Clinical trial NCT03192150
Conditions: Inflammation and Pain Associated With Cataract Surgery
Sponsor: Sun Pharmaceutical Industries Limited
Start date: 2018-01-03; Completion date: 2019-11-18
Enrollment: 246 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate the ocular safety, tolerability, and efficacy of ISV-305 (Dexamethasone in DuraSite® 2) compared to Vehicle in the treatment of inflammation and pain associated with cataract surgery.

Detailed description:
The purpose of this study is to evaluate the ocular safety, tolerability, and efficacy of topical administration of ISV-305 (0.1% dexamethasone in DuraSite® 2) compared with Vehicle when dosed twice daily for 1 day prior to surgery, the day of surgery and 14 days post cataract surgery.

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 16 days intervention 2: Vehicle twice daily for 16 days

Protocol documents:
SAP_002.pdf: 
 
A PHASE 3, RANDOMIZED, MULTICENTER, 
DOUBLE-MASKED STUDY TO COMPARE 
THE OCULAR SAFETY, TOLERABILITY, 
AND EFFICACY OF ISV-305 (0.1% 
DEXAMETHASONE IN DURASITE® 2) TO 
DURASITE 2 VEHICLE FOR THE 
TREATMENT OF INFLAMMATION AND 
PAIN ASSOCIATED WITH CATARACT 
SURGERY 
 
 
 
NCT03192150  
 
 
 
12AUG2020 
 


 
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Final Analysis 
Statistical Analysis Plan (SAP) 
STUDY NO. C-16-305-003 
 
 
Protocol Title: 
A PHASE 3, RANDOMIZED, MULTICENTER, DOUBLEMASKED  
STUDY 
TO 
COMPARE 
THE 
OCULAR 
SAFETY, 
TOLERABILITY, 
AND 
EFFICACY 
OF 
ISV-305 
(0.1% 
DEXAMETHASONE IN DURASITE® 2) TO DURASITE 2 
VEHICLE FOR THE TREATMENT OF INFLAMMATION AND 
PAIN ASSOCIATED WITH CATARACT SURGERY 
 
 
Protocol Number: 
C-16-305-003 
 
 
Protocol Version, Date 
Original Protocol, 31 May 2017 
 
Document Version, Date:  Version 1.0, 27 Dec 2017, and  
Version 1.1, 12 Aug 2020 (administrative correction) 
 
 


 
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TABLE OF CONTENTS 
1.0 
INTRODUCTION............................................................................................................. 4 
2.0 
Study Objectives ............................................................................................................... 4 
3.0 
Study Design ...................................................................................................................... 4 
3.1 
General Study Design ............................................................................................ 4 
3.2 
Randomization and Masking ................................................................................. 4 
3.3 
Study Treatments and Assessments ....................................................................... 5 
4.0 
Study Endpoints ................................................................................................................ 6 
4.1 
Primary Efficacy Endpoint .................................................................................... 6 
4.2 
Key Secondary Endpoints ...................................................................................... 6 
4.3 
Safety Endpoints .................................................................................................... 6 
5.0 
Analysis Populations ......................................................................................................... 6 
5.1 
Intention-To-Treat Population (ITT) ..................................................................... 6 
5.2 
Modified Intent-To-Treat Population (mITT)........................................................ 7 
5.3 
Per-Protocol Population (PP) ................................................................................. 7 
5.4 
Safety Population (Safety) ..................................................................................... 7 
6.0 
STATISTICAL CONSIDERATIONS AND ANALYSIS ............................................. 7 
6.1 
Derived Variables .................................................................................................. 7 
6.1.1 
Definitions Relative to Efficacy Parameters 
8 
6.1.2 
Definitions Relative to Safety and Tolerability Parameters 
8 
6.2 
Handling of Missing Data and/or Invalid Data and Outliers ................................. 9 
6.2.1 
Missing Data Analysis Methods for Efficacy Data 
9 
6.2.2 
Handling of Missing or Incomplete Dates 
9 
7.0 
STATISTICAL METHODS .......................................................................................... 10 
7.1 
General Statistical Conventions ........................................................................... 10 
7.2 
Subject Disposition .............................................................................................. 10 
7.3 
Demographics and Baseline Characteristics ........................................................ 10 
7.3.1 
Demographics 
11 
7.4 
Efficacy Analyses ................................................................................................ 11 
7.4.1 
Analysis Methods 
11 
7.4.2 
Analysis of Primary Efficacy Endpoint 
11 
7.4.3 
Analysis of Key Secondary Efficacy Endpoints 
12 
7.5 
Safety Analyses .................................................................................................... 12 
 


