Clinical trial NCT03536949
Conditions: Blepharoptosis
Sponsor: RVL Pharmaceuticals, Inc.
Start date: 2018-06-20; Completion date: 2019-03-27
Enrollment: 234 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 3 study to evaluate the extended safety of RVL-1201 compared to placebo for treatment of blepharoptosis. Eligible subjects will be randomized to one of 2 treatment arms.

Detailed description:

Arms: arm 1: RVL-1201 (oxymetazoline hydrochloride) ophthalmic solution 0.1% arm 2: Vehicle placebo ophthalmic solution
Interventions: intervention 1: RVL-1201 intervention 2: Vehicle ophthalmic solution
Intervention descriptions: intervention 1: RVL-1201 ophthalmic solution, 0.1% intervention 2: Vehicle placebo ophthalmic solution

Protocol documents:
Prot_000.pdf: 
RVL-1201 Ophthalmic Solution 
 
RevitaLid Inc. 
Study RVL-1201-203 
 
  
 
CLN.RVL-1201.RVL-1201-203.PR.A02 
 
1 
CLINICAL STUDY PROTOCOL 
CONFIDENTIAL 
 
A Randomized, Double-Masked, Placebo-Controlled Phase 3 
Study of the Safety of RVL-1201 in the Treatment of 
Acquired Blepharoptosis  
(Study RVL-1201-203) 
 
Study Phase: 
Phase 3 
Product Name: 
RVL-1201 (oxymetazoline hydrochloride) ophthalmic solution, 
0.1% 
Document Number: 
CLN.RVL-1201.RVL-1201-203.PR.A02 
Indication: 
Treatment of acquired blepharoptosis 
IND: 
116915 
Sponsor: 
RevitaLid Inc. 
400 Crossing Boulevard 
Bridgewater, NJ 08807 
Medical Monitor: 
Charles Slonim, MD 
Protocol Version: 
Amendment 2: 24 October 2018 
Amendment 1: 08 March 2018 
Original Protocol: 12 February 2018 
 
This Protocol and the information contained herein is the property of RevitaLid Inc. and it may 
not, in full or in part, be passed on, reproduced, published, or otherwise employed without the 
express permission of Osmotica Pharmaceutical US LLC. 




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INVESTIGATOR’S AGREEMENT 
Study Title: 
A Randomized, Double-Masked, Placebo-Controlled Phase 3 
Study of the Safety of RVL-1201 in the Treatment of Acquired 
Blepharoptosis (Study RVL-1201-203) 
Study Number: 
Study RVL-1201-203 
Document Number: 
CLN.RVL-1201.RVL-1201-203.PR.A02 
 
I have received and read the Study RVL-1201-203 protocol. The signature below constitutes the 
approval of this protocol and the attachments, and provides the necessary assurances that this 
trial will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and in compliance with International Council for Harmonisation (ICH) 
guidelines, and all applicable United States (U.S.) federal regulations and local legal and 
regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


RVL-1201 Ophthalmic Solution 
 
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PROCEDURES IN CASE OF EMERGENCY  
Table 1: 
Emergency Contact Information (Study RVL-1201-203) 
Role in Study 
Name 
Contact Information 
Clinical Study Leader 
Medical Monitor 
 


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1. 
SYNOPSIS 
Name of Sponsor/Company: RevitaLid Inc. 
Name of Investigational Product: RVL-1201 Ophthalmic Solution  
Name of Active Ingredient: Oxymetazoline hydrochloride 
Title of Study: A Randomized, Double-Masked, Placebo-Controlled Phase 3 Study of the Safety of 
RVL-1201 in the Treatment of Acquired Blepharoptosis (Study RVL-1201-203) 
Studied Period (Years):  
Estimated date first patient enrolled: March 2018 
Estimated date last patient completed: October 2018 
Phase of Development:  
3 
Objectives: The objective of this study is to evaluate the safety of RVL-1201 Ophthalmic Solution in 
the treatment of acquired blepharoptosis over an extended dosing period of 12 weeks. 
Methodology: This will be a Phase 3, randomized, multicenter, double-masked, placebo-controlled 
study to evaluate the extended safety of RVL-1201 conducted over 84 days (12 weeks).  
Eligible subjects will be randomized in a 2:1 ratio to one of the following treatment arms and treated 
for 84 days: 
• 
RVL-1201 Ophthalmic Solution 1 drop in each eye once daily (QD) in the morning (N = 150) 
• 
Vehicle (placebo) 1 drop in each eye QD in the morning (N = 75) 
Both eyes will be treated and assessed.  
Following screening evaluations at the Screening/Baseline visit (Day 1), a determination of eligibility 
will be made, and eligible subjects will be randomized and receive study medication.  
Study medication, RVL-1201 or Vehicle (placebo), will be provided in identical-appearing unit-dose 
vials. The identity of the study medications will be masked to the subject, Investigator, study 
personnel responsible for ophthalmic evaluations, and Sponsor personnel.  
Subjects (or their caregiver, if necessary) will administer study medication QD in the morning during 
the study period. 
Safety follow-up visits will be conducted at Day 14 (Visit 2), Day 42 (Visit 3), and Day 84 (Visit 4). 
Number of Patients (Planned): Approximately 225 subjects will be enrolled (150 subjects in the 
RVL-1201 group and 75 subjects in the Vehicle group) at approximately 30 clinical sites. 
Inclusion Criteria: 
1. Males or females ≥ 9 years of age. 
2. Presence of both of the following at Screening/Baseline: 
a. The marginal reflex distance (MRD), the distance from the central pupillary light 
reflex to the central margin of the upper lid, must be ≤ 2 mm (no visible central 
pupillary light reflex defaults to 0) in either eye. 


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Inclusion Criteria (continued): 
b. Snellen visual acuity (VA) of 20/80 or better in the same eye as Inclusion Criteria 
#2a. 
3. Females must be 1-year postmenopausal, surgically sterilized, or females of childbearing 
potential with a negative urine pregnancy test at Visit 1. Females of childbearing potential 
(females who have started their menstrual cycles) must use an acceptable form of 
contraception throughout the study. Acceptable methods include the use of at least one of the 
following: intrauterine (intrauterine device), hormonal (oral, injection, patch, implant, ring), 
barrier with spermicide (condom, diaphragm), or abstinence. 
4. Must be able to self-administer study medication or to have the study medication 
administered by a caregiver/guardian/parent throughout the study period. 
5. Must be able to understand and sign an informed consent form (ICF) prior to participation in 
any study-related procedures. For minor subjects, the subject’s parent or legal guardian must 
provide informed consent on behalf of the subject and the subject should provide assent, per 
Institutional Review Board guidelines. If a subject becomes 18 years of age during the study, 
the subject will need to sign an ICF to continue in the study. 
Exclusion Criteria: 
In both eyes 
1. Dermatochalasis that extends less than 3 mm above the upper eyelid margin; dermatochalasis 
extending < 3 mm above the upper eyelid margin of a single eye is permitted. 
2. Pseudoptosis (upper eyelid dermatochalasis that overhangs the upper eyelid margin); 
pseudoptosis in a single eye is permitted. 
In either eye 
3. Congenital ptosis. 
4. Horner syndrome. 
5. Marcus Gunn jaw-winking syndrome. 
6. Myasthenia gravis. 
7. Mechanical ptosis, including ptosis due to orbital or lid tumor, cicatricial processes affecting 
the movements of the upper lid, and enophthalmos. 
8. Previous ptosis surgery (previous blepharoplasty [only] is allowed provided the surgery took 
place > 3 months prior to Visit 1). 
9. Lid position affected by lid or conjunctival scarring. 
10. History of herpes keratitis. 
11. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been 
performed > 3 months prior to Visit 1). 
12. Periocular neurotoxin (e.g., Botox, Xeomin, Dysport, Myobloc) injections within 3 months 
prior to Visit 1 and during the study. 
13. Topical application of bimatoprost (i.e., Latisse®) to the eyelashes within 7 days prior to Visit 
1 and during the study. 


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Exclusion Criteria: 
In either eye (continued) 
14. Use of topical ophthalmic medications (including anti-allergy [e.g., antihistamines], dry eye 
[i.e., Restasis®, Xiidra®] antimicrobial drugs [e.g., antibiotics and antivirals] and 
anti-inflammatory drugs (including nonsteroidal anti-inflammatory drugs [NSAIDs] and 
steroids) other than the assigned study medication within 7 days prior to Visit 1 and during 
the study. Topical ophthalmic prostaglandin analogues for the treatment of elevated 
intraocular pressure are permitted if dosed in the evening in accordance with the approved 
prescribing information. All other topical antiglaucoma medications are prohibited. 
15. Intravitreal injections (e.g., Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days prior to 
Visit 1 and during the study. 
16. Current punctal plugs or placement of punctal plugs during the study.  
17. Current use of over-the-counter (OTC) vasoconstrictor/decongestant eye medication (e.g., 
Visine® L.R.®) or any ophthalmic or non-ophthalmic α-adrenergic agonist including OTC 
products (e.g., Afrin®) at any time during the study; artificial tears are allowed. 
General: 
18. Resting heart rate (HR) outside the normal range (50–110 beats per minute). 
19. Hypertension with resting diastolic blood pressure (BP) > 105 mm Hg or systolic BP 
> 220 mm Hg. 
20. Use of monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, phenelzine, 
tranylcypromine) within 14 days prior to Visit 1 and during the study. 
21. Advanced arteriosclerotic disease or history of cerebrovascular accident (CVA). 
22. History of hyperthyroidism or thyroid eye disease (i.e., exophthalmos, upper eyelid retraction, 
diplopia secondary to extraocular muscle involvement). Hypothyroidism that is controlled on 
medication is allowed. 
23. Patients with proliferative diabetic retinopathy may not be enrolled. However, patients with 
insulin dependent diabetes, diabetes requiring oral hypoglycemic drugs, or diet-controlled 
diabetes, with or without stable background diabetic retinopathy, are allowed. 
24. Pregnancy or lactation. 
25. Diagnosed benign prostatic hypertrophy requiring medicinal therapy; previous prostatectomy 
is allowed. 
26. History of contact or systemic allergic reaction to oxymetazoline hydrochloride or other 
sympathomimetic drugs (e.g., phenylephrine, pseudoephedrine, ephedrine, 
phenylpropanolamine, fepradinol, or methoxamine). 
27. Participation in any drug or device clinical investigation within 30 days prior to entry into this 
study and/or during the period of study participation. Previous screening in Study 
RVL-1201-202 is allowed. 
28. Randomization into any previous clinical study of RVL-1201 (Study RVL-1201-001, 
Study RVL-1201-201 or Study RVL-1201-202) or into this study (Study RVL-1201-203). 
Investigational Product, Dosage and Mode of Administration: RVL-1201 (oxymetazoline 
hydrochloride) Ophthalmic Solution, 0.1%: 1 drop per eye QD, topical ocular administration for 
12 weeks 
Reference Therapy, Dosage and Mode of Administration: Vehicle (placebo): 1 drop per eye QD, 
topical ocular administration for 12 weeks 


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Duration of Treatment: The duration of treatment will be 12 weeks (3 months) 
Study Procedures: All ophthalmic evaluations will be conducted bilaterally. 
Day 1 (Visit 1): Screening/Baseline Subjects will provide written informed consent before any 
study-related screening procedures are conducted. For minor subjects, signed informed consent will 
be obtained from the subject’s parent or legal guardian, and assent will be obtained from the subject 
following IRB guidelines.  
Subjects will undergo screening/baseline evaluations to determine eligibility for the study including a 
urine pregnancy test for subjects of childbearing potential, external photographs of the eyes to 
measure MRD and pupil diameter, and safety evaluations (Snellen VA, slit-lamp examination [SLE], 
corneal fluorescein staining [CFS], intraocular pressure [IOP], and dilated ophthalmoscopy/fundus 
examination). 
Study Procedures: 
Day 1 (Visit 1): Screening/Baseline (continued): 
For subjects who meet all eligibility criteria, the site will access the Interactive Web Response System 
(IWRS) to randomize the subject to study treatment and assign the study medication kit to be 
dispensed. Subjects (or caregivers, if the subject is not able to self-administer the medication) will 
then receive instruction on administration procedures and administer the first dose. Adverse events 
will be assessed post dose, and study material accountability will be performed. 
From Days 2 through 14, randomized study medication will be administered in each eye QD in the 
morning and subjects will return to the clinical site on Day 14 ± 3 days in the morning after 
instillation of study medication at home. Note: Contact lenses must be removed prior to instillation of 
study medication and must not be reinserted for at least 15 minutes after study medication 
instillation. Contact lenses must not be worn during study visits. 
Day 14 ± 3 Days (Visit 2):  
Subjects will return all opened and unopened study medication materials and undergo safety 
assessments as specified on the Schedule of Procedures. Site personnel will dispense study 
medication (Box 2) and conduct study medication accountability procedures. 
From Days 15 through 42, randomized study medication will be administered in each eye QD in the 
morning and subjects will return to the clinical site on Day 42 ± 3 days in the morning after 
instillation of study medication at home. Note: Contact lenses must be removed prior to instillation of 
study medication and must not be reinserted for at least 15 minutes after study medication 
instillation. Contact lenses must not be worn during study visits.  
Day 42 ±3 Days (Visit 3): 
Subjects will return all opened and unopened study medication materials and undergo safety 
assessments as specified on the Schedule of Procedures. Site personnel will dispense study 
medication (Box 3) and conduct study medication accountability procedures. 
From Day 43 through the morning of Day 84, randomized study medication will be administered in 
each eye QD in the morning and subjects will return to the clinical site on Day 84 ± 3 days in the 
morning after instillation of study medication at home. Note: Contact lenses must be removed prior to 
instillation of study medication and must not be reinserted for at least 15 minutes after study 
medication instillation. Contact lenses must not be worn during study visits.  
Day 84 ±3 Days (Visit 4) Final Treatment Visit:  
Subjects will return all opened and unopened study medication materials and participate in safety and 
tolerability assessments as specified on the Schedule of Procedures. Site personnel will conduct final 
study medication accountability procedures.  


