Clinical trial NCT04324359
Conditions: Post-surgical Ocular Inflammation Post-surgical Ocular Pain
Sponsor: Surface Ophthalmics, Inc.
Start date: 2020-03-03; Completion date: 2020-11-20
Enrollment: 91 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
SURF-201 is being studied for the treatment of eye inflammation and pain in people who are undergoing cataract surgery. SURF-201 is an investigational drug (which means the study drug is currently being tested) in the form of a sterile eye drop.

The purpose of this research study is to see how well SURF-201 works and what side effects there are, and to compare it with Vehicle (placebo). This study will involve about 80 study participants at several different research sites in the United States.

Detailed description:

Arms: arm 1: 0.2% topical preservative-free corticosteroid solution (0.2% betamethasone sodium phosphate) arm 2: Topical preservative-free vehicle (Placebo)
Interventions: intervention 1: SURF-201 intervention 2: Placebo
Intervention descriptions: intervention 1: One drop twice daily (BID) in the study eye for 16 days. intervention 2: One drop twice daily (BID) in the study eye for 16 days.

Protocol documents:
Prot_SAP_000.pdf: 
 
NCT04324359 
 
 
Sponsor:  Surface Ophthalmics Inc. 
 
 
09 October 2020 
 
 
Study Number C-201-001 
Phase 2 Clinical Study Protocol, Amendment 02 including Statistical Analysis Plan 
 
 
A Multicenter, Randomized, Double-masked Study To Compare the Ocular Safety, 
Tolerability, and Efficacy of SURF-201 Ophthalmic Solution (0.2% Betamethasone Sodium 
Phosphate) to Vehicle in Cataract Surgery Subjects 
 
 
Original Protocol: 
Protocol Amendment 01 Date: 
Protocol Amendment 02 Date: 
30Sep2019 
15Jan2020 
09 Oct 2020 
 
 
 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
2 
 
 
TABLE OF CONTENTS 
 
LIST OF ABBREVIATIONS ................................................................................................................. 3 
1. 
STUDY OBJECTIVE ................................................................................................................. 4 
2. 
STUDY DESIGN ........................................................................................................................ 4 
3. 
STUDY CONDUCT ................................................................................................................... 5 
4. 
STUDY POPULATION ............................................................................................................. 5 
4.1. 
Inclusion Criteria ....................................................................................................................... 5 
4.2. 
Exclusion Criteria ...................................................................................................................... 6 
5. 
STUDY DRUG/INSTRUCTIONS FOR USE AND ADMINISTRATION ........................... 8 
6. 
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS ......................................... 9 
7. 
CONCOMITANT MEDICATIONS....................................................................................... 10 
8. 
CLINICAL ASSESSMENTS/EXAMINATION PROCEDURES ....................................... 11 
9. 
ADVERSE EVENTS ................................................................................................................ 12 
10. 
STATISTICAL ANALYSES ................................................................................................... 13 
10.1. 
Randomization, Stratification, and Masking ......................................................................... 13 
10.2. 
Efficacy and Safety Variables ................................................................................................. 14 
10.3. 
Analysis Populations ................................................................................................................ 14 
10.4. 
Data Handling: Handling of Missing Data ............................................................................. 15 
10.5. 
Statistical Methods: General Principles ................................................................................. 15 
10.6. 
Efficacy ...................................................................................................................................... 16 
10.6.1. Primary Efficacy Analysis ....................................................................................................... 16 
10.6.2. Secondary Efficacy Analysis.................................................................................................... 16 
10.7. 
Safety ......................................................................................................................................... 16 
10.7.1. Adverse Events ......................................................................................................................... 16 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
3 
 
 
LIST OF ABBREVIATIONS 
 
Abbreviation or Acronym  
Definition 
ACC 
anterior chamber cell  
AE 
adverse event 
BCVA 
best-corrected visual acuity 
BID 
twice daily 
CI 
Confidence interval 
COVID-19 
Coronavirus Disease 2019 
CRO 
contract research organization 
CSCR 
central serous chorioretinopathy 
eCRF 
electronic case report form 
e.g. 
exempli gratia; for example 
etc. 
et cetera 
ETDRS 
early treatment diabetic retinopathy study 
FDA 
United States Food and Drug Administration 
GCP 
Good Clinical Practice 
ICF 
informed consent form 
i.e. 
id est; in other words 
IOL 
intraocular lens 
IOP 
intraocular pressure 
IRB 
institutional review board 
ITT 
intent to treat 
IUD 
intrauterine device 
LASIK 
laser-assisted in situ keratomileusis 
LOCF 
last observation carried forward 
logMAR 
log of the minimum angle of resolution 
MedDRA® 
Medical Dictionary for Regulatory Activities 
mm 
millimeter 
mmHg 
millimeters of mercury 
NDA 
new drug application 
No. 
number 
NSAID 
nonsteroidal anti-inflammatory drug 
PP 
per protocol 
PT 
preferred term 
SAE 
serious adverse event 
SOC 
system organ class 
SOP 
standard operating procedure 
TLF 
tables, listings, and figures 
VA 
visual acuity 
VAS 
visual analog scale 
 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
4 
 
