Clinical trial NCT03565887
Conditions: Blepharoptosis
Sponsor: RVL Pharmaceuticals, Inc.
Start date: 2018-06-28; Completion date: 2019-04-22
Enrollment: 164 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Phase 3 study to evaluate the safety and efficacy of treatment with 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-1201-202 
 
  
CLN.RVL-1201.RVL-1201-202.PR.A03 
1 
 
 
 
CLINICAL STUDY PROTOCOL 
CONFIDENTIAL 
 
A Randomized, Double-Masked, Placebo-Controlled Phase 3 
Study of the Safety and Efficacy of RVL-1201 in the 
Treatment of Acquired Blepharoptosis 
(Study RVL-1201-202) 
 
Study Phase: 
Phase 3 
Product Name: 
RVL-1201 (oxymetazoline hydrochloride) ophthalmic solution, 0.1% 
Document Number: 
CLN.RVL-1201.RVL-1201-202.PR.A03 
Indication: 
Treatment of acquired blepharoptosis 
IND: 
116915 
Sponsor: 
RevitaLid Inc. 
400 Crossing Boulevard 
Bridgewater, NJ 08807 
Medical Monitor: 
Charles Slonim, MD 
 
Protocol Version: 
Amendment 3: 09 October 2018 
Amendment 2: 10 July 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 and Efficacy of RVL-1201 in the Treatment of Acquired 
Blepharoptosis (Study RVL-1201-202) 
Study Number: 
Study RVL-1201-202 
Document Number: 
CLN.RVL-101.RVL-1201.202.PR.A03 
 
I have received and read the Study RVL-1201-202 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 US federal 
regulations and local legal and regulatory requirements. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Signature of Investigator 
 
 
 
 
 
 
 
 
Date 


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PROCEDURES IN CASE OF EMERGENCY 
Table 1: 
Emergency Contact Information (Study RVL-1201-202) 
 


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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 and 
Efficacy of RVL-1201 in the Treatment of Acquired Blepharoptosis (Study RVL-1201-202) 
Studied Period (Years):  
Estimated date first patient enrolled: March 2018 
Estimated date last patient completed: February 2019 
Phase of Development:  
3 
Objectives: The primary objectives of this study are to evaluate the efficacy of RVL-1201 Ophthalmic 
Solution in the treatment of acquired blepharoptosis at 2 weeks and to assess the safety of RVL-1201 for 
a dosing period of 6 weeks. 
Methodology: This will be a randomized, multicenter, double-masked, placebo-controlled study 
conducted over 42 days (6 weeks).  
Eligible subjects will be randomized in a 2:1 ratio to one of 2 treatment arms and treated for 42 days: 
• 
RVL-1201 Ophthalmic Solution 1 drop in each eye once daily (QD) in the morning (N = 104) 
• 
Vehicle (placebo) 1 drop in each eye QD in the morning (N = 52) 
Both eyes will be treated and assessed, but the more ptotic eye (the eye with the smaller marginal reflex 
distance (MRD) measurement) will be the study eye. If the MRD = 0 in either eye where both eyes are 
eligible, the eye with the measurable MRD (≥ 0.5 mm) will be the study eye. If the MRD is the same in 
both eyes, the eye with the greater visual field defect (the lower Leicester Peripheral Field Test [LPFT] 
Total Score from Visit 1, Hour 6, based on number of points seen on the top 4 rows) will be the study 
eye. If the MRD and LPFT are the same in both eyes, the right eye will be the study eye.  
Following screening evaluations, a determination of eligibility will be made following review of external 
photographs and LPFT printouts for each subject by the Medical Monitor, who will also designate the 
study eye. The Medical Monitor will subsequently inform the site whether the subject is eligible and 
which eye will be the study eye. Eligibility must be confirmed by efficacy evaluations at Baseline, 
Day 1, Hour 0 (Visit 2), before subjects are randomized to and receive study treatment and undergo 
efficacy and safety evaluations at specified intervals. Safety and efficacy evaluations will also be 
conducted at Day 14 (Visit 3), and final safety and tolerability assessments will take place at Day 42 
(Visit 4), the last day of study treatment. 
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. 
Number of Patients (Planned): Approximately 156 subjects will be enrolled (104 subjects in the 
RVL-1201 group and 52 subjects in the Vehicle group) at approximately 30 clinical sites. 


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Inclusion Criteria: 
1. Males or females ≥ 9 years of age. 
2. Presence of all the following at Screening: 
a. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score); 
subjects must see at least 9 total points in the top 4 rows (LPFT Total Score).  
i. This criterion must be met at both the Visit 1 Hour 0 (V1H0) and Visit 1 Hour 6 
(V1H6) LPFT assessments  
ii. There must be ≤ 4 points of variance between the V1H0 and the V1H6 LPFT 
Eligibility Score; AND 
b. 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 
the same eye as Inclusion Criterion #2a; AND 
c. Snellen VA of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b. 
3. Presence of all the following at Baseline: 
a. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score) in the 
same eye as Inclusion Criterion #2a; subjects must see at least 9 total points in the top 4 
rows (LPFT Total Score).  
i. These criteria must be met at the Visit 2 Hour 0 (V2H0) LPFT assessment.  
ii. There must be ≤ 4 points of variance between the V1H6 and the V2H0 LPFT 
Eligibility Score; AND 
b. 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 
the same eye as Inclusion Criterion #2a; AND 
c. Snellen VA of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b. 
4. Females must be 1-year postmenopausal, surgically sterilized, or females of childbearing 
potential (females who have started their menstrual cycles) with a negative urine pregnancy test 
at Visits 1 and 2. Females of childbearing potential 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. 
5. Must be able to self-administer study medication or to have the study medication administered 
by a caregiver throughout the study period. 
6. 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 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. 


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Exclusion Criteria: 
In the study eye only 
1. Dermatochalasis that extends less than 3 mm above the upper eyelid margin. 
2. Pseudoptosis (upper eyelid dermatochalasis that overhangs the upper eyelid margin). 
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. Visual field loss from any cause other than ptosis. 
11. History of herpes keratitis. 
12. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been 
performed > 3 months prior to Visit 1). 
13. Periocular neurotoxin (e.g., Botox, Xeomin, Dysport, Myobloc) injections within 3 months prior 
to Visit 1 and during the study. 
14. Topical application of bimatoprost (i.e., Latisse®) to the eyelashes within 7 days prior to Visit 1 
and during the study. 
15. 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. 
16. Intravitreal injections (e.g., Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days prior to 
Visit 1 and during the study. 
17. Current punctal plugs or placement of punctal plugs during the study.  
18. 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 
19. Resting heart rate (HR) outside the normal range (50–110 beats per minute). 
20. Hypertension with resting diastolic blood pressure (BP) > 105 mm Hg or systolic BP 
> 220 mm Hg. 
21. Use of monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, phenelzine, 
tranylcypromine) within 14 days prior to Visit 1 and during the study. 


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Exclusion Criteria 
General (continued): 
22. Advanced arteriosclerotic disease or history of cerebrovascular accident (CVA). 
23. 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. 
24. 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. 
25. Pregnancy or lactation. 
26. Diagnosed benign prostatic hypertrophy requiring medicinal therapy; previous prostatectomy is 
allowed. 
27. History of contact or systemic allergic reaction to oxymetazoline hydrochloride or other 
sympathomimetic drugs (e.g., phenylephrine, pseudoephedrine, ephedrine, 
phenylpropanolamine, fepradinol, or methoxamine). 
28. 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. 
29. Previous randomization into any previous clinical study of RVL-1201 (Study RVL-1201-001 or 
Study RVL-1201-201) or into this study (Study RVL-1201-202). 
Investigational Product, Dosage and Mode of Administration: RVL-1201 (Oxymetazoline 
Hydrochloride) Ophthalmic Solution, 0.1%: 1 drop per eye QD, topical ocular administration for 
6 weeks 
Reference Therapy, Dosage and Mode of Administration: Vehicle (placebo): 1 drop per eye QD, 
topical ocular administration for 6 weeks 
Duration of Treatment: The duration of treatment will be 6 weeks 
Study Procedures: 
Screening eligibility assessments are obtained on or between Day -7 to Day -3. Key eligibility 
determinants will be MRD measured from external digital color photographs, 2 LPFTs per subject with 
≤ 4 points of variance in the LPFT Eligibility Score between the V1H0 and V1H6 LPFTs as well as 
between the V1H6 and V2H0 LPFTs, and Snellen VA (if corrected or uncorrected VA is 20/80 or better, 
no additional refraction is necessary). All assessments of efficacy (LPFT, MRD) and safety (VA, pupil 
diameter, slit lamp exam [SLE])/corneal fluorescein staining [CFS], intraocular pressure [IOP], dilated 
ophthalmoscopy/fundus exam) will be conducted in both eyes (OU) at Screening. External photographs 
and LPFT printouts will be sent to the Medical Monitor for reading/confirmation of 
eligibility/determination of study eye. Note: Contact lenses must not be worn during study visits. 


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Study Procedures (continued): 
Day -7 to Day -3 (Visit 1): Screening 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 Institutional Review Board (IRB) guidelines. External photographs of the subject’s eyes will 
be taken. The LPFT will be administered twice, with 6 hours intervening. If the Humphrey Visual Field 
(HVF) Analyzer issues an “XX” for fixation losses, false positives, and/or false negatives, the test will 
be deemed unreliable. If deemed unreliable, the test must be retaken (once per scheduled test). There 
must be ≤ 4 points of variance in the LPFT Eligibility Score between the V1H0 and the V1H6 LPFTs. 
Safety assessments will be conducted. Inclusion/exclusion criteria will be reviewed and the external 
photograph and LPFT printouts will be sent to the Medical Monitor for reading/confirmation of 
eligibility/determination of study eye.  
Subjects determined by the Medical Monitor as eligible for randomization will be scheduled to return to 
the clinical site for Visit 2 at Day 1. All LPFT assessments after the study eye has been designated by the 
medical monitor will be conducted on the study eye ONLY. All assessments will be conducted OU. For 
subjects with surgical monovision correction where the study eye is the near vision eye, a neutralizing 
trial lens may be put in the lens holder located in front of the chin rest. 
Day 1 (Visit 2): Baseline/Randomization/First Dose/Duration of Action Assessment Subjects will 
undergo safety and efficacy assessments at Hour 0. An LPFT will be obtained in the study eye and there 
must be ≤ 4 points of variance in the LPFT Eligibility Score between this test (V2H0) and the V1H6 
LPFT performed at Screening. Subjects who meet all eligibility criteria will complete the remainder of 
baseline assessments and 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 receive instruction on 
administration procedures. The first dose will be administered at the clinical site. Safety and efficacy 
assessments will be conducted at Hours 2, 6, and 8 as specified on the Schedule of Procedures. Site 
personnel will dispense study medication (Box 1) and conduct study medication accountability 
procedures. 
From Days 2 through 13, 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 prior to instillation of study 
medication. Subjects who have dosed prior to arriving at the clinical site must be rescheduled. 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 3): Onset of Action Assessment Subjects will return all opened and unopened 
study medication materials and undergo safety and efficacy assessments at Hour 0. Study medication 
will be administered at the clinical site (using a vial taken from Box 1), and subjects will undergo safety 
and efficacy assessments at Hours 2, 6, and 8 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 41, randomized study medication will be administered in each eye QD in the 
morning, and subjects will return on Day 42 ± 3 days in the morning prior to instillation of study 
medication. Subjects who have dosed prior to arriving at the clinical site must be rescheduled. 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 4): End of Treatment Visit Subjects will return all opened and unopened study 
medication materials, study medication will be administered at the clinical site (using a vial taken from 
Box 2), and subjects will undergo final safety and efficacy assessments, and rate the ocular tolerability 
of study medication as specified on the Schedule of Procedures. Site personnel will conduct final study 
medication accountability procedures. 


