Conditions: Presbyopia
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 18
Healthy volunteers: yes

Brief summary:
Safety and Efficacy Study of BRIMOCHOL™ vs. BRIMOCHOL™ F vs. Carbachol Monotherapy Topical Ophthalmic Solutions in Subjects with Emmetropic Phakic and Pseudophakic Presbyopia

Detailed description:
A 3-Dose, Multicenter, Randomized, Double-Masked, Crossover Phase 2 Safety and Efficacy Study of BRIMOCHOL™ Topical Ophthalmic Solution vs. BRIMOCHOL™ F Topical Ophthalmic Solution vs. Monotherapy with Carbachol Topical Ophthalmic Solution in Subjects with Emmetropic Phakic and Pseudophakic Presbyopia

Arms:
arm 1: A single drop in each eye at a visit. arm 2: A single drop in each eye at a visit. arm 3: A single drop in each eye at a visit.

Interventions: intervention 1: BRIMOCHOL™ intervention 2: BRIMOCHOL™ F intervention 3: Carbachol
Intervention descriptions: intervention 1: A single drop in each eye at a visit. intervention 2: A single drop in each eye at a visit. intervention 3: A single drop in each eye at a visit.

Protocol document:
Prot_002.pdf: 
Protocol VT-001 
 
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Page 1 of 98 
 
 
 
 
Clinical Study Protocol VT-001 
 
 
A 3-Dose, Multicenter, Randomized, Double-Masked, Crossover Phase 2 
Safety and Efficacy Study of BRIMOCHOL™ (Carbachol/Brimonidine 
Tartrate Fixed-Dose Combination) Topical Ophthalmic Solution vs. 
BRIMOCHOL™ F (Carbachol /Brimonidine Tartrate Fixed-Dose 
Combination) Topical Ophthalmic Solution vs. Monotherapy with Carbachol 
Topical Ophthalmic Solution in Subjects with Emmetropic Phakic and 
Pseudophakic Presbyopia 
 
Sponsor: 
Visus Therapeutics, Inc. 
500 Yale Ave. N. 
Seattle, WA 98109 
Medical Monitor: 
  
 
Development Phase: 
2 
IND number: 
150905 
Clinical Trial Compliance: 
This clinical trial will be conducted in accordance with 
standards of Good Clinical Practice, as defined by the 
International Council for Harmonisation (ICH) and all 
applicable federal and local regulations. 
Version and Date: 
Version 9.0/ 29 July 2021 
 
Confidential Information 
The confidential information in this document is provided to you as a Principal Investigator, potential Principal 
Investigator, or Consultant, for review by you, your staff, and applicable institutional review committees. This 
information will not be disclosed to others without written authorization from Visus Therapeutics, Inc. except 
to the extent necessary to obtain informed consent from those persons to whom the drug may be administered. 


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Signature Page 
 
Sponsor Signatory: 
 
Date 
 
 
07-29-21


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Principal Investigator Signature Page 
Protocol Title 
A 3-Dose, Multicenter, Randomized, Double-Masked, Crossover 
Phase 2 Safety and Efficacy Study of BRIMOCHOL™ 
(Carbachol/Brimonidine Tartrate Fixed-Dose Combination) 
Topical Ophthalmic Solution vs. BRIMOCHOL™ F (Carbachol 
/Brimonidine Tartrate Fixed-Dose Combination) Topical 
Ophthalmic Solution vs. Monotherapy with Carbachol Topical 
Ophthalmic Solution in Subjects with Emmetropic Phakic and 
Pseudophakic Presbyopia 
Protocol Number 
VT-001 
 
Version and Date 
Version 9.0/29 July 2021 
I, the undersigned, have read this protocol and agree to personally supervise conduct of this 
protocol in accordance with ethical principles as outlined in the ICH guidelines on GCP, any 
applicable laws and requirements (including Part 54: Financial Disclosure by Clinical 
Investigators) and any additional conditions mandated by a regulatory authority and/or 
Institutional Review Board (IRB). 
I acknowledge that I am responsible for the overall study conduct; I approve of and will comply 
with all conditions, instructions, and restrictions described in this protocol. I am aware that my 
adherence to the above protocol is mandatory and that any changes in the protocol or consent 
form, except those necessary to eliminate apparent immediate hazards to human subjects, must 
first be approved in writing by Visus Therapeutics, Inc. and the respective IRB. 
I also agree that all information provided to me by Visus Therapeutics, Inc., including this 
document, Investigator’s Brochure, case report form, and verbal and written information, will be 
kept strictly confidential and confined to the clinical personnel involved in conducting the study. 
It is recognized that this information may be related in confidence to the IRB. I also understand 
that reports of information about the study or its progress will not be provided to anyone not 
involved in the study other than to the Principal Investigator, or in confidence to the IRB or to 
the Food and Drug Administration (FDA) or other legally constituted authority. 
 
 
Principal Investigator Signature 
Date 
 
 
Printed Name 
Institution 
City, State 
 
 
 








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LIST OF ABBREVIATIONS 
AE 
Adverse event 
AUC 
Area under the curve 
AUC(0-last) 
Area under the plasma concentration-time curve from time 0 to time of last quantifiable 
concentration 
BAK 
Benzalkonium chloride 
BUCDVA 
Binocular uncorrected distance visual acuity 
BUCNVA 
Binocular uncorrected near visual acuity 
COVID-19 
Coronavirus Disease 2019 
Cmax 
Observed maximum plasma concentration 
CRA 
Clinical Research Associate 
CV 
Coefficient of variation 
D 
Diopters 
eCRF 
Electronic case report form 
EDC 
Electronic data capture 
EOS 
End of study 
ETDRS 
Early Treatment Diabetic Retinopathy Study 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
GeoCV 
Geometric coefficient of variation 
IB 
Investigator Brochure 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonisation 
IOL 
Intraocular lens 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
MUCDVA 
Monocular uncorrected distance visual acuity  
MUCNVA 
Monocular uncorrected near visual acuity  
NRS 
Numeric rating scale 
PD 
Pharmacodynamics 
PI 
Principal Investigator 
PK 
Pharmacokinetics 
PT 
Preferred term 
OD 
Oculus dexter (right eye) 
OD/OS 
Each eye separately 
OS 
Oculus sinister (left eye) 
OU 
Both eyes at the same time 
SAE 
Serious adverse event 
SAP 
Statistical analysis plan 
SD 
Standard deviation 
 


