Conditions: Active, Symptomatic Blepharitis
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 558
Healthy volunteers: no

Brief summary:
The purpose of this study is to evaluate the clinical efficacy and safety of ISV-305 (Dexamethasone in DuraSite® 2) compared to Vehicle in the treatment of subjects with active, symptomatic Blepharitis.

Detailed description:

Arms:
arm 1: 0.1% dexamethasone in DuraSite® 2 arm 2: DuraSite® 2 vehicle

Interventions: intervention 1: ISV-305 intervention 2: Vehicle
Intervention descriptions: intervention 1: Dexamethasone in DuraSite® 2 twice daily for 2 weeks intervention 2: Vehicle twice daily for 2 weeks

Protocol document:
Prot_001.pdf: 
 
 
A PHASE 3, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, PARALLEL-GROUP, 
COMPARATIVE STUDY TO EVALUATE THE 
CLINICAL EFFICACY AND SAFETY OF ISV-
305 (0.1% DEXAMETHASONE) COMPARED 
TO VEHICLE IN THE TREATMENT OF 
SUBJECTS WITH BLEPHARITIS 
 
 
 
 
NCT01543490 
 
 
 
22Jun2017 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
 
Clinical Study Protocol 
STUDY NO. C-12-305-001 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, PARALLEL-
GROUP, COMPARATIVE STUDY TO EVALUATE THE CLINICAL EFFICACY AND 
SAFETY OF ISV-305 (0.1% DEXAMETHASONE) COMPARED TO VEHICLE IN THE 
TREATMENT OF SUBJECTS WITH BLEPHARITIS 
 
 
 
Original Protocol Date: 
 
January 31, 2012 
 
Amendment Number: 
 
Amendment 1 
 
Date of Amendment: 
 
June 22, 2017 
 
Sponsor: 
InSite Vision, Inc. 
 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
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1.0 
TABLE OF CONTENTS 
1.0 
STUDY OBJECTIVES ......................................................................................................4 
2.0 
OVERALL STUDY DESIGN ...........................................................................................4 
3.0 
SELECTION AND WITHDRAWAL OF SUBJECTS ..................................................5 
3.1 
Number of Study Subjects .......................................................................................5 
3.2 
Inclusion Criteria .....................................................................................................5 
3.3 
Exclusion Criteria ....................................................................................................6 
4.0 
STUDY TREATMENTS ...................................................................................................8 
4.1 
Investigational Product ............................................................................................8 
4.2 
Instructions for Use and Administration ..................................................................8 
5.0 
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS .................................8 
6.0 
CLINICAL ASSESSMENTS/PROCEDURES ...............................................................9 
6.1 
Schedule of Assessments .........................................................................................9 
6.2 
Examination Procedures ..........................................................................................9 
7.0 
EVALUATION, RECORDING AND REPORTING OF ADVERSE EVENTS .......10 
7.1 
Definitions..............................................................................................................11 
7.2 
Adverse Events Associated with Study Procedures...............................................12 
7.3 
Reporting and Evaluation of AEs and SAEs .........................................................13 
7.4 
Follow-up of Adverse Events and Serious Adverse Events ..................................14 
8.0 
STATISTICAL ASSESSMENTS ...................................................................................14 
8.1 
Study Endpoints, Subsets, and Baseline Covariates ..............................................14 
8.1.1 
Primary Efficacy Endpoint ....................................................................14 
8.1.2 
Secondary Efficacy Endpoint ................................................................14 
8.1.3 
Safety Endpoints ...................................................................................14 
 
 
 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
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1.0 
STUDY OBJECTIVES 
To evaluate the ocular safety and efficacy of topical administration of ISV-305 
(0.1% dexamethasone in DuraSite 2) compared to vehicle when dosed BID for 14 days in 
subjects diagnosed with blepharitis. 
 