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Efficacy Assessments: Efficacy will be assessed with the LPFT, a validated visual field test using the 
HVF Analyzer and photographic measurement of MRD (the distance from the central pupillary light 
reflex to the central margin of the upper lid). External digital photographs will be used to measure MRD.  
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). Ocular tolerability will be rated by the subject on a 4-point scale.  
Criteria for Evaluation: 
Efficacy Endpoints 
Primary Efficacy Endpoints: 
The primary efficacy endpoints will be the mean change from Baseline (Day 1, Hour 0) in the 
RVL-1201 group versus the Vehicle group in number of points seen in the top 4 rows on the LPFT test 
at each of 2 time points: 
1. Day 1 Hour 6 (Visit 2)  
2. Day 14 Hour 2 (Visit 3)  
A hierarchical analysis will be conducted to compare RVL-1201 against Vehicle (placebo) at the 2 time 
points listed above. 
Secondary Endpoints: Secondary endpoints will include the mean observed values and change from 
baseline values for MRD data in the RVL-1201 group versus the Vehicle group assessed at Day 1 
(Visit 2), Day 14 (Visit 3), and at Day 42 (Visit 4). 
Safety Endpoints The safety of RVL-1201 will be compared to Vehicle with analysis of safety 
variables including ophthalmic safety assessments (VA, SLE/CFS, pupil diameter, dilated 
ophthalmoscopy/fundus examination, and tonometry), vital signs (BP/HR), and AEs. The ocular 
tolerability of study medication will be rated by the subject. 
Statistical Methods:  
A detailed Statistical Analysis Plan (SAP) will be finalized prior to database lock. 
Analysis Populations: 
The primary efficacy analysis of the LPFT endpoints at Day 1 Hour 6 and Day 14 Hour 2 will be 
conducted on the intent-to-treat (ITT) population (all randomized subjects). Supportive efficacy analysis 
will also be conducted on the per protocol population (those subjects in the ITT population who had no 
major protocol deviations). Safety analyses will be performed using the safety population (all 
randomized subjects who received at least one dose of the randomized study medication). 
Sample Size:  
A two-group t-test with a 0.05 two-sided significance level will have 90% power to detect a difference in 
LPFT means of 3.50, assuming that the common standard deviation is 6.0, when the sample sizes in the 
2 groups are 94 and 47, respectively (a total sample size of 141). The planned total of 156 subjects will 
allow for a 10% drop-out rate. 


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Statistical Methods (continued):  
Efficacy Analysis: 
The primary efficacy endpoints will be tested sequentially in the order specified. For a claim of 
statistical significance, the null hypothesis being tested, and all higher ordered null hypotheses must be 
rejected, i.e., the Day 1 Hour 6 time point will be tested first, and if P < 0.05, the Day 14 Hour 2 time 
point will be tested at a significance level of 0.05. Thus, both hypotheses in the hierarchy will be tested 
against placebo at a significance level of 0.05. It is important to note that if the Day 1 Hour 6 endpoint is 
statistically significant (at the 0.05 level) but Day 14 Hour 2 is not statistically significant (at the 0.05 
level), the study will still be considered positive. 
If both primary efficacy endpoints are significant at the 0.05 significance level, then the secondary 
efficacy endpoints (MRD) will also be tested sequentially. Testing will stop if a P value ≥ 0.05 for a 
comparison. 
The order of testing for the secondary efficacy endpoints is as follows: 
1. Day 1 Hour 2 
2. Day 14 Hour 2 
3. Day 1 Hour 6 
4. Day 14 Hour 6 
5. Day 1 Minute 15 
6. Day 14 Minute 15 
7. Day 1 Minute 5 
8. Day 14 Minute 5 
All other comparisons are considered exploratory. 
The efficacy measures (LPFT and MRD) taken on Day 1, Hour 0 (Visit 2) prior to dosing will serve as 
baseline. The mean change from baseline (at each corresponding time point) in each efficacy measure 
after the initial dose will be compared between treatment groups. 
The analysis of continuous and ordinal variables will use the applicable parametric methods (t-test, 
analysis of variance [ANOVA], analysis of covariance [ANCOVA]). 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. 
A summary of the efficacy endpoints will be prepared at each time point and will include an estimate of 
the mean change from baseline for each treatment group and of the adjusted treatment difference and 
95% confidence interval. The between-treatment comparison will employ ANCOVA with treatment as a 
fixed factor and baseline as a covariable. A t-test on least square means will be used to compare 
RVL-1201 to Vehicle with a 2-sided significance level of 0.05. Wilcoxon rank sum tests will also be 
used to compare treatments at each time point. 
All efficacy analyses will be based on observed cases (without imputation). Multiple imputation will be 
performed only for the primary time points if more than 5% of data are missing for either treatment 
group; if 5% or fewer data are missing, an analysis with last observation carried forward (LOCF) for 
missing data will be conducted on the ITT population only. 


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Statistical Methods (continued): 
Safety Analysis 
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, LIST OF TABLES, AND LIST OF 
FIGURES 
TABLE OF CONTENTS 
SPONSOR SIGNATURE ................................................................................................................2
INVESTIGATOR’S AGREEMENT ...............................................................................................3
PROCEDURES IN CASE OF EMERGENCY ...............................................................................4
1.
SYNOPSIS ...................................................................................................................5
2.
TABLE OF CONTENTS, LIST OF TABLES, AND LIST OF FIGURES ...............13
TABLE OF CONTENTS ...............................................................................................................13
LIST OF TABLES .........................................................................................................................16
LIST OF FIGURES .......................................................................................................................16
3.
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS.............................17
4.
INTRODUCTION ......................................................................................................19
4.1.
Justification of Route, Dose, Regimen, and Treatment Period ...................................19
4.2.
Good Clinical Practice Statement ...............................................................................20
4.3.
Population to Be Studied ............................................................................................20
5.
TRIAL OBJECTIVES ................................................................................................21
6.
INVESTIGATIONAL PLAN .....................................................................................22
6.1.
Overall Study Design ..................................................................................................22
6.2.
Number of Subjects ....................................................................................................26
6.3.
Criteria for Study Termination ...................................................................................26
7.
SELECTION AND WITHDRAWAL OF SUBJECTS ..............................................27
7.1.
Inclusion Criteria ........................................................................................................27
7.2.
Exclusion Criteria .......................................................................................................28
7.3.
Subject Withdrawal Criteria .......................................................................................29
8.
TREATMENT OF SUBJECTS ..................................................................................31
8.1.
Description of Study Medications ..............................................................................31
8.2.
Randomization and Masking ......................................................................................31
8.2.1.
Unmasking During the Study Period ..........................................................................31
8.3.
Concomitant Medications ...........................................................................................32
8.3.1.
Permitted Medications and Treatments ......................................................................32
8.3.2.
Prohibited Medications ...............................................................................................32


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8.4.
Treatment Compliance ................................................................................................33
8.5.
Discontinuation of Study Medication .........................................................................33
8.6.
Study Medication Materials and Management ...........................................................33
8.6.1.
Packaging and Labeling ..............................................................................................33
8.6.2.
Storage and Administration ........................................................................................33
8.6.3.
Study Medication Accountability ...............................................................................34
9.
STUDY ASSESSMENTS ..........................................................................................35
9.1.
Demographic and Background Characteristics ..........................................................35
9.1.1.
Demographic/Medical History ...................................................................................35
9.1.2.
Concomitant Medications History ..............................................................................35
9.1.3.
Ophthalmic History and Ophthalmic Intervention History ........................................35
9.1.4.
Urine Pregnancy Test .................................................................................................35
9.2.
Efficacy Assessments .................................................................................................35
9.2.1.
Leicester Peripheral Field Test ...................................................................................36
9.2.2.
External Photography .................................................................................................37
9.2.2.1.
Marginal Reflex Distance Measurement ....................................................................37
9.3.
Safety Assessments .....................................................................................................37
9.3.1.
Vital Signs ..................................................................................................................37
9.3.2.
Snellen Visual Acuity Assessment .............................................................................37
9.3.3.
Pupil Diameter Measurement .....................................................................................38
9.3.4.
Slit Lamp Exam/Corneal Fluorescein Staining ..........................................................38
9.3.5.
Dilated Ophthalmoscopy/Fundus Exam .....................................................................38
9.3.6.
Intraocular Pressure Tonometry .................................................................................38
9.3.7.
Study Medication Tolerability Assessment ................................................................39
9.4.
Adverse and Serious Adverse Events .........................................................................39
9.4.1.
Definition of Adverse Events .....................................................................................39
9.4.1.1.
Adverse Event (AE) ....................................................................................................39
9.4.1.2.
Serious Adverse Event (SAE) ....................................................................................39
9.5.
Relationship to Study Drug ........................................................................................40
9.6.
Recording Adverse Events .........................................................................................40
9.7.
Reporting Adverse Events ..........................................................................................41
10.
STUDY ACTIVITIES ................................................................................................43
10.1.
Screening Visit ............................................................................................................43


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10.1.1.
Day -7 to Day -3 (Visit 1): Screening .........................................................................43
10.2.
Treatment Visits ..........................................................................................................44
10.2.1.
Day 1 (Visit 2): Baseline/Randomization/First Dose/Duration of Action 
Assessment .................................................................................................................44
10.2.2.
Days 2 through 13 .......................................................................................................46
10.2.3.
Day 14 ± 3 (Visit 3): Onset of Action Assessment ....................................................46
10.2.4.
Days 15 through 41 .....................................................................................................47
10.2.5.
Day 42 ± 3 (Visit 4): Last Day of Treatment ..............................................................47
10.3.
Early Discontinuation Assessment Procedures ..........................................................48
11.
STATISTICS ..............................................................................................................50
11.1.
General Considerations ...............................................................................................50
11.1.1.
Handling of Missing Data ...........................................................................................50
11.2.
Determination of Sample Size ....................................................................................50
11.3.
Analysis Populations ..................................................................................................51
11.3.1.
Populations for Efficacy Analysis ..............................................................................51
11.3.1.1.
Intent-to-Treat (ITT) Population .................................................................................51
11.3.1.2.
Per-Protocol (PP) Population ......................................................................................51
11.3.2.
Safety Population ........................................................................................................51
11.4.
Demographics and Baseline Characteristics ...............................................................51
11.5.
Efficacy Analysis ........................................................................................................51
11.5.1.
Hypothesis Testing .....................................................................................................51
11.5.2.
Primary Efficacy Endpoints ........................................................................................52
11.5.3.
Primary Efficacy Analysis ..........................................................................................52
11.5.4.
Secondary Efficacy Endpoints ....................................................................................52
11.5.5.
Secondary Efficacy Analysis ......................................................................................52
11.6.
Safety Analyses ..........................................................................................................53
12.
QUALITY CONTROL AND QUALITY ASSURANCE .........................................54
13.
ADMINISTRATIVE CONSIDERATIONS ..............................................................55
13.1.
Institutional Review Board (IRB) ...............................................................................55
13.2.
Ethical Conduct of the Study ......................................................................................55
13.3.
Written Informed Consent/Assent ..............................................................................55
13.4.
Subject Confidentiality and Confidentiality of Data ..................................................55
13.5.
Study Monitoring ........................................................................................................56