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Safety and Tolerability Assessments: Safety assessment will include bilateral SLE/CFS, 
measurement of pupil diameter from external photographs, dilated ophthalmoscopy/fundus 
examination, tonometry, Snellen VA using recent correction, if applicable, vital signs (BP/HR), and 
collection of adverse events (AEs). Tolerability will be rated by the subject on a 4-point scale. 
Criteria for Evaluation: 
The safety of RVL-1201 compared to Vehicle will be evaluated by the following endpoints: 
1. Comparison of ocular and non-ocular AEs by: 
a. Frequency 
b. Intensity 
c. Relationship to treatment 
d. Serious adverse events 
e. Adverse events leading to withdrawal of study medication 
2. Comparison of subjects with findings on the following measures: 
a. Slit-lamp examination 
b. Corneal fluorescein staining 
c. Pupil diameter 
d. Dilated ophthalmoscopy/fundus examination 
e. Tonometry  
f. Snellen VA (corrected) 
g. Vital signs (BP/HR) 
3. Comparison of tolerability as measured by the tolerability scale 
Statistical Methods:  
A detailed Statistical Analysis Plan (SAP) will be finalized prior to database lock. Descriptive 
statistics (n, mean, median, standard deviation [SD], minimum, and maximum for continuous data; 
frequencies and percentages for categorical data) will be used to summarize study data. No statistical 
tests will be performed for any of the assessments. 
Sample Size:  
The sample size for this study is not based on statistical calculations. The sample size was based on 
the need to obtain sufficient safety data to meet regulatory obligations for the development of 
RVL-1201. 
Analysis Populations: 
The Safety population will be used for all analyses. The Safety population includes all subjects who 
receive at least one dose of double-masked study treatment and have at least one post-dose visit. 
Subjects will be analyzed according to the treatment received. 
Safety Analyses: 
Safety endpoints will be reported on the Safety population. Safety assessments include AEs, vital 
signs (BP/HR), ophthalmic assessments (Snellen VA, bilateral SLE/CFS, measurements of pupil 
diameter from external photographs, dilated ophthalmoscopy/fundus examination, and tonometry), 
and a tolerability assessment. Safety assessment will be based on descriptive statistics utilizing actual 
and change from baseline values, where appropriate, and individual subject listings. 


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2. 
TABLE OF CONTENTS AND LIST OF TABLES 
TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2
INVESTIGATOR’S AGREEMENT ...............................................................................................3
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4
1.
SYNOPSIS....................................................................................................................5
2.
TABLE OF CONTENTS AND LIST OF TABLES ..................................................10
TABLE OF CONTENTS ...............................................................................................................10
3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................13
4.
INTRODUCTION ......................................................................................................14
4.1.
Justification of Route, Dose, Regimen, and Treatment Period...................................14
4.2.
Good Clinical Practice Statement ...............................................................................15
4.3.
Population to Be Studied ............................................................................................15
5.
TRIAL OBJECTIVE ..................................................................................................16
6.
INVESTIGATIONAL PLAN .....................................................................................17
6.1.
Overall Study Design ..................................................................................................17
6.2.
Number of Subjects ....................................................................................................20
6.3.
Criteria for Study Termination ...................................................................................20
7.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................21
7.1.
Inclusion Criteria ........................................................................................................21
7.2.
Exclusion Criteria .......................................................................................................21
7.3.
Subject Withdrawal Criteria .......................................................................................23
8.
TREATMENT OF SUBJECTS ..................................................................................24
8.1.
Description of Study Medications ..............................................................................24
8.2.
Randomization and Masking ......................................................................................24
8.2.1.
Unmasking During the Study Period ..........................................................................24
8.3.
Concomitant Medications ...........................................................................................25
8.3.1.
Permitted Medications and Treatments ......................................................................25
8.3.2.
Prohibited Medications ...............................................................................................25
8.4.
Treatment Compliance................................................................................................26
8.5.
Discontinuation of Study Medication .........................................................................26
8.6.
Study Medication Materials and Management ...........................................................26


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8.6.1.
Packaging and Labeling ..............................................................................................26
8.6.2.
Storage and Administration ........................................................................................26
8.6.3.
Study Medication Accountability ...............................................................................27
9.
STUDY ASSESSMENTS ..........................................................................................28
9.1.
Demographic and Background Characteristics...........................................................28
9.1.1.
Demographic/Medical History ...................................................................................28
9.1.2.
Concomitant Medications History ..............................................................................28
9.1.3.
Ophthalmic History and Ophthalmic Intervention History ........................................28
9.1.4.
Urine Pregnancy Test..................................................................................................28
9.2.
External Photography .................................................................................................28
9.2.1.
Marginal Reflex Distance Measurement ....................................................................29
9.3.
Safety Assessments .....................................................................................................29
9.3.1.
Vital Signs...................................................................................................................29
9.3.2.
Snellen Visual Acuity Assessment .............................................................................29
9.3.3.
Pupil Diameter Measurement .....................................................................................29
9.3.4.
Slit Lamp Exam/Corneal Fluorescein Staining ..........................................................29
9.3.5.
Dilated Ophthalmoscopy/Fundus Exam .....................................................................30
9.3.6.
Intraocular Pressure Tonometry..................................................................................30
9.3.7.
Study Medication Tolerability Assessment ................................................................30
9.4.
Adverse and Serious Adverse Events .........................................................................30
9.4.1.
Definition of Adverse Events .....................................................................................30
9.4.1.1.
Adverse Event (AE) ....................................................................................................30
9.4.1.2.
Serious Adverse Event (SAE).....................................................................................31
9.5.
Relationship to Study Drug.........................................................................................31
9.6.
Recording Adverse Events..........................................................................................32
9.7.
Reporting Adverse Events ..........................................................................................33
10.
STUDY ACTIVITIES ................................................................................................34
10.1.
Day 1 (Visit 1): Screening/Baseline/Randomization/First Dose ................................34
10.2.
Days 2 through 14 .......................................................................................................35
10.3.
Safety Follow-up Visits ..............................................................................................35
10.3.1.
Day 14 ± 3 (Visit 2) ....................................................................................................35
10.3.2.
Days 15 through 42 .....................................................................................................36


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10.3.3.
Day 42 ± 3 (Visit 3) ....................................................................................................36
10.3.4.
Days 43 through Day 84 .............................................................................................36
10.3.5.
Day 84 ± 3 (Visit 4): Final Treatment Visit................................................................36
10.4.
Early Discontinuation Assessment Procedures...........................................................37
11.
STATISTICS ..............................................................................................................38
11.1.
General Considerations ...............................................................................................38
11.1.1.
Handling of Missing Data ...........................................................................................38
11.2.
Determination of Sample Size ....................................................................................38
11.3.
Analysis Populations...................................................................................................38
11.3.1.
Safety Population ........................................................................................................38
11.4.
Demographics and Baseline Characteristics ...............................................................38
11.5.
Safety Endpoints .........................................................................................................39
11.6.
Safety Analyses...........................................................................................................39
12.
QUALITY CONTROL AND QUALITY ASSURANCE..........................................40
13.
ADMINISTRATIVE CONSIDERATIONS...............................................................41
13.1.
Institutional Review Board (IRB) ...............................................................................41
13.2.
Ethical Conduct of the Study ......................................................................................41
13.3.
Written Informed Consent/Assent ..............................................................................41
13.4.
Subject Confidentiality and Confidentiality of Data ..................................................41
13.5.
Study Monitoring ........................................................................................................42
13.6.
Case Report Forms and Study Records ......................................................................42
13.7.
Protocol Deviations.....................................................................................................43
13.8.
Access to Source Documentation ...............................................................................43
13.9.
Data Generation and Analysis ....................................................................................43
13.9.1.
Retention of Data ........................................................................................................43
13.10.
Publication and Disclosure Policy ..............................................................................44
14.
REFERENCES ...........................................................................................................45
15.
SUMMARY OF CHANGES ......................................................................................46
15.1.
Changes Implemented in Protocol RVL-1201-203 Amendment 1 ............................46
15.2.
Changes Implemented in Protocol RVL-1201-203 Amendment 2 ............................46


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3. 
 LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Explanation 
Α 
Alpha 
AE 
Adverse event 
BID 
Twice daily 
BP 
Blood pressure 
CFS 
Corneal fluorescein staining 
eCRF 
Electronic case report form 
eDC 
Electronic data capture 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HR  
Heart rate 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IOP 
Intraocular pressure 
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
MAOI 
Monoamine oxidase inhibitor  
MRD 
Marginal reflex distance 
OTC 
Over-the-counter 
OU 
Both eyes 
QD 
Once daily 
RVL-1201 
Oxymetazoline hydrochloride ophthalmic solution, 0.1% 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SLE  
Slit lamp examination  
SOP 
Standard operating procedure 
U.S. 
United States  
VA  
Visual acuity  
 


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4. 
INTRODUCTION 
RevitaLid Inc. (RevitaLid) is pursuing the development of RVL-1201 Ophthalmic Solution 
(oxymetazoline hydrochloride ophthalmic solution, 0.1%) for the treatment of acquired 
blepharoptosis (ptosis). Ptosis is experienced by approximately 12% of adults over the age of 50 
(Sridharan et al, 1995). It is a unilateral or bilateral abnormal drooping of the upper eyelid that 
usually occurs from a partial or complete dysfunction of the muscle(s) that elevate the upper 
eyelid: the levator palpebrae superioris and/or Müller’s muscle. Patients with ptosis may 
experience significant superior visual field defects, which can affect daily activities such as 
driving, crossing streets, and reading. 
Treatment for acquired ptosis usually involves surgery, with risks of infection, bleeding, over- or 
undercorrection, reduced vision, and lagophthalmos (inability to close the eyelids completely) 
(Finsterer, 2003). Mechanical treatment of ptosis (scleral contact lenses with a bar to lift the 
eyelid (Shah-Desai et al, 2010), eyelid ptosis crutches attached to glasses, or adhesive tape or 
putty to affix the upper eyelid to the supraorbital structures) is limited by patient dissatisfaction 
with physical appearance, contact allergies, or skin irritation. Pharmacologic treatment of ptosis 
has not been pursued because the agents that have been evaluated (e.g., epinephrine, dipivefrin, 
apraclonidine, phenylephrine, brimonidine) either caused mydriasis, resulting in blurred vision or 
photophobia, or unacceptable systemic side effects (Matjucha, 2011; Scheinfeld, 2005; 
Kass et al, 1979; Fraunfelder and Scafidi, 1978).  
Oxymetazoline is a direct-acting α2-adrenergic agonist that has been used at a 0.025% 
concentration as an ocular vasoconstrictor for nearly 30 years and at a 0.05% concentration as a 
nasal decongestant for almost 50 years. When administered at a 0.1% concentration it stimulates 
the α2 adrenergic receptors in Müller’s muscle causing it to contract, thereby lifting the upper 
eyelid, and retracting the lower eyelid to a lesser degree. Topical ophthalmic administration of 
oxymetazoline hydrochloride at lower concentrations (0.01%, 0.025%) results in 
vasoconstriction and reduction of hyperemia but does not have the pharmacologic effect of 
raising the upper eyelid. 
RVL-1201 Ophthalmic Solution contains oxymetazoline hydrochloride 0.1% as the active 
ingredient, and it is provided in preservative-free unit-dose vials. 
Oxymetazoline hydrochloride, a well-characterized and selective α2-adrenergic agonist, was first 
approved as the active ingredient in the vasoconstrictor/decongestant nasal spray, Afrin® 
(oxymetazoline hydrochloride, 0.05%) in 1966.  
Detailed information on the nonclinical and clinical studies performed with RVL-1201 may be 
found in the Investigator’s Brochure. 
4.1. 
Justification of Route, Dose, Regimen, and Treatment Period 
Topical ocular administration of oxymetazoline hydrochloride at lower concentrations (0.01%, 
0.025%) results in vasoconstriction and reduction of hyperemia but does not have the 
pharmacologic effect of improving the superior visual field or increasing the marginal reflex 
distance (MRD). This effect is present at a concentration of 0.1%, the concentration of 
RVL-1201, based on the results of the Phase 3 study, Study RVL-1201-201. The pilot study, 
Study RVL-1201-001, showed that RVL-1201 administered once daily (QD) and twice daily 


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(BID) was more effective at elevating the upper eyelid than Vehicle, but BID dosing did not 
result in increased upper eyelid elevation compared to QD dosing. The safety profile of 
RVL-1201 QD in both studies was satisfactory, with AEs that were mild, and did not require 
treatment. In the pilot study, slightly more subjects in the BID treatment group than in the QD 
treatment group reported AEs. These were deciding factors in going forward with QD dosing in 
the first Phase 3 study. The current Phase 3 study, Study RVL-1201-203 will evaluate the safety 
of 1 drop of RVL-1201 Ophthalmic Solution in each eye QD for 84 days. This dosing duration 
was chosen to evaluate the safety of longer-term dosing than the 42-day period evaluated in 
Study RVL-1201-201. 
4.2. 
Good Clinical Practice Statement 
This study will be conducted according to all stipulations of the protocol including all statements 
regarding confidentiality and in compliance with International Council for Harmonisation (ICH) 
guidelines and all applicable United States (U.S.) federal regulations and local legal and 
regulatory requirements. 
4.3. 
Population to Be Studied 
Study subjects will be male or female subjects ≥ 9 years of age with acquired blepharoptosis. See 
Section 7 for inclusion and exclusion criteria. Written informed consent will be obtained prior to 
enrollment in the trial; for minor subjects, written informed consent from the parent/guardian and 
assent from the subject will be obtained following IRB guidelines. 


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5. 
TRIAL OBJECTIVE 
The objective of this study is to evaluate the safety of RVL-1201 Ophthalmic Solution in the 
treatment of acquired blepharoptosis over 12 weeks. 


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6. 
INVESTIGATIONAL PLAN 
6.1. 
Overall Study Design 
This will be a Phase 3, randomized, multicenter, double-masked, placebo-controlled study to 
evaluate the extended safety of RVL-1201 Ophthalmic Solution compared to Vehicle (placebo) 
for the treatment of acquired ptosis. The study will be conducted over 84 days (12 weeks).  
Eligible subjects will be randomized in a 2:1 ratio to one of the following 2 treatment arms and 
treated for 84 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 150) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 75) 
Both eyes will be treated and assessed.  
Following screening evaluations at the Screening/Baseline visit (Day 1), a determination of 
eligibility will be made, and eligible subjects will be randomized and receive study medication.  
Study medication, RVL-1201 or Vehicle (placebo), will be provided in identical-appearing 
unit-dose vials. The identity of the study medications will be masked to the subject, Investigator, 
study personnel responsible for ophthalmic evaluations, and Sponsor personnel.  
Subjects (or their caregiver, if necessary) will administer study medication QD in the morning 
during the study period. 
Safety follow-up visits will be conducted at Day 14 (Visit 2), Day 42 (Visit 3), and Day 84 
(Visit 4).  
Table 2 provides a tabular summary of all scheduled visits and procedures to be performed 
during the clinical study. 
 