2.0 
OVERALL STUDY DESIGN 
This study is a Phase 3, randomized, multicenter, double-masked, vehicle-controlled, parallel-
group clinical study. Patients ≥ 1 year of age diagnosed with active, symptomatic blepharitis 
(e.g., flare-up) will be enrolled.  
Prior to enrollment, the study will be discussed with prospective subjects, and those wishing to 
enter will be asked to give written informed consent. For subjects who, according to local 
regulations, have not yet reached the age of majority, the subject’s parent(s) or legally authorized 
representative must sign the Informed Consent Form (ICF) and the minor’s written assent will be 
obtained according to the local requirements. 
Once informed consent has been obtained, the subjects will be questioned regarding their 
medical history to determine whether or not they are in satisfactory health to enter the study and 
to determine if they meet the specific entry criteria.  
Clinically-diagnosed, active, symptomatic blepharitis (e.g., flare-up) is defined by a minimum 
combined score of 6 for the following signs and symptom in at least one eye, with a minimum 
score of 2 for eyelid redness, and a minimum score of 1 for eyelid irritation. 
1) 
Eyelid redness 
2) 
Eyelid swelling 
3) 
Eyelid debris 
4) 
Eyelid irritation 
Subjects meeting all entry requirements will be asked to use lid scrubs for at least 7 days prior to 
Day 1, and will then be reassessed for eligibility prior to being randomized into the study. 
Subjects still meeting the entry criteria will be randomized into the study and begin a 14-day 
dosing phase (Day 1 – Day 14) followed for approximately 2 weeks during the follow-up phase 
(Day 15 – Day 29). Five visits will be required for full study participation: Screening Visit (Day 
-10 to Day -7), Rescreening/Randomization/Dosing visit (Day 1), Dosing visit (Day 7), and the 
Follow-up visits (Day 15 and Day 29). 
Approximately 550 evaluable subjects with blepharitis will be randomized into the study in a 2:1 
ratio: ISV-305: approximately 366 subjects and vehicle: approximately 184 subjects. 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
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Some subjects may have both eyes qualify for the study. In these cases, data from the eye with 
the highest combined clinical signs and symptoms score on Day 1 will be designated by the 
investigator as the study eye and analyzed for efficacy.  
Subjects (or parent or caregiver for subjects too young or otherwise unable to self-apply the IP) 
will be instructed to self-apply their first dose of IP at the study site on Day 1, and will receive 
instructions for dosing at home and completing a dosing diary, to be used as a memory aid. 
Subject safety will be evaluated throughout the study. The safety parameters to be assessed are 
the incidence of AEs and SAEs, discontinuations due to AEs, changes in best corrected visual 
acuity (BCVA) and IOP, and biomicroscopic and ophthalmoscopic findings.  
Efficacy will be assessed by biomicroscopic measurement of the clinical improvement in signs 
of eyelid swelling, eyelid redness, eyelid debris, and subject-reported symptom of eyelid 
irritation. Improvement is defined as a reduction in baseline signs and symptoms score by at least 
2 units by Day 15 with no worsening of any sign or symptom. Other secondary efficacy analyses 
will be performed as outlined in the statistical analysis plan (SAP). 
3.0 
SELECTION AND WITHDRAWAL OF SUBJECTS 
3.1 
Number of Study Subjects 
The study will enroll approximately 550 subjects ≥ 1 year of age with active, symptomatic 
blepharitis (e.g., flare-up). Subjects will be enrolled in the US. 
3.2 
Inclusion Criteria 
The following are inclusion criteria for prospective study subjects to be confirmed at the 
Screening Visit 1 (Day -10 – Day -7) and reconfirmed prior to randomization at Visit 2 (Day 1). 
The sponsor will not grant any protocol eligibility waivers. 
a. Have a clinical diagnosis of active, symptomatic blepharitis (e.g., flare-up) defined by a 
minimum combined score of 6 for the following signs and/or symptoms in at least one 
eye, with a minimum score of 2 for eyelid redness, and a minimum score of 1 for eyelid 
irritation: 
1) Eyelid redness 
2) Eyelid swelling 
3) Eyelid debris 
4) Eyelid irritation 
b. Are ≥ 1 year of age at Screening Visit (-10 to Day -7, Visit 1) of either sex and any race. 
c. Signature of the subject or parent(s) or legally authorized representative on the ICF, and 
when appropriate the minor’s assent in accordance with local regulations. 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
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d. Are willing and able to follow all instructions and attend all study visits. This applies to 
parent or caregiver for subjects too young or otherwise unable to self-apply the IP. 
e. Are willing to avoid disallowed medication for the duration of the study.  
f. If female is of childbearing potential, agree to and submit a urine sample for pregnancy 
testing (prior to enrollment and at the end of the study), and use effective contraception 
for the duration of the study. 
Male subjects whose female partners are not post-menopausal must agree to one of the 
following: 1) completely abstain from sexual intercourse, 2) use a barrier method 
(condoms) with spermicide during sexual intercourse for the duration of the study, 
3) provide documentation for having had a vasectomy (with documented infertility).  
g. Have an intraocular pressure (IOP) > 8 mmHg and ≤ 22 mmHg in either eye. 
h. Have used non-prescription lid scrubs for at least 7 days prior to Day 1 (Visit 2) and 
willing to continue lid scrub use throughout the duration of the study. Prescription lid 
scrubs are disallowed. 
3.3 
Exclusion Criteria 
The following are exclusion criteria for prospective study subjects to be confirmed at the 
Screening Visit 1 (Day -10 – Day -7) and reconfirmed prior to randomization at Visit 2 (Day 1). 
The sponsor will not grant any protocol eligibility waivers. 
a. Have known sensitivity or poor tolerance to any component of the IP. 
b. Have had eyelid surgery in the study eye within twelve (12) months prior to the 
Screening visit (Day -10 to -7, Visit 1) or plan to have eyelid surgery during the study 
that, in the investigator’s opinion, would interfere with the study parameters. 
c. Have an acute ocular infection (bacterial, viral or fungal) or active ocular inflammation 
other than blepharitis in the study eye. 
d. Are currently suffering from moderate or severe Dry Eye in the study eye. 
e. Have used prescription medication lid scrubs within 4 weeks prior to dosing and/or plan 
to use them throughout the 14-day dosing period of the study. 
f. Have used topical medications on the eyelids or topical ophthalmic corticosteroid 
medications or systemic use of a corticosteroid medication within 14 days prior to dosing 
and/or plan to use them throughout the duration of the study. Stable use (greater than one 
month prior to dosing of an unchanged dose) of inhaled or nasal corticosteroids, topical 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
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dermal corticosteroid or antibiotic medication (except on the eyelids), or glaucoma eye 
medication is allowed.  
g. Have used tear substitutes (e.g., artificial tears) within 2 hours prior to dosing and/or plan 
to use them throughout the 14-day dosing period of the study. 
h. Use of any eye make-up (including lid skin, lid margins, and lashes) during the 2-week 
dosing period of the study. 
i. Have had a micropigmentation (permanent eye makeup) procedure on the eyelid skin 
within 4 weeks prior to dosing, or plan to have such a procedure during the study. 
j. Be currently pregnant, nursing, or planning a pregnancy, or be a woman who has a 
positive pregnancy test. 
k. Have any uncontrolled systemic disease or debilitating disease (e.g., cardiovascular 
disease, hypertension, diabetes, or cystic fibrosis). 
l. Have any clinically significant cardiovascular disorders (e.g., unstable angina, 
myocardial infarction or cerebrovascular accident within the past six months, Class III or 
IV congestive heart failure, ventricular arrhythmias). 
m. Have any history of liver or kidney disease resulting in persisting dysfunction that, in the 
investigator’s opinion, would interfere with the study parameters. 
n. Have clinically significant lash or lid abnormality other than blepharitis (e.g. trichiasis, 
entropion or ectropion) in the study eye. 
o. Are currently suffering from alcohol and/or drug abuse. 
p. Have prior (within 30 days prior to dosing) or anticipated concurrent use of an 
investigational drug or device. 
q. Have a condition or a situation which, in the investigator’s opinion, may put the subject 
at increased risk, confound study data, or interfere significantly with the subject’s study 
participation. 
r. Use of any medication the investigator feels may interfere with the study parameters. 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
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4.0 
STUDY TREATMENTS  
4.1 
Investigational Product 
ISV-305 is a topical ophthalmic formulation of 0.1% dexamethasone in DuraSite 2. The vehicle 
utilized in this study is the same formulation as ISV-305 (i.e., DuraSite 2) without 
dexamethasone. 
4.2 
Instructions for Use and Administration 
Subjects will be randomly assigned to receive either ISV-305 or vehicle which will be 
administered BID to the closed study eyelid and if needed to the closed non-study eyelid along 
the eyelash line as a topical ophthalmic: 1 drop per eye in the morning and 1 drop per eye in the 
evening for 14 days. Subjects (including parent and/or caregiver) will be instructed to smear 1 
drop of IP to the closed study eyelid along the eyelash line on Day 1 at the study site upon 
randomization and 1 drop in the evening, and to continue dosing BID at approximately 12-hour 
intervals for a total of 14 days. Subjects will then be followed for an additional 15 days. Subjects 
will be given a dosing diary to record IP application times, and will be questioned to determine if 
they have followed the dosing schedule.  
5.0 
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS 
Contraindications, warning and precautions for ophthalmic dexamethasone as described in the 
labeling of the approved product Maxidex (0.1% dexamethasone) are presented below.  
Use of ophthalmic dexamethasone is contraindicated in epithelial herpes simplex (dendritic 
keratitis), vaccinia, varicella, and most other viral diseases of the cornea and conjunctiva, 
tuberculosis of the eye and fungal disease of ocular structures.  
Class warnings for corticosteroids such as dexamethasone are well known and state that 
prolonged use may result in ocular hypertension and/or glaucoma, with damage to the optic 
nerve, defects in VA and fields of vision, and posterior subcapsular cataract formation. 
Prolonged use may also suppress the host response and thus increase the hazard of secondary 
ocular infections. In diseases causing thinning of the cornea or sclera, perforations have been 
known to occur with the use of topical corticosteroids. In acute purulent conditions of the eye, 
corticosteroids may mask infection or enhance existing infection. It is recommended that if 
corticosteroids are used for 10 days or longer, intraocular pressure should be routinely monitored 
even though it may be difficult in children and uncooperative patients.  
The possibility of persistent fungal infections of the cornea should be considered after prolonged 
corticosteroid dosing.  
Subjects are excluded from participating in the study if there is known hypersensitivity or poor 
tolerance to any component of the IP or any of the procedural medications such as anesthetic 
and/or fluorescein drops, dilating drops, etc. See Exclusion Criterion a. 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-12-305-001 Amendment 1, Redacted – Clinicaltrials.gov 
June 22, 2017 
 
