/intensive care 
inpatient unit.  Inpatient hospitalization does not include:  emergency room 
visits; outpatient/same-day/ambulatory procedures; observation/short stay 
units; rehabilitation facilities; hospice facilities; nursing homes; or clinical 
research/phase 1 units. 
o Note:  The term “prolongation of existing hospitalization” refers to any 
extension of an inpatient hospitalization beyond the stay anticipated or 
required for the reason for the initial admission as determined by the 
investigator or treating physician. 
• A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions; 
o Note:  A serious adverse event (SAE) specifically related to visual threat 
would be interpreted as any potential impairment or damage to the subject’s 
eyes (e.g., hemorrhage, retinal detachment, central corneal ulcer or damage to 
the optic nerve). 
• A congenital anomaly/birth defect. 
Important medical events that may not result in death, are life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical 
judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. 
9.3 Procedures for Reporting Adverse Events 
All AEs and their outcomes must be reported to 
 the study sponsor, and the 
IRB/IEC as required by the IRB/IEC, federal, state, or local regulations and 
governing health authorities and recorded on the appropriate eCRF. 


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9.3.1 Reporting a Suspected Unexpected Adverse Reaction 
All AE that are ‘suspected’ and ‘unexpected’ are to be reported to 
 the 
study sponsor and the IRB/IEC as required by the IRB/IEC, federal, state, or 
local regulations and governing health authorities. 
9.3.2 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of relationship to the 
investigational product, must be immediately reported (i.e. within a maximum 
24 HOURS after becoming aware of the event).  All information relevant to 
the SAE must be recorded on the appropriate case report forms.  The 
investigator is obligated to pursue and obtain information requested by 
 
and/or the sponsor in addition to that information reported on the case report 
form.  All subjects experiencing a SAE must be followed up and the outcome 
reported. 
In the event of a SAE, the investigator must notify 
 and the sponsor 
immediately; obtain and maintain in his/her files all pertinent medical records, 
information, and medical judgments from colleagues who assisted in the 
treatment and follow-up of the subject; provide 
 and the study sponsor 
with a complete case history, which includes a statement as to whether the 
event was or was not suspected to be related to the use of the investigational 
product; and inform the IRB of the AE within their guidelines for reporting 
SAEs. 
Contact information for reporting SAEs: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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9.4 Procedures for Unmasking (if applicable) 
All subjects, investigators, and study personnel involved with the conduct of the study 
will be masked with regard to treatment assignments. When medically necessary, the 
investigator may need to determine what treatment arm has been assigned to a 
subject. When possible (i.e., in non-emergent situations), 
 and/or the study 
sponsor should be notified before unmasking study drug. 
 and/or the study 
sponsor must be informed immediately about any unmasking event. 
If an investigator identifies a medical need for unmasking the treatment assignment of 
a subject, he/she should contact 
 and/or the medical monitor prior to unmasking 
the identity of the IP, if possible. 
 will ask the site to complete and send them the 
Unmasking Request Form. 
 will notify Novaliq and jointly will determine if the 
unmasking request should be granted. They may consult the medical monitor as 
needed. The result of the request will be documented on the Unmasking Request 
Form. If approval is granted to unmask a subject, written permission via the 
Unmasking Request Form will be provided to the investigator. The investigator will 
unmask the subject using IWRS. The investigator will complete the Unmasking 
Memo form and include it in the subject’s study file and provide a copy for the Trial 
Master File (TMF). For each unmasked request, the reason, date, signature, and name 
of the person who unmasked the subject, must be noted in the subject’s study file.  
Unmasked subjects will be discontinued from the study. 
9.5 Type and Duration of the Follow-up of Subjects after Adverse 
Events 
The investigator will follow unresolved AEs to resolution until the subject is lost to 
follow-up or until the AE is otherwise classified. Resolution means the subject has 
returned to baseline state of health or the investigator does not expect any further 
improvement or worsening of the AE. If the subject is lost to follow-up, the 
investigator should make 3 reasonable attempts to contact the subject via telephone, 
post, or certified mail. All follow-up will be documented in the subject’s source 
document. Non-serious AEs identified on the last scheduled contact must be recorded 
on the AE eCRF with the status noted.  
If the investigator becomes aware of any new information regarding an existing SAE 
(i.e., resolution, change in condition, or new treatment), a new SAE/Unanticipated 
Report Form must be completed and faxed to 
 within 24 hours of the site’s 
awareness of the new information. The original SAE form is not to be altered. The 
report should describe whether the event has resolved or continues and how the event 
was treated. 


