Clinical trial NCT04739709
Conditions: Ocular Inflammation and Pain
Sponsor: Formosa Pharmaceuticals, Inc.
Start date: 2021-01-11; Completion date: 2022-03-17
Enrollment: 378 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This Phase 3 study will evaluate APP13007 in comparison to the matching vehicle placebo in a randomized, parallel-group, double-masked fashion. The subjects will have undergone routine cataract surgery on Day 0 of the study and will be assessed the next day (Post-operative Day 1; POD1) after uncomplicated surgery for eligibility for randomization to study treatment.

Detailed description:

Arms: arm 1: 1 drop APP13007 0.05% twice daily for 14 days to study (operated) eye arm 2: 1 drop matching vehicle place twice daily for 14 days to study (operated) eye
Interventions: intervention 1: APP13007, 0.05% intervention 2: Matching Vehicle Placebo for APP13007, 0.05%
Intervention descriptions: intervention 1: APP13007 eye drop, 0.05% intervention 2: Matching vehicle placebo eye drop

Protocol documents:
Prot_000.pdf: 
  
  
 
CLINICAL STUDY PROTOCOL 
 
A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group Study 
to Evaluate the Efficacy and Safety of APP13007 for the Treatment of Inflammation and 
Pain after Cataract Surgery. 
 
PROTOCOL NUMBER:  CPN-301 
 
Protocol Version: 
1.3 (Amendment 1) 
Version Date: 
18 May 2021 
Study Sponsor: 
 
Formosa Pharmaceuticals, Inc. 
8F-6, No. 57, Fuxing North Road 
Songshan District, Taipei 
Taiwan 105, Republic of China 
Sponsor US 
Representative: 
 
 
 
Contract Research 
Organization for Study 
Management and 
Monitoring: 
 
 
 
Study Medical Monitor: 
 
 
 
 
 
 
CONFIDENTIAL INFORMATION 
This document is the property of Formosa Pharmaceuticals, Inc.
 
 This document and 
any and all information contained herein has to be considered and treated as strictly confidential. This document shall 
be used only for the purpose of the disclosure herein provided. No disclosure or publication shall be made without the 
prior written consent o
 


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APPROVAL SIGNATURE PAGE 
 
Approved by 
 
 
 
18 May 2021 
 
 
Date 
Chief Medical Officer 
 
 
 
 
 
 
18 May 2021 
 
 
 
Date 
Biostatistician 
 
 
 
 
 
 
 
 
 
______________________  
May 18, 2021 
 
 
Date 
Chief Development Officer 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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APP13007 
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PRINCIPAL INVESTIGATOR’S AGREEMENT 
I have read and understand the contents of this clinical Protocol No. CPN-301 (Version 1.3, 
Amendment 1) dated 18 May 2021 and will adhere to the study requirements as presented, 
including all statements regarding confidentiality. In addition, I will conduct the Study in 
accordance with this protocol, current Good Clinical Practices and applicable FDA regulatory 
requirements: 
Name of Principal Investigator: 
Name: 
 
Title: 
 
Clinic: 
 
Address: 
 
Phone: 
 
 
 
 
 
 
Signature 
 
Date 
 
 
 


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STUDY CONTACTS 
SPONSOR REPRESENTATIVE 
 
 
 
 
PRIMARY CONTACT OF SPONSOR REPRESENTATIVE  
SPONSOR MEDICAL MONITOR 
 
 
 
 
 
 
STUDY MEDICAL MONITOR CONTACT 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAE REPORTING CONTACT 
 
 
 
  
 
 
SECONDARY CONTACT OF SPONSOR REPRESENTATIVE  
 
 
 
 
 
 
 


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168B 
CHANGES IN PROTOCOL AMENDMENT 1 
This protocol is being amended to: 
 Clarify the permitted and prohibited medications based on feedback from investigators 
and to permit vaccinations/immunizations 
 Indicate that prohibited medications preferably should be withheld until after the POD22 
assessments 
 Correct minor formatting errors 
This amendment applies to all clinical sites participating in this study. 
 
TABLE OF CHANGES IN AMENDMENT 1 
Protocol Section 
Original Text 
Amended Text (Bolded) 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
Subjects receiving therapy for 
macular degeneration (in either 
eye) with Eylea® (aflibercept), 
Avastin® (bevacizumab), 
Lucentis® (ranibizumab) or 
Visudyne® (verteporfin) are 
excluded 
Subjects receiving therapy for 
macular degeneration (in either 
eye) with Eylea® (aflibercept), 
Avastin® (bevacizumab), 
Lucentis® (ranibizumab), 
Beovu® (brolucizumab-dbll) 
or Visudyne® (verteporfin) are 
excluded 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
 
ii. PROKERA (preserved 
amniotic membrane) is 
excluded from 1 year prior to 
the Screening visit to the end 
of the study. 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
from the beginning of the 
‘Washout’ period in “List of 
Prohibited Medications” until 
after the POD15 assessments 
from the beginning of the 
‘Washout’ period in “List of 
Prohibited Medications” until 
after the POD15 assessments, 
but preferably until after the 
POD22 assessments 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
Anti-inflammatory agents, 
analgesics (including opioids, 
narcotics, nonsteroidal anti-
inflammatory drugs (NSAIDs), 
aspirin, acetaminophen and 
other pain medications) or 
immune-modulating agents 
systemically or in either eye 
from the beginning of the 
‘Washout’ period in the “List 
of Prohibited Medications” 
Anti-inflammatory agents, 
analgesics (including opioids, 
narcotics, nonsteroidal anti-
inflammatory drugs (NSAIDs), 
aspirin, acetaminophen and 
other pain medications) or 
immune-modulating agents 
systemically or in either eye 
from the beginning of the 
‘Washout’ period in the “List 
of Prohibited Medications” 


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until after the POD15 
assessments. Note: 
acetaminophen is permitted on 
the day of surgery. 
until after the POD15 
assessments, but preferably 
until after the POD22 
assessments. Note: 
(i) acetaminophen is permitted 
on the day of surgery; (ii) 
immunizations/vaccinations 
are permitted before and 
during the study. 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
Systemic anti-inflammatory 
agents including 
acetaminophen, NSAIDS, 
acetylsalicylic acid (aspirin), 
and Lifitegrast.   
Note: (i) Use of acetylsalicylic 
acid for cardiovascular 
prophylaxis (i.e., 81 mg dose 
QD) is allowed if dosage has 
been stable for at least 30 days 
prior to surgery and will 
remain stable for the duration 
of the study.  (ii) 
Acetaminophen may be 
administered as needed pre- 
and post-operatively on the day 
of surgery. 
Systemic anti-inflammatory 
agents including 
acetaminophen, NSAIDS, 
acetylsalicylic acid (aspirin), 
and Lifitegrast.   
Note: (i) Use of acetylsalicylic 
acid for cardiovascular 
prophylaxis (i.e., 81 mg dose 
QD) is allowed if dosage has 
been stable for at least 30 days 
prior to surgery and will 
remain stable for the duration 
of the study.  (ii) 
Acetaminophen may be 
administered as needed pre- 
and post-operatively on the day 
of surgery, (iii) Over-the-
Counter preparations such as 
Fish Oils, Turmeric and 
Ginseng that may have mild 
anti-inflammatory effects are 
allowed. 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
Systemic analgesics/pain 
relievers such as gabapentin, 
pregabalin, opioids 
 
Systemic analgesics/pain 
relievers such as gabapentin, 
pregabalin, opioids 
Note: Marijuana/CBD-
containing products have the 
same washout restrictions as 
“Systemic Analgesics” 
because they can affect pain 
perception 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
Medications for benign 
prostatic hypertrophy (BPH) 
(e.g., finasteride). Note: 
Investigators should consider 
excluding subjects who are 
taking or have taken α-1 
Medications for benign 
prostatic hypertrophy (BPH) 
(e.g., finasteride, α-1 
adrenergic receptor 
antagonists) are allowed 
based on the judgment of the 


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adrenergic receptor 
antagonists (eg. tamsulosin, 
silodosin, alfuzosin) because of 
the risk of intraoperative floppy 
iris syndrome. 
 
[28 Days] 
investigator. Note: 
Investigators should consider 
the potential risk of 
intraoperative floppy iris 
syndrome in subjects who are 
taking or have taken α-1 
adrenergic receptor 
antagonists (eg. tamsulosin, 
silodosin, alfuzosin). 
 
[Stable dose for 28 days] 
Synopsis and Section 4.3 
(Exclusion Criterion 7) and 
Section 5.4.2 
Stable doses of anticholinergics 
and antidepressants are 
allowed. Alterations of the dose 
of anticholinergics and 
antidepressants (other than for 
prn use as a sleep aid) may be 
allowed following consultation 
with the Study Medical 
Monitor. Anticholinergic eye 
drops used to dilate the eye are 
allowed.  Systemic 
anticholinergic drugs are 
allowed on the day of surgery.  
 
[90 days if altering the dose] 
Additional new text 
 
Note 1 
For anti-depressants used to 
treat depression: (i) 
Medication must not be 
washed-out for the purpose of 
enrollment in the study; (ii) 
Stable doses of anti-
depressants are allowed; (iii) 
When the dose of an anti-
depressant has been altered, 
the subject needs to be on the 
stable altered dose for at least 
90 days prior to the day of 
surgery (Day 0). 
 
Note 2 
For anti-depressants used to 
treat pain: (i) The 
instructions provided for 
systemic analgesics/pain 
relievers apply, viz. at least a 
14 day washout of the 
medication is required prior 
to the day of surgery (Day 0) 
continuing until the POD15 
assessments have been 
completed. 
 
[See Note 1 and Note 2] 
Synopsis and Section 4.3 
(Exclusion Criterion 14)  
14. Have corneal dystrophies or 
dysthyroid ophthalmopathy in 
the study eye. 
14. Have corneal dystrophies, 
including corneal guttae and 
Fuchs’ dystrophy, or 
dysthyroid ophthalmopathy in 
the study eye. 


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Section 6.2.2 Day of Surgery 
On Day 0, the surgeon will 
perform his/her routine cataract 
surgical procedure using 
phacoemulsification and 
implantation of a posterior 
chamber intraocular lens in the 
operated eye following the 
surgeon’s usual pre-operative, 
operative, and post-operative 
procedures (with the exception 
of avoiding use of prohibited 
medications).   
On Day 0, the surgeon will 
perform his/her routine cataract 
surgical procedure using 
phacoemulsification and 
implantation of a posterior 
chamber intraocular lens in the 
operated eye following the 
surgeon’s usual pre-operative, 
operative, and post-operative 
procedures (with the exception 
of avoiding use of prohibited 
medications).  Aqueous 
release procedures are not 
permitted. 
 
 


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TABLE OF CONTENTS 
 
INTRODUCTION ................................................................................................................... 25 
1.1 
Overview ................................................................................................................................. 25 
1.2 
Background ............................................................................................................................. 25 
1.2.1 
Clobetasol Propionate .............................................................................................................. 25 
1.2.2 
Pain and Inflammation Following Cataract Surgery ............................................................... 25 
1.2.3 
Rationale for Development of APP13007 ............................................................................... 26 
1.3 
Nonclinical Studies.................................................................................................................. 26 
1.3.1 
Primary Pharmacology ............................................................................................................ 26 
1.3.2 
Pharmacokinetics..................................................................................................................... 26 
1.3.3 
Toxicology .............................................................................................................................. 27 
1.4 
Human Studies ........................................................................................................................ 27 
1.4.1 
CPN-201: A Phase 2 Safety and Preliminary Efficacy Study Post Cataract Surgery ............. 27 
1.4.1.1 
Safety Results .......................................................................................................................... 28 
1.4.1.2 
Efficacy Results ....................................................................................................................... 28 
1.4.1.3 
Conclusion ............................................................................................................................... 29 
1.4.2 
CPN-102: A Phase 1 Pharmacokinetic Study in Healthy Subjects ......................................... 29 
1.4.2.1 
Safety Results .......................................................................................................................... 29 
1.4.2.2 
Pharmacokinetic Results ......................................................................................................... 29 
1.4.2.3 
Conclusion ............................................................................................................................... 30 
1.5 
Risk/Benefit Assessment ......................................................................................................... 30 
1.5.1 
Potential Risks ......................................................................................................................... 30 
1.5.1.1 
Potential Risks Anticipated Based on Results from the GLP Rabbit Toxicology Studies 
with APP13007........................................................................................................................ 30 
1.5.1.2 
Potential Risks Anticipated Based on Results from the Human Studies with APP13007 ...... 30 
1.5.1.3 
Potential Risks Associated with the Use of CP in the Treatment of Corticosteroid-
Responsive Dermatoses ........................................................................................................... 31 
1.5.1.4 
Potential Class-Related Ocular Risks Associated with Corticosteroid Therapies for the 
Treatment of Ocular Inflammation and Pain after Ocular Surgery ......................................... 31 
1.5.1.5 
Potential Risks Associated with the APP13007 Formulation ................................................. 32 
1.5.2 
Risk Mitigation Plan ................................................................................................................ 33 
1.5.3 
Contraindications..................................................................................................................... 33 
1.5.4 
Potential Benefits .................................................................................................................... 33 
1.5.5 
Assessment of Potential Risks and Benefits ............................................................................ 34 
 
STUDY OBJECTIVES AND ENDPOINTS .......................................................................... 38 
 
STUDY DESIGN .................................................................................................................... 40 
3.1 
Study Design Overview ........................................................................................................... 40 
3.2 
Study Visit Overview .............................................................................................................. 40 
3.2.1 
Study Visits and Procedures .................................................................................................... 40 
3.2.2 
Contingencies relating to the COVID-19 Pandemic ............................................................... 41 
3.3 
Rationale for Study Design ..................................................................................................... 41 
3.3.1 
Rationale for Number of Subjects to be Randomized ............................................................. 41 


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3.3.2 
Rationale for the Primary Efficacy Endpoints ......................................................................... 41 
3.3.3 
Rationale for Dosing Regimen ................................................................................................ 42 
 
STUDY POPULATION .......................................................................................................... 43 
4.1 
Number of Subjects ................................................................................................................. 43 
4.2 
Inclusion Criteria ..................................................................................................................... 43 
4.2.1 
Additional Inclusion Criteria on Postoperative Day (POD) 1/Day of Randomization 
(Visit 2) ................................................................................................................................... 44 
4.3 
Exclusion Criteria .................................................................................................................... 44 
 
STUDY DRUG AND TREATMENTS .................................................................................. 47 
5.1 
Study Drug Administration ..................................................................................................... 47 
5.1.1 
Study Drug Description ........................................................................................................... 47 
5.1.2 
Study Drug Dosing and Administration .................................................................................. 48 
5.1.2.1 
Dispensing and Replacing Study Drug .................................................................................... 48 
5.1.2.2 
Subject Diaries ........................................................................................................................ 48 
5.1.2.3 
Study Drug Compliance .......................................................................................................... 49 
5.1.2.4 
Study Treatments ..................................................................................................................... 49 
5.1.2.5 
Study Drug Dosing .................................................................................................................. 49 
5.2 
Study Drug Return and Accountability ................................................................................... 50 
5.3 
Masking and Unmasking ......................................................................................................... 50 
5.4 
Prior/Concomitant Therapy and Rescue Medication............................................................... 51 
5.4.1 
Rescue Medication .................................................................................................................. 52 
5.4.2 
Prohibited Medications ............................................................................................................ 52 
 
STUDY CONDUCT ............................................................................................................... 55 
6.1 
Study Subject Number ............................................................................................................. 55 
6.2 
Description of Study Visits ..................................................................................................... 55 
6.2.1 
Visit 1 - Screening ................................................................................................................... 55 
6.2.2 
Day of Surgery (Day 0) ........................................................................................................... 56 
6.2.3 
Visit 2 - POD1 (Day of Randomization) ................................................................................. 56 
6.2.4 
Visit 3 (POD4 ± 1) and Visit 4 (POD8 ± 1) ............................................................................ 57 
6.2.5 
Day of Subject Contact on POD14 .......................................................................................... 57 
6.2.6 
Visit 5 (POD15 + 1) ................................................................................................................ 58 
6.2.7 
Visit 6 (POD22 ± 2) ................................................................................................................ 58 
6.2.8 
Early Termination/Withdrawal ................................................................................................ 58 
6.2.9 
Unscheduled Visits .................................................................................................................. 58 
6.2.10 
Study Visit Schedule for Rescued Subjects ............................................................................. 58 
6.3 
Subject Early Termination (Withdrawal) ................................................................................ 59 
6.4 
Study Discontinuation Criteria ................................................................................................ 60 
6.4.1 
Early Discontinuation of the Study ......................................................................................... 60 
6.4.2 
Discontinuation of a Study Site ............................................................................................... 60 
 
STUDY ASSESSMENTS AND PROCEDURES .................................................................. 61 
7.1 
Demography and Medical History .......................................................................................... 61 
7.2 
Efficacy Assessments .............................................................................................................. 61 
7.2.1 
List of Efficacy Assessments .................................................................................................. 61 


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7.2.2 
Procedures for Assessment of Efficacy Endpoints .................................................................. 61 
7.2.2.1 
Anterior Chamber Cell Count and Anterior Chamber Flare ................................................... 61 
7.2.2.2 
Subject-Rated Ocular Pain Assessment ................................................................................... 62 
7.2.2.3 
Best Corrected Visual Acuity .................................................................................................. 62 
7.3 
Safety Assessments ................................................................................................................. 62 
7.3.1 
List of Safety Assessments ...................................................................................................... 62 
7.3.1.1 
Assessment of Adverse Events ................................................................................................ 63 
7.3.1.2 
ETDRS Best Corrected Visual Acuity Measurement by Pinhole Method .............................. 63 
7.3.1.3 
Slit Lamp Biomicroscopy ........................................................................................................ 64 
7.3.2 
IOP Measurement .................................................................................................................... 64 
7.3.3 
Dilated Ophthalmoscopy ......................................................................................................... 65 
 
ADVERSE EVENTS .............................................................................................................. 66 
8.1 
Definition of Adverse Events (AEs)........................................................................................ 66 
8.1.1 
Subjects who are Randomized................................................................................................. 66 
8.1.2 
Subjects who are Not Eligible for Randomization (Screen Failures) ...................................... 67 
8.2 
Definition of Serious Adverse Events (SAEs) ........................................................................ 67 
8.3 
Classification of an Adverse Event ......................................................................................... 68 
8.3.1 
Severity of Event ..................................................................................................................... 68 
8.3.2 
Relationship to Ocular Surgical Procedure or Study Drug ...................................................... 68 
8.3.3 
Expectedness ........................................................................................................................... 69 
8.3.4 
Action Taken with Study drug ................................................................................................ 69 
8.3.5 
Adverse Event Outcome .......................................................................................................... 70 
8.4 
Adverse Event Follow-Up ....................................................................................................... 70 
8.5 
Overdose/Under-dose for Assessment of Compliance ............................................................ 70 
8.5.1 
Overdose .................................................................................................................................. 70 
8.5.2 
Under-dose .............................................................................................................................. 71 
8.6 
Pregnancies .............................................................................................................................. 71 
8.7 
Serious Adverse Event Reporting ........................................................................................... 72 
8.7.1 
Reporting Requirements .......................................................................................................... 72 
8.7.2 
Reporting of Serious and Unexpected Suspected Adverse Reactions (SUSARS) .................. 73 
 
SAFETY MANAGEMENT .................................................................................................... 74 
9.1 
Stopping Criteria ..................................................................................................................... 74 
9.1.1 
Individual Subject.................................................................................................................... 74 
9.1.1.1 
Lack of Efficacy (See Section 9.4) .......................................................................................... 74 
9.1.1.2 
Elevated Intraocular Pressure (See Section 9.5) ...................................................................... 74 
9.1.1.3 
Deleterious Effects of the Study Drug ..................................................................................... 74 
9.1.1.4 
Lack of Compliance ................................................................................................................ 74 
9.1.2 
Study Termination ................................................................................................................... 74 
9.2 
Dose Modification ................................................................................................................... 75 
9.3 
Dosing Interruptions ................................................................................................................ 75 
9.4 
Rescue Management ................................................................................................................ 75 
9.4.1 
Criteria for Starting Rescue Medication .................................................................................. 75 
9.4.2 
Management ............................................................................................................................ 76 


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9.5 
Management of Increased IOP ................................................................................................ 76 
9.5.1 
Criteria for Starting IOP-Lowering Medication ...................................................................... 76 
9.5.2 
Management ............................................................................................................................ 77 
 
STATISTICAL CONSIDERATIONS .................................................................................... 78 
10.1 
Statistical Analytical Plan ....................................................................................................... 78 
10.2 
Analysis Populations ............................................................................................................... 78 
10.3 
Statistical Methods .................................................................................................................. 78 
10.3.1 
General Approach .................................................................................................................... 78 
10.3.2 
Analysis of Efficacy ................................................................................................................ 78 
10.3.2.1 
Analyses of Primary Efficacy Endpoints: ............................................................................... 79 
10.3.2.2 
Analyses of Secondary Efficacy Endpoints: ........................................................................... 79 
10.3.3 
Analysis of Safety ................................................................................................................... 79 
10.3.4 
Interim Analysis ...................................................................................................................... 80 
10.4 
Sample Size Estimation ........................................................................................................... 80 
10.5 
Level of Significance ............................................................................................................... 80 
10.6 
Procedure for Accounting for Missing, Unused, or Spurious Data ......................................... 80 
10.7 
Procedure for Reporting Deviations from the Statistical Plan ................................................ 81 
10.8 
Subjects to be Included in the Analysis ................................................................................... 81 
 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS .......... 82 
11.1 
Regulatory, Ethical and Legal Obligations ............................................................................. 82 
11.1.1 
Declaration of Helsinki ........................................................................................................... 82 
11.1.2 
Good Clinical Practice ............................................................................................................. 82 
11.1.3 
Institutional Review Boards .................................................................................................... 82 
11.1.4 
Informed Consent Process ....................................................................................................... 82 
11.1.5 
Subject Confidentiality and Disclosure ................................................................................... 83 
11.2 
Monitoring and Auditing Study Documentation ..................................................................... 83 
11.2.1 
Clinical Monitoring ................................................................................................................. 83 
11.2.2 
Auditing of Sites and Study Documentation ........................................................................... 84 
11.3 
Data Handling and Record Keeping ........................................................................................ 84 
11.3.1 
Data Collection and Management Responsibilities ................................................................. 84 
11.3.2 
Study Records Retention ......................................................................................................... 85 
11.4 
Protocol Deviations ................................................................................................................. 85 
11.5 
Publication and Data Sharing Policy ....................................................................................... 85 
 
REFERENCES ........................................................................................................................ 86 
APPENDIX A 
CONTINGENCY PLANS RELATED TO THE COVID-19 PANDEMIC ................. 88 
APPENDIX B 
GUIDANCE THAT MAY BE USED FOR GRADING THE SEVERITY OF A 
NUCLEAR, CORTICAL OR POSTERIOR SUBCAPSULAR CATARACT IN THE NON-
STUDY EYE ........................................................................................................................... 89 
 


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LIST OF TABLES 
Table 1: 
Schedule of Events .................................................................................................................. 24 
Table 2: 
Risk Mitigation Plan ................................................................................................................ 34 
Table 3: 
Study Objectives and Endpoints .............................................................................................. 38 
Table 4: 
Prohibited Medications and Minimum Washout Periods ........................................................ 53 
Table 5: 
Definitions of AE Severity ...................................................................................................... 68 
Table 6: 
Guidelines for Determining the Relationship (if any) between an Adverse Event and the 
Ocular Surgical Procedure ....................................................................................................... 68 
Table 7: 
Guidelines for Determining the Relationship (if any) between an Adverse Event and the 
Study Drug .............................................................................................................................. 69 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic ...................................................................................................................... 23 


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LIST OF ABBREVIATIONS 
ACC 
Anterior Chamber Cell 
ACF 
Anterior Chamber Flare 
AE 
Adverse Event 
ANCOVA 
Analysis of Covariance. 
BID 
Twice Daily 
BPH 
Benign Prostatic Hyperplasia 
CME 
Cystoid Macular Edema 
ConMed 
Concomitant Medications 
CP 
Clobetasol Propionate 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
U.S. Food and Drug Administration 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
HPA 
Hypothalamic-Pituitary-Adrenal 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IOP 
Intraocular Pressure 
IP 
Investigational Product 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
IU/L 
international units per liter 
IWRS 
Integrated Web Response System 
kg 
kilogram 
LLOQ 
Lower Limit of Quantification 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
mg/kg 
milligrams per kilogram 
mm 
millimeter 
mmHg 
millimeters of mercury 
NSAID 
Nonsteroidal Anti-inflammatory Drug 
OTC 
Over the Counter 
PDR 
Proliferative Diabetic Retinopathy 
PHI 
Protected Health Information 
PI 
Principal Investigator 


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PK 
Pharmacokinetics 
POD 
Post-Operative Day 
PP 
Per-Protocol 
PRN 
As Needed 
QD 
Once Daily 
QID 
Four Times Daily 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAR 
Suspected Adverse Reaction 
SOA 
Schedule of Assessments 
SOP 
Standard Operating Procedure 
SRM 
Study Reference Manual 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
 


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PROTOCOL SYNOPSIS 
Protocol Synopsis 
Sponsor:  Formosa Pharmaceuticals, Inc. 
US Representative:  
 
Title of Study:  A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Parallel-Group 
Study to Evaluate the Efficacy and Safety of APP13007 for the Treatment of Inflammation and Pain 
after Cataract Surgery 
Protocol Number:  CPN-301 
Phase:  3 
Active Ingredient:  
 
Name of Investigational Product:  APP13007 
 
 
Description of Investigational Drug:  APP13007 
Study Center(s):  ~26 in the USA 
Study Duration:  ~ 3-7 weeks from Screening to Final visit  
Study Objectives 
Study Endpoints 
Primary Efficacy Objective 
The primary efficacy objective is to investigate 
the efficacy of APP13007 versus matching 
vehicle placebo for the treatment of inflammation 
and pain through post-operative day (POD) 15 
after cataract surgery in the study eye. 
Primary Efficacy Endpoints 
 
The proportion of subjects with Anterior 
Chamber Cell (ACC) Count = 0 [ACC Grade = 
0] at post-operative day 8   (POD8), maintained 
through POD15  
 
The proportion of subjects with Ocular Pain 
Grade = 0 at POD4, maintained through POD15  
Secondary Efficacy Objective 
The secondary efficacy objective of this study is 
to investigate the effect of APP13007 versus 
matching vehicle placebo on markers of 
inflammation, ocular pain and visual acuity after 
cataract surgery in the study eye. 
Secondary Efficacy Endpoints 
 
Proportion of subjects with ACC count = 0 
[ACC Grade = 0] at PODs 4, 8 and 15 
 
Proportion of subjects with Ocular Pain Grade = 
0 at PODs 4, 8 and 15  
 
Proportion of subjects with Anterior chamber 
flare (ACF) Grade = 0 at POD8 maintained 
through POD15  
 
Proportion of subjects with ACF Grade = 0 at 
PODs 4, 8 and 15 
 
Mean change-from-baseline in ACC Grade at 
PODs 4, 8, and 15 
 
Mean change-from-baseline in Ocular Pain 
Grade at PODs 4, 8 and 15 
 
Mean change-from-baseline in ACF Grade on 
PODs 4, 8 and 15  
 
Number of subjects rescued on or prior to each 
visit and overall 
 
Mean change-from-baseline in best corrected 
visual acuity by pinhole method using an Early 
Treatment Diabetic Retinopathy Study 
(ETDRS) chart at PODs 4, 8 and 15 


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APP13007 
 
 
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Protocol Synopsis 
Safety Objective 
The safety objective is to investigate the safety 
and tolerability of APP13007 versus matching 
vehicle placebo for the treatment of inflammation 
and pain after cataract surgery. 
Safety Endpoints 
 
Adverse events (AEs)  
 
Best corrected visual acuity by pinhole method 
using an ETDRS chart from baseline to each 
post-surgery visit 
 
Slit-lamp biomicroscopy 
o Change-from-baseline in ocular signs to 
each post-surgery visit 
 
Dilated indirect ophthalmoscopy 
o Change-from-baseline in ocular signs to 
Visit 6 (POD22) 
 
Intraocular pressure (IOP) at each visit and 
change-from-baseline to Visit 6 (POD22) 
measured with a Goldmann applanation 
tonometer 
Study Design & Summary of Visit Schedule: 
This Phase 3 study will evaluate APP13007 in comparison to the matching vehicle placebo in a 
randomized, parallel-group, double-masked fashion. The subjects will have undergone routine cataract 
surgery on Day 0 of the study and will be assessed the next day (POD1) after uncomplicated surgery for 
eligibility for randomization to study treatment. 
Subjects who experience postoperative inflammation on POD1 and who meet all other eligibility criteria 
will be randomized to one of two study treatments (either Treatment 1 or Treatment 2) at a 1:1 ratio:   
 
Treatment 1:  1 drop APP13007 twice daily (BID) (morning and evening) for 14 days instilled to 
the operated study eye 
 
Treatment 2:  1 drop matching vehicle placebo BID (morning and evening) for 14 days instilled to 
the operated study eye 
 
Study Visits and Procedures 
Visit 1: Screening. Sign informed consent prior to the conduct of any study procedures or 
discontinuation of any medications related to this study. Screening will occur between 28 days to 1 day 
prior to cataract surgery. Review Inclusion and Exclusion criteria for eligibility.  
Day 0/Day of Surgery: Subjects undergo routine cataract surgery via phacoemulsification and posterior 
chamber intraocular lens implantation according to the Investigator’s normal procedures.  
Visit 2: POD1 will occur ~ 18-34 h after cataract surgery. Review Inclusion and Exclusion criteria. 
Baseline pre-Randomization assessments (ocular inflammation, pain and safety parameters). 
Randomization of eligible subjects. Instillation of first dose of study drug in the operated study eye in 
the clinic under the supervision of Investigator or designee.  
Visit 3: POD4 (± 1 day). Ocular inflammation, pain and safety assessments. 
Visit 4: POD8 (± 1 day). Ocular inflammation, pain and safety assessments. 
[Note: Subjects will be contacted on POD14 to remind them to stop study drug after that day and to 
bring the study drug bottle and dosing diary to the clinic the next day.] 
Visit 5: POD15 (+ 1 day). Ocular inflammation, pain and safety assessments. Urine pregnancy test. 
Visit 6: POD22 (± 2 days). Ocular inflammation, pain and safety assessments. Final visit.  
A detailed summary of study events is provided in Table 1 (Schedule of Events) and a study design 
schematic is provided in Figure 1 (Study Schematics).  