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Table 2: 
Schedule of Procedures (Study RVL-1201-203) 
Assessment  
Screening/Baseline 
Randomization 
Day 1 
Day 14  
(± 3 Days) 
 
Day 42 
(± 3 Days) 
Day 84 
(± 3 Days) 
Early 
Discontinuation 
Visit 
1 
2 
3 
4 
 
Informed consent 
X 
 
 
 
 
Demographics/medical/ocular history 
X 
 
 
 
 
Collect study medication materials 
 
X 
X 
X 
X 
Urine pregnancy testa 
X 
 
 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Adverse event assessmentb 
X 
X 
X 
X 
X 
Tolerability assessment 
 
 
 
X 
X 
Blood pressure/heart ratec 
X 
X 
X 
X 
X 
External digital photograph 
X 
X 
X 
X 
X 
   Marginal reflex distance (OU)d 
X 
 
 
 
 
   Pupil diameter measurement (OU)d 
X 
X 
X 
X 
X 
Snellen visual acuity (OU)e 
X 
X 
X 
X 
X 
Slit lamp exam (OU) 
X 
X 
X 
X 
X 
Corneal fluorescein staining (OU) 
X 
X 
X 
X 
X 
Intraocular pressure tonometry (OU) 
X 
 
X 
X 
X 
Dilated ophthalmoscopy/fundus exam 
(OU)f 
X 
 
 
X 
X 
Review inclusion/exclusion criteria / 
Randomize eligible participants 
X 
 
 
 
 
Dispense/administer study medicationg 
X 
X 
X 
 
 


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Assessment  
Screening/Baseline 
Randomization 
Day 1 
Day 14  
(± 3 Days) 
 
Day 42 
(± 3 Days) 
Day 84 
(± 3 Days) 
Early 
Discontinuation 
Visit 
1 
2 
3 
4 
 
Study medication accountability 
X 
X 
X 
X 
X 
MRD = marginal reflex distance; OU = both eyes; VA = visual acuity 
a Females of childbearing potential only (females who have started their menstrual cycles). 
b For precise timing of adverse events at each visit, please refer to details of each individual visit in Section 10. 
c Resting blood pressure and heart rate are taken seated after 3 minutes rest. 
d MRD and pupil diameter will be measured from the external photograph.  
e If the corrected or uncorrected VA is 20/80 or better, no additional refraction is necessary. If corrected or uncorrected VA is worse than 20/80 an updated 
refraction must be performed, which must be used for all VA assessments during the study. The subject must wear the same glasses, if applicable, at each visit. 
For subjects with surgical monovision correction, VA assessment may be conducted in the near vision eye with a near vision reading card held at 
approximately 14 inches from the subject’s eye. 
f Only tropicamide (Mydriacyl) should be used for this exam. Phenylephrine hydrochloride (Neosynephrine) may NOT be used. 
g Study medication will be dispensed at Day 1 (Visit 1), Day 14 (Visit 2), and Day 42 (Visit 3). Study medication will be administered at the study site on Day 1. 
Otherwise, study medication will be administered QD in the morning at home daily. 
 


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6.2. 
Number of Subjects 
The planned sample size is approximately 225 subjects, 150 subjects in the RVL-1201 group, 
and 75 in the Vehicle group, to be enrolled at approximately 30 clinical sites in the U.S.  
6.3. 
Criteria for Study Termination 
The study may be terminated at any time for any reason by RevitaLid Inc. 


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7. 
SELECTION AND WITHDRAWAL OF SUBJECTS 
7.1. 
Inclusion Criteria 
1. Males or females ≥ 9 years of age. 
2. Presence of both of the following at Screening/Baseline: 
a. The MRD, the distance from the central pupillary light reflex to the central margin of 
the upper lid, must be ≤ 2 mm (no visible central pupillary light reflex defaults to 0) 
in either eye. 
b. Snellen visual acuity (VA) of 20/80 or better in the same eye as Inclusion Criteria 
#2a. 
3. Females must be 1-year postmenopausal, surgically sterilized, or females of childbearing 
potential with a negative urine pregnancy test at Visit 1. Females of childbearing 
potential (females who have started their menstrual cycles) must use an acceptable form 
of contraception throughout the study. Acceptable methods include the use of at least one 
of the following: intrauterine (intrauterine device), hormonal (oral, injection, patch, 
implant, ring), barrier with spermicide (condom, diaphragm), or abstinence. 
4. Must be able to self-administer study medication or to have the study medication 
administered by a caregiver throughout the study period. 
5. Must be able to understand and sign an informed consent form (ICF) prior to 
participation in any study-related procedures. For minor subjects, the subject’s parent or 
legal guardian must provide permission by signing the ICF on behalf of the subject and 
the subject should provide assent, per Institutional Review Board (IRB) guidelines. If a 
subject becomes 18 years of age during the study, the subject will need to sign an ICF to 
continue in the study. 
7.2. 
Exclusion Criteria 
In both eyes 
1. Dermatochalasis that extends less than 3 mm above the upper eyelid margin; 
dermatochalasis extending < 3 mm above the upper eyelid margin of a single eye is 
permitted. 
2. Pseudoptosis (upper eyelid dermatochalasis that overhangs the upper eyelid margin); 
pseudoptosis in a single eye is permitted. 
In either eye 
3. Congenital ptosis. 
4. Horner syndrome. 
5. Marcus Gunn jaw-winking syndrome. 
6. Myasthenia gravis. 
7. Mechanical ptosis, including ptosis due to orbital or lid tumor, cicatricial processes 
affecting the movements of the upper lid, and enophthalmos. 


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8. Previous ptosis surgery (previous blepharoplasty [only] is allowed provided the surgery 
took place > 3 months prior to Visit 1). 
9. Lid position affected by lid or conjunctival scarring. 
10. History of herpes keratitis. 
11. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been 
performed > 3 months prior to Visit 1). 
12. Periocular neurotoxin (e.g., Botox, Xeomin, Dysport, Myobloc) injections within 3 
months prior to Visit 1 and during the study. 
13. Topical application of bimatoprost (i.e., Latisse®) to the eyelashes within 7 days prior to 
Visit 1 and during the study. 
14. Use of topical ophthalmic medications (including anti-allergy [e.g., antihistamines], dry 
eye [i.e., Restasis®, Xiidra®], antimicrobial drugs [e.g., antibiotics and antivirals], and 
anti-inflammatory drugs [including nonsteroidal anti-inflammatory drugs (NSAIDs) and 
steroids] other than the assigned study medication within 7 days prior to Visit 1 and 
during the study. Topical ophthalmic prostaglandin analogues for the treatment of 
elevated intraocular pressure are permitted if dosed in the evening in accordance with the 
approved prescribing information. All other topical antiglaucoma medications are 
prohibited. 
15. Intravitreal injections (e.g., Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days prior 
to Visit 1 and during the study. 
16. Current punctal plugs or placement of punctal plugs during the study. 
17. Current use of over-the-counter (OTC) vasoconstrictor/decongestant eye medication 
(e.g., Visine® L.R.®) or any ophthalmic or non-ophthalmic α-adrenergic agonist including 
OTC products (e.g., Afrin®) at any time during the study; artificial tears are allowed. 
General 
18. Resting heart rate (HR) outside the normal range (50–110 beats per minute). 
19. Hypertension with resting diastolic blood pressure (BP) > 105 mm Hg or systolic BP 
> 220 mm Hg. 
20. Use of monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, phenelzine, 
tranylcypromine) within 14 days prior to Visit 1 and during the study. 
21. Advanced arteriosclerotic disease or history of cerebrovascular accident (CVA). 
22. History of hyperthyroidism or thyroid eye disease (i.e., exophthalmos, upper eyelid 
retraction, diplopia secondary to extraocular muscle involvement). Hypothyroidism that 
is controlled on medication is allowed. 
23. Patients with proliferative diabetic retinopathy may not be enrolled. However, patients 
with insulin dependent diabetes, diabetes requiring oral hypoglycemic drugs, or 
diet-controlled diabetes, with or without stable background diabetic retinopathy, are 
allowed. 


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24. Pregnancy or lactation. 
25. Diagnosed benign prostatic hypertrophy requiring medicinal therapy; previous 
prostatectomy is allowed.  
26. History of contact or systemic allergic reaction to oxymetazoline hydrochloride or other 
sympathomimetic drugs (e.g., phenylephrine, pseudoephedrine, ephedrine, 
phenylpropanolamine, fepradinol, or methoxamine). 
27. Participation in any drug or device clinical investigation within 30 days prior to entry into 
this study and/or during the period of study participation. Previous screening in 
Study RVL-1201-202 is allowed. 
28. Randomization into any previous clinical study of RVL-1201 (Study RVL-1201-001, 
Study RVL-1201-201, or Study RVL-1201-202) or into this study (Study 
RVL-1201-203). 
7.3. 
Subject Withdrawal Criteria 
The following are the criteria for considering withdrawal from the study: 
• Withdrawal of subject consent/assent. The subject may request for any reason at any 
time to be withdrawn from the study. 
• The Sponsor terminates the study (see Section 6.3). 
If a subject withdraws from the study, the principal reason for withdrawal will be recorded in the 
electronic case report form (eCRF). 
If a study subject fails to attend a study visit at any point during the study period, every effort 
should be made to keep the subject in the study and conduct all study visits as scheduled; all 
attempts to contact the subject must be documented. If the subject relocates during the study 
period, Oculos Clinical Research (Oculos), the clinical research organization, should be 
contacted to determine if there is a possibility that the subject could continue at another clinical 
site.  


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8. 
TREATMENT OF SUBJECTS 
8.1. 
Description of Study Medications 
RVL-1201 and Vehicle (placebo) are formulated for topical ocular delivery as aseptically 
prepared, sterile, non-preserved ophthalmic solutions and contain 0.1% or 0% of the active 
ingredient, oxymetazoline hydrochloride, respectively. Both RVL-1201 and Vehicle will be 
packaged in identical unit-dose vials to maintain masking of treatment identity. 
8.2. 
Randomization and Masking 
Study medication will be randomized in a 2:1 ratio (RVL-1201 Ophthalmic Solution [N = 150]; 
Vehicle [placebo] [N = 75]). A randomized block design will be used, and the randomization 
will be created by a biostatistician independent of the trial. The randomization schedule will not 
be stratified by any factors. 
If subjects meet eligibility criteria (see Section 7) at Screening/Baseline, Day 1 (Visit 1), sites 
will access the Interactive Web Response System (IWRS) to randomize subjects to study 
treatment and assign the study medication kit to be dispensed. The drug kit and randomization 
numbers will be recorded in the subject’s eCRF. Study medication from the IWRS-assigned kit 
will be dispensed to the subject after initial dosing at the study site on Day 1 (Visit 1), on 
Day 14 ± 3 (Visit 2) and on Day 42 ± 3 (Visit 3). 
The study will be double masked. The study medication will be provided in identical-appearing 
pouches with no labeling indicating the identity of the study group or the contents of the 
unit-dose vials. The pouches will contain identical-appearing unit-dose vials (see Section 8.1). 
Study subjects, Investigators and staff, and study management personnel will be masked to the 
identity of treatment until after the final database lock. 
8.2.1. 
Unmasking During the Study Period 
Should it be necessary to unmask a subject’s treatment assignment in case of emergency, the 
Investigator may obtain the treatment code for a given randomized subject from the IWRS. The 
treatment code is to be obtained only if a medical emergency exists and knowledge of the 
medication being taken will influence the medical management of the subject.  
The following procedure should be followed: 
1. The Investigator should contact the Medical Monitor via phone immediately before 
unmasking a subject unless it is not possible to do so without risk to the subject. 
2. The Investigator should document the AE and justification for unmasking in the Study 
Summary and Comments pages of the eCRF.  
3. If the subject is to be discontinued from study medication, then ALL procedures 
described in the Early Discontinuation Visit (Section 10.4) should be completed. 
4. The Investigator should contact Oculos at Revitalid-Safety@oculos.com within 24 hours 
with the subject number and details of the AE or SAE and any action taken. 


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8.3. 
Concomitant Medications 
8.3.1. 
Permitted Medications and Treatments 
Therapy considered necessary for the subject’s welfare that will not interfere with the evaluation 
of the study medication may be given at the discretion of the Investigator. If there is any question 
as to whether the medication may interfere, the Investigator should contact the Medical Monitor 
or Sponsor. Whenever possible, medications should be administered in dosages that remain 
constant throughout the study duration. Note: Contact lens wear is permitted during the study. 
Contact lenses must be removed prior to instillation of study medication and must not be 
reinserted for at least 15 minutes after study medication instillation. Contact lenses must not be 
worn during study visits. 
8.3.2. 
Prohibited Medications 
The Medical Monitor should be notified before prohibited medication or therapy is administered 
unless the safety of the subject requires immediate action. The decision to administer a 
prohibited medication or therapy should be done with the safety of the subject as the primary 
consideration. The Medical Monitor MUST be contacted to determine the permissibility of a 
specific medication or therapy and whether the subject should continue with study medication. 
Prohibited medications and therapies include:  
• Periocular neurotoxin (e.g., Botox, Xeomin, Dysport, Myobloc) injections within 
3 months prior to Visit 1 and during the study. 
• MAOIs (e.g., isocarboxazid, phenelzine, tranylcypromine) within 14 days prior to 
Visit 1 and during the study. 
• Topical application of bimatoprost (i.e., Latisse®) to the eyelashes within 7 days prior 
to Visit 1 and during the study. 
• Topical ophthalmic medications (including anti-allergy [e.g., antihistamines], dry eye 
[i.e., Restasis®, Xiidra®], antimicrobial drugs [e.g., antibiotics and antivirals], and 
anti-inflammatory drugs [including nonsteroidal anti-inflammatory drugs (NSAIDs) 
and steroids] other than the assigned study medication within 7 days prior to Visit 1 
and during the study. Topical ophthalmic prostaglandin analogues for the treatment of 
elevated intraocular pressure are permitted if dosed in the evening in accordance with 
the approved prescribing information. All other topical antiglaucoma medications are 
prohibited. 
• Intravitreal injections (e.g., Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days 
prior to Visit 1 and during the study. 
• Current punctal plugs or placement of punctal plugs during the study. 
• OTC vasoconstrictor/decongestant eye medication (e.g., Visine® L.R.®) or any 
ophthalmic or non-ophthalmic α-adrenergic agonist including OTC products (e.g., 
Afrin®); at any time during the study, artificial tears are allowed. 