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13.6.
Case Report Forms and Study Records ......................................................................56
13.7.
Protocol Deviations ....................................................................................................57
13.8.
Access to Source Documentation ...............................................................................57
13.9.
Data Generation and Analysis ....................................................................................57
13.9.1.
Retention of Data ........................................................................................................57
13.10.
Publication and Disclosure Policy ..............................................................................58
14.
REFERENCES ...........................................................................................................59
15.
SUMMARY OF CHANGES ......................................................................................60
15.1.
Changes Implemented in Protocol RVL-1201-202 Amendment 1 ............................60
15.2.
Changes Implemented in Protocol RVL-1201-202 Amendment 2 ............................60
15.3.
Changes Implemented in Protocol RVL-1201-202 Amendment 3 ............................63
 
LIST OF TABLES 
Table 1:
Emergency Contact Information (Study RVL-1201-202) ............................................4
Table 2:
Schedule of Procedures (Study RVL-1201-202) ........................................................24
 
LIST OF FIGURES 
Figure 1:
Leicester Peripheral Field Test Grids .........................................................................36
 
 
 


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3. 
LIST OF ABBREVIATIONS AND DEFINITIONS OF TERMS 
Abbreviation  
Explanation 
α 
Alpha 
AE 
Adverse event 
ANCOVA  
Analysis of covariance  
ANOVA  
Analysis of variance 
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 
HVF 
Humphrey Visual Field 
ICF 
Informed consent form 
ICH 
International Council for Harmonisation 
IOP 
Intraocular pressure 
ITT  
Intent-to-treat population  
IRB 
Institutional Review Board 
IWRS 
Interactive Web Response System 
LOCF 
Last observation carried forward 
LPFT 
Leicester Peripheral Field Test  
LPFT Eligibility Score 
Total number of points missed in the top 2 rows on the LPFT 
LPFT Total Score 
Total number of points seen in the top 4 rows on the LPFT 
MAOI 
Monoamine oxidase inhibitor  
MAR 
Missing at random 
MRD 
Marginal reflex distance 
OTC 
Over-the-counter 
OU 
Both eyes 
NZW 
New Zealand White (rabbits) 
PP 
Per protocol population 


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Abbreviation  
Explanation 
QD 
Once daily 
RVL-1201 
Oxymetazoline hydrochloride ophthalmic solution 0.1% 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SE 
Study eye 
SLE  
Slit lamp examination  
SOP 
Standard operating procedure 
US 
United States  
VA  
Visual acuity  
V1H0 
Visit 1 Hour 0 
V1H6 
Visit 1 Hour 6 
V2H0 
Visit 2 Hour 0 
 


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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, 


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Study RVL-1201-001, showed that RVL-1201 administered once daily (QD) and twice daily 
(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-1201-202 will evaluate 1 drop of 
RVL-1201 in each eye QD for 42 days.  
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 US 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 Institutional Review Board (IRB) guidelines. 


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5. 
TRIAL OBJECTIVES 
The primary objectives of this study are to evaluate the efficacy of RVL-1201 Ophthalmic 
Solution in the treatment of acquired blepharoptosis at 2 weeks and to assess the safety of 
RVL-1201 for a dosing period of 6 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 safety and efficacy of QD treatment with RVL-1201 compared to Vehicle (placebo) 
for the treatment of acquired ptosis. The study will be conducted over 42 days (6 weeks).  
Eligible subjects will be randomized in a 2:1 ratio to one of 2 treatment arms and treated for 
42 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 104) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 52) 
Both eyes will be treated and assessed, but the more ptotic eye (the eye with the smaller MRD 
measurement) will be the study eye. If the MRD = 0 in either eye where both eyes are eligible, 
the eye with the measurable MRD (≥ 0.5 mm) will be the study eye. If the MRD is the same in 
both eyes, the eye with the greater visual field deficit (the lower LPFT Total Score from Visit 1, 
Hour 6 [V1H6] LPFT, based on number of points seen in the top 4 rows) will be the study eye. If 
the MRD and LPFT are the same in both eyes, the right eye will be the study eye.  
Prior to randomization, each subject will attend a screening visit on or between Day -7 to Day -3 
(Visit 1). The Visit 1 LPFT will be administered twice, with 6 hours intervening. If the HVF 
Analyzer issues an “XX” for fixation losses, false positives, and/or false negatives, the test will 
be deemed unreliable. If deemed unreliable, the test must be retaken (once per scheduled test). 
There must be ≤ 4 points of variance in LPFT Eligibility Score between the test at Visit 1 Hour 0 
(V1H0) and Visit 1 Hour 6 (V1H6). External photographs of the subject’s eyes will be taken, and 
safety assessments will be conducted. Inclusion/exclusion criteria will be reviewed, and the 
external photograph and LPFT printouts will be sent to the Medical Monitor for 
reading/confirmation of eligibility/determination of study eye. The Medical Monitor will 
subsequently inform the site whether the subject is eligible and which eye will be the study eye. 
At Day 1, Baseline (Visit 2), subjects will undergo safety and efficacy assessments at Hour 0 
beginning with a baseline LPFT in the study eye only. There must be ≤ 4 points of variance in 
LPFT Eligibility Score between this test at Visit 2 Hour 0 (V2H0) and the V1H6 test performed 
at Screening. Subjects who meet all eligibility criteria will complete the remaining baseline 
assessments and 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. The subject 
(or caregiver, if the subject is not able to self-administer the medication) will then administer the 
first dose of allocated masked study medication at the clinical site and undergo safety and 
efficacy assessments at Hours 2, 6 and 8. Site personnel will dispense study medication and 
conduct study medication accountability procedures. 
Study medication, RVL-1201 or Vehicle, 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.  


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From Days 2 through 13, 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 (Visit 3) in the morning prior to 
instillation of study medication. Subjects will return all opened and unopened study medication 
materials and undergo safety and efficacy assessments at Hour 0. After instillation of study 
medication at the clinical site, the subject will undergo safety and efficacy assessments at Hours 
2, 6, and 8. Site personnel will dispense study medication and conduct study medication 
accountability procedures. 
From Day 15 through the morning of Day 42, randomized study medication will be administered 
QD (in the morning), and subjects will return to the clinic on Day 42 ± 3 days (Visit 4) prior to 
instillation of study medication. After returning all opened and unopened study medication 
materials, study medication will be administered, and subjects will undergo safety and efficacy 
assessments and rate the ocular tolerability of study medication. Site personnel will conduct final 
study medication accountability procedures. 
Table 2 provides a tabular summary of all scheduled visits and procedures to be performed 
during the clinical study. 




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LPFT = Leicester Peripheral Field Test; MRD = marginal reflex distance; OU = both eyes; PD = post dose; SE = study eye; 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. On Day 1 (Visit 2), Day 14 (Visit 3), and Day 42 (Visit 4), the timing of MRD 
measurements must be at 5 minutes (+2 minutes) and 15 minutes (+ 2 minutes) post dose. For a description of the timing of all MRD measurements, please 
refer to details of each individual visit in Section 10. 
e LPFT will be conducted bilaterally at Screening (Visit 1). All other LPFT examinations will be conducted unilaterally on the study eye. For subjects with 
surgical monovision correction, a neutralizing trial lens may be put in the lens holder located in front of the chin rest of the HVF Analyzer. Instruct the subjects 
to keep their chin and forehead against the chin and forehead rests, to keep their brows relaxed, and to look at the fixation point throughout the test. 
f The LPFT assessment must be performed approximately 6 hours post-administration of study medication at Day 1 (Visit 2), and approximately 2 hours 
post-administration of study medication at Day 14 (Visit 3). This requirement supersedes the order of procedures shown in the table above and in the text in 
Section 10.2.1 and Section 10.2.3. 
g 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. 
h Only tropicamide (Mydriacyl) should be used for this exam. Phenylephrine hydrochloride (Neosynephrine) may NOT be used. The dilated 
ophthalmoscopy/fundus exam at Screening (Visit 1) must be conducted after the LPFT assessment at Hour 6. 
i Study medication will be administered at the study site at Hour 0 on Day 1 (Visit 2), Day 14 (Visit 3), and Day 42 (Visit 4). Subjects should be instructed not to 
dose before coming for Day 14 (Visit 3) or Day 42 (Visit 4); if the subject has dosed, the visit must be rescheduled. 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 156 subjects, 104 subjects in the RVL-1201 group, 
and 52 in the Vehicle group, to be enrolled at approximately 30 clinical sites in the US.  
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 all the following at Screening: 
a. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score); 
subjects must see at least 9 total points in the top 4 rows (LPFT Total Score).  
i. These criteria must be met in both the V1H0 and V1H6 LPFT assessments  
ii. There must be ≤ 4 points of variance between the V1H0 and the V1H6 
LPFT Eligibility Score; AND 
b. The MRD, the distance from the central pupillary light reflex to the central 
margin of the upper lid, ≤ 2 mm (no visible central pupillary light reflex defaults 
to 0) in the same eye as Inclusion Criterion #2a; AND 
c. Snellen VA of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b). 
3. Presence of all the following at Baseline: 
a. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score) 
in the same eye as Inclusion Criterion #2a; subjects must see at least 9 total points 
in the top 4 rows (LPFT Total Score).  
i. These criteria must be met in the V2H0 LPFT assessment.  
ii. There must be ≤ 4 points of variance between the V1H6 and the V2H0 
LPFT Eligibility Score; AND 
b. MRD, the distance from the central pupillary light reflex to the central margin of 
the upper lid, ≤ 2 mm (no visible central pupillary light reflex defaults to 0) in the 
same eye as Inclusion Criterion #2a; AND 
c. Snellen VA of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b). 
4. Females must be 1-year postmenopausal, surgically sterilized, or females of childbearing 
potential (females who have started their menstrual cycles) with a negative urine 
pregnancy test at Visits 1 and 2. Females of childbearing potential 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. 
5. Must be able to self-administer study medication or to have the study medication 
administered by a caregiver throughout the study period. 


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6. 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 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 the study eye only 
1. Dermatochalasis that extends less than 3 mm above the upper eyelid margin. 
2. Pseudoptosis (upper eyelid dermatochalasis that overhangs the upper eyelid margin). 
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. Visual field loss from any cause other than ptosis. 
11. History of herpes keratitis. 
12. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been 
performed > 3 months prior to Visit 1). 
13. Periocular neurotoxin (e.g., Botox, Xeomin, Dysport, Myobloc) injections within 3 
months prior to Visit 1 and during the study. 
14. Topical application of bimatoprost (i.e., Latisse®) to the eyelashes within 7 days prior to 
Visit 1 and during the study. 
15. 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. 
16. Intravitreal injections (e.g., Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days prior 
to Visit 1 and during the study. 