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10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
10.1 Analysis Populations 
The following analysis population will be considered: 
• Full Analysis Set (FAS) – The FAS includes all randomized subjects who received at 
least one dose of investigation product. The primary analysis will be performed on the 
FAS. Subjects in the FAS will be analyzed as randomized. 
 
• Per Protocol Set (PPS) – The PPS includes subjects in the FAS who do not have 
significant protocol deviations and who complete the study. Protocol deviations will 
be assessed prior to database lock and unmasking. The PPS will be analyzed using 
observed data only for efficacy variables. Subjects in the PPS will be analyzed as 
treated. 
 
• Safety Set (SAF) – The SAF includes all randomized subjects who have received at 
least one dose of the investigational product. The SAF will be analyzed for all safety 
assessments. Subjects in the SAF will be analyzed as treated.  
 
The statistical analysis of safety data will be performed for the SAF.  The analysis of baseline 
and efficacy data will be performed for the FAS.  The primary efficacy analyses will also be 
performed on the PPS as sensitivity analyses. 
 
10.2 Statistical Hypotheses 
The primary endpoints will be tested in a hierarchical fixed sequence in the following order.  
The statistical hypotheses for the primary endpoint of change from baseline corneal 
fluorescein staining (NEI scale) total score at Day 29 are as follows: 
 
H01: 
The difference, between study eyes treated with CyclASol and study eyes treated 
with vehicle, in the mean change from baseline corneal fluorescein staining (NEI scale) 
total score at Day 29 = 0.  
 
HA1:  The difference, between study eyes treated with CyclASol and study eyes treated 
with vehicle, in the mean change from baseline corneal fluorescein staining (NEI scale) 
total score at Day 29 ≠ 0, with superiority claimed if the difference is less than 0 
(CyclASol minus vehicle). 
The statistical hypotheses for the primary endpoint of the change from baseline total OSDI 
score at Day 29 are as follows: 
 
H02:  
The difference, between subjects treated with CyclASol and subjects treated with 
vehicle, in the mean change from baseline total OSDI score at Day 29 = 0. 


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HA2:  The difference, between subjects treated with CyclASol and subjects treated with 
vehicle, in the mean change from baseline total OSDI score at Day 29 ≠ 0, with 
superiority claimed if the difference is less than 0 (CyclASol minus vehicle). 
Hierarchical fixed sequence testing will be employed to maintain the type I error rate. The 
primary analyses will first test the difference in the mean change from baseline corneal 
fluorescein staining (NEI scale) total score between treatments at Day 29. If the test of the 
difference is statistically significant at the two-sided alpha = 0.05 level in favor of CyclASol, 
then the study will be considered a success; CyclASol will be declared to be superior to 
vehicle in the mean change from baseline corneal fluorescein staining (NEI scale) total score 
at Day 29; and the difference in the mean change from baseline total OSDI score between 
treatments at Day 29 will be tested at the two-sided alpha = 0.05 level. 
If in addition to a statistically significant test of the difference in the mean change from 
baseline corneal fluorescein staining (NEI scale) total score at Day 29 in favor of CyclASol, 
the test of the difference in the mean change from baseline total OSDI score at Day 29 is also 
statistically significant in favor of CyclASol, then CyclASol  will be declared to be superior 
to vehicle in both the mean change from baseline corneal fluorescein staining (NEI scale) 
total score and the mean change from baseline total OSDI score at Day 29. 
10.3 Sample Size 
One-hundred forty-two (142) ITT subjects (study eyes) per treatment group yields 90% 
power to reject H01 in favor of HA1 and conclude superiority of CyclASol over vehicle in the 
mean change from baseline corneal fluorescein staining (NEI scale) total score at Day 29 
assuming a true difference (CyclASol minus vehicle) of -0.85, a common standard deviation 
of 2.2, and a two-sided alpha = 0.05.  Additionally, 142 ITT subjects per treatment group 
yields 82% power to reject H02 in favor of HA2 and conclude superiority of CyclASol over 
vehicle in the mean change from baseline total OSDI score at Day 29 assuming a true 
difference (CyclASol minus vehicle) of -5.0, a common standard deviation of 14.5, and a 
two-sided alpha = 0.05. Accounting for subject discontinuations, 316 total subjects will be 
enrolled 
. 
For justification of clinical relevance of selected differences see Section 6.1.4. 
10.4 Statistical Analysis 
10.4.1 General Considerations 
The quantitative variables will be summarized using number of subjects (n), 
mean, median, standard deviation, minimum and maximum. The qualitative 
variables will be summarized using counts and percentages.  
All summaries will be presented by treatment group.  Summaries will be provided 
for demographics, baseline medical history, concurrent therapies, and subject 
disposition. 