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Protocol Synopsis 
Test Product, Dose and Mode of Administration:   
Study Drugs (APP13007 or matching vehicle placebo) will be supplied in an eye drop bottle. The 
formulations are preserved with benzalkonium chloride filled in a multi-dose opaque low density 
polyethylene (LDPE) 5 mL round dropper bottle with a LDPE tip and tightly closed with a pink high 
density polyethylene (HDPE) cap. The bottle will be labelled in accordance with FDA regulations for an 
investigational product.  
One bottle of study drug will be dispensed to each randomized subject in the trial. Study drug will be 
administered twice daily (morning and evening) by instilling one drop at each dosing time into the 
conjunctival sac of the study eye. If the subject misses his/her eye during instillation, then a second drop 
will be instilled and this will be documented in the dosing diary. 
Randomization:  Subjects who meet all eligibility criteria on POD1 will be randomized to one of the 
two study treatments at a 1:1 ratio (APP13007:placebo).  
Number of Subjects:   
A sufficient number of subjects will be screened to allow approximately 370 subjects (185 on 
APP13007 and 185 on placebo) to be randomized.  
Inclusion Criteria: 
To be eligible, a participant must meet the following criteria: 
At the Screening Visit (Visit 1): 
1. 
Provide signed and dated informed consent 
2. 
Age ≥ 18 years at time of informed consent  
3. 
Males or females of non-childbearing potential. Females of non-childbearing potential is defined as 
women who have been permanently sterilized or are postmenopausal. Postmenopausal is defined as 
amenorrhea for a minimum of 12 months (without an alternative medical cause). Note: Pregnant 
women or nursing (breast-feeding) mothers are excluded from the study.  
4. 
Women-of-childbearing-potential are eligible for enrollment if they have a negative urine 
pregnancy test on POD1 prior to Randomization and they agree to abstain from sexual activity or 
use a highly effective contraceptive such as occlusive cap (diaphragm or cervical/vault cap) plus 
spermicidal agent (foam/gel/film/cream/suppository), oral contraceptive, injectable progesterone, 
implant of etonogestrel or levonorgestrel, estrogenic vaginal ring, percutaneous contraceptive 
patches, or intrauterine device from POD1 to Visit 6 (POD22). 
5. 
Expected to undergo unilateral uncomplicated cataract extraction via phacoemulsification and 
posterior chamber intraocular lens implantation in one eye (designated the ‘Study Eye’) 
6. 
Have a pin-hole corrected visual acuity without other correction of ≤ 1.3 logarithm of the minimum 
angle of resolution (logMAR) in the study eye to be operated and contralateral eye as measured 
using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart at Visit 1. Subjects who are 
unable to read the lines in an ETDRS chart because of the density of the cataract in the study eye 
may be enrolled if, in the opinion of the Investigator, there is no other significant ocular pathology 
that would account for the low visual acuity. 
7. 
Willing and able to comply with study requirements and visit schedule; Able to either self-
administer study medication or have someone available (e.g., spouse, caregiver, etc.) who can 
administer study medication according to the study schedule and instructions.  
Additional Inclusion Criteria on Postoperative Day (POD) 1/Day of Randomization (Visit 2): 
8. 
Have undergone unilateral cataract extraction via phacoemulsification and posterior chamber 
intraocular lens implantation in the study eye without any additional procedures or complications 
that would, in the opinion of the Investigator, interfere with study procedures or confound study 
objectives. 


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Protocol Synopsis 
9. 
No significant ocular pathology affecting visual acuity that is identified after posterior chamber 
intraocular lens implantation in the study eye.  
10. Have ≥ 10 cells in the anterior chamber (excluding red blood and pigment cells) 
11. Have an IOP ≤ 30 mmHg. Note: If the IOP is elevated post-surgery, the investigator may use non-
prostaglandin based IOP-lowering medication(s) at their discretion on the day of surgery (Day 0) 
only. The IOP will be measured and recorded on POD1 to determine eligibility for Randomization. 
 
Exclusion Criteria: 
Participants will be excluded if they meet any of the following criteria:  
1. 
Have a known sensitivity or allergy to clobetasol propionate, corticosteroids, or any of the study 
medication’s components including benzalkonium chloride and soybean lecithin or any routine 
medication required during cataract surgery or for the conduct of study procedures 
2. 
Have an ACC count > 0 or any evidence of intraocular inflammation (e.g., flare) in either eye at the 
Screening visit  
3. 
Have a Grade > 0 on the Ocular Pain Assessment in either eye at the Screening visit 
4. 
Have an immunosuppressive or autoimmune disease that in the opinion of the Investigator could 
affect intraocular inflammation or the normal healing process of the eye 
5. 
Have active or chronic/recurrent ocular or systemic disease that is uncontrolled and could affect 
wound healing and/or resolution of inflammation after cataract surgery 
6. 
Suspected or known malignancy or be currently receiving antineoplastic therapy. Note: subjects 
with basal cell carcinoma will not be excluded unless the Investigator believes that the condition 
has the potential to interfere with study procedures or analysis of results. 
7. 
Are using certain medications, namely: 
i. 
Subjects receiving therapy for macular degeneration (in either eye) with Eylea® (aflibercept), 
Avastin® (bevacizumab), Lucentis® (ranibizumab), Beovu® (brolucizumab-dbll) or Visudyne® 
(verteporfin) are excluded. 
ii. 
PROKERA (preserved amniotic membrane) is excluded from 1 year prior to the Screening 
visit to the end of the study. 
iii. 
Anti-inflammatory agents, analgesics (including opioids, narcotics, nonsteroidal anti-
inflammatory drugs (NSAIDs), aspirin, acetaminophen and other pain medications) or 
immune-modulating agents systemically or in either eye from the beginning of the ‘Washout’ 
period in the “List of Prohibited Medications” until after the POD15 assessments, but 
preferably until after the POD22 assessments. Note: (i) acetaminophen is permitted on the day 
of surgery; (ii) immunizations/vaccinations are permitted before and during the study. 
iv. 
Use of any of the prohibited medications in the “List of Prohibited Medications” within a time 
period prior to surgery that is less than the minimum ‘washout’ period noted in the table. 
NOTE: (i) These medications may not be used from the beginning of the ‘Washout’ period in 
“List of Prohibited Medications” until after the POD15 assessments, but preferably until 
after the POD22 assessments; (ii) Medications for anesthesia related to cataract surgery, 
ocular pain control and non-prostaglandin-based therapy for the treatment of raised 
intraocular pressure (IOP) are allowed on the day of surgery only. 
v. 
Non-approved drugs or investigational products other than the study drug in this study are 
prohibited from 28 days before surgery until after the subject has been released from the 
study. 


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Protocol Synopsis 
Medication 
Minimum ‘Washout’ 
Period Prior to Day 0 
All topical ophthalmic gels or ointments  
2 days 
Ocular mast cell stabilizers 
2 days 
Ocular antihistamines 
2 days 
Ocular and nasal decongestants 
2 days 
All eye drops (except antibiotic eye drops considered to be part of pre-
cataract surgery standard-of-care). Note: Antibiotics with anti-
inflammatory activity and Besifloxacin Ophthalmic suspension are not 
permitted. Note: (i) Artificial tears are allowed, but should not be used 
within 10 minutes of study procedures or medication dosing; (ii) specific 
restrictions for ocular products are listed below. 
2 days 
Topical ocular corticosteroids  
14 days 
Topical ocular NSAIDs 
7 days 
Topical prostaglandin eyelash growth medications 
7 days 
Systemic anti-inflammatory agents including acetaminophen, NSAIDS, 
acetylsalicylic acid (aspirin), and Lifitegrast.  
Note: (i) Use of acetylsalicylic acid for cardiovascular prophylaxis 
(i.e., 81 mg dose QD) is allowed if dosage has been stable for at least 
30 days prior to surgery and will remain stable for the duration of the 
study (ii) Acetaminophen may be administered as needed pre- and post-
operatively on the day of surgery, (iii) Over-the-Counter preparations 
such as Fish Oils, Turmeric and Ginseng that may have mild anti-
inflammatory effects are allowed. 
7 days 
Topical dermatologic corticosteroids including OTC preparations (use of 
topical 0.1% hydrocortisone dermal preparations for less than 3 days 
over a small area of skin [~2 inches x ~2 inches] are allowed). 
14 days 
Systemic (oral, injectable), inhaled and/or nasal corticosteroids 
21 days 
Systemic analgesics/pain relievers such as gabapentin, pregabalin, 
opioids 
Note: Marijuana/CBD-containing products have the same washout 
restrictions as “Systemic Analgesics” because they can affect pain 
perception 
14 days 
Medications for benign prostatic hypertrophy (BPH) (e.g., finasteride, 
α-1 adrenergic receptor antagonists) are allowed based on the judgment 
of the investigator. Note: Investigators should consider the potential risk 
of intraoperative floppy iris syndrome in subjects who are taking or have 
taken α-1 adrenergic receptor antagonists (eg. tamsulosin, silodosin, 
alfuzosin). 
Stable dose for 28 days 
Topical or systemic cyclosporine 
60 days 
Periocular injection of corticosteroid 
28 days 
Intraocular treatment with corticosteroid - dexamethasone drug delivery 
system 
90 days after 
implantation 
Intraocular treatment with corticosteroid – fluocinolone acetonide drug 
delivery system 
48 months after 
implantation 


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Protocol Synopsis 
Stable doses of anticholinergics and antidepressants are allowed. 
Alterations of the dose of anticholinergics and antidepressants (other than 
for prn use as a sleep aid) may be allowed following consultation with 
the Study Medical Monitor. Anticholinergic eye drops used to dilate the 
eye are allowed. Systemic anticholinergic drugs are allowed on the day 
of surgery.  
 
Note 1 
For anti-depressants used to treat depression: (i) Medication must not be 
washed-out for the purpose of enrollment in the study; (ii) Stable doses 
of anti-depressants are allowed; (iii) When the dose of an anti-depressant 
has been altered, the subject needs to be on the stable altered dose for at 
least 90 days prior to the day of surgery (Day 0). 
 
Note 2 
For anti-depressants used to treat pain: (i) The instructions provided for 
systemic analgesics/pain relievers apply, viz. at least a 14 day washout of 
the medication is required prior to the day of surgery (Day 0) continuing 
until the POD15 assessments have been completed. 
See Note 1 and Note 2 
 
8. Have an IOP < 5 mmHg or > 22 mmHg in either eye or a difference of > 5 mmHg between the eyes 
at the Screening visit.  
9. Have a history of documented and repeated elevated IOP or glaucoma 
10. History of herpes keratitis in the study eye 
11. Have active corneal abrasions or ulcers in the study eye 
12. Have active or a history of chronic or recurrent inflammatory eye disease (e.g., iritis, scleritis, 
uveitis, iridocyclitis, rubeosis iridis) in the study eye 
13. Have evidence of acute external ocular infections (bacterial, viral and/or fungal infections including 
vaccinia, varicella and other viral diseases of the cornea and conjunctiva); tuberculosis of the eye; 
intraocular infections, active chalazion, or uncontrolled severe blepharitis in the study eye 
14. Have corneal dystrophies, including corneal guttae and Fuchs’ dystrophy, or dysthyroid 
ophthalmopathy in the study eye 
15. Have uncontrolled and clinically significant dry eye syndrome in the study eye (mild dry eye with 
the use of artificial tears is allowed) 
16. Have proliferative diabetic retinopathy, significantly compromised macular function; significant 
macular disease; have clinically-significant macular edema or a history of cystoid macular edema in 
the study eye; have cup:disc ratio > 0.8 
17. Have had corneal or retinal surgery (laser or incisional) in the study eye within 6 months of the 
Screening visit, or planning to have laser or incisional surgery during the study period in the study 
eye (other than cataract surgery) 
18. Have ocular surgery planned, scheduled or performed on the contralateral eye within the 2 months 
prior to the surgery on the study eye 
19. Have previous ocular trauma with visible scarring or any deformities due to the trauma in the study 
eye that in the opinion of the Investigator may affect the pharmacokinetics of the study drug, or 
post-surgical outcome (including, but not limited to intraocular inflammation, IOP or the normal 
healing process) 


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Protocol Synopsis 
20. Require the use of a contact lens or a collagen shield within 72 hours prior to cataract surgery or for 
the remainder of the study period in either eye 
21. Require use of non-diagnostic topical ophthalmic medications in either eye for the duration of the 
study with the exception of the following which are allowed: mydriatics, anesthetics, antiseptics, 
balanced salt solution, viscoelastics, osmotic agents (e.g., Muro 128), prophylactic antibiotics, non-
prostaglandin analog IOP-lowering agents for IOP increases on the day of cataract surgery, lid 
scrubs for mild blepharitis, or artificial tears for the management of mild dry eye.  
22. In the opinion of the investigator, have the potential for ocular hemorrhage in the study eye that may 
interfere with evaluation of post-surgery inflammation 
23. Have a planned use of or use of femtosecond laser or any other ophthalmic surgical procedure 
(e.g., vitrectomy, relaxing incisions, iridectomy, conjunctival excisions, use of iris hooks or other 
iris dilators, etc.) in addition to the cataract extraction procedure via phacoemulsification and PCIOL 
implantation in the study eye 
24. Have a planned use of or use anterior capsule staining for capsulorhexis (i.e., trypan blue) during 
cataract surgery 
25. Have planned to participate in another clinical trial during the duration of this study 
26. Have participated in another clinical study or received any investigational product within the past 
28 days prior to the Screening Visit. Subjects who previously participated in Study CPN-201 are 
eligible if the planned cataract surgery is for the eye that was the ‘non-study’ eye in that study.  
27. Have any other condition that the Investigator determines should exclude the subject from the trial.  
28. Are an employee of the clinical site that is directly involved in the management, administration, or 
support of this study or are an immediate family member of the same. 
Statistical Methods: 
All analysis variables will be summarized descriptively by treatment group. Summary statistics for 
continuous measures will include the number of subjects (n), mean, standard deviation, median, and 
range. Categorical measures will be summarized by the number and percent of subjects.  
Analyses of Primary Efficacy Endpoints: 
The primary efficacy analyses to compare APP13007 against placebo will be conducted on the Intent-
To-Treat (ITT) population using the Pearson Chi-square statistic. Fixed sequence testing will be 
employed to maintain the 2-sided alpha = 0.05. The primary analyses will first test the difference in the 
proportion of subjects with ACC count = 0 (Grade = 0) at POD8 (Visit 4) maintained through POD15 
(Visit 5) between treatment groups. If the test is statistically significant at the 2-sided alpha = 0.05 level 
in favor of APP13007, the difference in the proportion of subjects with Ocular Pain Grade = 0 at POD4 
(Visit 3) maintained through POD15 (Visit 5) between treatment groups will be tested at the two-sided 
alpha = 0.05 level.  
Analyses of Secondary Efficacy Endpoints: 
Mean change-from-baseline in ACC Grade, Ocular Pain Grade, ACF Grade and visual acuity at PODs 4, 
8 and 15 will be analyzed using an analysis of covariance (ANCOVA). The ANCOVA model will 
include treatment as a fixed effect and baseline as a covariate. The rest of secondary efficacy endpoints 
will be analyzed using the same method described for the primary efficacy endpoints. Rescued subjects 
will be considered to be treatment failures. 
Safety Analysis: 
The safety analysis will summarize ocular treatment emergent AEs (TEAEs) in the study eye and ocular 
AEs for the non-study eye. Ocular and non-ocular TEAEs will be summarized similarly.  
 
The other safety endpoints will be summarized as discussed in the Statistical Considerations section of 
the protocol. 


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STUDY DESIGN 
Figure 1: 
Study Schematic 
 
 
 


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Table 1: 
Schedule of Events 
PROCEDURE/ASSESSMENTS 1  
Visit 1 
Screening  
(Day -28 to -1) 
Surgery 2 
Day 0 
Visit 2 
POD1 3 
Visit 3 
POD4 
(±1 Day) 
Visit 4 
POD8 
(±1 Day) 
Contact 
POD14 
Visit 5 
POD15 
(+1 Day) 4 
Visit 6 
POD22 
(±2 Days) 5 
ICF, Demography, Medical History  
X 
 
 
 
 
 
 
 
Determine Eligibility, Review Inclusion/Exclusion Criteria  
X 
 
X 
 
 
 
 
 
Urine pregnancy test only for women of child-bearing potential  
 
 
X 
 
 
 
X 
 
Ocular Symptoms Assessment 6  
X 
 
X 
X  
X 
 
X 
X 
ETDRS Visual Acuity 
X 
 
X 
X 
X 
 
X 
X 
Slit Lamp Biomicroscopy 7  
X 
 
X 
X 
X 
 
X 
X 
Indirect Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
X 
lOP (Goldmann applanation tonometry) 8 
X 
 
X 
X 
X 
 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
Dispense Study Drug  
 
 
X 
 
 
 
 
 
Study Drug Dosing BID for 14 days (POD1 to POD14) 9 
 
 
X 
X 
X 
X 
 
 
Dispense Diary Card (with instructions for completion) 
 
 
X 
X 
X 
 
 
 
Contact Subject 10 
 
 
 
 
 
X 
 
 
Collect Study Drug 
 
 
 
 
 
 
X 
 
Collect and Check Diary Cards for Accuracy and Compliance  
 
 
 
X 
X 
 
X 
 
AEs 7 and Concomitant Medications 11 
X 
X 12 
X 
X 
X 
X 13 
X 
X 
1 Ophthalmic assessments will be performed in the study eye only at Visits 2-5; and performed on both eyes at Visit 1 (Screening) and at Visit 6 (POD22) or at subject Early Termination/Withdrawal. 
2 Surgery must occur between one to 28 days after Screening, preferably in the morning. If, due to unexpected events, surgery is postponed and would occur > 28 days past the Screening visit, contact the Study 
Medical Monitor to determine which, if any, of the screening procedures should be repeated. Subjects will be determined to be a suitable candidate for surgery during a pre-surgery medical assessment, where the 
routine medication list prescribed by the cataract surgeon should be reviewed to rule out prohibited medications (Section 5.4.2). 
3 Visit 2 (POD1) should be scheduled between 18 to 34 hours following conclusion of surgery on Day 0. All assessments done on POD1 are done prior to Randomization to ensure eligibility. Note: Women-of-
childbearing-potential are eligible for enrollment if they have a negative urine pregnancy test on POD1 prior to Randomization and they agree to abstinence from sexual activity or use of highly effective method of 
contraception. 
4 Visit 5 (POD15) occurs on the day after the subject completes the study drug administration for 14 days. Women-of-childbearing-potential should have a urine pregnancy test. 
5 Visit 6 (POD22) is the last visit for subjects who complete the study. Subjects who are withdrawn early should have the Visit 6 assessments and a urine pregnancy test performed before they are released from the 
study. 
6 Includes assessments of ocular pain and irritation. See Section 8.0 of protocol for information on how to record AEs and how to determine attributability (relatedness) of AE to study procedures (including 
cataract surgery) or study drug. 
7 Ocular inflammation assessment using ACC count, anterior chamber flare grade, bulbar conjunctival injection, sclera - ciliary flush and corneal edema. 
8 IOP should (but not required) be assessed at each visit within ± 2 h of the IOP assessment time at Visit 1. 
9 The first dose of study drug should be instilled into the study eye at the clinic visit under supervision of clinic staff. The second dose on POD1 can be administered at home. Subjects who are rescued will not 
continue to instill study drug or receive further diary cards but will remain in the study to complete the procedures/assessments through Visit 6 (POD22).  
10 The site must contact the subject via the subject’s preferred method on POD14 to remind him/her not to instill study drug on POD15 and to bring the bottle of study drug and the dosing diary back to the site at 
the POD15 visit. 
11 Concomitant medications used for rescue should be reported in the eCRF. 
12 AEs and Concomitant Medications should only be recorded on Day 0 if they result in disqualification (i.e., screen failure) of the subject; otherwise, the AEs and Concomitant Medications applicable to Day 0 
should be recorded when the subject returns for Visit 2 (POD1). 
13 Any AEs reported to the site during the POD14 contact must be recorded in the source documents. Further assessment of any reported AEs may require an Unscheduled Visit on POD14 if medically significant 
or they may be assessed, as appropriate, during Visit 5 (POD15). 


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INTRODUCTION 
1.1 
Overview 
APP13007 is an ophthalmic nanosuspension that is prepared by dispersing nanomilled 
 
, a corticosteroid, with a mixture of excipients in a multi-dose preserved aqueous 
 
1.2 
Background 
1.2.1 
 
Corticosteroids regulate cellular signaling, immune function, inflammation and protein synthesis, 
and like other corticosteroids, CP has anti-inflammatory and vasoconstrictive properties. The 
mechanism of the anti-inflammatory activity of CP is unclear, but it is thought to act by inducing 
lipocortins, proteins that inhibit phospholipase A2, an enzyme that releases arachidonic acid 
from membrane phospholipids. By inhibiting phospholipase A2, lipocortins control the 
biosynthesis of potent mediators of inflammation such as prostaglandins and leukotrienes. 
CP is an analog of prednisolone with a very high degree of activity at the glucocorticoid receptor 
and only slight degree of mineralocorticoid activity (Clobex® 2018). It is reported to be the most 
potent corticosteroid in terms of binding affinity to the glucocorticoid receptor and resulting 
pharmacological effects (Olsen 1986), (Jacob 2006). CP has been used in dermal applications 
including ointments, creams and shampoos, where its efficacy and safety has been well-
established (Clobex® 2018); (Temovate® 2000); (Olsen 1986); (Hengge 2006); (Feldman 2009). 
1.2.2 
Pain and Inflammation Following Cataract Surgery 
Despite modern advances in surgical technique, trauma that occurs during cataract removal and 
intraocular lens placement regularly leads to some degree of inflammation. The cellular damage 
on the surface of the cornea activates an inflammatory process that manifests initially as 
hyperemia, corneal edema, and increased anterior chamber cells and flare. More serious 
complications such as corneal edema, increases in intraocular pressure (IOP), cystoid macular 
edema (CME), and posterior capsule opacification may result if the inflammatory process is not 
managed appropriately (Tennant 1978) (Apple 1992). For this purpose, a post-cataract surgery 
regimen of anti-inflammatory agents (such as corticosteroids) is typically prescribed because it 
reverses inflammation, pain and discomfort and reduces the risk of further complications. When 
administered at the time of surgery and during the immediate postoperative period, 


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corticosteroids can reverse the clinical and non-clinical manifestations of inflammation (Leopold 
1985) (Aptel 2017). 
1.2.3 
Rationale for Development of APP13007 
Topical ocular administration of corticosteroids is a well-established therapy for the treatment of 
inflammation and pain after ocular surgery (Aptel 2017), and several marketed products are 
currently available that contain active ingredients such as dexamethasone, prednisolone, 
loteprednol etabonate and difluprednate.  
CP has been used for over 30 years in the US, Europe and Japan to treat the inflammatory and 
pruritic manifestations of corticosteroid responsive dermatoses such as psoriasis, eczema and 
atopic dermatitis. CP has not been previously developed for ophthalmic use, presumably due to 
its lack of aqueous solubility. Nevertheless, given its increased potency, an aqueous ophthalmic 
formulation of CP has the potential to produce rapid clearance of anterior chamber cells (ACC), 
return of visual acuity and relief of pain after ocular surgery, surpassing the effectiveness of 
corticosteroids currently on the market.  
APP13007 is an ophthalmic nanosuspension that is prepared by dispersing nanomilled CP with a 
mixture of excipients. The proprietary nanomilling technology allows CP to be formulated as an 
aqueous suspension. This suspension of CP nanoparticles in APP13007 is designed to promote 
efficient penetration of CP into the eye upon ocular surface instillation, thus delivering 
therapeutically relevant concentrations of CP to the target tissues within the eye. 
1.3 
Nonclinical Studies 
Multiple nonclinical pharmacology, pharmacokinetics, and toxicology studies have been 
conducted with various formulations of APP13007, and these are summarized in the APP13007 
Investigator Brochure. 
1.3.1 
Primary Pharmacology 
 
 
 
 
 
1.3.2 
Pharmacokinetics 
 


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1.3.3 
Toxicology 
Data from non-GLP and 14-day and 28-day Good Laboratory Practice (GLP) toxicity studies of 
APP13007 are summarized in the APP13007 Investigator Brochure.  
 
n 
 
) 
 
 
 The toxicology studies suggest that 
potential systemic effects in human subjects with ocular instillations of APP13007 are those 
typical of corticosteroids in general and that have been seen with approved dermal CP products, 
such as Temovate® and Clobex® (Temovate® 2000); (Clobex® 2018). 
The data from repeat dose toxicology studies did not identify any unacceptable risk for human 
subjects.  
1.4 
Human Studies 
Two clinical studies have been completed with APP13007, and details of the subject populations, 
study dosing, conduct and results are summarized in the APP13007 Investigator Brochure. 
1.4.1 
CPN-201: A Phase 2 Safety and Preliminary Efficacy Study Post Cataract Surgery  
This was a multi-center, randomized, double-masked, placebo-controlled, parallel-group Phase 2 
study conducted in two parts (Parts A and B) to evaluate two APP13007 dose strengths and two 
dosing frequencies in subjects who had undergone routine cataract surgery and lens implantation. 
On Post-Operative Day 1 (POD1), subjects who met eligibility criteria were enrolled in the study 
and randomized  to one of the study treatments instilled in the operated study eye: Treatment 1 or 
2 in Part A (1:1 ratio); Treatment 3, 4, 5, or 6 in Part B (1:1:1:1 ratio). A total of 45 subjects were 
randomized in Part A and 87 subjects randomized in Part B. 