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8.4. 
Treatment Compliance 
Treatment compliance will be monitored by study medication accountability. The amount of 
opened and unopened medication returned at Visits 2, 3, and 4 will be documented in the eCRF 
to provide an assessment of compliance in the form of percentage compliance for each subject 
that will be calculated by the electronic data capture (eDC) system. 
8.5. 
Discontinuation of Study Medication 
If a subject becomes pregnant during the study, the subject will be withdrawn from study 
medication and followed through the conclusion of the pregnancy (Section 9.6). 
Subjects may be discontinued from study medication because of either of the following: 
• Adverse event: A clinically significant or serious AE that in the Investigator’s or 
Medical Monitor’s judgment, suggests that continued administration of study 
medication is not in the subject’s best interests for safety reasons. Additionally, if an 
AE requires treatment, the Investigator in consultation with the Medical Monitor may 
determine that study medication should not be concurrently administered with a 
required concomitant medication. 
• Subject request: Subject requests to be withdrawn from study medication. 
When possible, a decision to discontinue a subject from study medication should first be 
discussed with the Medical Monitor. If a subject is discontinued from study medication, every 
effort should be made to encourage the subject to continue to attend study visits to be followed 
for safety, rather than withdrawing the subject from the study or, failing that, to perform all early 
discontinuation assessment procedures at the visit the subject is withdrawn (Section 10.4). 
Reasons for considering subject withdrawal from the study are discussed in Section 7.3.  
8.6. 
Study Medication Materials and Management 
8.6.1. 
Packaging and Labeling 
Study medication will be packaged and labeled at a central packaging facility. Study sites will 
utilize the IWRS to assign kits to subjects.  
8.6.2. 
Storage and Administration 
Study medication must be stored at room temperature 15°-25° C (59°-77° F). A room 
temperature log will be maintained at each study site. Subjects should be instructed not to store 
or place the study medication where it can be exposed to extreme temperatures (e.g., 
refrigeration or leaving it in a hot car) or light. The study medication will be provided in a 
child-resistant package. Importantly, subjects MUST store the eye drops out of reach of children 
at all times. Accidental ingestion by young children can result in serious adverse events. If a 
child accidentally swallows these eye drops, call the National Capital Poison Center 
(1-800-222-1222) and seek emergency medical care immediately. 
Site personnel will instruct the subject on the proper instillation technique at Day 1 (Visit 1) and 
the subject (or caregiver, if the subject is not able to self-administer the medication) will 
administer the first dose at the study site, instilling 1 full drop in each eye from the unit-dose vial 


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(Note: if a full drop is not instilled into the eye, the subject should wait approximately 
10-15 seconds and administer a second drop). The subject should be in a seated position and 
should tilt his or her head backward for administration of the study medication. The vial of study 
medication should be held at an almost vertical position above the eye while the lower eyelid is 
pulled down gently, and 1 full drop is placed into the conjunctival cul-de-sac. The tip of the vial 
should not touch the eye. After a full drop is instilled in each eye, the subject should keep the 
eyes gently closed for approximately 30 seconds. The subject will then empty the remaining 
contents of the unit-dose vial and place the empty vial in the pouch. 
Each subsequent morning of dosing, the subject will open a pouch from the box, administer one 
full drop to each eye from a single new unit-dose vial and close the eyes gently for 30 seconds, 
empty the remaining contents of the unit-dose vial, then store the opened vial in the foil pouch, 
and place it in the box for return to the study site. On Day 14 ± 3 days (Visit 2), subjects will 
return all opened and unopened study medication materials (the box, pouches, and unit-dose 
vials), and site personnel will conduct study medication accountability procedures and dispense 
study medication for the next study period. On Day 42 ± 3 days (Visit 3) all study medication 
materials will be returned to the study site, study medication accountability will be conducted, 
and study medication for the remaining study period will be dispensed. Lastly, on Day 84 ± 3 
days (Visit 4) all study medication materials will be returned to the study site and final study 
medication accountability will be conducted. The Day 84 visit will be the last day of study 
treatment; no further study medication will be dispensed at this visit. 
Note: Contact lens wear is permitted during the study. Contact lenses must be removed prior to 
instillation of study medication and must not be reinserted for at least 15 minutes after study 
medication instillation. Contact lenses must not be worn during study visits. 
8.6.3. 
Study Medication Accountability 
The Investigator or clinical site staff will maintain a full accountability record for the study 
medication and will be responsible for recording the receipt, dispensing, and return of all 
supplies of the study medication using the inventories supplied by the Sponsor. Each subject’s 
kit will contain sufficient study medication for the duration of the trial. Final study medication 
accountability will be conducted at Day 84 ± 3 days (Visit 4); study medication will not be 
re-dispensed at this visit. The Investigator or clinical site staff will account for all received and 
returned study medication. The monitor will review dispensing and study medication 
accountability records during site visits and at the completion of the study and note any 
discrepancies. All investigational study medication must be stored in a secure facility with access 
limited to the Investigator and authorized staff.  


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9. 
STUDY ASSESSMENTS 
Prior to entry into the study or initiation of any study-related procedures, the subject must read, 
sign, and date the current IRB-approved version of the informed consent form. For minor 
subjects, the subject’s parent or legal guardian must provide permission by signing the ICF on 
behalf of the subject, and assent from the minor subject should also be obtained following IRB 
guidelines. If a subject becomes 18 years of age during the study, the subject will need to sign an 
ICF to continue in the study. A full discussion of informed consent is presented in Section 13.3. 
Procedures must be performed in the order specified in Table 2. 
9.1. 
Demographic and Background Characteristics 
9.1.1. 
Demographic/Medical History 
A complete medical history will be obtained from each subject. Demographic information 
including date of birth, gender, race, ethnicity, iris color, and date of informed consent will be 
recorded. 
9.1.2. 
Concomitant Medications History 
All concomitant medications (prescription and OTC) taken at Visit 1 (Screening/Baseline, 
Day 1) and for 3 months prior to Visit 1 and throughout the course of the study will be recorded 
in the Concomitant Medications page of the eCRF. Information regarding the dates of first and 
last dose, site of dosing (e.g., right eye, left eye, both eyes [OU], systemic), and the reason the 
concomitant medication is being taken must be recorded in the eCRF. When a concomitant 
medication has been taken at a stable dose for longer than 6 months, an estimation of the start 
date is adequate. Standard procedural medications will not be captured in the eCRF but are 
recorded on a standard procedural medication log provided by Oculos. 
9.1.3. 
Ophthalmic History and Ophthalmic Intervention History 
Clinically significant ophthalmic history and ophthalmic intervention history will be documented 
and will include any previously diagnosed ophthalmic abnormalities and ocular surgeries, 
including laser procedures. 
9.1.4. 
Urine Pregnancy Test 
A urine pregnancy test will be performed for females of childbearing potential only (females 
who have started their menstrual cycles). 
9.2. 
External Photography 
An external photograph of the subject’s face will be taken using the provided digital camera. It is 
crucial that the same level of ambient lighting be maintained for each photograph throughout the 
study. The subject will be required to remove mascara and any other eyelid makeup if applicable. 
The subject will also be asked to relax his/her facial muscles. The photograph will frame the 
subject’s face from mid-forehead to the tip of the nose vertically and from ear-to-ear 
horizontally. A standardized millimeter ruler label will be placed vertically on the forehead, 
centered above the eyebrows, as a measurement legend. Measurements (MRD and pupil 


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diameter) will be made from the digital image or color printed copy of the photograph using a 
handheld caliper and the millimeter ruler label as the legend. 
9.2.1. 
Marginal Reflex Distance Measurement 
The distance from the center pupillary light reflex to the central margin of the upper eyelid is the 
MRD. The MRD will be measured from the external photograph. 
9.3. 
Safety Assessments 
Assessment of the safety and tolerability of RVL-1201 Ophthalmic Solution compared to 
Vehicle will include bilateral ophthalmic examinations (Snellen VA, pupil diameter 
measurement, SLE/CFS, intraocular pressure (IOP) tonometry, dilated ophthalmoscopy/fundus 
exam), measurement of vital signs, and recording of adverse events. Subject rating of study 
medication tolerability will also be obtained. 
9.3.1. 
Vital Signs 
Blood pressure (from the same arm, and with the same cuff size, appropriate for arm 
circumference, throughout study) and heart rate will be measured after at least 3 minutes rest in 
the sitting position. Vital signs may be repeated once, after at least 5 minutes rest in the seated 
position, if they are out of range. 
9.3.2. 
Snellen Visual Acuity Assessment 
Corrected or uncorrected Snellen VA measurement will be performed with the Snellen eye chart 
using the subject’s current corrective lens prescription, if applicable, at a distance equivalent to 
20 feet (6 meters). If the corrected or uncorrected visual acuity is 20/80 or better, no additional 
refraction is necessary. If corrected or uncorrected visual acuity is worse than 20/80, then an 
updated refraction must be performed. This refraction must be used for all VA and visual field (if 
applicable) assessments during the study. The subject must wear the same glasses (if applicable) 
at each visit. The updated refraction can be placed in a trial frame or phoropter for VA 
assessments, and the trial frame only for visual field (if applicable) assessments. 
For subjects with surgical monovision correction, VA assessment may be conducted in the near 
vision eye with a near vision reading card held at approximately 14 inches from the subject’s 
eye. 
9.3.3. 
Pupil Diameter Measurement 
Pupil diameter will be measured (either horizontally or vertically if top of pupil is not visible in 
photograph) from the external photograph (see Section 9.2). 
9.3.4. 
Slit Lamp Exam/Corneal Fluorescein Staining 
A routine SLE will be performed to evaluate the anterior segment of the eye, including lids, 
cornea, conjunctiva, anterior chamber, iris, and lens. Abnormalities will be documented. 
Fluorescein staining of the corneal epithelium will be performed in both eyes according to the 
Investigator’s standard of care.  


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Staining will be graded on a 5-point scale: 
0 = No staining 
1 = Trace 
2 = Mild 
3 = Moderate 
4 = Severe 
9.3.5. 
Dilated Ophthalmoscopy/Fundus Exam 
Direct dilated ophthalmoscopy will include assessment of the optic nerve head for pallor and 
cupping. A fundus exam consisting of the vitreous, optic nerve, macula, and peripheral retina 
will be conducted, and the structures will be graded as normal or abnormal. Only tropicamide 
(Mydriacyl) should be used for this exam. Phenylephrine hydrochloride (Neosynephrine) may 
NOT be used.  
9.3.6. 
Intraocular Pressure Tonometry 
Intraocular pressure will be measured utilizing a Goldmann, Tono-Pen, or iCare tonometer 
(whichever is chosen, it must be used for the duration of the trial; no combination is permitted) 
and using the standard of care. If possible, the same calibrated instrument should be used for a 
given subject throughout the study.  
9.3.7. 
Study Medication Tolerability Assessment 
Subjects will be asked to rate the ocular tolerability of the medication according to the following 
4-point scale: 
0 = No discomfort 
1 = Mild discomfort 
2 = Moderate discomfort 
3 = Severe discomfort 
9.4. 
Adverse and Serious Adverse Events 
9.4.1. 
Definition of Adverse Events 
9.4.1.1. 
Adverse Event (AE) 
An AE is any untoward medical occurrence in a patient or clinical study subject administered a 
study medication (pharmaceutical/biological product) that does not necessarily have a causal 
relationship to this medication. An AE can therefore be any unfavorable and unintended sign 
(including abnormal laboratory findings), symptom, or disease temporally associated with the 
use of the study medication, whether or not related to the study medication. Study medication 
includes the investigational drug under evaluation and the comparator product or vehicle placebo 
that is given during any phase of the study. 


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Medical conditions/diseases present before starting the investigational treatment are only 
considered AEs if they worsen after starting the investigational treatment. Abnormal test results 
constitute AEs only if they induce clinical signs or symptoms, are considered clinically 
significant, or require therapy. 
The occurrence of AEs should be sought by open-ended questioning of the subject at each visit 
during the study. At each clinic visit, study personnel should ask the following question: "Have 
you had any problems since your last visit?” AEs also may be detected when they are 
volunteered by the subject during or between visits or through study assessments. 
9.4.1.2. 
Serious Adverse Event (SAE) 
An SAE is any untoward medical occurrence that at any dose: 
• Results in death, 
• Is life-threatening, 
Note: The term "life-threatening" refers to an event in which the subject was at risk of 
death at the time of the event; it does not refer to an event which hypothetically might 
have caused death if it were more severe. 
• Results in persistent or significant disability/incapacity (excluding 
progression/outcome of the disease under study); 
• Is a congenital anomaly/birth defect, 
• Requires inpatient hospitalization or prolongation of existing hospitalization, or 
• Is medically significant; i.e., defined as an event that jeopardizes the health of the 
subject or may require medical or surgical intervention to prevent one of the 
outcomes listed above. 
Treatment on an outpatient emergency basis that does not result in hospital admission, or a 
hospitalization that is elective or is a preplanned treatment for a pre-existing condition that is 
unrelated to the indication under study and has not worsened since the start of the study, is not 
considered an SAE. 
All SAEs that are ongoing at the time of completion or discontinuation from the study will be 
followed until stabilization or resolution of the event. 
9.5. 
Relationship to Study Drug 
The relationship of AEs to the study medication should be assessed by the Investigator using the 
definitions below. 
Not suspected: The temporal relationship of the event to the study medication makes a causal 
relationship unlikely, or, other drugs, therapeutic interventions or underlying conditions provide 
a sufficient explanation for the observed event. 
Suspected: The temporal relationship of the event to the study medication makes a causal 
relationship possible or other drugs, therapeutic interventions or underlying conditions do not 
provide a sufficient explanation for the observed event. 


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If there is any valid reason, even if undetermined, for suspecting a possible cause-and-effect 
relationship between the study medication and the occurrence of the AE, then the AE should be 
considered “suspected.” 
If the relationship between the AE/SAE and the investigational product is determined by the 
Sponsor to be “suspected” the event will be considered to be related to the investigational 
product for the purposes of expedited regulatory reporting. 
9.6. 
Recording Adverse Events 
Adverse events spontaneously reported by the subject and/or in response to an open question 
from the study personnel or revealed by observation, regardless of severity or potential 
association with the study medication or study procedures, will be recorded in the eCRF. 
Changes from baseline assessments that are part of the disease being studied will not necessarily 
be recorded as adverse events unless the Investigator deems them as such. Clinically significant 
changes in blood pressure and heart rate should be reported as AEs. All AEs that occur following 
consent and until the final study visit (Day 84, Visit 4) should be collected and recorded on the 
AE eCRF page. Serious adverse events will be followed until the event is resolved or stabilized.  
The AE term should be reported in standard medical terminology when possible. For each AE, 
the Investigator will evaluate and report the following: 
• Onset (date and time); 
• Resolution (date and time); 
• Severity grade (mild, moderate, severe); 
• Relationship to study medication (not suspected, suspected); 
• Action taken (none, study medication temporarily interrupted, study medication 
permanently discontinued; concomitant medication taken; hospitalization/prolonged 
hospitalization; other); 
• Serious outcome (yes/no). 
The severity grade should be determined by the Investigator using the definitions below. 
• Mild: Discomfort noticed but no disruption of normal daily activity  
• Moderate: Discomfort sufficient to cause interference with normal daily activity  
• Severe: Incapacitating, with inability to perform normal activities 
It is important to distinguish between serious and severe AEs. Severity is a measure of intensity 
(as defined directly above) whereas seriousness is defined by the criteria under Section 9.4.1.2. 
An AE of severe intensity may not be considered serious. 
Should a pregnancy occur, it must be reported and recorded on the pregnancy form. Pregnancy in 
itself is not regarded as an AE unless there is a suspicion that an investigational product may 
have interfered with the effectiveness of a contraceptive medication. The subject will be 
withdrawn from study medication and followed through conclusion of pregnancy. The outcome 
of all pregnancies (spontaneous miscarriage, elective termination, normal birth or congenital 
abnormality) must be followed up and documented. 