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SOC 
System organ class 
SOP 
Standard operating procedure 
SUSAR 
Suspected unexpected serious adverse reactions 
TEAE 
Treatment-emergent adverse event 
tmax 
Time of maximum plasma concentration 
 
 


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1 PROTOCOL SUMMARY AND SCHEDULE 
1.1 
Protocol Summary 
Protocol Number 
VT-001 
Title 
A 3-Dose, Multicenter, Randomized, Double-Masked, Crossover Phase 2 Safety 
and Efficacy Study of BRIMOCHOL™ (Carbachol/Brimonidine Tartrate Fixed-
Dose Combination) Topical Ophthalmic Solution vs. BRIMOCHOL™ F (Carbachol 
/Brimonidine Tartrate Fixed-Dose Combination) Topical Ophthalmic Solution vs. 
Monotherapy with Carbachol Topical Ophthalmic Solution in Subjects with 
Emmetropic Phakic and Pseudophakic Presbyopia 
Brief Title 
Safety and Efficacy Study of BRIMOCHOL™ vs. BRIMOCHOL™ F vs. Carbachol 
Monotherapy Topical Ophthalmic Solutions in Subjects with Emmetropic Phakic 
and Pseudophakic Presbyopia 
Sponsor 
Visus Therapeutics, Inc. 
Development Phase 
2 
Purpose and Rationale 
Presbyopia is an inevitable, age-related, gradual loss in the ability to focus at 
intermediate and near targets without spectacle or surgical correction due to a 
progressive loss of elasticity in the crystalline lens. The pharmacologic effects of 
clinical studies of BRIMOCHOL suggest the addition of an alpha-2 agonist to a 
cholinergic agent, could have additive direct and indirect effects on both the iris 
constrictor and dilator muscles leading to robust and durable miosis and 
improvement in near visual acuity over monotherapy alone. Prior clinical studies 
and more recent nonclinical studies conducted by Visus demonstrate that the fixed-
dose combination of BRIMOCHOL and BRIMOCHOL F both demonstrate a 
contribution of elements vs. the individual monotherapies formulated similarly not 
only on pupil size, but that iris/ciliary body carbachol area under the curve (AUC) 
concentrations are ~50% higher with BRIMOCHOL than carbachol alone. Ex vivo 
studies in bovine ciliary muscle suggest alpha-2 receptors inhibit the contraction of 
cholinergically innervated ciliary muscle that does not occur when the ciliary 
muscle is at rest. These findings support the rationale for combining an alpha-2 
agonist with a cholinergic agent to minimize the adverse events (AEs) of 
browache/headache, myopic shift, and intraocular pressure (IOP) changes 
associated with cholinergics alone, and indeed, clinical studies with BRIMOCHOL 
suggest this is the case. There are currently no Food and Drug Administration 
(FDA)-approved drug products to treat presbyopia. 
Study Objectives  
1. To compare the efficacy, pharmacodynamics (PD), safety, tolerability and 
perception of treatment of topically administered, BRIMOCHOL (carbachol 
2.75%/brimonidine tartrate 0.1% fixed-dose combination with benzalkonium 
chloride [BAK]) vs. BRIMOCHOL F (carbachol 2.75%/brimonidine tartrate 
0.1% fixed-dose combination BAK-free) vs. carbachol 2.75% monotherapy 
BAK-free Topical Ophthalmic Solutions administered 
 
once-daily dose in inducing miosis and improving near visual acuity among 
subjects with emmetropic phakic and pseudophakic presbyopia 
2. To characterize the systemic pharmacokinetic (PK) profile of fixed-dose 
combinations BRIMOCHOL and BRIMOCHOL F topical ophthalmic solutions 
in subjects with emmetropic phakic and pseudophakic presbyopia 
















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1.2 
Schedule of Visits and Procedures 
 


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2 BACKGROUND 
2.1 
Presbyopia 
Presbyopia is an inevitable, age-related, gradual loss in the ability to focus at intermediate and 
near targets without spectacle or surgical correction due to a progressive loss of elasticity in the 
crystalline lens. Symptoms of presbyopia include blurred vision, ocular discomfort/headache, 
fatigue/drowsiness from near work, increased working distance (arms too short), and need for 
brighter light for reading. In childhood, an amplitude of accommodation of 12 diopters (D) is 
typical (Benzoni 2012). Amplitude of accommodation declines linearly at a rate of about 0.3 D 
per year, falling below a threshold at which near vision is noticeably impaired by approximately 
40-45 years of age. An estimated 1.27 billion people have presbyopia globally, and this number 
is projected to increase to 1.78 billion people by 2050 (Frick 2015), including virtually all adults 
>50 years old.  
Therapeutic approaches to presbyopia cover a spectrum of nonsurgical to surgical techniques 
(Moarefi 2017). Non-invasive methods of correcting presbyopia (e.g., bifocal or multifocal 
progressive addition lenses) can be effective, but many patients are dissatisfied for cosmetic or 
other reasons and desire independence from spectacles. Various surgical techniques have been 
applied on the cornea, lens, or sclera (Gil-Cazorla 2016). However, surgery is invasive and 
difficult to reverse in the event of complications or patient dissatisfaction. Moreover, surgical 
corrections usually require that patients choose for one eye to be corrected for distance and one 
for near, or monovision. Many patients do not like this outcome as this leaves them without 
binocular vision or depth perception at distance and near (Goertz 2014, McDonnell 2003). There 
are currently no Food and Drug Administration (FDA)-approved drug products to treat 
presbyopia. 
2.2 
Investigational Products 
Visus Therapeutics, Inc. (Visus) is developing BRIMOCHOL (carbachol 2.75%/brimonidine 
tartrate 0.1% fixed-dose combination with BAK) and BRIMOCHOL F (carbachol 
2.75%/brimonidine tartrate 0.1% fixed-dose combination BAK-free) Topical Ophthalmic 
Solutions as novel fixed-dose combination eye drops for improvement in near visual acuity in 
emmetropic phakic and pseudophakic presbyopia.  
The active pharmaceutical ingredients carbachol and brimonidine tartrate are currently approved 
for topical ophthalmic use. Both carbachol and brimonidine tartrate have been used extensively 
in ophthalmic applications, and the approved products have been administered chronically at 
higher total daily doses than that in these combination products.   
Five Investigator-initiated trials of a pharmacy-compounded formulation of BRIMOCHOL 
containing up to 3.0% carbachol and 0.2% brimonidine tartrate were conducted in presbyopic 
subjects; the results of 4 of these studies were published (Abdelkader 2015, 2016, 2018, 2019). 
These studies evaluated pupillometry and near visual acuity: across a range of carbachol 
concentrations from 1.5% to 3.0%, the effects of BRIMOCHOL in older and younger presbyopes 
and in pseudophakes, the occurrence of tachyphylaxis over 3 months, and whether the fixed-dose 