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For the purpose of summarization, medical history, concurrent therapies, and AEs 
will be coded to MedDRA and WHO Drug dictionaries, as appropriate. 
Baseline is defined as the last non-missing measure prior to administration of 
study drug and change from baseline will be calculated as Visit – Baseline. 
10.4.2 Unit of Analysis 
Safety endpoints will be analyzed for both eyes. For efficacy endpoints, the unit 
of analysis will be the “study eye” as defined by the following: 
 
 
 
 
10.4.3 Missing Data 
The primary analysis will use the FAS with available data per subject. Additional 
robustness analyses will include repeating the primary analysis on the PPS; the 
FAS imputing missing data using LOCF; the FAS imputing missing data using 
Markov Chain Monte Carlo (MCMC) multiple imputation methodology under 
different assumptions of missingness (at random and not at random); and an 
analysis of trimmed means (Permutt et al., 2017). 
No secondary efficacy endpoints or safety endpoints will be imputed. 
10.4.4 Multiplicity Considerations 
Fixed sequence testing will be employed to maintain the type I error rate. The 
primary analyses will first test the difference in the mean change from baseline 
corneal fluorescein staining (NEI scale) total score between treatments at Day 29. 
If the test of the difference is statistically significant at the two-sided alpha = 0.05 
level in favor of CyclASol, then the study will be considered a success; CyclASol 
will be declared to be superior to vehicle in the mean change from baseline 
corneal fluorescein staining (NEI scale) total score at Day 29; and the difference 
in the mean change from baseline total OSDI score between treatments at Day 29 
will be tested at the two-sided alpha = 0.05 level. 
If in addition to a statistically significant test of the difference in the mean change 
from baseline corneal fluorescein staining (NEI scale) total score at Day 29 in 
favor of CyclASol, the test of the difference in the mean change from baseline 
total OSDI score at Day 29 is also statistically significant in favor of CyclASol, 
then CyclASol will be declared to be superior to vehicle in both the mean change 
from baseline corneal fluorescein staining (NEI scale) total score and the mean 
change from baseline total OSDI score at Day 29. 


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10.4.5 Primary Efficacy Analyses 
The primary comparisons in this study will be between CyclASol versus vehicle 
at Day 29. The primary efficacy endpoints (e.g. change from baseline in corneal 
fluorescein staining [total NEI] and OSDI) will be analyzed separately using an 
ANCOVA model with terms for baseline value, treatment, and the interaction of 
treatment by baseline value (the interaction term will be maintained in the model 
only if the p-value for the term is <0.10). 
Least squares mean for each treatment group and for the difference between 
treatment groups will be presented from the model together with two-sided p-
values and 95% confidence intervals. In the event that the interaction of treatment 
by baseline value is significant, estimate and contrast statements will be used to 
determine the treatment group means and differences at the 25th, 50th, and 75th 
percentile of the baseline score over treatment groups. 
Two-sample t-tests and Wilcoxon rank sum tests comparing treatment groups will 
be performed as sensitivity analyses. A mixed-effect repeated measures model 
will also be used as an additional sensitivity analysis of mean scores and mean 
changes from baseline at each visit.  This model will include treatment, visit, and 
the interaction between treatment and visit as fixed effects, and subject as a 
random effect.  An unstructured covariance matrix will initially be used to model 
the covariance among repeated measures; however, if the model fails to converge 
using this covariance structure, either heterogeneous TOEPLITZ, homogeneous 
TOEPLITZ, or CS (compound symmetry) will be implemented according to the 
Akaike information criterion with a correction for finite sample sizes (AICc).  As 
an additional sensitivity analysis, a mixed-effect repeated measures model will be 
used with the covariance matrix selected from unstructured, heterogeneous 
TOEPLITZ, homogeneous TOEPLITZ and CS according to AICc. 
 