 
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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-16-305-003 “A PHASE 
3, RANDOMIZED, MULTICENTER, DOUBLE-MASKED STUDY TO COMPARE THE 
OCULAR 
SAFETY, 
TOLERABILITY, 
AND 
EFFICACY 
OF 
ISV-305 
(0.1% 
DEXAMETHASONE IN DURASITE® 2) TO DURASITE 2 VEHICLE FOR THE 
TREATMENT OF INFLAMMATION AND PAIN ASSOCIATED WITH CATARACT 
SURGERY” dated 31st May 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, tolerability, and efficacy of topical administration of ISV-305 (0.1% 
dexamethasone in DuraSite 2 ophthalmic suspension) compared with DuraSite 2 Vehicle when 
dosed BID for 1 day prior to surgery, the day of surgery, and 14 days post cataract surgery. 
 
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 3 phases: 
• 
Screening/Randomization Phase (~2 weeks, Visit 1, Days −14 to −2) 
• 
Dosing Phase (~2 weeks, Phone call Visit to Visit 4, Days -1 to 14) 
• 
Evaluation Phase (~2 weeks, Visit 5 to Visit 7, Days 15 to 29) 
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. 
Subjects ≥ 17 years of age scheduled to undergo uncomplicated unilateral cataract surgery and 
who meet all inclusion and none of the exclusion criteria will be randomized in a 2:1 ratio: 160 in 
the ISV- 305 group and 80 in the vehicle group. Subjects will be enrolled at approximately 15 
study centers in the US. 
 
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 


 
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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 (blinded) study, the study site, the study subjects (including caregiver), and 
sponsor/designee (other than as stated above) are masked to the identity of the IP. Dosing will be 
performed by the subject 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.  
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 evaluation 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. 
All subjects eligible for study participation will enter from Screening/Randomization Phase (Visit 
1) to the Dosing Phase. During the Dosing Phase (Day -1 to Day 14), subjects will be dosed BID 
for 16 days: the day before cataract surgery, the day of cataract surgery, and for 14 days after 
cataract surgery. Subjects will then be followed for approximately 2 weeks during the Evaluation 
Phase (Day 15 to Day 29). There will be 7 study visits for full study participation: 1 visit during 
the Screening/Randomization Phase, 3 visits (Day 0, Day 1 and Day 8) during the Dosing Phase, 
and 3 visits (Day 15, Day 18, and Day 29) during the Evaluation Phase. 
 
 
 


 
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4.0 
STUDY ENDPOINTS 
4.1 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with an ACC grade of 0 at Day 15.  
Anterior Chamber Cells 
Grade* 
Cell Count 
0 
0 
1 
1-5 
1 
6-10 
2 
11-20 
3 
21-50 
4 
> 50 
*Grade 1 includes cell count 1-5 and cell count 6-10. 
 
4.2 
Key Secondary Endpoints 
The secondary efficacy endpoints are the proportion of subjects who achieve a pain score of 0 on 
the visual analog scale (VAS) (0-100 mm scale) for each post-surgical assessment at Days 1, 8, 
15, 18, and 29. 
 
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 in the study eye at each scheduled visit 
for the following ocular-specific parameters: 
o BCVA 
o IOP 
o Slit-lamp biomicroscopy 
o Ophthalmoscopy findings 
o Photophobia 
 
5.0 
ANALYSIS POPULATIONS 
All efficacy endpoints will be analyzed using the modified intent-to-treat (mITT) population. The 
Per-Protocol (PP) population will be used for the analysis of the primary and secondary endpoints 
to examine the robustness of the primary analyses.  
Safety and tolerability will be analyzed using the safety population.  
 
