Clinical trial NCT04523142
Conditions: Dry Eye Disease (DED)
Sponsor: Novaliq GmbH
Start date: 2021-01-04; Completion date: 2022-05-23
Enrollment: 202 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
The objective of this trial is to evaluate safety and tolerability of CyclASol during long-term use in subjects with Dry Eye Disease.

Detailed description:
Phase 3 multicenter, open-label, single-arm clinical trial to evaluate the safety, tolerability and efficacy of CyclASol in subjects with signs and symptoms of Dry Eye Disease. Subjects who completed the trial CYS-004, had a subject-reported history of dry eye in both eyes and met all other study eligibility criteria were dosed CyclASol bilaterally BID for 12 months.

Arms: arm 1: Cyclosporine A solution in vehicle
Interventions: intervention 1: CyclASol Ophthalmic Solution
Intervention descriptions: intervention 1: Cyclosporine A solution in vehicle

Protocol documents:
Prot_SAP_000.pdf: 
CyclASol® 0.1% Ophthalmic Solution 
Novaliq GmbH 
Clinical Trial Protocol: CYS-005 
Version 3.0 10th December 2020 
 
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Clinical Trial Protocol: CYS-005 
 
 
Protocol Title: 
 
 
A Phase 3, multi-center, open-label, single-arm clinical 
trial to assess the long-term safety and tolerability of 
topical CyclASol® for the treatment of Dry Eye Disease 
in subjects who completed the clinical trial CYS-004 
 
Protocol Number: 
CYS-005 
 
Trial Phase: 
3 
 
Investigational Product Name: 
CyclASol® 0.1 % Ophthalmic Solution (Cyclosporine A 
0.1%) 
 
IND Number: 
128163 
 
Indication: 
Dry Eye Disease (keratoconjunctivitis sicca) 
 
Sponsor: 
Novaliq GmbH 
Im Neuenheimer Feld 515 
69120 Heidelberg 
Germany 
 
Contract Research Organization: 
 
 
 
 
 
 
 
Original Protocol: 
27th August 2020 
Amendment 1:  
10th December 2020 
 
 
 
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. 
Regulatory Statement 
This trial will be performed in compliance with the protocol and in accordance with Good Clinical 
Practice (International Conference on Harmonisation [ICH], Guidance E6), principles of human 
subject protection, and applicable country-specific regulatory requirements. 
 
 


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1 SYNOPSIS AND TRIAL CONTACT INFORMATION 
 
1.1 TRIAL CONTACT INFORMATION 
 
SPONSOR PERSONNEL 
 
Scientific Lead: 
 
 
 
Clinical Operations: 
 
 
 
 
MEDICAL MONITOR 
 
Medical Monitor 
 
 
 
 
 
 
 PERSONNEL 
 
Clinical Project Manager: 
 
 
 
 
 
Biostatistician: 
 
 
 
 
 
 


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1.2 SYNOPSIS 
 
Protocol Title: 
A Phase 3, multi-center, open-label, single-arm clinical trial to 
assess the long-term safety and tolerability of topical CyclASol® 
for the treatment of Dry Eye Disease in subjects who completed 
the clinical trial CYS-004 
Protocol Number: 
CYS-005 
 
Investigational Product: 
CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 0.1% 
solution) 
Trial Phase: 
3 
Trial Objectives: 
The primary objective of this trial is to evaluate safety and 
tolerability of CyclASol during long-term use in subjects with 
Dry Eye Disease.  
The secondary objective is to evaluate efficacy of CyclASol 
during long-term use in subjects with Dry Eye Disease. 
 
Overall Trial Design 
 
Structure: 
Open-label, multi-center, single-arm 
Duration: 
An individual subject’s participation is estimated to be 
approximately 52 weeks (12 months). The estimated trial 
duration is 16 months. 
Dosage/Dose Regimen: 
Subjects who completed the clinical trial CYS-004 and are 
eligible for participation will receive the following treatment to 
be administered bilaterally BID for approximately 52 weeks 
(from Visit 1 to Visit 6): 
CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 0.1% 
solution)  
Summary of Visit 
Schedule: 
6 onsite-visits over the course of approximately 52 weeks 
· Visit 1 = Day 1, start of open label treatment (preferably on 
Day 29 (Visit 3) of CYS-004) 
· Visit 2 = week 4 ± 2 days, 
· Visit 3 = week 12 ± 7 days, 
· Visit 4 = week 26 ± 7 days, 
· Visit 5 = week 40 ± 7 days, 
· Visit 6= week 52 ± 7 days / trial exit 
7 telephone calls (TC; optionally onsite visits) 
· TC 1= week 8 follow-up ± 7 days 
· TC 2 = week 16 follow-up ± 7 days 
· TC 3 = week 22 follow-up ± 7 days 


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· TC 4 = week 30 follow-up ± 7 days 
· TC 5 = week 36 follow-up ± 7 days 
· TC 6 = week 44 follow-up ± 7 days 
· TC 7 = week 48 follow-up ± 7 days 
 
Study Population Characteristics 
Number of Subjects: 
Up to
 subjects who completed trial CYS-004 will be enrolled 
at approximately 13 sites to achieve at least 100 subjects 
completing 
 52 weeks dosing with respective 
follow-up visits. 
Condition/Disease: 
Dry Eye Disease (keratoconjunctivitis sicca) 
Inclusion Criteria:  
Subjects must: 
1. Have completed the clinical trial CYS-004  
2. Have a subject reported history of dry eye disease (DED)  
 
 
3. Have been compliant with trial procedures and application 
of investigational medicinal product (IMP) in CYS-004 
according to investigators assessment of dosing diary; 
4. Provide written informed consent; and 
5. Be able and willing to follow instructions, including 
participation in all trial assessments and visits. 
Exclusion Criteria:  
Subjects must not: 
1. Have early terminated application of the investigational 
medicinal product during CYS-004 for any reason;  
2. Have any clinically significant slit-lamp findings or ocular 
conditions at Visit 1 that require prescriptive medical 
treatment and/or in the opinion of the investigator may 
interfere with trial parameters;  
3. Have a history of herpetic keratitis;  
4. Have an ocular or periocular malignancy; 
5. Be unwilling to avoid wearing contact lenses during the 
trial; 
6. Have any planned ocular or eyelid surgeries during the trial 
period; 
7. Be a woman who is pregnant, nursing, or planning a 
pregnancy; 
8. Be unwilling to submit a urine pregnancy test at all onsite 
visits (including 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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9. 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 
trial, she must agree to use adequate birth control as defined 
above for the remainder of the trial; 
10. 
 
 
 
11. Be currently using an investigational drug or device or have 
used an investigational drug or device 
 
4; 
12. 
 
 
 
 
13. 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 trial results, or may 
interfere with the subject’s participation in the trial 
significantly. 
Trial Formulation: 
CyclASol 0.1% Ophthalmic Solution (Cyclosporine A 0.1% 
) 
 
 


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Evaluation Criteria 
 
Endpoint(s):  
Primary Safety Endpoints: 
· Ocular and non-ocular adverse events. 
 