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combination demonstrated contribution of elements, i.e., that the combination is more effective 
to the individual monotherapies). These studies were not conducted by Visus. 
In brief, the studies concluded that there was a dose-response to carbachol concentration with the 
3% carbachol given the greatest peak and duration of effect on pupil size and near visual acuity 
(Abdelkader 2019). Commercially available carbachol and brimonidine tartrate was given 
concomitantly 5 minutes apart or as the fixed-dose BRIMOCHOL combination was more 
effective than carbachol and brimonidine tartrate given as monotherapy (Abdelkader 2016), 
suggesting contribution of elements. No tachyphylaxis was noted over 3 months of daily dosing 
and clinical response was comparable in subjects older or younger than 50 years of age and in 
pseudophakes (Abdelkader 2015). Additionally, there was no reports of headache in the largest 
of these studies in 57 patients (Abdelkader 2019); suggesting the addition of brimonidine tartrate 
may have mitigated the incidence of headache, a common adverse event associated with the use 
of cholinergic agents alone. 
Please see the Investigator Brochure (IB) for additional information on the nonclinical and 
clinical support for BRIMOCHOL development. 
3 RATIONALE FOR THE STUDY AND STUDY DESIGN 
3.1 
Therapeutic Rationale for BRIMOCHOL in Presbyopia 
In recent years, various miotics have been investigated alone or in combination with one or more 
other agents as treatments for presbyopia (Benozzi 2012, Karanfil 2017, Renna 2017). There are 
two currently marketed miotic agents in the U.S.: pilocarpine (ISOPTOCARPINE [Prescribing 
Information]) for the lowering of intraocular pressure (IOP) and carbachol (MIOSTAT® 0.01% 
[Prescribing Information]) for obtaining miosis during surgery. Carbachol was also marketed as 
ISTOPO® CARBACHOL for the lowering of IOP for more than 50 years but was withdrawn 
from the market for commercial and not safety reasons. Carbachol is generally regarded as a 
stronger and longer-acting miotic than pilocarpine (Gelatt 1984) though with less corneal 
permeability with a dosing frequency of up to 2 drops 3 times daily rather than up to 4 times 
daily for pilocarpine. 
Both carbachol and pilocarpine are parasympathomimetic agents that induce miosis by 
promoting contraction of the iris sphincter muscle through activation of muscarinic receptors. 
However, both miotics also contract the ciliary muscle, thereby reducing IOP by putting traction 
on the scleral spur and trabecular meshwork, thereby increasing aqueous outflow (Nardin 1966). 
It is also by this mechanism that miotics cause their main adverse events (AEs): 
browache/headache (a referred pain from the ciliary muscle contraction/spasm) and a decrease in 
distance acuity by inducing a myopic shift (Poinoosawmy 1976).  
Brimonidine tartrate is a selective alpha-2 adrenergic agonist that works presynaptically in the 
management of elevated IOP to inhibit the release of norepinephrine (Kato 2018) at the nerve 
terminals, thereby decreasing aqueous production, episcleral venous pressure and improving 
trabecular outflow. By inhibiting norepinephrine’s release, brimonidine tartrate’s main effect at 
the pupil is to inhibit contraction of the iris dilator muscle, which is classically stimulated as part 














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10. Women of childbearing potential must agree to use one of the following methods of birth 
control from the date they sign the ICF until after the last study visit (Visit 5 or exit): 
a. Abstinence, when it is in line with the preferred and usual lifestyle of the subject; 
b. Maintenance of a monogamous relationship with a male partner who has been surgically 
sterilized by vasectomy (vasectomy procedure must have been conducted at least 60 days 
prior to the Screening Visit or confirmed via sperm analysis); 
c. Barrier method (e.g., condom or occlusive cap) with spermicidal foam/gel/film/cream 
AND either hormonal contraception (oral, implanted or injectable) or an intrauterine 
device or system 
Note: Non-childbearing potential is defined as surgical sterilization (i.e., bilateral 
oophorectomy, hysterectomy, or tubal ligation) or postmenopausal (defined as not having 
a period for at least 12 consecutive months prior to Screening). 
11. Able to give informed consent and willing and able to comply with all study visits and 
examinations. 
6.2 
Exclusion Criteria 
A subject who meets any of the following criteria will be excluded from the study: 
1. Narrow iridocorneal angles (Shaffer grade ≤2 or lower on gonioscopy examination) or 
previous iridotomy 
2. Pupil size smaller than 
, under mesopic conditions, in either eye 
3. History of hyphema, microhyphema, cyclodialysis, iridodynesis, or trauma to either eye 
4. Use of systemic or topical antihistamines, anticholinergics or cholinergics, or alpha-2 
agonists within 90 days prior to Visit 1 or throughout the duration of the study 
5. Use of systemic alpha-antagonists such as tamsulosin at any time 
6. Participation in other investigational drug or device clinical trials within 30 days prior to 
Visit 1, or planning to participate in any other investigational drug or device clinical trials 
within 30 days of study completion 
7. History of participation in an interventional clinical trial investigating the use of a 
pharmacologic agent for treatment of cataract within 120 days and/or presbyopia within 
60 days prior to Visit 1 
8. Any other ocular pathology requiring treatment with topical prescription ophthalmic drops or 
intravitreal injection (e.g., glaucoma, allergic conjunctivitis).  
 