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 Treatment 1:  1 drop 0.05% APP13007 BID for 21 days  
 Treatment 2:  1 drop 0.05% matching vehicle placebo BID for 21 days  
 Treatment 3:  1 drop 0.05% APP13007 BID for 3 days followed by 1 drop 0.05% APP13007 
QD for 11 days  
 Treatment 4:  1 drop 0.05% matching vehicle placebo BID for 3 days followed by 1 drop 
0.05% matching vehicle placebo QD for 11 days  
 Treatment 5:  1 drop 0.1% APP13007 BID for 3 days followed by 1 drop 0.1% APP13007 
QD for 11 days   
 Treatment 6:  1 drop 0.1% matching vehicle placebo BID for 3 days followed by 1 drop 0.1% 
matching vehicle placebo QD for 11 days  
1.4.1.1 
Safety Results   
The 0.05% APP13007 and 0.1% APP13007 dosing regimens were well-tolerated with a safety 
profile similar to the matching placebo vehicles.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1.4.1.2 
Efficacy Results 
 
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1.4.1.3 
Conclusion  
The safety and efficacy results from study CPN-201 support the further clinical evaluation of 
0.05% APP13007 BID for the treatment of inflammation and pain following ocular surgery. 
1.4.2 
CPN-102: A Phase 1 Pharmacokinetic Study in Healthy Subjects 
CPN-102 was an open-label, sequential dosing, Phase 1 pharmacokinetic (PK) study to evaluate 
the systemic exposure of CP following ocular instillation of 0.05% APP13007 in healthy 
subjects. 
 
 
   
 
  
 
 
 
   
 
 
 
  
1.4.2.1 
Safety Results 
The 0.05% APP13007 drops were well-tolerated. There were no AEs related to the study drug. 
1.4.2.2 
Pharmacokinetic Results  
 
 
 


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1.4.2.3 
Conclusion 
  
 
 
 
 
1.5 
Risk/Benefit Assessment 
1.5.1 
Potential Risks 
1.5.1.1 
Potential Risks Anticipated Based on Results from the GLP Rabbit Toxicology 
Studies with APP13007  
 
 
 
 
 
 
1.5.1.2 
Potential Risks Anticipated Based on Results from the Human Studies with 
APP13007 
As summarized in the APP13007 Investigator Brochure and in Section 1.4.1.2 and Section 
1.4.2.2, 0.05% APP13007 BID for 21 days was well-tolerated. 
 
 
 
 
 
 
 
 
.  
 
 
 
 
 
 
 the 
systemic tolerability profile after ocular instillation of 0.05% APP13007 BID for 14 days is 
expected to be considerably better than that for dermal CP products summarized below.  


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1.5.1.3 
Potential Risks Associated with the Use of CP in the Treatment of 
Corticosteroid-Responsive Dermatoses 
There is extensive experience with CP in the treatment of inflammatory and pruritic 
manifestations of corticosteroid-responsive dermatoses, where its safety and anti-inflammatory 
profile has been well defined (Olsen 1986); (Hengge 2006); (Feldman 2009). These risks are 
summarized in the APP13007 Investigator’s Brochure. 
Potential non-ocular risks include: 
 Hypothalamic-Pituitary-Adrenal (HPA) Axis Suppression. Recovery of HPA axis function is 
generally prompt upon discontinuation of topical corticosteroids.  
 Cushing's syndrome, hyperglycemia, and unmasking of latent diabetes mellitus. Use of more 
than one corticosteroid-containing product at the same time may increase the total systemic 
corticosteroid exposure. 
 Skin:  Allergic contact dermatitis may occur.  
 Pregnancy and Nursing (Breast-feeding) Mothers:  
o Corticosteroids are teratogenic in laboratory animals when administered systemically at 
relatively low dosage levels (Pregnancy Category C). When administered 
subcutaneously, CP was a significant teratogen in both the rabbit and mouse. Females of 
child-bearing potential are eligible to participate in this study only if they have a negative 
urine pregnancy test on POD1 pre-randomization and they agree to use highly effective 
contraception from POD1 to POD22. Note: Pregnant and/or nursing (breast-feeding) 
mothers are excluded from participation in this study.  
o Systemically administered corticosteroids appear in human milk and could suppress 
growth, interfere with endogenous corticosteroid production, or cause other untoward 
effects. It is not known whether ocular administration of APP13007 could result in 
sufficient systemic absorption of CP to produce detectable concentrations in human milk. 
Potential ocular risks are summarized below. 
1.5.1.4 
Potential Class-Related Ocular Risks Associated with Corticosteroid Therapies 
for the Treatment of Ocular Inflammation and Pain after Ocular Surgery 
The active ingredient in APP13007, 
 is a potent corticosteroid so it has the following 
anticipated ocular risks associated with the corticosteroid class: 
 Intraocular pressure (IOP) increase – prolonged use may result in glaucoma with damage to 
the optic nerve, defects in visual acuity and field of vision.  
 Cataracts – Prolonged use 
 may result in posterior subcapsular cataract 
formation in the non-operated eye.  


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 Delayed healing – Use 
 after cataract surgery may delay healing and increase 
the incidence of bleb formation. In those diseases causing thinning of the cornea or sclera, 
perforations have been known to occur with the use of topical corticosteroids.  
 Risk of Infection 
o Bacterial infections – Prolonged use 
 may suppress the host immune 
response and thus increase the hazard of secondary ocular infections. In acute purulent 
conditions, corticosteroids may mask infection or enhance existing infection. 
o Viral infections – Use of ocular corticosteroids may prolong the course and may 
exacerbate the severity of many viral infections of the eye (including herpes simplex).  
o Fungal Infections – Fungal infections of the cornea are particularly prone to develop 
coincidentally with long-term local corticosteroid application. Fungus invasion must be 
considered in any persistent corneal ulceration while a subject is participating in this 
clinical trial. 
In clinical studies evaluating the use of corticosteroids after ocular surgery, ocular adverse 
reactions that occurred in 5% to 15% of subjects included corneal edema, ciliary and 
conjunctival hyperemia, eye pain, photophobia, posterior capsule opacification, anterior chamber 
cells, anterior chamber flare, conjunctival edema, and blepharitis. Other ocular adverse reactions 
occurring in 1% to 5% of subjects included reduced visual acuity, punctate keratitis, eye 
inflammation, and iritis. Ocular adverse reactions occurring in less than 1% of subjects included 
application site discomfort or irritation, corneal pigmentation and striae, episcleritis, eye pruritus, 
eyelid irritation and crusting, foreign body sensation, increased lacrimation, macular edema, 
sclera hyperemia, and uveitis. Most of these reactions may have been the consequence of the 
surgical procedure. 
1.5.1.5 
Potential Risks Associated with the APP13007 Formulation 
 
 
 
 
 
 
 


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1.5.2 
Risk Mitigation Plan 
Given the potential risks noted above, a risk mitigation plan will be used to mitigate risks for 
subjects enrolled into the study. The Risk Mitigation Plan is shown in Table 2. 
1.5.3 
Contraindications 
 
APP13007, as with other corticosteroids, is contraindicated in the presence of active viral 
diseases of the cornea and conjunctiva including epithelial herpes simplex keratitis (dendritic 
keratitis), vaccinia, and varicella, and also in subjects with mycobacterial infection of the eye and 
fungal diseases of ocular structures. 
APP13007 must not be administered (i) to women of child-bearing potential without a negative 
urine pregnancy test on POD1 prior to randomization and agreement to use highly effective 
contraception or abstain from sexual activity from POD1 to POD22 or (ii) to pregnant or nursing 
(breast-feeding) woman. 
1.5.4 
Potential Benefits 
Topical ocular administration of corticosteroids is a well-established therapy for the treatment of 
inflammation and pain after ocular surgery, with multiple marketed products currently available 
that utilize corticosteroids as the active ingredient such as dexamethasone (Maxidex®), 
prednisolone (PredForte®), loteprednol etabonate (Lotemax®, Inveltys®, Lotemax SM®), and 
difluprednate (Durezol®). In all clinical trials, corticosteroid therapies were dosed at a frequency 
of twice daily or more frequently.  
As summarized in the APP13007 Investigator’s Brochure, in Study CPN-201 a greater 
proportion of subjects treated with APP13007 0.05% BID had complete clearing of anterior 
chamber cells and complete resolution of ocular pain compared to placebo-treated subjects. 
Thus, it is likely that subjects randomized to active APP13007 will experience a clinically-
meaningful reduction in inflammation and pain following cataract surgery. 
It is known from large clinical trials of products for the treatment of inflammation and pain after 
ocular surgery that a proportion of subjects randomized to placebo improve in the days following 
surgery (Lotemax® Product Insert 2018; Durezol® Product Insert 2017). Thus, there may be a 
marginal benefit observed in some of the subjects enrolled into the study who are randomized to 
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1.5.5 
Assessment of Potential Risks and Benefits 
This is a placebo-controlled study in which subjects will be randomized 1:1 to APP13007 or 
matching vehicle placebo. Subjects randomized to active APP13007 may benefit from the 
treatment by reduction in inflammation and pain, while the risks associated with active 
APP13007 treatment are likely to be low and manageable. This assessment is supported by the 
results of the nonclinical (See Section 1.3) and clinical studies (See Section 1.4) that are 
summarized in detail in the APP13007 Investigator’s Brochure. 
Subjects randomized to placebo are not expected to benefit from the study treatment, but a 
proportion of subjects receiving placebo may show improvement of inflammation in the days 
following surgery. Furthermore, the risks to subjects randomized to placebo in this study are 
mitigated as much as possible. Specifically, the protocol contains instructions for careful 
monitoring of safety and efficacy endpoints during the trial to identify subjects who show 
minimal improvement or worsening of the clinical conditions so that appropriate mitigation steps 
can be taken, including, but not limited to, withdrawal from study treatment and commencement 
of appropriate rescue medication. 
Overall, the risk:benefit analysis supports the evaluation of 0.05% APP13007 and matching 
vehicle placebo administered BID for 14 days after cataract surgery.  
Table 2: 
Risk Mitigation Plan 
Potential Risk 
Management 
Comments 
Risk Associated with Lack of Efficacy 
Minimal reduction or 
worsening of 
inflammation and pain 
endpoints or other 
factors suggesting lack 
of efficacy  
Inflammation and pain endpoints will be 
monitored during the study. 
Guidance criteria and procedures for the 
rescue of subjects are provided in Section 
9.4 of this protocol. 
Minimal reduction or worsening of 
inflammation and pain endpoints or 
other factors suggesting lack of 
efficacy  
Risk Associated with Unexpected Safety Events 
Unexpected safety 
events  
Safety endpoints will be monitored during 
the trial.  
The Investigator will discuss unexpected 
safety events with the Study Medical 
Monitor who will then discuss 
unexpected safety events with the 
Sponsor to determine whether study drug 
should be stopped and rescue procedures 
commenced.  
The toxicology studies with 
APP13007 indicate that there is a 
low risk of ocular toxicity. The 
risks of systemic exposure to CP 
following dermal application are 
well characterized. 
 
 
 
 
 
  
Nevertheless, the Investigator 
should be alert to the possibility 


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Potential Risk 
Management 
Comments 
that unexpected safety events may 
occur. The list of expected safety 
events is including in Section 1.5.5 
and in the APP13007 Investigator’s 
Brochure. 
Risks Associated with the Corticosteroid Class 
Intraocular pressure 
(IOP) increase 
IOP will be monitored during the study. 
The protocol excludes subjects who may 
be at increased risk of steroid-induced 
IOP increase, e.g. subjects with a history 
of raised IOP/glaucoma and subjects with 
IOP >30 mmHg at the POD1 pre-
randomization assessment.  
Section 9.5 includes stopping criteria for 
study drug due to IOP increase and 
criteria for initiation of IOP-lowering 
medication. 
After Randomization, the management of 
IOP > 30 mmHg or IOP ≥ 21 mmHg 
AND an IOP increase > 10 mmHg from 
pre-dose baseline is described in Section 
9.5.2. 
There was no clinically-meaningful 
APP13007-related elevation of IOP 
in the toxicology studies and in 
Study CPN-201. 
Prolonged use of CP may result in 
glaucoma with damage to the optic 
nerve, defects in visual acuity and 
fields of vision.  
An IOP ≥ 30 mmHg after 
randomization should be reported 
as an AE. 
Cataracts 
The lens structure and posterior capsular 
opacification (POC) in the study eye will 
be monitored at each clinic visit 
throughout the study. The lens in the non-
operated eye will be evaluated at 
Screening, Visit 6 (POD22) and Early 
Termination/Withdrawal visits. 
 
 
 
 
 
 
 
 
 
 
 
 
Delayed Healing 
Subjects with thinning of the cornea or 
sclera are excluded because of the greater 
risk of perforations with the use of topical 
steroids.  
Protocol includes stopping criteria for 
study drug if the Investigator, in 
consultation with the Study Medical 
Monitor, is concerned about delayed 
healing. 
Use of APP13007 may delay 
healing after cataract surgery and 
increase the incidence of bleb 
formation. There were no reports of 
delayed healing after cataract 
surgery in Study CPN-201.  


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Potential Risk 
Management 
Comments 
Risk of Infection 
Subjects with on-going ocular bacterial, 
viral or fungal infections are excluded 
from the study. 
Ocular infections occurring during the 
study should be assessed and treated 
appropriately.  
The Investigator should discuss with the 
Study Medical Monitor whether to stop 
study drug if ocular infection occurs. 
Use of APP13007 may suppress the 
host immune response and increase 
the hazard of ocular infections. This 
risk is likely to be low based on 
data from studies of other steroids 
products approved for the treatment 
of inflammation and pain after 
ocular surgery. 
Hypothalamic-Pituitary-
Adrenal Axis (HPA) 
Suppression 
Monitor for symptoms and signs of 
reduced adrenal function (including 
fatigue, muscle weakness, loss of appetite 
and weight, abdominal pain, nausea and 
diarrhea, low blood pressure, depression 
and irritability, salt craving and 
hypoglycemia). 
The Investigator should discuss with the 
Study Medical Monitor who will then 
discuss with the Sponsor whether to stop 
study drug. 
While systemic absorption of 
topical corticosteroids can produce 
reversible HPA axis suppression 
with the potential for glucocorticoid 
insufficiency after withdrawal from 
treatment, this risk is likely to be 
very low 
 
 
 
-
 
 
 
-
 
Nevertheless, Investigators should 
be aware that the symptoms and 
signs of reduced adrenal function 
can be nonspecific and they should 
remain alert to the possibility that 
this may occur.  
Effects related to 
excessive corticosteroid 
pharmacology 
Monitor for symptoms and signs of 
excess corticosteroid pharmacology such 
as Cushing's syndrome, hyperglycemia, 
and unmasking of latent diabetes mellitus. 
The Investigator should discuss with the 
Study Medical Monitor who will then 
discuss with the Sponsor whether to stop 
study drug. 
These effects have been reported 
after dermal use of CP and result 
from systemic absorption of topical 
CP. 
The risk is likely to be very small 
 
 
 
 
Pregnancy Category 
C/Fetal effects 
Women of child-bearing potential are 
excluded from the study if they have a 
positive urine pregnancy test on POD1 
pre-randomization and/or do not agree to 
use highly effective contraception or 
abstain from sexual activity. 
Pregnant and/or nursing (breast-feeding) 
mothers are excluded from the study. 
Corticosteroids are known 
teratogens in laboratory animals 
when administered systemically at 
relatively low dosage levels. 
 
 
  


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Potential Risk 
Management 
Comments 
Skin Irritation   
If irritation develops appropriate therapy 
should be instituted. 
The Investigator should notify the Study 
Medical Monitor in advance if study drug 
is going to be stopped. 
Allergic contact dermatitis may 
occur with CP.  
Other skin reactions have been 
described with topical dermal 
products (See APP13007 
Investigator’s Brochure). 
Other Potential Risks 
 
 
 
 
 
 
 
 
-
 
 
 
 
 
 
 
 
 
Hypersensitivity 
Reactions  
Subjects are excluded from the study if 
they have a history of hypersensitivity to 
CP, corticosteroids, 
 
 
 
 
If hypersensitivity reaction occurs, the 
Investigator should discuss with the Study 
Medical Monitor who will then discuss 
with the Sponsor Medical Monitor 
whether to stop study drug. 
 
Adverse reactions 
reported in clinical 
studies evaluating the 
use of corticosteroids 
after ocular surgery. 
Most of these adverse reactions may have 
been the consequence of the surgical 
procedure and should be managed 
according to standard-of-care procedures. 
Ocular adverse reactions reported in 
completed clinical studies of 
APP13007 are summarized in 
Section 1.5.1.  
 
 


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STUDY OBJECTIVES AND ENDPOINTS 
The objectives and corresponding study endpoints are presented in Table 3 below: 
Table 3: 
Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Efficacy Objective 
The primary efficacy objective is to investigate 
the efficacy of APP13007 versus matching 
vehicle placebo for the treatment of 
inflammation and pain through post-operative 
day (POD) 15 after cataract surgery in the study 
eye. 
Primary Efficacy Endpoints 
 
The proportion of subjects with Anterior 
Chamber Cell (ACC) Count = 0 [ACC Grade = 
0] at post-operative day 8 (POD8), maintained 
through POD15  
 
The proportion of subjects with Ocular Pain 
Grade = 0 at POD4, maintained through POD15 
Secondary Efficacy Objective 
The secondary efficacy objective of this study is 
to investigate the effect of APP13007 versus 
matching vehicle placebo on markers of 
inflammation, ocular pain and visual acuity 
after cataract surgery in the study eye. 
Secondary Efficacy Endpoints 
 
Proportion of subjects with ACC count = 0 
[ACC Grade = 0] at PODs 4, 8 and 15 
 
Proportion of subjects with Ocular Pain Grade = 
0 at PODs 4, 8 and 15  
 
Proportion of subjects with Anterior chamber 
flare (ACF) Grade = 0 at POD8 maintained 
through POD15  
 
Proportion of subjects with ACF Grade = 0 at 
PODs 4, 8 and 15 
 
Mean change-from-baseline in ACC Grade at 
PODs 4, 8, and 15 
 
Mean change-from-baseline in Ocular Pain 
Grade at PODs 4, 8 and 15 
 
Mean change-from-baseline in ACF Grade on 
PODs 4, 8 and 15  
 
Number of subjects rescued on or prior to each 
visit and overall 
 
Mean change-from-baseline in best corrected 
visual acuity by pinhole method using an Early 
Treatment Diabetic Retinopathy Study 
(ETDRS) chart at PODs 4, 8 and 15 


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Objectives 
Endpoints 
Safety Objective 
The safety objective is to investigate the safety 
and tolerability of APP13007 versus matching 
vehicle placebo for the treatment of 
inflammation and pain after cataract surgery. 
Safety Endpoints 
 
Adverse events (AEs)  
 
Best corrected visual acuity by pinhole method 
using an ETDRS chart from baseline to each 
post-surgery visit 
 
Slit-lamp biomicroscopy 
o Change-from-baseline in ocular signs to 
each post-surgery visit 
 
Dilated indirect ophthalmoscopy 
o Change-from-baseline in ocular signs to 
Visit 6 (POD22) 
 
Intraocular pressure (IOP) at each visit and 
change-from-baseline to Visit 6 (POD22) 
measured with a Goldmann applanation 
tonometer 
 


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STUDY DESIGN 
3.1 
Study Design Overview 
This Phase 3 study will evaluate 0.05% APP13007 in comparison to the matching vehicle 
placebo in a randomized, parallel-group, double-masked fashion. Subjects will have routine 
cataract surgery on Day 0 of the study and will be assessed the next day (POD1) after 
uncomplicated surgery for eligibility for randomization to study treatment. 
Subjects who experience postoperative inflammation on POD1 and who meet all other eligibility 
criteria will be randomized to one of two study treatments (either Treatment 1 or Treatment 2) at 
a 1:1 ratio:   
 Treatment 1:  1 drop APP13007 twice daily (BID) (morning and evening) for 14 days 
instilled to the operated study eye 
 Treatment 2:  1 drop matching vehicle placebo BID (morning and evening) for 14 days 
instilled to the operated study eye 
 
Subjects will be discharged from the study after the assessments for Visit 6 (POD22) have been 
performed. 
3.2 
Study Visit Overview 
This will include up to 7 clinic visits (including the surgery day) over a range of 24 to 
approximately 52 days. 
Note: The study drug will be dosed BID for 14 days. 
3.2.1 
Study Visits and Procedures 
Visit 1: Screening. Sign informed consent prior to the conduct of any study procedures or 
discontinuation of any medications related to this study. Screening will occur between 28 days to 
1 day prior to cataract surgery. Review Inclusion and Exclusion criteria for eligibility.  
Between Screening and the day of surgery (Day 0), the prospective subjects will be determined 
to be a suitable candidate for surgery during a pre-surgery medical assessment, where the routine 
medication list prescribed by the cataract surgeon should be reviewed to rule out prohibited 
medications (See Section 5.4.2). 
Day 0/Day of Surgery: Subjects undergo routine cataract surgery via phacoemulsification and 
posterior chamber intraocular lens implantation according to the Investigator’s normal 
procedures.  


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Visit 2: POD1 will occur ~ 18-34 h after cataract surgery. Review Inclusion and Exclusion 
criteria. Baseline pre-Randomization assessments (ocular inflammation, pain and safety 
assessments). Randomization of eligible subjects. Instillation of first dose of study treatment in 
the operated study eye in the clinic under the supervision of Investigator or designee.  
Visit 3: POD4 (± 1 day). Ocular inflammation, pain and safety assessments. 
Visit 4: POD8 (± 1 day). Ocular inflammation, pain and safety assessments. 
[Note: Subjects will be contacted on POD14 to remind them to stop study drug after that day 
and to bring the study drug bottle and dosing diary to the clinic the next day.] 
Visit 5: POD15 (+ 1 day). Ocular inflammation, pain and safety assessments. Urine pregnancy 
test. 
Visit 6: POD22 (± 2 days). Ocular inflammation, pain and safety assessments. Final visit.  
A detailed summary of study events is provided in Table 1 (Schedule of Events) and a study 
design schematic is provided in Figure 1 (Study Schematic).  
3.2.2 
Contingencies relating to the COVID-19 Pandemic 
Appendix A describes the procedures that may be implemented because of the COVID-19 
pandemic. 
3.3 
Rationale for Study Design 
3.3.1 
Rationale for Number of Subjects to be Randomized 
This is a Phase 3 study. See Section 10.4 for rationale for the number of subjects to be enrolled 
in the study. 
3.3.2 
Rationale for the Primary Efficacy Endpoints 
The two primary endpoints are clinically-meaningful to clinicians and the subjects undergoing 
ocular surgery and have been applied to support the approval of other corticosteroid ophthalmic 
drug products for the treatment of post-operative inflammation and pain following ocular 
surgery.  
The efficacy data from Part A of Study CPN-201 summarized in the APP13007 Investigator’s 
Brochure show that APP13007 0.05% BID, compared to matching vehicle placebo, produced a 
statistically and clinically-meaningful increase in the proportion of subjects who had an ACC 
Count = 0 at POD8 that was maintained through POD15.  


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A greater proportion of subjects dosed with APP13007 as compared to placebo had resolution of 
ocular pain (grade = 0) at POD4 that was maintained through POD15.  
The US FDA has agreed with the primary endpoints in this study at an End-of-Phase 2 meeting.  
3.3.3 
Rationale for Dosing Regimen 
The results from Study CPN-201 summarized in the APP13007 Investigator’s Brochure show 
that 0.05% APP13007 BID as compared to its matching vehicle placebo produced a clinically-
meaningful reduction of inflammation and pain after cataract surgery. In addition, all APP13007 
dosing regimens were well-tolerated with a safety profile similar to the matching vehicle 
placebos.  
These data support the selection of 1 drop of 0.05% APP13007 administered BID for 14 days as 
the dosage regimen for this Phase 3 clinical study. 
The US FDA has agreed with the selection of the dosing regimen to be used in this study at an 
End-of-Phase 2 meeting.  


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STUDY POPULATION 
4.1 
Number of Subjects 
Approximately 370 subjects who have undergone routine, uncomplicated cataract surgery and (i) 
meet the inclusion criteria, including having >10 anterior chamber cells in the study eye 
(operated eye) at POD1, and (ii) do not meet any of the exclusion criteria, will be randomized to 
study treatment. 
4.2 
Inclusion Criteria 
To be eligible, a participant must meet the following criteria: 
At the Screening Visit (Visit 1): 
1. Provide signed and dated informed consent 
2. Age ≥ 18 years at time of informed consent  
3. Males or females of non-childbearing potential. Females of non-childbearing potential is 
defined as women who have been permanently sterilized or are postmenopausal. 
Postmenopausal is defined as amenorrhea for a minimum of 12 months (without an 
alternative medical cause). Note: Pregnant women or nursing (breast-feeding) mothers are 
excluded from the study.  
4. Women-of-childbearing-potential to be eligible for enrollment if they have a negative urine 
pregnancy test on POD1 prior to Randomization and they agree to abstain from sexual 
activity or use a highly effective contraceptive such as occlusive cap (diaphragm or 
cervical/vault cap) plus spermicidal agent (foam/gel/film/cream/suppository), oral 
contraceptive, injectable progesterone, implant of etonogestrel or levonorgestrel, estrogenic 
vaginal ring, percutaneous contraceptive patches, or intrauterine device from POD1 to Visit 6 
(POD22). 
5. Expected to undergo unilateral uncomplicated cataract extraction via phacoemulsification 
and posterior chamber intraocular lens implantation in one eye (designated the ‘Study Eye’). 
6. Have a pin-hole corrected visual acuity without other correction of ≤ 1.3 logarithm of the 
minimum angle of resolution (logMAR) in the study eye to be operated and contralateral eye 
as measured using an Early Treatment Diabetic Retinopathy Study (ETDRS) chart at Visit 1. 
Subjects who are unable to read the lines in an ETDRS chart because of the density of the 
cataract in the study eye may be enrolled if, in the opinion of the Investigator, there is no 
other significant ocular pathology that would account for the low visual acuity. 