 
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6.0 
CLINICAL ASSESSMENTS/PROCEDURES 
6.1 
Schedule of Assessments 
The procedures and measurements to be evaluated at each study visit are shown in Table 1, 
Schedule of Assessments. 
Table 1: 
Schedule of Assessments: 
 
 
 
Dosing Phase  
(14 Days) 
Follow-Up Phase  
(15 Days) 
Evaluation1 
Visit 1  
Day -10 to 
Day -7 
Visit 2  
Day 1 
Visit 3  
Day 7  
(+/- 1) 
Visit 4  
Day 15  
(+ 1) 
Visit 5  
Day 29  
(+/- 2) 
Written Informed Consent 
X 
 
 
 
 
Demographics 
X 
 
 
 
 
Entry Criteria 
X 
X 
 
 
 
Medical/Medication History 
X 
X 
 
 
 
Urine Pregnancy Test 
 
X 
 
 
X 
Slit Lamp Biomicroscopy2 
X 
X 
X 
X 
X 
Clinical Signs Evaluation 
X 
X 
X 
X 
X 
Subject-Reported Eyelid Irritation 
X 
X 
X 
X 
X 
Intraocular Pressure 
X 
X 
X 
X 
X 
Best Corrected Visual Acuity 
X 
X 
X 
X 
X 
Ophthalmoscopy2 
X 
 
 
X 
X3 
Confirm non-prescription Lid Scrub Use4 
X 
X 
X 
X 
X 
Confirm and Document Subject Eligibility 
X 
X 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
Dispense IP and Dosing Diary 
 
X 
 
 
 
Instruct Subject on IP and Dosing Diary 
 
X 
 
 
 
Update Concomitant Medications 
 
X 
X 
X 
X 
Review IP and Dosing Diary 
 
X 
X 
X 
X3 
Collect IP and Dosing Diary 
 
 
 
X 
X3 
Exit Subject From Study 
 
 
 
 
X 
AE = Adverse Event; BSIQ= Blepharitis Symptoms and Impacts Questionnaire; eCRF = electronic case report form; IP = Investigational Product. 
1Some procedures are completed for both eyes, study eye only, or eye(s) dosed with IP, depending on the visit.  
2Performed by a board-certified ophthalmologist 
3If not completed at previous visit  
4 Use of non-prescription lid scrubs is required for at least 7 days prior to Visit 2 and throughout the study period (prescription lid scrubs are 
prohibited) 
Note: Unscheduled visits may occur during the study period. All assessments will be recorded on the eCRF for unscheduled visits, but it is up to 
the investigator which assessments to conduct. If the subject exits early, all Visit 5 assessments should be conducted, including ophthalmoscopy if 
not obtained at Day 15 (Visit 5). 
 
6.2 
Examination Procedures 
The following ophthalmic examinations will be conducted at intervals specified in Table 1 
Schedule of Assessments. 