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9. Concurrent use of temporary or permanent punctal plugs or history of punctal cautery in one 
or both eyes 
10. Corneal abnormalities in either eye that interfere with visual acuity or measurement of IOP 
including a corneal staining grade of ≥1 central corneal staining on the National Eye Institute 
(NEI) corneal grading scale 
11. Congenital or traumatic cataracts or congenital aphakia, central lens opacity on visual axis. 
12. History of intraocular surgery other than uncomplicated cataract surgery.  
Note: Prior LASIK refractive surgery is acceptable if the subject meets all other eligibility 
criteria. 
13. For phakic subjects, phacodynesis or subluxation of the lens or suspected loose zonules 
14. For pseudophakic subjects, complicated cataract surgery resulting in capsular tear, placement 
of IOL outside the bag (e.g., sulcus, scleral or iris fixation or anterior chamber placement) or 
yttrium aluminum garnet (YAG) capsulotomy or an axial length of ≥25 mm or multifocal or 
enhanced depth of focus IOLs 
15. History of uveitis 
16. History of pseudoexfoliation 
17. Diagnosis of glaucoma or ocular hypertension or IOP of >21 mm Hg in either eye 
18. Any active ocular or peri-ocular infection; any history of recurrent or chronic infection, 
including herpetic infection, in either eye. 
19. Current or previous retinal detachment or retinal pathology including age-related macular 
degeneration 
20. Current use (within 4 weeks of Visit 1) or likely need for the use of contact lens at any time 
during the study 
21. Concurrent disease in either eye that could require medical or surgical intervention during the 
study period 
22. Known to be immunocompromised or receiving immunosuppression 
23. History of allergic reaction to the study drug or any of its components 
24. Substance abuse (alcohol and/or drug including nicotine, marijuana, heroin, cocaine)  
25. Women who are pregnant or lactating 
26. Unwilling or unable to give informed consent 


















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9 PHARMACOKINETICS 
At the visits and times specified in the Schedule of Visits and Procedures (Section 1.2), venous 
blood samples of approximately 2.5 mL each will be collected and processed to plasma to 
determine the plasma concentrations of carbachol and brimonidine tartrate. Instructions for the 
collection and handling of blood samples will be provided in a Laboratory/PK Manual. The 
actual date and time (24-hour clock time) of each sampling will be recorded. 
Plasma samples will be analyzed by a laboratory approved by Visus. Concentrations of carbachol 
and brimonidine tartrate will be assayed using a validated method. 
10 SAFETY MONITORING AND REPORTING 
10.1 
Adverse Events 
10.1.1 
Definition and Reporting  
An adverse event (AE) is defined as any untoward medical occurrence in a subject or clinical 
investigational subject who has been administered a pharmaceutical product that does not 
necessarily have a causal relationship with this treatment.  
AEs include: 
• Unfavorable changes in general condition 
• Subjective or objective signs/symptoms 
• Concomitant diseases or accidents 
• Clinically relevant adverse changes in laboratory parameters observed in a subject during 
a clinical study 
• Loss of ≥3 lines of distance or near visual acuity 
AEs comprise all disturbances of general health status, subjective and objective disease 
symptoms (including laboratory abnormalities), and accidents observed in the context of a 
clinical trial, irrespective of a possible causal relationship with the administration of the trial 
substance. Events occurring in the framework of a clinical trial during drug-free and post-
treatment periods are also to be designated as AEs. 
All AEs, whether volunteered, elicited, or noted on physical examination, will be recorded 
throughout the study (i.e., from Screening until EOS). 
Subjects will be queried for resolution of ongoing AEs or until any unresolved AEs are judged 
by the Investigator to have stabilized or if lost to follow-up. Resolution of all AEs will be 
promptly documented by the site in the subject’s CRF. 
Any AE related to COVID-19 should be recorded as such. 


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10.2 
Serious Adverse Events 
10.2.1 
Definitions  
An SAE is any untoward medical occurrence at any dose that results in any of the following 
outcomes: 
• Death 
• A life-threatening event (i.e., puts the subject, in the view of the Principal Investigator 
(PI), at immediate risk of death) 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant disability/incapacity 
• A congenital anomaly/birth defect 
• Important medical event that may require medical or surgical intervention to prevent one 
of the above outcomes 
An unexpected adverse drug event is any adverse drug event, the specificity or severity of which 
is not consistent with the current IB. 
An AE is associated with the use of the drug if a reasonable possibility exists that the drug may 
have caused the event. 
10.2.2 
Reporting 
SAEs that are unexpected and related to BRIMOCHOL are reportable to Regulatory Authorities. 
All SAEs, regardless of causality will be reported by the Investigator to the Medical Monitor 
through the 30-day period after the last dose of study treatment. Deaths and SAEs occurring after 
the 30-day safety follow-up period AND considered related to study treatment or study 
procedures must also be reported. 
Report all SAEs (initial and follow-up information) on an SAE form and send the form to the 
Sponsor or designee within 24 hours of the discovery of the event or information (see below). 
The Sponsor or designee may request follow-up and other additional information from the 
Investigator (e.g., hospital admission or discharge notes, laboratory results). SAEs will be 
followed up through completion or treatment termination.  
Report all deaths with the primary cause of death as the SAE term, as death is the outcome of the 
event, not the event itself. If an autopsy was performed, report the primary cause of death on the 
autopsy report as the SAE term. Forward autopsy and postmortem report(s) to the Sponsor or 
designee, as outlined above. 
If study treatment is discontinued, temporarily suspended, or the dose reduced because of an 
SAE, include this information in the SAE report. 


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Suspected unexpected serious adverse reactions (SUSARs) are SAEs that qualify for mandatory 
expedited reporting to regulatory authorities where the SAE is suspected to be caused by the 
study treatment and is considered unexpected (i.e., not defined as expected in the current IB 
clinical study protocol, or approved labeling for marketed drugs). In this case, the Sponsor or 
designee will report to the relevant regulatory authorities and forward a formal notification 
describing the SUSAR to Investigators, according to regulatory requirements. Each Investigator 
must then notify his or her institutional review board (IRB) of the SUSAR as required by local 
regulatory authorities and in accordance with IRB policy. 
10.2.3 
Classification of Severity of Adverse Event 
The severity of AEs will be categorized, as shown below.  
Categorization of Severity of Adverse Events   
Mild 
The event is minor and does not cause significant discomfort to subject or change in 
activities of daily living (ADL); subject is aware of symptoms, but symptoms are easily 
tolerated. 
Moderate 
The event is an inconvenience or concern to the subject and causes interference with ADL, 
but the subject is able to continue with ADL. 
Severe 
The event significantly interferes with ADL and the subject is incapacitated and/or unable 
to continue with ADL. 
Potentially 
life- 
threatening  
An event/reaction in which the subject was at risk of death at the time of the event/reaction; 
it does not refer to an event/reaction which hypothetically might have caused death if it 
were more severe. 
10.2.4 
Relationship to Study Drug 
The Investigator will make a determination of the relationship of the AE to the study drug using 
a 4-category system (not related, possible, probable, definite), as shown below. 
 
