Conditions: Rosacea
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 1105
Healthy volunteers: yes

Brief summary:
A Randomized, Double-blind, Parallel-group, Three-arm, Placebo-controlled, Multi-Site Therapeutic Equivalence Study with Clinical End-points Comparing Test Product "Oxymetazoline hydrochloride Cream, 1%" to Reference Product "RHOFADE™ Cream, 1%" in the Treatment of Moderate to Severe Persistent Facial Erythema of Rosacea

Detailed description:

Arms:
arm 1: Oxymetazoline hydrochloride cream, 1% arm 2: RHOFADE Cream, 1% arm 3: Vehicle cream

Interventions: intervention 1: Oxymetazoline Hydrochloride intervention 2: Rhofade Cream, 1% intervention 3: Placebo
Intervention descriptions: intervention 1: Test Comparator intervention 2: Reference Comparator intervention 3: Placebo Comparator

Protocol document:
Prot_000.pdf: 
TEVA Pharmaceuticals USA, Inc. 
Protocol No.: OXY2018-01 
Version No.: 3.0;  
29 JAN 2020
 
Confidential 
 
Page 1 of 102
 
TITLE PAGE 
Study Title: A Randomized, Double-blind, Parallel-group, Three-arm, Placebo-controlled, 
Multi-Site Therapeutic Equivalence Study with Clinical End-points Comparing Test Product 
“Oxymetazoline hydrochloride Cream, 1%” to Reference Product “RHOFADETM Cream, 
1%” in the Treatment of Moderate to Severe Persistent Facial Erythema of Rosacea. 
Short Title: A Clinical Endpoint Bioequivalence study of “Oxymetazoline hydrochloride 
Cream” 
Test Drug: 
Oxymetazoline hydrochloride Cream, 1% 
Clinical Study Phase: 
Clinical Endpoint Bioequivalence study 
Protocol No.: 
OXY2018-01 
 
Protocol Version: 
3.0;  
 
Protocol Effective Date: 
 
29 JAN 2020 
Supersedes Protocol Version: 
2.0; Amendment 2 
Sponsor: 
TEVA Pharmaceuticals USA, Inc.  
 
 
 
The study will be conducted in compliance with the protocol, ICH-GCP and any applicable 
regulatory requirements. 
 
 
CONFIDENTIAL AND PROPRIETARY 
The information contained in this document is privileged and confidential and is the property of 
TEVA Pharmaceuticals USA, Inc. Nothing herein is to be reproduced, published, or disclosed to 
others in any way without the prior express written authorization from TEVA Pharmaceuticals USA, 
Inc.  Persons to whom any information is to be disclosed must be informed that the information is 
privileged and confidential and may not be further disclosed by them. 


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SPONSOR SIGNATURE PAGE 
 
Protocol No.: 
OXY2018-01 
Protocol Version: 
3.0;  
Protocol Effective Date: 
 
Study Title: 
A Randomized, Double-blind, Parallel-group, 
Three-arm, 
Placebo-controlled, 
Multi-Site 
Therapeutic Equivalence Study with Clinical End-
points Comparing Test Product “Oxymetazoline 
hydrochloride Cream, 1%” to Reference Product 
“RHOFADETM Cream, 1%” in the Treatment of 
Moderate to Severe Persistent Facial Erythema of 
Rosacea. 
 
Signatures of the noted individuals ensure that all designated persons have agreed this version is final: 
 
 
 
Date: ______________ 
 
 
 
 
Date: ______________ 




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CRO SIGNATURE PAGE 
 
 
Protocol No.: 
OXY2018-01 
Protocol Version: 
3.0;  
Protocol Effective Date: 
 
Study Title: 
A Randomized, Double-blind, Parallel-group, 
Three-arm, 
Placebo-controlled, 
Multi-Site 
Therapeutic Equivalence Study with Clinical End-
points Comparing Test Product “Oxymetazoline 
hydrochloride Cream, 1%” to Reference Product 
“RHOFADETM Cream, 1%” in the Treatment of 
Moderate to Severe Persistent Facial Erythema of 
Rosacea. 
 