5.1 
Intention-To-Treat Population (ITT) 
The ITT population includes all randomized subjects, regardless of whether post-baseline 
measures are collected or IP is received. Subjects in the ITT population will be analyzed in the 
treatment group to which they were assigned by the randomization scheme, regardless of which 


 
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IP, if any, they receive. This population will be used in the disposition and protocol deviation 
summaries. 
 
5.2 
Modified Intent-To-Treat Population (mITT) 
The mITT population includes randomized subjects that undergo cataract surgery, receive at least 
one dose of IP, and have at least one post-surgery efficacy assessment. Subjects who receive rescue 
medications will be included in the mITT but will be treated as failures. This population will be 
used in all efficacy analyses. Subjects in the mITT population will be analyzed in the treatment 
group to which they were assigned by the randomization scheme, regardless of which IP if any, 
they receive. 
 
5.3 
Per-Protocol Population (PP) 
The per protocol (PP) population includes all subjects in the mITT population excluding those 
subjects who receive rescue medications or have major protocol violations that may compromise 
their efficacy data. 
 
5.4 
Safety Population (Safety) 
The Safety population includes all randomized subjects who receive at least 1 dose of IP.  Subjects 
in the safety population will be analyzed according to the IP they actually received. This population 
will be used in all safety analyses. 
 
6.0 
STATISTICAL CONSIDERATIONS AND ANALYSIS  
 
6.1 
Derived Variables  
The below text 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  
Study Day 0 represents the day of surgery. Subjects will instill doses daily, starting on Day –1 and 
continuing through Day 14.  
Study days for the remaining visits will be based on the date of surgery and calculated as:  
• 
(visit/assessment date – date of surgery).  
 
Baseline  
Unless stated otherwise the baseline value for a variable will be the value taken at Visit 
1/Screening Visit.  
 
Definitions Relative to Demographic and Other Baseline Characteristics - Age  
Age at informed consent will be calculated as:  


 
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Age (years) = (date of informed consent - date of birth + 1) / 365.25  
 
6.1.1 
Definitions Relative to Efficacy Parameters  
 
Proportion of Subjects with ACC Grade 0 at a Given Time Point  
Proportion = Number of responders at Day X /Total number of subjects in the mITT population  
Notes:  
1. Responders are those subjects who had ACC grade of 0 either at Day X or the last 
assessment prior to Day X visit (in case the Day X was not completed). 
2. Those subjects who received a rescue medication between and including Day 0 and X will be 
considered as treatment failure or non-responder, despite a subject with zero cell count either 
at Day X or the last assessment prior to Day X visit (in case the Day X was not completed). 
 
Proportion of Subjects with VAS Pain Score 0 at Each Time Point 
Proportion = Number of subjects with zero score for VAS Pain /Total number of subjects in the 
mITT population 
The VAS is a measure of overall self-rated health status. It ranges from 0 to 100 using a mark on 
a 100 mm line, with 0 score indicative of no pain and 100 indicative of maximum pain. 
 
6.1.2 
Definitions Relative to Safety and Tolerability Parameters 
In order to assess the safety and tolerability of ISV-305 compared to Vehicle group in subjects 
with cataract surgery, 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 unfavorable and 
unintended sign, 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 


 
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• 
a congenital anomaly/birth defect 
• 
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 
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 preexisting 
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 Last Observation Carried Forward (LOCF) method will be used to impute missing values for 
the primary and all secondary endpoints. In LOCF imputation, missing Day X values will be 
imputed using the last non-missing observation prior to Day X. 
 
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 
first IP dose. Events with an onset date at or after the subject has signed the ICF and prior to the 
first IP dose 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 IP dose date (worst case approach). 


 
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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 IP date, then: 
• 
If the full (or partial) AE end date is NOT before the first dose of IP date or AE end date is 
missing, then impute the AE start day as the day of first IP 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 IP year, then: 
• 
If the full (or partial) AE end date is NOT before the first dose of IP date or AE end date is 
missing, then impute the AE start Month and Day as the Month and Day of first dose of IP 
date. 
• 
Otherwise, impute the AE start MONTH as January and the DAY as 1. 
 