Categorization for Determining Relationship of AEs to Study Treatment   
Not related 
An AE that does not follow a reasonable temporal sequence from administration of the drug 
and that can be reasonably explained by other factors, including underlying disease, 
complications, concomitant drugs, or concurrent treatment. 
Possible 
An AE that follows a reasonable temporal sequence from the administration of the drug 
(including the course after withdrawal of the drug) and that cannot be excluded as being 
possibly caused by the drug (e.g., existence of similar reports attributed to the drug and/or its 
analogues; reactions attributable to the pharmacological effect of the drug), although other 
factors such as underlying disease, complications, concomitant drugs, or concurrent treatment 
are presumable. 
Probable 
An AE that follows a reasonable temporal sequence from administration of the drug (including 
the course after withdrawal of the drug) and that can be excluded as being possibly caused by 
other factors, such as underlying disease, complications, concomitant drugs, or concurrent 
treatment. 
Definite 
An AE that follows a reasonable temporal sequence from administration of the drug (including 
the course after withdrawal of the drug), follows a known or hypothesized cause-effect 
relationship, and (if appropriate) satisfies the following: 


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• 
Positive results obtained in drug sensitivity tests; 
• 
Toxic level of the drug present in blood or other body fluids. 
10.2.5 
Ocular Events of Special Interest 
For this study medically important events comprise the following ocular events, which are 
considered to be of special interest and by default are to be reported as SAEs:  
• Decrease in visual acuity of >15 ETDRS letters or > +0.3 LogMAR in uncorrected 
distance visual acuity at 24 hours  
• Moderate to severe intraocular inflammation (i.e., ≥2+ anterior chamber cell/flare)  
• Acute angle glaucoma or moderate to severe increase in IOP of >25mm Hg 
• Retinal tear or detachment 
10.3 
Pregnancies 
Females of childbearing potential must have a negative urine pregnancy test at Visit 1 to 
participate. If a female has a positive urine pregnancy test during the study, the subject will be 
withdrawn from the study and the Investigator will notify IQVIA and/or the Sponsor within 
24 hours of knowledge of the positive pregnancy test. 
The pregnancy will be followed to term and/or outcome, and this outcome must be reported to 
the Sponsor. A pregnancy is not regarded as an AE or SAE unless the birth results in a 
congenital anomaly/birth defect, or there is suspicion that the study treatment may have 
interfered with the effectiveness of a contraceptive medication or method. 
11 DATA COLLECTION AND MANAGEMENT 
11.1 
Data Confidentiality 
All data collected during the study will be recorded in the subject’s eCRF. To maintain 
confidentiality, subjects will be identified only by Subject Number and initials. 
11.2 
Site Monitoring 
The Sponsor or designee (e.g., Clinical Research Associate [CRA]) will be responsible for 
monitoring this clinical trial. The CRA will monitor the study conduct, proper eCRF and source 
documentation completion and retention, and accurate study drug accountability. To this end, the 
CRA will visit the study site at suitable intervals and be in frequent contact through verbal and 
written communication. The Investigator will grant access to all documents (related to the study 
and subjects) at any time these are requested. In turn, the CRA will adhere to all requirements for 
subject confidentiality as outlined in the ICF. The Investigator and study staff will be expected to 
cooperate with the CRA, to be available during a portion of the monitoring visit to answer 
questions, and to provide any missing information. 


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11.3 
Data Collection 
All primary source data or copies thereof (e.g., eCRFs, data worksheets, correspondence, 
photographs, and computer records) that are a result of the original observations and activities of 
the study and are necessary for the reconstruction and evaluation of any study report will be 
retained in the clinic archives. 
12 STATISTICAL METHODS AND DATA ANALYSIS 
Data analysis will be performed according to the Sponsor’s or designee’s standard operating 
procedures (SOPs). A detailed statistical analysis plan (SAP) will be provided prior to database 
lock.  
The general analytical approach for all endpoints will be descriptive in nature. Unless otherwise 
stated, continuous variables will be summarized using the number of subjects, mean, standard 
deviation (SD), median, minimum, and maximum; and categorical variables will be summarized 
using the frequency count and the percentage of subjects in each category.  
All subject study data collected in the eCRFs will be presented in data listings. 
12.1 
Analysis Sets 
12.1.1 
Safety Population 
All subjects who received any amount of study drug will be included in the Safety population. 
Subjects will be analyzed as treated. 
12.1.2 
Modified Intent-to-Treat (mITT) Population 
All subjects who receive at least 1 dose of study drug, have the primary efficacy assessments 
available at Baseline (pre-dose at Hour 0 on a dosing day) and at Hour 1 (on the same dosing 
day) for at least 1 dosing day will be included in the modified Intent-to-treat (mITT) Population. 
Subjects will be analyzed as treated. 
12.1.3 
Per Protocol (PP) Population 
All mITT subjects who do not significantly violate the protocol. The PP population will be 
identified prior to locking the database. 
12.1.4 
Pharmacodynamic (PD) Population 
All subjects who received study drug and had at least one evaluable, post-dose PD 
(pupillometry) assessments without protocol deviations or events deemed to affect the PD.  










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13 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
13.1 
Regulatory and Ethical Compliance 
The study will be conducted in accordance with the International Council for Harmonisation 
Good Clinical Practice (ICH GCP) guidelines, principles enunciated in the Declaration of 
Helsinki, and all applicable FDA regulations. 
13.2 
Responsibilities of the Investigator and IRB 
This protocol, the informed consent document, and all relevant supporting data must be 
submitted to the IRB for approval. IRB approval of the protocol, informed consent document, 
any advertisement used to recruit study subjects must be obtained before initiating the study. 
The PI is responsible for keeping the IRB advised of the progress of the study and of any 
changes made to the protocol as deemed appropriate, but in any case, at least once a year. The PI 
is also responsible for notifying the IRB of any reportable AEs that occur during the study. 
13.3 
Informed Consent Procedures 
At the first visit, prior to initiation of any study-related procedures, subjects must give their 
written consent to participate in the study after having been informed about the nature and 
purpose of the study, participation/termination conditions, and risks and benefits. The ICF must 
be signed and dated by the subject prior to study participation. A copy of the ICF must be 
provided to the subject. Signed consent forms must remain in the subject’s study file and be 
available for verification by the Sponsor or its representative at any time. 
Subjects included in the PK analyses will be required to sign a separate ICF. 
13.4 
Discontinuation of the Study 
The entire study may be discontinued at the discretion of the Sponsor as specified in 
Section 13.10. 
13.5 
Publication of Study Protocol and Results 
Visus will retain ownership of all data. All proposed publications based on this study will be 
subject to the Sponsor’s approval requirements. 
13.6 
Study Documentation, Recordkeeping, and Retention of Documents 
All study data will be captured using an EDC system. All source documents, records, and reports 
will be retained by the clinic. 
All primary source data or copies thereof (e.g., laboratory records, eCRFs, data worksheets, 
correspondence, photographs, and computer records) that are a result of the original observations 