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17. Current punctal plugs or placement of punctal plugs during the study. 
18. 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 
19. Resting heart rate (HR) outside the normal range (50–110 beats per minute). 
20. Hypertension with resting diastolic blood pressure (BP) > 105 mm Hg or systolic BP 
> 220 mm Hg. 
21. Use of monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, phenelzine, 
tranylcypromine) within 14 days prior to Visit 1 and during the study. 
22. Advanced arteriosclerotic disease or history of cerebrovascular accident (CVA). 
23. 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. 
24. 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. 
25. Pregnancy or lactation. 
26. Diagnosed benign prostatic hypertrophy requiring medicinal therapy; previous 
prostatectomy is allowed.  
27. History of contact or systemic allergic reaction to oxymetazoline hydrochloride or other 
sympathomimetic drugs (e.g., phenylephrine, pseudoephedrine, ephedrine, 
phenylpropanolamine, fepradinol, or methoxamine). 
28. 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. 
29. Previous randomization into any previous clinical study of RVL-1201 (Study 
RVL-1201-001 or Study RVL-1201-201) or into this study (Study RVL-1201-202). 
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 


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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 = 104]; 
Vehicle [placebo] [N = 52]). 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 (see Section 7) at Screening (Visit 1) as well as at Baseline 
(Visit 2), 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 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 2) and Day 14 ± 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 attempt to contact the Medical Monitor via phone 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 10.3) should be completed. 
4. The Investigator should contact Oculos at Revitalid-Safety@oculoscr.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 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 10.3). 
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 2) 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 drop in each eye from the unit-dose vial  


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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 drop is placed 
into the conjunctival cul-de-sac. The tip of the vial should not touch the eye. After a 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 
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 3), subjects will 
return all opened and unopened study medication materials, and site personnel will conduct study 
medication accountability procedures and dispense study medication for the remaining study 
period. On Day 42 ± 3 days (Visit 4) the box, complete with opened unit-dose vials/pouches and 
any unopened study medication will be returned to the study site, and final study medication 
accountability will be conducted. The Day 42 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 42 ± 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) 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. 
Efficacy Assessments 
The efficacy of RVL-1201 Ophthalmic Solution compared to the Vehicle for the pharmacologic 
treatment of acquired blepharoptosis will be measured by improvement in visual field (as 
determined by LPFT assessment) and increase in MRD. 


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9.2.1. 
Leicester Peripheral Field Test 
The LPFT, a customized visual field test designed specifically to assess ptosis (Ho et al, 2011), 
will be performed using a Humphrey Visual Field Analyzer. It is an age-corrected screening test 
with a three-zone strategy. Thirty-five points are tested in the superior field while 14 points are 
tested in the inferior field. A maximum of 48° is tested in the superior visual field. The center of 
fixation is shifted 15o inferiorly to allow for maximum superior field testing (Ho et al, 2011). The 
inferior field test serves as a reference but is not used in the analysis. 
 
Figure 1: 
Leicester Peripheral Field Test Grids 
Clinical site staff must instruct the subjects to keep their chin and forehead against the chin and 
forehead rests, and to keep their brows relaxed. Clinical site staff must also instruct the subjects 
to look at the fixation target throughout the test. A corrective lens is not necessary on the LPFT 
UNLESS the subject would have a difficult time seeing the target without it (e.g., high myope, 
high hyperope, or high astigmat). 
There are two types of scores for the LPFT assessment: 
LPFT Eligibility Score: The total number of points missed in the top 2 rows on the LPFT. 
LPFT Total Score: The total number of points seen in the top 4 rows on the LPFT. 
Leicester Peripheral Field Test assessments will be performed OU until the point of study eye 
designation by the medical monitor. After designation, LPFT assessments will be performed only 
on the study eye. For subjects with surgical monovision correction where the study eye is the 
near vision eye, a neutralizing trial lens may be put in the lens holder located in front of the chin 
rest of the HVF Analyzer.  


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The HVF Analyzer will determine if the LPFT test is reliable. If the HVF Analyzer issues an 
“XX” for fixation losses, false positives, and/or false negatives, the test will be deemed 
unreliable. If deemed unreliable, the test must be retaken (once per scheduled test). If the 
outcome of the repeated test is reliable it will be used in the efficacy analysis, and if the repeated 
test is unreliable it will be included in the ITT analysis set but excluded from the PP analysis set. 
9.2.2. 
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) 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. 
9.2.2.1. 
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. 


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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 9.2.2). 
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.  
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. 


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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. 
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, 


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• 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. 
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 42, 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. 


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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); 
• Resolution (date); 
• 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. 
9.7. 
Reporting Adverse Events 
All SAEs (related and unrelated) will be recorded following consent and until the final study 
visit, Day 42 (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 
. 


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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 Inc. will report all SAEs to the US 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. 
Hour number (when not “0”) refers to hours passed since administration of study medication. 
10.1. 
Screening Visit 
Screening eligibility assessments are obtained during the Screening Visit conducted on or 
between Day -7 to Day -3 (Visit 1). Key eligibility determinants will be MRD measured from 
external digital color photographs, 2 LPFTs per subject with ≤ 4 points of variance in the LPFT 
Eligibility Score between the V1H0 and V1H6 LPFTs, and Snellen VA. All assessments of 
efficacy (LPFT and MRD) and safety (VA, pupil diameter, SLE)/CFS, IOP, dilated 
ophthalmoscopy/fundus exam) will be conducted in both eyes (OU) at Screening. External 
photographs and LPFT printouts will be sent to the Medical Monitor for reading/confirmation of 
eligibility/determination of study eye.  
10.1.1. 
Day -7 to Day -3 (Visit 1): Screening 
At Screening, Day -7 to Day -3 (Visit 1), subjects will provide informed consent before any 
study-related procedures are conducted. For minor subjects, permission will be obtained from the 
subject’s parent or legal guardian by signing the ICF on behalf of the subject, and assent will be 
obtained from the minor subject following IRB guidelines. Subjects will then participate in 
screening procedures to establish eligibility for the study. At the end of the visit, 
inclusion/exclusion criteria will be reviewed and external photograph and LPFT printouts will be 
sent to the Medical Monitor for reading/confirmation of eligibility/determination of study eye.  
Screening 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 
• Snellen visual acuity (OU) 
• MRD (OU) (from external photograph) 
• Pupil diameter measurement (OU) (from external photograph) 
• LPFT (OU); administered twice, with 6 hours intervening. If the HVF Analyzer 
issues an “XX” for fixation losses, false positives, and/or false negatives, the test will 
be deemed unreliable. If deemed unreliable, the test must be retaken (once per 
scheduled test). 


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• SLE (OU) 
• CFS (OU) 
• IOP (OU) 
• Dilated ophthalmoscopy/fundus exam (OU); must be conducted after the LPFT 
assessment at Hour 6 
• AE assessment 
At the end of the visit, inclusion/exclusion criteria will be reviewed and external photographs 
and LPFT printouts will be uploaded through the eDC system to the Medical Monitor for 
reading/confirmation. The Medical Monitor will subsequently inform the site whether the subject 
is eligible and which eye will be the study eye.  
If both eyes qualify, the more ptotic eye (the eye with the smaller MRD measurement), will be 
the study eye. If the MRD = 0 in either eye where both eyes are eligible, the eye with the 
measurable MRD (≥ 0.5 mm) will be the study eye. If the MRD is the same in both eyes, the eye 
with the greater visual field defect (the lower LPFT Total Score from the V1H6 LPFT, based on 
the number of points seen in the top 4 rows) will be the study eye. If the MRD and LPFT are the 
same in both eyes, the right eye will be the study eye. 
10.2. 
Treatment Visits 
For all treatment visits, LPFT assessments will be performed in the study eye; safety assessments 
(VA, pupil diameter, SLE/CFS, IOP, dilated ophthalmoscopy/fundus exam) and efficacy 
assessment from external photography (MRD) will be conducted OU. The window for each 
hourly assessment time point is ±30 minutes. 
10.2.1. 
Day 1 (Visit 2): Baseline/Randomization/First Dose/Duration of Action 
Assessment 
On Day 1 (Visit 2), subjects determined to be eligible after review by the Medical Monitor will 
be given a confirmatory LPFT (in the study eye), randomized into the study if the LPFT in the 
chosen study eye conforms to inclusion criteria (see Section 8.2 for randomization procedures, 
and Section 7.1 for inclusion criteria), receive a dose of allocated masked study medication, and 
undergo safety and efficacy assessments over approximately 8 hours. 
Day 1 procedures include the following: 
Hour 0 
• Urine pregnancy test (females of childbearing potential only) 
• AE assessment 
• Concomitant medication review 
• BP/HR 
• Snellen VA (OU) 
• MRD (from external photograph) (OU) 


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• Pupil diameter measurement (from external photograph) (OU) 
• LPFT test (study eye only) 
• Compare V2H0 LPFT Eligibility Score with V1H6 LPFT Eligibility Score 
• SLE (OU) 
• Randomize the subject to double-masked study medication (see Section 8.2) 
Administer Study Medication 
• 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 drop in each eye. After a drop is 
instilled in each eye, the subject should keep the eyes gently closed for approximately 
30 seconds. 
Post Dose 
• MRD (from external photograph) (OU) at 5 minutes (+ 2 minutes) and 15 minutes 
(+ 2 minutes) post dose 
• AE assessment at approximately10 to 30 minutes post dose 
Hour 2 
• AE assessment 
• BP/HR 
• MRD (from external photograph) (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
Hour 6 
• AE assessment 
• MRD (from external photograph) (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
• LPFT test (study eye only) (this test must be performed approximately 6 hours post 
administration of study medication. This requirement supersedes the order of 
procedures provided here and in the schedule of procedures) 
Hour 8 
• AE assessment 
• BP/HR  
• Snellen VA (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
• SLE (OU) 


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• CFS (OU) 
• Dispense study medication Box 1 
• Study medication accountability 
10.2.2. 
Days 2 through 13 
From Days 2-13, study medication will be administered QD (in the morning) and subjects will 
return on Day 14 ± 3 days (Visit 3) BEFORE instillation of study medication. Subjects will be 
instructed to bring Box 1 with all study medication materials (opened and unopened unit-dose 
vials and pouches) to the study site at Visit 3 (Day 14) for study medication 
accountability/treatment compliance determination. 
10.2.3. 
Day 14 ± 3 (Visit 3): Onset of Action Assessment 
On Day 14 ± 3 (Visit 3), confirm the subject did not instill their morning dose of study 
medication. Subjects who dosed prior to the morning visit MUST be rescheduled. 
Day 14 procedures include the following: 
Hour 0 
• 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 
• Snellen VA (OU) 
• MRD (from external photograph) (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
• SLE (OU) 
Administer Study Medication 
• The subject (or caregiver, if the subject is not able to self-administer the medication) 
will administer allocated study medication from Box 1, 1 drop in each eye. After a 
drop is instilled in each eye, the subject should keep the eyes gently closed for 
approximately 30 seconds. 
Post Dose 
• MRD (from external photograph) (OU) at 5 minutes (+ 2 minutes) and 15 minutes 
(+ 2 minutes) post dose 
• AE assessment at approximately 10 to 30 minutes post dose 


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Hour 2 
• AE assessment 
• BP/HR 
• MRD (from external photograph) (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
• LPFT test (study eye only) (this test will must be performed approximately 2 hours 
post administration of study medication. This requirement supersedes the order of 
procedures provided here and in the schedule of procedures) 
Hour 6 
• AE assessment 
• MRD (from external photograph) (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
Hour 8 
• AE assessment 
• BP/HR 
• Snellen VA (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
• SLE (OU) 
• CFS (OU) 
• Dispense study medication Box 2 
• Study medication accountability 
10.2.4. 
Days 15 through 41 
From Days 15-41, subjects (or caregivers, if the subject is not able to self-administer the 
medication) will administer study medication QD (administered in the morning) and return on 
Day 42 (Visit 4) in the morning BEFORE instillation of study medication. Subjects will be 
instructed to bring all study medication materials (opened and unopened unit-dose vials and 
pouches) to the study site for study medication accountability/treatment compliance assessment. 
10.2.5. 
Day 42 ± 3 (Visit 4): Last Day of Treatment  
At Day 42 ± 3 (Visit 4), confirm the subject did not instill their morning dose of study 
medication. Subjects who dosed prior to the morning visit MUST be rescheduled. 
Subjects will undergo final efficacy and safety assessments and rate the ocular tolerability of 
study medication. 
Visit 4 procedures include the following: 