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7. Willing and able to comply with study requirements and visit schedule; Able to either self-
administer study medication or have someone available (e.g., spouse, caregiver, etc.) who 
can administer study medication according to the study schedule and instructions  
4.2.1 
Additional Inclusion Criteria on Postoperative Day (POD) 1/Day of 
Randomization (Visit 2) 
8. Have undergone unilateral cataract extraction via phacoemulsification and posterior chamber 
intraocular lens implantation in the study eye without any additional procedures or 
complications that would, in the opinion of the Investigator, interfere with study procedures 
or confound study objectives 
9. No significant ocular pathology affecting visual acuity that is identified after posterior 
chamber intraocular lens implantation in the study eye. 
10. Have ≥ 10 cells in the anterior chamber (excluding red blood and pigment cells) 
11. Have an IOP ≤ 30 mmHg. Note: If the IOP is elevated post-surgery, the investigator may use 
non-prostaglandin based IOP-lowering medication(s) at their discretion on the day of surgery 
(Day 0) only. The IOP will be measured and recorded on POD1 to determine eligibility for 
Randomization.  
4.3 
Exclusion Criteria 
Participants will be excluded if they meet any of the following criteria:  
1. Have a known sensitivity or allergy to clobetasol propionate, corticosteroids, or any of the 
study medication’s components including benzalkonium chloride and soybean lecithin or any 
routine medication required during cataract surgery or for the conduct of study procedures. 
2. Have an ACC count > 0 or any evidence of intraocular inflammation (e.g., flare) in either eye 
at the Screening visit. 
3. Have a Grade > 0 on the Ocular Pain Assessment in either eye at the Screening visit. 
4. Have an immunosuppressive or autoimmune disease that in the opinion of the Investigator 
could affect intraocular inflammation or the normal healing process of the eye. 
5. Have active or chronic/recurrent ocular or systemic disease that is uncontrolled and could 
affect wound healing and/or resolution of inflammation after cataract surgery. 
6. Suspected or known malignancy or be currently receiving antineoplastic therapy. 
Note: subjects with basal cell carcinoma will not be excluded unless the Investigator believes 
that the condition has the potential to interfere with study procedures or analysis of results. 


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7. Are using certain medications, namely: 
i. Subjects receiving treatment for macular degeneration (in either eye) with Eylea® 
(aflibercept), Avastin® (bevacizumab), Lucentis® (ranibizumab) Beovu® (brolucizumab-
dbll) or Visudyne® (verteporfin) are excluded. 
ii. PROKERA (preserved amniotic membrane) is excluded from 1 year prior to the Screening visit 
to the end of the study. 
iii. Anti-inflammatory agents, analgesics (including opioids, narcotics, nonsteroidal anti-
inflammatory drugs (NSAIDs), aspirin, acetaminophen and other pain medications) or 
immune-modulating agents systemically or in either eye from the beginning of the 
‘Washout’ period in the List of Prohibited Medications (Section 5.4.2) until after the 
POD15 assessments, but preferably until after the POD22 assessments. Note: 
(i) acetaminophen is permitted on the day of surgery; (ii) immunizations/vaccinations are 
permitted before and during the study. 
iv. Use of any of the prohibited medications listed Section 5.4.2 within a time period prior to 
surgery that is less than the minimum ‘washout’ period noted in Table 4. 
[NOTE: (i) These medications may not be used from the beginning of the ‘Washout’ 
period in Table 4 until after the POD15 assessments, but preferably until after the POD22 
assessments; NOTE: (ii) Medications for anesthesia related to cataract surgery, ocular 
pain control and non-prostaglandin-based therapy for the treatment of raised intraocular 
pressure (IOP) are allowed on the day of surgery only] 
v. Non-approved drugs or investigational products other than the study drug in this study 
are prohibited from 28 days before surgery until after the subject has been released from 
the study. 
8. Have an IOP < 5 mmHg or > 22 mmHg in either eye or a difference of > 5 mmHg between 
the eyes at the Screening visit.  
9. Have a history of documented and repeated elevated IOP or glaucoma. 
10. History of herpes keratitis in the study eye. 
11. Have active corneal abrasions or ulcers in the study eye. 
12. Have active or a history of chronic or recurrent inflammatory eye disease (e.g., iritis, 
scleritis, uveitis, iridocyclitis, rubeosis iridis) in the study eye. 
13. Have evidence of acute external ocular infections (bacterial, viral and/or fungal infections 
including vaccinia, varicella and other viral diseases of the cornea and conjunctiva); 
tuberculosis of the eye; intraocular infections, active chalazion, or uncontrolled severe 
blepharitis in the study eye. 
14. Have corneal dystrophies, including corneal guttae and Fuchs’ dystrophy, or dysthyroid 
ophthalmopathy in the study eye. 


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15. Have uncontrolled and clinically significant dry eye syndrome in the study eye (mild dry eye 
with the use of artificial tears is allowed). 
16. Have proliferative diabetic retinopathy, significantly compromised macular function; 
significant macular disease; have clinically-significant macular edema or a history of cystoid 
macular edema in the study eye; have cup:disc ratio > 0.8. 
17. Have had corneal or retinal surgery (laser or incisional) in the study eye within 6 months of 
the Screening visit, or planning to have laser or incisional surgery during the study period in 
the study eye (other than cataract surgery). 
18. Have ocular surgery planned, scheduled or performed on the contralateral eye within the 
2 months prior to the surgery on the study eye. 
19. Have previous ocular trauma with visible scarring or any deformities due to the trauma in the 
study eye that in the opinion of the Investigator may affect the pharmacokinetics of the study 
drug, or post-surgical outcome (including, but not limited to intraocular inflammation, IOP or 
the normal healing process). 
20. Require the use of a contact lens or a collagen shield within 72 hours prior to cataract surgery 
or for the remainder of the study period in either eye. 
21. Require use of non-diagnostic topical ophthalmic medications in either eye for the duration 
of the study with the exception of the following which are allowed: mydriatics, anesthetics, 
antiseptics, balanced salt solution, viscoelastics, osmotic agents (e.g., Muro 128), 
prophylactic antibiotics, non-prostaglandin analog IOP-lowering agents for IOP increases on 
the day of cataract surgery, lid scrubs for mild blepharitis, or artificial tears for the 
management of mild dry eye. 
22. In the opinion of the investigator, have the potential for ocular hemorrhage in the study eye 
that may interfere with evaluation of post-surgery inflammation. 
23. Have a planned use of or use of femtosecond laser or any other ophthalmic surgical 
procedure (e.g., vitrectomy, relaxing incisions, iridectomy, conjunctival excisions, use of iris 
hooks or other iris dilators, etc.) in addition to the cataract extraction procedure via 
phacoemulsification and PCIOL implantation in the study eye. 
24. Have a planned use of or use anterior capsule staining for capsulorhexis (i.e., trypan blue) 
during cataract surgery. 
25. Have planned to participate in another clinical trial during the duration of this study. 
26. Have participated in another clinical study or received any investigational product within the 
past 28 days prior to the Screening Visit. Subjects who previously participated in Study 
CPN-201 are eligible if the planned cataract surgery is for the eye that was the ‘non-study’ 
eye in that study.  
27. Have any other condition that the Investigator determines should exclude the subject from 
the trial. 
28. Are an employee of the clinical site that is directly involved in the management, 
administration, or support of this study or are an immediate family member of the same.  


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STUDY DRUG AND TREATMENTS 
5.1 
Study Drug Administration 
5.1.1 
Study Drug Description 
Dosage Form, Appearance, Packaging and Labelling 
 
 
 The 
nanosuspension of APP13007 and matching vehicle placebo have the appearance of an 
opalescent liquid. 
 
 
 
 
 
 
 
 
 
Each subject will be supplied with a single dropper bottle throughout the study period 
(see Section 5.1.2 below). Individual dropper bottles will be labelled according to FDA 
requirements. The labels will include the following information: 
 Protocol number: CPN-301 
 Bottle number 
 Subject Number 
 Study Eye: R or L 
 Content: APP13007 
 or Placebo 
 
 
 For Topical Ophthalmic Use in Clinical Trials Only. Keep Out of the Reach of Children. 
 CAUTION: New drug – Limited by Federal (or United States) Law to Investigational Use 
 
Acquisition 
Individual dropper bottles packaged with proper labels will be shipped to each study site from a 
central drug product labeling, packaging and distribution vendor. Sufficient quantity of 
APP13007 and matching vehicle placebo will be provided to each site to accommodate the initial 
randomization rate, with the option to resupply high-enrolling sites. Once a subject is 


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randomized via the IWRS, the subject will be dispensed a dropper bottle with the specific bottle 
number assigned to the subject number based on the randomization schedule. 
Storage and Stability 
 
5.1.2 
Study Drug Dosing and Administration 
5.1.2.1 
Dispensing and Replacing Study Drug 
Study drug will be dispensed by personnel assigned to do so at the study site as indicated on the 
Site Delegation Log. One bottle will be dispensed to each subject for the duration of the study 
treatment period. If the subject discontinues study drug, the study drug bottle should be collected 
at the next clinic visit. 
If a subject loses the single bottle of study drug or if it becomes compromised (e.g., damaged or 
dropped into the toilet) prior to the POD15 visit, the bottle of study drug should be replaced as 
soon as possible. The site should use the IWRS system to identify a replacement bottle. Subjects 
are instructed to notify the study site as soon as the study drug bottle is lost or compromised, so 
that the site can arrange for the replacement bottle to be provided as soon as possible. Any 
missed doses due to loss of study drug bottle will be documented in the diary and eCRF.  
Failure to dose from the replacement bottle (issued prior to POD 15) will be considered a 
protocol deviation. 
5.1.2.2 
Subject Diaries 
A study diary will be given to each subject at the visits indicated on the Schedule of Events 
(Table 1). The subject will record the date and time of each dose of study drug as well as the 
total number of drops applied (including missed drops) and the number of drop(s) instilled 
correctly into the conjunctival sac of the study eye at each dosing time. The diary will remind the 
subject to instill the study drug a minimum of 5 minutes prior to administration of other eye 
medications in the study eye.  
At each study visit noted in the Schedule of Events, site personnel will collect the diary and 
dispense a new diary to the subject. Site personnel will review the diary to ensure compliance 
with drug dosing and diary recording procedures. Diary data will be entered into the eCRF. If 
there is an issue with dosing or recording compliance, site personnel will instruct the subject 
again on correct procedures at each visit. If the subject is unable to comply with required dosing 
procedures, the subject may be discontinued from the study. However, site personnel must 
contact the Study Medical Monitor prior to discontinuing a subject for compliance-related issues. 


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5.1.2.3 
Study Drug Compliance 
Site personnel will record the dosing record taken from the diary into the eCRF. This will 
include the number of drop(s) applied in the study eye, date/time of application and verification 
that no other drugs were administered within 5 minutes of study drug application in the study 
eye. If patient states that other drugs were administered in the study eye within 5 minutes of 
instillation of study drug, this will be recorded in the eCRF as a protocol deviation. Instillation of 
the study drug in the non-study eye will be recorded as a protocol deviation. 
5.1.2.4 
Study Treatments 
The treatments are as follows:  
 Treatment 1:  1 drop APP13007 twice daily (BID) (morning and evening) for 14 days 
instilled to the operated study eye 
 Treatment 2:  1 drop matching vehicle placebo BID (morning and evening) for 14 days 
instilled to the operated study eye 
 
5.1.2.5 
Study Drug Dosing 
Study drug (APP13007 or matching vehicle placebo) will be supplied in an eye drop bottle with 
a drop tip, and the bottle is labeled in accordance with FDA regulations for investigational drug. 
One bottle will be dispensed to each subject throughout the study. Study drug will be self-
administered twice daily as indicated per protocol by instilling one drop into the conjunctival sac 
near the medial corner of the operated (study) eye.  
If the subject misses the conjunctival cul-de-sac when dosing the first drop of study drug, the 
subject should use a tissue to wipe away the study drug around the eye, and then instill a second 
drop into the conjunctival cul-de-sac so that at least one drop of study drug is administered into 
the study eye. If the second drop also misses the conjunctival sac, then the subject should record 
the missed dose in the diary, but should not instill a third drop. 
Study drug should be administered twice daily. If other concomitant eye drops/drugs are to be 
instilled into the study eye, the study drug should be instilled first followed by a minimum of a 
5 minute lag time before any other ocular medications are applied to the study eye. 
After randomization, the first dose of study drug should be administered in the clinic on POD1 
so that the site personnel can ensure the subject is able to apply study drug correctly. The second 
drop of the study drug on POD1 should be administered by the subject a minimum of 6 hours 
later. For all other days the first dose should be instilled in the morning and the second dose 
instilled a minimum of 6 hours, but preferably 8 to 12 hours, later. The number of drops instilled 
and the date/time of instillation of each dose must be recorded by the subject in the subject’s 


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diary. Subjects will be instructed on POD1 of recording the necessary information on the diary 
on each dosing day. 
5.2 
Study Drug Return and Accountability 
Study monitors 
 will conduct accountability of APP13007 
and matching vehicle placebo. Accountability will be ascertained by performing reconciliation 
between the number of bottles of study drug, along with bottle ID numbers, sent to the site and 
the number of bottles dispensed (used), unused or un-dispensed (along with bottle ID numbers) 
at the time of reconciliation. In addition, the number of bottles of study drug (along with bottle 
ID numbers) dispensed and returned will also be accounted for. 
Clinical trial materials will be shipped to the investigational sites under sealed conditions with a 
temperature tracking device. Study drugs shipment records will be verified by comparing the 
shipment inventory sheet to the actual quantity of study drug (number of bottles and bottle ID 
numbers) received at the site. Accurate records of receipt and disposition of the study drug (e.g., 
dates, number of bottles and each bottle ID number received, dispensed, lost or compromised, 
and returned) and subject number associated with the bottle ID number must be maintained by 
the Investigator or his/her designee. 
 
  
At the end of the study, all study materials, including any used (and returned) and unused study 
drugs bottles, even if empty, will be returned to the drug packaging and distribution vendor in 
accordance with Sponsor or designee’s standard operations procedures (SOPs), following 
approval by the Sponsor. All returns of study drugs will be documented. The study monitor or 
designee will verify drug accountability. All drug accounting procedures must be completed 
before the study is considered complete. 
5.3 
Masking and Unmasking 
The Sponsor, the management and project team at the CRO responsible for trial management, 
monitoring and data collection and management, the study monitors, the Study Medical Monitor, 
the study subjects, the Investigators and the study site staff responsible for managing and 
administering the study, communicating with the study subjects, and/or performing assessments 
of study endpoints will be masked to study treatment assignment of each subject throughout the 
entire study.  
The Study Medical Monitor will remain masked throughout the study unless unmasked 
information becomes necessary as part of the management of a medical emergency or SAE for a 
particular subject, as described below. 


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A randomization schedule will be computer-generated by a qualified biostatistician independent 
of the study conduct and management and will be uploaded into the EDC system by a designated 
person not involved in the study conduct, data collection or management. The EDC/IWRS 
system will be used for randomization and unmasking of treatment assignment when necessary.  
In case of a medical emergency or occurrence of an SAE, the Investigator will treat each subject 
as needed and should contact the Study Medical Monitor, if required, to discuss whether it is 
appropriate to unmask the subject to reveal the subject’s treatment assignment. If deemed 
necessary, the Investigator will log into the EDC system to obtain unmasking information. The 
Investigator must use their individual login information to gain access to the unmasking 
information. The Investigator will also notify the IRB and the CRO managing and monitoring 
this study when treatment assignment for a particular subject is unmasked. The Study Medical 
Monitor will notify the Sponsor Medical Monitor when treatment assignment for a particular 
subject is unmasked due to a medical emergency or SAE. It is important to note that the study 
treatment assignment will be revealed only on a subject-by-subject basis and the treatment 
assignment of the other subjects in the study, as described above, will remain masked until the 
final database is locked. Once the treatment assignment for a specific subject is unmasked, it will 
be made available to the Investigator and the Sponsor. Other personnel involved in the 
monitoring or conduct of this study will remain masked. 
5.4 
Prior/Concomitant Therapy and Rescue Medication 
All prior/concomitant medications (prescription and OTC) a subject is receiving at the Screening 
visit and 90 days prior to the Screening visit and taken throughout the course of the study will be 
recorded as follows:    
 Information regarding the duration of a prior/concomitant medication (including start and 
stop dates), dose, frequency, site of dosing (right eye, left eye, both eyes, non-ocular) and the 
reason why the prior/concomitant medication is being taken will be recorded in the source 
documents and in the Prior/Concomitant Medications (ConMeds) page of the eCRF.  
 Medications used for the surgical procedure will be recorded in the source documents and in 
the ConMeds page of the eCRF.  
 The ocular medications (mydriatics and topical analgesics) used to perform the dilated 
ophthalmoscopy and Goldmann applanation tonometry assessments will be recorded in the 
source documents only. 
 
Note: The information on prior/concomitant medications will be used to determine whether a 
subject is taking or has taken prohibited medications as outlined in Section 5.4.2. 


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5.4.1 
Rescue Medication 
Any subjects who have evidence of persistent or worsening inflammation as described in Section 
9.4 may be rescued and placed on appropriate alternate therapy. The choice of rescue medication 
is at the Investigator's discretion. Rescue medication should be entered into the eCRF with 
annotation indicating that the medication was used for rescue. 
Rescued subjects will be considered as treatment failures, and the need for rescue therapy will 
not be considered an adverse event (AE). Rescued subjects will stop study drug and should not 
be withdrawn from the study, and will be assessed at each subsequent visit, if possible, through 
completion of the Visit 6 (POD22) assessments or until the Investigator has deemed the subject 
is stable and can be released from the study as detailed in Section 6.3. 
5.4.2 
Prohibited Medications 
The subject must provide signed informed consent before any prior medication is changed or 
discontinued because of participation in this study. The following medications may not be used 
after randomization as indicated below. If used prior to surgery (Day 0), the medications must 
have been used in a timeframe that equals or exceeds the minimum ‘washout’ period noted 
below.  
The following medications are prohibited: 
i. 
Eylea® (aflibercept), Avastin® (bevacizumab), Lucentis® (ranibizumab), Beovu® 
(brolucizumab-dbll) or Visudyne® (verteporfin) (in either eye). 
ii. 
PROKERA (preserved amniotic membrane) is excluded from 1 year prior to the Screening visit 
to the end of the study. 
iii. 
Anti-inflammatory agents, analgesics (including opioids, narcotics, nonsteroidal anti-
inflammatory drugs (NSAIDs), aspirin, acetaminophen and other pain medications) or 
immune-modulating agents systemically or in either eye from the beginning of the 
‘Washout’ period in Table 4 until after the POD15 assessments, but preferably until after 
the POD22 assessments. Note: (i) acetaminophen is permitted on the day of surgery; 
(ii) immunizations/vaccinations are permitted before and during the study. 
iv. 
Use of any of the prohibited medications listed Table 4 below within a time period prior 
to surgery that is less than the minimum ‘washout’ period noted in the table. 
NOTE: (i) These medications may not be used from the beginning of the ‘Washout’ 
period in Table 4 until after the POD15 assessments, but preferably until after the 
POD22 assessments; NOTE: (ii) Medications for anesthesia related to cataract surgery, 
ocular pain control and non-prostaglandin-based management of raised intraocular 
pressure (IOP) are allowed on the day of surgery only. 


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v. 
Non-approved drugs or investigational products other than the study drug in this study are 
prohibited from 28 days before surgery until after the subject has been released from the 
study. 
Table 4: 
Prohibited Medications and Minimum Washout Periods 
Medication 
Minimum ‘Washout’ 
Period Prior to Day 0 
All topical ophthalmic gels or ointments  
2 days 
Ocular mast cell stabilizers 
2 days 
Ocular antihistamines 
2 days 
Ocular and nasal decongestants 
2 days 
All eye drops (except antibiotic eye drops considered to be part of pre-
cataract surgery standard-of-care). Note: Antibiotics with anti-
inflammatory activity and Besifloxacin Ophthalmic suspension are not 
permitted. Note: (i) Artificial tears are allowed, but should not be used 
within 10 minutes of study procedures or medication dosing; (ii) specific 
restrictions for ocular products are listed below. 
2 days 
Topical ocular corticosteroids  
14 days 
Topical ocular NSAIDs 
7 days 
Topical prostaglandin eyelash growth medications 
7 days 
Systemic anti-inflammatory agents including acetaminophen, NSAIDS, 
acetylsalicylic acid (aspirin), and Lifitegrast.  
Note: (i) Use of acetylsalicylic acid for cardiovascular prophylaxis 
(i.e., 81 mg dose QD) is allowed if dosage has been stable for at least 
30 days prior to surgery and will remain stable for the duration of the 
study (ii) Acetaminophen may be administered as needed pre- and post-
operatively on the day of surgery, (iii) Over-the-Counter preparations 
such as Fish Oils, Turmeric and Ginseng that may have mild anti-
inflammatory effects are allowed. 
7 days 
Topical dermatologic corticosteroids including OTC preparations (use of 
topical 0.1% hydrocortisone dermal preparations for less than 3 days over 
a small area of skin [~2 inches x ~2 inches] are allowed). 
14 days 
Systemic (oral, injectable), inhaled and/or nasal corticosteroids 
21 days 
Systemic analgesics/pain relievers such as gabapentin, pregabalin, opioids 
Note: Marijuana/CBD-containing products have the same washout 
restrictions as “Systemic Analgesics” because they can affect pain 
perception 
14 days 
Medications for benign prostatic hypertrophy (BPH) (e.g., finasteride, 
α-1 adrenergic receptor antagonists) are allowed based on the judgment of 
the investigator. Note: Investigators should consider the potential risk of 
intraoperative floppy iris syndrome in subjects who are taking or have 
taken α-1 adrenergic receptor antagonists (eg. tamsulosin, silodosin, 
alfuzosin). 
Stable dose for 28 days 
Topical or systemic cyclosporine 
60 days 
Periocular injection of corticosteroid 
28 days 


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Medication 
Minimum ‘Washout’ 
Period Prior to Day 0 
Intraocular treatment with corticosteroid - dexamethasone drug delivery 
system 
90 days after 
implantation 
Intraocular treatment with corticosteroid – fluocinolone acetonide drug 
delivery system 
48 months after 
implantation 
Stable doses of anticholinergics and antidepressants are allowed. 
Alterations of the dose of anticholinergics and antidepressants (other than 
for prn use as a sleep aid) may be allowed following consultation with the 
Study Medical Monitor. Anticholinergic eye drops used to dilate the eye 
are allowed. Systemic anticholinergic drugs are allowed on the day of 
surgery.  
 
Note 1 
For anti-depressants used to treat depression: (i) Medication must not be 
washed-out for the purpose of enrollment in the study; (ii) Stable doses of 
anti-depressants are allowed; (iii) When the dose of an anti-depressant has 
been altered, the subject needs to be on the stable altered dose for at least 
90 days prior to the day of surgery (Day 0). 
 
Note 2 
For anti-depressants used to treat pain: (i) The instructions provided for 
systemic analgesics/pain relievers apply, viz. at least a 14 day washout of 
the medication is required prior to the day of surgery (Day 0) continuing 
until the POD15 assessments have been completed. 
See Note 1 and Note 2 
 


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STUDY CONDUCT 
Refer to the Schedule of Events (Table 1) for the list of study procedures/assessments to be 
conducted at each visit. 
Data should be entered into the eCRF as soon as possible, preferably within 72 hours of 
collection from each subject. 
6.1 
Study Subject Number 
Subject Number – assigned upon Screening examination. 
Randomization Number – assigned by IWRS upon randomization of a subject on POD1. 
Bottle Number – associated with the Randomization Number, assigned by IWRS. 
If a subject requires a replacement study drug bottle, then a replacement Bottle Number will be 
identified through IWRS. 
6.2 
Description of Study Visits 
6.2.1 
Visit 1 - Screening 
The Screening visit should occur no more than 28 days and no less than one (1) day prior to 
surgery. After obtaining written informed consent and HIPAA authorization, site staff will 
perform the assessments as shown in the Schedule of Events (Table 1). All ocular assessments 
must be performed on both eyes at the Screening visit. 
If surgery is not performed on the planned scheduled day such that screening procedures would 
fall outside of the 28 day screening window, site staff must contact the Study Medical Monitor to 
determine which, if any, of the screening procedures must be repeated. 
Subjects may be rescreened, if, in the opinion of the Investigator, the subject would qualify for 
the study if a procedure/assessment is repeated/redone (in this case, the subject keeps the same 
subject number). Note: If subject who has failed screening is rescreened at a later time, the 
subject will be assigned a new subject number.  
Subjects who sign the informed consent form (ICF) and have undergone study 
procedures/assessments, but do not meet eligibility criteria any time prior to randomization on 
POD1 will be considered as screen failures. Limited information on screen failures will be 
transcribed to the eCRF. 
After the screening assessments and before surgery, the subject may have a pre-surgery medical 
assessment to determine whether the subject is a suitable candidate for surgery. At this time, the 


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routine medication list prescribed by the cataract surgeon should be reviewed to rule out 
prohibited medications (Table 4, Section 5.4.2).  
6.2.2 
Day of Surgery (Day 0) 
Prior to surgery, the surgeon’s routine medication list should be reviewed to exclude prohibited 
medications (Table 4, Section 5.4.2). Surgery should preferably be scheduled in the morning to 
accommodate BID dosing on POD1. However, if surgery has to be scheduled in the afternoon, 
subjects should still instill two doses of study drug on POD1 at least 6 hours apart. 
On Day 0, the surgeon will perform his/her routine cataract surgical procedure using 
phacoemulsification and implantation of a posterior chamber intraocular lens in the operated eye 
following the surgeon’s usual pre-operative, operative, and post-operative procedures (with the 
exception of avoiding use of prohibited medications). Aqueous release procedures are not 
permitted. 
Following surgery, the following should be performed: 
 Give the subject instructions regarding routine post-surgical care and instructions regarding 
the use of concomitant medications and restricted medications during the study. 
 Record surgery parameters (surgery time, phaecoemulsion energy and an assessment of 
surgery difficulty) in the source documents and eCRF. 
 Record the medications routinely administered for cataract surgery in the source documents. 
These medications will be reported as being used for routine cataract surgery. 
 If a medication is administered due to an AE, the medication must be entered in the source 
documents, indicating that the medication was used to treat an AE.  
 If a non-prostaglandin medication is used to lower IOP, the medication must be entered in the 
source documents and in the ConMeds page of the eCRF. 
 AEs and ConMeds associated with an AE should only be recorded in the source document on 
Day 0 if they result in screen failure of the subject. If a subject is not a screen failure on Day 
0, the AEs and ConMeds applicable to Day 0 should be recorded in the source documents 
when the subject returns for Visit 2 on POD1. 
 Only for subjects who are randomized, enter the medications routinely used for cataract 
surgery and concomitant medications in the ConMeds page of the eCRF and AEs in the AE 
page of the eCRF. 
 Schedule the subject to return to the clinic on the following day, ie., POD1, in the morning 
(if possible). 
6.2.3 
Visit 2 - POD1 (Day of Randomization) 
Subjects will return to the clinic for the study visit on POD1 between 18 to 34 hours following 
conclusion of surgery on Day 0. This visit should be scheduled in the morning, as much as 


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possible, to allow for administration of two doses of study drug during the day on POD1 for 
randomized subjects. However, if surgery is to be performed in the afternoon, subjects should 
still instill two doses of study drug on POD1 at least 6 hours apart. 
All assessments will be performed as shown in the Schedule of Events (Table 1). Ocular 
assessments will be performed only on the operated, study eye. 
The site will review eligibility criteria (Section 4.2 and Section 4.3) to determine if the subject 
qualifies for randomization. If the subject meets all criteria, the subject will be randomized by 
site personnel using the EDC/IWRS system. The site should follow the instructions provided in 
the Study Reference Manual)/eCRF Completion Guidelines to enter appropriate subject data into 
the eCRF and randomize the subject. A study drug bottle number will be assigned to the subject 
based on the predetermined randomization by the EDC/IWRS system. The designated site 
personnel should supervise the administration of the first dose of study drug by the subject in the 
clinic before dispensing the assigned study drug bottle along with written dosing instructions and 
diary to the subject. The second dose will be administered at home.  
A subject who fails to qualify for the study on POD1 will not be rescreened.  
Note that the use of IOP-lowering medications or aqueous release procedures are not allowed on 
POD1.  
Study drug dosing/administration procedures including handling bottle replacement, diary/dosing 
compliance and the list of treatments are presented in Section 5.1.2. Subjects are reminded to 
bring the diary to each clinic visit in order for site staff to review dosing compliance. 
6.2.4 
Visit 3 (POD4 ± 1) and Visit 4 (POD8 ± 1) 
All assessments will be performed as shown in the Schedule of Events (Table 1).  
Ocular assessments will be performed only on the operated, study eye at Visit 3 (POD4) and 
Visit 4 (POD8). 
6.2.5 
Day of Subject Contact on POD14 
POD14 is the last day of dosing. Site personnel will contact the subject on POD14 (no specific 
window) to remind the subject not to take study drug on POD15 and onward and to bring the 
bottle of study drug and diary back to the clinical site at Visit 5 (POD15). Site personnel will 
contact the subject using the subject’s preferred reliable method of communication, 
e.g., telephone call, cell phone text or email. The site staff must make an effort to ensure that the 
subject receives and acknowledges the receipt of the message. Method of contact and whether or 
not the subject was reached is to be documented in the source document. 