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and activities of the study and are necessary for the reconstruction and evaluation of any study 
report will be retained in the clinic archives. 
The Investigator must retain study documents for a period of 2 years following the date a 
marketing application is approved for the study product for the indication for which it is being 
investigated; or, if no application is to be filed or if the application is not approved for such 
indication until 2 years after the investigation is discontinued and the FDA is notified. The site 
should not destroy records until authorized to do so by Visus. 
13.7 
Confidentiality of Study Documents and Subject Records 
All information provided regarding the study, as well as all information collected or documented 
during the study, will be regarded as confidential. The Investigator agrees not to disclose such 
information in any way without prior written permission from the Sponsor. 
Any publication of the results, either in part or in total (articles in journals or newspapers, oral 
presentations, abstracts, etc.) by the Investigator or their representative(s), shall require prior 
notification and review, within a reasonable time frame, by the Sponsor, and cannot be made in 
violation of the Sponsor’s confidentiality restrictions or to the detriment of the Sponsor’s 
intellectual property rights. 
The results from Screening and data collected during the study will be recorded in the subject’s 
eCRF. To maintain confidentiality, subjects will be identified only by numbers and initials. 
13.8 
Monitoring and Quality Assurance 
During the study, the Sponsor, an 
 CRA, or designee may complete routine 
monitoring visits to review protocol compliance, assess study drug accountability, and ensure the 
study is being conducted according to regulatory requirements. The review of the subjects’ 
medical records will be performed in a manner that adequately maintains subject confidentiality.  
Further details of the study monitoring will be outlined in a clinical monitoring plan (CMP). 
Regulatory authorities of domestic and foreign agencies, the Sponsor, and 
 
Quality Assurance and/or its designees may carry out on-site inspections and/or audits that may 
include source data checks. Therefore, direct access to the original source data will be required 
for inspections and/or audits.  
All inspections and audits will be carried out considering data protection as well as subject 
confidentiality to the extent that local, state, and federal laws apply.  
13.9 
Protocol Adherence 
The Investigator must adhere to the protocol as detailed in this document and agree that the 
Sponsor must approve any changes to the protocol prior to seeking approval from the IRB. There 
will be no alterations in the protocol without agreement between the Sponsor and the 
Investigator. There will be no alterations in the protocol affecting subject safety without the 
express written approval of the Sponsor, Investigator, and the IRB. 


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13.10 Study Termination 
The study may be stopped at a study site at any time by the Investigator. The Sponsor may stop 
the study (and/or the study site) for any reason with appropriate notification.  
 
 


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14 REFERENCES 
Abdelkader A. A novel pharmacological treatment of pseudophakic presbyopia. Int J 
Ophthalmic Res. 2018;4(2):291-4. 
Abdelkader A. Improved presbyopic vision with miotics. Eye & Contact Lens 
2015;41(5):323–7. 
Abdelkader A. Influence of different concentrations of carbachol drops on the outcome of 
presbyopia treatment – a randomized study. Int J Ophthalmic Res. 2019;5(1):317-20. 
Abdelkader A, Kaufman HE. Clinical outcomes of combined versus separate carbachol and 
brimonidine drops in correcting presbyopia. Eye Vis (Lond). 2016 Dec 5;3:31. 
Allergan patent application Pub. No.: US 2018 / 0078500 A1. 
Benozzi J, Benozzi G, Orman B. Presbyopia: a new potential pharmacological treatment. 
Med Hypothesis Discov Innov Ophthalmol. 2012 Spring;1(1):3-5. 
Benzoni JA, Rosenfield M. Clinical amplitude of accommodation in children between 5 and 
10 years of age. Optom Vis Dev. 2012;43(3):109-14. 
Frick KD, Joy SM, Wilson DA, Naidoo KS, Holden BA. The global burden of potential 
productivity loss from uncorrected presbyopia. Ophthalmology. 2015 Aug;122(8):1706-10. 
Gelatt KN, Gum GG, Wolf ED, White MM. Dose response of topical carbamylcholine 
chloride (carbachol) in normotensive and early glaucomatous beagles. Am J Vet Res. 1984 
Mar;45(3):547-54. 
Gil-Cazorla R, Shah S, Naroo SA. A review of the surgical options for the correction of 
presbyopia. Br J Ophthalmol. 2016 Jan;100(1):62-70. 
Goertz DA, Stewart WC, Burns WR, et al. Review of the impact of presbyopia on quality of 
life in the developing and developed world. Acta Ophthalmol. 2014:92:497-500. 
ISOPTO® CARBACHOL (carbachol ophthalmic solution) 1.5% [prescribing information 
(PI)]. Fort Worth, TX: Alcon Laboratories, Inc.; 2007. 
Karanfil FC, Turgut B. Update on presbyopia-correcting drops. European Ophthalmic 
Review. 2017;11(2):99–102. 
Kato S, Shimizu K, Kamiya K, Ishikawa H, Igarashi A. Effects of brimonidine tartrate 0.1% 
ophthalmic solution on the pupil, refraction, and light reflex. Sci Rep. 2018;8:9003. 
Kubo C, Suzuki R. Involvement of prejunctional alpha2-adrenoceptor in bovine ciliary 
muscle movement. J Ocul Pharmacol. 1992;8(3):225-31. 
McDonnell PJ, Lee P, Spritzer K, Lindblad AS, Hays RD. Associations of presbyopia with 
vision- targeted health-related quality of life. Arch Ophthalmol. 2003 Nov;121(11):1577-81. 
MIOSTAT® (Carbachol Intraocular Solution, USP) 0.01% [prescribing information (PI)]. 
Fort Worth, TX: Alcon Laboratories, Inc.; 2015. 
Moarefi MA, Bafna S, Wiley W. A review of presbyopia treatment with corneal inlays. 
Ophthalmol Ther. 2017 Jun;6(1):55-65. 