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9.7. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded following consent and until the final study 
visit, Day 84 (Visit 4), following the end of treatment exposure. Any SAEs “suspected” to be 
related to the investigational product and discovered by the Investigator at any time after the 
study should be reported.  
Any SAE that occurs must be reported to Oculos within 24 hours of its occurrence or within 
24 hours of learning of its occurrence. Recurrent episodes, complications, or progression of the 
initial SAE must be reported to Oculos as follow-up to the original episode within 24 hours of 
the Investigator receiving the information. Information about all SAEs will be collected and 
recorded on the SAE form. All pertinent medical records and information collected during the 
treatment and follow-up of the subject should be maintained at the site with a copy emailed to 
. The Investigator must assess the SAE relationship and complete 
the SAE form. Oculos/RevitaLid Inc. may request additional information. Follow-up information 
(e.g., discharge summary) will be retained in the subject’s chart and a copy will be emailed to 
 
In addition, all SAEs should be recorded on the Adverse Event eCRF page with the serious 
question marked “Yes”. 
It is the Investigator’s responsibility to notify the approving IRB of any SAEs on a timely basis 
as instructed by the Sponsor following the Sponsor’s determination of causality. 
All subjects who experience an SAE should be followed clinically and undergo the appropriate 
diagnostic evaluations until stabilization or resolution of the event. 
RevitaLid will report all SAEs to the U.S. Food and Drug Administration (FDA) on the 
appropriate schedule depending if the event is drug related or not drug related, expected or 
unexpected (based on the available information in the Investigator’s Brochure). 
Any death occurring during the study and follow up period should be reported as an SAE. For 
any death occurring through the end of the study, regardless of the degree of relationship to study 
medication, the SAE resulting in the death must be reported to Oculos. A death occurring after 
completion of the study does not require completion of the SAE form. 


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10. 
STUDY ACTIVITIES 
Table 2 provides a tabular summary of all scheduled visits and procedures to be performed 
during the clinical study. 
All ophthalmic assessments will be performed bilaterally. 
10.1. 
Day 1 (Visit 1): Screening/Baseline/Randomization/First Dose 
Subjects will provide written informed consent before any study-related screening procedures are 
conducted. For minor subjects, signed informed consent will be obtained from the subject’s 
parent or legal guardian, and assent will be obtained from the subject following IRB guidelines.  
Subjects will undergo screening/baseline evaluations to determine eligibility for the study. 
Following review of inclusion/exclusion criteria, the site will access the IWRS to randomize the 
subject to study treatment and assign the study medication kit to be dispensed. Subjects (or 
caregivers, if the subject is not able to self-administer the medication) will receive instruction on 
administration procedures and administer the first dose. Adverse events will be assessed post 
dose, and study material accountability will be performed. 
Day 1 procedures include the following: 
• Informed consent/assent 
• Demographics 
• Medical and ocular histories 
• Urine pregnancy test (females of childbearing potential only) 
• Prior and concomitant medications/therapies 
• BP/HR 
• MRD (from external photograph) 
• Pupil diameter measurement (from external photograph) 
• Snellen visual acuity  
• SLE  
• CFS  
• IOP  
• Dilated ophthalmoscopy/fundus exam  
• Review inclusion/exclusion criteria 
• Randomization of eligible subjects via IWRS (see Section 8.2) 
• Dispense study medication Box 1 per IWRS assignment 
• Instruct the subject on use and storage of study medication (see Section 8.6.2) 
• The subject (or caregiver, if the subject is not able to self-administer the medication) 
will administer allocated study medication, 1 full drop in each eye (if a full drop is 


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not instilled into the eye, the subject will wait approximately 10-15 seconds and 
administer a second drop). After a full drop is instilled in each eye, the subject should 
keep the eyes gently closed for approximately 30 seconds. 
• AE assessment 
• Study medication accountability 
10.2. 
Days 2 through 14 
From Days 2 through 14, randomized study medication will be administered in each eye QD in 
the morning and subjects will return to the clinical site on Day 14 ± 3 days in the morning after 
instillation of study medication at home. Note: Contact lenses must be removed prior to 
instillation of study medication and must not be reinserted for at least 15 minutes after study 
medication instillation. Contact lenses must not be worn during study visits. 
10.3. 
Safety Follow-up Visits 
10.3.1. 
Day 14 ± 3 (Visit 2)  
On Day 14 ± 3 (Visit 2), subjects will return all opened and unopened study medication materials 
and undergo safety assessments. Site personnel will dispense study medication (Box 2) and 
conduct study medication accountability procedures. 
Day 14 procedures include the following: 
• Collect Box 1, containing all opened and unopened study medication materials 
(unit-dose vials and pouches), from the subject 
• Concomitant medication review 
• AE assessment 
• BP/HR 
• Pupil diameter measurement (from external photograph)  
• Snellen VA  
• SLE  
• CFS  
• Dispense study medication Box 2 
• Study medication accountability 


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10.3.2. 
Days 15 through 42 
From Days 15 through 42, randomized study medication will be administered in each eye QD in 
the morning and subjects will return to the clinical site on Day 42 ± 3 days in the morning after 
instillation of study medication at home. Note: Contact lenses must be removed prior to 
instillation of study medication and must not be reinserted for at least 15 minutes after study 
medication instillation. Contact lenses must not be worn during study visits.  
10.3.3. 
Day 42 ± 3 (Visit 3) 
On Day 42 ± 3 (Visit 3), subjects will return all opened and unopened study medication materials 
and undergo safety assessments. Site personnel will dispense study medication (Box 3) and 
conduct study medication accountability procedures. 
Day 42 procedures include the following: 
• Collect Box 2, containing all opened and unopened study medication materials 
(unit-dose vials and pouches), from the subject 
• Concomitant medication review 
• AE assessment 
• BP/HR 
• Pupil diameter measurement (from external photograph)  
• Snellen VA  
• SLE  
• CFS  
• IOP 
• Dispense study medication Box 3 
• Study medication accountability 
10.3.4. 
Days 43 through Day 84 
From Day 43 through the morning of Day 84, randomized study medication will be administered 
in each eye QD in the morning and subjects will return to the clinical site on Day 84 ± 3 days in 
the morning after instillation of study medication at home. Note: Contact lenses must be 
removed prior to instillation of study medication and must not be reinserted for at least 
15 minutes after study medication instillation. Contact lenses must not be worn during study 
visits.  
10.3.5. 
Day 84 ± 3 (Visit 4): Final Treatment Visit 
On Day 84 ± 3, subjects will return all opened and unopened study medication materials and 
participate in final safety and tolerability assessments. Site personnel will conduct final study 
medication accountability procedures. 


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Visit 4 procedures include the following: 
• Collect Box 3, containing all opened and unopened study medication materials 
(unit-dose vials and pouches), from the subject 
• Urine pregnancy test (females of childbearing potential only) 
• Concomitant medication review 
• AE assessment 
• Study medication tolerability assessment 
• BP/HR 
• Pupil diameter measurement (from external photograph)  
• Snellen VA  
• SLE  
• CFS  
• IOP 
• Dilated ophthalmoscopy/fundus exam 
• Final study medication accountability 
10.4. 
Early Discontinuation Assessment Procedures 
If a study subject is discontinued from study medication before Day 84 (Visit 4) and after Day 1 
(Visit 1), procedures performed will include the following:  
• Collect all opened and unopened study medication materials (opened and unopened 
unit-dose vials and pouches) from the subject 
• Urine pregnancy test (for females of childbearing potential only) 
• Concomitant medication review 
• AE assessment  
• Study medication tolerability assessment (rating by subject) 
• BP/HR (taken after 3 minutes at rest) 
• Pupil diameter measurement (from external photograph) 
• Snellen VA 
• SLE 
• CFS 
• IOP 
• Dilated ophthalmoscopy/fundus exam  
• Study medication accountability  


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11. 
STATISTICS 
11.1. 
General Considerations 
This is a Phase 3 study to evaluate the safety of QD treatment with RVL-1201 Ophthalmic 
Solution (oxymetazoline hydrochloride ophthalmic solution, 0.1%) compared to Vehicle 
(placebo) for the treatment of acquired ptosis over an extended dosing period of 12 weeks. 
Subjects will be randomized in a 2:1 ratio of RVL-1201 Ophthalmic Solution to Vehicle into 
2 treatment groups and treated for 84 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 150) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 75). 
A biostatistician will perform statistical analyses as agreed with the Sponsor according to the 
Statistical Analysis Plan (SAP).  
A detailed SAP will be finalized prior to database lock. Descriptive statistics (n, mean, median, 
standard deviation [SD], minimum, and maximum for continuous data; frequencies and 
percentages for categorical data) will be used to summarize study data. No statistical tests will be 
performed for any of the assessments.  
11.1.1. 
Handling of Missing Data 
No missing data will be imputed. The reasons for missing data will be recorded in the eCRF. 
11.2. 
Determination of Sample Size 
The sample size for this study is not based on statistical calculations. The sample size was based 
on the need to obtain sufficient safety data to meet regulatory obligations for the development of 
RVL-1201. 
11.3. 
Analysis Populations 
The Safety population will be used for all analyses. No efficacy analyses will be performed. 
11.3.1. 
Safety Population 
The Safety population includes all subjects who receive at least one dose of double-masked study 
treatment and have at least one post-dose visit. Subjects will be analyzed according to the 
treatment received. 
11.4. 
Demographics and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized for all analysis 
populations. Summary tables will be supported with individual subject data listings. 


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11.5. 
Safety Endpoints 
The safety of RVL-1201 compared to Vehicle will be evaluated by the following endpoints: 
1. Comparison of ocular and non-ocular AEs by: 
a. Frequency 
b. Intensity 
c. Relationship to treatment 
d. Serious adverse events 
e. Adverse events leading to withdrawal of study medication 
2. Comparison of subjects with findings on the following measures: 
a. Slit-lamp examination 
b. Corneal fluorescein staining 
c. Pupil diameter 
d. Dilated ophthalmoscopy/fundus examination 
e. Tonometry  
f. Snellen VA (corrected) 
g. Vital signs (BP/HR) 
3. Comparison of tolerability as measured by the tolerability scale. 
11.6. 
Safety Analyses 
The safety of RVL-1201 will be compared to Vehicle with analysis of safety variables including 
bilateral ophthalmic examinations (Snellen VA, SLE/CFS, measurement of pupil diameter from 
external photographs, dilated ophthalmoscopy/fundus examination, and tonometry), vital signs 
(BP/HR), and AEs. The ocular tolerability of study medication will be rated by the subject. 
Safety data will be presented in tables of descriptive statistics and frequency distribution. All 
summary tables will be supported with individual subject data listings. 


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12. 
QUALITY CONTROL AND QUALITY ASSURANCE 
Oculos Clinical Research/RevitaLid Inc. and/or their contracted agents utilize standard operating 
procedures (SOPs) designed to ensure that research procedures and documentation are 
consistently conducted/prepared to the highest quality standards. These SOPs require compliance 
with FDA regulations and the ICH Good Clinical Practice (GCP) guidance. 
The study will be monitored by Oculos to verify that the rights and well-being of human subjects 
are being protected, the reported data are accurate, complete, and verifiable, and that the conduct 
of the study is in compliance with the currently approved protocol, with ICH GCP, and with the 
applicable regulatory requirements. 
To ensure compliance with GCP and all applicable regulatory requirements, RevitaLid or its 
agent may conduct a quality assurance audit at any time during or after completion of a study. 
The Investigator will be given adequate notice if he/she is selected for an audit. The audit will 
include, but is not limited to: a review of all informed consent/assent forms, medical records, and 
regulatory documentation; an assessment of study conduct and protocol compliance; and a 
review of the investigational drug product receipt, storage, and administration. At the conclusion 
of an audit, the auditor will conduct a brief meeting with the Investigator to review the findings 
of the audit. 


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13. 
ADMINISTRATIVE CONSIDERATIONS 
13.1. 
Institutional Review Board (IRB) 
The IRB must review, approve, and provide continuing review of the clinical study protocol, 
protocol amendments, the informed consent documents, subject recruitment advertisements, and 
any other written information to be provided to the subjects. Initial IRB approval is an 
affirmative decision that the clinical study has been reviewed and may be conducted at the study 
site within the constraints set forth by the IRB, the institution, GCP, and applicable regulatory 
requirements. A copy of the IRB approval letter for the protocol, the informed consent, the 
intended advertising, and any written material to be provided to the subject must be submitted to 
Oculos prior to release of investigational supplies to the study site. Progress reports and 
notifications of serious adverse drug reactions will be provided to the IRB according to local 
regulations and guidelines. The IRB must be notified of completion or termination of the study. 
The study site must maintain an accurate and complete record of all reports, documents, and 
other submissions made to the IRB concerning this protocol. 
13.2. 
Ethical Conduct of the Study 
The study will be conducted according to all stipulations of the protocol, including all statements 
regarding confidentiality, and in compliance with ICH guidelines, and all applicable US federal 
regulations and local legal and regulatory requirements. 
13.3. 
Written Informed Consent/Assent 
A sample ICF containing the required elements of informed consent will be provided by Oculos. 
Sample minor assent form(s) will be provided as required by IRB guidelines. Any changes made 
to these samples must be approved by Oculos prior to submission to the IRB. After approval by 
Oculos, the informed consent form and minor assent form must be submitted to and approved by 
the IRB. The informed consent must be written in a language in which the subject is fluent. 
Regulations require that foreign language informed consent and assent forms be submitted to the 
IRB for approval. The foreign language translation is required to contain a statement of 
certification of the translation. The Investigator must forward a copy of the consent and assent 
forms, the certified foreign language translation, and an IRB approval letter to Oculos. 
It is the responsibility of the Investigator to inform each subject of the purpose of this clinical 
trial, including possible risks and benefits, and to document the informed consent process. Prior 
to undergoing any study-related procedures, the subject must read, sign, and date the current 
IRB-approved version of the informed consent form. For minor subjects, the assent form must be 
signed and dated per IRB guidelines. If subjects become 18 years of age during the study, they 
will need to sign an ICF to continue in the study. The original informed consent form is to be 
retained by the study site, and a copy is to be given to the subject. 
13.4. 
Subject Confidentiality and Confidentiality of Data 
Data generated for the study should be stored in a limited-access file area and be accessible only 
to representatives of the study site, Oculos/RevitaLid Inc., the IRB, and FDA/relevant regulatory 
agencies. Medical information resulting from a subject’s participation in this study may be given 


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to the subject’s personal physician or to the appropriate medical personnel responsible for the 
subject’s welfare. No information that can be related to a specific individual subject will be 
released or used in any fashion without the signed written consent of that subject. All reports and 
communications relating to study subjects will identify subjects only by initials and subject 
identification number. Complete subject identification will be kept by the Investigator for 
purposes of long-term follow-up, if needed. This information will be treated with strict 
adherence to professional standards of confidentiality. 
13.5. 
Study Monitoring 
The study will be monitored by Oculos on behalf of RevitaLid Inc. to assure compliance with the 
study protocol and the quality of the data collected. Monitoring visits may occur as required and 
could include a study initiation visit, interim monitoring visits, and a study close-out visit. 
Training will be provided for key investigative personnel in all aspects of study conduct. The 
Investigator will be responsible for making sure that clinical site personnel are provided adequate 
training on conducting their designated tasks. 
The sites will record data directly into the eCRF in order to optimize the eCRF source 
verification process with limited hand-written source documentation. Monitors will review e-
source data and overall study data/consistency remotely and query discrepancies based upon 
eCRF entries (eCRF initial entry is the source). During this monitoring, data are reviewed as 
entered by the site, and the monitors will flag any abnormalities, trends, or safety signals for 
Medical Monitor review and monitor follow-up onsite, if necessary. 
During visits to the clinical site, the monitor may review the source documents including but not 
limited signed informed consent forms, study medication accountability and storage, and the 
reporting procedures for AEs and SAEs. All data generated during this study and the medical 
records/documents from which they originated are subject to inspection by Oculos/RevitaLid 
Inc., the FDA, and other regulatory agencies. The Investigator must notify Oculos promptly of 
any inspections scheduled by regulatory authorities. 
Upon completion of the study, the clinical monitor will conduct a final visit (closeout) to the site. 
The objectives of this visit are to ascertain that all regulatory records and reports are complete, 
verify that the study medication and other supplies have been accounted for, and ensure that the 
Investigators are aware of their responsibilities once the study ends.  
The Investigator is responsible for permitting the Oculos direct access to any study documents 
for monitoring and auditing purposes, for providing adequate space for monitoring, and for 
addressing any questions or issues that might be raised by the monitor or auditor on a timely 
basis. 
13.6. 
Case Report Forms and Study Records  
All data relating to study procedures will be entered by site personnel onto eCRFs provided by 
Oculos. The eCRF is the first place the majority of the study data will be recorded and therefore 
considered to be the source document. In general, paper source documents will not be created, 
but when generated, source documents (e.g., discharge summaries, etc.) will be retained at the 
study site. 