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Hour 0 
• Collect Box 2, containing all opened and unopened study medication materials 
(unit-dose vials and pouches), from the subject 
• Urine pregnancy test (females of childbearing potential only) 
Administer Study Medication 
• The subject (or caregiver, if the subject is not able to self-administer the medication) 
will administer allocated study medication from Box 2, 1 drop in each eye. After a 
drop is instilled in each eye, the subject should keep the eyes gently closed for 
approximately 30 seconds. 
Post Dose 
• MRD (from external photograph) (OU) at 5 minutes (+ 2 minutes) and 15 minutes 
(+ 2 minutes) post dose  
• Pupil diameter measurement (from external photograph) (OU) 
• Concomitant medication review 
• AE assessment 
• Study medication tolerability assessment (rating by subject) 
• BP/HR (taken after 3 minutes at rest) 
• Snellen VA (OU) 
• SLE (OU) 
• CFS (OU) 
• IOP (OU) 
• Dilated ophthalmoscopy/fundus exam (OU) 
• Final study medication accountability  
10.3. 
Early Discontinuation Assessment Procedures 
If a study subject is discontinued from study medication before Day 42 (Visit 4) but after Day 1 
(Visit 2), 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 
• Concomitant medication review 
• AE assessment  
• Study medication tolerability assessment (rating by subject) 
• Urine pregnancy test (females of childbearing potential only) 
• BP/HR (taken after 3 minutes at rest) 


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• Snellen VA (OU) 
• MRD (from external photograph) (OU) 
• Pupil diameter measurement (from external photograph) (OU) 
• SLE (OU) 
• CFS (OU) 
• IOP (OU) 
• Dilated ophthalmoscopy/fundus exam (OU) 
• Study medication accountability  


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11. 
STATISTICS 
11.1. 
General Considerations 
This is a Phase 3 study to evaluate the efficacy and 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. 
Subjects will be randomized in a 2:1 ratio of RVL-1201 Ophthalmic Solution to Vehicle into 
2 treatment groups and treated for 42 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 104) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 52) 
All efficacy variables will be compared between the RVL-1201 QD treatment regimen and 
placebo. 
A biostatistician will perform statistical analyses as agreed with the Sponsor according to the 
Statistical Analysis Plan (SAP). Any additional or supplemental data analysis performed 
independently by an Investigator shall be submitted to the Sponsor for review. 
A detailed SAP will be finalized prior to database lock. The analysis of continuous and ordinal 
variables will use the applicable parametric methods (t-test, analysis of variance [ANOVA], and 
analysis of covariance [ANCOVA]). 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 (the time points at which data are collected are specified in the schedule of 
observations—see Table 2). 
Final analyses of efficacy will be conducted when all subjects complete Day 42 (Visit 4). 
11.1.1. 
Handling of Missing Data 
All efficacy analyses will be based on observed cases (without imputation). If more than 5% of 
data in any treatment group are missing, multiple imputation will be employed to analyze 
incomplete data sets under the assumption that the mechanism responsible for the missing data is 
at worst characterized as missing at random (MAR). The reasons for missing data will be 
recorded and the impact of these reasons and any treatment group imbalance on the assumption 
of MAR will be evaluated. If 5% or fewer data are missing, an analysis with last observation 
carried forward (LOCF) for missing data will be conducted on the ITT population only. 
11.2. 
Determination of Sample Size 
A two-group t-test with a 0.05 two-sided significance level will have 90% power to detect a 
difference in LPFT means of 3.50, assuming that the common standard deviation is 6.0, when the 
sample sizes in the 2 groups are 94 and 47, respectively (a total sample size of 141). The planned 
total of 156 subjects will allow for a 10% drop-out rate. 


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11.3. 
Analysis Populations 
Three populations will be used for analysis, as described below. 
11.3.1. 
Populations for Efficacy Analysis 
11.3.1.1. Intent-to-Treat (ITT) Population 
The intent-to-treat (ITT) population is defined as all randomized subjects who received at least 
one dose of the allocated study medication. The primary efficacy analysis of the LPFT endpoints 
at Day 1 Hour 6 and Day 14 Hour 2 will be conducted on the ITT population. 
11.3.1.2. Per-Protocol (PP) Population 
The per-protocol (PP) population consists of those subjects in the ITT population who had no 
major protocol deviations. Supportive efficacy analysis will be conducted on the PP population. 
11.3.2. 
Safety Population  
The safety population is defined as all randomized subjects who received at least one dose of the 
allocated study medication. All safety analyses will be performed using the safety population. 
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. 
11.5. 
Efficacy Analysis 
Efficacy analyses will be performed on the ITT population for the primary efficacy variables. 
Analysis of the hierarchical efficacy variables will also be conducted with the PP population 
using only observed data. 
Efficacy data will be presented in tables of descriptive statistics and frequency distribution. All 
summary tables will be supported with individual subject data listings. 
The efficacy measures (LPFT and MRD) taken on Visit 2 (Day 1, Hour 0) prior to dosing will 
serve as baseline. 
11.5.1. 
Hypothesis Testing 
The primary efficacy endpoints will be tested sequentially in the order specified. For a claim of 
statistical significance, the null hypothesis being tested, and all higher ordered null hypotheses 
must be rejected, i.e., the Day 1 Hour 6 time point will be tested first, and if P < 0.05, the Day 14 
Hour 2 time point will be tested at a significance level of 0.05. Thus, each of the hypotheses in 
the hierarchy will be tested within the treatment regimen against placebo at a significance level 
of 0.05. It is important to note that if the Day 1 Hour 6 endpoint is statistically significant (at the 
0.05 level) but Day 14 Hour 2 is not statistically significant (at the 0.05 level), the study will still 
be considered positive.  


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If both primary efficacy endpoints are significant at the 0.05 significance level, then the 
secondary efficacy endpoints (MRD) will also be tested sequentially. Testing will stop if a 
P value ≥ 0.05 for a comparison.  The order of testing is as follows:   
1. Day 1 Hour 2 
2. Day 14 Hour 2 
3. Day 1 Hour 6 
4. Day 14 Hour 6 
5. Day 1 Minute 15 
6. Day 14 Minute 15 
7. Day 1 Minute 5 
8. Day 14 Minute 5 
All other comparisons are considered exploratory. 
11.5.2. 
Primary Efficacy Endpoints 
The primary efficacy endpoints will be the mean change from Baseline (Day 1, Hour 0) in the 
RVL-1201 group versus the Vehicle group in number of points seen in the top 4 rows on the 
LPFT test at: 
1. Day 1 Hour 6 (Visit 2)  
2. Day 14 Hour 2 (Visit 3) 
11.5.3. 
Primary Efficacy Analysis 
A summary of the efficacy endpoints will be prepared at each time point and will include an 
estimate of the mean change from baseline for each treatment group and of the adjusted 
treatment difference and 95% confidence interval. The between-treatment comparison will 
employ ANCOVA with treatment as a fixed factor and baseline as a covariable. A t-test on least 
squares means will be used to compare RVL-1201 to Vehicle with a 2-sided significance level of 
0.05. Wilcoxon rank sum tests will also be used to compare treatments at each time point. 
11.5.4. 
Secondary Efficacy Endpoints 
Secondary endpoints will include the mean observed values and change from baseline values for 
MRD data in the RVL-1201 group versus the Vehicle group assessed at Day 1 (Visit 2), Day 14 
(Visit 3), and at Day 42 (Visit 4). 
11.5.5. 
Secondary Efficacy Analysis 
The same analysis methods that are used for the primary efficacy endpoints will be utilized for 
the secondary efficacy endpoints. 


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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 


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agencies. Medical information resulting from a subject’s participation in this study may be given 
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 to LPFT tests, 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. 
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. 


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15. 
SUMMARY OF CHANGES 
15.1. 
Changes Implemented in Protocol RVL-1201-202 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 years of age” 
 
To correct a typographical 
error 
15.2. 
Changes Implemented in Protocol RVL-1201-202 Amendment 2 
The following changes were made to Amendment 1: 
Location 
Description of Change 
Rationale for Change 
Synopsis Methodology;  
6.1. Overall Study Design; 
10.1.1. Day -7 to Day -3 
(Visit 1): Screening 
Change  
“If the MRD is the same in both eyes, 
the eye with the greater visual field 
defect (the higher Leicester Peripheral 
Field Test [LPFT] Total Score, based 
on number of points not seen on the top 
4 rows) will be the study eye.” 
to  
“If the MRD is the same in both eyes, 
the eye with the greater visual field 
defect (the lower Leicester Peripheral 
Field Test [LPFT] Total Score from 
Visit 1, Hour 6, based on number of 
points seen on the top 4 rows) will be 
the study eye.” 
To clarify that the LPFT 
Total Score is based on 
points seen (rather than 
points missed) and indicate 
that the LPFT Total Score at 
Visit 1, Hour 6 is used by 
the Medical Monitor to 
make the study eye 
designation if the MRD is 
the same in both eyes.  


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Location 
Description of Change 
Rationale for Change 
Synopsis Inclusion Criteria; 
Table 2: Schedule of 
Procedures;  
7.1. Inclusion Criteria; 
10.2.1. Day 1 (Visit 2): 
Baseline/Randomization/First 
Dose/Duration of Action 
Assessment 
Change (Synopsis and 7.1) 
“4. Females must be 1-year 
postmenopausal, surgically sterilized, 
or females of childbearing potential 
(females who have started their 
menstrual cycles) with a negative urine 
pregnancy test at Visit 1.” 
to  
“4. Females must be 1-year 
postmenopausal, surgically sterilized, 
or females of childbearing potential 
(females who have started their 
menstrual cycles) with a negative urine 
pregnancy test at Visits 1 and 2.” 
Add (to 10.2.1) 
Hour 0 
• 
“Urine pregnancy test (females of 
childbearing potential only)” 
To add a urine pregnancy 
test to Baseline procedures 
to ensure that female 
subjects of childbearing 
potential continue to have a 
negative result following the 
-7 to -3 days between 
Screening and Baseline. 
Synopsis Study Procedures; 
8.6.2. Storage and 
Administration;  
10.2.1. Day 1 (Visit 2): 
Baseline/Randomization/First 
Dose/Duration of Action 
Assessment;  
10.2.5. Day 42 ± 3 (Visit 4): 
Last Day of Treatment 
Change  
“full drop” to “drop” 
Delete  
if a full drop is not instilled into the eye, 
the subject should wait approximately 
10 15 seconds and administer a second 
drop 
To clarify that only one drop 
should be administered to 
each eye at each dose.  
3. List of Abbreviations and 
Definitions of Terms; 
9.2.1. Leicester Peripheral 
Field Test 
Change  
“LPFT Eligibility Score: Total number 
of missed points in the top 2 rows on 
the LPFT. 
LPFT Total Score: The total number of 
missed points in the top 4 rows on the 
LPFT.” 
to 
“LPFT Eligibility Score: Total number 
of points missed in the top 2 rows on 
the LPFT. 
LPFT Total Score: Total number of 
points seen in the top 4 rows on the 
LPFT.”  
To clarify that the LPFT 
Eligibility Score is based on 
points missed while the 
LPFT Total Score is based 
on points seen. 