Clinical Protocol  
 
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 Clinical Signs and Symptom: The clinical signs of blepharitis: eyelid redness, eyelid 
swelling and eyelid debris will be evaluated at every visit and will be scored by the 
investigator using a 0-3 grading scale. The subject symptom of eyelid irritation will also 
be evaluated at every visit and graded by the subject using a 0-3 grading scale. 
 Best Corrected Visual Acuity (BCVA): BCVA will be measured at every visit. The 
Early Treatment Diabetic Retinopathy Study (ETDRS) log of the minimum angle of 
resolution (logMAR) will be used to measure BCVA. As appropriate, Lea Symbols® will 
be used in children. 
 Intraocular Pressure (IOP) IOP will be measured in mmHg using an applanation 
tonometer at every visit. IOP is to be measured in all subjects.  
 Ophthalmoscopy: Ophthalmoscopy will be performed by a board-certified 
ophthalmologist at Day -10 to -7 (Visit 1) and Day 15 (Visit 4) or Day 29 (Visit 5) if not 
completed at Visit 4.    
 Biomicroscopy: Slit lamp biomicroscopy will be performed at every visit during the 
study to observe the overall health of the eye, including the lid/lashes, conjunctiva, 
cornea anterior chamber, iris, and lens. Any observations at the screening visit should be 
recorded as ocular medical history, and any new or worsened observations may be 
recorded as AEs. Slit lamp biomicroscopy will be conducted by a board-certified 
ophthalmologist at every visit. 
7.0 
EVALUATION, RECORDING AND REPORTING OF ADVERSE EVENTS 
All AEs either observed by the investigator or study site staff or reported by the subject 
spontaneously or in response to a direct question regarding the subject’s health by the 
investigator will be recorded in the source document and AE eCRF.  
Events reported before signing the consent form should be recorded as medical history; once the 
ICF is signed new conditions or worsening of existing conditions or episodes that increase in 
frequency should be recorded as AEs in the source document and AE eCRF. 
To standardize the collection of AEs during a study, subjects should be asked a standard question 
to elicit AEs: “Have you had any problems since your last visit or telephone call?” and “What is 
the status of [list previously reported unresolved AEs]?” Subjects will also be instructed to 
contact the investigator immediately if they note any unusual systemic or ocular AEs between 
visits.   
Throughout the course of the study, the investigator must remain alert to possible adverse 
experiences or untoward findings. If adverse experiences occur, the first concern will be the 
safety of the subject. Appropriate medical intervention will be provided by the investigator. 
The collection, review and management of safety data (AEs and SAEs) will be conducted in 
compliance with the requirements of the FDA as well as the local IRB/Independent Ethics 
Committee (IEC).  


Clinical Protocol  
 
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7.1 
Definitions 
Adverse Event 
An AE is any untoward medical occurrence associated with the use of an IP in humans, whether 
or not considered related to the IP. 
An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding, for example), symptom, or disease temporally associated with the use of an IP, without 
any judgment about causality. An AE can arise from any use of the IP (e.g., off-label use, use in 
combination with another drug) and from any route of administration, formulation or dose, 
including overdose. 
Medical conditions or diseases present before a subject starts study treatment are only considered 
AEs if they worsen after the subject signs informed consent. 
Diagnostic and therapeutic non-invasive and invasive procedures, such as surgery, should not be 
reported as AEs. However, the medical condition for which the procedure was performed should 
be reported if it meets the definition of an AE. For example, an acute appendicitis that begins 
during the AE-reporting period should be reported as the AE and the resulting appendectomy 
noted according to the eCRF completion guideline. 
Adverse Event Reporting Period 
The AE reporting period for this study begins upon signing the consent form and ends at the 
completion of the subjects’ final visit exam. All AEs that occur in study subjects during the AE-
reporting period must be reported in the source documents and on the AE eCRF, whether or not 
the event is considered related to the IP. In addition, any known untoward event that occurs 
subsequent to the AE reporting period that the investigator assesses as possibly related to the IP 
should be recorded in the source documents and reported to the sponsor or designee. 
Serious Adverse Event (SAE) 
An SAE is an event that, in the view of either the investigator or sponsor, results in any of the 
following outcomes: 
 death 
 a life-threatening AE or sight-threatening AE, where ophthalmics are involved 
 inpatient hospitalization or prolongation of existing hospitalization 
 a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
 a congenital anomaly/birth defect 


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 an important medical event that may not result in death, be life-threatening/sight-
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 above. Examples of such 
events are intensive treatment in emergency room or at home for allergic bronchospasm; 
blood dyscrasias or convulsions that do not result in hospitalization; or development of 
drug dependency or drug abuse. 
The criterion of inpatient hospitalization is met if the subject is admitted to the hospital as the 
result of an AE, even if the subject is released on the same day. An emergency room visit does 
not qualify as “inpatient hospitalization” unless the subject is admitted to the hospital during the 
visit; however, the reason for the emergency room visit may qualify as an SAE based on another 
SAE criteria (e.g., life threatening or medically significant event). 
Pre-existing Conditions 
In this study, a pre-existing condition is a disorder/disease present before the AE-reporting 
period starts (i.e., prior to the subject signing the ICF) and noted on the Medical History eCRF. 
A pre-existing condition should not be reported as an AE unless the condition worsens or 
episodes increase in frequency during the AE-reporting period.  
7.2 
Adverse Events Associated with Study Procedures 
Visual Acuity 
A worsening of BCVA of 3 lines or more in logMAR score should be captured in the source 
documents and the appropriate AE eCRF. 
IOP 
An increase in IOP of ≥ 10 mmHg from Visit 1 or any subsequent visit should be captured as an 
AE in the source documents and on the AE eCRF. 
Biomicroscopy 
Slit lamp biomicroscopy will be performed during the study to observe the overall health of the 
eye, including the lid/lashes, conjunctiva, cornea, anterior chamber, iris, and lens. Any 
observations prior to signing the ICF should be recorded as ocular medical history. Any new or 
worsened observations after signing the ICF may be recorded as an AE. 
Ophthalmoscopy 
A new finding or a significant worsening (2 units or more) from Visit 1 should be recorded as an 
AE. 