7.0 
STATISTICAL METHODS 
 
7.1 
General Statistical Conventions 
All statistical procedures will be completed using SAS version 9.4 or higher.  
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. Two-
sided 95% confidence intervals (CI) will be provided when relevant. 
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 Visit 1, the screening visit value; all summaries 
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 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 primary 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.  
 


 
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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, key secondary, and 
secondary efficacy variables. All definitions relative to efficacy endpoints are detailed in Section 
4.0. 
 
7.4.1 
Analysis Methods 
 
7.4.1.1 
Analysis of Proportions Using Two-sided Z-test 
The proportion of subjects with ACC grade of 0 at a given time point in the ISV-305 (PISV) and 
vehicle (PVEH) groups will be compared using a two-sided Z-test with continuity correction and 
pooled variance. 
 
7.4.1.2 
Multiplicity 
Multiplicity adjustments will control the overall type I error rate at 0.05 for testing two treatment 
groups and multiple endpoints. 
Among the primary and key secondary endpoints, the tests will be performed using a serial 
gatekeeping procedure based on the hierarchical order of the primary and key secondary endpoints. 
Therefore, the statistical tests on the key secondary endpoints across all five postsurgical time 
points will only be performed in case the null hypothesis for the primary endpoint is rejected. 
The following multiplicity adjustment will be used to strongly control the overall type I error rate 
at 0.05 for the key secondary endpoints at each assessment. Multiplicity will be addressed via 
Hochberg’s step-up method. 
 
7.4.2 
Analysis of Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with an ACC grade of 0 at Day 15. 
The difference between treatment groups will be tested using a two-sided Z-Test with continuity 
correction and pooled variance using the mITT population. A subject with an ACC grade of 0 at 
the Day 15 visit or the last assessment prior to the Day 15 visit (in the event that Day 15 was not 
completed) will be considered a responder to therapy. If a subject has an ACC score of >0 at Day 
15 or the last assessment prior to the Day 15 visit (in the event that Day 15 was not completed), 
that subject will be considered a failure (or non-responder) in the primary efficacy endpoint 
analysis. Additionally, any subject receiving a rescue medication between Day 0 and the Day 15 
visit (inclusive) will be considered a treatment failure.  
 


 
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7.4.3 
Analysis of Key Secondary Efficacy Endpoints 
If the null hypothesis for the primary endpoint is rejected, the statistical tests on the key secondary 
endpoints across all five post-surgical time points will be performed using the serial gatekeeping 
procedure known as Hochberg’s step-up method. 
For the key secondary efficacy endpoint of proportion of subjects who achieve a pain score of 0 
on the VAS, the difference between the treatment groups at each post-surgical assessment will be 
tested using a two-sided Z-Test with continuity correction and pooled variance. Missing values 
will be imputed using the LOCF method. Hochberg’s method will be applied to the ordered p- 
values from these tests across the five time points. A 95% CI for the difference of the proportions 
at each time point will also be constructed. The effect of imputing missing values for this secondary 
endpoint analysis of proportions using the LOCF method will be assessed via a multiple 
imputations procedure. 
 
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 population (treated subjects) and will be 
performed for all safety variables specified below. 
All safety data will be summarized by treatment group. 
No statistical test will be performed. 
 
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. 
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). 

Prot_000.pdf: 
 
A PHASE 3, RANDOMIZED, MULTICENTER, 
DOUBLE-MASKED STUDY TO COMPARE 
THE OCULAR SAFETY, TOLERABILITY, 
AND EFFICACY OF ISV-305 (0.1% 
DEXAMETHASONE IN DURASITE® 2) TO 
DURASITE 2 VEHICLE FOR THE 
TREATMENT OF INFLAMMATION AND 
PAIN ASSOCIATED WITH CATARACT 
SURGERY 
 
 
 
NCT03192150  
 
 
 
31May2017 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
2 
Clinical Study Protocol 
STUDY NO. C-16-305-003 
A PHASE 3, RANDOMIZED, MULTICENTER, DOUBLE-MASKED STUDY TO 
COMPARE THE OCULAR SAFETY, TOLERABILITY, AND EFFICACY OF ISV-305 
(0.1% DEXAMETHASONE IN DURASITE® 2) TO DURASITE 2 VEHICLE FOR THE 
TREATMENT OF INFLAMMATION AND PAIN ASSOCIATED WITH CATARACT 
SURGERY 
 
 
 
Original Protocol Date: 
 
May 31, 2017 
 
Sponsor: 
 
InSite Vision, Inc. 
 