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Location 
Description of Change 
Rationale for Change 
Table 2: Schedule of 
Procedures, Footnote h; 
10.1.1. Day -7 to Day -3 
(Visit 1): Screening 
Change ( to Schedule of Procedures) 
“X” was moved from Screening Hour 0 
to Screening Hour 6. 
Add (to Schedule of Procedures, 
Footnote h)  
“Only tropicamide (Mydriacyl) should 
be used for this exam. Phenylephrine 
hydrochloride (Neosynephrine) may 
NOT be used. The dilated 
ophthalmoscopy/fundus exam at 
Screening (Visit 1) must be 
conducted after the LPFT assessment 
at Hour 6.” 
Add (to 10.1.1) 
• 
“Dilated ophthalmoscopy/fundus 
exam (OU); must be conducted after 
the LPFT assessment at Hour 6” 
To clarify that the dilated 
ophthalmoscopy/fundus 
exam should be conducted 
after the Visit 1, Hour 6 
LPFT. This is to avoid any 
possible residual effect from 
the dilation drops during the 
visual field testing. 
8.2.1. Unmasking During the 
Study Period; 
9.7. Reporting Adverse 
Events 
Change 
“Revitalid-Safety@oculos.com” to 
“Revitalid-Safety@oculoscr.com” 
To correct a typographical 
error 
9.6. Recording Adverse 
Events 
Change  
“For each AE, the Investigator will 
evaluate and report the following: 
• 
Onset (date and time); 
• 
Resolution (date and time);” 
to 
“For each AE, the Investigator will 
evaluate and report the following: 
• 
Onset (date); 
• 
Resolution (date);” 
Time of onset and resolution 
of AEs will not be collected. 


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Location 
Description of Change 
Rationale for Change 
10.1.1. Day -7 to Day -3 
(Visit 1): Screening 
Change 
“At the end of the visit, 
inclusion/exclusion criteria will be 
reviewed and external photographs and 
LPFT printouts will be uploaded to the 
Medical Monitor for 
reading/confirmation at 
cslonim@pointguardllc.com.” 
to 
“At the end of the visit, 
inclusion/exclusion criteria will be 
reviewed and external photographs and 
LPFT printouts will be uploaded 
through the eDC system to the 
Medical Monitor for 
reading/confirmation.” 
The external photographs 
and LPFT printouts will not 
be emailed to the Medical 
Monitor, they will be 
uploaded through the eDC 
system. 
10.2. Treatment Visits 
Change  
“The window for each hourly 
assessment time point is +30 minutes.” 
to “The window for each hourly 
assessment time point is ±30 minutes.” 
To clarify that the window 
for the hourly assessment 
time points is “±”30 
minutes, not “+”30 minutes. 
Table 2: Schedule of 
Procedures 
10.2.1. Day 1 (Visit 2): 
Baseline/Randomization/First 
Dose/Duration of Action 
Assessment;  
10.2.3. Day 14 ± 3 (Visit 3): 
Onset of Action Assessment; 
10.3. Early Discontinuation 
Assessment Procedures 
Change order of procedures from 
• 
“BP/HR (taken after 3 minutes at 
rest) 
• 
MRD (from external photograph) 
(OU) 
• 
Pupil diameter measurement (from 
external photograph) (OU) 
• 
Snellen VA (OU)” 
to 
• 
“BP/HR (taken after 3 minutes at 
rest) 
• 
Snellen VA (OU) 
• 
MRD (from external photograph) 
(OU) 
• 
Pupil diameter measurement (from 
external photograph) (OU)” 
To create a more efficient 
flow of procedures for the 
clinical site. 
15.3. 
Changes Implemented in Protocol RVL-1201-202 Amendment 3 
The following changes were made to Amendment 2: 


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Location 
Description of Change 
Rationale for Change 
Synopsis Methodology;  
6.1. Overall Study Design; 
10.1.1. Day -7 to Day -3 
(Visit 1): Screening 
Add  
Both eyes will be treated and assessed, but 
the more ptotic eye (the eye with the smaller 
marginal reflex distance (MRD) 
measurement) will be the study eye. If the 
MRD = 0 in either eye where both eyes are 
eligible, the eye with the measurable MRD 
(≥ 0.5 mm) will be the study eye. If the 
MRD is the same in both eyes, the eye with 
the greater visual field defect (the lower 
Leicester Peripheral Field Test [LPFT] Total 
Score from Visit 1, Hour 6, based on number 
of points seen on the top 4 rows) will be the 
study eye. If the MRD and LPFT are the 
same in both eyes, the right eye will be the 
study eye. 
Potential improvements in 
MRD can be more accurately 
determined if the eligible eye 
has a measurable MRD. 
Synopsis Exclusion Criteria;  
7.2. Exclusion Criteria 
Change from 
In either eye 
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 the study eye only 
1. Dermatochalasis that extends less than 
3 mm above the upper eyelid margin. 
2.    Pseudoptosis (upper eyelid 
dermatochalasis that overhangs the 
upper eyelid margin). 
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 
24. 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. 
24. 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. 
Synopsis Study Procedures; 
6.1. Overall Study Design 
9.2.1. Leicester Peripheral Field 
Test 
10.1.1. Day  7 to Day  3 
(Visit 1): Screening 
Change from 
If the Humphrey Visual Field (HVF) 
Analyzer issues an “XX” for fixation losses, 
false positives, and/or false negatives, the 
test will be deemed unreliable. If deemed 
unreliable, the test may be retaken once per 
scheduled test. 
to 
If the Humphrey Visual Field (HVF) 
Analyzer issues an “XX” for fixation losses, 
false positives, and/or false negatives, the 
test will be deemed unreliable. If deemed 
unreliable, the test must be retaken (once per 
scheduled test). 
To clarify that it is not optional 
to repeat an “unreliable” test 
once, it is mandatory. 
Table 2: Schedule of Procedures 
Footnote d 
Change from 
d  
MRD and pupil diameter will be 
measured from the external photograph. 
For a description of the precise timing of 
MRD measurements, please refer to 
details of each individual visit in Section 
10. 
d  
MRD and pupil diameter will be 
measured from the external photograph. 
On Day 1 (Visit 2), Day 14 (Visit 3), 
and Day 42 (Visit 4), the timing of 
MRD measurements must be at 5 
minutes (+2 minutes) and 15 minutes 
(+ 2 minutes) post dose. For a 
description of the timing of all MRD 
measurements, please refer to details of 
each individual visit in Section 10. 
To establish consistency 
between the description of the 
timing of assessments between 
the schedule and Section 10. 
 

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STATISTICAL ANALYSIS PLAN 
 
Confidential 
 
 
PROTOCOL TITLE: 
A Randomized, Double-Masked, Placebo-Controlled Phase 3 
Study of the Safety and Efficacy of RVL-1201 in the 
Treatment of Acquired Blepharoptosis, Study RVL-1201-202 
PROTOCOL NUMBER: 
CLN.RVL-1201.RVL-1201-202.PR.A03 
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-1201-202.SAP.02 
Supersedes CLN.RVL-1201-202.SAP.01 
 
 
Issue Date: 
 
 
15 April 2019 
 
 
 
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 ..........................................................................................9
2.4
Subject Withdrawal Criteria .....................................................................................10
2.5
Study Plan/Procedures ..............................................................................................11
2.6
Randomization and Masking ....................................................................................12
3.
STUDY ASSESSMENTS/ENDPOINTS ...............................................................12
3.1
Demographic and Background Characteristics .........................................................12
3.1.1
Demographic/Medical History ..........................................12
3.1.2
Concomitant Medications History .....................................12
3.1.3
Ophthalmic History and Ophthalmic Intervention 
History ...............................................................................13
3.1.4
Urine Pregnancy Test ........................................................13
3.2
Efficacy Assessments................................................................................................13
3.2.1
Leicester Peripheral Field Test ..........................................13
3.2.2
External Photography ........................................................15
3.2.3
Marginal Reflex Distance Measurement ...........................15
3.3
Safety Assessments ...................................................................................................15
3.3.1
Vital Signs .........................................................................15
3.3.2
Snellen Visual Acuity Assessment ....................................15
3.3.3
Pupil Diameter Measurement ............................................15
3.3.4
Slit Lamp Exam/Corneal Fluorescein Staining .................16
3.3.5
Dilated Ophthalmoscopy/Fundus Exam ............................16
3.3.6
Intraocular Pressure Tonometry ........................................16
3.3.7
Study Medication Tolerability Assessment .......................16
3.3.8
Adverse Events ..................................................................16
4.
SAMPLE SIZE AND POWER CONSIDERATIONS ........................................17
5.
ANALYSIS POPULATIONS ................................................................................17
6.
DATA HANDLING ................................................................................................18
6.1
Study Data .................................................................................................................18
6.1.1
Clinical Data – CDISC Study Data Tabulation Model 
(SDTM)..............................................................................18
6.1.2
Analysis Data – CDISC Analysis Data Model (ADaM) ...18
6.2
Handling of Early Termination Visit Information ....................................................18
6.3
Handling of Missing Data .........................................................................................18
6.4
Multiple Imputation Details ......................................................................................19
7.
STATISTICAL ANALYSIS ..................................................................................20


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7.1
General Considerations .............................................................................................20
7.1.1
Definition of Study Eye .....................................................21
7.1.2
Definition of Baseline ........................................................21
7.2
Subject Disposition ...................................................................................................21
7.3
Demographic and Baseline Characteristics ..............................................................22
7.4
Concomitant Medications .........................................................................................22
7.5
Treatment Compliance and Exposure .......................................................................22
8.
EFFICACY ANALYSES .......................................................................................22
8.1
Hypothesis Testing....................................................................................................22
8.2
Primary Efficacy - LPFT ..........................................................................................23
8.3
Secondary Efficacy - MRD .......................................................................................23
9.
SAFETY MEASURES ...........................................................................................24
9.1
Intraocular Pressure ..................................................................................................24
9.2
Snellen Visual Acuity ...............................................................................................24
9.3
Pupil Diameter ..........................................................................................................24
9.4
Corneal Fluorescein Staining ....................................................................................24
9.5
Slit Lamp Examination .............................................................................................24
9.6
Ophthalmoscopy and Fundus Exam .........................................................................24
9.7
Tolerability Assessment ............................................................................................24
9.8
Vital Signs: Heart Rate and Blood Pressure .............................................................25
9.9
Adverse Events .........................................................................................................25
10.
INTERIM ANALYSIS ...........................................................................................25
11.
TABLES, LISTINGS AND FIGURES .................................................................25
12.
REFERENCES........................................................................................................26
13.
SCHEDULE OF PROCEDURES .........................................................................27
14.
REVISION HISTORY ...........................................................................................29






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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 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 primary objectives of this study are to evaluate the efficacy of RVL-1201 Ophthalmic 
Solution in the treatment of acquired blepharoptosis at 2 weeks and to assess the safety of RVL-
1201 for a dosing period of 6 weeks. 
 


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2.2 
Inclusion Criteria 
1. Male or female subjects ≥9 years of age. 
2. Presence of all the following at Screening: 
a. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score); 
subjects must see at least 9 total points in the top 4 rows (LPFT Total Score).  
i. 
These criteria must be met in both the V1H0 and V1H6 LPFT 
assessments  
ii. 
There must be ≤ 4 points of variance between the V1H0 and the V1H6 
LPFT Eligibility Score; AND 
b. The MRD, the distance from the central pupillary light reflex to the central 
margin of the upper lid, ≤ 2 mm (no visible central pupillary light reflex defaults 
to 0) in the same eye as Inclusion Criterion #2a; AND 
c. Snellen VA of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b). 
3. Presence of all the following at Baseline: 
a. Loss on a reliable LPFT of ≥ 8 points in the top 2 rows (LPFT Eligibility Score) 
in the same eye as Inclusion Criterion #2a; subjects must see at least 9 total points 
in the top 4 rows (LPFT Total Score).  
i. 
These criteria must be met in the V2H0 LPFT assessment.  
ii. 
There must be ≤ 4 points of variance between the V1H6 and the V2H0 
LPFT Eligibility Score; AND 
b. MRD, the distance from the central pupillary light reflex to the central margin of 
the upper lid, ≤ 2 mm (no visible central pupillary light reflex defaults to 0) in the 
same eye as Inclusion Criterion #2a; AND 
c. Snellen VA of 20/80 or better in the same eye as Inclusion Criteria #2a and #2b). 
4. Females must be 1-year postmenopausal, surgically sterilized, or females of childbearing 
potential (females who have started their menstrual cycles) with a negative urine 
pregnancy test at Visits 1 and 2. Females of childbearing potential 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. 
5. Must be able to self-administer study medication or to have the study medication 
administered by a caregiver throughout the study period. 
6. 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 


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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 the study eye only 
1. Dermatochalasis that extends less than 3 mm above the upper eyelid margin. 
2. Pseudoptosis (upper eyelid dermatochalasis that overhangs the upper eyelid margin). 
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. Visual field loss from any cause other than ptosis. 
11. History of herpes keratitis. 
12. History of closed/narrow angle glaucoma (unless patent peripheral iridotomy has been 
performed > 3 months prior to Visit 1). 
13. Periocular neurotoxin (e.g., Botox, Xeomin, Dysport, Myobloc) injections within 3 
months prior to Visit 1 and during the study. 
14. Topical application of bimatoprost (i.e., Latisse®) to the eyelashes within 7 days prior to 
Visit 1 and during the study. 
15. 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. 
16. Intravitreal injections (e.g., Lucentis®, Eylea®, Avastin®, Triesence®) within 7 days prior 
to Visit 1 and during the study. 
17. Current punctal plugs or placement of punctal plugs during the study. 