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7.3 
Reporting and Evaluation of AEs and SAEs  
Table 2Table 2 presents the reporting guidelines for AEs and SAEs. It is important that the 
investigator comply with the SAE reporting timelines in order to assure that safety reporting 
timelines of IRB/IEC and regulatory authorities such as the FDA can be met. 
Table 2: 
Requirements for Reporting Adverse Events and Serious Adverse 
Events to Sponsor 
Type 
Reporting Time 
Type of Report 
Serious 
Within 24 hours  
Adverse Event Report (AE eCRF) 
Serious Adverse Event Report Form 
Non-serious 
Per eCRF submission procedure 
Adverse Event Report (AE eCRF)  
 
All information relevant to the SAE must be recorded on the appropriate SAE Report Form, and 
the form submitted immediately (within 24 hours of learning of the event) to the sponsor 
Medical Monitor or designee. 
The investigator must also provide sponsor or designee a copy of all pertinent medical records 
such as source documents, hospitalization records, death certificates etc. that are de-identified 
and contain only the study subject number and the subject initials. The investigator should 
maintain a copy of these medical records in his/her files, as well as any information and medical 
judgments from colleagues or other medical personnel who assisted in the treatment and follow-
up of the subject.  
The investigator should ensure that the subject receives appropriate medical treatment and 
follow-up. Subjects should receive follow-up until the SAE resolves or resolves with sequelae 
(as judged by the investigator). 
Institutional Review Board or Independent Ethics Committee 
The investigator will inform the IRB/IEC of any SAE/serious, unexpected, suspected adverse 
reaction according to the IRB/IEC’s specific reporting guidelines. 
For all serious, unexpected, suspected adverse reactions, the sponsor or designee will provide 
documentation to the investigator for the investigator’s report to the IRB/IEC or local regulatory 
authorities.  
The investigator must provide documentation of all such IRB/IEC notifications to the sponsor or 
designee. Copies of each report must be kept in the investigator's files.  


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7.4 
Follow-up of Adverse Events and Serious Adverse Events 
All AEs, regardless of severity, will be followed throughout the study to the final study visit, 
until they resolve or resolve with sequelae (as judged by the investigator).  
At the final study visit, new AEs, as well as follow-up information for continuing AEs, will be 
recorded in the eCRF and source document. Non-serious ongoing AEs will be followed beyond 
the final study visit at the discretion of the investigator and recorded in the source documents.  
If an SAE is unresolved at the final study visit, it will be followed by the investigator until it 
resolves or resolves with sequelae (as judged by the investigator). Follow-up data for such SAEs 
will be recorded in the source document and reported to the sponsor or designee. 
Subjects withdrawn from the study due to an AE or SAE will be followed by the investigator 
until the outcome is determined (resolved or resolved with sequelae) and, where appropriate, 
additional written reports and documentation will be provided to the sponsor. 
8.0 
STATISTICAL ASSESSMENTS 
8.1 
Study Endpoints, Subsets, and Baseline Covariates 
8.1.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the reduction in the Day 1 (baseline) total clinical sign and 
symptom score (eyelid swelling, eyelid redness, eyelid debris, and eyelid irritation) by at least 2 
units at Day 15 with no worsening of any sign or symptom. 
8.1.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoint is complete resolution of eyelid irritation at Day 15. 
8.1.3 
Safety Endpoints 
• 
Incidence of ocular adverse events and serious adverse events 
• 
Incidence of non-ocular adverse events and serious adverse events  
• 
Measurement/evaluation and change from baseline at each scheduled visit for the 
following ocular-specific parameters: 
 Best corrected visual acuity (BCVA) 
 Intraocular pressure (IOP) 
 Slit-lamp biomicroscopy 
 Ophthalmoscopy findings 

SAP_000.pdf: 
A PHASE 3, MULTICENTER, RANDOMIZED, 
DOUBLE-MASKED, PARALLEL-GROUP, 
COMPARATIVE STUDY TO EVALUATE THE 
CLINICAL EFFICACY AND SAFETY OF ISV-
305 (0.1% DEXAMETHASONE) COMPARED 
TO VEHICLE IN THE TREATMENT OF 
SUBJECTS WITH BLEPHARITIS 
 
 
 
 
NCT01543490 
 
 
 
24Jun2020 
 
 


 
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Final Analysis 
Statistical Analysis Plan (SAP) 
STUDY NO. C-12-305-001 
 
Protocol Title: 
A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-
MASKED, PARALLEL GROUP, COMPARATIVE STUDY TO 
EVALUATE THE CLINICAL EFFICACY AND SAFETY OF 
ISV-305 
(0.1% 
DEXAMETHASONE) 
COMPARED 
TO 
VEHICLE IN THE TREATMENT OF SUBJECTS WITH 
BLEPHARITIS 
 
Protocol Number: 
C-12-305-001 
 
Protocol Version, Date 
Amendment 01, 22 June 2017 
 
Document Version, Date: 
Version 2.1, 21APR2020, and  
 
Version 2.3, 24JUN2020 (administrative updates) 
 
 
 
 


 
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TABLE OF CONTENTS 
 
1.0 
INTRODUCTION..............................................................................................................5 
2.0 
STUDY OBJECTIVES ......................................................................................................5 
3.0 
STUDY DESIGN ................................................................................................................5 
3.1 
General study design ..............................................................................................5 
3.2 
Randomization and Masking .................................................................................6 
3.3 
Study treatments and assessments .........................................................................7 
4.0 
STUDY ENDPOINTS ........................................................................................................7 
4.1 
Primary efficacy endpoint ......................................................................................7 
4.2 
Secondary efficacy endpoint ..................................................................................7 
4.3 
Safety endpoints .....................................................................................................8 
5.0 
ANALYSIS POPULATIONS ...........................................................................................8 
5.1 
Intention-to-Treat (ITT) Analysis Set ...................................................................8 
5.2 
Per-Protocol (PP) Analysis Set ..............................................................................8 
5.3 
Safety Set ................................................................................................................9 
6.0 
STATISTICAL CONSIDERATIONS AND ANALYSIS ..............................................9 
6.1 
Derived Variables ...................................................................................................9 
6.1.1 
Definitions relative to efficacy parameters ........................................10 
6.1.2 
Definitions relative to safety parameters ...........................................10 
6.2 
Handling of missing data and/or invalid data and outliers ................................11 
6.2.1 
Missing data analysis methods for efficacy data ...............................11 
6.2.2 
Handling of missing or incomplete dates ...........................................12 
7.0 
STATISTICAL METHODS ...........................................................................................13 
7.1 
General statistical conventions ............................................................................13 
7.2 
Subject disposition ...............................................................................................13 
7.3 
Demographics and baseline characteristics ........................................................13 
7.3.1 
Demographics .......................................................................................14 
7.4 
Efficacy analyses ..................................................................................................14 
7.4.1 
Analysis methods ..................................................................................14 
7.4.2 
Analysis of primary efficacy endpoint................................................14 