 
 
 
 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
3 
TABLE OF CONTENTS 
1.0 
Study Objective(s) ............................................................................................................. 4 
2.0 
Study Design ...................................................................................................................... 4 
3.0 
Study Population ............................................................................................................... 5 
3.1 
Inclusion Criteria ............................................................................................................... 5 
3.2 
Exclusion Criteria .............................................................................................................. 5 
4.0 
Study Treatment and Drug/Dosage Administration ...................................................... 7 
5.0 
Contraindications, Warnings and Precautions .............................................................. 7 
6.0 
Clinical Assessments/Procedures ..................................................................................... 8 
6.1 
Schedule of Assessments ................................................................................................... 8 
6.2 
Examination Procedures .................................................................................................... 9 
7.0 
Evaluation, Recording and Reporting of Adverse Events ............................................. 9 
7.1 
Definitions........................................................................................................................ 10 
7.2 
Adverse Events Associated with Study Procedures ......................................................... 11 
7.3 
Reporting and Evaluation of AEs and SAEs .................................................................... 12 
7.4 
Follow-up of Adverse Events and Serious Adverse Events ............................................. 13 
8.0 
STATISTICAL ASSESSMENTS .................................................................................. 13 
8.1 
Primary Efficacy Endpoint ............................................................................................... 13 
8.2 
Secondary Efficacy Endpoint ........................................................................................... 13 
8.3 
Safety Endpoints .............................................................................................................. 13 
 
 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
4 
1.0 
STUDY OBJECTIVE(S) 
To evaluate the ocular safety, tolerability, and efficacy of topical administration of ISV-305 (0.1% 
dexamethasone in DuraSite® 2 ophthalmic solution) compared with DuraSite 2 Vehicle when 
dosed twice daily (BID) for 1 day prior to surgery, the day of surgery, and 14 days post cataract 
surgery. 
 