Secondary Safety Endpoints: 
· Visual acuity (BCVA using EDTRS) 
· Slit-lamp biomicroscopy 
· Intraocular pressure (IOP) 
· Dilated fundoscopy 
 
Prespecified Efficacy Endpoints: 
· tCFS score (NEI scale) and CFB at each visit 
· CFS scores per sub-regions (NEI scale) and CFB at each 
measured visit 
· Conjunctival lissamine green staining score by region 
and total (Oxford scale) and CFB at each measured visit  
· Visual analogue scale (VAS) scores for Dryness score, 
frequency of dryness, awareness of dryness, blurred 
vision, reading problems, fluctuating vision, looking at 
screens and driving at night and CFB at each measured 
visit 
· Ocular Surface Disease Index (OSDI) total, individual 
and subtotal scores and CFB at each measured visit 
· Tear Film Break-Up Time (TBUT) and CFB at each 
measured visit 
· Unanesthetized Schirmer’s Test and CFB at each 
measured visit. 
· Proportion of subjects with improvements in tCFS 
(NEI) score of 1, 2 and 3 units at each measured visit 
· Proportion of subjects with improvements in cCFS 
(NEI) score of 1 unit at each measured visit 
Other: 
· 
 
General Statistical Methods and Types of Analyses 
Sample Size: 
Up to 
subjects will be enrolled in order to ensure that at least 100 evaluable participants 
complete the week 26 (6-month) treatment period and at least 100 evaluable subjects 
complete the week 52 (12-month) treatment period.  


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With 100 subjects completing the 52 weeks 
 treatment period, the study will 
have 95% or greater chance of observing adverse events that occur at a true incident rate of 
3.0% or higher. Therefore, with 100 subjects completing 52 weeks 
 of treatment, 
if an adverse event of a specific type is not observed, then with 95% confidence, the true 
incidence rate of the adverse event is less than 3.0%. 
Primary Safety Analyses: 
Adverse events (AEs) will be coded using the MedDRA dictionary. An AE is treatment 
emergent if it occurs or worsens after the first dose of trial treatment.  
Frequencies and percentages of subjects with treatment-emergent adverse events (TEAEs), 
serious TEAEs, and TEAEs causing premature discontinuation will be provided. 
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.  
Secondary Safety Analyses: 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, dilated fundoscopy, 
and intraocular pressure will be summarized by visit using descriptive statistics.  
Assessments performed by eye, study eye and fellow eye will be summarized separately. 
Changes or shifts from baseline (as defined in clinical trial CYS-004) will also be 
summarized where appropriate.  
Exploratory Analyses:  
Quantitative prespecified efficacy variables will be summarized descriptively (n, mean, 
standard deviation, median, min, and max) and analyzed at each measured visit and with 
change from baseline (as defined in clinical trial CYS-004). Assessments performed by eye, 
study eye and fellow eye will be summarized separately 
Dichotomous secondary efficacy variables will be summarized descriptively (frequency and 
percentage).  
 


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TABLE OF CONTENTS 
1 
SYNOPSIS AND TRIAL CONTACT INFORMATION ..................................................2 
1.1 
TRIAL CONTACT INFORMATION ..................................................................... 2 
1.2 
SYNOPSIS ................................................................................................................. 3 
TABLE OF CONTENTS ..............................................................................................................8 
LIST OF ABBREVIATIONS .....................................................................................................11 
2 
INTRODUCTION...............................................................................................................13 
2.1 
Dry Eye Disease (DED) ........................................................................................... 13 
2.2 
Product Rational ...................................................................................................... 13 
2.3 
Trial Rational ........................................................................................................... 14 
2.4 
Summary of Known and Potential Risks and Benefits to Human Subjects ...... 14 
3 
TRIAL OBJECTIVES........................................................................................................17 
3.1 
Primary objective .................................................................................................... 17 
3.2 
Secondary objectives ............................................................................................... 17 
4 
TRIAL DESIGN..................................................................................................................17 
4.1 
Overall Trial Design ................................................................................................ 17 
4.2 
End of Trial Definition ............................................................................................ 17 
4.3 
Visit Description ...................................................................................................... 17 
4.4 
Trial Flow ................................................................................................................. 18 
4.5 
Enrollment and Treatment Assignment ................................................................ 19 
4.6 
Justification of Trial Design ................................................................................... 19 
4.7 
Justification for Dose ............................................................................................... 19 
5 
TRIAL POPULATION ......................................................................................................20 
5.1 
Number of Subjects (approximate) ........................................................................ 20 
5.2 
Trial Population Characteristics ............................................................................ 20 
5.3 
Inclusion Criteria .................................................................................................... 20 
5.4 
Exclusion Criteria .................................................................................................... 20 
5.5 
Subject/ Trial Withdrawal Criteria ....................................................................... 21 
6 
TRIAL PARAMETERS .....................................................................................................23 
6.1 
Safety Endpoints ...................................................................................................... 23 
6.1.1 
Primary Safety Endpoint ...............................................................................23 
6.1.2 
Secondary Safety Endpoints: ........................................................................23 
6.2 
Efficacy Endpoints .................................................................................................. 23 
6.2.1 
Prespecified Efficacy Endpoints ...................................................................23 
 
 
7 
TRIAL MATERIALS .........................................................................................................24 
7.1 
Investigational Medicinal Product ......................................................................... 24 
7.1.1 
IMP/ Formulation..........................................................................................24 
7.1.2 
Labeling and Packaging of IMP ...................................................................24 


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7.1.3 
IMP Storage ..................................................................................................24 
7.1.4 
IMP Dispensation..........................................................................................25 
7.1.5 
Instructions for Use and Administration .......................................................25 
7.2 
IMP Accountability ................................................................................................. 25 
7.3 
IMP Handling and Disposal ................................................................................... 26 
7.4 
Other Trial Supplies ................................................................................................ 26 
8 
TRIAL METHODS AND PROCEDURES ......................................................................27 
8.1 
Concurrent Medications and Therapies ................................................................ 27 
8.2 
Prohibited Treatments ............................................................................................ 27 
8.3 
Restrictions and Prohibitions ................................................................................. 28 
8.4 
Examination Procedures ......................................................................................... 28 
8.4.1 
Procedures to be Performed at Each Trial Visit with Regard to Trial 
Objective(s) ............................................................................................................28 
8.4.2 
Early Termination/Discontinuations .............................................................31 
8.4.3 
Unscheduled Visits .......................................................................................31 
8.5 
Compliance with Dosing/Protocol Deviations ....................................................... 31 
8.6 
Subject Disposition .................................................................................................. 32 
8.6.1 
Completed Subjects ......................................................................................32 
8.6.2 
Discontinued Subjects ...................................................................................32 
8.7 
Trial Termination .................................................................................................... 32 
8.8 
Trial Duration .......................................................................................................... 33 
9 
ADVERSE EVENTS ..........................................................................................................34 
9.1 
Adverse Event .......................................................................................................... 34 
9.1.1 
Severity .........................................................................................................34 
9.1.2 
Relationship to Investigational Product ........................................................35 
9.1.3 
Expectedness .................................................................................................35 
9.1.4 
Outcome ........................................................................................................35 
9.1.5 
Period of Observation ...................................................................................36 
9.2 
Serious Adverse Events ........................................................................................... 36 
9.3 
Procedures for Reporting Adverse Events ............................................................ 37 
9.3.1 
Reporting a Serious Adverse Event ..............................................................37 
9.3.2 
Reporting a Suspected Unexpected Serious Adverse Reaction ....................38 
9.4 
Procedures for Unmasking of IMP ........................................................................ 38 
9.5 
Type and Duration of the Follow-up of Subjects after Adverse Events ............. 38 
9.6 
Procedures for Reporting Pregnancies .................................................................. 38 
10 
STATISTICAL HYPOTHESES AND METHODS OF ANALYSES............................40 
10.1 Analysis Populations ............................................................................................... 40 
10.2 Statistical Hypotheses .............................................................................................. 40 
10.3 Sample Size .............................................................................................................. 40 
10.4 Statistical Analysis ................................................................................................... 40 