 
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7.4.3 
Analysis of secondary efficacy endpoints ..........................................14 
7.5 
Safety analyses ......................................................................................................14 
7.5.1 
Adverse events .....................................................................................15 
 
 
 
 


 
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1.0 
INTRODUCTION 
 
The purpose of this Statistical Analysis Plan (SAP) is to provide detailed descriptions of the 
statistical methods, data derivations and data displays for study protocol C-12-305-001 
Amendment 01 “A PHASE 3, MULTICENTER, RANDOMIZED, DOUBLE-MASKED, 
PARALLEL GROUP, COMPARATIVE STUDY TO EVALUATE THE CLINICAL 
EFFICACY AND SAFETY OF ISV-305 (0.1% DEXAMETHASONE) COMPARED TO 
VEHICLE IN THE TREATMENT OF SUBJECTS WITH BLEPHARITIS” dated 22nd June 
2017 for final analysis. The table of contents and templates for the tables, figures, and listings 
(TFLs) will be produced in a separate document. 
Any deviations from this SAP will be described and justified in the Clinical Study Report 
(CSR). 
The preparation of this SAP has been based on International Conference on Harmonisation 
(ICH) E3 and E9. 
All data analyses and generation of TFLs will be performed using Statistical Analysis System 
(SAS®) 9.4 or higher version. 
 
 
2.0 
STUDY OBJECTIVES 
To evaluate the ocular safety and efficacy of topical administration of ISV-305 (0.1% 
dexamethasone in DuraSite 2) compared to vehicle when dosed BID for 14 days in subjects 
diagnosed with blepharitis. 
 
 
3.0 
STUDY DESIGN 
 
3.1 
General study design 
This study is a Phase 3, randomized, multicenter, double-masked, vehicle-controlled, parallel- 
group clinical trial, with total study duration of 29 days, consisting of 2 phases: 
• Dosing Phase (2 weeks, Visit 2 and Visit 3, Days 1 to 14) 
• Follow-up Phase (~2 weeks, Visit 4 and Visit 5, Days 15 to 29) 
Prior to enrollment, the study will be discussed with prospective subjects and those wishing to 


 
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enter will be asked to give written informed consent. For subjects who, according to local 
regulations, have not yet reached the age of majority, the subject’s parent(s) or legally 
authorized representative must sign the Informed Consent Form (ICF) and the minor’s written 
assent will be obtained according to the local requirements. 
Subject’s ≥ 1 year of age with active, symptomatic blepharitis (e.g., flare-up) subjects will be 
enrolled at study centers in the US. Approximately 550 evaluable subjects will be randomized 
into the study in a 2:1 ratio: approximately 366 subjects in the ISV-305 group and 
approximately 184 subjects in the vehicle group. 
 
 
3.2 
Randomization and Masking 
In this double-masked trial, subject randomization is managed in accordance with InSite 
Vision’s Standard Operating Procedure (SOP).  The randomization is generated by a 
statistician that is not affiliated with the study. Once the randomization plan is generated it is 
provided to the Head of Quality Assurance (QA) only. 
The central randomization plan contains the coded treatment assignments for each 
randomization number. The randomization plan is shared with Manufacturing to allow for 
proper packaging and labeling of study supplies. Once the packaging of the IP is complete 
and the product released, all records are sealed and secured in a locked area of Document 
Control. The randomization plan remains under the confidential control of the InSite Vision 
QA Department or designee until the study is completed. 
Eligible subjects will be randomly assigned to the ISV-305 and vehicle groups in a 2:1 ratio 
according to the central randomization plan. At each site, subjects will be randomized 
sequentially to the appropriate treatment group by assigning the number corresponding to the 
lowest numbered drug kit available at the site. 
In this double-masked study, the study site, the study subjects (including parent[s] and/or 
caregiver), and sponsor/designee are masked to the identity of the study drug. Dosing will be 
performed by the subject (parent and/or caregiver) and not by study site personnel. 
Unmasking of the randomization code prior to study completion due to a medical emergency 
or suspected AE is also managed in accordance with InSite Vision’s SOP.  


 
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The randomization is not unmasked until the study is complete and the database is locked.  
 
 
3.3 
Study treatments and assessments 
The maximum study duration from screening to end of the follow-up phase is 29 (± 2) days. 
There will be two treatment groups in this study. 
• ISV-305 group 
• Vehicle group 
ISV-305 is a topical ophthalmic formulation of 0.1% dexamethasone in DuraSite 2. The 
vehicle utilized in this study is the same formulation as ISV-305 (i.e., DuraSite 2) without 
dexamethasone. 
Subjects meeting all entry requirements will be asked to use lid scrubs for at least 7 days prior 
to Day 1, and will then be reassessed for eligibility prior to being randomized into the study. 
Subjects still meeting the entry criteria will be randomized into the study and begin a 14-day 
dosing phase (Day 1 – Day 14) followed for approximately 2 weeks during the follow-up phase 
(Day 15 – Day 29). Five visits will be required for full study participation: Screening Visit 
(Day -10 to Day -7), Rescreening/Randomization/Dosing visit (Day 1), Dosing visit (Day 7), 
and the Follow-up visits (Day 15 and Day 29). 
 
 
 
4.0 
STUDY ENDPOINTS 
 
4.1 
Primary efficacy endpoint 
The primary efficacy endpoint is the reduction in the Day 1 (baseline) total clinical sign and 
symptom score (eyelid swelling, eyelid redness, eyelid debris, and eyelid irritation) by at least 
2 units at Day 15 with no worsening of any sign or symptom. 
 