 
1. STUDY OBJECTIVE 
 
To evaluate the ocular safety, tolerability, and efficacy of topical administration of SURF-201 
(0.2% betamethasone sodium phosphate [BSP] ophthalmic solution) compared with vehicle 
when dosed twice daily (BID) for 1 day prior to cataract surgery, the day of cataract surgery, and 
14 days post cataract surgery. 
 
2. STUDY DESIGN 
 
This study is a Phase 2, multicenter, randomized, double-masked, vehicle-controlled, parallel-
group clinical trial. The investigator and his/her staff will not know which study medication the 
subject is receiving but will be able to determine this in the event of an emergency. 
 
Prior to enrollment, the study will be discussed with prospective subjects and those wishing to 
enter will be asked to give written informed consent. Informed consent will be obtained prior to 
any study related procedures being performed. Once informed consent has been obtained, the 
subjects will be questioned regarding their medical history to determine whether or not they are 
in satisfactory health to enter the study and to determine if they meet the specific entry criteria. 
 
During the screening phase (Day -2 to Day -14) of the study, subjects who meet all inclusion and 
none of the exclusion criteria will be randomized in a 1:1 ratio: 40 subjects in the 0.2% BSP 
group and 40 subjects in the vehicle group.  
 
During the dosing phase (Day -1 to Day 14), subjects will dose BID for 16 days: the day before 
cataract surgery, the day of cataract surgery, and for 14 days after cataract surgery. Subjects will 
then be followed for approximately 2 weeks during the evaluation phase (Day 15 to Day 32).  
 
There will be 7 study visits for full study participation: 1 visit during the screening phase, 3 visits 
(Day 0, Day 1 and Day 8) during the dosing phase, and 3 visits (Day 15, Day 22, and Day 32) 
during the evaluation phase. 
 
Subjects will instill 3 doses of study drug prior to surgery (2 doses on Day -1, and 1 dose on Day 
0 prior to surgery), 1 dose in the evening after surgery and continue dosing BID for 14 days after 
surgery.  
 
Subject safety will be evaluated throughout the study. The safety parameters to be assessed are 
the incidence of adverse events (AEs) and serious adverse events (SAEs), discontinuations due to 
AEs, changes in visual acuity (VA) and intraocular pressure (IOP), and biomicroscopic and 
ophthalmoscopic findings.  
 
Efficacy will be assessed by biomicroscopic measurement of anterior chamber cells (ACCs) and 
measurement of the subject’s pain level at each visit using a visual analog scale (VAS). Subject 
pain will also be assessed by subjects at home using a subject diary.  
 
All ratings and procedures should be performed by the same examiner from visit to visit whenever 
possible.  


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
5 
 
 
 
Additional exams may be scheduled as necessary to ensure the safety of the subjects during the 
study period. 
 
3. STUDY CONDUCT 
 
Initiation of this study requires acceptance and approval by a qualified, properly constituted 
Institutional Review Board (IRB). Approval of the study by the governing IRB will be secured 
prior to the initiation of the study at each site and a copy of the approval provided to the study 
Sponsor or designee. The IRB must function in compliance with 21 CFR, Part 56 of the US Food 
and Drug Administration's (FDA) Code of Federal Regulations (CFR). 
 
This study will be conducted in compliance with the protocol approved by the IRB, and according 
to Good Clinical Practice (GCP) standards. No deviation from the protocol will be implemented 
without the prior review and approval of the IRB except where it may be necessary to eliminate 
an immediate hazard to a research subject. In such cases, the deviation will be reported, in writing, 
to the IRB and the Sponsor or designee as soon as possible. 
 
4. STUDY POPULATION 
 
Approximately 80 subjects, 18 years of age and older, who are scheduled to undergo 
uncomplicated unilateral cataract surgery (phacoemulsification or extracapsular extraction; 
surgery must not be performed with the aid of a femto [femtosecond] laser) and who meet all 
study entry criteria will participate in the study.  
 
4.1.Inclusion Criteria 
 
The following are inclusion criteria for prospective study subjects to be confirmed at Visit 1 
(Day -14 – Day -2) prior to randomization.  
 
1. Adult subjects, age 18 years or older, scheduled for uncomplicated unilateral cataract surgery 
(phacoemulsification or extracapsular extraction; surgery must not be performed with the aid 
of a femto [femtosecond] laser) with posterior chamber intraocular lens implantation. 
 