 
 
 
 
 
 
 
 
 
 
 
 
  


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10.4.8 Safety Variables 
Adverse events (AEs) will be coded using the MedDRA dictionary. Frequencies 
and percentages of subjects with TEAEs, serious TEAEs, and TEAEs causing 
premature discontinuation will be provided by treatment group. An AE is 
treatment emergent if it 1) occurs after the first dose of randomized study 
treatment or 2) if it is present prior to receipt of randomized study treatment but 
worsens in severity or increases in frequency after the first dose of randomized 
study treatment. Furthermore, frequencies will be given of subjects with TEAEs 
by system organ class and preferred term; by system organ class, preferred term 
and maximal severity; by system organ class, preferred term and strongest 
relationship; by system organ class and preferred term for SAEs; and by system 
organ class, preferred term, and day of onset. Separate analyses will be performed 
for ocular specific and all AEs (including systemic). 
Other safety endpoints including visual acuity, slit lamp biomicroscopy, 
intraocular pressure (IOP) and dilated fundoscopy, will be summarized by 
treatment group and visit using descriptive statistics. Changes or shifts from 
baseline will also be summarized where appropriate. 
 
 
10.4.9 Interim Analyses 
No interim analyses are planned for this study. 


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10.5 Additional Analyses 
 
 
 
 
 
 
 
 
  
 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This study will be conducted in compliance with the protocol, current Good Clinical 
Practices (GCPs), including the International Conference on Harmonization (ICH) 
Guidelines, and in general, consistent with the Declaration of Helsinki.  In addition, all 
applicable local, state, and federal requirements relevant to the use of investigational 
products in the countries involved will be adhered to. 
11.1 Protection of Human Subjects 
11.1.1 Subject Informed Consent 
Informed consent/assent must take place before any study specific procedures 
are initiated.  Signed and dated written informed consent must be obtained 
from each subject and/or from the subject’s parent or legal guardian prior to 
enrollment into the study.  If the subject is under the legal age of consent, the 
consent form must be signed by a legal guardian or as required by state and/or 
local laws and regulations. 
All informed consent/assent forms must be approved for use by the sponsor 
and receive approval/favorable opinion from an IRB prior to their use.  If the 
consent form requires revision (e.g., due to a protocol amendment or 
significant new safety information), it is the investigator’s responsibility to 
ensure that the amended informed consent is reviewed and approved by 
 
prior to submission to the governing IRB and that it is read, signed and dated 
by all subjects subsequently enrolled in the study as well as those currently 
enrolled in the study. 
If informed consent is taken under special circumstances (oral informed 
consent), then the procedures to be followed must be determined by 
 
and/or study sponsor and provided in writing by 
 and/or study sponsor 
prior to the consent process. 


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11.1.2 Institutional Review Board (IRB) Approval 
This study is to be conducted in accordance with Institutional Review Board 
regulations (U.S. 21 CFR Part 56.103).  The investigator must obtain 
appropriate IRB approval before initiating the study and re-approval at least 
annually. 
Only an IRB approved version of the informed consent form will be used. 
11.2 Ethical Conduct of the Study 
This study will be conducted in accordance with the ethical principles that originated 
with the Declaration of Helsinki. 
11.3 Subject Confidentiality 
All personal study subject data collected and processed for the purposes of this study 
should be maintained by the investigator and his/her staff with adequate precautions 
as to ensure that the confidentiality of the data in accordance with local, state, and 
federal laws and regulations. 
Monitors, auditors and other authorized representatives of 
 the sponsor, the IRB 
approving this study, the FDA, the DHHS, other domestic government agencies, and 
other foreign regulatory agencies will be granted direct access to the study subject’s 
original medical and study records for verification of the data and/or clinical trial 
procedures.  Access to this information will be permitted to the aforementioned 
individuals to the extent permitted by law. 
A report of the results of this study may be published or sent to the appropriate health 
authorities in any country in which the investigational product may ultimately be 
marketed, but the subject’s identity will not be disclosed in these documents. 
11.4 Documentation 
Source documents may include a subject’s medical records, hospital charts, clinic 
charts, the investigator’s study subject files, as well as the results of diagnostic tests 
such as X-rays, laboratory tests, and EKGs.  The investigator’s copy of the eCRFs 
serves as the investigator’s record of a subject’s study-related data. 
11.4.1 Retention of Documentation 
All study related correspondence, patient records, consent forms, record of the 
distribution and use of all investigational products and copies of case report 
forms should be maintained on file for at least two years after the last approval 
of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region; or until at least two 
years have elapsed since the formal discontinuation of clinical development of 
the investigational product. These documents will be retained for a longer 
period if required by the applicable regulatory requirements or by an 
agreement with the sponsor.  It is the responsibility of the sponsor to inform 