Signatures of the noted individuals ensure that all designated persons have agreed this version is final: 
 
 
 
 
Date: ______________ 
 
 
 
 
 
 



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Version No.: 3.0;  
29 JAN 2020
 
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STUDY ACKNOWLEDGMENT / DISCLOSURE 
 
Protocol No.: 
OXY2018-01 
Protocol Version: 
3.0;  
Protocol Effective Date: 
 
Study Title: 
A Randomized, Double-blind, Parallel-group, 
Three-arm, 
Placebo-controlled, 
Multi-Site 
Therapeutic Equivalence Study with Clinical End-
points Comparing Test Product “Oxymetazoline 
hydrochloride Cream, 1%” to Reference Product 
“RHOFADETM Cream, 1%” in the Treatment of 
Moderate to Severe Persistent Facial Erythema of 
Rosacea. 
 
I have carefully read and understand the foregoing protocol and agree that it contains all the necessary 
information for conducting this study safely. I will conduct this study in strict accordance with this 
protocol, International Council on Harmonisation of Technical Requirements for Registration of 
Pharmaceuticals for Human Use (ICH) guidelines for Good Clinical Practice (GCP), the Code of 
Federal Regulations (CFR), the Health Insurance Portability and Accountability Act (HIPAA), if 
applicable, the World Medical Association Declaration of Helsinki and local regulatory guidelines. I 
will attempt to complete the study within the time designated. 
I will ensure that the rights, safety and welfare, of study subjects under my care are protected. I will 
ensure control of the drugs under investigation in this study. 
I will provide access to the protocol and all other study-related information supplied by the Sponsor to 
all personnel responsible to me & who participate in the study. I will discuss this information with 
them to assure that they are adequately informed regarding the drug and conduct of the study. 
I agree to keep records on all study subject information (Case Report Forms, shipment and drug return 
forms and all other information collected during the study) and drug disposition in accordance with 
FDA regulations. I agree to retain and maintain strict accountability of the Investigational Products 
supplied to the study site. 
I will not enroll any subjects into this study until applicable Regulatory approval & IRB approval are 
obtained. 
 
 
_________________________________ 
Principal Investigator’s Signature 
 
Address: 
…………………… 
… … … … … … … 
 
 
 
Date: ______________ 


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CONTACT DETAILS 
CRO  
 
 
 
 
 
 
BIOSTATISTICS,  DATA MANAGEMENT and CLINICAL STUDY REPORT 
PREPARATION 
 
 
 
 
 
Clinical Monitoring 
 
 
 
 
 
 
 
 
  
  
 
 
MEDICAL MONITOR 
 
 
 
 
 
 
 
IWRS 


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IRB 
 
 
 
  
 
RETENTION SAMPLES STORAGE FACILITY 
 
 
 
 
 
DocuSign Envelope ID: FD9AAB15-DA1A-4112-BC21-4497C72CB751


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PROTOCOL SYNOPSIS 
Title 
A 
Randomized, 
Double-blind, 
Parallel-group, 
Three-arm, 
Placebo-controlled, Multi-Site Therapeutic Equivalence Study with 
Clinical Endpoints, Comparing Test Product “Oxymetazoline 
hydrochloride Cream, 1%” to Reference Product “RHOFADETM 
Cream, 1%” in the Treatment of Moderate to Severe Persistent Facial 
Erythema of Rosacea. 
Short title 
A Clinical Endpoint Bioequivalence study of “Oxymetazoline 
hydrochloride Cream” 
Clinical phase 
 Clinical Endpoint Bioequivalence study 
Study Site(s) 
 
 
Objectives 
Primary Objectives:  
To establish the therapeutic equivalence between Test Product 
(Oxymetazoline hydrochloride Cream, 1%, manufactured by Actavis 
Laboratories, Salt Lake City, UT) and Reference Product 
(RHOFADETM Cream, 1%, Allergan) using the primary endpoint 
(proportion of subjects with treatment success at all time-points 3, 6, 
9, and 12 hours post application on Day 29) , in subjects with 
moderate to severe persistent facial erythema of rosacea. 
To evaluate study sensitivity, the Test and Reference products will be 
statistically evaluated with regard to their superiority (P < 0.05) over 
placebo for the primary endpoint. 
Safety Objectives:  
 
(1) To monitor adverse events (AEs) and assess the safety and 
tolerability of Test Product and Reference Product in subjects with 
moderate to severe persistent facial erythema of rosacea. 
 