2. Subjects must be able to understand and sign the Informed Consent Form (ICF). 
 
3. Female subjects of childbearing potential must agree to and submit a negative urine 
pregnancy test before any study-specific procedures are performed. The subjects must be 
using and continue to use a suitable method of contraception for the duration of the study: 
spermicide with barrier, oral contraceptive, transdermal contraceptive, injectable or 
implantable contraceptive, intrauterine device (IUD), abstinence or surgical sterilization of a 
partner. If a subject is not of childbearing potential (e.g., has been postmenopausal for at least 
12 months or is premenarchal, or has undergone a hysterectomy, bilateral oophorectomy or a 
bilateral tubal ligation), a urine pregnancy test and use of a suitable method of contraception 
for the duration of the study will not be required. 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
6 
 
 
4. Subjects must have a best-corrected visual acuity (BCVA) of at least +1.0 log of the 
minimum angle of resolution (logMAR) (Snellen equivalent of 20/200) in the non-study eye 
(fellow eye). 
 
5. Subjects must have an intraocular pressure (IOP) of >8 mmHg and ≤22 mmHg in the study 
eye (surgery eye). 
 
6. Subject must agree to maintain their current dosing regimen throughout the study period 
(from Screening through Day 32) if they are currently using topical cyclosporin-A or Xiidra 
(lifitegrast 5%). 
 
7. Subjects must be willing and able to attend all study visits and follow all instructions. 
 
8. Subjects must be able to self-instill the study drug (if unable, a caregiver must be available to 
instill all doses of the study drug). 
 
9. Subjects must agree to avoid any medications which are disallowed (as defined by the 
protocol). 
 
4.2. 
Exclusion Criteria 
 
The following are exclusion criteria for prospective study subjects to be confirmed from  
Day -14 – Day -2 (at Visit 1) prior to randomization: 
 
1. Subject has any intraocular inflammation (cells and flare in the anterior chamber) or ocular 
pain (pain score of >0) in either eye prior to surgery. 
 
2. Subject has any extraocular inflammation in the study eye prior to surgery (blepharitis is 
allowed if only scurf is present without any concurrent conjunctivitis or lid erythema/edema) 
or ongoing uveitis. 
 
3. Subject has a history of diabetic retinopathy and/or previous vitrectomy in the study eye 
within the last 2 years prior to Screening which, in the investigator’s opinion, is clinically 
significant and could impact the normal outcome of an uncomplicated cataract surgery. 
 
4. Subject has a diagnosis of severe dry eye in the study eye. 
 
5. Subject has any sign of iritis or scleritis in the study eye. 
 
6. Subject has a history of glaucoma surgery in the study eye within the last 2 years prior to 
Screening. 
 
7. Subject has a history of retinal surgery in the study eye within the last 2 years or plans to 
undergo retinal surgery in the study eye during the study period (from Screening through  
Day 32)  
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
7 
 
 
8. Subject has a history of Fuchs’ dystrophy in the study eye. 
 
9. Subject has guttata or chalazion in the study eye. 
 
10. Subject has undergone radial keratotomy, photorefractive keratotomy, advanced surface 
ablation, corneal transplant, or LASIK in the study eye within the last 2 years prior to 
Screening. 
 
11. Subject plans to undergo cataract surgery in the non-study (fellow) eye during the study 
period (from Screening through Day 32). 
 
12. Subject plans to undergo additional ocular surgery (including femtosecond laser-assisted 
cataract surgery, minimally invasive glaucoma surgery, astigmatic keratotomy, limbal 
relaxing incision surgery, mechanical pupillary expanders, conjunctival incisions, and 
vitrectomy) in either eye during the study period (from Screening through Day 32).  
 
13. Subject has a history of intraocular injections in the study eye within 6 months prior to 
Screening.  
 
14. Subject has a history of herpes simplex infection in either eye.  
 
15. Subject has active corneal, conjunctival or canalicular pathology (including ocular infection 
[bacterial, viral or fungal]) in the study eye. Specifically, active viral diseases of the cornea 
and conjunctiva including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, 
and varicella, and also in mycobacterial infection of the eye and fungal diseases of the ocular 
structures (such as fungal keratitis). 
 
16. Subject has thinning of the cornea or sclera. 
 
17. Subject plans to undergo uncomplicated unilateral cataract surgery with the aid of anterior 
capsular staining products (e.g., Trypan blue) or with the aid of a femto (femtosecond) laser. 
 
18. Subject has undergone anti-neoplastic therapy within the last 2 years prior to Screening or 
plans to undergo anti-neoplastic therapy during the study period. 
 