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Nardin G, Zimmerman T. (1966). Ocular cholinergic agents. In Ritch R, Shields MB, Krupin 
T,  eds. The glaucomas. 2nd ed. St. Louis: Mosby. 1966;3:1399-1407. 
Renna A, Alió JL, Vejarano LF. Pharmacological treatments of presbyopia: a review of 
modern perspectives. Eye Vis (Lond). 2017 Feb 7;4:3. 
Poinoosawmy D, Nagasubramanian S, Brown NA. Effect of pilocarpine on visual acuity and 
on the dimensions of the cornea and anterior chamber. Br J Ophthalmol. 1976;60:676-9. 
Suzuki G, Kunikane E, Shinno K, Kozai S, Kurata M, Kawamura A. Ocular and systemic 
pharmacokinetics of brimonidine and timolol after topical administration in rabbits: 
comparison between fixed-combination and single drugs. Ophthalmol Ther. 2020;9:115–25. 
 
 


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15 PROTOCOL AMENDMENT 
 


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17 PROTOCOL AMENDMENT 
 


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SAP_003.pdf: 
DocuSign Envelope ID: 313E12B2-7CEA-4179-8979-B4FC151BF1C0 
Statistical Analysis Plan 
Template No.: NVA_TP_CR694 Revision 3 
Reference: SOPCR008, WPCR013 
CONFIDENTIAL 
Template Effective Date:25Aug2020 
Page 1 of 40 
 
 
VISUS Therapeutics 
Protocol #: VT-001 
 
A 3-Dose, Multicenter, Randomized, Double-Masked, Crossover 
Phase 2 Safety and Efficacy Study of BRIMOCHOL™ 
(Carbachol/Brimonidine Tartrate Fixed-Dose Combination) Topical 
Ophthalmic Solution vs. BRIMOCHOL™ F (Carbachol /Brimonidine 
Tartrate Fixed-Dose Combination) Topical Ophthalmic Solution vs. 
Monotherapy with Carbachol Topical Ophthalmic Solution in 
Subjects with Emmetropic Phakic and Pseudophakic Presbyopia 
Statistical Analysis Plan 
 
Version 1.0 
Document last saved: 1-Nov-2021 8:02 PM 
 
 
Prepared by: 
 
Approved by: 
 
 
 
 
 




DocuSign Envelope ID: 313E12B2-7CEA-4179-8979-B4FC151BF1C0 
Statistical Analysis Plan 
Template No.: NVA_TP_CR694 Revision 3 
Reference: SOPCR008, WPCR013 
CONFIDENTIAL 
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Page iii of 40 
 
 
VISUS/ Protocol: VT-001 
 #: UZA81693 
IX. Pharmacodynamic Analyses ................................................................................ 26 
X. Pharmacokinetic Analyses .................................................................................... 27 
A. Pharmacokinetic Concentrations ............................................................... 27 
B. Pharmacokinetic Parameters .................................................................... 28 
XI. Safety Analyses ................................................................................................... 30 
A. Adverse Events ......................................................................................... 30 
B. Ocular Assessments ................................................................................. 32 
C. Clinical Laboratory Results ........................................................................ 33 
D. Vital Signs ................................................................................................. 33 
E. Physical Examination ................................................................................ 33 
F. Prior and Concomitant Medications ........................................................... 33 
G. 12 Lead Electrocardiogram ....................................................................... 34 
XII.
 ........................................................................................... 34 
XIII. 
 ..................................................................... 35 
XIV. References ........................................................................................................ 36 
Appendix A Example SAS codes ............................................................................. 36 


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VISUS/ Protocol: VT-001 
 #: UZA81693 
I. Introduction 
A. Background 
Presbyopia is an inevitable, age-related, gradual loss in the ability to 
focus at intermediate and near targets without spectacle or surgical 
correction due to a progressive loss of elasticity in the crystalline lens. 
The known pharmacology and the results of previous investigator-initiated 
clinical studies of BRIMOCHOL suggest the addition of an alpha-2 
agonist to a cholinergic agent, could have additive direct and indirect 
effects on both the iris constrictor and dilator muscles leading to robust 
and durable miosis and improvement in near visual acuity over 
monotherapy alone. Prior clinical studies and more recent nonclinical 
studies conducted by Visus demonstrate that the fixed-dose combination 
of BRIMOCHOL and BRIMOCHOL F both demonstrate a contribution of 
elements vs. the individual monotherapies formulated similarly not only on 
pupil size, but that iris/ciliary body carbachol area under the curve (AUC) 
concentrations are ~50% higher with BRIMOCHOL than carbachol alone. 
Ex vivo studies in bovine ciliary muscle suggest alpha-2 receptors inhibit 
the contraction of cholinergically innervated ciliary muscle that does not 
occur when the ciliary muscle is at rest. These findings support the 
rationale for combining an alpha-2 agonist with a cholinergic agent to 
minimize the adverse events (AEs) of browache/headache, myopic shift, 
and intraocular pressure (IOP) changes associated with cholinergics 
alone, and indeed, clinical studies with BRIMOCHOL suggest this is the 
case. There are currently no Food and Drug Administration (FDA)- 
approved drug products to treat presbyopia. The protocol describes the 
general approach to analysis of data from the study. This analysis plan 
describes additional detail needed to complete such an analysis. 
 
B. Protocol and Amendment History 
This Statistical Analysis Plan (SAP) is based on Protocol VT-001 
Amendment 8 Version 9 dated on 28 July 2021. 


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VISUS/ Protocol: VT-001 
 #: UZA81693 
 
Version 
Approval Date 
Salient Changes, if any* 


DocuSign Envelope ID: 313E12B2-7CEA-4179-8979-B4FC151BF1C0 
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VISUS/ Protocol: VT-001 
 #: UZA81693 
 
 
 
 
*Only changes related to statistical analysis are included here. 
This SAP will govern the analysis of data from this study. The plan may 
be modified until the time of treatment unblinding. Any deviations from 
the analysis plan, including any after the time of treatment unblinding, will 
be documented as such in the study report. 
II. Protocol Objectives 
The main objectives of this study are: 
1. To compare the efficacy, pharmacodynamics (PD), safety, 
 
t of topically administered, BRIMOCHOL 
2.75% (carbachol 2.75%/brimonidine tartrate fixed-dose combination 
0.1% with benzalkonium chloride [BAK]) vs. BRIMOCHOL F 2.75% 
(carbachol 2.75%/brimonidine tartrate fixed-dose combination 0.1% 
BAK free) vs. carbachol 2.75% monotherapy (BAK free) topical 
ophthalmic solutions administered 
 
 in inducing miosis and improving near visual acuity among 
subjects with emmetropic phakic and pseudophakic presbyopia 
2. To characterize the systemic pharmacokinetic (PK) profile of fixed- 
dose combinations BRIMOCHOL and BRIMOCHOL F topical 
ophthalmic solutions in subjects with emmetropic phakic and 
pseudophakic presbyopia 
 