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Any AEs reported to the site during the POD14 contact must be recorded in the source 
documents and eCRF. Further assessment of any reported AEs may require an Unscheduled Visit 
on POD14 if medically significant or they may be assessed, as appropriate, at Visit 5 (POD15). 
6.2.6 
Visit 5 (POD15 + 1) 
All assessments will be performed as shown in the Schedule of Events (Table 1).  
Ocular assessments will be performed only on the operated, study eye.  
Study drug bottle and final diaries will be collected at this visit. 
6.2.7 
Visit 6 (POD22 ± 2) 
This is the final visit for the subjects.  
All assessments will be performed as shown in the Schedule of Events (Table 1).  
Ocular assessments will be performed on both eyes.  
Subjects with ongoing AEs or SAEs should be handled as discussed in Section 8.0.  
6.2.8 
Early Termination/Withdrawal 
Subjects who are terminated/withdrawn from the study early will have the Visit 6 (POD22) 
assessments and a urine pregnancy test performed at the time of early termination, or as soon 
thereafter as possible. At an Early Termination/Withdrawal visit the ocular assessments are to be 
performed on both eyes. 
Appendix A describes the Early Termination/Withdrawal procedures that may be implemented 
because of the COVID-19 pandemic. 
6.2.9 
Unscheduled Visits 
Any visits performed beyond those specified within the protocol must be documented in the 
Unscheduled Visit pages of the eCRF. Unscheduled visits may include, but are not limited to, 
reporting and/or follow-up of AEs/SAEs, changes in concomitant medications, follow-up of 
subjects receiving rescue or IOP-lowering medications or ophthalmic assessments as deemed 
appropriate by the Investigator.  
6.2.10 
Study Visit Schedule for Rescued Subjects 
Subjects who are rescued as discussed in Section 9.4 will discontinue study drug and receive 
rescue medication.  


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The Investigator should make every effort to keep subjects who are rescued in the study until 
they complete the Visit 6 (POD22) assessments (Table 1). 
6.3 
Subject Early Termination (Withdrawal) 
Any subject who wishes to voluntarily discontinue study drug or withdraw from participation in 
the study for any reason is entitled to do so without obligation. If a subject requests to 
discontinue the study drug, the subject will be withdrawn from the study as an Early Termination 
(see Section 6.2.7). 
The Investigator may discontinue any subject from study drug or from study participation, if 
deemed necessary at any time during the study for any reason including, but not limited to: 
 The investigator considers that the subject requires alternative medication that is 
incompatible with further continuation of the study drug or participation in the study.  
 Occurrence of any medical condition or circumstance that exposes the subject to substantial 
risk and/or does not allow the subject to adhere to the requirements of the protocol. 
 Any SAE, clinically significant AE, severe laboratory abnormality, intercurrent illness, or 
other medical condition that indicates to the Investigator that continued participation in the 
study is not in the best interest of the subject or that continued participation could affect 
study objectives. 
 Any woman who reports becoming pregnant while participating in the study. Information on 
the pregnancy and outcome will be requested by the Investigator.  
 Subject’s continued failure to comply with protocol requirements or study-related procedures 
after being instructed on the correct requirements or procedures by the Investigator or site 
personnel. 
 Termination of the study by the Sponsor, FDA, or other regulatory authority. 
 
In the event that early termination/withdrawal of a randomized subject is necessary (‘withdrawn’ 
subject), the Investigator should make every attempt to complete the Visit 6 assessments and 
perform a urine pregnancy test as soon as possible (Table 1). Note: the Visit 6 ocular 
assessments need to be performed on both eyes.  
The reason for early termination/withdrawal of a subject should be recorded in the source 
documents and entered in the eCRF. 
Subjects who are terminated early from the study will not be replaced. 


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6.4 
Study Discontinuation Criteria 
6.4.1 
Early Discontinuation of the Study  
The study or parts of the study may be discontinued by the Sponsor or at the recommendation of 
the Investigator after consultation with the Sponsor. This may be based on a significant number 
of AEs of a similar nature that warrant such action.  
6.4.2 
Discontinuation of a Study Site 
The Sponsor may discontinue the study at a site for reasons that include GCP violations, protocol 
deviations, lack of enrollment or for the protection of the safety and wellbeing of a subject. 


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STUDY ASSESSMENTS AND PROCEDURES 
7.1 
Demography and Medical History 
Subjects’ demographic information will be collected and recorded in the eCRF. A complete 
systemic and ocular medical and surgical history will be taken at screening, and abbreviated 
assessment will be taken at the subsequent visits. 
7.2 
Efficacy Assessments 
7.2.1 
List of Efficacy Assessments  
The ocular efficacy assessments apply to the Study (Operated) Eye Only. 
 Slit Lamp Biomicroscopy assessment of (i) ACC count and (ii) ACF grade using a 5 point 
scale (0-4). 
 Subject-Rated Ocular Pain Assessment (0-4 Scale) 
 Number of subjects who are rescued 
 Best corrected visual acuity by pinhole method using an ETDRS chart 
 
7.2.2 
Procedures for Assessment of Efficacy Endpoints 
7.2.2.1 
Anterior Chamber Cell Count and Anterior Chamber Flare  
The biomicroscopy examination will be performed with the slit lamp using a slit-beam. The 
Investigator should use their usual examination technique. Anterior chamber cells should be 
counted using the high light intensity level and the high magnification (Haag-Streit 16 X or 
comparable), with the slit beam set at an oblique angle, and the height and width of the beam set 
to 1.0 X 1.0 mm. 
ACF will be graded as shown below: 
Grade 
Description 
0 
None 
1 
Faint 
2 
Moderate (iris and lens details clear) 
3 
Marked (iris and lens details hazy) 
4 
Intense (fibrin or plastic aqueous) 


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7.2.2.2 
Subject-Rated Ocular Pain Assessment 
Ocular pain is defined as throbbing, or aching, and will be graded by the subject on a 5-point 
scale. At the visits shown in Table 1, subjects will be required to subjectively rate their pain in 
the study eye before any other ocular assessments are performed.  
Ocular Pain will be graded a shown below: 
Grade Description 
0 
None: No pain. 
1 
Minimal: Presence of minimal throbbing or aching pain (expected 
following cataract surgery). 
2 
Mild: Presence of mild throbbing or aching pain, easily tolerated. 
3 
Moderate: Presence of moderate throbbing or aching pain leading to the 
desire to use an analgesic. 
4 
Severe: Presence of severe throbbing or aching pain that is not tolerable 
 
7.2.2.3 
Best Corrected Visual Acuity 
The assessment of best corrected visual acuity in the study (operated) eye will be performed as 
described in Section 7.3.1.2. 
7.3 
Safety Assessments 
The safety assessments are applied to both eyes at Visit 1 (Screening) and Visit 6 (POD22) or 
Early Termination/Withdrawal or to the Study (operated) eye only at Visit 2 through Visit 5. 
(Table 1 Schedule of Events). The safety assessments in Table 1 are not performed on the day of 
surgery.  
7.3.1 
List of Safety Assessments  
 AEs 
 ETDRS Assessment of Best Corrected Visual Acuity by Pinhole Method 
 Slit Lamp Biomicroscopy assessment of the following signs of inflammation: corneal edema, 
ciliary flush, bulbar conjunctival injection. The assessments in the non-study eye will include 
an assessment of the lens  
 IOP Measurement using Goldmann applanation tonometry 
 Dilated Ophthalmoscopy assessment of the vitreous, retina, macula, choroid, and optic nerve 
with cup/disc ratio, and an assessment of the presence and severity of a cataract if present in 
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7.3.1.1 
Assessment of Adverse Events 
All AEs spontaneously reported by the subject or in response to an AE query from study 
personnel or revealed by observation, physical examination or other diagnostic procedures will 
be recorded in the source document and on the appropriate pages of the eCRF. Any clinically 
relevant deterioration in a clinical finding is considered an AE and must be recorded. When 
possible, signs and symptoms indicating a common underlying pathology should be noted as one 
(1) comprehensive event. Any pre-existing medical condition that worsens after administration 
of study drug will also be considered as an AE.  
Ocular complaints associated with and expected as a result of the surgery, that are not recorded 
as AEs in the eCRFs will be recorded in the source documents. An ocular complaint will be 
recorded in the eCRF as AE when the complaint is outside the normal limits for cataract surgery 
or is associated with clinical sequelae (i.e., adverse slit lamp examination finding).  
See Section 8.0 for information on how to record AEs and how to attribute relatedness of an AE 
to study procedures, cataract surgery or study drug. 
7.3.1.2 
ETDRS Best Corrected Visual Acuity Measurement by Pinhole Method 
Best corrected visual acuity measurement will be performed using the ETDRS eye chart at a 
preferred (but not required) distance of 4 meters. The testing should be conducted under 
standardized lighting conditions using the pinhole method for the study visits indicated in Table 
1. Other testing distances may be used as long as it is consistent with the recommendations 
provided for the ETDRS chart being used and will be used consistently at each visit.  
The subject starts at the top of the chart and reads down until the subject reaches a row where the 
subject is unable to correctly read any letters on that line.  
The ETDRS Acuity Log Score was calculated as follows: 
1. Determine the last row where the subject can correctly identify at least one (1) letter in 
that row. This is the Base Logarithm of the Minimum Angle of Resolution (logMAR) 
line. 
2. Determine the log score for the Base logMAR line. 
3. Add 0.02 (T=0.02) log units for every letter that is incorrectly identified up to and 
including the Base logMAR line. 
The results will be recorded in the source documentation and the eCRF. 


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7.3.1.3 
Slit Lamp Biomicroscopy 
In addition to the assessment of ACC and ACF (Section 7.2.2.1), the following safety parameters 
will be evaluated at Visits 1 through 6 as indicated in Table 1 using the following scales during 
the slit lamp examination: 
Bulbar Conjunctival Injection 
Grade Description 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
 
Sclera - Ciliary Flush 
Grade Description 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
 
Corneal Edema 
Grade Description 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
 
The lens in the non-study eye will be classified as phakic, pseudo-phakic or non-phakic.  
7.3.2 
IOP Measurement 
IOP measurements will be performed utilizing Goldmann applanation tonometry according to 
the Investigator’s standard procedure. All pressures will be recorded in mmHg. IOP assessments 
will be performed at Visits 1 (Screening) through Visit 6 (POD22) or Early 
Termination/Withdrawal as indicated in Table 1. 


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7.3.3 
Dilated Ophthalmoscopy 
A dilated fundus examination will be performed according to the Investigator’s standard 
technique at the Visits indicated in Table 1. The Investigator should evaluate the vitreous, retina, 
macula, choroid, and optic nerve with cup/disc ratio and will note normal/abnormal findings. If a 
cataract is present in the non-study eye, the Investigator will make an assessment of its location 
and severity as described below. 
The Investigator will determine whether or not abnormalities observed at Visit 1 (Screening) 
would exclude a subject from study participation.  
If a subject had an abnormality in the study eye or non-study eye at Visit 1 (Screening), the 
Investigator should make an assessment whether there has been a change at Visit 6 (POD22) or 
at Early Termination/Withdrawal and record this in the source document and eCRF. It is 
recommended that the Investigator refer to the documentation at Visit 1 (Screening) when 
making the assessment of a change in status. 
Grading a Cataract in the Non-Study Eye 
For subjects with a natural lens in the non-study eye, when present, a cataract will be assessed 
(a) by location - Nuclear, Cortical, and Posterior Subcapsular, and (b) by severity (minimal, 
mild, moderate or severe). Appendix B provides a guidance that may be used to grade the 
severity of a nuclear, cortical or posterior subcapsular cataract in the non-study eye. 
If a subject had a cataract in the non-study eye at Visit 1 (Screening), the Investigator should 
make an assessment whether there has been a change in the size or composition of the cataract at 
Visit 6 (POD22) or at Early Termination/Withdrawal and record this in the source document and 
eCRF. It is recommended that (i) the cataract grading is performed by the same Investigator at 
Screening and Visit 6 (POD22) or at Early Termination/Withdrawal, and (ii) the Investigator 
refers to the documentation of the non-study eye at Visit 1 (Screening) when making the 
assessment of change in the lens status. 
 


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ADVERSE EVENTS 
8.1 
Definition of Adverse Events (AEs) 
Adverse event means any untoward medical occurrence in a subject or clinical investigation 
subject administered a pharmaceutical product and which does not necessarily have a causal 
relationship with this treatment (21CFR312.32 (a); ICF E6 Section 1). An AE can therefore be 
any unfavorable sign and unintended sign (including an abnormal laboratory finding), symptom, 
or disease temporally associated with the use of a medicinal (investigational) product, whether or 
not related to the medicinal (investigational) product. 
In addition to the considerations in Sections 8.2 to 8.4, AEs will be reported in the source 
document from the time of signature of the informed consent form as indicated in Section 8.1.1 
and Section 8.1.2.  
8.1.1 
Subjects who are Randomized 
 An AE related to cataract surgery will be recorded in the Surgical AE log table in the source 
documents and in the eCRF. 
 AEs occurring prior to study drug administration will be recorded in the source documents 
only. 
 AEs occurring from the start of study drug administration will be reported in the source 
documents and eCRF. 
 Rescued subjects are considered to be treatment failures, and being rescued itself is not 
considered to be an AE. 
 Adverse events occurring in rescued subjects will be reported in the source documents and 
eCRF.  
 An IOP > 30 mmHg after Randomization will be reported as an AE in the source documents 
and eCRF. 
 An IOP ≥ 21 mmHg AND an IOP increase > 10 mmHg from pre-dose baseline will be 
reported as an AE in the source documents and eCRF. 
 Serious Adverse Events will be collected from the time of signature of the informed consent 
form and reported in the source documents and eCRF. 
 
The term “severe” is used to describe the intensity of an AE; the event itself could be of 
relatively minor clinical significance (e.g., ‘severe’ headache). This is not the same as “serious”. 
Seriousness of AEs is based on the outcome of an AE and usually associated with events that 
pose a threat to a subject’s life or functioning. 


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A Treatment Emergent Adverse Event (TEAE) will be defined as any AE that occurs from the 
start of study drug administration through Visit 6 (POD22).  
8.1.2 
Subjects who are Not Eligible for Randomization (Screen Failures) 
 AEs will be reported in the source documents only 
 Serious Adverse Events will be collected from the time of signature of the informed consent 
form and reported in the source documents and eCRF 
 
8.2 
Definition of Serious Adverse Events (SAEs) 
An AE is considered "serious" if the event results in any of the following outcomes:  
 death,  
 a life-threatening adverse event (i.e. the subject is, in the view of the investigator, at 
immediate risk of death from the AE as it occurs),  
 subject hospitalization or prolongation of existing hospitalization,  
 a persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions, or  
 a congenital anomaly/birth defect.  
 
Important medical events that may not result in death, but may be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one of 
the outcomes listed in this definition. Examples of such medical events include allergic 
bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in subject hospitalization, or the development of drug 
dependency or drug abuse. 
A serious and unexpected suspected adverse reaction (SUSAR) is defined as a serious adverse 
reaction or suspected serious adverse reaction that is not listed in the APP13007 Investigator’s 
Brochure or is not listed at the specificity or severity that has been observed, or that is mentioned 
in the APP13007 Investigator’s Brochure as occurring with a class of drugs or as anticipated 
from the pharmacological properties of the study drug, but is not specifically mentioned as 
occurring with the particular drug under investigation (See Section 8.7.2). 


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8.3 
Classification of an Adverse Event 
8.3.1 
Severity of Event 
Assessment of severity of an AE will be rated according to the definitions below in Table 5 and 
the worst grade documented. 
Table 5: 
Definitions of AE Severity 
Mild 
Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
Moderate 
Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference with 
functioning. 
Severe 
Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
potentially life-threatening or incapacitating. Of note, the term “severe” 
does not necessarily equate to “serious”. 
 
8.3.2 
Relationship to Ocular Surgical Procedure or Study Drug 
Determination of the relationship (if any) between the AE and the study drug will be made using 
the guidelines presented in Table 6 and Table 7. 
Table 6: 
Guidelines for Determining the Relationship (if any) between an Adverse 
Event and the Ocular Surgical Procedure 
Related 
This causal relationship is assigned if the AE starts at a reasonable time during 
or after the surgical intervention and could reasonably be explained by the 
known characteristics of the surgical intervention. 
Not 
Related 
This causal relationship is assigned when the time association or the subject’s 
clinical state is such that the surgical intervention was not likely to have had an 
association with the observed AE. 
 


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Table 7: 
Guidelines for Determining the Relationship (if any) between an Adverse 
Event and the Study Drug 
Definite 
This causal relationship is assigned if the AE starts a reasonable time after the 
administration of study drug, stops/improves when the study drug is stopped, 
and could reasonably be explained by known characteristics of the study drug. 
Probable 
This causal relationship is assigned when the AE starts a reasonable time after 
the administration of study drug, stops/improves when the study drug is 
stopped, and could not be reasonably explained by known characteristics of the 
subject’s clinical state. 
Possible 
This causal relationship is assigned when the AE starts a reasonable time after 
the administration of study drug, but could be produced by the subject’s clinical 
state or other modes of therapy administered to the subject. 
Not Related 
This causal relationship is assigned when the time association or the subject’s 
clinical state is such that the study drug was not likely to have had an 
association with the observed AE. 
 
The attributability (relatedness) of an AE to the surgical procedure or to the study drug will be 
reported in the source documents and in the eCRF as described in Section 8.1.1 and Section 
8.1.2.  
8.3.3 
Expectedness 
An AE or a suspected adverse reaction (SAR) is considered “unexpected” if it is not listed in the 
APP13007 Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed. Expected events for APP13007 administration include those events described in the 
APP13007 Investigator’s Brochure. 
8.3.4 
Action Taken with Study drug 
The action to be taken in response to an AE will be to either discontinue or continue study drug.  
Subjects will be permitted to restart study drug if there is a temporary interruption of study drug 
dosing not more than 1 day due to an AE.  
Decrease in the dosing frequency or dosing duration of the study drug is not allowed in this 
study. 


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8.3.5 
Adverse Event Outcome 
If an AE occurs, the Investigator will institute support and/or treatment as deemed 
appropriate. 
The outcome of the adverse event will be categorized as follows: 
 Resolved 
 Resolved with sequelae 
 Ongoing 
 Death 
 Unknown 
 
The Investigator should make every attempt to follow SAEs to resolution. 
8.4 
Adverse Event Follow-Up 
If a non-serious AE is unresolved at the time of the subject’s final study visit, the subject will 
still be released from the study, but an effort will be made to follow up until the AE is resolved 
or stabilized, the subject is lost to follow-up, or there is some other resolution of the event. The 
Investigator should make every attempt to follow all SAEs to resolution.  
8.5 
Overdose/Under-dose for Assessment of Compliance 
8.5.1 
Overdose 
Dosing compliance will be assessed via a daily dosing diary completed by the subject and 
reviewed by the designated site personnel.  
The following will be classified as an overdose event and a protocol deviation (further explained 
in Note below): 
 Subject instills > 2 doses of study drug (each dose = 1 drop) into the study eye on 
2 consecutive days.  
 
Note:  (i) As described in Section 5.1.2, if the subject misses the conjunctival cul-de-sac when 
dosing the study drug, the subject should use a tissue to wipe away the study drug around the eye 
and then instill a second drop into the conjunctival cul-de-sac. This will not be considered a 
protocol deviation. However, if the subject administers a third drop or more into the conjunctival 
sac, no matter if the previous drops were missed, this will be considered to be a protocol 


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deviation; (ii) the importance of the protocol deviation (major/minor) will be determined by the 
amount dosing over that specified in the protocol. 
8.5.2 
Under-dose 
Under-dosing will not be reported as a protocol deviation until the subject has missed both of the 
doses on 2 or more consecutive days. 
The importance of the protocol deviation (major/minor) will be determine by the amount of 
dosing under that specified in the protocol. 
8.6 
Pregnancies 
All female subjects enrolled into the study must be of non-childbearing potential or have a 
negative urine pregnancy test on POD1 prior to randomization (and agree to abstain from sexual 
activity or use an effective method of contraception). Therefore, no pregnancies should occur. A 
urine pregnancy test will also be performed at Visit 5 (POD15) or Early Termination/Withdrawal 
visit prior to POD15.  If there is an unexpected pregnancy, it will be handled on a case-by-case 
basis by discussing with the Study Medical Monitor and then the Sponsor Medical Monitor. 
Additionally, the Investigator should report the information to the Sponsor in a Pregnancy-
specific CRF as per the procedures to be followed for an SAE. Although a pregnancy itself is not 
an SAE, it has potentially serious consequences in subjects exposed to investigational drugs that 
can result in an SAE. 
The pregnancy and follow-up of the pregnancy must be reported on the appropriate pregnancy 
CRF and Pregnancy Reporting Form. The expected date of delivery or expected date of the end 
of the pregnancy, last menstruation, estimated fertility date, pregnancy result and neonatal data 
etc., should be included in this information. 
The investigator will follow the medical status of the mother, as well as the fetus, as if the 
pregnancy is an SAE and will report the outcome to the Sponsor. Follow-up visits must continue 
until the end of the pregnancy, even if that lasts beyond the end of the study. 
When the outcome of the pregnancy falls under the criteria for SAEs (spontaneous abortion, 
induced abortion, stillbirth, death of newborn, congenital anomaly [including anomaly in a 
miscarried fetus]), the investigator should respond in accordance with the report procedure for 
SAEs. Additional information regarding the outcomes of a pregnancy which are categorized as 
an SAE is mentioned below: 
 "Spontaneous abortion" includes abortion and missed abortion. 
 Death of an infant within 1 month after birth should be reported as an SAE regardless of its 
relationship with the study drug. 


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 If an infant dies more than 1 month after the birth, it should be reported if a relationship 
between the death and intrauterine exposure to the study drug is judged as "possible" by the 
investigator. 
 In the case of a delivery of a living newborn, the "normality" of the infant is evaluated at 
birth. 
 "Normality" of a miscarried fetus is evaluated by visual examination unless test results which 
indicate a congenital anomaly are obtained prior to miscarriage. 
8.7 
Serious Adverse Event Reporting 
8.7.1 
Reporting Requirements 
It is the responsibility of the Investigators or their designees to report any event of this nature to 
the Sponsor or a designee within 24 hours of the event being brought to the Investigators’ or 
their staffs’ attention. It is also the responsibility of the Investigator to report all SAEs reported at 
their site to the IRB, as required. The Investigator should make every attempt to follow all SAEs 
to resolution.  
All SAEs have to be reported on a separate SAE Report Form, whether or not considered 
causally related to the study drug, or to the study procedure(s). All SAEs will be recorded in the 
eCRF. SAEs will be recorded from the time the informed consent form is signed.  
The Sponsor will be responsible for reporting all SAEs to regulatory authorities and the 
Investigator is responsible for reporting all SAEs to the IRB (see NOTE below) in accordance 
with IRB guidelines and FDA regulations. As soon as the Investigator is aware of a potential 
SAE he/she should contact 
 
 and in any case no later than 24 hours after the 
knowledge of such a case. At the time of initial reporting the Investigator must provide as a 
minimum requirement, subject number, birth date, description of the SAE and a preliminary 
assessment of causality.  
For fatal or life-threatening adverse events where important or relevant information is missing, 
active follow-up is undertaken immediately. Investigators or other site personnel inform the 
Study Medical Monitor, the Sponsor, and the CRO for Study Management and Monitoring of 
any follow-up information on a previously reported SAE immediately but no later than within 
24 hours of when the Investigator becomes aware of it. The Study Medical Monitor or Sponsor 
Medical Monitor will advise the Investigator/study site personnel how to proceed. The 
Investigator will immediately follow-up events deemed by the Sponsor to be Serious and 
Unexpected Suspected Adverse Reactions (SUSARs) or possible SUSAR events needing 
immediate follow-up in order to meet the 15 calendar day reporting requirements. 


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The SAE reporting procedures are detailed in the study-specific Safety Management Plan. This 
plan is an agreement between the Sponsor, the CRO for Study Management and Monitoring and 
. 
NOTE: If an unexpected SAE occurs at any one site that is determined to be related, probably 
related or possibly related to study drug, all study sites will be notified by the Sponsor via the 
CRO for Study Management and Monitoring and each Investigator will report it to the IRB.  
8.7.2 
Reporting of Serious and Unexpected Suspected Adverse Reactions (SUSARS) 
A serious suspected adverse reaction is any serious adverse event for which there is a reasonable 
possibility that the study drug caused the adverse event. A serious adverse reaction is considered 
"unexpected" (serious and unexpected suspected adverse reaction; SUSAR) if it is not listed in 
the APP13007 Investigator’s Brochure or is not listed at the specificity or severity that has been 
observed.  
SUSARs with an outcome of death or are life threatening must be reported to the relevant 
Regulatory Authorities within 7 calendar days, all other SUSARs must be submitted within 
15calendar days. The SUSAR reporting procedures are detailed in the study Safety Management 
Plan. This plan is an agreement between the Sponsor, the CRO for Study Management and 
Monitoring and Synergy Research Pharmacovigilance.  
NOTE: The Sponsor will notify the U.S. Food and Drug Administration (FDA) and all 
participating site Investigators of any SUSARs (via the CRO for Study Management and 
Monitoring) on an expedited basis and in accordance with applicable regulations. In addition the 
sponsor is responsible for informing all Investigators in all ongoing studies involving the study 
drug about all SUSARs.  
Medical and administrative data related to Individual Case Safety Reports which qualify for 
expedited and periodic reporting, should be provided in compliance with U.S. FDA Code of 
Federal Regulations (CFR) 21, 312.32. 
It is the responsibility of the Investigator to promptly notify the IRB and other appropriate 
institutional regulatory bodies of all unexpected serious adverse reactions involving risk to 
human subjects as per their applicable requirements. 