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18. 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 
19. Resting heart rate (HR) outside the normal range (50–110 beats per minute). 
20. Hypertension with resting diastolic blood pressure (BP) > 105 mm Hg or systolic BP 
> 220 mm Hg. 
21. Use of monoamine oxidase inhibitors (MAOIs; e.g., isocarboxazid, phenelzine, 
tranylcypromine) within 14 days prior to Visit 1 and during the study. 
22. Advanced arteriosclerotic disease or history of cerebrovascular accident (CVA). 
23. 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. 
24. 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. 
25. Pregnancy or lactation. 
26. Diagnosed benign prostatic hypertrophy requiring medicinal therapy; previous 
prostatectomy is allowed.  
27. History of contact or systemic allergic reaction to oxymetazoline hydrochloride or other 
sympathomimetic drugs (e.g., phenylephrine, pseudoephedrine, ephedrine, 
phenylpropanolamine, fepradinol, or methoxamine). 
28. 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. 
29. Previous randomization into any previous clinical study of RVL-1201 (Study RVL-1201-
001 or Study RVL-1201-201) or into this study (Study RVL-1201-202). 
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 


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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 safety and efficacy of QD treatment with RVL-1201 compared to Vehicle (placebo) 
for the treatment of acquired ptosis. The study will be conducted over 42 days (6 weeks).  
Eligible subjects will be randomized in a 2:1 ratio to one of 2 treatment arms and treated for 
42 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 104) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 52) 
Both eyes will be treated and assessed, but the more ptotic eye (the eye with the smaller MRD 
measurement) will be the study eye. If the MRD = 0 in either eye where both eyes are eligible, 
the eye with the measurable MRD (≥ 0.5 mm) will be the study eye.  If the MRD is the same in 
both eyes, the eye with the greater visual field deficit (the lower LPFT Total Score from Visit 1, 
Hour 6 [V1H6] LPFT, based on number of points seen in the top 4 rows) will be the study eye. If 
the MRD and LPFT are the same in both eyes, the right eye will be the study eye.  
Prior to randomization, each subject will attend a screening visit on or between Day -7 to Day -3 
(Visit 1). The Visit 1 LPFT will be administered twice, with 6 hours intervening. If the HVF 
Analyzer issues an “XX” for fixation losses, false positives, and/or false negatives, the test will 
be deemed unreliable. If deemed unreliable, the test must be retaken (once per scheduled test). 
There must be ≤ 4 points of variance in LPFT Eligibility Score between the test at Visit 1 Hour 0 
(V1H0) and Visit 1 Hour 6 (V1H6). External photographs of the subject’s eyes will be taken, and 
safety assessments will be conducted. Inclusion/exclusion criteria will be reviewed, and the 
external photograph and LPFT printouts will be sent to the Medical Monitor for 
reading/confirmation of eligibility/determination of study eye. The Medical Monitor will 
subsequently inform the site whether the subject is eligible and which eye will be the study eye. 
At Day 1, Baseline (Visit 2), subjects will undergo safety and efficacy assessments at Hour 0 
beginning with a baseline LPFT in the study eye only. There must be ≤ 4 points of variance in 
LPFT Eligibility Score between this test at Visit 2 Hour 0 (V2H0) and the V1H6 test performed 
at Screening. Subjects who meet all eligibility criteria will complete the remaining baseline 
assessments and 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. The subject 
(or caregiver, if the subject is not able to self-administer the medication) will then administer the 
first dose of allocated masked study medication at the clinical site and undergo safety and 
efficacy assessments at Hours 2, 6 and 8. Site personnel will dispense study medication and 
conduct study medication accountability procedures. 
Study medication, RVL-1201 or Vehicle, 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.  


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From Days 2 through 13, 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 (Visit 3) in the morning prior to 
instillation of study medication. Subjects will return all opened and unopened study medication 
materials and undergo safety and efficacy assessments at Hour 0. After instillation of study 
medication at the clinical site, the subject will undergo safety and efficacy assessments at Hours 
2, 6, and 8. Site personnel will dispense study medication and conduct study medication 
accountability procedures. 
From Day 15 through the morning of Day 42, randomized study medication will be administered 
QD (in the morning), and subjects will return to the clinic on Day 42 ± 3 days (Visit 4) prior to 
instillation of study medication. After returning all opened and unopened study medication 
materials, study medication will be administered, and subjects will undergo safety and efficacy 
assessments and rate the ocular tolerability of study medication. Site personnel will conduct final 
study medication accountability procedures. 
2.6 
Randomization and Masking 
Study medication will be randomized in a 2:1 ratio (RVL-1201 Ophthalmic Solution [N = 104]; 
Vehicle [placebo] [N = 52]). 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 (Visit 1) as well as at baseline (Visit 2), 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 2) and Day 14 ± 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 during Visit 1 (Screening) as part 
of the eligibility assessment. 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 


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All concomitant medications (prescription and OTC) taken at Visit 1 (Screening) 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 
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) and repeated at Day 42 (Visit 4, 
End of Treatment) or the Early Discontinuation Visit for women of childbearing potential only. 
3.2 
Efficacy Assessments 
The efficacy of RVL-1201 Ophthalmic Solution compared to the Vehicle for the pharmacologic 
treatment of acquired blepharoptosis will be measured by improvement in visual field (as 
determined by LPFT assessment) and increase in MRD. For the timing of all efficacy 
assessments, please refer to the Schedule of Procedures. 
3.2.1 Leicester Peripheral Field Test 
The LPFT, a customized visual field test designed specifically to assess ptosis (Ho et al, 2011), 
will be performed using a Humphrey Visual Field Analyzer. It is an age-corrected screening test 
with a three-zone strategy. Thirty-five points are tested in the superior field while 14 points are 
tested in the inferior field. A maximum of 48° is tested in the superior visual field. The center of 
fixation is shifted 15o inferiorly to allow for maximum superior field testing. (Ho et al, 2011) The 
inferior field test serves as a reference but is not used in the analysis. 


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Figure 1: 
Leicester Peripheral Field Test Grids 
Clinical site staff must instruct the subjects to keep their chin and forehead against the chin and 
forehead rests, and to keep their brows relaxed. Clinical site staff must also instruct the subjects 
to look at the fixation target throughout the test. A corrective lens is not necessary on the LPFT 
UNLESS the subject would have a difficult time seeing the target without it (e.g., high myope, 
high hyperope, or high astigmat). 
There are two types of scores for the LPFT assessment: 
LPFT Eligibility Score: The total number of points missed in the top 2 rows on the LPFT. 
LPFT Total Score: The total number of points seen in the top 4 rows on the LPFT. 
LPFT assessments will be performed OU until the point of study eye designation by the medical 
monitor. After designation, LPFT assessments will be performed only on the study eye. For 
subjects with surgical monovision correction where the study eye is the near vision eye, a 
neutralizing trial lens may be put in the lens holder located in front of the chin rest of the HVF 
Analyzer.  
The HVF Analyzer will determine if the LPFT test is reliable. If the HVF Analyzer issues an 
“XX” for fixation losses, false positives, and/or false negatives, the test will be deemed 
unreliable. If deemed unreliable, the test must be retaken (once per scheduled test). If the 
outcome of the repeated test is reliable it will be used in the efficacy analysis, and if the repeated 
test is unreliable it will be included in the ITT analysis set but excluded from the PP analysis set. 


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3.2.2 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 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. 
3.2.3 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. 
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 
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 


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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. 
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 


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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 
A two-group t-test with a 0.05 two-sided significance level will have 90% power to detect a 
difference in LPFT means of 3.50, assuming that the common standard deviation is 6.0, when the 
sample sizes in the 2 groups are 94 and 47, respectively (a total sample size of 141). The planned 
total of 156 subjects will allow for a 10% drop-out rate.   
 
5. 
ANALYSIS POPULATIONS 
Intent-to-treat (ITT) Population: 
The intent-to-treat (ITT) population is defined as all randomized subjects who received at least 
one dose of the allocated study medication. The primary efficacy analysis of the LPFT endpoints 
at Day 1 Hour 6 and Day 14 Hour 2 will be conducted on the ITT population. 
Per-protocol (PP) Population: 
The per-protocol (PP) population consists of those subjects in the ITT population who had no 
major protocol deviations that may impact efficacy.  The PP population will be used as a 
supportive analysis of efficacy using only observed data.   
Safety Population: 
The safety analysis population is defined as all randomized subjects who received at least one 
dose of the allocated study medication.  All safety analyses will be performed using the safety 
population. 


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6. 
DATA HANDLING 
6.1 
Study Data 
Study data identified in the schedule of procedures are collected, and source verified, in 
electronic Case Report Forms (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. 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 efficacy analyses will be based on observed cases (without imputation).  If more than 5% of 
data in any treatment group are missing, multiple imputation will be employed to analyze 
incomplete data sets under the assumption that the mechanism responsible for the missing data is 
at worst characterized as missing at random (MAR). The reasons for missing data will be 
recorded and the impact of these reasons and any treatment group imbalance on the assumption 
of MAR will be evaluated.  See Section 6.4 for more details on the multiple imputation analysis.  
If 5% or fewer data are missing, an analysis with last observation carried forward (LOCF) for 


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missing data will be conducted on the ITT population only.  LOCF imputation will be performed 
for LPFT and MRD variables only. 
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. 
6.4 
Multiple Imputation Details 
Multiple imputation is a simulation-based approach where missing values are replaced by 
multiple Bayesian draws from the conditional distribution of missing data given the observed 
data and covariates, creating multiple completed data sets.  These completed datasets can then 
be analyzed using standard analysis methods.  Rubin (1987) presented rules for how to combine 
the multiple sets of estimates to produce overall estimates, confidence intervals, and tests that 
adequately incorporate missing data uncertainty. 
Missing values for LPFT and MRD will be imputed simultaneously based on an underlying 
joint normal distribution using a Markov Chain Monte Carlo (MCMC) method.   
The imputations will be done separately for each treatment group and will include the following 
variables in the imputation model: LPFT at baseline, LPFT at Day 1 Hour 6, LPFT at Day 14 
Hour 2, MRD at baseline, MRD at Day 1 (5 Minutes, 10 Minutes, 15 Minutes, 2 Hours, 6 Hours, 
and 8 Hours), MRD at Day 14 (pre-dose, 5 Minutes, 10 Minutes, 15 Minutes, 2 Hours, 6 Hours, 
and 8 Hours), and MRD at Day 42 (5 Minutes, 10 Minutes, and 15 Minutes). 
The number of imputations will be set to 500.  The outcomes of interest (change from baseline) 
will be calculated from these imputed datasets.  The treatment difference for each imputed 
dataset will be evaluated using ANCOVA models.  See Section 11.5.3 for details on these 
models.  The estimates and standard errors of the differences in LS means based on the 500 
imputed datasets are then combined by applying Rubin’s rules for multiple imputed datasets.  
T-tests are also provided.  SAS Proc MI, Proc GLM, and Proc MIANALYZE will be utilized 
for these analyses.  The averaged difference in LS means with the corresponding 95% 
confidence interval will also be presented.  
Example SAS code is provided below: 
 