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13.7. 
Protocol Deviations 
The Investigator should not deviate from the requirements of this protocol without prior written 
approval of the Medical Monitor at Oculos, with the exception of a medical emergency.  
All protocol deviations will be documented. A significant protocol deviation must be reported to 
Oculos upon discovery. A reportable protocol deviation is defined as nonadherence to the 
protocol that involves inclusion/exclusion criteria, affects subject safety, or has the potential to 
affect the integrity of the data. Protocol deviations should be reported to the IRB in accordance 
with IRB guidelines. If there is any question as to whether the deviation is reportable, Oculos and 
the IRB should be contacted. 
All changes to the protocol will be made by the Sponsor/Oculos or designee as an approved 
amendment to the protocol, submitted to the FDA, and approved by the IRB prior to 
implementation. 
13.8. 
Access to Source Documentation 
A trial-related monitoring audit, review by the IRB, and/or regulatory inspection may be 
conducted at any time during or after completion of a study (Section 12). The Investigator will 
be given adequate notice if he/she is selected for an audit and must provide direct access to study 
documentation. The audit may include, but is not limited to, a review of all ICFs; a review of 
medical records; a review of regulatory documentation; an assessment of study conduct and 
protocol compliance; and a review of the investigational drug product receipt, storage, and 
administration. 
13.9. 
Data Generation and Analysis 
Management of data and the production of the clinical study report will be the responsibility of 
Oculos or their designee. 
During the course of the trial, data queries will be generated for data items that are potentially 
erroneous and require appropriate clarification or correction. Such clarifications and corrections 
will be discussed with and approved by study site personnel and appropriately documented. Prior 
to database lock, data listings will be generated, and anomalous values investigated. 
13.9.1. 
Retention of Data 
The Investigator must maintain essential study documents (protocol and amendments, source 
documentation corresponding to all information contained in the CRFs/eCRFs, signed ICFs, 
relevant correspondence, and all other supporting documentation) until at least 2 years after the 
last approval of a marketing application in an ICH region and until there are no pending or 
contemplated marketing applications in an ICH region, or at least 2 years after the formal 
discontinuation of clinical development of the investigational product. If the principal 
Investigator moves from the current study site, RevitaLid Inc. should be notified of the name of 
the person who will assume responsibility for maintenance of the records at the study site or the 
new address at which the records will be stored. The Investigator will notify RevitaLid Inc. as 
soon as possible in the event of accidental loss or destruction of any study documentation. 


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If it becomes necessary for Oculos/RevitaLid Inc. or the FDA or relevant regulatory authority to 
review any documentation relating to the study, the Investigator must permit access to such 
records. 
13.10. 
Publication and Disclosure Policy 
All information concerning RVL-1201 and the operations of RevitaLid Inc., such as patent 
applications, formulas, manufacturing processes, basic scientific data or formulation information 
not previously published, are considered CONFIDENTIAL and shall remain the sole property of 
RevitaLid Inc. The Investigator agrees to use this information only in accomplishing this study 
and will not use it for other purposes without the written consent of RevitaLid Inc. 
The publication policy is addressed in a separate agreement. 


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14. 
REFERENCES 
Finsterer J. Ptosis: causes, presentation, and management. Aesthetic Plast Surg. 2003 
May-Jun;27(3):193-204. 
Fraunfelder FT, Scafidi AF. Possible adverse effects from topical ocular 10% phenylephrine. Am 
J Ophthalmol. 1978;85(4):447-53. 
Kass MA, Mandell AI, Goldberg I, Paine JM, Becker B. Dipivefrin and epinephrine treatment of 
elevated intraocular pressure: a comparative study. Arch Ophthalmol. 1979 Oct;97(10):1865-6. 
Matjucha IC. The nonsurgical treatment of ptosis. In: Cohen AJ, Weinberg DA, editors: 
Evaluation and management of blepharoptosis. New York: Springer, 2011. p. 155-61. 
Scheinfeld N. The use of apraclonidine eyedrops to treat ptosis after the administration of 
botulinum toxin to the upper face. Dermatol Online J. 2005 Mar 1;11(1):9. 
Shah-Desai SD, Aslam SA, Pullum K, Beaconsfield M, Rose GE. Scleral contact lens usage in 
patients with complex blepharoptosis. Ophthal Plast Reconstr Surg. 2011 Mar-Apr;27(2):95-8. 
Sridharan GV, Tallis RC, Leatherbarrow B, Forman WM. A community survey of ptosis of the 
eyelid and pupil size of elderly people. Age Ageing. 1995 Jan;24(1):21-4. 


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15. 
SUMMARY OF CHANGES 
15.1. 
Changes Implemented in Protocol RVL-1201-203 Amendment 1 
The following changes were made to the original protocol:  
Location 
Description of Change 
Rationale for Change 
Synopsis Inclusion 
Criteria;  
4.3. Population to be 
Studied; 
7.1. Inclusion Criteria  
Change  
“> 9 years of age” to “≥ 9 year of age” 
 
To correct typographical error 
15.2. 
Changes Implemented in Protocol RVL-1201-203 Amendment 2 
The following changes were made to Amendment 1: 
Location 
Description of Change 
Rationale for Change 
Synopsis Exclusion Criteria;  
7.2. Exclusion Criteria 
Change from 
In either eye 
1. Congenital ptosis 
2. Presence of either of the following: 
a. 
Pseudoptosis (upper eyelid 
dermatochalasis that overhangs the 
upper eyelid margin) 
or 
b. Dermatochalasis that extends less 
than 3 mm above the upper eyelid 
margin  
to 
In both eyes 
1. Dermatochalasis that extends less than 
3 mm above the upper eyelid margin; 
dermatochalasis extending < 3 mm 
above the upper eyelid margin of a 
single eye is permitted. 
2. Pseudoptosis (upper eyelid 
dermatochalasis that overhangs the 
upper eyelid margin); pseudoptosis in 
a single eye is permitted. 
In either eye 
3. Congenital ptosis 
Dermatochalasis of < 3 mm or 
pseudoptosis should only 
exclude the eye that it occurs 
in, not the opposing upper 
eyelid that might otherwise be 
eligible for the study. 
Synopsis Exclusion Criteria;  
7.2. Exclusion Criteria 
Change from  
18. Resting heart rate (HR) outside the 
normal range (60–100 beats per 
minute). 
to 
18. Resting heart rate (HR) outside the 
normal range (50–110 beats per 
minute). 
To allow enrollment of healthy 
individuals with heart rates that 
are normal for them and do not 
require treatment. 


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Location 
Description of Change 
Rationale for Change 
Synopsis Exclusion Criteria;  
7.2. Exclusion Criteria 
Change from 
23. Patients with diabetic retinopathy may 
not be enrolled. However, patients with 
insulin dependent diabetes, diabetes 
requiring oral hypoglycemic drugs, or 
diet controlled diabetes are allowed. 
23. Patients with proliferative diabetic 
retinopathy may not be enrolled. 
However, patients with insulin 
dependent diabetes, diabetes requiring 
oral hypoglycemic drugs, or diet 
controlled diabetes, with or without 
stable background diabetic 
retinopathy, are allowed. 
To allow patients with stable 
background diabetic 
retinopathy to participate in the 
study, if otherwise eligible. 
 

SAP_001.pdf: 
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STATISTICAL ANALYSIS PLAN 
 
Confidential 
 
 
PROTOCOL TITLE: 
A Randomized, Double-Masked, Placebo-Controlled Phase 3 
Study of the Safety of RVL-1201 in the Treatment of Acquired 
Blepharoptosis, Study RVL-1201-203 
PROTOCOL NUMBER: 
CLN.RVL-1201.RVL-1201-203.PR.A02 
Study Phase: 
Phase 3 
Product Name: 
RVL-1201, Oxymetazoline hydrochloride ophthalmic solution, 0.1% 
Indication: 
Treatment of acquired blepharoptosis 
Sponsor: 
RevitaLid, Inc.  
400 Crossing Boulevard 
Bridgewater, NJ 08807 
Document No: 
CLN.RVL-1201-203.SAP.00 
 
 
Issue Date: 
 
 
20 November 2018 
 
 
 
 
 
Confidentiality Statement 
 
CONFIDENTIAL: The information contained in this document is confidential and is the 
property of RevitaLid, Inc. Do not copy, print or transmit in electronic or any other format 
without the permission of RevitaLid, Inc. 
 
 




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TABLE OF CONTENTS 
 
TABLE OF CONTENTS ..............................................................................................................3
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS ..................................................5
1.
INTRODUCTION ....................................................................................................7
2.
STUDY DESCRIPTION ..........................................................................................7
2.1
Objectives ...................................................................................................................7
2.2
Inclusion Criteria ........................................................................................................8
2.3
Subject Exclusion Criteria ..........................................................................................8
2.4
Subject Withdrawal Criteria .....................................................................................10
2.5
Study Plan/Procedures ..............................................................................................10
2.6
Randomization and Masking ....................................................................................11
3.
STUDY ASSESSMENTS/ENDPOINTS ...............................................................11
3.1
Demographic and Background Characteristics .........................................................11
3.1.1
Demographic/Medical History ..........................................11
3.1.2
Concomitant Medications History .....................................11
3.1.3
Ophthalmic History and Ophthalmic Intervention History12
3.1.4
Urine Pregnancy Test ........................................................12
3.2
External Photography................................................................................................12
3.2.1
Marginal Reflex Distance Measurement ...........................12
3.3
Safety Assessments ...................................................................................................12
3.3.1
Vital Signs .........................................................................12
3.3.2
Snellen Visual Acuity Assessment ....................................12
3.3.3
Pupil Diameter Measurement ............................................13
3.3.4
Slit Lamp Exam/Corneal Fluorescein Staining .................13
3.3.5
Dilated Ophthalmoscopy/Fundus Exam ............................13
3.3.6
Intraocular Pressure Tonometry ........................................13
3.3.7
Study Medication Tolerability Assessment .......................14
3.3.8
Adverse Events ..................................................................14
4.
SAMPLE SIZE AND POWER CONSIDERATIONS ........................................14
5.
ANALYSIS POPULATIONS ................................................................................14
6.
DATA HANDLING ................................................................................................14
6.1
Study Data .................................................................................................................14
6.1.1
Clinical Data – CDISC Study Data Tabulation Model 
(SDTM)..............................................................................15
6.1.2
Analysis Data – CDISC Analysis Data Model (ADaM) ...15
6.2
Handling of Early Termination Visit Information ....................................................15
6.3
Handling of Missing Data .........................................................................................15
7.
STATISTICAL ANALYSIS ..................................................................................15
7.1
General Considerations .............................................................................................15
7.1.1
Definition of Baseline ........................................................16
7.2
Subject Disposition ...................................................................................................16
7.3
Demographic and Baseline Characteristics ..............................................................16


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7.4
Concomitant Medications .........................................................................................17
7.5
Treatment Compliance and Exposure .......................................................................17
8.
SAFETY MEASURES ...........................................................................................17
8.1
Intraocular Pressure ..................................................................................................17
8.2
Snellen Visual Acuity ...............................................................................................17
8.3
Pupil Diameter ..........................................................................................................17
8.4
Corneal Fluorescein Staining ....................................................................................17
8.5
Slit Lamp Examination .............................................................................................18
8.6
Ophthalmoscopy and Fundus Exam .........................................................................18
8.7
Tolerability Assessment ............................................................................................18
8.8
Vital Signs: Heart Rate and Blood Pressure .............................................................18
8.9
Adverse Events .........................................................................................................18
9.
INTERIM ANALYSIS ...........................................................................................19
10.
TABLES, LISTINGS AND FIGURES .................................................................19
11.
REFERENCES........................................................................................................19
12.
SCHEDULE OF PROCEDURES .........................................................................20
13.
REVISION HISTORY ...........................................................................................22






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1. 
INTRODUCTION 
RevitaLid Inc.(RevitaLid) is pursuing the development of RVL-1201 Ophthalmic Solution 
(oxymetazoline hydrochloride ophthalmic solution, 0.1%) for the treatment of acquired 
blepharoptosis (ptosis). Ptosis is experienced by approximately 12% of adults over the age of 50 
(Sridharan et al, 1995). It is a unilateral or bilateral abnormal drooping of the upper eyelid that 
usually occurs from a partial or complete dysfunction of the muscle(s) that elevate the upper 
eyelid: the levator palpebrae superioris and/or Müller’s muscle. Patients with ptosis may 
experience significant superior visual field defects, which can affect daily activities such as 
driving, crossing streets, and reading. 
Treatment for acquired ptosis usually involves surgery, with risks of infection, bleeding, over- or 
undercorrection, reduced vision, and lagophthalmos (inability to close the eyelids completely) 
(Finsterer, 2003). Mechanical treatment of ptosis (scleral contact lenses with a bar to lift the 
eyelid (Shah-Desai et al, 2010), eyelid ptosis crutches attached to glasses, or adhesive tape or 
putty to affix the upper eyelid to the supraorbital structures) is limited by patient dissatisfaction 
with physical appearance, contact allergies, or skin irritation. Pharmacologic treatment of ptosis 
has not been pursued because the agents that have been evaluated (e.g., epinephrine, dipivefrin, 
apraclonidine, phenylephrine, brimonidine) either caused mydriasis, resulting in blurred vision or 
photophobia, or unacceptable systemic side effects (Matjucha, 2011; Scheinfeld, 2005; 
Kass et al, 1979; Fraunfelder and Scafidi, 1978]).  
Oxymetazoline hydrochloride is a direct-acting α2-adrenergic agonist that has been used at a 
0.025% concentration as an ocular vasoconstrictor for nearly 30 years and at a 0.05% 
concentration as a nasal decongestant for almost 50 years. When administered at a 0.1% 
concentration it stimulates the α2 adrenergic receptors in Müller’s muscle causing it to contract, 
thereby lifting the upper eyelid, and retracting the lower eyelid to a lesser degree. Topical 
ophthalmic administration of oxymetazoline hydrochloride at lower concentrations (0.01%, 
0.025%) results in vasoconstriction and reduction of hyperemia but does not have the 
pharmacologic effect of raising the upper eyelid. 
RVL-1201 Ophthalmic Solution contains oxymetazoline hydrochloride 0.1% as the active 
ingredient, and it is provided in preservative-free unit-dose vials. 
Oxymetazoline hydrochloride, a well-characterized and selective α2-adrenergic agonist, was first 
approved as the active ingredient in the vasoconstrictor/decongestant nasal spray, Afrin® 
(oxymetazoline hydrochloride, 0.05%) in 1966.  
 