19. Subject has a history of use of medications to treat benign prostatic hyperplasia that, in the 
opinion of the investigator, limits adequate dilation of the pupil to safely perform 
uncomplicated cataract removal and IOL implantation.   
 
20. Subject has a history of liver disease within the last 5 years prior to Screening. 
 
21. Subject has a history of previous ocular trauma in the study eye that places the study eye at 
risk of increased post-surgical complications or inflammation.  
 
22. Subject has or had a known blood dyscrasia or bone marrow suppression. 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
8 
 
 
23. Subject has an active or chronic/recurrent ocular or systemic disease that is not controlled 
and may have an impact on would healing (e.g., diabetes mellitus, systemic connective tissue 
disease, severe atopic disease). 
 
24. Subject is suffering from alcohol and/or drug abuse. 
 
25. Subject has a known hypersensitivity or poor tolerance to betamethasone and/or 
betamethasone sodium phosphate or any component of the study drug or any of the 
procedural medications such as anesthetic and/or fluorescein drops, dilating drops, etc. 
 
26. Female subjects who are currently pregnant or nursing or are planning to become pregnant 
during the study or have a positive pregnancy test. 
 
27. Subject has previously participated in this study protocol. 
 
28. Subject used (within 30 days of initiation of study treatment) or is anticipating concurrent use 
of an investigational drug or device. 
 
29. Subject has a condition or a situation which, in the investigator’s opinion, might put the 
subject at increased risk, confound the study data or interfere significantly with the subject’s 
study participation. 
 
30. Subject would be wearing contact lens in either eye during the dosing period of Day -1 to 
Day 14. 
 
31. Subject is taking a medication that the investigator feels might interfere with the study 
parameters. 
 
32. Subject tests positive for the COVID-19 virus prior to Visit 1 (Day -14 to Day -2). 
 
5. 
STUDY DRUG/INSTRUCTIONS FOR USE AND ADMINISTRATION 
 
The study drug will be masked, packaged and labeled in a manner consistent with the study design. 
The Sponsor or designee shall provide the packaging of the study drug and the labeling of subject 
numbers according to a validated SAS® computer-generated randomization list. The study drug 
will be identified as a new drug, limited by Federal law to investigational use, manufactured and 
packaged for Surface Pharmaceuticals.  
 
Subjects will be randomly assigned to receive masked study drug (either 0.2% BSP ophthalmic 
solution or vehicle) for 16 days BID. Subjects will receive instructions for dosing at home and for 
completing a dosing and pain assessment diary during the study dosing phase (Day -1 to Day 14).  
 
During the 16-day dosing period, a total of 32 doses (2 doses each day, once in the morning and 
once in the evening, preferably 8-12 hours apart) will be instilled in the study eye by the subject 
(or their caregiver). 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
9 
 
 
6. 
CONTRAINDICATIONS, WARNINGS AND PRECAUTIONS 
 
Contraindications: Betamethasone sodium phosphate (BSP), as with other ophthalmic 
corticosteroids, is contraindicated in most active viral diseases of the cornea and conjunctiva 
including epithelial herpes simplex keratitis (dendritic keratitis), vaccinia, and varicella, and also 
in mycobacterial infection of the eye and fungal diseases of ocular structures. 
 
Warnings and Precautions: Ocular adverse reactions which may occur with SURF-201 based on 
marketed ophthalmic corticosteroids include the following: 
• Prolonged intensive use of corticosteroids may result in intraocular pressure (IOP) increase, 
glaucoma with damage to the optic nerve, posterior subcapsular cataracts, thinning of the globe 
and eventual perforation, secondary ocular infection, reduced visual acuity and visual field 
defects, mydriasis, ptosis, epithelial punctate keratitis, and corneal calcification may occur.  
• Delayed healing - The use of steroids 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 steroids.  
• Bacterial infections - Prolonged use of corticosteroids may suppress the host response and thus 
increase the hazard of secondary ocular infections. In acute purulent conditions, steroids may 
mask infection or enhance existing infection. 
• Viral infections - Use of ocular steroids may prolong the course and may exacerbate the 
severity of many viral infections of the eye (including herpes simplex).  
• Fungal infections - Fungal infections of the cornea are particularly prone to develop 
coincidentally with long-term local steroid application. Fungus invasion must be considered in 
any persistent corneal ulceration where a steroid has been used or is in use. Fungal culture 
should be taken when appropriate. 
 
Special Warnings and Precautions for Use: 
• Topical corticosteroids should never be given for an undiagnosed red eye as inappropriate use 
is potentially blinding. 
• Persistent visual disturbance may be reported with systemic and topical corticosteroid use. 
Persistent symptoms such as blurred vision or other visual disturbances should be evaluated 
for possible causes which may include cataract, glaucoma or rare diseases such as central 
serous chorioretinopathy (CSCR) which have been reported after use of systemic and topical 
corticosteroids. 
 