 
 
 
 
 
 
 


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PROC MI: 
proc mi data=original out=imputed seed=1223 nimpute=500;
mcmc initial = EM;
var LPFT0 LPFTD1_6 LPFTD14_2
MRD0 MRDD1_M5 MRDD1_M10 MRDD1_M15 MRDD1_H2 MRDD1_H6 MRDD1_H8
MRDD14_0 MRDD14_M5 MRDD14_M10 MRDD14_M15 MRDD14_H2 MRDD14_H6 MRDD14_H8
MRDD42_M5 MRDD42_M10 MRDD42_M15;
by treat;
ods output misspattern=msgpat varianceinfo=varinfo
parameterestimates=param;
run;
 
PROC GLM: 
proc glm data=imputed;
by _imputation;
class trtname;
model lpftd1_6_c=trtname lpft0;
estimate 'RVL-1201 - Placebo' trtname -1 1;
lsmeans trtname/pdiff;
ods output estimates=est_ds;
run;
 
PROC MIANALYZE; 
 
 
 
proc mianalyze data=est_ds;
by parameter;
modeleffects estimate;
stderr stderr;
ods select ParameterEstimates;
run; 
 
7. 
STATISTICAL ANALYSIS 
7.1 
General Considerations 
This is a Phase 3 study to evaluate the efficacy and 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. 
Subjects will be randomized in a 2:1 ratio of RVL-1201 Ophthalmic Solution to Vehicle into 
2 treatment groups and treated for 42 days: 
• RVL-1201 Ophthalmic Solution 1 drop in each eye QD in the morning (N = 104) 
• Vehicle (placebo) 1 drop in each eye QD in the morning (N = 52) 


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All efficacy variables will be compared between the RVL-1201 QD treatment regimen and 
placebo. 
The analysis of continuous and ordinal variables will use the applicable parametric methods 
(t-test, analysis of variance [ANOVA], and analysis of covariance [ANCOVA]). 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.   
Final analyses of efficacy will be conducted when all subjects complete Day 42 (Visit 4) and the 
data base has been locked. 
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 Study Eye 
Both eyes will be treated and followed, but the more ptotic eye (the eye with the smaller MRD 
measurement) will be the study eye. If the MRD = 0 in either eye where both eyes are eligible, 
the eye with the measurable MRD (≥ 0.5 mm) will be the study eye.  If the MRD is the same in 
both eyes, the eye with the greater visual field defect (the lower LPFT Total Score from V1H6 
LPFT, based on number of points seen in the top 4 rows) will be the study eye. If the MRD and 
LPFT are the same in both eyes, the right eye will be the study eye.  
Only the study eye will be used in the analysis of efficacy, but the data for both eyes will be 
included in the analysis of safety. 
7.1.2 Definition of Baseline 
Measures collected prior to dosing on Day 1 will serve as baseline.  For measures not collected 
on Day 1 the measure taken prior to Day 1 but closest in time to 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 each of the analysis populations will be 
summarized by treatment group, with percentages based on the total number randomized 
subjects. 


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7.3 
Demographic and Baseline Characteristics 
Subject demographic and baseline characteristics will be summarized using descriptive statistics 
for the ITT population. The comparability of groups used in comparison analyses will be 
characterized in tables of demographic data.  
Demographic information including age, gender, race, ethnicity and iris color will be 
summarized.  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. 
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 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. 
EFFICACY ANALYSES 
Efficacy analyses will be performed on the ITT population for the primary efficacy variables. 
Analysis of the hierarchical efficacy variables will also be conducted with the PP population 
using only observed data. 
Efficacy data will be presented in tables of descriptive statistics and frequency distribution. All 
summary tables will be supported with individual subject data listings.  
The efficacy measures (LPFT and MRD) taken on Visit 2 (Day 1, Hour 0) prior to dosing will 
serve as baseline. 
8.1 
Hypothesis Testing 
The primary efficacy endpoints will be tested sequentially in the order specified. For a claim of 
statistical significance, the null hypothesis being tested, and all higher ordered null hypotheses 
must be rejected, i.e., the Day 1 Hour 6 time point will be tested first and if P < 0.05, the Day 14 
Hour 2 time point will be tested at a significance level of 0.05. Thus, each of the hypotheses in 
the hierarchy will be tested within the treatment regimen against placebo at a significance level 


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Study RVL-1201-202 Statistical Analysis Plan 
 
  
 
 
CLN.RVL-1201-202.SAP.02 
CONFIDENTIAL 
Page 23 of 29 
 
of 0.05.   It is important to note that if the Day 1 Hour 6 endpoint is statistically significant (at 
the 0.05 level) but Day 14 Hour 2 is not statistically significant (at the 0.05 level), the study will 
still be considered positive. 
If both primary efficacy endpoints (LPFT) are significant at the 0.05 significance level then the 
secondary efficacy endpoints (MRD) will also be tested sequentially.  Testing will stop if a  
P ≥ 0.05 for a comparison.  The order of MRD testing is as follows.   
1. Day 1 Hour 2 
2. Day 14 Hour 2 
3. Day 1 Hour 6 
4. Day 14 Hour 6 
5. Day 1 Minute 15 
6. Day 14 Minute 15 
7. Day 1 Minute 5 
8. Day 14 Minute 5 
All other MRD comparisons are to be considered exploratory and informative of efficacy. 
8.2 
Primary Efficacy - LPFT 
The primary efficacy endpoints will be the mean change from Baseline (Day 1, Hour 0) in the 
RVL-1201 group versus the Vehicle group in number of points seen in the top 4 rows on the 
LPFT test at: 
• Day 1 Hour 6 (Visit 2)  
• Day 14 Hour 2 (Visit 3) 
Descriptive statistics of the observed and change from baseline in the number of points detected 
will be tabulated by visit and treatment group. The difference between treatment groups will be 
compared using an ANCOVA model with treatment as a fixed factor and baseline score as a 
covariate. The 95% confidence limits on the difference will be provided.  Wilcoxon rank sum 
tests will also be used to compare treatments on change from baseline at each time point. 
8.3 
Secondary Efficacy - MRD 
Descriptive statistics of the observed and change from baseline in MRD will be tabulated by 
visit, time point, and treatment group. The difference between treatment groups will be compared 
using an ANCOVA model with treatment as a fixed factor and baseline score as a covariate. The 
95% confidence limits on the difference will be provided.  Wilcoxon rank sum tests will also be 
used to compare treatments on change from baseline at each time point.  The analyses will be 
performed for both the study eye and the non-study eye. 
 


RVL-1201 Ophthalmic Solution  
 
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Study RVL-1201-202 Statistical Analysis Plan 
 
  
 
 
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9. 
SAFETY MEASURES 
Safety data will be presented in tables of descriptive statistics and frequency distribution. All 
summary tables will be supported with individual subject data listings. 
9.1 
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 for both the study eye and the non-
study eye. 
9.2 
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 for both the study eye and the 
non-study eye.  Note that any repeat tests due to refraction issues will be utilized in the analyses. 
9.3 
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 for both the study eye and 
the non-study eye. 
9.4 
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. 
9.5 
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. 
9.6 
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)). 
9.7 
Tolerability Assessment 
Tolerability assessments will be summarized in frequency tables based on the ordinal scale for 
each treatment group at the Day 42 assessment. 


RVL-1201 Ophthalmic Solution  
 
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Study RVL-1201-202 Statistical Analysis Plan 
 
  
 
 
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9.8 
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. 
9.9 
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). 
Events that are possibly or probably related will be counted as an event related to study drug.  
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. 
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. 
10. 
INTERIM ANALYSIS 
No interim analyses are planned. 
11. 
TABLES, LISTINGS AND FIGURES 
Table, listing and figure shells will be prepared. 


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12. 
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. 
Rubin, D.B. (1987). Multiple Imputation for Nonresponse in Surveys. New York: Wiley. 
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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Study RVL-1201-202 Statistical Analysis Plan 
 
  
 
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LPFT = Leicester Peripheral Field Test; MRD = marginal reflex distance; OU = both eyes; PD = post dose; SE = study eye; 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. On Day 1 (Visit 2), Day 14 (Visit 3), and Day 42 (Visit 4), the timing of MRD measurements 
must be at 5 minutes (+2 minutes) and 15 minutes (+ 2 minutes) post dose.  For a description of the timing of all MRD measurements, please refer to details of each 
individual visit in Section 10 of the protocol. 
e LPFT will be conducted bilaterally at Screening (Visit 1). All other LPFT examinations will be conducted unilaterally on the study eye. For subjects with surgical 
monovision correction, a neutralizing trial lens may be put in the lens holder located in front of the chin rest of the HVF Analyzer. Instruct the subjects to keep their chin 
and forehead against the chin and forehead rests, to keep their brows relaxed, and to look at the fixation point throughout the test. 
f The LPFT assessment must be performed approximately 6 hours post-administration of study medication at Day 1 (Visit 2), and approximately 2 hours 
post-administration of study medication at Day 14 (Visit 3). This requirement supersedes the order of procedures shown in the table above and in the text in 
Section 10.2.1 and Section 10.2.3 of the protocol. 
g 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. 
h Only tropicamide (Mydriacyl) should be used for this exam. Phenylephrine hydrochloride (Neosynephrine) may NOT be used. The dilated ophthalmoscopy/fundus 
exam at Screening (Visit 1) must be conducted after the LPFT assessment at Hour 6. 
i Study medication will be administered at the study site at Hour 0 on Day 1 (Visit 2), Day 14 (Visit 3), and Day 42 (Visit 4). Subjects should be instructed not to dose 
before coming for Day 14 (Visit 3) or Day 42 (Visit 4); if the subject has dosed, the visit must be rescheduled. Otherwise, study medication will be administered QD in 
the morning at home daily. 


RVL-1201 Ophthalmic Solution 
 
RevitaLid, Inc. 
Study RVL-1201-202 Statistical Analysis Plan 
 
  
 
CLN.RVL-1201-202.SAP.02 
CONFIDENTIAL 
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14. 
REVISION HISTORY 
Changes from CLN.RVL-1201-202.SAP.00 to CLN.RVL-1201-202.SAP.01:  The SAP was 
revised to incorporate changes corresponding to the revised Protocol CLN.RVL-1201.RVL-
1201-202.PR.A03.   
A section was added to describe the multiple imputation methodology (Section 6.4 Multiple 
Imputation Details). 
Changes from CLN.RVL-1201-202.SAP.01 to CLN.RVL-1201-202.SAP.02:  The SAP was 
revised to clarify that subjects with major protocol deviations that may impact efficacy will be 
excluded from the per-protocol population and removed sentences about using t-tests to test 
efficacy endpoints to make it clear that ANCOVA models will be utilized.  In section 5 Analysis 
Populations, for the per protocol population “protocol violation” was revised to “protocol 
deviation”.