2. 
STUDY DESCRIPTION 
2.1 
Objectives 
The objective of this study is to evaluate the safety of RVL-1201 Ophthalmic Solution in the 
treatment of acquired blepharoptosis over 12 weeks. 
 


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2.2 
Inclusion Criteria 
1. Males or females ≥ 9 years of age. 
2. Presence of both of the following at Screening/Baseline: 
a. The marginal reflex distance (MRD), the distance from the central pupillary light 
reflex to the central margin of the upper lid, must be ≤ 2 mm (no visible central 
pupillary light reflex defaults to 0) in either eye. 
b. Snellen visual acuity (VA) of 20/80 or better in the same eye as Inclusion Criteria 
#2a. 
3. Females must be 1-year postmenopausal, surgically sterilized, or females of 
childbearing potential with a negative urine pregnancy test at Visit 1. Females of 
childbearing potential (females who have started their menstrual cycles) must use an 
acceptable form of contraception throughout the study. Acceptable methods include 
the use of at least one of the following: intrauterine (intrauterine device), hormonal 
(oral, injection, patch, implant, ring), barrier with spermicide (condom, diaphragm), 
or abstinence. 
4. Must be able to self-administer study medication or to have the study medication 
administered by a caregiver throughout the study period. 
5. Must be able to understand and sign an informed consent form (ICF) prior to 
participation in any study-related procedures. For minor subjects, the subject’s parent 
or legal guardian must provide permission by signing the ICF on behalf of the subject 
and the subject should provide assent, per Institutional Review Board (IRB) 
guidelines. If a subject becomes 18 years of age during the study, the subject will 
need to sign an ICF to continue in the study. 
 
2.3 
Subject Exclusion Criteria 
In both eyes 
1. Dermatochalasis that extends less than 3 mm above the upper eyelid margin; 
dermatochalasis extending < 3 mm above the upper eyelid margin of a single eye is 
permitted. 
2. Pseudoptosis (upper eyelid dermatochalasis that overhangs the upper eyelid margin); 
pseudoptosis in a single eye is permitted. 
In either eye 
3. Congenital ptosis. 
4. Horner syndrome. 
5. Marcus Gunn jaw-winking syndrome. 
6. Myasthenia gravis. 


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7. Mechanical ptosis, including ptosis due to orbital or lid tumor, cicatricial processes 
affecting the movements of the upper lid, and enophthalmos. 
8. Previous ptosis surgery (previous blepharoplasty [only] is allowed provided the surgery 
took place > 3 months prior to Visit 1). 
9. Lid position affected by lid or conjunctival scarring. 
10. History of herpes keratitis. 
11. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been 
performed > 3 months prior to Visit 1). 
12. Periocular neurotoxin (e.g., Botox, Xeomin, Dysport, Myobloc) injections within 3 
months prior to Visit 1 and during the study. 
13. Topical application of bimatoprost (i.e., Latisse®) to the eyelashes within 7 days prior to 
Visit 1 and during the study. 
14. Use of topical ophthalmic medications (including anti-allergy [e.g., antihistamines], dry 
eye [i.e., Restasis®, Xiidra®], antimicrobial drugs [e.g., antibiotics and antivirals], and 
anti-inflammatory drugs [including nonsteroidal anti-inflammatory drugs (NSAIDs) and 
steroids] other than the assigned study medication within 7 days prior to Visit 1 and during 
the study. Topical ophthalmic prostaglandin analogues for the treatment of elevated 
intraocular pressure are permitted if dosed in the evening in accordance with the approved 
prescribing information. All other topical antiglaucoma medications are prohibited. 
15. Intravitreal injections (e.g., Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days prior 
to Visit 1 and during the study. 
16. Current punctal plugs or placement of punctal plugs during the study. 
17. Current use of over-the-counter (OTC) vasoconstrictor/decongestant eye medication (e.g., 
Visine® L.R.®) or any ophthalmic or non-ophthalmic α-adrenergic agonist including OTC 
products (e.g., Afrin®) at any time during the study; artificial tears are allowed. 
General 
18. Resting heart rate (HR) outside the normal range (50–110 beats per minute). 
19. Hypertension with resting diastolic blood pressure (BP) > 105 mm Hg or systolic BP 
> 220 mm Hg. 
20. Use of monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, phenelzine, 
tranylcypromine) within 14 days prior to Visit 1 and during the study. 
21. Advanced arteriosclerotic disease or history of cerebrovascular accident (CVA). 
22. History of hyperthyroidism or thyroid eye disease (i.e., exophthalmos, upper eyelid 
retraction, diplopia secondary to extraocular muscle involvement).  Hypothyroidism that is 
controlled on medication is allowed. 


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23. Patients with proliferative diabetic retinopathy may not be enrolled. However, patients 
with insulin dependent diabetes, diabetes requiring oral hypoglycemic drugs, or diet-
controlled diabetes, with or without stable background diabetic retinopathy, are allowed. 
24. Pregnancy or lactation. 
25. Diagnosed benign prostatic hypertrophy requiring medicinal therapy; previous 
prostatectomy is allowed.  
26. History of contact or systemic allergic reaction to oxymetazoline hydrochloride or other 
sympathomimetic drugs (e.g., phenylephrine, pseudoephedrine, ephedrine, 
phenylpropanolamine, fepradinol, or methoxamine). 
27. Participation in any drug or device clinical investigation within 30 days prior to entry into 
this study and/or during the period of study participation.  Previous screening in Study 
RVL-1201-202 is allowed. 
28. Randomization into any previous clinical study of RVL-1201 (Study RVL-1201-001 or 
Study RVL-1201-201, or Study RVL-1201-202) or into this study (Study RVL-1201-203). 
2.4 
Subject Withdrawal Criteria 
The following are the criteria for considering withdrawal from the study: 
• Withdrawal of subject consent/assent. The subject may request for any reason at any 
time to be withdrawn from the study. 
• The Sponsor terminates the study. 
If a subject withdraws from the study, the principal reason for withdrawal will be recorded in the 
electronic case report form (eCRF). 
If a study subject fails to attend a study visit at any point during the study period, every effort 
should be made to keep the subject in the study and conduct all study visits as scheduled; all 
attempts to contact the subject must be documented. If the subject relocates during the study 
period, Oculos Clinical Research (Oculos), the clinical research organization, should be 
contacted to determine if there is a possibility that the subject could continue at another clinical 
site.  
2.5 
Study Plan/Procedures 
This will be a Phase 3, randomized, multicenter, double-masked, placebo-controlled study to 
evaluate the extended safety of RVL-1201 Ophthalmic Solution compared to Vehicle (placebo) 
for the treatment of acquired ptosis. The study will be conducted over 84 days (12 weeks).  
Eligible subjects will be randomized in a 2:1 ratio to one of 2 treatment arms and treated for 
84 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 150) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 75) 
Both eyes will be treated and assessed. 


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Following screening evaluations at the Screening/Baseline visit (Day 1), a determination of 
eligibility will be made, and eligible subjects will be randomized and receive study medication. 
Study medication, RVL-1201 or Vehicle (placebo), will be provided in identical-appearing unit-
dose vials. The identity of the study medications will be masked to the subject, Investigator, 
study personnel responsible for ophthalmic evaluations, and Sponsor personnel. 
Subjects (or their caregiver, if necessary) will administer study medication QD in the morning 
during the study period. 
Safety follow-up visits will be conducted at Day 14 (Visit 2), Day 42 (Visit 3), and Day 84 (Visit 
4). 
2.6 
Randomization and Masking 
Study medication will be randomized in a 2:1 ratio (RVL-1201 Ophthalmic Solution [N = 150]; 
Vehicle [placebo] [N = 75]). A randomized block design will be used, and the randomization 
will be created by a biostatistician independent of the trial.  Randomization will not be stratified 
by any factors. 
If subjects meet eligibility criteria at Screening/Baseline, Day 1 (Visit 1), sites will access the 
IWRS to randomize subjects to study treatment and assign the study medication kit to be 
dispensed. The drug kit and randomization number will be recorded in the subject’s eCRF. Study 
medication from the IWRS-assigned kit will be dispensed to the subject after initial dosing at the 
study site on Day 1 (Visit 1), on Day 14 ± 3 (Visit 2) and on Day 42± 3 (Visit 3). 
The study will be double masked. The study medication will be provided in identical-appearing 
pouches with no labeling indicating the identity of the study group or the contents of the 
unit-dose vials. The pouches will contain identical-appearing unit-dose vials. Study subjects, 
Investigators and staff, and study management personnel will be masked to the identity of 
treatment until after the final database lock. 
 
3. 
STUDY ASSESSMENTS/ENDPOINTS 
3.1 
Demographic and Background Characteristics 
3.1.1 Demographic/Medical History 
A complete medical history will be obtained from each subject. Demographic information 
including date of birth, gender, race, ethnicity, iris color, and date of informed consent will be 
recorded. 
3.1.2 Concomitant Medications History 
All concomitant medications (prescription and OTC) taken at Visit 1 (Screening/Baseline, Day 
1) and for 3 months prior to Visit 1 and throughout the course of the study will be recorded in the 
Concomitant Medications page of the eCRF. Information regarding the dates of first and last 
dose, site of dosing (e.g., right eye [OD], left eye [OS], both eyes [OU], systemic), and the 
reason the concomitant medication is being taken must be recorded in the eCRF. When a 


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concomitant medication has been taken at a stable dose for longer than 6 months, an estimation 
of the start date is adequate. Standard procedural medications will not be captured in the eCRF 
but are recorded on a standard procedural medication log provided by Oculos. 
3.1.3 Ophthalmic History and Ophthalmic Intervention History 
Clinically significant ophthalmic history and ophthalmic intervention history will be documented 
and will include any previously diagnosed ophthalmic abnormalities and ocular surgeries, 
including laser procedures. 
3.1.4 Urine Pregnancy Test 
A urine pregnancy test will be performed at Visit 1 (Screening/Baseline, Day 1) and repeated at 
Day 84 (Visit 4, End of Treatment) or the Early Discontinuation Visit for women of childbearing 
potential only. 
3.2 
External Photography 
An external photograph of the subject’s face will be taken using the provided digital camera. It is 
crucial that the same level of ambient lighting be maintained for each photograph throughout the 
study. The subject will be required to remove mascara and any other eyelid makeup if applicable. 
The subject will also be asked to relax his/her facial muscles. The photograph will frame the 
subject’s face from mid-forehead to the tip of the nose vertically and from ear-to-ear 
horizontally. A standardized millimeter ruler label will be placed vertically on the forehead, 
centered above the eyebrows, as a measurement legend. All measurements (MRD and pupil 
diameter (PD)) will be made from the digital image or color printed copy of the photograph 
using a handheld caliper and the millimeter ruler label as the legend. 
3.2.1 Marginal Reflex Distance Measurement 
The distance from the center pupillary light reflex to the central margin of the upper eyelid is the 
MRD. The MRD will be measured from the external photograph at Visit 1. 
3.3 
Safety Assessments 
Assessment of the safety and tolerability of RVL-1201 Ophthalmic Solution compared to 
Vehicle will include bilateral ophthalmic examinations (Snellen VA, PD measurement, 
SLE/CFS, intraocular pressure (IOP) tonometry, dilated ophthalmoscopy/fundus exam), 
measurement of vital signs, and recording of adverse events. Subject rating of study medication 
tolerability will also be obtained. For the timing of all safety assessments, please refer to the 
Schedule of Procedures. 
3.3.1 Vital Signs 
Blood pressure (from the same arm, and with the same cuff size, appropriate for arm 
circumference, throughout study) and heart rate will be measured after at least 3 minutes rest in 
the sitting position. Vital signs may be repeated once, after at least 5 minutes rest in the seated 
position, if they are out of range. 
3.3.2 Snellen Visual Acuity Assessment 


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Corrected or uncorrected Snellen VA measurement will be performed with the Snellen eye chart 
using the subject’s current corrective lens prescription, if applicable, at a distance equivalent to 
20 feet (6 meters). If the corrected or uncorrected visual acuity is 20/80 or better, no additional 
refraction is necessary. If corrected or uncorrected visual acuity is worse than 20/80, then an 
updated refraction must be performed. This refraction must be used for all VA and visual field (if 
applicable) assessments during the study. The subject must wear the same glasses (if applicable) 
at each visit. The updated refraction can be placed in a trial frame or phoropter for VA 
assessments, and the trial frame only for visual field (if applicable) assessments. 
For subjects with surgical monovision correction, VA assessment may be conducted in the near 
vision eye with a near vision reading card held at approximately 14 inches from the subject’s 
eye. 
3.3.3 Pupil Diameter Measurement 
Pupil diameter will be measured (either horizontally or vertically if top of pupil is not visible in 
photograph) from the external photograph. 
3.3.4 Slit Lamp Exam/Corneal Fluorescein Staining 
A routine SLE will be performed to evaluate the anterior segment of the eye, including lids, 
cornea, conjunctiva, anterior chamber, iris, and lens. Abnormalities will be documented. 
Fluorescein staining of the corneal epithelium will be performed in both eyes according to the 
Investigator’s standard of care.  
Staining will be graded on a 5-point scale: 
0 = No staining 
1 = Trace 
2 = Mild 
3 = Moderate 
4 = Severe 
3.3.5 Dilated Ophthalmoscopy/Fundus Exam 
Direct dilated ophthalmoscopy will include assessment of the optic nerve head for pallor and 
cupping. A fundus exam consisting of the vitreous, optic nerve, macula, and peripheral retina 
will be conducted, and the structures will be graded as normal or abnormal. Only tropicamide 
(Mydriacyl) should be used for this exam. Phenylephrine hydrochloride (Neosynephrine) may 
NOT be used. 
3.3.6 Intraocular Pressure Tonometry 
Intraocular pressure will be measured utilizing a Goldmann, Tono-Pen, or iCare tonometer 
(whichever is chosen, it must be used for the duration of the trial; no combination is permitted) 
and using the standard of care. If possible, the same calibrated instrument should be used for a 
given subject throughout the study. 