Undesirable Effects:  
• Hypersensitivity reactions usually of the delayed type, leading to irritation, burning, stinging, 
itching and dermatitis. 
• Corneal calcification has been reported very rarely in association with the use of phosphate-
containing eye drops in some patients with significantly damaged corneas. 
 
Overdose: Long term intensive topical use may lead to ocular corticosteroid specific class effects. 
Oral ingestion of the contents of a single-dose container of SURF-201 is unlikely to lead to any 
serious adverse effects. 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
10 
 
 
 
Drug-Drug Interactions: No topical ophthalmic drug-drug interactions are known for SURF-201. 
Corticosteroids (including betamethasone) are metabolized by CYP3A4.  Ketoconazole has been 
reported to decrease the metabolism of certain corticosteroids by up to 60%, leading to an increased 
risk of corticosteroid side effects.  Coadministration with other strong CYP3A4 inhibitors (e.g. 
itraconazole, clarithromycin, ritonavir, cobicistat-containing products) may lead to increased 
exposures of corticosteroids and therefore the potential for increased risk of systemic 
corticosteroid side effects.  (Celestone Soluspan PI, 2018). 
 
Effects on Ability to Drive and Use Machines: SURF-201 may cause transient blurring of vision 
on instillation into the eye. Patients should be warned not to drive or operate hazardous 
machinery unless vision is clear. 
 
7. 
CONCOMITANT MEDICATIONS 
 
Disallowed medications include:  
• Any corticosteroid at least 15 days before surgery and throughout the duration of the study; 
• Depot-corticosteroids in either eye at least 45 days before surgery and throughout the 
duration of the study;  
• Administration of any nonsteroidal anti-inflammatory drugs (NSAIDs) including but not 
limited to topical, systemic (including sleep-aids containing NSAIDs), inhaled, or irrigation 
solution at least 1 week before surgery and throughout the duration of the study, with the 
exception of aspirin, where oral doses of 165 mg/day or lower are allowed;  
• Ocular or systemic antihistamines (including sleep-aids containing an antihistamine), or mast 
cell stabilizers in either eye at least 1 week before surgery and throughout the study’s dosing 
period;  
• Triamcinolone in either eye at least 90 days before surgery and throughout the study’s dosing 
period; 
• Medications used to treat benign prostatic hyperplasia throughout the duration of the study; 
• Inhaled, ingested, sublingual, transdermal or topical products containing marijuana, 
tetrahydrocannabinol (THC) or cannabidiol (CBD) at least 1 week before surgery and 
throughout the study’s dosing period and for one day after the study’s dosing period ends;  
• Systemic pain relievers, analgesics (e.g., pregabalin, gabapentin, opioids) 14 days before 
surgery and throughout the duration of the study; 
• Any supplement, prescribed medication or over-the-counter product that the investigator 
feels may interfere with the study parameters, including homeopathic remedies, analgesics, 
and pain medication.  
 
During the study dosing period (Day -1 through Day 14), if the investigator determines that a 
rescue medication is necessary due to lack of efficacy (whether at a planned study visit or at an 
unscheduled visit), the subject should be discontinued from the study drug and the appropriate 
rescue medication prescribed. The subject should continue to be seen for all remaining study visits 
to assess safety and efficacy.  This information must be recorded in the subject’s source record and 
on the appropriate eCRF.   
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
11 
 
 
8. 
CLINICAL ASSESSMENTS/EXAMINATION PROCEDURES 
 
The ophthalmic examinations listed below will be conducted in the surgery eye (study eye) and 
in the order specified. The fellow eye (non-study eye) may be examined at the investigators’ 
discretion.  
 
Subject Assessment of Pain via Diary: Surgery eye (study eye) pain will be evaluated prior to 
each study drug dose using a pain scale included in the dosing and pain assessment diary that 
subjects complete at home. 
 
Investigator Assessments include the following: 
 
Visual Analog Scale (VAS) (ocular symptoms): Eye pain/discomfort will be evaluated at 
Screening Visit 1 (Day -14 to Day -2) and at Visit 3 through Visit 7 (Day 1 through Day 32) 
using a VAS, scoring from 0 to 100 using a mark on a 100 mm line (0 = absent; 100 = 
maximum). 
 
Best-Corrected Visual Acuity (BCVA): BCVA will be measured at Screening Visit 1 (Day -14 to 
Day-2) and at Visit 3 through Visit 7 (Day 1 through Day 32) (log of the minimum angle of 
resolution [logMAR] score using ETDRS [Early Treatment Diabetic Retinopathy Study] chart 
will be used to measure BCVA). A pinhole test may be performed at Visit 3 (Day 1). 
 