2.0 
STUDY DESIGN 
This study is a Phase 3, randomized, multicenter, double-masked, vehicle-controlled, parallel-
group clinical trial. Approximately 240 subjects will participate in the study and will be 
randomized in a 2:1 ratio to the ISV-305 group (160 subjects) and the vehicle group (80 subjects). 
Written informed consent will be obtained from all subjects prior to any study-specific procedure. 
Subjects will be enrolled into a 16-day dosing phase, followed by a 2-week evaluation phase. There 
will be 7 visits scheduled during the study: a screening visit between 2 and 14 days prior to surgery; 
3 visits during the dosing phase (Day 0 [Surgery Day], Day 1, and Day 8); and 3 visits during the 
evaluation phase (Day 15, Day 18, and Day 29). In addition, there will be a telephone call on Day 
-3 to remind subjects to begin dosing on Day -1, the day before surgery. Subjects will instill 3 
doses prior to surgery (2 doses on Day -1, and 1 dose on Day 0 prior to surgery), 1 dose in the 
evening after surgery and continue dosing BID for 14 days after surgery.  
Subjects will be randomized and receive instructions for dosing at home and completing a pain 
and dosing diary. Subjects will be cautioned to dose only for the specified amount of time. One 
bottle of investigational product (IP) will be dispensed to the subject, and a second bottle will 
remain at the site as a precaution only in the event of loss, etc., and will not be dispensed unless 
necessary. Throughout this protocol, the surgery eye is referred to as the study eye, and the fellow 
eye is referred to as the non-study eye. 
All ratings and procedures should be performed by the same examiner from visit to visit whenever 
possible. Additional exams may be scheduled as necessary to ensure the safety of the subjects 
during the study period.  
Subjects who terminate use of IP for any reason will be withdrawn from the study, the reason(s) 
clearly described on the subject’s electronic Case Report Form (eCRF) and source documents, and 
the sponsor or designee will be notified. 
If the investigator determines lack of efficacy during the dosing period, administration of a rescue 
medication (i.e., another medication to treat ocular inflammation and/or ocular pain in the surgery 
eye [study eye]) must occur after subject is withdrawn from the study, and be clearly documented 
on the source documents and the designated eCRF.  
All adverse events (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). Ongoing 
AEs will be followed beyond the final study visit at the discretion of the investigator and recorded 
in the source documents. 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
5 
3.0 
STUDY POPULATION 
Patients ≥ 17 years of age who are scheduled to undergo uncomplicated unilateral cataract surgery 
and who meet all study entry criteria. Approximately 240 subjects will be enrolled in the United 
States.  
3.1 
Inclusion Criteria 
The following are inclusion criteria for prospective study subjects to be confirmed at Visit 1 (Day 
-14 – Day -2) prior to randomization. The sponsor will not grant any protocol eligibility waivers. 
a. Are ≥ 17 years of age at Visit 1 (Day -14 – Day -2) prior to randomization, of either sex 
and any race, and scheduled for uncomplicated unilateral cataract surgery 
(phacoemulsification or extracapsular extraction) with posterior chamber intraocular lens 
implantation  
b. Signature of the subject or parent(s) or legally authorized representative on the Informed 
Consent Form (ICF), and when appropriate the minor’s assent in accordance with local 
regulations 
c. Are willing and able to follow all instructions and attend all study visits  
d. Are willing to avoid disallowed medication for the duration of the study 
e. 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) 
f. Have best corrected visual acuity (BCVA) of +1.0 log of the minimum angle of resolution 
(logMAR -Snellen equivalent of 20/200) or better in the fellow eye (non-study eye)  
g. Able to self-instill the IP (or have a caregiver available to instill all doses of the IP, as 
instructed) 
h. Have an intraocular pressure (IOP) of > 8 mmHg and ≤ 22 mmHg in the surgery eye (study 
eye) 
3.2 
Exclusion Criteria 
The following are exclusion criteria for prospective study subjects to be confirmed at Visit 1 (Day 
-14 – Day -2) prior to randomization. The sponsor will not grant any protocol eligibility waivers. 
a. Have a history of Fuchs’ dystrophy in the study eye 
b. Have a history of diabetic retinopathy (with visual impairment) and/or previous vitrectomy 
in the study eye within the last 2 years 
c. Have any sign of iritis or scleritis in the study eye 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
6 
d. Have a history of glaucoma surgery in the study eye within the last 2 years 
e. Have an existing diagnosis of severe dry eye in the study eye  
f. Have 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. 
g. Have an acute ocular infection (bacterial, viral or fungal) or active ocular inflammation in 
the study eye 
h. Have any extraocular/intraocular inflammation in the study eye noted prior to surgery 
(blepharitis is allowed if scurf only without any concurrent conjunctivitis or lid 
erythema/edema) or ongoing, unresolved uveitis 
i. Use of the following disallowed medications within a specified amount of time before 
surgery:  
• 
topical, inhaled, or oral corticosteroids within 15 days  
• 
depot-corticosteroids within 45 days (triamcinolone within 90 days)  
• 
topical, systemic, or inhaled nonsteroidal anti-inflammatory drugs (NSAIDs) within 1 
week (with the exception of low-dose aspirin)  
• 
ocular or systemic antihistamines, or mast cell stabilizers within 1 week 
• 
other analgesics and use of acetaminophen (Tylenol®) within 48 hours 
• 
any medication that the investigator feels may interfere with the study parameters  
j. Have any active or chronic/recurrent ocular or systemic disease that is uncontrolled and 
likely to affect wound healing (e.g., diabetes mellitus, systemic connective tissue disease, 
severe atopic disease) 
k. Have known blood dyscrasia or bone marrow suppression 
l. Have any active corneal pathology noted in the study eye 
m. Have any intraocular inflammation (cells or flare in anterior chamber) or ocular pain 
(greater than 0) on the pain scale in either eye 
n. Have had radial keratotomy, corneal transplant, or LASIK in the study eye within the last 
2 years 
o. Be currently pregnant, nursing, or planning a pregnancy, or be a woman that has a positive 
pregnancy test 
p. Are currently suffering from alcohol and/or drug abuse 
q. Prior participation in this study protocol 
r. Prior participation in InSite Vision Protocol C-13-305-002 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
7 
s. Have prior (within 30 days of beginning study treatment) or anticipated concurrent use of 
an investigational drug or device 
t. 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 
u. Contact lens wear during the dosing period on Days -1 to Day 14 
v. Use of any medication the investigator feels may interfere with the study parameters 
 