Study Treatment 
Duration 
The total treatment duration for each subject will be of approximately 
29 days. The 4 study visits will include:  
- 
Visit 1: Screening visit 
 
- 
Visit 2: Baseline visit (Day 1
)  
- 
Visit 3: Telephone Follow-up visit (Day 14
) 
- 
Visit 4: EoT visit (Day 29
) 


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Investigational 
products 
Test drug: Oxymetazoline hydrochloride Cream, 1%  
Name of active ingredient(s): Oxymetazoline hydrochloride 
Manufactured by: Actavis Laboratories, Salt Lake City, UT (a 
subsidiary of Teva Pharmaceuticals USA, Inc.)  
Strength: 1% (each gram of cream contains 10 mg [1%] 
oxymetazoline hydrochloride, equivalent to 8.8 mg [0.88%] of 
oxymetazoline free base) 
Reference drug: RHOFADETM Cream, 1%  
Name of active ingredient(s): Oxymetazoline hydrochloride 
Marketed by: Allergan, Inc. 
Strength: 1% (each gram of cream contains 10 mg [1%] 
oxymetazoline hydrochloride, equivalent to 8.8 mg [0.88%] of 
oxymetazoline free base) 
Placebo: Vehicle Cream 
Name of active ingredient(s): Not applicable 
Manufactured by: Actavis Laboratories, Salt Lake City, UT (a 
subsidiary of Teva Pharmaceuticals USA, Inc.)  
Strength: Not applicable 
Indication 
Treatment of moderate to severe persistent facial erythema of rosacea 
Route of 
Administration 
Topical 
Dosage Regimen 
Subjects will be instructed to apply a pea-sized amount, as a thin 
layer, once daily at approximately the same time of day for 29 
 
days. Subjects will apply the first dose of study product at Visit 2 
under supervision of the independent dispenser. The last dose should 
be administered at the clinic during the last visit (Visit 4).  
Study Design 
A randomized, double-blind, parallel-group, three-arm, placebo-
controlled, multi-site therapeutic equivalence study with clinical 
endpoints. 
Study Population 
Approximately 
 males and non-pregnant females, 18 years of age 
and older, with a clinical diagnosis of persistent (non-transient) facial 
erythema associated with rosacea. 
 
 
 
 
Diagnosis and Key 
Inclusion criteria: 


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Inclusion/Exclusion 
Criteria 
(1) Study subjects must have provided IRB approved written 
informed consent using the latest version of the IRB informed 
consent form, (or assent in applicable states/countries). In 
addition, study subjects must sign a HIPAA authorization, if 
applicable. 
(2) Healthy male or non-pregnant females, ≥18 years-of-age with a 
clinical diagnosis of rosacea with persistent (non-transient) facial 
erythema. 
(3) Ability to follow study instructions and complete subject diary 
without assistance. 
(4) Females of child bearing potential must not be pregnant or 
lactating at screening visit and at baseline visit, as documented 
by a negative urine pregnancy test. 
(5) Female subjects of childbearing potential must be willing to use 
an acceptable form of birth control from the day of the first dose 
administration to 30 days after the last administration of 
Investigational Product (IP). A sterile sexual partner is NOT 
considered an adequate form of birth control. 
(6) Moderate to severe persistent facial erythema associated with 
rosacea, defined as a grade of ≥3 on the CEA scale as assessed 
by the Investigator at Screening and on Baseline (Day 1) visit 
prior to study drug application. 
(7) Moderate to severe persistent facial erythema associated with 
rosacea, defined as a grade of ≥3 on the SSA scale as assessed by 
the subject at Screening and on Baseline (Day 1) visit prior to 
study drug application. 
(8) Stable erythema (for at least 3 months prior to screening) 
associated with rosacea, with minimal variation from day to day 
and within each day, in the opinion of the subject. 
 