Biomicroscopy: Slit lamp biomicroscopy, including the evaluation of anterior chamber cell 
(ACC) and anterior chamber flare, chemosis, bulbar conjunctival injection, ciliary injection, 
corneal edema, and keratic precipitates will be conducted by a board-certified ophthalmologist at 
Screening Visit 1 (Day -14 to Day -2) and at Visit 3 through Visit 7 (Day 1 through Day 32). 
 
Ophthalmoscopy: Ophthalmoscopy will be performed at Screening Visit 1 (Day -14 to Day-2) 
and Visit 5 (Day 15) by a board-certified ophthalmologist. Ophthalmoscopy will be performed at 
Visit 7/Early Discontinuation Visit only if not performed at Visit 5.  
 
Intraocular Pressure (IOP): IOP will be measured at Screening Visit 1 (Day -14 to Day-2) and at 
Visit 3 through Visit 7 (Day 1 through Day 32) in mmHg using a Goldmann applanation 
tonometer.  
 
Standard examinations for subjects undergoing cataract surgery will be conducted by the 
investigator or qualified designated staff. However, ophthalmoscopy and biomicroscopy 
examinations will be performed by the same board-certified ophthalmologist who performs a 
subject’s cataract surgery. All ratings and procedures should be performed by the same examiner 
from visit to visit whenever possible.  
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
12 
 
 
Adverse Events and Concomitant Medications: At each study visit, subjects will be queried for 
new adverse events and, if applicable, previously unresolved adverse events. Also, concomitant 
medications will be documented. 
 
Diary: At Visit 2 through Visit 5 (Day 0 through Day 15), subjects’ diaries will be reviewed and 
compliance with study drug dosing and completion of pain assessments will be evaluated. 
 
9. 
ADVERSE EVENTS 
 
Throughout the course of the study, the investigator must remain alert to possible adverse events 
or untoward findings. If adverse events occur, the first concern will be the safety of the subject. 
Appropriate medical intervention will be provided by the investigator. 
 
Adverse Event (AE) Definition: An AE is any untoward medical occurrence associated with the 
use of a study drug in a clinical investigation subject, whether or not considered related to the 
study drug. 
 
Adverse Event Reporting Period: The AE reporting period for this trial begins upon signing the 
ICF and ends at the completion of the subjects’ final study visit exam. All AEs reported by the 
subject during the course of the study, or elicited by questions from the investigator, or noted as 
a result of procedures carried out on the subject, during the AE-reporting period must be 
recorded by site staff in the source documents and on the AE eCRF, whether or not the event is 
considered related to the study drug. In addition, any known untoward event that occurs 
subsequent to the AE reporting period that the investigator assesses as related to the study drug 
should also be reported as an AE. 
 
Serious Adverse Event (SAE) Definition: A serious adverse event (SAE) or reaction is any 
untoward medical occurrence that at any dose: 
• Results in death 
• Is immediately life-threatening or immediately sight-threatening in the study eye (surgery eye)  
• Requires inpatient hospitalization or prolongation of existing hospitalization 
• Results in persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions 
• Is a congenital anomaly/birth defect 
• Is an important medical event that may jeopardize the subject or may require medical 
intervention to prevent one of the outcomes listed above 
 
SAE Reporting: SAEs must be immediately reported (within 24 hours of awareness of the event) 
to designated CRO and will be clearly documented in the source documents and on the 
appropriate AE eCRF and SAE Report Form. The investigator must also notify the IRB of any 
SAEs, according to the IRB’s guidelines. 
 
Pre-existing Conditions: In this trial, a pre-existing condition (i.e., a disorder present before the 
AE-reporting period started and noted on the Systemic and/or Ocular Medical History Forms) 
should not be reported as an AE unless the condition worsens or episodes increase in frequency 
or severity during the AE-reporting period.  


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
13 
 
 
 
BCVA: A worsening of 3 lines or more in log of the minimum angle of resolution (logMAR) 
score in the study eye from baseline or any prior visit should be captured in the source 
documents and on the appropriate case report form as an AE. 
 
IOP: An increase from baseline or any prior study visit of 10 millimeters of mercury (mmHg) in 
IOP in the study eye should be captured in the source documents and on the appropriate eCRF as 
an AE. An IOP of 30 mmHg or higher will be reported as an SAE. 
 
Biomicroscopy: Anterior chamber cell and flare, chemosis, bulbar conjunctival injection, ciliary 
injection, corneal edema, and keratic precipitates will be assessed in the study. Since the severity 
of these assessments will be recorded and carefully monitored during the study, worsenings do 
not need to be recorded as AEs unless the investigator judges it appropriate. Any treatment-
emergent findings (i.e., findings that were not present prior to treatment or a worsening relative 
to the pretreatment baseline) outside of these assessments should be recorded as an AE. 
 