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10.4.1 General Considerations .................................................................................40 
10.4.2 Unit of Analysis ............................................................................................41 
10.4.3 Missing Data .................................................................................................41 
10.4.4 Primary Safety Analyses ...............................................................................41 
10.4.5 Secondary Safety Analyses ...........................................................................41 
10.4.6 Exploratory Analyses ....................................................................................41 
 
 
 
 
11 
COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES .....................................................42 
11.1 Protection of Human Subjects................................................................................ 42 
11.1.1 Subject Informed Consent.............................................................................42 
11.1.2 Institutional Review Board (IRB) Approval .................................................43 
11.2 Ethical Conduct of the Trial ................................................................................... 43 
11.3 Subject Confidentiality ........................................................................................... 43 
11.4 Documentation ......................................................................................................... 43 
11.4.1 Retention of Documentation .........................................................................43 
11.5 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) ..................................................................................................................... 44 
11.6 Monitoring and Quality Assurance ....................................................................... 44 
11.7 Handling of Biological Samples.............................................................................. 45 
11.8 Publications .............................................................................................................. 45 
12 
REFERENCES ....................................................................................................................46 
Appendix 1:  Schedule of Assessments .......................................................................................47 
Appendix 2: Examination Procedures, Tests, Equipment, and Techniques ..........................49 
Appendix 3: Protocol Amendment 1 Summary ........................................................................63 
Appendix 4:  Change History......................................................................................................65 
Appendix 5:  Sponsor and 
 Approvals ................................................................................66 
Appendix 6:  Investigator’s Signature .......................................................................................67 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
BCVA 
Best-Corrected Visual Acuity 
BID 
Twice Daily 
BLQ 
Below the Limit of Quantification 
CD 
Compact Disc 
cCFS 
Central corneal fluorescein staining 
CFB 
Change from Baseline 
CFR 
Code of Federal Regulations 
CFS 
Corneal fluorescein staining 
CI 
Confidence Interval 
CRA 
Clinical Research Associate 
eCRF 
Electronic Case Report Form 
CRO 
Contract Research Organization 
CsA 
Cyclosporine A 
DED 
Dry Eye Disease 
DEWS 
(International) Dry Eye Workshop 
ECG 
Electrocardiography, Electrocardiogram 
ET 
Early termination 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Information Portability and Accountability Act 
IB 
Investigators’ Brochure 
ICH 
International Conference on Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
Investigational Medicinal Product 
IND 
Investigational New Drug Application 
IOP 
Intraocular Pressure 
IRB 
Independent Review Board 
IRT 
Interactive Response Technology 
IUD 
Intrauterine Device 
logMAR 
Logarithm of the Minimum Angle of Resolution 
MedDRA 
Medical Dictionary for Regulatory Activities 
mL 
Milliliter 
µL  
Microliter  
mm 
Millimeter 
mmHg 
Millimeters of Mercury 
NDA 
New Drug Application 
NEI 
National Eye Institute 
OD 
Right Eye 
OS 
Left Eye 
OSDI 
Ocular Surface Disease Index 
OU 
Both Eyes 


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SAE 
Serious Adverse Event 
SAF 
Safety Set 
SFA 
Semifluorinated Alkane 
SOP 
Standard Operating Procedures 
tCFS 
Total corneal fluorescein staining 
TEAE 
Treatment-emergent Adverse Event 
TFBUT 
Tear Film Break-up Time 
US 
United States 
VA 
Visual Acuity 
VAS 
Visual Analog Scale 
WHO 
World Health Organization  
w/v 
Weight per volume 
w/w 
Weight per weight 
 
 


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2 INTRODUCTION 
2.1 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 (Craig et 
al. 2017). Symptoms of DED such as feeling of dryness, burning, a sandy/gritty sensation, foreign 
body sensation, pain or itchiness are quite debilitating. In addition, visual function related 
symptoms such as fluctuating vision with blinking, blurred vision, and difficulty with reading 
despite perfect visual acuity is an important and underestimated aspect of the disease. In 
consequence, DED negatively impacts quality of life comparably to other severe diseases 
(Schiffman et al. 2003), and adverse effects on mental health, such as depression and anxiety, have 
been observed (Le et al. 2012). DED is a serious disorder that, if left untreated or undertreated, 
progressively damages the ocular surface and may lead to vision loss due to corneal complications 
(Lemp et al. 1995). 
As many as 5 - 35% of subjects visiting ophthalmic clinics report dry eye symptoms, making it 
one of the most common conditions seen by ophthalmic specialists (McCarty et al. 1998; Lin et 
al. 2003). Estimates of the prevalence of dry eye vary considerably, depending on the criteria used 
to define the disease, but in the United States (US), it has been estimated that as many as 3.2 
million women and 1.7 million men over the age of 50 have DED, with a projected 40% increase 
in the number of patients affected by 2030 (Schaumberg et al. 2002; Schaumberg et al. 2003; 
Schaumberg et al. 2009) With the aging population in the US and other countries of the developed 
world, and with increasing use of visual displays / computers, DED is expected to continue to 
become more prevalent and finding a treatment is becoming more important (Benitez-del-Castillo 
et al. 2017).  
 
2.2 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 diseases of the ocular surface such as DED. In the US, CsA eye 
drops formulated as an emulsion have been approved and marketed as Restasis 0.05% for this 
indication since 2002. In Europe - IkervisTM, a 0.1% CsA emulsion formulation, received a 
marketing authorization by the European Medicines Agency for the treatment of DED in early 
2015. A second CsA containing product, CequaTM, a nano-emulsion was approved in the US in 
2018. 
CyclASol, in contrast, is a clear ophthalmic solution of CsA developed with the goal of avoiding 
the use of oils, surfactants and preservatives. Potential benefits from this 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. 


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For the solubilization of CsA in CyclASol the semifluorinated alkane (SFA) 
 
 F4H5 
 
 is used as the vehicle. 
 
 F4H5 is colourless, has a high 
vapor pressure, and is immiscible with water while having nearly the same refractory index. 
F4H5’s physical properties make it an optimal vehicle for topical ocular use. As a result of its high 
vapor pressure (Krafft et al. 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) (Agarwal et al. 2019). 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. The dissemination 
and spreading properties are further thought to improve the local bioavailability. 
 