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SAFETY MANAGEMENT 
9.1 
Stopping Criteria  
9.1.1 
Individual Subject 
9.1.1.1 
Lack of Efficacy (See Section 9.4) 
The Investigator should consider whether to stop the study drug because of lack of efficacy and 
rescue the subject with alternative therapy (see Section 9.4).  
Rescued subjects shall continue in the study and be assessed at each subsequent scheduled visit 
until Visit 6 (POD22). The study drug will be stopped as indicated in Section 9.4.2. 
9.1.1.2 
Elevated Intraocular Pressure (See Section 9.5) 
The Investigator should consider whether to stop the study drug because of an elevation of IOP. 
The study drug may or may not be continued as indicated in Section 9.5.2. 
9.1.1.3 
Deleterious Effects of the Study Drug 
The investigator may stop the study drug and withdraw the subject if in their opinion the study 
drug is having a deleterious effect on the subject’s health or wellbeing. The investigator should 
make an effort to follow up the subject until the deleterious effect is resolved. 
9.1.1.4 
Lack of Compliance 
The investigator may stop the study drug and withdraw the subject if in their opinion the subject 
is not complying with study procedures, including, but not limited to, dosing of the study drug. 
9.1.2 
Study Termination  
 The study can be stopped at any time if deemed necessary by the Sponsor Medical Monitor, 
in consultation with the Study Medical Monitor, due to safety concerns. Safety will be 
monitored on an ongoing basis via periodic masked review of AEs and other safety 
endpoints.  
O If it is observed that visual acuity worsens by 2 lines (Base LogMAR change of 0.2 using 
ETDRS chart) at Visit 6 (POD22) in the treated study eye as compared to Visit 2 
(POD1), in 6 consecutive subjects, no further doses of study drug will be administered to 
any subjects in the study until a comprehensive evaluation can be performed, and, if 
possible, a cause is identified.  
 Safety assessments will be performed throughout the course of the study. The APP13007 
Investigator’s Brochure, Section 1.4.1 and the Risk Mitigation plan in Table 2 provide 
guidance for the Investigator on potential anticipated AEs that may occur. Any potential 


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important safety issues that arise will be reviewed by the Study Medical Monitor, in 
consultation with the Sponsor Medical Monitor, to identify the appropriate course of action.  
 If the Sponsor elects to terminate the study for any reason, the Investigator will be 
responsible for notification of the IRB and will withhold further dosing of study drug. 
9.2 
Dose Modification 
No dose modification is permitted.  
All instances of missed doses must be recorded.  
Note:  Study drug bottle will be replaced if a bottle is lost or otherwise compromised before Visit 
5 (POD15) (see Section 5.1.2).  
9.3 
Dosing Interruptions 
Investigator is not allowed to modify the dosing regimen due to an AE or any other 
circumstance, but the Investigator has the option of stopping study drug after consultation with 
the Study Medical Monitor, if feasible.  
Subjects will be permitted to restart study drug if there is a temporary dosing interruption of 
study drug of not more than 1 day due to an AE. 
9.4 
Rescue Management 
9.4.1 
Criteria for Starting Rescue Medication 
Any subject not responding to the study drug because of lack of efficacy at any time after 
randomization at Visit 2 (POD1) may be rescued and placed on an appropriate alternative 
therapy determined by the Investigator.  
In general, at any visit, a subject with worsening inflammation or showing no improvement in 
degree of inflammation compared with the previous visit is eligible for rescue therapy at the 
discretion of the Investigator. However, the following guidance is provided to Investigators for 
consistency in the way subjects are rescued:  
1. Subjects who, on examination of the anterior chamber, have one or more of the following 
quantitative criteria should be rescued and discontinued from study drug dosing and placed 
on rescue mediation: 
o An increase of ACC count by > 15 cells from the Visit 2 (POD1) pre-dose baseline. 
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2. Subjects who have the following qualitative criteria may be rescued. If the subject is rescued, 
the study drug should be discontinued and rescue mediation started: 
o Subjects who have pain and/or photophobia that does not improve, even when there is an 
improvement in ACC count and/or ACF grade, may be rescued at the discretion of the 
investigator. 
o Subjects who have pain and/or photophobia that worsens may be rescued at the discretion 
of the investigator. 
Initiation of rescue medication is at the discretion of the Investigator. However, it is 
recommended that the Investigator uses the above guidance to determine when to rescue a 
subject. If the quantitative ACC count or ACF grade criteria are not met, the Investigator should 
discuss the qualitative reason(s) for rescue with the Study Medical Monitor for consistency 
across the study.  
9.4.2 
Management 
Investigators will use clinical judgment to determine when to rescue a subject using the guidance 
provided in Section 9.4.1 and the appropriate rescue medication to use. All rescued subjects will 
stop study drug at the time of rescue and will continue in the study through completion of the 
Visit 6 (POD22) assessments (Table 1). 
If a subject needs to be rescued at Visit 5 (POD15), the Visit 5 (POD15) assessments (Table 1) 
should be completed before the subject is administered rescue medication. 
Rescued subjects will be considered treatment failures, and the need for rescue medication will 
not be considered as an AE.  
An AE occurring at the time of rescue will be recorded in the eCRF and will be followed by the 
Investigator to stabilization or resolution of the AE or the end of the study (whichever comes 
last).  
If a subject is rescued, this event will be recorded in the eCRF (not as an AE). Medications used 
for rescue will be recorded in the ConMeds section of the eCRF, indicating that they were used 
for rescue.  
9.5 
Management of Increased IOP 
9.5.1 
Criteria for Starting IOP-Lowering Medication 
Investigators should use the following criteria to determine whether to start IOP-lowering 
medication:  
o After randomization, an IOP > 30 mmHg in the study eye 


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o After randomization, an IOP ≥ 21 mmHg AND an increase of > 10 mmHg from the Visit 
2 (POD1) pre-dose baseline in the study eye (both of these criteria must be met) 
Initiation of IOP-lowering medication is at the discretion of the Investigator even if neither of the 
above criteria are met, however, it is recommended that the Investigator uses these criteria to 
determine when to consider a subject for IOP-lowering medication.  
9.5.2 
Management 
Investigator will use clinical judgment to determine the appropriate IOP-lowering medication to 
use and when to withdraw study drug and procedures, in consultation with the Study Medical 
Monitor.  
It is important to note that prostaglandin-based IOP lowering medications are prohibited in this 
study. 
 After randomization and start of study drug, if a subject has an IOP > 30 mmHg the 
Investigator may commence non-prostaglandin-based IOP-lowering medication while 
continuing the study drug, with appropriate follow-up at the next planned visit or at an 
unscheduled visit. The subject may require assessment at an unscheduled visit at the 
investigator’s discretion. 
o If the IOP is < 30 mmHg at the next visit, the subject may continue on study drug.  
o If at the next visit, the IOP remains > 30 mmHg while on IOP-lowering medication, then 
the study drug may be discontinued and alternative IOP-lowering medication may be 
started, after consultation with the Study Medical Monitor. The subject should continue 
in the study and complete the assessments indicated in Table 1 through Visit 6 (POD22). 
The Study Medical Monitor should discuss the persistent elevation of IOP with the 
Sponsor Medical Monitor.  
 After randomization and start of study drug, an IOP of ≥ 21 mmHg AND an increase 
> 10 mmHg from the Visit 2 (POD1)/pre-dose baseline (both criteria must be met) is 
considered clinically significant and the Investigator should consider starting 
non-prostaglandin-based IOP-lowering medication while continuing the study drug, with 
appropriate follow-up at the next planned visit or at an unscheduled visit.  
o If the IOP reduction is satisfactory at the next visit, the subject may continue on study 
drug. 
o If the IOP reduction of IOP is not satisfactory at the next visit, then the study drug may 
be discontinued and alternative IOP-lowering medication may be started, after 
consultation with the Study Medical Monitor. The subject should continue in the study 
and complete the assessments indicated in Table 1 through Visit 6 (POD22). The Study 
Medical Monitor should discuss the persistent elevation of IOP with the Sponsor Medical 
Monitor.  
Medications used for treating increased IOP will be recorded in the Concomitant Medications 
section of the eCRF, noting that they were used to reduce IOP.  


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STATISTICAL CONSIDERATIONS 
10.1 
Statistical Analytical Plan 
The Statistical Analysis Plan (SAP) will describe the details of all efficacy and safety analyses 
and will be finalized prior to database lock. 
10.2 
Analysis Populations 
The analysis populations are defined as follows: 
 Intent-to-Treat (ITT) Population: All subjects who are randomized to study drug. Following 
the ITT principle, subjects will be analyzed according to the treatment they are assigned to at 
randomization. 
 Per-protocol (PP) Population: All subjects in the ITT population who (i) received at last 
1 dose of study drug, (ii) do not have major protocol deviations that would impact the 
evaluation of efficacy and (iii) have at least 80% overall dosing compliance.  
 Safety Population: All randomized subjects who receive at least one dose of study drug.  
10.3 
Statistical Methods 
10.3.1 
General Approach 
All analysis variables will be summarized descriptively by treatment group. Summary statistics 
for continuous measures will include mean, standard deviation, median, and range. Categorical 
measures will be summarized by the number and percent of subjects. 
10.3.2 
Analysis of Efficacy 
All efficacy analyses and summaries will be based on assessments in the study eye for each 
subject. 
Subjects who are rescued at any time prior to Visit 5 (POD15) will be considered as treatment 
failures for the primary efficacy endpoints and the relevant secondary efficacy endpoints. For 
subjects who discontinue from the study prior to Visit 5 (POD15), the last observation carried 
forward (LOCF) approach will be used to impute missing data.  
For continuous secondary efficacy endpoints, the LOCF approach will also be used to impute the 
data at visits after subjects are rescued. 
The ACC count will be graded as shown below:  
Grade 
0 
1 
2 
3 
4 
ACC Count 
0 cell 
1-5 cells 
6-15 cells 
16-30 cells 
> 30 cells 


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10.3.2.1 
Analyses of Primary Efficacy Endpoints: 
The primary efficacy analyses to compare APP13007 against placebo will be conducted on the 
ITT population using the Pearson Chi-square statistic. Fixed sequence testing will be employed 
to maintain the 2-sided alpha = 0.05. The primary analyses will first test the difference between 
treatments in the proportion of subjects with ACC count = 0 (Grade = 0) at POD8 (Visit 4) 
maintained through POD15 (Visit 5). If the test is statistically significant at the 2-sided alpha = 
0.05 level in favor of APP13007, the difference between treatments in the proportion of subjects 
with Ocular Pain grade = 0 at POD4 (Visit 3) maintained through POD15 (Visit 5) will be tested 
at the two-sided alpha = 0.05 level.  
To confirm the robustness of primary analysis results, sensitivity analyses, including using 
observed data from all subjects, will be performed. The detailed sensitivity analyses will be 
described in the SAP.  
10.3.2.2 
Analyses of Secondary Efficacy Endpoints: 
Mean change-from-baseline in ACC Grade, ocular Pain Grade, ACF Grade and visual acuity at 
PODs 4, 8 and 15 will be analyzed using an analysis of covariance (ANCOVA). The ANCOVA 
model will include treatment as a fixed effect and baseline as a covariate. The rest of secondary 
efficacy endpoints will be analyzed using the same method described for the primary efficacy 
endpoints.  
10.3.3 
Analysis of Safety 
Analysis of safety data will be performed for all subjects in the Safety Population.  
Adverse events will be coded using Medical Dictionary for Regulatory Activities (MedDRA) 
and classified by system organ class and preferred terms. Adverse events will be summarized by 
total number of TEAEs, number of subjects reporting TEAEs, ocular TEAEs (affecting the study 
eye and/or the non-study eye and/or both eyes, when appropriate), non-ocular TEAEs, SAEs, 
serious and unexpected suspected adverse reaction (SUSARs), discontinuing study drug due to 
an AE, by relationship to study drug and/or ocular surgical procedure, and by severity.  
The IOP data for both eyes will be summarized at screening, Visit 6 (POD22)/Early Termination 
(Withdrawal) visit and change from screening. The observed IOP data and change-from-baseline 
(POD1) for the study eye will be summarized at each post-surgery visit. 
The data for slit lamp biomicroscopy examination endpoints will be summarized at each visit. 
The summary of change-from-baseline at each post-surgery visit will be presented for the study 
eye.  


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Dilated indirect ophthalmoscopic examination findings for the study and non-study eye will be 
summarized at screening and Visit 6 (POD22)/Early Termination (Withdrawal).  
Visual Acuity data will be summarized at each visit. The summary of change-from-baseline at 
each post-surgery visit will be presented for the study eye. 
10.3.4 
Interim Analysis 
No interim analyses are planned for this study. 
10.4 
Sample Size Estimation 
The assumption for the sample size determination was estimated using the Package Inserts of 
Durezol®, Lotemax® and Inveltys® and results from the APP13007 Phase 2 study (CPN-201). 
The sample size for ACC count primary efficacy endpoint is based on the assumption of 26% of 
subjects in APP13007 group with ACC Count = 0 at POD8 and maintained through POD15 and 
12% of subjects in matching vehicle placebo group. The two-group chi-square test, with a two-
sided significance level of 5% and 92% power, requires 175 subjects per treatment group to 
detect the difference between APP13007 and placebo. 
The same sample size using the assumption of 57% of subjects with Ocular Pain Grade = 0 at 
POD4 and maintained through POD15 in APP13007 group and 38% of subjects in placebo group 
will provide 95% power to detect the treatment difference. 
With an estimated 5% dropout rate, this study will randomize approximately 185 subjects per 
treatment group for a total of approximately 370 subjects.  
10.5 
Level of Significance 
Unless otherwise specified, all statistical tests will be two-sided and the statistical significance 
will be tested at the 5% level.  
The primary efficacy endpoints will be evaluated using the fixed sequence testing described in 
Section 10.3.2.1.  
10.6 
Procedure for Accounting for Missing, Unused, or Spurious Data 
If more than 5% of data points are missing at POD15 in any treatment group, a tipping point 
analysis will be performed to assess the sensitivity of the primary efficacy results to the 
distribution of the allocation of treatment success and failure to the missing data points. Other 
missing data imputations will be detailed in the SAP.  


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10.7 
Procedure for Reporting Deviations from the Statistical Plan 
Any deviations from the SAP will be described and a justification given in the final clinical study 
report. 
10.8 
Subjects to be Included in the Analysis 
All efficacy analyses will be performed using the ITT population. In addition, the analysis of the 
primary efficacy endpoints will be performed using the PP population as a supportive analysis. 
AEs and other safety endpoints will be analyzed using the Safety Population. 


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SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
11.1 
Regulatory, Ethical and Legal Obligations 
11.1.1 
Declaration of Helsinki 
The Principal Investigator will ensure that this study is conducted in accordance with the most 
recent revision of the Declaration of Helsinki. 
11.1.2 
Good Clinical Practice 
The Study will be conducted according to the study protocol and to Standard Operating 
Procedures (SOPs) that meet the guidelines provided by the International Conference on 
Harmonisation (ICH) for Good Clinical Practice in clinical studies and applicable regulatory 
requirements. 
11.1.3 
Institutional Review Boards 
This protocol and the informed consent form must be approved by an appropriately constituted 
and qualified IRB and the approvals made available to the Sponsor or designee prior to the start 
of enrollment into the study. Materials used to recruit subjects or supplied to subjects for the 
study will be approved by the appropriate IRB and the approvals made available to the Sponsor 
or designee prior to their use. In addition, the APP13007 Investigator’s Brochure will be 
submitted to the IRB. Written IRB approval must adequately identify the protocol and informed 
consent form. Copies of all approved materials, all correspondence with the IRB, and written 
approval from the IRB must be made available to the Sponsor (or designated Study Monitor). 
Any modification of study procedures or amendments to the protocol must be approved by the 
IRB and submitted to FDA prior to implementation. In the event that a modification or 
amendment is considered by the Investigator to be immediately necessary to ensure subject 
safety, the Investigator will promptly notify his or her IRB, the Study Medical Monitor, and the 
CRO for Study Management and Monitoring who will then notify the Sponsor. 
Investigators will report all SAEs reported at their site to their IRB, as appropriate.  
11.1.4 
Informed Consent Process 
Written informed consent will be obtained from each participant prior to any study-related 
procedures being performed (prior to or on the Screening visit). A copy of the signed and dated 
informed consent document will be given to each subject. The original signed and dated 
informed consent document must be maintained in the study files at the investigative site and be 
available for the CRO for Study Management and Monitoring and the Sponsor or designee(s) to 
review.  


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Each informed consent will contain Investigator contact information with a telephone number the 
subject or the subject’s authorized representative can call 24 hours a day and 7 days a week if 
they have medical concerns. 
11.1.5 
Subject Confidentiality and Disclosure 
Study personnel will have access to a subject’s protected health information (PHI). This 
information may be obtained by the Sponsor, which includes any persons or companies that are 
working with, working for, or owned by the Sponsor. PHI may be given to the U.S. FDA 
Department of Health and Human Services agencies, other governmental agencies in the U.S., 
governmental agencies in other countries, and governmental agencies to which certain diseases 
(reportable diseases) must be reported. 
11.2 
Monitoring and Auditing Study Documentation 
The Investigator(s)/institution(s)  will permit trial-related monitoring, audits, IRB review, and 
regulatory inspection(s) by providing direct access to source data and documents (such as tests 
performed as a requirement for participation in the study and other medical records) to the Study 
Monitor or the Sponsor or its designee. 
11.2.1 
Clinical Monitoring 
Before an investigational site can enter a subject into the study, a representative of the Sponsor 
or its designee such as the CRO for Study Management and Monitoring 
 
 and its Study Monitor will perform pre-study site evaluation at each of the 
investigational study sites in person or remotely to: 
 Determine the adequacy of the facilities 
 Discuss with the Investigator(s) and other personnel their responsibilities about protocol 
adherence, and the responsibilities of the Sponsor or its designated Study Monitor and 
representatives. This will be documented in a Clinical Study Agreement between the Sponsor 
(Formosa Pharmaceuticals, Inc.) and the Investigator. 
 Confirm qualified staff are trained on the protocol, study processes and systems. 
 Confirm all supplies and study product are onsite and stored accordingly. 
 Collect any outstanding essential documents. 
During the study, a monitor from the Sponsor or its designated CRO for Study Management and 
Monitoring 
 and its Study Monitor or representative will have 
regular contacts with the investigational site, for the following: 
 Provide information and support to the Investigator(s). 
 Confirm that facilities remain acceptable. 


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 Confirm that the investigational team is adhering to the protocol, that data are being 
accurately recorded in the eCRFs, and that study treatment accountability checks are being 
performed. 
 Perform source data verification. This includes a comparison of the data in the eCRFs with 
the subject’s medical records at the investigational site, and other records relevant to the 
study. This will require direct access to all original records for each subject (e.g. clinic charts 
or electronic records). 
 Record and report any protocol deviations not previously sent to the Sponsor and the IRB. 
 Confirm the site has adequate supplies and study drugs. 
 Confirm AEs and SAEs have been properly documented on eCRFs and confirm that any and 
all SAEs have been forwarded to the Sponsor via the CRO for Study Management and 
Monitoring and those SAEs that met criteria for reporting have been forwarded to the IRB. 
The Study Monitor and other representatives at the CRO for Study Management and Monitoring 
will be available between visits if the Investigator(s) or other staff needs information or advice. 
11.2.2 
Auditing of Sites and Study Documentation 
Quality control and quality assurance may be performed before, during, and after the study by 
the Sponsor or Sponsor’s designee, such as the CRO for Study Management and Monitoring and 
its Study Monitors. Regulatory authorities in certain countries reserve the right to audit study 
sites following submission of data in regulatory applications. The Investigator may be given due 
notice of any intended audit by a regulatory body. By signing this protocol and the FDA Form 
1572, the Investigator acknowledges that these inspection procedures may take place and agrees 
to provide access to the required subject records and other study documentation. Furthermore, 
the Investigator agrees to inform the Sponsor via the CRO for Study Management and 
Monitoring immediately of any known or suspected inspection by authorities. If the Investigator 
does not comply with the protocol, GCP, or regulations, the Sponsor reserves the right to 
disqualify the Investigator and/or site from the current or future protocols. 
11.3 
Data Handling and Record Keeping 
All procedures for the handling and analysis of data will be conducted using GCP and will meet 
ICH guidelines and US FDA regulations for the handling and analysis of data for clinical trials. 
11.3.1 
Data Collection and Management Responsibilities 
After data have been entered into the study database, a system of computerized data validation 
checks will be implemented and applied to the database. Query reports pertaining to data 
omissions and discrepancies will be forwarded to the Investigator and Study Monitor(s) from the 
CRO for Study Management and Monitoring for resolution. The study database will be updated 


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in accordance with the resolved query reports. All changes to the study database will be 
documented. 
11.3.2 
Study Records Retention 
The study center will retain all records related to the study in accordance with local and ICH 
GCP guidelines. 
11.4 
Protocol Deviations 
Monitoring will be conducted to verify compliance. Instances of minor, major and critical 
deviations that occur at investigative sites will be documented and communicated to the Sponsor 
and documented at the investigative site and recorded in the eCRF. Any noted protocol 
deviations meeting the IRB reporting requirements will reported to the IRB. 
11.5 
Publication and Data Sharing Policy 
The Institutions and Investigators participating in this trial shall have no right to publish or 
present the results of this study without the prior written consent of the Sponsor. 
 


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E. Castaneda, J. P. Hoggatt, A. M. Kostick. 1992. "Posterior capsule opacification." Surv 
Ophthalmol 37(2): 73-116. 
Aptel, F., C. Colin, S. Kaderli, C. Deloche, A. M. Bron, M. W. Stewart, C. Chiquet and O. 
group. 2017. "Management of postoperative inflammation after cataract and complex ocular 
surgeries: a systematic review and Delphi survey." Br J Ophthalmol 101(11): 1-10. 
Baudouin, C., A. Labbe, H. Liang, A. Pauly and F. Brignole-Baudouin. 2010. "Preservatives in 
eyedrops: the good, the bad and the ugly." Prog Retin Eye Res 29(4): 312-334. 
Clobex®. 2018. Clobex® (Clobetasol Propionate) Spray 0.05% [Package Insert]. Fort Worth-
TX: Galderma-Laboratores L.P. 
Feldman, S. R. and B. A. Yentzer. 2009. "Topical clobetasol propionate in the treatment of 
psoriasis: a review of newer formulations." Am J Clin Dermatol 10(6): 397-406. 
Hengge, U. R., T. Ruzicka, R. A. Schwartz and M. J. Cork. 2006. "Adverse effects of topical 
glucocorticosteroids ." J Am Acad Dermatol 54(1): 1-15; quiz 16-18. 
Jacob, S. E. and T. Steele. 2006. "Corticosteroid classes: a quick reference guide including patch 
test substances and cross-reactivity." J Am Acad Dermatol 54(4): 723-727. 
Kaur, I. P., S. Lal, C. Rana, S. Kakkar and H. Singh. 2009. "Ocular preservatives: associated 
risks and newer options." Cutan Ocul Toxicol 28(3): 93-103. 
Leopold, I. 1985. "Nonsteroidal and steroidal anti-inflammatory agents." In Surgical 
Pharmacology of the Eye, by Sears M and T. A., 83-133. New York, NY: Raven Press. 
Olsen, E. A. and R. C. Cornell. 1986. "Topical clobetasol-17-propionate: review of its clinical 
efficacy and safety." J Am Acad Dermatol 15(2 Pt 1): 246-255. 
Sparidans, R.W., van Velsen S.G., de Roos M.P., Schellens J.H., Bruijnzeel-Koomen C.A., 
Beijnen J.H. 2010 "Liquid chromatography-tandem mass spectrometric assay for clobetasol 
propionate in human serum from subjects with atopic dermatitis." J Chromatogr B Analyt 
Technol Biomed Life Sci 878(23):2150-4. 
Temovate®. 2000. Clobetasol Propionate Cream 0.05% [Package Insert]. Research Triangle 
Park, NC: GlaxoWellcome Inc. 


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CONFIDENTIAL 
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Tennant, J.L. 1978. "Cystoid maculopathy: 125 prostaglandins in ophthalmology." Current 
Concepts in Cataract Surgery: Selected proceedings of the fifth biennial cataract surgical 
congress, Section 3. E. J.M St. Louis, MO: CV Mosby. 360-362. 
van Velsen, S. G., M. P. De Roos, I. M. Haeck, R. W. Sparidans, C. A. Bruijnzeel-Koomen. 
2012. "The potency of clobetasol propionate: serum levels of clobetasol propionate and adrenal 
function during therapy with 0.05% clobetasol propionate in subjects with severe atopic 
dermatitis." J Dermatolog Treat 23(1): 16-20. 
 
 
 
 
 
 


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APPENDIX A 
CONTINGENCY PLANS RELATED TO THE COVID-19 
PANDEMIC 
In March 2020 the FDA issued the Guidance: “Conduct of Clinical Trials of Medical Products 
during COVID-19 Pandemic”.  
Based on the stated goal in this FDA Guidance, the following plans may be implemented: 
1. 
When a clinical site plans to or has to close operations and visits cannot be 
scheduled per protocol:  
 If possible, schedule an Early Termination/Withdrawal visit before the clinical site closes. 
o Ask subject to stop the study drug, if before Visit 5 (POD15). 
o Collected study drug and dosing diary. 
o Conduct the Visit 6 (POD22) assessments. 
 A Protocol Deviation is documented as “Early Termination/Withdrawal visit performed 
because the study site closed for operations prior to completion of the study visits due to 
COVID-19 infection-control requirements”. 
2. 
When a subject cannot or does not want to return for an in-person visit:  
 The clinical site coordinator contacts the subject by telephone (or alternative method of 
communication) and asks the subject to stop the study drug, if before Visit 5 (POD15), and 
collects AE and concomitant medication information.  
o The available information is entered in the Early Termination/Withdrawal section of the 
eCRF.  
o If before Visit 5 (POD15), the study coordinator requests the subject to send the study 
drug bottle and dosing diary to the study coordinator at the clinical site. 
 The Investigator withdraws the subject from the study and considers alternative methods of 
assessing the subject. 
 A Protocol Deviation is documented as “Subject withdrawn early (Early Termination) and 
the assessments for Visits X, Y and Z were not performed because the subject could not or 
did not want to return for an in-person visit due to COVID-19 infection-control 
requirements”. 