4.0 
STUDY TREATMENT AND DRUG/DOSAGE ADMINISTRATION 
Subjects will be randomized in a 2:1 ratio to 1 of 2 treatment groups: 
1. ISV-305 (0.1% dexamethasone in DuraSite 2) BID (160 subjects) 
2. DuraSite 2 Vehicle BID (80 subjects) 
One drop of IP will be self-instilled by the subject (or instilled by caregiver) BID, in the surgery 
eye (study eye) for 16 days: the day prior to surgery, the day of surgery and postoperatively for 
14 days. 
The study coordinator or investigator will instruct the subjects on the proper administration of their 
IP. 
Subjects (and caregiver as appropriate) will be instructed to bring their pain and dosing diary to 
each visit for review with site staff and for collection of diary on Day 18 (Visit 6), and to return 
all bottles of IP on Day 15 (Visit 5) for collection. 
 
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.  


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
8 
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 f. 
 
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 
 
Screening/ 
Randomization 
Phase 
Dosing Phase (16 Days) 
Evaluation Phase (15 Days) 
Evaluation1 
Visit 1 Day -14 
to Day -2 
Phone 
Call 
Day -3 
(1) 
Visit 2 
Day 
0 
(Day 
of 
Surgery) 
Visit 3 
Day 1 
(+ 1) 
Visit 4 
Day 8 
( 1) 
Visit 5 
Day 15 
(+1) 
Visit 6 
Day 18 
(-1/+2) 
Visit 7 
Day 29 
( 2) 
Written Informed Consent 
X 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
Entry Criteria 
X 
 
 
 
 
 
 
 
Medical/Medication 
History 
X 
 
 
 
 
 
 
 
Urine Pregnancy Test 
X 
 
 
 
 
 
 
X 
Slit Lamp Biomicroscopy2 
X 
 
 
X 
X 
X 
X 
X 
Visual Analog Scale 
X 
 
 
X 
X 
X 
X 
X 
Intraocular Pressure 
X 
 
 
X 
X 
X 
X 
X 
Best 
Corrected 
Visual 
Acuity 
X 
 
 
X3 
 
X 
X 
X 
X 
Ophthalmoscopy2 
X 
 
 
 
 
X 
X5 
X5 
Confirm 
and 
Document 
Subject Eligibility 
X 
 
 
 
 
 
 
 
Randomization 
X 
 
 
 
 
 
 
 
Dispense 
IP 
and 
Pain/Dosing Diary 
X 
 
 
 
 
 
 
 
Instruct Subject on IP and 
Dosing/Pain Diary 
X 
 
 
 
 
 
 
 
AE Assessment 
X 
X 
X 
X 
X 
X 
X 
X 
Dosing Reminder Call 
 
X 
 
 
 
 
 
 
Update 
Concomitant 
Medications 
 
 
X 
X 
X 
X 
X 
X 
Review Pain/Dosing Diary 
 
 
X 
X 
X 
X 
X4 
X5 
Collect IP  
 
 
 
 
 
X 
X5 
X5 
Collect Pain/Dosing Diary 
 
 
 
 
 
 
X 
X5 
Exit Subject From Study 
 
 
 
 
 
 
 