2.3 Trial Rational 
After successful preclinical testing and early clinical testing, a Phase 2b/3 clinical trial (CYS-003, 
ESSENCE) confirmed the effects and good tolerability seen in the Phase 1 and Phase 2 clinical 
trials.  
CyclASol 0.1% met the primary endpoint showing superiority compared to vehicle in change from 
baseline in total corneal fluorescein staining (tCFS) at Day 29 with high statistical significance 
(p=0.0002). Additionally, the CyclASol 0.1% group consistently showed statistically significant 
improvements over time in total and central corneal and conjunctival staining compared to vehicle. 
The therapeutic effects observed had an early onset after 14 days of treatment that continued over 
the 84-day treatment period. CyclASol 0.1% also showed trends of more improvement in the 
second primary endpoint of change from baseline in total Ocular Surface Disease Index (OSDI©) 
at Day 29. Additionally, statistically significant and greater improvements in dryness-related 
symptoms as measured by VAS (Dryness Score) at Day 29 were demonstrated in the CyclASol 
0.1% treatment group compared to the vehicle group. 
CyclASol 0.1% was safe and comfortable, and showed an excellent tolerability in all clinical trials 
conducted to date with instillation site reactions as low as 2.5% and a very low drop-out rate due 
to treatment emergent adverse events (TEAE) of 3 subjects in each CYS-002 in CYS-003. 
This phase 3 open label safety extension trial is designed to investigate the long-term safety and 
tolerability of CyclASol 0.1% BID dosing of subjects completing the 4-weeks treatment trial CYS-
004, 
.  
 
2.4 Summary of Known and Potential Risks and Benefits to Human Subjects  
The investigational medicinal product (IMP) 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 chemically inert, without pharmacologic activity and not undergoing 


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metabolism in the human body. 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. 
282 subjects have been exposed to CyclASol 0.05% or 0.1% up to 4 months duration in clinical 
trials to date (clinical trials CYS-001: Phase 1; CYS-002: Phase 2; CYS-003: Phase 2b/3) with a 
favorable outcome in safety and tolerability. 
 
 
 
 
 
 
 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
In summary, based on the preclinical and clinical data obtained to date, risks to subjects in the 
planned CYS-005 trial are considered very low. Furthermore, the subjects in the trial will be 


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closely monitored, and current standard ophthalmic safety assessments will be performed during 
the entire treatment period. The results to date demonstrate the efficacy of CyclASol on signs and 
symptoms of DED. Treatment with CyclASol therefore provides a favorable benefit-risk profile 
in subjects with DED, addressing a clinical need that is currently not optimally addressed with 
available treatment options for DED.  
The 
 subjects qualifying for participation in CYS-005 will have completed the pivotal 
clinical trial CYS-004 with four weeks treatment according to protocol and tolerated exposure to 
IMP (randomized 1:1 to CyclASol or vehicle) well enough to continue treatment for one year. 
They are experienced in handling the IMP bottle and familiar with all safety and efficacy 
assessments they will undergo in CYS-005. 
This clinical trial CYS-005 is designed to confirm the positive benefit-risk profile for long-term 
treatment with CyclASol.  
 
 


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3 TRIAL OBJECTIVES 
 
3.1  Primary objective 
· The primary objective of this trial is to evaluate safety and tolerability of CyclASol during 
long-term use in subjects with Dry Eye Disease. 
3.2 Secondary objectives 
· The secondary objective is to evaluate efficacy of CyclASol during long-term use in subjects 
with Dry Eye Disease. 
 
 
4 TRIAL DESIGN 
4.1 Overall Trial Design 
This is a Phase 3 multicenter, open-label, single-arm clinical trial to evaluate the safety, tolerability 
and efficacy of CyclASol 0.1% Ophthalmic Solution in subjects with signs and symptoms of DED. 
 subjects who completed the clinical trial CYS-004 and meeting all other trial 
eligibility criteria will be included at approximately 13 sites in the US to receive treatment with 
CyclASol.  
Eligible subjects will dose the IMP (CyclASol) bilaterally BID for approximately 12 months (52 
weeks).  
 
4.2 End of Trial Definition 
The “end of the trial” for an individual subject is defined as that subject’s last visit as specified in 
the Schedule of Assessments. 
 
The “end of the trial” for the overall trial is defined as completion of the last visit or procedure as 
specified in Schedule of Assessments for all subjects in the trial. 
 
4.3 Visit Description 
Subjects will be required to sign an Informed Consent before completing any trial related 
procedure. All examination procedures are listed in Section 8.4 and in the Schedule of 
Assessments. For consistency and to avoid interference, they should be performed in the respective 
order as listed. Trial Drug Dispensation is described in Section 7.1.4. 


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Visit 1
The results of assessments at Visit 3 (Day 29) in study CYS-004 (final visit) will be taken as Day 1 
data for CYS-005. Further data/assessments to be captured will be the CYS-005 Informed Consent, 
Inclusion/Exclusion Criteria to determine CYS-005 eligibility, and IMP dispensation. 
Each subject will be given a dosing diary to record that their doses 
were taken. Study staff will help the subject to understand how to use the dosing diary and when 
the remaining doses should be taken. Subjects will be instructed to take their first dose at home. If 
needed, at the discretion of the Investigator and/or request of the subject, self-dosing can occur at 
this visit under staff supervision for instruction purposes.
Visits 2-6
Subjects will return to the clinic on week 4 ± 2 days (Visit 2), week 12 ± 7 days (Visit 3), week 26
± 7 days (Visit 4), week 40 ± 7 days (Visit 5) and week 52 ± 7 days (Visit 6) to investigate ocular 
and non-ocular safety and tolerability of IMP and assess signs and symptoms of dry eye disease. 
At those visits all used and unused trial medication should be returned to the clinic. 
The dosing diary will be collected 
during each visit and checked for compliance. Subjects will be discharged from the trial after all 
Visit 6 assessments have been completed.
Interim Telephone Calls
In order to keep a monthly contact with the subjects, interim telephone calls on a monthly basis 
will be performed asking about the subject’s well-being with non-leading AE questioning, BID 
dosing, issues with IMP and any changes in medical history or concomitant treatments.
Early Termination (ET)
Subjects who terminate early during the treatment period will be asked to complete all assessments 
as indicated at Visit 6 on the schedule of assessments prior to commencement of any alternative 
dry eye therapy (if considered possible). Dosing diary and trial medication will be collected. 
Subjects who are terminated early from the trial will not be replaced.
4.4
Trial Flow


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4.5 Enrollment and Treatment Assignment 
Subjects will keep the assigned unique subject number as allocated in clinical trial CYS-004. If all 
inclusion and none of the exclusion criteria are met at Visit 1, 
 qualifying subjects 
will be included in CYS-005. 
 
 
Each subject will spend approximately 52 weeks in the trial. The total duration of the trial from 
“first subject in” to “last subject out” is expected to be approximately 16 months. 
 
4.6 Justification of Trial Design 
This trial is designed as an open-label, single-arm extension trial to clinical trial CYS-004 to 
investigate long-term safety and tolerability of 52 weeks treatment with CyclASol 0.1% BID in at 
least 100 subjects. 
 
 
An open-label design is deemed adequate as there are no eye-drops available acting purely as 
placebo in DED, thus influencing the background incidence of AEs in this indication. In addition, 
the vehicle F4H5 previously used as control in clinical trials with CyclASol 0.1% is as well part 
of the CyclASol formulation. 
 
4.7 Justification for Dose 
The CyclASol 0.1% BID dosing regimen was selected for the first pivotal trial CYS-003 based on 
results of CYS-002. The trial CYS-004 is designed to replicate the efficacy and safety results of 
CYS-003 with the same dosing regimen, consequently the open label extension trial CYS-005 will 
use the same dose and schedule of application. 
 