Ophthalmoscopy: A new finding or a significant worsening (2 units or more) from baseline 
should be recorded as an AE. 
 
VAS: Pain/discomfort will be assessed in the study eye. Since the severity of these assessments 
will be recorded and carefully monitored during the study, worsenings do not need to be 
recorded as AEs unless the investigator judges it appropriate. 
 
AE Considerations: Additional exams may be scheduled as necessary to ensure the safety of the 
subjects during the study period. Subjects discontinued due to an AE should be seen for post-
study follow-up visits, as needed. Adverse events considered related to study drug that have not 
resolved or stabilized by the final study visit will be followed during post-study follow-up visits 
at the discretion of the investigator until the incident has resolved or stabilized and will be 
documented in the source documents and AE eCRF. Where appropriate, additional written 
reports and documentation will be provided. Adverse events considered not related to study drug 
that have not resolved or stabilized by the final study visit will be noted as ongoing in the eCRF, 
followed at the discretion of the investigator, and recorded in the source documents. 
 
Pregnancy: Although pregnancy is not considered an AE, any complication related to pregnancy 
would be considered an AE and recorded in the source documents and, if applicable, on the AE 
eCRF. If an SAE is associated with the pregnancy, the SAE should be reported on the SAE 
Report Form. 
 
10. STATISTICAL ANALYSES 
 
10.1. 
Randomization, Stratification, and Masking 
 
Eligible subjects will be randomly assigned to each of treatment groups in a 1:1 ratio according to 
a validated SAS® computer-generated central randomization schedule. The randomization 
schedule contains the coded treatment assignments for each randomization number. The 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
14 
 
 
randomization plan will be based on the study design, number of treatment groups and number of 
sites.  
 
The randomization is generated by an un-masked statistician who is not affiliated with the study. 
The randomization plan is shared with the Sponsor’s designee responsible for final clinical 
packaging and labeling to allow for proper packaging and labeling of the study drug supply. Access 
to the randomization code will be strictly controlled according to the Sponsor designee’s Standard 
Operating Procedures (SOPs).  
 
The randomization is not unmasked until the study is complete and the database is locked. The 
Sponsor will confirm in writing that there are no regulatory or quality issues which preclude the 
unmasking of the study. 
 
Unmasking of the randomization code prior to study completion due to a medical emergency will 
be managed in accordance with the Sponsor designee’s SOP. All unmasked cases will be fully 
documented. Otherwise, the study mask will remain intact. 
 
In this double-masked study, the investigator and his/her study staff, the subject (including 
caregiver, if applicable) and Sponsor/designee (other than as stated above) are masked to the 
identity of the study drug. 
 
10.2. 
Efficacy and Safety Variables 
 
Primary Efficacy Endpoint(s): The primary efficacy endpoint will be the proportion of subjects 
with ACC grade of 0 (cell count=0) at Day 15. Subjects with an ACC grade of >0 at Day 15 or 
who receive rescue medication prior to Day 15 will be treated as failures. Last-observation-
carried-forward (LOCF) will be used for the intent-to-treat (ITT) analysis.  
 
Secondary Efficacy Endpoint: The secondary efficacy endpoint is the proportion of subjects who 
achieve a pain score of 0 at each post-surgical VAS (0-100 millimeter [mm] scale) assessment 
(Days 1, 8, 15, 22 and 32).  
 
Safety Variables: AEs, BCVA, IOP, biomicroscopic and ophthalmoscopic findings. 
 
10.3. 
Analysis Populations 
 
Safety Population: The safety population includes all randomized subjects who receive at least 1 
dose of the study drug. Subjects in the safety population will be analyzed in the treatment group 
for the study drug they received. 
 
Intent-to-Treat Population: The Intent-to-Treat (ITT) population will include all randomized 
subjects who undergo routine uncomplicated unilateral cataract surgery. Subjects in the ITT 
population will be analyzed in the treatment group to which they were assigned by the 
randomization scheme, regardless of which study drug they receive. 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
15 
 
 
Per Protocol Population: The per-protocol (PP) population will include all subjects in the ITT 
population who have no major protocol deviations during the study.  
 
10.4. 
Data Handling: Handling of Missing Data 
 
The primary efficacy analysis for the ITT population will use the LOCF method to impute missing 
observations due to COVID-19 or otherwise [EMA. Guideline on Missing Data in Confirmatory 
Clinical Trials [Internet]. 2010. Available from: https://www.ema.europa.eu/en/missing-data-
confirmatory-clinical-trials].  
 