4.2 
Secondary efficacy endpoint 
The secondary efficacy endpoint is complete resolution of eyelid irritation at Day 15. 
 


 
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4.3 
Safety endpoints 
The safety endpoints of this study are: 
• Incidence of ocular adverse events and serious adverse events 
• Incidence of non-ocular adverse events and serious adverse events 
• Measurement/evaluation and change from baseline at each scheduled visit for the 
following ocular-specific parameters: 
o best corrected visual acuity (BCVA) 
 
o Intraocular pressure (IOP) 
o Slit-lamp biomicroscopy 
o Ophthalmoscopy findings 
 
 
 
5.0 
ANALYSIS POPULATIONS 
 
All efficacy endpoints will be analyzed using the Intent-to-Treat (ITT) analysis set. The Per 
Protocol (PP) analysis set will be used for the sensitivity analysis of the efficacy endpoints to 
examine the robustness of the ITT analyses. 
Safety will be analyzed using the safety set. 
 
5.1 
Intention-to-Treat (ITT) Analysis Set 
The ITT analysis dataset includes all randomized subjects regardless of whether post-baseline 
measures are collected or IP is received. Subjects in the ITT dataset will be analyzed in the 
treatment group to which they were assigned by the randomization scheme, regardless of 
which IP, if any, they receive. 
 
5.2 
Per-Protocol (PP) Analysis Set 
The PP analysis dataset includes all randomized subjects in who received at least one dose of 
IP and had no significant protocol deviations. Subjects in the PP dataset will be analyzed in 
the treatment group to which they were assigned by the randomization scheme, regardless of 
which IP they receive. 
 


 
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5.3 
Safety Set 
The Safety analysis dataset includes all randomized subjects who received at least one dose of 
IP. Subjects in the Safety dataset will be analyzed according to the IP they actually received. 
If both treatments were received, the subject will be included within the active treatment group 
for analysis. 
 
 
6.0 
STATISTICAL CONSIDERATIONS AND ANALYSIS 
 
6.1 
Derived Variables 
The below table provides the list of derived variables for demographic and baseline 
characteristics, various duration derivations, drug compliance, baseline derivations and other 
important derivations applicable for this study. 
Study days 
Subjects will be dosed BID for 14 days, starting on Day 1 and continuing through Day 14. 
Study days for the given visit will be based on the date of first dose of study drug and 
calculated as: 
• (visit/assessment date – date of first dose of IP) + 1. 
Baseline 
Unless stated otherwise the baseline value for a variable will be the last measurement taken 
on or before Day 1 (Visit 2). 
Change from baseline 
Change from baseline value at each post baseline assessment (scheduled and unscheduled 
assessments) will be calculated as post baseline value - baseline value for each post baseline 
time point. 
Definitions relative to demographic and other baseline characteristics - Age 
Age at informed consent will be calculated as: 
Age (years) = (date of informed consent - date of birth + 1) / 365.25 
 


 
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6.1.1 
Definitions relative to efficacy parameters 
Individual/Total clinical sign and symptoms score 
The clinical signs of blepharitis: eyelid redness, eyelid swelling and eyelid debris will be 
evaluated at every visit and will be scored by the investigator using a 0-3 grading scale. The 
subject symptom of eyelid irritation will also be evaluated at every visit and graded by the 
subject using a 0-3 grading scale. The total score is obtained by adding each of the item scores 
in a given domain. 
 
6.1.2 
Definitions relative to safety parameters 
In order to assess the safety of ISV-305 compared to Vehicle group in subjects with 
blepharitis, adverse events will be observed throughout the entire study. 
Adverse Event (AE) 
An AE is defined as any untoward medical occurrence associated with the use of an IP in 
humans, whether or not considered related to the IP. An AE can therefore be any unfavourable 
and unintended sign (including an abnormal laboratory finding, for example), symptom, or 
disease temporally associated with the use of an IP, without any judgment about causality. An 
AE can arise from any use of the IP (e.g., off-label use, use in combination with another drug) 
and from any route of administration, formulation or dose, including overdose. 
Medical conditions or diseases present before a subject starts study treatment are only 
considered AEs if they worsen after the subject signs informed consent. 
Serious Adverse Event (SAE) 
A Serious Adverse Event (SAE) is defined as an event that, in the view of either the investigator 
or sponsor, results in any of the following outcomes: 
• death 
• a life-threatening AE or sight-threatening AE, where ophthalmics are involved 
• inpatient hospitalization or prolongation of existing hospitalization 
• a persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• a congenital anomaly/birth defect 
• an important medical event that may not result in death, be life-threatening/sight- 


 
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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 above. Examples of such 
events are intensive treatment in emergency room or at home for allergic 
bronchospasm; blood dyscrasias or convulsions that do not result in hospitalization; or 
development of drug dependency or drug abuse. 
The criterion of inpatient hospitalization is met if the subject is admitted to the hospital as the 
result of an AE, even if the subject is released on the same day. An emergency room visit does not 
qualify as “inpatient hospitalization” unless the subject is admitted to the hospital during the visit; 
however, the reason for the emergency room visit may qualify as an SAE based on another SAE 
criteria (e.g., life threatening or medically significant event). 
Pre-existing Conditions 
Pre-existing condition is defined as a disorder/disease present before the AE-reporting period 
starts (i.e., prior to the subject signing the ICF) and noted on the Medical History eCRF. A pre-
existing condition will not be reported as an AE unless the condition worsens or episodes 
increase in frequency during the AE-reporting period. 
Duration of AEs 
The duration of an AE will be calculated as the resolution date minus the date of onset plus 1. 
In the case of an AE still continuing at the end of the study, the duration will be considered as 
unknown. 
 
6.2 
Handling of missing data and/or invalid data and outliers 
 
6.2.1 
Missing data analysis methods for efficacy data 
The sensitivity analyses of the primary and/or secondary efficacy endpoints will be performed 
using Last Observation Carried Forward (LOCF) will be assessed. 
In LOCF, missing Day X values will be imputed using the last non-missing observation prior to 
Day X. 
 