(9) Willingness to complete the required visits including short stay 
for at least 12 hours at the investigational site for 2 separate 
visits. 
(10) Subjects who use make-up, facial moisturizers, creams, lotions, 
cleansers and/or sunscreens must have used the same product 
brands/types for a minimum period of 4 weeks prior to Baseline, 
must agree not to change brand/type or frequency of use 
throughout the study and must agree not to use make-up, facial 
moisturizers, creams, lotions, cleansers and/or sunscreens on the 


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scheduled clinic visit day(s) before the visit. 
(11) Subject must be willing to avoid the use of abrasive cleansers or 
washes (e.g., exfoliating facial scrubs), adhesive cleansing strips 
(e.g., Bioré® Pore Strips) and wax epilation on the face, during 
the entire duration of their study participation. 
(12) Subject’s willingness to minimize external factors that might 
trigger rosacea flare-ups (e.g., spicy foods, thermally hot foods 
and drinks, hot environments, prolonged sun exposure, strong 
winds, alcoholic beverages). 
(13) Subject must be in good health and free from any systemic or 
dermatological disorder (other than rosacea) that, in the opinion 
of the Investigator, will interfere with the study evaluations or 
increase the risk of AEs. 
(14) Any skin type or race, providing the skin pigmentation will allow 
discernment of erythema. 
Exclusion criteria  
(1) Any of the following conditions: severe or unstable or 
uncontrolled cardiovascular disease, clinically unstable 
hypertension, orthostatic hypotension, and uncontrolled 
hypertension or hypotension, cerebral or coronary insufficiency, 
Raynaud’s Syndrome, thromboangiitis obliterans, scleroderma, 
Sjögren’s syndrome, renal or hepatic impairment. 
(2) Subjects with narrow angle glaucoma. 
(3) Females who are pregnant, breast feeding, or planning a 
pregnancy during the study. 
(4) Females of childbearing potential who do not agree to utilize an 
adequate form of contraception during their participation in the 
study. 
(5) Clinical signs of particular forms of rosacea (rosacea conglobata, 
rosacea fulminans, isolated rhinophyma, isolated pustulosis of 
the chin) on the face or other concomitant facial dermatoses that 
are similar to rosacea such as peri-oral dermatitis, demodicidosis, 
facial keratosis pilaris, seborrheic dermatitis, acute lupus 
erythematosus, or actinic telangiectasia that may interfere with 
the study evaluations, in the opinion of the Investigator. 
(6) Presence of ≥3 facial inflammatory lesions of rosacea at 
screening and baseline. 
(7) Presence of any skin condition on the face that would interfere 
with the diagnosis or assessment of rosacea, as determined by the 
Investigator. 
(8) Excessive facial hair (e.g., beards, sideburns, moustaches, etc.) 
that would interfere with the study treatments or study 