III. Study Endpoints 
A. Efficacy Endpoints 
Primary Efficacy Endpoints: 






















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VISUS/ Protocol: VT-001 
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• Body Mass Index (BMI, kg/m²) 
 
Ocular Characteristics: Data will be summarized by dose cohort for all 
subjects in the safety and mITT populations. 
Data collected about the following ocular assessments at the screening 
visit will be summarized: 
• Lens Status (Phakic vs. Pseudophakic) 
• 
 
 
• Pupil Diameter 
• Pupil Area 
• Intraocular Pressure measurement 
• Corneal stain total score 
 
Medical/Ocular History. Medical/Ocular history will be summarized for all 
subjects in the safety population. 
Medical history will be coded using Medical Dictionary for Regulatory 
Activities (MedDRA Version 23.1 September 2020) and summarized by 
system organ class (SOC) and preferred term (PT). Ocular history will be 
summarized for each eye. Ocular history involving both eyes will be 
counted for each eye separately. 
B. Disposition 
Subject disposition will be summarized for all screened subjects, the 
numbers of subjects who were screened, randomized, and either 
completed the study or prematurely withdrew from study participation. 
Study completion will be indicated by the response “Yes” on the study 
completion status form. Any other response on this form will be counted 
as a premature withdrawal. 
 
Premature withdrawals will be further characterized as the number of 
subjects who withdrew prematurely for each of the following reasons 
listed on the study completion status form: 
• Adverse Event 
• Non-compliance with study drug 
• Withdrawal by Subject 
• Death 
• Pregnancy 
• Study terminated by sponsor 
• Lack of Efficacy 
• Protocol Deviation 


































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VISUS/ Protocol: VT-001 
 #: UZA81693 
separate category of missing severity will be included in the summary 
table, and no imputation of severity will be performed. Through the data 
cleaning process, all attempts will be made to avoid missing values for 
relationship and severity. 
 
TEAEs occur on or after the administration of BRIMOCHOL F, 
BRIMOCHOL and carbachol will be summarized separately. An AE 
starting after the administration of the study drug at a treatment visit and 
continuing into the next treatment visit will only be categorized under the 
treatment given at the onset visit if the severity is not worsened in the 
next period. On the other hand, if an AE continues into the next treatment 
visit and the severity is worsened during the next treatment period, the AE 
will be attributed twice: once to the first treatment for the onset and the 
other time to the second treatment for worsening. Similarly, if an AE 
occurs and stops during one treatment period but recurs in the next 
treatment period, the AE will be attributed to both treatments. 
 
AEs will be summarized by treatment and overall, as incidence rates of: 
• All AEs 
• All TEAEs 
• All Ocular TEAEs 
• All Non-ocular TEAEs 
• Serious TEAEs 
• Deaths 
• Ocular Events of Special Interest 
• Treatment-related TEAEs 
• TEAEs leading to study drug withdrawal 
• TEAEs by maximum severity 
In addition, the following AE summaries will be produced: 
• All ocular TEAEs by preferred term (PT) in descending order of 
overall frequency 
• All non-ocular TEAEs by system organ class (SOC) in alphabetical 
order and preferred term (PT) in descending order of overall 
frequency 
• Serious TEAEs by SOC and PT 
• Ocular events of special interest by PT 
• TEAEs leading to study drug withdrawal by SOC and PT. This 
subset includes TEAEs with an Action Taken of “Permanent 
Discontinuation.” 
• Treatment-related TEAEs by SOC and PT. This table will include 
TEAEs with a drug relationship of “Possible,” “Probable,” and 




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C. Clinical Laboratory Results 
Central labs are performed at the screening visit only. Laboratory test 
results (including hematology, coagulation, serum chemistry, and 
urinalysis) and abnormal laboratory values will be summarized for all 
subjects in the safety population and presented in data listings. 
 
D. Vital Signs 
Vital signs measurements including pulse rate, temperature, systolic 
blood pressure, and diastolic blood pressure, at each scheduled visit and 
changes from the Screening visit will be summarized by treatment. All 
vital signs measurements will be listed by subject. 
 
E. Physical Examination 
Physical examination are performed at the screening visit only. 
Categories of findings (normal, abnormal, not done) on physical 
examination will be presented in a by-subject listing. 
 
F. Prior and Concomitant Medications 
Prior and concomitant medications will be coded using the WHODrug 
Version 01 September 2020 (Global, B3 format) 
Missing medications start date will be imputed using the following 
approach: 
• If completely blank, assume 01Janyyyy, where yyyy is the year of 
the Stop date (if available) or the year of Screening visit date 
(otherwise). 
•  If only year is recorded, assume 01Jan for the missing month and 
day. 
•  If only month and year are recorded, assume 01 for the missing 
day. 
Missing medications stop date will be imputed using the following 
approach: 
• If completely blank, assume the day of the last study visit. 
•  When only year is recorded, assume the 31Dec for the missing 
date (if the year is before the year of the last study visit) or the date 
of the last study visit (otherwise). 
• If only month and year are recorded, assume the last day of the 
month. 
Prior medication: Any medication with a start date prior to the first dose 
of study drug is classified as a prior medication. 
Concomitant medication: Any medication is classified as a concomitant 
medication if the start date is on or after the first dose of study drug or any 






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XIV. References 
1. Carpenter, J. R. and Kenward, M. G. (2013), Multiple Imputation and Its 
Application, New York: John Wiley & Sons. 
2. Carey, V., Zeger, S. L., and Diggle, P. J. (1993). “Modelling Multivariate 
Binary Data with Alternating Logistic Regressions.” Biometrika 80:517– 
526. 
3. Dmitrienko A, Tamhane AC. (2011). Mixtures of multiple testing 
procedures for gatekeeping applications in clinical trials. Statistics in 
Medicine. 30, 1473–1488.Rubin DB. Multiple imputation for nonresponse 
in surveys. New York, NY: John Wiley and Sons; 1987.SAS Institute Inc: 
SAS® 9.4 Statements: Reference, Third Edition. Cary, NC: SAS Institute 
Inc; 2014. 
4. Rubin DB. Multiple imputation for nonresponse in surveys. New York, NY: 
John Wiley and Sons; 1987. 
 
Appendix A Example SAS codes 


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