X 
IP = Investigational Product; AE = adverse event; eCRF = electronic case report form 
1All eye exams are to be conducted in the study eye only. The fellow eye (non-study eye) may be examined at the investigators’ discretion. 
2Performed by a board-certified ophthalmologist. 
3A pinhole test may be employed at Day 1 (Visit 3). 
4Dosing terminates on Day 14. Pain is assessed through the evening of Day 17. 
5If not completed at previous visit. 
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 7 assessments should be conducted, including ophthalmoscopy if not 
obtained at Day 15 (Visit 5). 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
9 
 
6.2 
Examination Procedures 
The following ophthalmic examinations will be conducted in the surgery eye (study eye) at 
intervals specified in Table 1, The Schedule of Assessments. The fellow eye (non-study eye) may 
be examined at the investigators’ discretion.  
 Best Corrected Visual Acuity (BCVA): BCVA will be measured at every visit except 
Visit 2 (Surgery; Day 0). The Early Treatment Diabetic Retinopathy (ETDRS) log of the 
minimum angle of resolution (logMAR) will be used to measure BCVA.  
 Intraocular Pressure (IOP): IOP will be measured at every visit except Visit 2 (Surgery; 
Day 0) in mmHg using an applanation tonometer. 
 Ophthalmoscopy: Ophthalmoscopy will be performed at Visit 1 (Day -14 to Day -2) and 
Visit 5 (Day 15) by a board-certified ophthalmologist.  
 Biomicroscopy: Slit lamp biomicroscopy, including the evaluation of ACC and anterior 
chamber flare (ACF), chemosis, bulbar conjunctival injection, ciliary injection, corneal 
edema, and keratic precipitates will be conducted by a board-certified ophthalmologist at 
every visit except Visit 2 (Surgery; Day 0). 
 Visual Analog Scale (VAS): Eye pain/discomfort and photophobia will be evaluated at 
every visit except Visit 2 (Surgery; Day 0) using a Visual Analog Scale (VAS), scoring 
from 0 to 100 using a mark on a 100 mm line (0 = absent; 100 = maximum).  
 Pain assessment via diary (Pain Diary): Surgery eye pain will be evaluated prior to each 
IP dose using a pain scale included in the pain and dosing diary that subjects complete at 
home.  
 
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.  


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
10 
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). 
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 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
11 
 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 
Anterior chamber cell (ACC) and ACF, chemosis, bulbar conjunctival injection, ciliary injection, 
corneal edema, and keratic precipitates will be assessed in the study. Since the severity of these 
assessments will be recorded and carefully monitored during the study, worsenings do not need to 
be recorded as AEs unless the investigator judges it appropriate. Any treatment emergent findings 
(findings that were not present prior to dosing with IP, or a worsening relative to baseline [before 
IP dosing]) outside of these assessments should be recorded as an AE. 
Ophthalmoscopy 
A new finding or a significant worsening (2 units or more) from baseline should be recorded as an 
AE. 
 
 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
12 
VAS 
Pain/discomfort and photophobia will be assessed in the study eye. Since the severity of these 
assessments will be recorded and carefully monitored during the study, worsenings do not need to 
be recorded as AEs unless the investigator judges it appropriate. 
7.3 
Reporting and Evaluation of AEs and SAEs  
Table 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.  


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
13 
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 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with an ACC grade of 0 at Day 15.  
Anterior Chamber Cells 
Grade* 
Cell Count 
0 
0 
1 
1-5 
1 
6-10 
2 
11-20 
3 
21-50 
4 
> 50 
*Grade 1 includes cell count 1-5 and cell count 6-10. 
 
8.2 
Secondary Efficacy Endpoint 
The secondary efficacy endpoints are the proportion of subjects who achieve a pain score of 0 on 
the visual analog scale (VAS) (0-100 mm scale) for each post-surgical assessment at Days 1, 8, 
15, 18, and 29. 
8.3 
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 in the study eye at each scheduled visit 
for the following ocular-specific parameters: 
o BCVA 
o IOP 


Clinical Protocol  
 
ISV-305 (0.1% dexamethasone) 
Study No. C-16-305-003 Original Protocol, Redacted – Clinicaltrials.gov 
May 31, 2017 
 
InSite Vision, Inc. 
 
14 
o Slit-lamp biomicroscopy 
o Ophthalmoscopy findings 
o Photophobia