Partial dates and missing dates will not be imputed. Any classifications based on partial or missing 
dates will assume a “worse case” scenario. If a medication cannot be classified as either prior or 
concomitant due to missing or partial start and stop dates, it will be considered to be concomitant. 
If an AE cannot be classified as resolved prior to the end of the study period due to missing or 
partial stop dates, it will be assumed to be ongoing. 
 
10.5. 
Statistical Methods: General Principles 
 
All data processing, summarization and analyses will be performed using Sponsor designee’s SAS 
Environment / Version 9.4 (or later) of the SAS® statistical software package. The principles that 
will be applied to all tables, listings and figures (TLFs) unless otherwise stated are outlined in 
Table 1. 
 
Table 1: Principles for All TLFs 
 
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
16 
 
 
10.6. 
Efficacy 
 
10.6.1. Primary Efficacy Analysis 
 
The primary efficacy analysis will test for a difference in the proportion of subjects with ACC 
grade zero (0) in the SURF-201 active treatment group versus the vehicle group only at Day 15. 
An ACC grade of zero is considered to be a success, and an ACC grade >0 or the use of rescue 
medication prior to Day 15 is counted as a failure (as described in Section 3.1). Missing data will 
be imputed using LOCF in the ITT population only. 
 
The test will be the z-test for proportions and will be reported with associated z-based 95% 
confidence interval (CI). The null hypothesis is that the proportions are equal, and this will be a 
two-sided test at the alpha = 5% level. If the assumptions of the z-test are not satisfied, a Barnard’s 
exact test and exact 95% CIs will be presented. 
 
10.6.2. Secondary Efficacy Analysis 
 
The differences in the proportion of subjects who achieve a pain score of 0 on the VAS at each 
post-surgical assessment between SURF-201 and vehicle will be tested using a z-test for 
proportions with a 95% CI. The null hypothesis is that the proportions are equal, and this will be 
a two-sided test at the alpha = 5% level. If the assumptions of the z-test are not satisfied, a 
Barnard’s exact test and exact 95% CIs will be presented. 
 
10.7. 
Safety 
 
10.7.1. Adverse Events  
 
Adverse Events (AEs) will be summarized. To select events for summarization when there are 
multiple occurrences of an event for a subject, AEs will be sorted by severity and relationship to 
study drug (i.e., severity will be sorted as mild, moderate, and severe; relationship will be sorted 
as not related and related). 
 
Adverse Events (AEs) will be coded according to MedDRA version 23.0 Update. All data will be 
listed and summarized in the safety population. 
 
Treatment emergent AEs (TEAEs) will be defined as AEs that first occurred or worsened on or 
after the date of first dose of study drug. Treatment emergent SAEs (TESAEs) will be defined as 
SAEs that first occurred or worsened on or after the date of first dose of study drug.   
 
Adverse event (AE) summaries will be provided for the number of subjects experiencing at least 
one event overall and in each treatment group. This will be provided for all AEs, TEAEs, SAEs 
and TESAEs. All will be presented overall and divided into ocular and non-ocular AEs where 
ocular events are defined as those where an eye is indicated in the eCRF form. Percentages for the 
subject based summaries will be calculated based on the number of subjects in the safety 
population.  
 


Clinical Study Protocol 
Study No. C-201-001 Amendment 2, Redacted – Clinicaltrials.gov 
(including Statistical Analysis Plan) 
SURF-201 ophthalmic solution 
09 October 2020 
Surface Ophthalmics Inc. 
17 
 
 
Incidence of Adverse Events (AEs): The per subject incidence of TEAEs for each system organ 
class (SOC) and preferred term (PT) will be summarized. If a subject reports the same PT multiple 
times, then that subject will only be counted once for that PT. As with the PT, if a subject reports 
multiple TEAEs within the same system organ class, then the subject will only be counted once 
for that system organ class. Summaries will be further divided by ocular and non-ocular.   
 
Relationship of Adverse Events (AEs) to the Study Drug: An overall summary of AEs by 
relationship to the study drug will be presented separately for each treatment group. The 
relationships indicate the possibility that the study drug caused the event. The possible grades of 
relationships are “Not Related” and “Related”. If a subject reports multiple occurrences of the 
same AE, only the most strongly related occurrence would be presented for all subject level 
summaries. The per subject incidence of TEAEs related to study drug for each SOC, and PT for 
AEs related to study drug will be summarized.  
 
Severity of Adverse Events (AEs): An overall summary of AEs by severity will be presented 
separately for each treatment group. If a subject reports multiple occurrences of the same AE, only 
the most severe event will be presented for all subject level summaries. The order of severity will 
be “Mild,” “Moderate,” and “Severe”. The per subject incidence of severe TEAEs for each SOC, 
and PT will be summarized. Percentages will be calculated based on the number of subjects in the 
safety population.