 


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5 TRIAL POPULATION 
 
5.1 Number of Subjects (approximate) 
 subjects who completed the clinical trial CYS-004 will be enrolled at approximately 13 
sites to achieve at least 100 subjects completing 
 and 52 weeks (12 months) 
dosing with respective safety and tolerability assessments. 
5.2 Trial Population Characteristics 
Subjects who completed trial CYS-004, have been compliant with CYS-004 trial procedures and 
application of IMP may be invited to enroll into trial CYS-005. 
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 
Subjects will be eligible to participate in this trial if they meet all following criteria: 
1. Have completed the clinical trial CYS-004;  
2. Have a subject reported history of DED 
 
 
3. Have been compliant with trial procedures and application of investigational medicinal 
product (IMP) in CYS-004 according to investigators assessment of dosing diary; 
4. Provide written informed consent; and 
5. Be able and willing to follow instructions, including participation in all trial assessments 
and visits. 
 
5.4 Exclusion Criteria 
Subjects will not be eligible to participate in this trial if any of the following criteria apply: 
Subjects must not: 
1. Have early terminated application of the investigational medicinal product during 
CYS-004 for any reason;  
2. Have any clinically significant slit-lamp findings or ocular conditions at Visit 1 that 
require prescriptive medical treatment and/or in the opinion of the investigator may 
interfere with trial parameters;  
3. Have a history of herpetic keratitis;  
4. Have an ocular or periocular malignancy; 
5. Be unwilling to avoid wearing contact lenses during the trial; 


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6. Have any planned ocular or eyelid surgeries during the trial period; 
7. Be a woman who is pregnant, nursing, or planning a pregnancy; 
8. Be unwilling to submit a urine pregnancy test at all onsite visits (including 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); 
9. 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 trial, she 
must agree to use adequate birth control as defined above for the remainder of the 
trial; 
10. 
 
 
11. 
 
 
12. 
 
 
 
13. 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 trial results, or may 
interfere with the subject’s participation in the trial significantly. 
5.5 Subject/ Trial Withdrawal Criteria 
Subjects are free to discontinue their participation in the trial at any time without giving their 
reasons. 
A subject must be discontinued from the trial for any of the following reasons:  
· If at any time during the trial the Investigator determines that a subject’s safety has been 
compromised; 
· Occurrence of an exclusion criterion that is clinically relevant and affects the subject’s 
safety;  
· If discontinuation is considered necessary by the investigator and/or sponsor; 
· Occurrence of AEs that present an unacceptable consequence or risk to the subject in the 
judgment of the investigator, sponsor, or the medical monitor;  
· Occurrence of pregnancy; 
· Withdrawal of subject`s consent. 
If a subject has failed to attend scheduled trial assessments, the Investigator must determine the 
reasons and the circumstances as completely and accurately as possible. 


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In case a subject has to be withdrawn from the trial, the sponsor will be informed immediately. If 
there is a medical reason for withdrawal, the subject will remain under the supervision of the 
Investigator until satisfactory health has returned or the subject´s health has reached a stable 
condition.  
Subjects who are withdrawn from the trial after dosing will not be replaced.  
In case of premature withdrawal from the trial, the processes outlined in Section 8.4.2 should be 
followed. In any case, the appropriate electronic Case Report Form (eCRF) section including the 
reason for discontinuation as defined in Section 8.6.2 must be completed. 
The trial can be prematurely discontinued as described in Section 8.7.  
 
 


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6 TRIAL PARAMETERS 
 
6.1 Safety Endpoints 
6.1.1 Primary Safety Endpoint 
 
· Ocular and non-ocular adverse events. 
 
6.1.2 Secondary Safety Endpoints: 
 
· Visual acuity and CFB at each measured post-baseline visit (BCVA using EDTRS) 
· Slit-lamp biomicroscopy findings and CFB at each measured post-baseline visit 
· Intraocular pressure and CFB at each measured post-baseline visit 
· Dilated fundoscopy findings and CFB at each measured post-baseline visit 
 
6.2 Efficacy Endpoints 
6.2.1 Prespecified Efficacy Endpoints 
· tCFS score (NEI scale) and CFB at each visit 
· CFS scores per sub-regions (NEI scale) and CFB at each measured visit 
· Conjunctival lissamine green staining score by region and total (Oxford scale) and CFB at 
each measured visit  
· Visual analogue scale (VAS) scores for Dryness score, frequency of dryness, awareness of 
dryness, blurred vision, reading problems, fluctuating vision, looking at screens and driving 
at night and CFB at each measured visit 
· Ocular Surface Disease Index (OSDI) total, individual and subtotal scores and CFB at each 
measured visit 
· Tear Film Break-Up Time (TBUT) and CFB at each measured visit 
· Unanesthetized Schirmer’s Test and CFB at each measured visit 
· Proportion of subjects with improvements in tCFS (NEI) score of 1, 2 and 3 units at each 
measured visit 
· Proportion of subjects with improvements in cCFS (NEI) score of 1 unit at each 
measured visit 
 
 
 
 
 
 
 
 
 


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7 TRIAL MATERIALS 
 
7.1 Investigational Medicinal Product 
7.1.1 IMP/ Formulation 
 
Table 1. 
Active Investigational Medicinal Product 
 
Investigational Product 
Product name: 
CyclASol 
Chemical name: 
Cyclosporine A 0.1% 
 
Dosage form: 
 
Unit dose: 
 
Route of administration: 
Topical ocular administration 
Physical description: 
Colorless and clear ophthalmic solution 
Excipients: 
 
Manufacturer: 
 
 
 
7.1.2 Labeling and Packaging of IMP 
IMP will be labelled according to the legal requirements and packaged into individual subject 
kits, 
 
 The subject should note bottle 
number and the day of opening in the diary. 
As per the Code of Federal Regulations 21 part 312, section 312.6, the labels for the IMP shall 
be comprised of: 
· Protocol number 
· Investigational new drug statement 
· Lot number 
· Storage conditions 
· Name and address of the sponsor 
 
7.1.3 IMP Storage 
The IMP must be stored in a secure area accessible only to the investigator or pharmacist and 
his/her designees. 
 
 
 
. 
 


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7.1.4 IMP Dispensation 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 
 
 
 
 
At Visit 2 (for visual inspection only), Visit 3, Visit 4, Visit 5 and Visit 6 used/unused IMP and 
diaries will be collected from subjects for drug accountability.  
 
7.1.5 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 at bedtime). 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 store and dose IMP, 
and how to complete their diary.  
Subjects will be instructed to immediately contact the site if there is any problem with the IMP 
(e.g. if the bottle was dropped or lost).  
 