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assessments. 
(9) History of drug or alcohol abuse within 12 months prior to the 
Screening visit. 
(10) Known hypersensitivity or allergies to any component of the 
study treatment. 
(11) Use within 12 hours prior to baseline of any topical products 
including, but not limited to, lotions, creams, ointments, and 
cosmetics applied to the face (facial cleanser is acceptable). 
(12) Use 1 week prior to baseline of niacin ≥500 mg/day. 
(13) Use within 2 weeks prior to baseline of products containing 
topical corticosteroids, topical retinoids, topical antibiotics, 
topical anti-inflammatory, topical treatment for rosacea, or 
topical treatment for acne.  
(14) Use 
within 
4 
weeks 
prior 
to 
baseline 
of 
topical 
immunomodulators, 
systemic 
antibiotics, 
systemic 
corticosteroids, systemic anti-inflammatory agents, systemic 
treatment for rosacea, or systemic treatment for acne (other than 
oral retinoids, which require a 6-month washout).  
(15) Undergone 4 weeks prior to baseline any dermatologic or 
surgical procedure on the face. 
(16) Use within 3 months prior to baseline of any systemic 
immunomodulators known to have an effect on rosacea. 
(17) Use within 6 months prior to baseline of any oral retinoids (e.g., 
isotretinoin) or therapeutic vitamin A supplements of greater 
than 10,000 units/day (multivitamins are allowed). 
(18) Undergone 6 months prior to baseline any laser, light-source 
(e.g. intense pulsed light, photodynamic therapy) or other 
energy-based therapy to the face. 
(19) Exposed to excessive ultraviolet (UV) radiation within 1 week 
before Screening visit and/or subject is unwilling to refrain from 
excessive exposure to UV radiation during the course of the 
study. 
(20) Current use of monoamine oxidase (MAO) inhibitors, 
barbiturates, opiates, 
sedatives, systemic 
anesthetics, or 
oxymetazoline (e.g., eye drops, nasal sprays). 
(21) Subject has participated in a clinical trial within 30 days or in a 
biologics study within 6 months preceding admission of this 
study. 
(22) Previous participation in this study.  


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(23) Inability to communicate well (i.e., language problem, poor 
mental development, psychiatric illness or poor cerebral 
function), that may impair the ability to provide written informed 
consent. 
(24) Subject has any evidence of organ dysfunction, chronic 
infectious disease, system disorder or has a condition or is in a 
situation that, in the Investigator’s opinion, that may put the 
subject at significant risk, may confound the study results, or 
may significantly interferes with the subject’s participation in the 
study. 
(25) Employees or family members of the research center or 
Investigator. 
 
Study Design and 
Methodology 
This is a multi-center, randomized, double-blind, parallel-group, 
three-arm, placebo-controlled, therapeutic equivalence study with 
clinical end-points. The study will compare the efficacy and safety of 
Test 
Product 
“Oxymetazoline 
hydrochloride 
Cream, 
1%” 
(manufactured by Actavis Laboratories, Salt Lake City, UT) with that 
of an approved topical formulation RHOFADETM (Oxymetazoline 
hydrochloride Cream, 1%) marketed by Allergan, in healthy males 
and non-pregnant females diagnosed with moderate to severe 
persistent facial erythema of rosacea. Both the test and the reference 
formulations will also be compared to a placebo (vehicle) formulation 
to test for superiority. 
Subjects with a conﬁrmed diagnosis of moderate to severe persistent 
facial erythema of rosacea will be randomized to either Test Group 
(Oxymetazoline hydrochloride Cream, 1%); Reference Group 
(RHOFADETM, Oxymetazoline hydrochloride Cream, 1%); or 
Placebo Group (Vehicle Cream). 
The study subject will receive treatment for approximately 29
 days 
from the Baseline visit to the EoT visit. There will be 4 study visits, 3 
to the study site and 1 telephone follow-up: Screening 
 
visit, Baseline (Day 1
) visit, Telephone Follow-up (Day 14
) visit, 
and EoT (Day 29
) visit. 
At screening a written Informed Consent Form (ICF) has to be signed 
by the subject and the eligibility criteria of the subject will be 
evaluated by clinical assessments.  
 
 
 
 Subjects should sign 
ICF prior to start of any study procedures, complete washout, and 


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return to the clinic to conduct the remainder of the screening 
procedures. 
Study subject numbers will be assigned to study subjects sequentially 
in the order in which study subjects are enrolled into the study.  
After the screening visit, each qualified subject will return to the clinic 
on Day 1 for confirmation of eligibility. Eligible subjects will be 
assigned to one of the three study treatment groups as per the 
computer-generated randomization schedule, and the assigned study 
medication will be dispensed by the study site staff. Since this is a 
double-blind study, neither the study team at the site nor the subjects 
will know the treatment the subject is assigned. 
The subject will be instructed to apply a pea-size amount of the study 
treatment to cover the entire face (forehead, chin, nose, and each 
cheek [avoiding the eyes and lips]), once daily preferably, at the same 
time each day, up to and including the day before scheduled Visit 4 
(Day 29±2). 
 