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APPENDIX B 
GUIDANCE THAT MAY BE USED FOR GRADING THE 
SEVERITY OF A NUCLEAR, CORTICAL OR POSTERIOR 
SUBCAPSULAR CATARACT IN THE NON-STUDY EYE 
Location 
Minimal 
Mild 
Moderate 
Severe 
Nuclear 
Minimal Changes 
in nuclear zone 
In the nuclear zone, 
the anterior and 
posterior embryonal 
nuclei are distinctly 
more opalescent 
(more visible) than 
normally seen, but 
the central clear zone 
is still easily 
distinguishable in its 
entirety 
The nuclear zone is 
more uniformly 
opaque and the 
central clear zone 
between the anterior 
and posterior nuclei 
is not clearly visible. 
The posterior part of 
the zone is often 
more opaque. 
The nuclear zone is 
densely opaque with 
more or less uniform 
nuclear opacity 
extending to the 
edge of the nuclear 
zone; nuclear 
features are only 
partially visible, if at 
all. 
Cortical  
Cataract involves 
< ⅛ of the 
circumference 
Cataract involves ⅛, 
but less than ¼, of the 
circumference. 
Cataract involves ¼, 
but less than ½, of the 
circumference. 
Cataract involves 
≥ ½ of the 
circumference. 
Posterior 
subcapsular < 1 mm 
≥ 1 mm, but < 2 mm  
≥2 mm, but < 3 mm 
≥ 3 mm  
 

SAP_001.pdf: 
 
  
  
 
 
STATISTICAL ANALYSIS PLAN 
 
PROTOCOL NUMBER:  CPN-301 
 
A Multicenter, Randomized, Double-Masked, Placebo-Controlled, Parallel-
Group Study to Evaluate the Efficacy and Safety of APP13007 for the 
Treatment of Inflammation and Pain after Cataract Surgery 
 
 
 
Version No.  
Final 1.1 
Version Date 
24 February 2022 
 
 


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APPROVAL SIGNATURE PAGE 
 
Approved by 
 
 
 
Prepared By: 
Date: 
24 February 2022 
Printed Name: 
 
 
 
Title: 
Biostatistician 
 
 
 
 
 
 
Approved By: 
Date: 
24 February 2022 
Printed Name: 
 
 
 
Title: 
Chief Medical Officer 
 
 
 
 
 
 
Approved By: 
 
Date: 
24 February 2022 
Printed Name: 
 
 
 
Title: 
Chief Development Officer 
 
 
 
 
 


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SUMMARY OF CHANGES IN SAP AMENDMENT 1 
 
 Clarified Study Day calculation corresponding to Surgery Day 0 and Screening Visit 
(Day -28 to Day -1) nomenclature in the protocol (Section 6.3.4) 
 Revised the range of study days for the Analysis Window and rules for handling data 
when multiple efficacy assessments fall within the same analysis window for an Analysis 
Visit (Section 6.3.5) 
 Clarified the LOCF approach to be used for the secondary efficacy endpoints in response 
to FDA’s comments (dated November 3, 2021) on the final SAP v1.0 (Sections 6.4.2 and 
6.4.3.1) 
 Included three iris color categories in the subgroup of iris color (Section 6.4.7) 
 Revised the data handling rule from using the LOCF approach to using observed data for 
the Additional Analysis (Section 10.1.4) 
 Provided the definition of rescue medication use during the treatment period and clarified 
that only the first time of rescue medication use will be included in the analysis and 
summary when multiple rescue medications are used by a subject (Section 10.2.2.3) 
 Added the categories of the number of doses received per subject and revised the 
categories of treatment duration (Section 11.1) 
 Clarified only ocular adverse events will be summarized by relationship to both study 
drug and surgery, and then separately by relationship to surgery only (Section 11.2) 
 Clarified the use of BCVA Base LogMar score (Section 11.3.2) 
 
 


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TABLE OF CONTENTS  
APPROVAL SIGNATURE PAGE ..............................................................................................2 
SUMMARY OF CHANGES IN SAP AMENDMENT 1 ............................................................3 
LIST OF TABLES .........................................................................................................................5 
LIST OF FIGURES .......................................................................................................................5 
1. 
INTRODUCTION..............................................................................................................7 
2. 
STUDY OBJECTIVES AND ENDPOINTS ....................................................................7 
3. 
STUDY DESIGN ................................................................................................................8 
3.1 
Study Design Overview......................................................................................................8 
3.2 
Schedule of Events .............................................................................................................9 
4. 
SAMPLE SIZE CONSIDERATION..............................................................................11 
5. 
ANALYSIS POPULATIONS .........................................................................................11 
5.1 
Intent-to-Treat (ITT) Population ...................................................................................11 
5.2 
Per-protocol (PP) Population ..........................................................................................11 
5.3 
Safety Population .............................................................................................................11 
6. 
DATA ANALYSIS CONSIDERATIONS......................................................................12 
6.1 
General Consideration.....................................................................................................12 
6.2 
General Presentation of Summaries and Analyses .......................................................12 
6.3 
Data Handling Rules ........................................................................................................12 
6.3.1 Baseline Values ................................................................................................................ 12 
6.3.2 Study Eye ......................................................................................................................... 12 
6.3.3 Non-Study Eye ................................................................................................................. 13 
6.3.4 Study Day and End of Study (EOS) .............................................................................. 13 
6.3.5 Analysis Visit for Efficacy Analyses .............................................................................. 13 
6.4 
Statistical/Analytical Issues .............................................................................................14 
6.4.1 Adjustments for Covariates ........................................................................................... 14 
6.4.2 Rescued Subjects ............................................................................................................. 14 
6.4.3 Handling Dropouts or Missing Data ............................................................................. 15 
6.4.4 Handling of Dropouts Due to the COVID-19 Pandemic ............................................. 16 
6.4.5 Multicenter Studies ......................................................................................................... 16 
6.4.6 Multiple Comparisons/Multiplicity ............................................................................... 16 
6.4.7 Subgroup Analyses.......................................................................................................... 17 
7. 
STUDY POPULATION CHARACTERISTICS ..........................................................17 
7.1 
Subject Disposition...........................................................................................................17 
7.2 
Protocol Deviations ..........................................................................................................17 
8. 
DEMOGRAPHICS AND BASELINE CHARACTERISTICS ...................................18 
8.1 
Demographics and Baseline Characteristics .................................................................18 


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8.2 
Medical/Surgical History.................................................................................................18 
8.3 
Prior and Concomitant Medications ..............................................................................18 
9. 
TREATMENT COMPLIANCE .....................................................................................18 
10. 
EFFICACY ANALYSES ................................................................................................19 
10.1 
Analyses of Primary Efficacy Endpoints .......................................................................19 
10.1.1 Primary Efficacy Endpoints........................................................................................... 19 
10.1.2 Primary Analysis ............................................................................................................. 20 
10.1.3 Sensitivity Analyses ......................................................................................................... 21 
10.1.4 Additional Analysis ......................................................................................................... 22 
10.2 
Analyses of Secondary Efficacy Endpoints....................................................................22 
10.2.1 Secondary Efficacy Endpoints ....................................................................................... 22 
10.2.2 Analysis of Secondary Efficacy Endpoints ................................................................... 23 
11. 
SAFETY ANALYSES .....................................................................................................24 
11.1 
Extent of Exposure ...........................................................................................................24 
11.2 
Adverse Events .................................................................................................................24 
11.3 
Other Safety Endpoints ...................................................................................................25 
11.3.1 Intraocular Pressure ....................................................................................................... 25 
11.3.2 Best Corrected Visual Acuity ......................................................................................... 26 
11.3.3 Slit Lamp Biomicroscopy ............................................................................................... 26 
11.3.4 Dilated Indirect Ophthalmoscopy ................................................................................. 27 
12. 
INTERIM ANALYSIS ....................................................................................................27 
13. 
REFERENCES .................................................................................................................27 
 
LIST OF TABLES 
Table 1: 
Study Objectives and Endpoints .......................................................................7 
Table 2: 
Schedule of Events ............................................................................................10 
Table 3: 
Analysis Windows for Efficacy Analysis ........................................................13 
 
LIST OF FIGURES 
Figure 1: 
Study Schematic ..................................................................................................9 
 


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LIST OF ABBREVIATIONS 
Abbreviation 
Definition 
ACC 
Anterior Chamber Cell 
ACF 
Anterior Chamber Flare 
AE 
Adverse Event 
ANCOVA 
Analyses of Covariance 
ATC 
Anatomical Therapeutic Chemical 
BCVA 
Best Corrected Visual Acuity  
BID 
Twice Daily 
CI 
Confidence Interval 
eCRF 
Electronic Case Report Form 
EOS 
End of Study 
ETDRS 
Early Treatment of Diabetic Retinopathy Study 
IOP 
Intraocular Pressure 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward 
MedDRA 
Medical Dictionary for Regulatory Activities 
OD 
Right Eye 
OS 
Left Eye 
OU 
Both Eyes 
POD 
Post-Operative Day 
PP 
Per-Protocol 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SOC 
System Organ Class 
SUSAR 
Serious and Unexpected Suspected Adverse Reaction 
TEAE 
Treatment-Emergent Adverse Event 
WHO 
World Health Organization 
 
 
 


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1. INTRODUCTION 
This document is prepared in compliance with International Conference on Harmonization E9 
and intended to provide details of statistical methodology and data handling rules to be used for 
the analyses of data from Protocol CPN-301 v1.3 (Amendment 1): A Multicenter, Randomized, 
Double-Masked, Placebo-Controlled, Parallel-Group Study to Evaluate the Efficacy and Safety 
of APP13007 for the Treatment of Inflammation and Pain after Cataract Surgery.  This Phase 3 
study is being conducted in the United States. 
2. STUDY OBJECTIVES AND ENDPOINTS 
The study objectives and corresponding study endpoints are presented in Table 1 below: 
Table 1: Study Objectives and Endpoints 
Objectives 
Endpoints 
Primary Efficacy Objective 
The primary efficacy objective is to 
investigate the efficacy of APP13007 versus 
matching vehicle placebo for the treatment 
of inflammation and pain through post-
operative day (POD) 15 after cataract 
surgery in the study eye. 
Primary Efficacy Endpoints 
 
The proportion of subjects with Anterior Chamber Cell 
(ACC) Count = 0 [ACC Grade = 0] at post-operative 
day 8 (POD8), maintained through POD15  
 
The proportion of subjects with Ocular Pain Grade = 0 
at POD4, maintained through POD15 
Secondary Efficacy Objective 
The secondary efficacy objective of this 
study is to investigate the effect of 
APP13007 versus matching vehicle placebo 
on markers of inflammation, ocular pain 
and visual acuity after cataract surgery in 
the study eye. 
Secondary Efficacy Endpoints 
 
Proportion of subjects with ACC count = 0 [ACC 
Grade = 0] at PODs 4, 8 and 15 
 
Proportion of subjects with Ocular Pain Grade = 0 at 
PODs 4, 8 and 15  
 
Proportion of subjects with Anterior chamber flare 
(ACF) Grade = 0 at POD8 maintained through POD15  
 
Proportion of subjects with ACF Grade = 0 at PODs 4, 
8 and 15 
 
Mean change-from-baseline in ACC Grade at PODs 4, 
8, and 15 
 
Mean change-from-baseline in Ocular Pain Grade at 
PODs 4, 8 and 15 
 
Mean change-from-baseline in ACF Grade on PODs 4, 
8 and 15  
 
Number of subjects rescued on or prior to each visit and 
overall 
 
Mean change-from-baseline in best corrected visual 
acuity by pinhole method using an Early Treatment 
Diabetic Retinopathy Study (ETDRS) chart at PODs 4, 
8 and 15 


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Objectives 
Endpoints 
Safety Objective 
The safety objective is to investigate the 
safety and tolerability of APP13007 versus 
matching vehicle placebo for the treatment 
of inflammation and pain after cataract 
surgery. 
Safety Endpoints 
 
Adverse events (AEs)  
 
Best corrected visual acuity by pinhole method using an 
ETDRS chart from baseline to each post-surgery visit 
 
Slit-lamp biomicroscopy 
o Change-from-baseline in ocular signs to each post-
surgery visit 
 
Dilated indirect ophthalmoscopy 
o Change-from-baseline in ocular signs to Visit 6 
(POD22) 
 
Intraocular pressure (IOP) at each visit and change-
from-baseline to Visit 6 (POD22) measured with a 
Goldmann applanation tonometer 
 
3. STUDY DESIGN 
3.1 
Study Design Overview  
This Phase 3 study will evaluate APP13007 
 
 in comparison to the matching vehicle placebo in a randomized, parallel-group, double-
masked fashion. Subjects will have routine uncomplicated cataract surgery on Day 0 of the study 
and will be assessed the next day (POD1) after the surgery for eligibility for randomization to 
study treatment. 
Subjects who experience postoperative inflammation on POD1 and who meet all other eligibility 
criteria will be randomized, at a 1:1 ratio, to one of two study treatments (either Treatment 1 or 
Treatment 2):   
• Treatment 1:  1 drop APP13007 twice daily (BID) (morning and evening) for 14 days 
instilled to the operated study eye 
• Treatment 2:  1 drop matching vehicle placebo BID (morning and evening) for 14 days 
instilled to the operated study eye 
 
After randomization, the first dose of study drug will be administered in the clinic on POD1 so 
that the site personnel can ensure the subject is able to administer the study drug correctly. The 
second drop of the study drug on POD1 will be administered by the subject a minimum of 
6 hours later. For all other days, the first dose will be instilled in the morning and the second 
dose instilled a minimum of 6 hours, but preferably 8 to 12 hours, later. The number of drop(s) 
instilled and the date/time of instillation of each dose will be recorded by the subject in the 
subject’s dosing diary. The study drug will be dosed BID for 14 days. 


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Any subjects who have evidence of persistent or worsening inflammation as described in the 
protocol Section 9.4 may be rescued and placed on appropriate alternate therapy. The choice of 
rescue medication is at the Investigator's discretion. Rescued subjects will stop study drug and 
will not be withdrawn from the study. The rescued subjects will continue to be assessed at each 
subsequent visit, if possible, through completion of the Visit 6 (POD22) assessments.  
This study will include up to 7 clinic visits (including the surgery day) over a range of 24 to 
approximately 52 days (Figure 1). Subjects will be discharged from the study after the 
assessments for Visit 6 (POD22) have been performed.  
Figure 1: Study Schematic 
 
3.2 
Schedule of Events  
All assessments including ocular assessments and safety assessments are outlined in Table 2. 
 


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Table 2: Schedule of Events 
PROCEDURE/ASSESSMENTS 1  
Visit 1 
Screening  
(Day -28 to -1) 
Surgery 2 
Day 0 
Visit 2 
POD1 3 
Visit 3 
POD4 
(±1 Day) 
Visit 4 
POD8 
(±1 Day) 
Contact 
POD14 
Visit 5 
POD15 
(+1 Day) 4 
Visit 6 
POD22 
(±2 Days) 5 
ICF, Demography, Medical History  
X 
 
 
 
 
 
 
 
Determine Eligibility, Review Inclusion/Exclusion Criteria  
X 
 
X 
 
 
 
 
 
Urine pregnancy test only for women of child-bearing potential  
 
 
X 
 
 
 
X 
 
Ocular Symptoms Assessment 6  
X 
 
X 
X  
X 
 
X 
X 
ETDRS Visual Acuity 
X 
 
X 
X 
X 
 
X 
X 
Slit Lamp Biomicroscopy 7  
X 
 
X 
X 
X 
 
X 
X 
Indirect Ophthalmoscopy (dilated) 
X 
 
 
 
 
 
 
X 
lOP (Goldmann applanation tonometry) 8 
X 
 
X 
X 
X 
 
X 
X 
Randomization 
 
 
X 
 
 
 
 
 
Dispense Study Drug  
 
 
X 
 
 
 
 
 
Study Drug Dosing BID for 14 days (POD1 to POD14) 9 
 
 
X 
X 
X 
X 
 
 
Dispense Diary Card (with instructions for completion) 
 
 
X 
X 
X 
 
 
 
Contact Subject 10 
 
 
 
 
 
X 
 
 
Collect Study Drug 
 
 
 
 
 
 
X 
 
Collect and Check Diary Cards for Accuracy and Compliance  
 
 
 
X 
X 
 
X 
 
AEs 7 and Concomitant Medications 11 
X 
X 12 
X 
X 
X 
X 13 
X 
X 
1 Ophthalmic assessments will be performed in the study eye only at Visits 2-5; and performed on both eyes at Visit 1 (Screening) and at Visit 6 (POD22) or at subject Early Termination/Withdrawal. 
2 Surgery must occur between one to 28 days after Screening, preferably in the morning. If, due to unexpected events, surgery is postponed and would occur > 28 days past the Screening visit, contact the Study 
Medical Monitor to determine which, if any, of the screening procedures should be repeated. Subjects will be determined to be a suitable candidate for surgery during a pre-surgery medical assessment, where the 
routine medication list prescribed by the cataract surgeon should be reviewed to rule out prohibited medications (protocol Section 5.4.2). 
3 Visit 2 (POD1) should be scheduled between 18 to 34 hours following conclusion of surgery on Day 0. All assessments done on POD1 are done prior to Randomization to ensure eligibility. Note: Women-of-
childbearing-potential are eligible for enrollment if they have a negative urine pregnancy test on POD1 prior to Randomization and they agree to abstinence from sexual activity or use of highly effective method of 
contraception. 
4 Visit 5 (POD15) occurs on the day after the subject completes the study drug administration for 14 days. Women-of-childbearing-potential should have a urine pregnancy test. 
5 Visit 6 (POD22) is the last visit for subjects who complete the study. Subjects who are withdrawn early should have the Visit 6 assessments and a urine pregnancy test performed before they are released from the 
study. 
6 Includes assessments of ocular pain and irritation. See protocol Section 8.0 for information on how to record AEs and how to determine attributability (relatedness) of AE to study procedures (including cataract 
surgery) or study drug. 
7 Ocular inflammation assessment using ACC count, anterior chamber flare grade, bulbar conjunctival injection, sclera - ciliary flush and corneal edema. 
8 IOP should (but not required) be assessed at each visit within ± 2 h of the IOP assessment time at Visit 1. 
9 The first dose of study drug should be instilled into the study eye at the clinic visit under supervision of clinic staff. The second dose on POD1 can be administered at home. Subjects who are rescued will not 
continue to instill study drug or receive further diary cards but will remain in the study to complete the procedures/assessments through Visit 6 (POD22).  
10 The site must contact the subject via the subject’s preferred method on POD14 to remind him/her not to instill study drug on POD15 and to bring the bottle of study drug and the dosing diary back to the site at 
the POD15 visit. 
11 Concomitant medications used for rescue should be reported in the eCRF. 
12 AEs and Concomitant Medications should only be recorded on Day 0 if they result in disqualification (i.e., screen failure) of the subject; otherwise, the AEs and Concomitant Medications applicable to Day 0 
should be recorded when the subject returns for Visit 2 (POD1). 
13 Any AEs reported to the site during the POD14 contact must be recorded in the source documents. Further assessment of any reported AEs may require an Unscheduled Visit on POD14 if medically significant 
or they may be assessed, as appropriate, during Visit 5 (POD15


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4. SAMPLE SIZE CONSIDERATION  
The assumption for the sample size determination was estimated using the Package Inserts of 
Durezol®, Lotemax® and Inveltys® and results from the APP13007 Phase 2 study (CPN-201). 
The sample size for ACC count primary efficacy endpoint is based on the assumption of 26% of 
subjects in APP13007 group with ACC Count = 0 at POD8 and maintained through POD15 and 
12% of subjects in the matching vehicle placebo group. The two-group Chi-square test, with a 
two-sided significance level of 5% and 92% power, requires 175 subjects per treatment group to 
detect the difference between APP13007 and placebo. 
The same sample size using the assumption of 57% of subjects with Ocular Pain Grade = 0 at 
POD4 and maintained through POD15 in APP13007 group and 38% of subjects in the placebo 
group will provide 95% power to detect the treatment difference. 
With an estimated 5% dropout rate, this study will randomize approximately 185 subjects per 
treatment group for a total of approximately 370 subjects. 
5. ANALYSIS POPULATIONS 
The analysis populations are defined below. 
5.1 
Intent-to-Treat (ITT) Population  
The ITT population will consist of all subjects who are randomized to the study drug.  
Following the ITT principle, subjects will be analyzed according to the treatment assignment at 
randomization.  
5.2 
Per-protocol (PP) Population 
The PP population will consist of all subjects in the ITT population who (i) receive at last 1 dose 
of study drug, (ii) do not have major protocol deviations that would impact the evaluation of 
efficacy, and (iii) have at least 80% overall treatment compliance.  
The subjects who are to be excluded from the PP population will be identified prior to database 
lock and unmasking of the treatment assignment and the reason for exclusion will be 
documented and listed. 
5.3 
Safety Population 
The safety population will consist of all randomized subjects who receive at least one dose of 
study drug.  
Subjects will be analyzed in the safety analysis according to the treatment actually received. 


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6. DATA ANALYSIS CONSIDERATIONS 
6.1 
General Consideration 
All statistical analyses and generation of tables, figures, subject data listings, and statistical 
output will be performed using SAS Version 9.3 or higher. 
6.2 
General Presentation of Summaries and Analyses 
Descriptive statistics will be displayed to provide an overview of the study results. For 
categorical variables, the number and percentage of subjects in each category will be presented. 
Unless otherwise noted, all percentages will be displayed to 1 decimal place. No percentage will 
be displayed for zero counts, and no decimal will be presented when the percentage is 100%. For 
continuous variables, descriptive statistics will include number of subjects with available 
measurements (n), mean, standard deviation, median, first quartile (Q1), third quartile (Q3), 
minimum, and maximum.  
Decimal places for descriptive statistics will apply the following rules unless otherwise stated: 
• “n” will be an integer 
• Mean, standard deviation, and median will use one additional decimal place compared to 
the original value 
• Minimum and maximum will have the same number of decimal places as the original 
value 
 
Continuous variables will be examined to ensure that they meet the required assumptions for the 
intended statistical analysis method. If the statistical assumptions are violated, alternative 
analytical methods, such as nonparametric statistics, will be used. 
Unless otherwise specified, all statistical tests will be two-sided and the statistical significance 
will be tested at the 5% level (α = 0.05). Statistical tests of efficacy variables will be presented as 
two-sided p-values rounded to three decimal places. P-values less than 0.001 will be presented as 
“<0.001” and p-values greater than 0.999 will be presented as “>0.999”.   
6.3 
Data Handling Rules 
6.3.1 
Baseline Values 
Baseline values is defined as the values obtained at the most recent assessment prior to the first 
dose of the study drug. Both scheduled and unscheduled visits will be considered.  
Screening values will be considered as the baseline values when the change from screening is of 
interest.  
6.3.2 
Study Eye 
Each subject’s study eye is defined as the eye that undergoes cataract surgery in the study.  


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6.3.3 
Non-Study Eye 
Each subject’s non-study eye is defined as the eye that does not have cataract surgery in the 
study. 
6.3.4 
Study Day and End of Study (EOS) 
Study Day for each subject is calculated relative to the date of the first dose of study drug: 
• Study Day = Visit Date/Event Date - Date of First Dose +1  
When the Visit Date/Event Date is on or after the Date of First Dose  
• Study Day = Visit Date/Event Date - Date of First Dose 
When the Visit Date/Event Date is prior to the Date of First Dose 
 
Study Day will be used to define analysis windows for efficacy analyses and to evaluate the 
timing of events or measurements occurring relative to the first dose of study drug. 
Study Day ‘-1’ corresponds to Surgery Day 0 and Study Days ‘-29’ to ‘-2’ correspond to 
Screening Visit (Days -28 to -1) as shown in the Schedule of Events (Table 2).   
EOS is defined as the last visit in the study. EOS will be either Visit 6/POD22 for subjects who 
complete the study or the Early Termination/Withdrawal visit for subjects who discontinue the 
study prior to Visit 6/POD22. 
6.3.5 
Analysis Visit for Efficacy Analyses 
The use of efficacy data collected in the study will be maximized by including the assessments 
that are performed outside the planned visit window. Each Analysis Visit (POD 4, 8 and 15) will 
use an analysis window to determine the efficacy data that will be used to derive the efficacy 
endpoints. The actual Study Day (Section 6.3.4) will be used to define the analysis window. The 
analysis window for each Analysis Visit is shown in Table 3.  
Table 3: Analysis Windows for Efficacy Analysis 
* Only for subjects who (i) complete at least 14 days of dosing, (ii) do not use rescue medication and (iii) have a 
scheduled POD15 visit after Study Day 17 
If the efficacy assessments are performed at unscheduled visits occurring after Visit 2/POD1 and 
before Visit 5/POD15, the date of the unscheduled visits will also be used to determine the 
appropriate analysis window.  
The efficacy assessments performed after two days following the last dose of study drug will not 
be used when the subjects have administered less than 14 days of study drug.  
Analysis Visit 
POD4 
POD8 
POD15 
Study Days in Analysis Window 
2 – 6 
7 –11 
12 – 17 or 
Scheduled Visit* 


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When multiple efficacy assessments fall within the same analysis window for an Analysis Visit 
(see Table 3), the following rules will be applied: 
 If two scheduled assessments fall within the same analysis window for an Analysis Visit and 
one of the Analysis Visits (either before or after the Analysis Visit with two scheduled 
assessments) has no scheduled assessment, then the scheduled assessment data will be used 
for the Analysis Visit without an assessment. For example, when a subject has a scheduled 
POD4 visit at Study Day 3 and a scheduled POD8 visit at Study Day 6, the Analysis Visit 
POD4 would have two scheduled assessments and the Analysis Visit POD8 would have no 
data. In this case, the scheduled POD8 visit assessments will be used for the Analysis Visit 
POD 8. 
 If one scheduled assessment and at least one unscheduled assessment fall within the same 
analysis window for an Analysis Visit, the latest value in the analysis window will be used 
for all relevant efficacy analyses. 
The definition of the Analysis Visit for the efficacy analyses will be re-examined prior to 
database lock.  If there is a need to adjust the analysis window in Table 3, the SAP will be 
amended to document the changes. 
6.4 
Statistical/Analytical Issues 
6.4.1 
Adjustments for Covariates 
The analysis of the continuous secondary efficacy endpoints will be adjusted for baseline values 
as a covariate in the analyses of covariance (ANCOVA).  
6.4.2 
Rescued Subjects 
Any subject not responding to the study drug because of lack of efficacy at any time after 
randomization at Visit 2/POD1 may be rescued and placed on an appropriate alternative therapy 
determined by the Investigator.  
The efficacy assessments performed after starting rescue medication will be excluded from the 
efficacy analyses. 
For the primary efficacy endpoints, subjects who are rescued at any time after the first dose of 
study drug and before the efficacy assessments at POD15 will be considered as treatment failures 
(Non-responders). The same approach will be applied to derive the secondary endpoint of 
sustained ACF grade =0. 
For both categorical and continuous secondary efficacy endpoints of ACC grade, ocular pain 
grade and ACF grade, the last observation carried forward (LOCF) approach will be used to 
impute the data for each Analysis Visit after starting rescue medication. 