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the investigator/institution as to when these documents no longer need to be 
retained. 
If the responsible investigator retires, relocates, or for other reasons withdraws 
from the responsibility of keeping study records, custody must be transferred 
to a person who will accept the responsibility.  The sponsor must be notified 
in writing of the name and address of the new custodian. 
11.5 Labeling, Packaging, Storage, Accountability, and Return or 
Disposal of Investigational Product 
11.5.1 Labeling/Packaging 
For the run-in period, 1 bottle of Systane Balance will be dispensed for two 
weeks of BID dosing. 
Investigational drug will be packaged and labeled into clinical kits. Study drug 
will be provided as subjects’ kits containing 3 bottles of CyclASol 0.1% 
Ophthalmic Solution or Vehicle Ophthalmic Solution. The required 
medication until the next visit will be dispensed to the subject (see Section 
7.1.2 for details). The kit with remaining medication will be kept at the site.  
11.5.2 Storage of Study Drug 
The study drug must be stored in a secure area accessible only to the 
investigator and his/her designees.  The study drug will be administered only 
to subjects entered into the clinical study, in accordance with the conditions 
specified in this protocol. 
Study drug must be stored at room temperature and must not be refrigerated, 
protected from light, and secured at the investigational site in a locked 
container. Subjects should be instructed to store study drug in the same 
manner at home. A bottle should not be used after 30 days after opening; 
based on the use of visit windows for a subject this may be prolonged at the 
discretion of the Investigator. 
11.5.3 Accountability of Study Drug 
The study drug is to only be prescribed by the principal investigator or his/her 
named sub investigator(s), and is to only be used in accordance with this 
protocol.  The study drug must only be distributed to subjects properly 
qualified under this protocol to receive study drug. 
The investigator must keep an accurate accounting of study drug received 
from the supplier. This includes the amount of study drug dispensed to 
subjects, amount of study drug returned to the investigator by the subjects, and 
the amount returned or disposed upon the completion of the study.  A detailed 
inventory must be completed for the study drug. 


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11.5.4 Return or Disposal of Study Drug 
All study drug will be returned to the sponsor or their designee.  The return 
and disposal of study drug will be specified in writing. 
11.6 Recording of Data on Source Documents and Electronic Case 
Reports Forms (eCRFs) 
The investigator is responsible for ensuring that study data is completely and 
accurately recorded on each subject’s eCRF, source document, and all study-related 
material.  All study data should also be attributable, legible, contemporaneous, and 
original.  Recorded datum should only be corrected in a manner that does not 
obliterate, destroy, or render illegible the previous entry (e.g., by drawing a single line 
through the incorrect entry and writing the revision next to the corrected data).  An 
individual who has corrected a data entry should make clear who made the correction 
and when, by adding to the correction his/her initials as well as the date of the 
correction. 
Data entry of all enrolled and randomized subjects will use software that conforms to 
21 CFR Part 11 requirements, and will be performed only by staff that have been 
trained on the system and have access to the system. Only AE data will be entered for 
screen failure subjects. An audit trail will be maintained within the electronic system 
to capture all changes made within the eCRF database. After the end of the study and 
database lock, compact discs (CDs) containing copies of all applicable subjects’ 
eCRFs will be provided to each investigator site to be maintained on file by the 
investigator.  
11.7 Handling of Biological Specimens 
Not Applicable. 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties 
involved in the study.  Authorship will be established before writing the manuscript.  
The study sponsor will have the final decision regarding authorship, manuscript and 
publication. 
 
 


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