 
 On Day 1 visit and Day 29±2 visit, the subject will apply the 
assigned medication at the clinic under the supervision of an 
Independent Dispenser (unblinded to the treatment the subject is 
receiving). 
 
 
 From Day 2 up to and including the day before scheduled 
Visit 4 (Day 29
), the subject will be asked to apply the assigned 
medication once daily preferably, at the same time each day, and 
complete the subject diary, handed over by the study site staff at 
Baseline visit.
 
 
The subject will note the date and time of 
application of the study medication, any AE experienced, and any 
concomitant medication taken or changes from the existing ones, in 
the subject diary from Visit 2 (Day 1) to Visit 4 (Day 29
). A phone 
call will be made around Day 14 to follow up for any change in 
concomitant medications, and check on compliance of study 
medication usage.  


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Schedule of Events 
Procedures 
 
Visit 
Visit 1a 
Visit 1b 
Visit 2 
Visit 3 
Visit 4 
Screening 
 
Screening 
 
Day 1 
(Baseline) 
] 
Day 14  
(Telephone 
Follow-up)a  
 
Day 29  
(EoT)  
 
Written informed consent 
X 
 
 
 
 
 
Demographics (height, weight, 
body mass index (BMI), gender, 
race, ethnicity) 
X 
 
 
 
 
Pregnancy test (Urine) 
X 
X 
X 
 
X 
Medical and surgical history 
X 
X 
 
 
 
Prior and concomitant medications 
and concurrent procedures 
X 
X 
X 
X 
X 
Vital signs measurements (blood 
pressure, heart rate, body 
temperature) 
X 
X 
Pre-dose 
and 12 hrs 
 
Pre-dose 
and 12 hrs 
Clinician Erythema Assessment 
(CEA) 
 
X 
 
X 
Pre-dose, 
3, 6, 9, and 
12 hrs (± 
30 minutes 
at each 
timepoint) 
 
Pre-dose, 3, 
6, 9, and 12 
hrs (± 30 
minutes at 
each 
timepoint) 
Subject Self-Assessment (SSA) for 
rosacea facial redness 
X 
 
X 
Pre-dose, 
3, 6, 9, and 
12 hrs (± 
30 minutes 
at each 
timepoint) 
 
Pre-dose, 3, 
6, 9, and 12 
hrs (± 30 
minutes at 
each 
timepoint) 
Physical examination 
X 
 
 
 
X 
Review of Inclusion/Exclusion  
X  
 
X 
Pre-dose 
(confirm 
eligibility) 
 
 
Randomization 
 
 
X 
 
 
Dispense study medication tube 
 
 
X 
 
 
Dosing (Days 1-29)b 
 
 
X 
 
X 
Adverse event monitoringc  
X 
X 
X 
X 
X 
Subject diary review 
 
 
X 
 
X 


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Confinement in study clinic 
 
 
≥12 hrs in 
clinic 
 
≥12 hrs in 
clinic 
Collection of study medication tube 
 
 
 
 
X 
 
a14 days after the first dose of study drug, a phone call will be made to follow-up on any 
changes in concomitant medications and check on compliance of study medication usage. 
bSubject will apply study medication once daily preferably at the same time each day from 
Day 2 to Day 28 at home, as instructed. 
cIncluding monitoring of application site dermatitis, application site pruritis, application site 
erythema, and application site pain, scaling or burning at Visit 2 and Visit 4. 
 
 
Number of 
Subjects to be 
Enrolled and 
Randomized 
(Planned) 
 
 
 
 
 
 
 
Additional subjects may be randomized to reach the planned number 
of evaluable subjects, if a higher drop out rate is experienced. 
Variables 
Efficacy variables: 
- Scores obtained from the Clinical Erythema Assessment (CEA) 
scale 
- Score obtained from the Self-Subject Assessment (SSA) scale 
Safety variables: 
- Serious Adverse Events (SAEs)  
- 
Non-SAEs 
Primary Endpoints 
 
The primary efficacy endpoint is the proportion of subjects with 
treatment success at all time-points 3, 6, 9, and 12 hours post 
application on Day 29. Treatment success is defined as having CEA 
score at least 2 grades lower than the baseline (Day 1 pre-dose) value. 
 