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6.4.3 
Handling Dropouts or Missing Data 
6.4.3.1 
Imputation of Missing Efficacy Data 
The missing data handling rule for the study eye will be applied for the efficacy endpoints.  
Missing data from subjects who discontinue the study before POD15 assessments without 
taking rescue medication: 
For subjects who prematurely discontinue the study without taking rescue medication, the LOCF 
approach will be used to impute the missing data. The last observation will be the last assessment 
value after the first dose of study drug and up to two days following the last dose of study drug. 
Missing data from subjects who discontinue the study and take rescue medication before 
POD15 assessments: 
For both categorical and continuous secondary efficacy endpoints of ACC grade, ocular pain 
grade and ACF grade, subjects who take rescue medication before POD15 assessments and 
prematurely discontinue the study, the LOCF approach will be used to impute the missing data. 
The last observation will be the last assessment value after the first dose of study drug and prior 
to starting rescue medication.   
Intermittent missing data: 
The likelihood of having intermittent missing data is low. For subjects with intermittent missing 
data for efficacy endpoints, the LOCF approach will be applied to impute the missing data, 
i.e., using the data collected from the most recent prior visit after the first dose of study drug.  
If no data can be carried forward (i.e., missing assessments at POD 4 visit or no available post-
baseline assessments), missing data will be treated as missing for the continuous endpoints and 
will be considered as ‘Non-responder’ for the categorical endpoints. 
6.4.3.2 
Imputation of Partial Dates for Birthday, AEs, and Medications 
The day of birth date will not be collected in order to protect subjects’ privacy. To calculate the 
age from birth date, the day will be assigned as the 1st day of the birth month. 
For analysis of AEs and medications (other than the study drug), a complete date should be 
established in order to determine treatment emergent AEs (TEAEs) or concomitant medications. 
The imputation rule of partial dates will be applied for missing components of partially-reported 
start and stop dates for AEs and for medication use. 
Partial start dates of AE and medication will be imputed as follow: 
• If only the month and year are reported and the month and year of the start date is not the 
same as the month and year of the date of first dose of study drug, then use the first day of 
the month. 


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• If only the month and year are reported and the month and year of start date is the same as 
the month and year of the date of the first dose of study drug, then use the date of first 
dose. 
• If only the year is reported, and the year of the start date is not the same as the year of first 
dose of study drug, then use the January 1st as the start day and month.  
• If only the year is reported, and the year of the start date is the same as the year of first 
dose of study drug, then use the date of first dose. 
• If the start date is completely unknown and the stop date is partially known or not prior to 
the date of first dose of study drug, then use the date of first dose. 
• If the imputed start date is after the known stop date, set the start date to be the same as 
the stop date. 
 
Partial stop dates of AE and medication will be imputed as follow: 
• If only the month and year are reported, then use the last day of the month 
• If only the year is reported, then use December 31st of that year 
 
If the unknown dates cannot be used to determine whether an AE is treatment emergent or a 
medication is concomitant, the AE will be considered as treatment emergent or the medication 
will be considered as concomitant. 
In subject data listings, birthday, start and stop date of AEs or medications (other than study 
drug) will be displayed as reported (i.e., no imputed values will be displayed in data listings). 
6.4.4 
Handling of Dropouts Due to the COVID-19 Pandemic 
The protocol Appendix A describes the Early Termination/Withdrawal procedures that may be 
implemented because of the COVID-19 pandemic. Subjects who discontinue the study due to 
COVID-19 will follow the imputation rules described in Section 6.4.3.1 to impute the missing 
efficacy data. 
6.4.5 
Multicenter Studies  
The randomization will be stratified by study site. No study sites will be pooled for analysis 
purposes, as the efficacy analyses will not be adjusted for study site differences. If there is a 
potential site issue identified, an exploratory analysis may be performed to adjust for ‘study site’ 
in the analysis of primary efficacy endpoints. 
6.4.6 
Multiple Comparisons/Multiplicity 
Since the comparisons of the primary efficacy endpoints will be performed in the pre-specified 
sequential order, the fixed-sequence hierarchical testing approach will be used to adjust for 
multiple comparisons. These endpoints will be tested in the sequence with the rule that once a 


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p-value exceeds 0.05, the endpoint further down in the sequence will not be claimed for 
statistical significance. 
6.4.7 
Subgroup Analyses 
The primary efficacy endpoints will be evaluated for subgroups of interest, including: 
• Age (< 65 or ≥ 65 years) 
• Race (White or Non-White) 
• Gender 
• Iris color (Blue, Brown or Other) 
 
Subgroup summary will be performed using the ITT population for the primary efficacy 
endpoints only if the number of subjects in a subgroup is appropriate. No statistical comparisons 
will be conducted. 
7. STUDY POPULATION CHARACTERISTICS 
7.1 
Subject Disposition 
Summaries of the number of subjects screened, the number of screen failures and the number of 
subjects randomized will be produced for all screened subjects. 
All randomized subjects will be tabulated by treatment group and study site. 
The number in each analysis population (ITT, PP and Safety) will be tabulated by treatment 
group for all randomized subjects. 
The number and percentage of subjects who complete the study and who prematurely 
discontinue the study, along with the reason for withdrawal, will be tabulated by treatment group 
for the ITT population. 
In addition, the numbers and percentages of subjects who discontinue the study drug before 
completing the 14-days of dosing and the reason for discontinuing the study drug will be 
tabulated by treatment group using the Safety population. 
Disposition data for all screened subjects will be listed.  
7.2 
Protocol Deviations 
Protocol deviations will be collected in the eCRF.  The protocol deviation data will be reviewed 
for major protocol deviations by the clinical team prior to database lock and unmasking of the 
study treatment.  
The subjects with major protocol deviations including the category of the major protocol 
deviations will be summarized by treatment group for the ITT population. The number and 


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percentage of subjects excluded from the PP population and the reason for exclusion will be 
tabulated by treatment group for the ITT population.  
The protocol deviation data will be listed. The data listing will include the type of deviation, the 
category of the deviation (major/minor), the status of being excluded from the PP population 
(yes/no) and reason for exclusion.  
A data listing of subjects who do not meet the inclusion and exclusion criteria will be provided.   
8. DEMOGRAPHICS AND BASELINE CHARACTERISTICS 
8.1 
Demographics and Baseline Characteristics 
Demographic data, including age, age category (< 65 or ≥ 65 years), gender, race, ethnicity, iris 
color, study eye (OD or OS) will be summarized by treatment group and overall. 
Demographic and baseline characteristics data, including the data collected on the surgery day 
(Day 0), will be listed in data listings. 
8.2 
Medical/Surgical History 
General medical and surgical history, and ocular medical and surgical history reported in eCRF 
will be coded using the Medical Dictionary for Regulatory Activities (MedDRA version 23.1 - 
September 2020). General medical and surgical history will be summarized by system organ 
class (SOC) and preferred term for past and current medical conditions separately. Subjects 
reporting more than one medical condition in a SOC will be counted only once in that SOC.  
Ocular medical and surgical history will be summarized by SOC and preferred term for the study 
eye and non-study eye separately. 
Data listings of general medical and surgical history, and ocular medical and surgical history will 
be provided. 
8.3 
Prior and Concomitant Medications 
Prior and concomitant medications, including rescue medications, will be coded using the World 
Health Organization (WHO) Drug Dictionary (B3 WHO Drug Global - September 2020). When 
medications cannot be coded, the name entered in the eCRF will be reported. 
A summary of concomitant medications taken during the course of the study will be tabulated by 
Anatomical Therapeutic Chemical (ATC) Classification and WHO drug name. The summary 
will exclude prior medications with a stop date prior to the date of first dose of the study drug or 
follow-up medications with a start date after the last day of the study (EOS). Medications used as 
part of the routine surgical procedure and rescue medications will be summarized separately.  
All prior and concomitant medications will be presented in a data listing. 
9. TREATMENT COMPLIANCE 
Overall treatment compliance per subject for the study eye is defined as: 


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Treatment compliance (%) = [Total number of doses instilled correctly / (Actual treatment 
duration) x 2] x100, 
where the actual treatment duration is calculated as the number of days between the first dose 
date and last dose date of study drug. 
The treatment compliance will be summarized using descriptive statistics for the Safety 
population. In addition, the overall treatment compliance will be further categorized as < 80%, 
80% – 100% and > 100%, and the number and percentage of subjects with compliance in each 
category will be presented.  
Subject dosing diary data will be listed. 
10. EFFICACY ANALYSES 
All efficacy analyses will be performed using the ITT population. In addition, analyses of the 
primary efficacy endpoints will be performed using the PP population as a sensitivity analysis. 
All efficacy analyses and summaries will be based on assessments in the study eye for each 
subject.  
The data for subjects who are rescued at any time after the first dose of study drug and before the 
efficacy assessments at POD15 will be handled as descried in Sections 6.4.2 and 6.4.3.1. The 
data for subjects who prematurely discontinue the study without taking any rescue medications 
will be handled as descried in Section 6.4.3.1. 
The Analysis Visits (PODs 4, 8 and 15) defined in Section 6.3.5 will be employed in the efficacy 
analyses.  
Baseline values for the efficacy endpoints are defined as the assessment values obtained at POD1 
pre-dose. 
All efficacy data will be presented in listings.  
10.1 Analyses of Primary Efficacy Endpoints 
10.1.1 
Primary Efficacy Endpoints 
The primary efficacy endpoints are: 
• The proportion of subjects with ACC count = 0 (ACC grade = 0) at POD8, maintained 
through POD15 
• The proportion of subjects with Ocular Pain grade = 0 at POD4, maintained through 
POD15 
 
The ACC count will be graded as shown below:  


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Grade 
0 
1 
2 
3 
4 
ACC Count 
0 cell 
1-5 cells 
6-15 cells 
16-30 cells 
> 30 cells 
 
The subject-rated Ocular Pain will be graded as follow: 
Grade 
Description 
0 
None: No pain. 
1 
Minimal: Presence of minimal throbbing or aching pain (expected following 
cataract surgery). 
2 
Mild: Presence of mild throbbing or aching pain, easily tolerated. 
3 
Moderate: Presence of moderate throbbing or aching pain leading to the 
desire to use an analgesic. 
4 
Severe: Presence of severe throbbing or aching pain that is not tolerable 
 
10.1.2 
Primary Analysis  
The Pearson’s Chi-square test will be used to test the null hypothesis that there is no difference 
between treatment groups for the primary efficacy endpoints: 
1. The proportion of subjects with ACC count = 0 (ACC grade = 0) at POD8, maintained 
through POD15 
2. The proportion of subjects with Ocular Pain grade = 0 at POD4, maintained through 
POD15 
 
Since the treatment comparisons of the primary efficacy endpoints are in sequential order, the 
fixed-sequence hierarchical testing approach will be used to adjust for multiple comparisons. The 
primary analysis will first compare the proportion of subjects with ACC count = 0 (ACC grade = 
0) at POD8, maintained through POD15, between APP13007 and placebo. If the test is 
statistically significant at the 2-sided α = 0.05 level in favor of APP13007, the comparison of the 
proportion of subjects with Ocular Pain grade = 0 at POD4, maintained through POD15, between 
APP13007 and placebo will be tested at the two-sided α = 0.05 level. 
Under the hierarchical testing scheme, once the two-sided p-value exceeds 0.05, the endpoint 
further down in the sequence will not be claimed for statistical significance. 
The tabulated summary of the two endpoints will include the Responder (Response =Yes) and 
Non-responder (Response=No) for ACC count = 0 (ACC grade = 0) at POD8, maintained 
through POD15, or for Ocular Pain grade = 0 at POD4, maintained through POD15, and the 95% 
confidence interval (CI) for Responder. The treatment difference of the Responder rates with the 
associated 95% CI will be presented. The Response will be further categorized as: 
 


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Yes (Responder):  
• Yes – Without imputed data 
• Yes – With imputed data  
 
No (Non-responder):  
• No – With Rescue Medication Use 
• No – Without Rescue Medication Use 
• No – With imputed data 
10.1.3 
Sensitivity Analyses  
Sensitivity analyses will be performed to confirm the robustness of the primary efficacy analysis 
results: 
1. Analysis of the primary endpoints will be performed using the PP population. 
2. “Completed-Case” analysis of the primary endpoints will be performed using the 
subgroup of Completers based on the ITT population. Completers are defined as the 
subjects who complete the study and have the data for the ACC count and ocular pain 
grade assessments at all visits up to POD15. 
3. “Observed-Case” analysis of the primary endpoints will be performed using the ITT 
population and the observed data for subjects who discontinue prior to POD15 without 
taking rescue medication. The subjects with missing data will be considered as treatment 
failures (Non-responders). 
4. “Worst-Case in the Analysis Window” analysis of the primary endpoints will be 
performed using the ITT population and using the worst Response at PODs 4, 8 and 15 
when multiple efficacy assessments fall within the same analysis window for each 
Analysis Visit. 
5. If more than 5% of data are missing for determining the primary efficacy endpoints in 
any treatment group, a tipping point analysis will be performed when the statistical 
significance of a treatment difference between two groups has been claimed for each of 
the two primary endpoints. Missing data for subjects who take a rescue medication will 
not be considered as ‘missing’ since the subjects will have been assigned as treatment 
failures (Non-responders). 
The tipping point analysis of the primary endpoints will be performed using the ITT 
population to determine the number of subjects with imputed data in the placebo group 
whose response status has to be changed from Non-Responder to Responder in order to 
make the treatment difference between the two treatment groups no longer statistically 
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10.1.4 
Additional Analysis 
The primary efficacy endpoints will be analyzed using the data collected up to POD15. The 
rescued subjects will not be considered as treatment failures (Non-responders) for this analysis. 
All subjects’ data collected up to POD15, including the data from subjects who take rescue 
medication, will be used to analyze the primary efficacy endpoints. Only observed data will be 
included to derive the primary efficacy endpoints. For the primary endpoint of ACC grade, 
subjects who miss one of POD 8 and POD15 assessments will be considered as treatment 
failures (Non-responders). For the primary endpoint of ocular pain grade, subjects who miss one 
of PODs 4, 8 and 15 assessments will be considered as treatment failures (Non-responders). The 
Pearson’s Chi-square test will be used to test the treatment difference. 
10.2 Analyses of Secondary Efficacy Endpoints 
10.2.1 
Secondary Efficacy Endpoints 
The secondary efficacy endpoints are: 
• Proportion of subjects with ACC count = 0 (ACC grade = 0) at PODs 4, 8 and 15 
• Proportion of subjects with Ocular Pain grade = 0 at PODs 4, 8 and 15  
• Proportion of subjects with ACF grade = 0 at POD8 maintained through POD15  
• Proportion of subjects with ACF grade = 0 at PODs 4, 8 and 15 
• Mean change from baseline in ACC grade at PODs 4, 8, and 15 
• Mean change-from baseline in Ocular Pain grade at PODs 4, 8 and 15 
• Mean change from baseline in ACF grade on PODs 4, 8 and 15  
• Number of subjects rescued on or prior to each visit and overall 
• Mean change from baseline in best corrected visual acuity (BCVA) by pinhole method 
using an ETDRS chart at PODs 4, 8 and 15 
 
The ACC count and Ocular Pain grade will be graded using the same grading scale described for 
primary efficacy endpoints (Section 10.1.1).  
The ACF will be graded as follow: 
Grade 
Description 
0 
None 
1 
Faint 
2 
Moderate (iris and lens details clear) 
3 
Marked (iris and lens details hazy) 
4 
Intense (fibrin or plastic aqueous) 
 


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Subjects who meet the rescue criteria may be rescued and placed on an appropriate alternative 
therapy as determined by the Investigator. The rescue criteria are provided in the protocol 
Section 9.4.  
The ETDRS visual acuity (logMAR score) will be calculated as follows using Original EDTRS 
Chart 1 and Chart 2: 
1. Determine the last row where the subject can correctly identify at least one (1) letter in 
that row. This is the base logMAR line. 
2. Determine the log score for the base logMAR line. 
3. Add 0.02 (T = 0.02) log units for every letter that is incorrectly identified up to and 
including the base logMAR line. 
10.2.2 
Analysis of Secondary Efficacy Endpoints 
10.2.2.1 
Analysis of Categorical Endpoints of ACC, Ocular Pain and ACF 
The secondary efficacy endpoints (categorical endpoints) of ACC grade, Ocular Pain grade and 
ACF grade will be analyzed and summarized in the same manner as described for the primary 
efficacy endpoints (Section 10.1.2). The imputation for missing values for the categorical 
endpoints is described in Section 6.4.3.1. The proportion of subjects with ACC grade = 0, Ocular 
Pain grade = 0, and ACF grade = 0 at PODs 4, 8, and 15 will be plotted separately for each of 
these endpoints.  
In addition, the ACC grade, Ocular Pain grade and ACF grade will be tabulated, including the 
number and percentage of subjects in each grade category, using the observed data only. 
10.2.2.2 
Analysis of Continuous Endpoints of ACC, Ocular Pain, ACF and BCVA  
Mean change from baseline in ACC grade, Ocular Pain grade, ACF grade and BCVA at PODs 4, 
8 and 15 will be analyzed using an analysis of covariance (ANCOVA). The ANCOVA model 
will include treatment as a fixed effect and baseline as a covariate. The imputation for missing 
values for the continuous endpoints is described in Section 6.4.3.1.  
The values of the endpoints and change from baseline at PODs 4, 8 and 15 will be summarized 
by treatment group using descriptive statistics, including 95% CI for the mean of the change-
from-baseline. The adjusted mean of the change from baseline and the treatment difference of 
adjusted means with associated 95% CI from ANCOVA will be presented. The mean change 
from baseline with 95% CI at PODs 4, 8 and 15 will be plotted. 
In addition, the ACC grade, Ocular Pain grade, ACF grade and BCVA, and change from baseline 
will be summarized descriptively using the observed data only. 
10.2.2.3 
Analysis of Endpoint of Rescue Medication Use 
The overall number of subjects rescued during the treatment period will be compared between 
treatment groups using the Pearson Chi-square test. “Rescued during treatment period” is defined 
as use of rescue medications during the 14-day study drug treatment period. When the treatment 


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duration of study drug is < 14 days, use of rescue medications will be excluded from the analysis 
when rescue medications are started > 2 day after the last dose of study drug.  
In addition, the cumulative number of subjects rescued at PODs 4, 8, and 15 will be summarized 
by treatment group and compared between treatment groups using the Pearson Chi-square test at 
each Analysis Visit.  In addition, the number and percentage of subjects rescued in each category 
of criteria for rescue will be presented for the overall study and at PODs 4, 8, and 15. If multiple 
rescue medications are used by a subject, only the first time a rescue medication is used will be 
included in the analysis and summary.  
11. SAFETY ANALYSES 
The extent of exposure and all safety endpoints will be summarized using the Safety population. 
For all safety endpoints, the observed data and scheduled visits will be used for summary 
statistics. No imputation of missing data will be employed. 
11.1 Extent of Exposure 
Exposure to study drug will be summarized by duration (days) on study drug (the number of 
days between the first dose date and last dose date of study drug) and total number of doses that 
are instilled correctly in the study eye using descriptive statistics.  In addition, the duration on 
study drug will be categorized as 1– 4 days, 5 – 8 days, and 9 – 13 days, and ≥ 14 days, and the 
number and percentage of subjects in each category will be presented. The number of doses 
received per subject will also be categorized as < 8 doses, 8 – < 16 doses, 16 – < 28 doses, = 28 
doses, and >28 doses, and the number and percentage of subjects in each category will be 
presented by treatment group. 
If the date of last dose is missing, the date of the last scheduled or unscheduled visit will be used 
as the date of last dose to calculate the treatment duration. 
11.2 Adverse Events 
Non-serious AEs occurring from the start of study drug administration until EOS will be reported 
in the eCRF. Serious AEs (SAEs) occurring after signing the informed consent form until EOS 
will be reported in the eCRF. All AEs will be coded using MedDRA version 23.1 - September 
2020, and classified by SOC and preferred term.  
All AEs occurring from the start of study drug administration through the last day of 
participation in the study (EOS) are considered as TEAEs.   
An overall TEAE summary by treatment group will be presented by the number of events and 
the number and percentage of subjects experiencing one or more events, including all TEAEs, 
treatment-related TEAEs, treatment-emergent SAEs, severe TEAEs, TEAEs leading to 
discontinuation, and death.  
The number and percent of subjects reporting one or more TEAEs and the number of TEAEs 
will be tabulated by SOC, preferred term, and treatment group for all TEAEs.  Results will be 
displayed in order of decreasing frequency based on the occurrence rate in the APP13007 group, 


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both across SOC and within each SOC term. Summaries of all ocular TEAEs, ocular TEAEs in 
the study eye, ocular TEAEs in the non-study eye, all non-ocular TEAEs, TEAEs related to study 
drug, ocular TEAEs related to study drug in the study eye, non-ocular TEAEs related to study 
drug, treatment-emergent SAEs, SAEs related to study drug and TEAEs leading to study 
discontinuation will also be presented in the same manner.  The number and percent of subjects 
reporting one or more TEAEs will also be summarized by maximum severity for all TEAEs, 
ocular TEAEs in the study eye and non-ocular TEAEs. 
The relationship of TEAEs will be determined by the relationship to study drug and/or to the 
ocular surgical procedure.  Ocular TEAEs related to both study drug and surgery or related to 
surgery only will be summarized separately. 
In addition, the incidence of TEAEs occurring in at least 5% of subjects in any treatment group 
and incidence of non-serious TEAEs above the threshold of 5% of subjects in any treatment 
group (for data transparency reporting) will be presented. 
For summaries by severity of TEAEs, the most severe occurrence for a particular preferred term 
will be used for a given subject. AEs with missing severity will be considered as ‘Severe’ events 
for summary purposes, but will be presented as missing in the AE listings.  
A TEAE related to study drug is defined as a TEAE with a “Possible”, “Probable” and 
“Definite” relationship to study drug as defined in protocol Section 8.3.2. These three 
relationships will be classified as “Related”.  For summaries of TEAEs related to study drug, the 
most related occurrence for a particular preferred term will be used for a given subject. AEs with 
missing relationship to study drug or surgery will be considered as “Related” for summary 
purposes, but will be presented as missing in the AE listings. 
All AEs will be listed in a data listing. All SAEs (including SAEs for all subjects who sign the 
informed consent), AEs leading to study discontinuation, and deaths will be listed separately. 
A serious and unexpected suspected adverse reaction (SUSAR) is defined in the protocol Section 
8.2. The SUSARs will be summarized and listed. 
11.3 Other Safety Endpoints 
The ophthalmic assessments for safety include IOP measurement using Goldmann applanation 
tonometry, ETDRS assessment of best corrected visual acuity by the Pinhole method, Slit Lamp 
biomicroscopy assessment of the relevant signs of inflammation, and dilated indirect 
ophthalmoscopy assessment.  
11.3.1 
Intraocular Pressure 
IOP assessments will be performed from Screening through EOS for the study eye. IOP 
assessments will be performed at Screening and EOS for the non-study eye.  
For the study eye, the IOP data and change from baseline (POD1 pre-dose) at each post-surgery 
scheduled visit through EOS will be summarized by treatment group using descriptive statistics, 
including 95% CI for the mean of change from baseline. The IOP change from Screening to each 


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scheduled post-surgery visit through EOS for the study eye will be summarized to evaluate any 
potential impact from IOP lowering medication use on the surgery day (Day 0). A box and 
whisker plot will be presented for the IOP change from baseline through EOS and for the IOP 
change from Screening through EOS for the study eye. The IOP change from POD15 to POD22 
for non-rescued subjects who complete the study will be summarized for the study eye. 
The IOP increase from baseline and increase from Screening will be categorized as ≤0, 1-5, 6-10, 
>10 (mmHg). The number and percentage of subjects in each category will be tabulated at each 
post-surgery visit for the study eye. In addition, subjects with an IOP ≥ 21 mmHg and an 
increase > 10 mmHg from baseline, and subjects with an IOP > 30 mmHg at any time following 
initiation of study drug will be summarized and listed for the study eye.  
The IOP data collected after taking rescue medication will be excluded from the summary tables 
and plots for the study eye. 
The IOP data at Screening and EOS, and change from Screening to EOS for the non-study eye 
will be summarized using descriptive statistics.  
All IOP data, including data collected after taking rescue medication, will be presented in a data 
listing. 
11.3.2 
Best Corrected Visual Acuity 
Since the BCVA endpoint will also be assessed for efficacy, this endpoint has been descripted in 
the Section 10.2.1. The assessments for the study eye will be performed from Screening through 
EOS for safety evaluation. The assessment for the non-study eye will be performed at Screening 
and EOS. 
The BCVA LogMAR scores and change from baseline (POD1 pre-dose) will be summarized 
descriptively by treatment group at each post-surgery scheduled visit through EOS for the study 
eye. The BCVA base LogMAR scores change from baseline will be classified as ≤ 0, 0 < – < 0.2 
and ≥ 0.2, which are equivalent to ≤ 0 line (visual acuity improved), 0 < – < 2 lines, and ≥ 2 lines 
(visual acuity worsened).  The number and percentage of subjects in each category will tabulated 
at each post-surgery scheduled visit for the study eye.  
The BCVA scores collected after taking rescue medication will be excluded from the summary 
tables for the study eye.  
The BCVA LogMAR scores at Screening and EOS, and change from Screening to EOS for the 
non-study eye will be summarized using descriptive statistics.  
All BCVA data, including data collected after taking rescue medication, will be presented in a 
listing. 
11.3.3 
Slit Lamp Biomicroscopy 
Slit Lamp biomicroscopy assessments will evaluate corneal edema, ciliary flush, bulbar 
conjunctival injection. The assessments for the study eye will be performed from Screening 


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through EOS. The assessments for the non-study eye will be performed at Screening and EOS. 
The following grades will be used for the assessments.   
Grade 
Description 
0 
Absent 
1 
Mild 
2 
Moderate 
3 
Severe 
 
The number and percentage of subjects in each grade category of the assessments will be 
tabulated by treatment group at each post-surgery scheduled visit through EOS for the study eye. 
A shift table of assessment grades from Screening to EOS for both eyes will be presented by 
treatment group.  
In addition, the non-study eye lens status (phakic, non-phakic or pseudophakic) will be assessed 
at Screening. The number and percentage of subjects in each status category will be tabulated. 
The data of the biomicroscopy assessments for safety evaluation will be presented in a data 
listing. 
11.3.4 
Dilated Indirect Ophthalmoscopy 
A dilated indirect ophthalmoscopic examination will be performed at Screening and EOS for 
both eyes to evaluate the vitreous, retina, macula, choroid, and optic nerve with cup/disc ratio 
and will note normal/abnormal findings. 
A shift table from Screening to EOS for each ophthalmoscopic parameter, except for the cup/disc 
ratio, will be presented by treatment group for both eyes. The cup/disc ratio and change from 
Screening to EOS will be summarized descriptively for both eyes. 
For the non-study eye only, when the non-study eye is reported as ‘Phakic’ at the Screening 
Visit, the lens will be assessed for the presence or absence of a cataract. If a cataract is present, it 
will be classified as Nuclear, Cortical, or Posterior Subcapsular and graded using the guidance 
provided in the protocol Appendix B. A shift table of the cataract grade from Screening to EOS 
for each cataract location will be presented by treatment group. 
The data of the dilated indirect ophthalmoscopic examinations will be presented in a data listing. 
12. INTERIM ANALYSIS 
No interim analyses are planned for this study. 
13. REFERENCES 
None.