7.2 IMP Accountability 
The investigator must keep an accurate accounting of IMP received from the supplier by 
maintaining a detailed inventory via IRT. This includes the amount of IMP received by the site, 


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amount dispensed to subjects, amount of IMP returned to the investigator by the subjects, and the 
amount returned to the sponsor or designee upon the completion of the trial. 
Investigational trial medication orders, records of receipts, dispensing records, and inventory 
forms will be examined and reconciled by designated site personnel. At each visit, subjects will 
return all bottles to designated site personnel for accountability purposes. Accountability will be 
ascertained by performing reconciliation between the amount of IMP cartons (kits and their 
components) sent to the site, the amount used and unused at the time of reconciliation. No 
investigative drugs or kits will be discarded prior to full accountability by sponsor’s monitor. 
7.3 IMP Handling and Disposal 
Unless otherwise directed, at the end of the trial all returned used and unused IMP must be shipped 
from the clinical site to the depot for disposal of medications.  
Note: The medications should not be disposed prior to full accountability by the sponsor’s 
designated monitor.  
The clinical site will provide a copy of all completed drug disposition forms to the sponsor after 
the completion of the trial. 
 
7.4 Other Trial Supplies 
Diaries, questionnaires, VAS rulers, Schirmer’s test strips, sodium fluorescein, lissamine strips, 
Fluress, Tropicamide, Urine pregnancy test. 
 
 


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8 TRIAL METHODS AND PROCEDURES 
 
8.1 Concurrent Medications and Therapies 
Therapy considered necessary for the subject’s welfare that will not interfere with the evaluation 
of the study medication may be given at the discretion of the Investigator. If there is any question 
as to whether the medication may interfere, the Investigator should contact the Medical Monitor 
or Sponsor. Whenever possible and indicated, medications should be administered in dosages that 
remain constant throughout the study duration.  
The use of any concurrent medication, prescription or over-the-counter, is to be recorded on the 
subject’s source document and corresponding eCRF along with the reason the medication was 
taken.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
8.2 Prohibited Treatments 
Disallowed treatments are listed in the Exclusion Criteria (Section 5.4). 
 
 
  
 
 
 
  
 
  
 
 
 


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8.3 Restrictions and Prohibitions 
 
 
 
 
 
 
 
 
 
 
 
 
8.4 Examination Procedures 
8.4.1 Procedures to be Performed at Each Trial Visit with Regard to Trial Objective(s) 
The procedures outlined in this section will performed as described in Appendix 1:  Schedule of 
Assessments. 
Visit 1 (Day 1):  
Assessments and procedures from Visit 3 of clinical trial CYS-004: 
· At the beginning of the visit the subject will be asked about the time of 
last dose. 
 
 
· Medical/medication history update 
· Urine pregnancy test for females of childbearing potential 
· Non-leading AE questioning 
· 
 
 
 
 
 
· Visual acuity 
· Slit-lamp biomicroscopy 
· 
 
· Fluorescein staining (NEI scale) 
· Lissamine green staining (Oxford scale) 
· 
  
· Intraocular pressure 
· Dilated fundoscopy 
 
CYS-005 specific assessments 
· Informed consent / HIPAA 
· Review of qualification criteria 
· 
 
· Non-leading AE questioning 
· Subjects are scheduled for Visit 2 


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Visit 2 (Week 4 ± 2 days)  
· At the beginning of the visit the subject will be asked about the time of 
last dose. 
 
.  
· Collection and review of IMP and subject diary 
o 
 
 
 
 
 
· Medical/Medication history update/Non-leading AE questioning 
· Urine pregnancy test for females of childbearing potential 
· 
 
 
 
 
 
· Visual acuity 
· Slit-lamp biomicroscopy 
· 
 
· Fluorescein staining (NEI scale) 
· Lissamine green staining (Oxford scale) 
· 
 
 
 
 
· Intraocular pressure 
· 
  
· Non-leading AE questioning 
· Schedule for Visit 3 
 
Visit 3 (week 12 ± 7 days), Visit 4 (week 26 ± 7 days), Visit 5 (week 40 ± 7 
days) 
· At the beginning of the visit the subject will be asked about the time of 
last dose. 
 
 
· Collection and review of IMP and subject diary; 
o 
 
 
 
 
 
· Medical/Medication history update/ Non-leading AE questioning 
· Urine pregnancy test for females of childbearing potential 
· 
 
 
 
 
 
· Visual acuity 


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· Slit-lamp biomicroscopy 
· 
 
· Fluorescein staining (NEI scale) 
· Lissamine green staining (Oxford scale) 
· 
 
 
 
 
· Intraocular pressure 
· Dilated fundoscopy 
· 
 
· Non-leading AE questioning 
· Subjects are scheduled for next Visit 
 
 
Visit 6 (week 52 ± 7 days) or ET  
· At the beginning of the visit the subject will be asked about the time of 
last dose. 
 
 
· Collection and review of IMP and subject diary; 
o 
 
 
 
 
 
· Medical/Medication history update/ Non-leading AE questioning 
· Urine pregnancy test for females of childbearing potential 
· 
 
 
 
 
 
 
  
· Visual acuity 
· Slit-lamp biomicroscopy 
· 
 
· Fluorescein staining (NEI scale) 
· Lissamine green staining (Oxford scale) 
· 
 
 
 
 
· Intraocular pressure 
· Dilated fundoscopy 
· Non-leading AE questioning 
· Trial exit 
 
 
 


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TC 1-7 (Weeks 8/ 16/ 22/ 30/ 36/ 44/ 48 ± 7 days) 
· Medical/Medication History Update 
· Non-leading AE questioning 
· Confirm dosing as instructed 
 
8.4.2 Early Termination/Discontinuations 
Data from subjects discontinuing after dosing will be captured completely in the eCRF including 
Early Termination Visit and reason for discontinuation. 
If a dosed subject is discontinued from the trial before Visit 6 and is not willing to perform all 
subsequent visits and assessments, all evaluations of Visit 6 (at least all safety related evaluations) 
should be performed at Early Termination Visit on the day of early termination/discontinuation or 
at the discretion of the investigator.  
 
8.4.3 Unscheduled Visits 
An unscheduled visit may be performed during the course of the trial 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 
· Visual acuity 
· Intraocular pressure 
· Urine pregnancy test (for women of childbearing potential) 
· Dilated fundoscopy 
· Assessment of AEs 
· Assessment of concomitant medications and/or treatments 
· Any other assessments needed in the judgement of the investigator 
 
8.5 Compliance with Dosing/Protocol Deviations 
Subjects will be instructed on the proper use and storage of the IMP at Visits 1, 2, 3, 4 and 5 and 
provided with written instructions. Subject diaries and IMP will be collected at each visit from 
Visit 2 up to and including Visit 6 to assess subject compliance with the protocol. 
 
 
 
  
A protocol deviation is any noncompliance with the clinical study protocol, GCP, or Study 
Operations manual requirements. The noncompliance may be on the part of the subject, the PI, or 


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study staff. As a result of deviations, corrective actions may need to be developed by the study 
staff and implemented promptly. 
These practices are consistent with PI and Sponsor obligations in ICH GCP guidelines: 
· Compliance with Protocol, Sections 4.5.1, 4.5.2, 4.5.3 and 4.5.4 
· Quality Assurance and Quality Control, Section 5.1.1 
· Noncompliance, Sections 5.20.1 and 5.20.2 
All deviations from the protocol must be addressed in study subject source documents and 
promptly reported to the IRB according to their requirements. 
 
8.6 Subject Disposition 
8.6.1 Completed Subjects 
A completed subject is one who has not been discontinued from the trial. 
 