 
 
 
 
Safety endpoints: Incidence of AEs. 
 


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Time point of 
Clinical 
Evaluations 
Clinical Evaluations will be performed at: 
x Visit Screening A: Demographics, vital signs, urine pregnancy 
test, physical examination, assessment of facial erythema using 
CEA scale (Investigator’s assessment) and SSA scale (subject’s 
assessment), AE monitoring, concomitant medications and 
concurrent procedures. 
x Visit Screening B: Urine pregnancy test, assessment of facial 
erythema using CEA scale (Investigator’s assessment) and SSA 
scale (subject’s assessment), AE monitoring, concomitant 
medications and concurrent procedures. 
  
x Visit Day 1 (Baseline): Vital signs, urine pregnancy test, 
assessment of facial erythema using CEA scale (Investigator’s 
assessment) and SSA scale (subject’s assessment), AE monitoring, 
concomitant medications and concurrent procedures. 
x Visit Day 14 (Telephone Follow Up): Any changes in 
concomitant medications and concurrent 
procedures, and 
compliance with study medication usage. 
x Visit Day 29 (End of Treatment): Vital signs, urine pregnancy 
test, 
assessment 
of 
facial 
erythema 
using 
CEA 
scale 
(Investigator’s assessment) and SSA scale (subject’s assessment), 
AE monitoring, concomitant medications 
and concurrent 
procedures. 
 
Sample Size 
 
 
 
 
 
 
 
 
Statistical Analysis 
Three analysis populations will be used: Per protocol (PP) population, 
mITT population, and safety population. 
Analysis of the primary endpoint 
Analyses will be conducted with the PP population for equivalence 
determination, and analyses with the mITT population will be for 
supportive superiority purposes. 


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x Equivalence testing 
Therapeutic equivalence will be concluded if the 90% confidence 
interval for the difference between test and reference products (πT – 
πR) of the treatment success rates at all timepoints 3, 6, 9, and 12 
hours post-application on Day 29 falls within the acceptance range of 
[-0.20, +0.20] using PP population.  
x Superiority testing 
A two-sided exact Cochran-Mantel-Haenszel test, stratified by clinical 
site, will be applied to test the difference between treatment success 
rates at all timepoints 3, 6, 9, and 12 hours post-application on Day 29 
of Test or Reference Product and Placebo. The sensitivity of the 
equivalence analysis (superiority of Test Product and Reference 
Product over Placebo) will be established if active treatment success 
rate is higher than and statistically significantly different from (p-
value < 0.05) that of the Placebo group for each active treatment using 
the mITT population. No adjustment will be made for multiplicity. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
 