 
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6.2.2 
Handling of missing or incomplete dates 
Definition of treatment-emergent AEs and handling of missing or incomplete dates 
A Treatment-Emergent AE (TEAE) is defined as an AE occurring or worsening on or after the 
receipt of the first dose of study drug. Events with an onset date at or after the subject has signed 
the ICF and prior to the first dose of study drug will be classified as pre-treatment AEs. 
In the event of an incomplete onset date, the event will be considered to be treatment-emergent 
unless the partial onset date information or complete or partial end date confirms onset or end 
prior to the first dose of study drug date (worst case approach). 
For AEs listings, dates will be presented as they have been recorded (missing and partial dates 
will not be replaced). 
Imputation rules for missing or partial AE start dates 
If only Day of AE start date is missing: 
If the AE start year and month are the same as that for the first dose of study drug date, then: 
• If the full (or partial) AE end date is NOT before the first dose of study drug date or AE 
end date is missing, then impute the AE start day as the day of first study drug date. 
• Otherwise, impute the AE start day as 1. 
If Day and Month of AE start date are missing: 
If AE start year = first dose of study drug year, then: 
• If the full (or partial) AE end date is NOT before the first dose of study drug date or AE 
end date is missing, then impute the AE start Month and Day as the Month and Day of first 
dose of study drug date. 
• Otherwise, impute the AE start MONTH as January and the DAY as 1. 
If Year of AE start date is missing: 
If the year of AE start is missing or AE start date is completely missing then query site with no 
imputation. Also compare the full (or partial) AE end date to the first dose of study drug date. 
If the AE end date is before the first dose of study drug date then the AE should be considered 
as a pre-treatment AE. Otherwise, the AE will be considered as TEAE. 
 


 
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7.0 
 STATISTICAL METHODS 
 
7.1 
General statistical conventions 
All statistical procedures will be completed using SAS version 9.4 or higher. 
Continuous variables will be summarized using descriptive statistics, including number of 
subjects with non-missing value (n), mean, median, standard deviation (SD), minimum (min) and 
maximum (max). 
For categorical variables, summaries will include counts of subjects (frequencies) and 
percentages. Percentages will be rounded to one decimal place. 
For summary purposes, baseline will be defined as the last measurement taken before the first 
dose of IP on Day 1 (Visit 2). 
Unless otherwise specified, all statistical hypothesis testing for the primary and secondary 
efficacy endpoints will be two-sided and will be performed using a significance (alpha) level of 
0.05, and missing data imputed using the last observation carried forward (LOCF) approach. 
Two-sided 95% confidence intervals (CI) will be provided when relevant. 
For the safety endpoints, no hypothesis will be tested, and missing data will not be imputed. 
All summaries and analyses will be presented by treatment group, unless otherwise specified. 
 
7.2 
 Subject disposition 
All subjects who provided informed consent will be included in a summary of subject 
accountability. The number of subjects screened, the number of screen failures, the number and 
percent of subjects randomized, and the number and percent of subjects will be summarized. 
Subject disposition information will be summarized by treatment group and overall. The 
number of subjects completing and withdrawing from the study will be tabulated in the study 
disposition table which will also include the reason for withdrawal of the subject as reported on 
the eCRF. 
 
7.3 
Demographics and baseline characteristics 
No formal comparison between treatment groups for demographic or baseline characteristics 
will be done. All demographic and baseline characteristics data will be listed. 


 
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7.3.1 
Demographics 
Age and other continuous demographic variables at baseline will be summarized descriptively. 
 
7.4 
Efficacy analyses 
This section addresses separately the analyses to be conducted on the primary and secondary 
efficacy variables.  All definitions relative to efficacy endpoints are detailed in Section 4.0. 
 
7.4.1 
Analysis methods 
Fisher’s exact test:  Distribution of categorical variables (such as response [yes/no]) in the 
efficacy tables will be compared using Fisher’s exact test. Exact unconditional 95% confidence 
intervals will also be provided. 
 
7.4.2 
Analysis of primary efficacy endpoint 
The primary efficacy endpoint is whether or not a subject’s Day 15 total clinical sign 
and symptom score has decreased by at least 2 units from baseline with no increase in 
any sign and symptom score. The primary analysis method for this endpoint is Fisher’s 
exact test conducted on the ITT analysis set. The point estimate of treatment effect 
(ISV-305 compared with vehicle), its 95% confidence interval (CI), and the 
corresponding p-value will be reported. 
 
7.4.3 
Analysis of secondary efficacy endpoints 
Complete resolution of eyelid irritation at Day 15 will be analyzed using the same 
approach as in the analysis of the primary efficacy endpoint, i.e., Fisher’s exact test 
conducted in the ITT analysis set with missing score imputed using LOCF. 
 
7.5 
Safety analyses 
All definitions relative to safety endpoints are detailed in Section 6.1.2. 
All the safety analyses will be based on the Safety set (treated subjects) and will be 


 
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performed for all safety variables specified below. 
All safety data will be summarized by treatment group. No statistical test will be 
performed. 
 
7.5.1 
Adverse events 
All Adverse events (AEs) will be coded by Primary System Organ Class (SOC) and 
Preferred Term (PT) according to the Medical Dictionary for Regulatory Activities 
(MedDRA®) Version 20.0 or higher. 
In summaries by SOC and PT, adverse events will be sorted by decreasing frequency 
within each SOC and PT according to the alphabetically order of ISV-305 treatment 
group. 
All AEs will be listed. However, only treatment-emergent AEs (TEAEs) will be 
summarized. An AE will be considered a TEAE if it occurs or worsens on or after 
receipt of the first dose of study drug. AEs will be presented by subject. 
Details for imputing missing or partial start dates of adverse events are described in 
Section 6.2.2. AE summary tables will be presented for TEAEs only and will include 
the following: 
• All TEAEs 
• Serious AEs/TEAEs 
• TEAEs leading to death 
All TEAEs will be summarized by SOC, PT and treatment group using frequency 
counts and percentages (i.e., number and percentage of subjects with an event).