8.6.2 Discontinued Subjects 
Notification of a subject’s discontinuation and the reason for discontinuation will be made to 
 
and/or trial sponsor and will be clearly documented on the eCRF as: 
· Adverse Events 
· Protocol violations 
· Lack of efficacy 
· Administrative reasons (e.g., inability to continue, lost to follow up) 
· Sponsor termination of trial 
· Subject choice (e.g. withdrawal of consent)  
· Other 
Discontinuations that are the direct result of SARS-CoV-2 (COVID-19) will be classified 
separately and clearly documented in the eCRF. A separate field will be completed to denote a 
COVID-19 related discontinuation and the specific reason will be documented utilizing the above 
noted list of subcategories. 
Subjects must be discontinued as outlined in Section 5.5.  
Subjects, who discontinue for any reason after dosing will not be replaced. 
 
8.7 Trial Termination 
The whole trial may be discontinued prematurely in the event of any of the following: 
· New information leading to unfavorable risk-benefit judgment of the IMP, e.g. due to: 


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• 
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 IMP. 
· Terminated or suspended upon request of Health Authorities 
Health Authorities and Institutional Review Boards (IRBs)/ Independent Ethics Committees 
(IECs) will be informed about the discontinuation of the trial in accordance with applicable 
regulations. 
 
8.8 Trial Duration 
An individual subject’s participation will involve six visits and 7 phone calls over approximately 
a 52-week period. After the trial, subjects will be treated according to the standard of care at the 
discretion of the treating physician. The total duration of the trial from “first subject in” to “last 
subject out” is expected to be 16 months. 
 
 


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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 IMP-related. An AE can therefore be any 
unfavorable and unintended sign (e.g., an abnormal laboratory finding), symptom, or disease 
temporally associated with the use of a medical (investigational) product, whether or not related 
to the medical (investigational) product. 
Resolved AEs and AE that are ongoing after Visit 3 (Day 29) in the CYS-004 trial, and prior to 
IMP administration at Visit 1 of CYS-005, will not be considered Adverse Events in CYS-005. 
These events will be considered medical history and will be transferred to CYS-005 database 
accordingly. If there is a worsening or reoccurring of such medical history after administration of 
the IMP, this should be considered a new AE and reported.  
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 relevant worsening of visual acuity from Visit 0 of CYS-004, 
 
 will be considered an AE. 
IMP includes the investigational drug under evaluation and any other medications required by the 
protocol given during any stage of the trial. 
Documentation regarding the AE should be made as to the nature, date of onset, end date, severity, 
relationship to IMP, expectedness, action(s) taken, seriousness, and outcome of any sign or 
symptom observed by the physician or reported by the subject upon non-leading questioning.  
AEs (both elicited and observed) will be monitored from the time of Informed Consent and 
throughout the trial. All AEs will be promptly reviewed by the investigator for accuracy and 
completeness. All AEs will be documented on the appropriate source document and eCRF. 
 
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 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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Severity is not the same as “seriousness”, which is based on the outcome or action criteria usually 
associated with events that pose a threat to life or functioning (see Section 9.2). Seriousness (not 
severity) serves as a guide for defining regulatory reporting obligations.  
 
9.1.2 Relationship to Investigational Product 
The relationship of each AE to the IMP 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 IMP and the AE. Types of evidence that would suggest 
a causal relationship between the IMP and the AE include: a single occurrence of an event that is 
uncommon and known to be strongly associated with IMP exposure (e.g., angioedema, hepatic 
injury, Stevens-Johnson Syndrome); one or more occurrences of an event that is not commonly 
associated with IMP exposure, but is otherwise uncommon in the population exposed to the IMP 
(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 trial population independent of drug therapy) that indicates those 
events occur more frequently in the IMP-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 IMP. CyclASol contains the active ingredient CsA and the vehicle F4H5 and has been tested 
in three 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 IMP. 
The Investigator should initially classify the expectedness of an AE, but the final classification is 
subject to the sponsor’s determination. 
 
9.1.4 Outcome 
The outcome of any AE will be determined and recorded using the following categories: 
· 
Recovered/Resolved 
· 
Recovering/Resolving 


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· 
Not Recovered/Not Resolved 
· 
Recovered/Resolved with Sequelae 
· 
Lost to Follow-up 
· 
Fatal 
· 
Unknown 
 
9.1.5 Period of Observation 
For the purpose of this study, the period of observation for collection of adverse events extends 
from the time the patient gives informed consent until the end of the Visit 6 at (Week 52 ± 1) or 
Early Termination. 
If the investigator detects a Serious Adverse Event (Section 9.2) in a study patient after the end of 
the period of observation this should be reported to the Sponsor only if the investigator considers 
the event related to prior study treatment or procedures. The investigator should contact the 
sponsor to determine how the adverse event should be documented and reported. 
 
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 subject 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 
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· A congenital anomaly/birth defect; 
· Medically important. 
o Note: 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 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 
, Novaliq, 
 
 and the IRB as required by the IRB, federal, state, or local regulations and governing 
health authorities and recorded on the appropriate eCRF. 
 
9.3.1 Reporting a Serious Adverse Event 
To ensure subject safety, all SAEs, regardless of their relationship to the IMP, 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 SAE report forms. The investigator is 
obligated to pursue and obtain information requested by 
 and/or Novaliq 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 
trial 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 IMP; and inform the IRB of the AE within their 
guidelines for reporting SAEs. 
 
Contact information for reporting SAEs: 
External safety service provider 
 
 
Email: 
 
Fax: 
 
 
Contact information for Medical Monitor: 
Medical Monitor: 
 
Office Telephone: 
 
Alternative Telephone 
(24-hr line): 
 
Fax: 
 
 


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9.3.2 Reporting a Suspected Unexpected Serious Adverse Reaction 
All SAE that are ‘suspected reactions’ and ‘unexpected’ are to be reported to the IRB as required 
by the IRB, federal, state, or local regulations and governing health authorities. 
9.4 Procedures for Unmasking of IMP  
All subjects, investigators, and trial personnel involved with the conduct of the trial will be 
unmasked as this is a single-arm and open label extension trial.  
 
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 page 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 Report Form must be completed 
and e-mailed/faxed 
 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. 
 
9.6 Procedures for Reporting Pregnancies 
Pregnancy in itself is not considered an AE or SAE (unless there is a suspicion that an IMP may 
have interfered with the effectiveness of a contraceptive medication), but it is an important medical 
event that must be followed up. Any pregnancy that occurs during the clinical trial where the fetus 
could have been exposed to IMP must be followed through the outcome of the pregnancy. 
 
It is the responsibility of the Investigator to obtain the outcome and condition of the infant 
information within 30 calendar days after the initial notification and approximately 30 calendar 
days postpartum. 
If a subject or Investigator suspects that the subject may be pregnant prior to IMP administration, 
the IMP must be withheld until the results of pregnancy testing are available. If pregnancy is 
confirmed, the subject must not receive IMP and must not be enrolled in the study. If pregnancy 
is suspected while the subject is receiving IMP treatment, the IMP must immediately be withheld 
until the result of pregnancy testing is known. 