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3.3.7 Study Medication Tolerability Assessment 
Subjects will be asked to rate the ocular tolerability of the medication according to the following 
4-point scale: 
0 = No discomfort 
1 = Mild discomfort 
2 = Moderate discomfort 
3 = Severe discomfort 
3.3.8 Adverse Events 
An adverse event (AE) is any untoward medical occurrence in a patient or clinical study subject 
administered a study medication (pharmaceutical/biological product) that does not necessarily 
have a causal relationship to this medication. An AE can therefore be any unfavorable and 
unintended sign (including abnormal laboratory findings), symptom, or disease temporally 
associated with the use of the study medication, whether or not related to the study medication. 
Study medication includes the investigational drug under evaluation and the comparator product 
or vehicle placebo that is given during any phase of the study. 
Adverse events will be evaluated and classified for: 
• Serious Adverse Events (SAE) 
• Relationship to Study Drug 
• Severity of Adverse Event 
• Outcome 
4. 
SAMPLE SIZE AND POWER CONSIDERATIONS 
The sample size for this study is not based on statistical calculations.  The sample size was based 
on the need to obtain sufficient safety data to meet regulatory obligations for the development of 
RVL-1201. 
5. 
ANALYSIS POPULATIONS 
Safety Population: 
The safety population includes all subjects who receive at least one dose of double-masked study 
treatment and have at least one post-dose visit.  All analyses will be performed using the safety 
population according to the treatment received. 
6. 
DATA HANDLING 
6.1 
Study Data 
Study data identified in the schedule of procedures are collected, and source verified, in eCRFs 
at the site conducting the study.  All relevant study data will be formulated into data sets to 
provide transparency, traceability, and integrity of trial analysis results from collection source. 


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Observed study data will be mapped to the CDISC Study Data Tabulation Model (SDTM) and 
serve as the source data from the trial. All study analyses will be completed using analysis data 
sets that are derived from the SDTM and follow the CDISC Analysis Data Model (ADaM) 
architecture. 
6.1.1 Clinical Data – CDISC Study Data Tabulation Model (SDTM) 
Domains will be mapped to CDISC SDTM version 3.2.  The SAP will not be amended to 
provide information on additional SDTM domains. All SDTM domains will be fully documented 
with define documents (DEFINE.XML) and a study data reviewer’s guide (SDRG) after 
database lock and final analyses are completed. 
6.1.2 Analysis Data – CDISC Analysis Data Model (ADaM) 
All planned and exploratory analyses will be completed using the ADaM data sets derived from 
the SDTM domains for this study. Analysis data sets will contain all derived study endpoints 
required for analysis. All analysis data sets will be fully documented with define documents 
(DEFINE.XML) and an analysis data reviewer’s guide (ADRG) after database lock and final 
analyses are completed. 
Additional analysis data sets may be developed to support unplanned analyses after database 
lock. The SAP will not be amended for additional analysis data sets defined for the study and 
these additional data sets will be documented in the define documentation completed after all 
analyses are completed for the trial and the clinical study report is written. 
6.2 
Handling of Early Termination Visit Information 
If a patient is terminated early from this study the early termination visit data will be analyzed at 
the closest scheduled visit.  If the closest visit has valid data, the early termination data will be 
assigned to the next available visit. 
6.3 
Handling of Missing Data 
All analyses will be based on observed cases (without imputation).   
If the intensity of an AE is missing, the event will be considered severe. If relationship of the AE 
to study drug is missing, the event will be counted as related.  
Adverse events will be considered treatment emergent unless it can be determined from the onset 
or end date information that the event cannot have been treatment emergent. 
 
7. 
STATISTICAL ANALYSIS 
7.1 
General Considerations 
This is a Phase 3 study to evaluate the safety of daily treatment with RVL-1201 Ophthalmic 
Solution (oxymetazoline hydrochloride ophthalmic solution, 0.1%) compared to Vehicle 
(placebo) for the treatment of acquired ptosis over an extended dosing period of 12 weeks. 


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Subjects will be randomized in a 2:1 ratio of RVL-1201 Ophthalmic Solution to Vehicle into 
2 treatment groups and treated for 84 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 150) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 75) 
Descriptive statistics will be used to summarize continuous outcomes (number of subjects [N], 
mean, standard deviation or standard error of the mean, median, maximum, and minimum) and 
categorical variables (frequency and percentage) at each assessment time point.   
All data collected in the study database will be presented in the listings. 
All statistical analyses and reporting will be performed using the SAS® System Version 9.4 or 
later. 
7.1.1 Definition of Baseline 
Measures collected prior to dosing on Day 1 will serve as baseline.   
7.2 
Subject Disposition 
Subject disposition, including the number of subjects randomized, treated, and completing the 
study (and completing each study visit), will be tabulated by treatment group. The percentage of 
subjects treated and completing the study will be based on the total number randomized.  
Discontinuations and the reasons for discontinuation will be summarized.  Discontinuations of 
study medication prior to study completion will also be summarized.  Subject disposition will 
also be summarized by study site.    
Eligibility criteria exemptions and protocol deviations will be summarized by treatment group 
and presented in a listing.  
The total number and percentage of subjects included in the safety population will be 
summarized by treatment group, with percentages based on the total number randomized 
subjects. 
7.3 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized using descriptive statistics 
for the safety population.   
Demographic information including age, gender, race, ethnicity and iris color will be 
summarized.  MRD captured at Visit 1 (Screening/Baseline, Day 1) will also be summarized by 
eye (left eye (OS) and right eye (OD)). Such tables will be supported with individual subject data 
listings. 
Age will be determined as the whole integer number of years from the date of birth (DOB) to the 
date of the screening visit, i.e., the truncated integer difference between the DOB and Visit 1. 
Prior medications will be tabulated. A prior medication is defined as any mediation that starts 
and stops prior to first dose of study medication. 


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Medical and surgical history classified using the Medical Dictionary for Regulatory Activities 
(MedDRA) will be summarized descriptively and presented in a listing.  
7.4 
Concomitant Medications 
All concomitant medications listed on the case report form will be provided in data listings in the 
clinical study report. The frequency distribution based on the generic drug name of all prior and 
concomitant medications used during the study will be provided for each treatment group.  
7.5 
Treatment Compliance and Exposure 
The amount of opened and unopened medication returned at Visits 2, 3 and 4 will be 
documented in the CRF to provide an assessment of compliance in the form of percentage 
compliance for each subject. Compliance is determined by counting opened/unopened bottles. 
The percent of opened bottles to the total that should have been used during the treatment period 
will be tabulated. 
8. SAFETY MEASURES 
Safety data will be presented in tables of descriptive statistics and frequency distribution using 
the safety population. All summary tables will be supported with individual subject data listings. 
8.1 
Intraocular Pressure 
Descriptive statistics of the observed and change from baseline IOP will be tabulated by visit and 
treatment group.  The descriptive statistics will be presented by eye (left eye (OS) and right eye 
(OD)). 
8.2 
Snellen Visual Acuity 
The Snellen fraction will be converted to an equivalent logMAR value.  The logMAR value is 
calculated by taking the log10 of the reciprocal of the Snellen fraction.  For example, if the 
Snellen fraction is 20/60, the log MAR value is log10 (60/20) = 0.477. 
Descriptive statistics of the observed and change from baseline logMAR will be tabulated by 
visit and treatment group.  The descriptive statistics will be presented by eye (left eye (OS) and 
right eye (OD)).  Note that any repeat tests due to refraction issues will be utilized in the 
analyses. 
8.3 
Pupil Diameter 
Descriptive statistics of the observed and change from baseline pupil diameter will be tabulated 
by visit and treatment group.  The descriptive statistics will be presented by eye (left eye (OS) 
and right eye (OD)). 
8.4 
Corneal Fluorescein Staining 
The status of the cornea epithelium will be graded on a 5-point scale (no staining, trace, middle, 
moderate, and severe) and will also be assessed for clinical significance (yes or no).  The clinical 
significance results will be tabulated (n, %) by visit and treatment group. 


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8.5 
Slit Lamp Examination 
The status of the anterior segment of the eye, including lids, cornea, conjunctiva, anterior 
chamber, iris, and lens with respect to normalcy, non-clinically significant or clinically 
significant changes will be tabulated (n, %) by visit and treatment group. 
8.6 
Ophthalmoscopy and Fundus Exam 
The status of the fundus with respect to normalcy, non-clinically significant or clinically 
significant changes will be tabulated (n, %) by visit and treatment group.  The summaries will be 
presented by eye (left eye (OS) and right eye (OD)). 
8.7 
Tolerability Assessment 
Tolerability assessments will be summarized in frequency tables based on the ordinal scale for 
each treatment group at the Day 84 assessment. 
8.8 
Vital Signs: Heart Rate and Blood Pressure 
Descriptive statistics of the observed and change from baseline HR and BP will be tabulated by 
visit and treatment group. 
8.9 
Adverse Events 
Treatment-emergent adverse events (TEAE) are those with onset after randomization or if 
occurring prior to randomization worsened after randomization. Only treatment-emergent events 
will be summarized. All events in the clinical database regardless of when they occurred will be 
provided in data listings. Adverse events will be classified according to the MedDRA system to 
the levels of system organ class (SOC) and primary preferred term (PT). 
An overall summary will be presented which gives the number and percentage of subjects within 
each treatment group who experienced any TEAE, experienced any TEAE by maximum 
severity, experienced any TEAE by greatest relationship, discontinued early from the study due 
to a TEAE, permanently discontinued treatment due to a TEAE, experienced a treatment-
emergent serious adverse event (TESAE), and who died. 
In summary tables, TEAEs occurring in both eyes will be counted once at the greater intensity 
and relationship to study drug.  When counting events, bilateral ocular events are counted twice, 
i.e., once for each eye.  Bilateral ocular events are listed separately in the eCRF (they will be 
identified as OD and OS). 
The number and percentage of subjects experiencing one or more events within a MedDRA 
system organ class and preferred term class without regard to intensity, relationship, or 
seriousness will be tabulated by treatment group. In addition, tabulations will display events by 
SOC, PT, and maximum intensity or greatest relationship to treatment. 
The number of deaths and TESAEs will also be presented, and TEAEs leading to premature 
discontinuation from the study and TEAEs leading to discontinuation of study medication will be 
listed and tabulated. 


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A glossary listing that shows the verbatim terms assigned to each SOC and PT will be provided.  
A listing of TEAEs by treatment group ordered by subject, SOC, PT, and onset date will be 
provided. 
A listing of serious TEAEs by treatment group ordered by subject, SOC, PT, and onset date will 
be provided. 
9. 
INTERIM ANALYSIS 
No interim analyses are planned. 
10. 
TABLES, LISTINGS AND FIGURES 
Table, listing and figure shells will be prepared. 
11. 
REFERENCES 
Absorption Systems. Study Number 12C145Q2R3G25. Evaluation of the ocular toxicity of the 
Sponsor’s test article, oxymetazoline, after repeat topical administration in the eyes of New 
Zealand white rabbits. 2012 Dec 14. 
Finsterer J. Ptosis: causes, presentation, and management. Aesthetic Plast Surg. 2003 May 
Jun;27(3):193 204. 
Fraunfelder FT, Scafidi AF. Possible adverse effects from topical ocular 10% phenylephrine. Am 
J Ophthalmol. 1978;85(4):447 53. 
Ho SF, Morawski A, Sampath R, Burns J. Modified visual field test for ptosis surgery (Leicester 
Peripheral Field Test). Eye (Lond). 2011 Mar;25(3):365 9. doi:10.1038/eye.2010.210. Epub 
2011 Jan 21 
Kass MA, Mandell AI, Goldberg I, Paine JM, Becker B. Dipivefrin and epinephrine treatment of 
elevated intraocular pressure: a comparative study. Arch Ophthalmol. 1979 Oct;97(10):1865 6. 
Matjucha IC. The nonsurgical treatment of ptosis. In: Cohen AJ, Weinberg DA, editors: 
Evaluation and management of blepharoptosis. New York: Springer, 2011. p. 155 61. 
Scheinfeld N. The use of apraclonidine eyedrops to treat ptosis after the administration of 
botulinum toxin to the upper face. Dermatol Online J. 2005 Mar 1;11(1):9. 
Shah Desai SD, Aslam SA, Pullum K, Beaconsfield M, Rose GE. Scleral contact lens usage in 
patients with complex blepharoptosis. Ophthal Plast Reconstr Surg. 2011 Mar Apr;27(2):95 8. 
Sridharan GV, Tallis RC, Leatherbarrow B, Forman WM. A community survey of ptosis of the 
eyelid and pupil size of elderly people. Age Ageing. 1995 Jan;24(1):21 4. 
Van den Bosch WA, Lemij HG. Blepharoptosis induced by prolonged hard contact lens wear. 
Ophthalmology. 1992 Dec;99(12):1759 65. 
 


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12. 
SCHEDULE OF PROCEDURES 
Assessment  
Screening/Baseline 
Randomization Day 
1 
Day 14  
(± 3 Days) 
 
Day 42 
(± 3 Days) 
Day 84 
(± 3 Days) 
Early 
Discontinuation 
Visit 
1 
2 
3 
4 
 
Informed consent 
X 
 
 
 
 
Demographics/medical/ocular history 
X 
 
 
 
 
Collect study medication materials 
 
X 
X 
X 
X 
Urine pregnancy testa 
X 
 
 
X 
X 
Prior/concomitant medications 
X 
X 
X 
X 
X 
Adverse event assessmentb 
X 
X 
X 
X 
X 
Tolerability assessment 
 
 
 
X 
X 
Blood pressure/heart ratec 
X 
X 
X 
X 
X 
External digital photograph 
X 
X 
X 
X 
X 
   Marginal reflex distance (OU)d 
X 
 
 
 
 
   Pupil diameter measurement (OU)d 
X 
X 
X 
X 
X 
Snellen visual acuity (OU)e 
X 
X 
X 
X 
X 
Slit lamp exam (OU) 
X 
X 
X 
X 
X 
Corneal fluorescein staining (OU) 
X 
X 
X 
X 
X 
Intraocular pressure tonometry (OU) 
X 
 
X 
X 
X 
Dilated ophthalmoscopy/fundus exam (OU)f 
X 
 
 
X 
X 
Review inclusion/exclusion criteria / 
Randomize eligible participants 
X 
 
 
 
 
Dispense/administer study medicationg 
X 
X 
X 
 
 
Study medication accountability 
X 
X 
X 
X 
X 


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MRD = marginal reflex distance; OU = both eyes; VA= Visual acuity 
a Females of childbearing potential only (females who have started their menstrual cycles). 
b For precise timing of adverse events at each visit, please refer to details of each individual visit in Section 10 of the protocol. 
c Resting blood pressure and heart rate are taken seated after 3 minutes rest. 
d MRD and pupil diameter will be measured from the external photograph.  
e If the corrected or uncorrected VA is 20/80 or better, no additional refraction is necessary. If corrected or uncorrected VA is worse than 20/80 an updated refraction 
must be performed, which must be used for all VA assessments during the study. The subject must wear the same glasses, if applicable, at each visit. For subjects with 
surgical monovision correction, VA assessment may be conducted in the near vision eye with a near vision reading card held at approximately 14 inches from the 
subject’s eye. 
f Only tropicamide (Mydriacyl) should be used for this exam. Phenylephrine hydrochloride (Neosynephrine) may NOT be used. 
g Study medication will be dispensed at Day 1 (Visit 1), Day 14 (Visit 2), and Day 42 (Visit 3). Study medication will be administered at the study site on Day 1. 
Otherwise, study medication will be administered QD in the morning at home daily. 
 


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13. 
REVISION HISTORY 
Not applicable.