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If a female has a positive pregnancy test during the trial, then the investigator must report the 
pregnancy and the outcome of the pregnancy to 
 within 24 hours of learning about the 
pregnancy. 
A Pregnancy Reporting Form will be completed by the trial site’s principal investigator and sent 
to 
 via the SAE Fax number or e-mail (see Section 9.3). 
 will forward the documentation 
to the medical monitor, 
 project manager and the sponsor for review.   
At the completion of the pregnancy, the Pregnancy Outcome Form is to be submitted to 
 via 
the SAE contact details. 
 will manage the query and reconciliation process until the pregnancy 
documentation is complete. 
 
 


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10 STATISTICAL HYPOTHESES AND METHODS OF ANALYSES 
 
10.1 Analysis Populations 
The following analysis population will be considered: 
· Safety Set (SAF) – The SAF includes all enrolled subjects who received at least one 
dose of the IMP. The SAF will be analyzed for all assessments.   
The statistical analysis of baseline, primary and secondary endpoint data will be performed for the 
SAF.  
10.2 Statistical Hypotheses 
There are no formal hypotheses to be tested in this open-label safety extension trial. 
10.3 Sample Size 
 subjects will be enrolled in order to ensure that at least 100 evaluable participants 
complete 
 
the 52 weeks (12-month) treatment period.  
With 100 subjects completing the 52 weeks 
 treatment period, the study will have 
95% or greater chance of observing adverse events that occur at a true incident rate of 3.0% or 
higher.  Therefore, with 100 subjects completing 52 weeks 
 of treatment, if an adverse 
event of a specific type is not observed, then with 95% confidence, the true incidence rate of the 
adverse event is less than 3.0%. 
10.4 Statistical Analysis 
10.4.1 General Considerations 
Quantitative variables will be summarized using number of subjects (n), mean, median, standard 
deviation, minimum and maximum. The dichotomous variables will be summarized using counts 
and percentages.  
Summaries will be provided for demographics, baseline medical history, concurrent therapies, and 
subject disposition. 
For the purpose of summarization, medical history, concurrent therapies, and AEs will be coded 
to MedDRA and WHO Drug dictionaries, as appropriate. 
Baseline measures are defined as the measure prior to the administration of IMP as defined in 
clinical trial CYS-004. CFB will be calculated as Visit CYS-005– Baseline CYS-004.  
Summaries will be presented separately for subjects treated with CyclASol in CYS-004 and 
subjects treated with vehicle in CYS-004 as well as overall. 
 


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10.4.2 Unit of Analysis 
For efficacy endpoints, the unit of analysis will be the “study eye” which was determined during 
CYS-004. This information is transferred to the CYS-005 trial.  
 
10.4.3 Missing Data 
The primary analysis will be completed with available data per subject from the Safety Set (SAF).  
 
 
10.4.4 Primary Safety Analyses 
All safety analyses will be performed on the Safety Population.  
Dosing information will be summarized overall subjects and listed for each subject will be listed. 
Discontinuation of treatment will be summarized by treatment received. The primary reason for 
trial drug discontinuation will also be summarized by treatment received. 
Adverse events (AEs) will be coded using the MedDRA dictionary. An AE is treatment emergent 
if it occurs or worsens after the first dose of trial treatment in clinical trial CYS-005. 
Frequencies and percentages of subjects with treatment-emergent adverse events (TEAEs), serious 
TEAEs, and TEAEs causing premature discontinuation will be provided. 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. 
Concomitant medications will be coded using the most recent version of WHO-Drug Dictionary 
and summarized by treatment group. 
 
10.4.5 Secondary Safety Analyses 
Other safety endpoints including visual acuity, slit-lamp biomicroscopy, intraocular pressure (IOP) 
and dilated fundoscopy will be summarized by visit using descriptive statistics. Changes or shifts 
from baseline (as defined in clinical trial CYS-004) will also be summarized where appropriate. 
Assessments performed by eye will be summarized separately for study eye and fellow eye.  
 
 
10.4.6 Exploratory Analyses 
 
The analysis of the prespecified efficacy endpoints and other endpoints will use the SAF with 
available data per subject.  


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Quantitative efficacy variables will be summarized descriptively (n, mean, standard deviation, 
median, min, and max) and analyzed similarly to the primary endpoint at each measured visit and 
CFB. Assessments performed by eye will be summarized separately for study eye and fellow eye. 
Dichotomous secondary efficacy variables will be summarized descriptively (frequency and 
percentage).  
 
 
 
 
 
 
 
 
 
 
 
 
 
11 COMPLIANCE WITH GOOD CLINICAL PRACTICES, ETHICAL 
CONSIDERATIONS, AND ADMINISTRATIVE ISSUES 
This trial 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 trial specific procedures are initiated. Signed 
and dated written informed consent must be obtained from each subject prior to performing any 
trial specific procedures and assessments. 
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 the 


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governing IRB and that it is read, signed and dated by all subjects subsequently enrolled in the 
trial as well as those currently enrolled in the trial. 
. 
11.1.2 Institutional Review Board (IRB) Approval 
This trial is to be conducted in accordance with Institutional Review Board regulations (U.S. 21 
CFR Part 56.103). 
Only an IRB/IEC approved version of the informed consent form will be used. 
11.2 Ethical Conduct of the Trial 
This trial will be conducted in accordance with the ethical principles that originated with the 
Declaration of Helsinki. 
 
11.3 Subject Confidentiality 
All personal trial subject data collected and processed for the purposes of this trial 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 
 drug safety, the sponsor, the 
IRB/IEC approving this trial, the FDA, the Department of Health and Human Services, other 
domestic government agencies, and other foreign regulatory agencies will be granted direct access 
to the trial subject’s original medical and trial 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 trial 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 trial subject files, as well as the results of diagnostic tests such as X-rays, laboratory 
tests, and ECGs. The investigator’s copy of the eCRFs serves as the investigator’s record of a 
subject’s trial-related data. 
 
 
11.4.1 Retention of Documentation 
All trial related correspondence, subject 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 
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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 the investigator/institution as to when these documents no longer need to be retained. 
The investigator must notify the sponsor prior to destroying trial documentation even after the 
above-mentioned time has passed. 
If the responsible investigator retires, relocates, or for other reasons withdraws from the 
responsibility of keeping trial 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 Recording of Data on Source Documents and Electronic Case Reports Forms 
(eCRFs) 
All subject data will be captured in the subject source documents which will be transcribed to the 
eCRFs. The investigator is responsible for ensuring that trial data is completely and accurately 
recorded on each subject’s eCRF, source document, and all trial-related materials. All trial data 
should also be attributable, legible, contemporaneous, and original. Recorded data 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 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. An audit trail will be maintained within the electronic system to capture all changes made 
within the eCRF database. After the end of the trial 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. 
  
11.6 Monitoring and Quality Assurance 
During the course of the trial a clinical research associate (CRA) will make routine site visits to 
review protocol compliance, assess IMP accountability, and ensure the trial 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 trial monitoring will be outlined in a monitoring plan. 
Domestic and foreign regulatory authorities, 
 and quality assurance, sponsor 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 with consideration to data protection as well as 
subject confidentiality to the extent that local, state, and federal laws apply. 
 


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11.7 Handling of Biological Samples 
Not applicable. 
11.8 Publications 
Authorship and manuscript composition will reflect cooperation among all parties involved in 
the trial.  Authorship will be established before writing the manuscript.  The trial sponsor will 
have the final decision regarding authorship, manuscript and publication. 
 
 


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