 
TITLE PAGE .................................................................................................................. 1 
SPONSOR SIGNATURE PAGE ................................................................................... 2 
CRO SIGNATURE PAGE ...................................................................................................3 
STUDY ACKNOWLEDGMENT / DISCLOSURE ............................................................4 
PROTOCOL SYNOPSIS ............................................................................................... 7 
TABLE OF CONTENTS ............................................................................................. 18 
LIST OF ABBREVIATIONS ...................................................................................... 22 
1 INTRODUCTION AND BACKGROUND.............................................................. 24 
1.1 
RATIONALE FOR THE STUDY ...................................................................................24 
1.2 
OVERVIEW OF STUDY INDICATION ..........................................................................24 
1.3 
REFERENCE PRODUCT INFORMATION (RHOFADETM)[12] .......................................24 
1.3.1 Dosage and administration ........................................................................24 
1.3.2 Pharmacokinetics .......................................................................................25 
1.3.3 Drug interactions .......................................................................................25 
1.3.4 Adverse effects ...........................................................................................26 
1.3.5 Contraindications ......................................................................................26 
1.3.6 Warnings and precautions .........................................................................26 
1.3.7 Use in specific populations ........................................................................27 
2 OBJECTIVES ............................................................................................................ 29 
2.1 
PRIMARY OBJECTIVE ..............................................................................................29 
2.2 
SAFETY OBJECTIVES ...............................................................................................29 
3 STUDY DESIGN ........................................................................................................ 29 
3.1 
DESIGN OVERVIEW .................................................................................................29 
3.2 
PRIMARY ENDPOINTS ..............................................................................................31 
3.3 
SAFETY ENDPOINTS ................................................................................................31 
4 STUDY POPULATION ............................................................................................ 32 
4.1 
INCLUSION CRITERIA ..............................................................................................32 
4.2 
EXCLUSION CRITERIA .............................................................................................33 
4.3 
RESTRICTIONS AND PROHIBITIONS ..........................................................................35 
4.4 
SUBJECT WITHDRAWAL / DROPOUT ........................................................................39 
5 TREATMENTS .......................................................................................................... 41 
5.1 
TREATMENTS TO BE ADMINISTERED .......................................................................41 
5.2 
TREATMENT ASSIGNMENT (RANDOMIZATION) .......................................................42 
5.3 
DOSAGE AND ADMINISTRATION ..............................................................................42 
5.4 
RECEIPT AND STORAGE ...........................................................................................42 
5.5 
PACKAGING AND LABELING ....................................................................................42 


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5.6 
BLINDING ................................................................................................................43 
5.7 
ASSESSMENT OF COMPLIANCE ................................................................................44 
5.8 
STUDY MEDICATION REPLACEMENT.......................................................................44 
5.9 
ACCOUNTABILITY OF STUDY MEDICATION .............................................................44 
5.10 
RETENTION OF STUDY MEDICATION SAMPLES .......................................................44 
5.11 
RETURN OF DRUG SUPPLIES ....................................................................................45 
6 STUDY PROCEDURES ........................................................................................... 46 
6.1 
SCHEDULE OF EVENTS ............................................................................................46 
6.2 
VISIT DESCRIPTION .................................................................................................49 
6.3 
POPULATION CHARACTERISTICS .............................................................................53 
6.3.1 Demographics ............................................................................................53 
6.3.2 Medical history ..........................................................................................53 
6.4 
EFFICACY ................................................................................................................53 
6.4.1 Efficacy variables.......................................................................................53 
6.4.2 Primary Efficacy Endpoints .......................................................................53 
6.5 
SAFETY ...................................................................................................................53 
6.5.1 Safety Variables .........................................................................................53 
6.5.2 Adverse events ............................................................................................54 
6.5.3 Follow-up of subjects after AE ..................................................................62 
6.5.4 Pregnancy ..................................................................................................63 
6.6 
OTHER PROCEDURES AND VARIABLES ....................................................................63 
6.6.1 Physical examination .................................................................................63 
6.6.2 Vital signs...................................................................................................64 
6.6.3 Laboratory evaluations ..............................................................................65 
6.7 
MEDICATION ERROR AND SPECIAL SITUATIONS .....................................................65 
6.8 
FOLLOW UP OF SUBJECTS AFTER AE .......................................................................65 
6.9 
RECONCILIATION OF SAES .....................................................................................66 
6.10 
APPROPRIATENESS OF PROCEDURES / MEASUREMENTS ..........................................66 
7 STATISTICAL AND ANALYTICAL PLANS ....................................................... 67 
7.1 
SAMPLE SIZE RATIONALE .......................................................................................67 
7.2 
RANDOMIZATION PROCEDURES ..............................................................................67 
7.3 
SIGNIFICANCE LEVEL ..............................................................................................68 
7.4 
DATASETS TO BE ANALYZED ..................................................................................68 
7.5 
COMPARABILITY OF STUDY GROUPS AT BASELINE .................................................68 
7.6 
SAFETY ASSESSMENT .............................................................................................69 
7.7 
EFFICACY ASSESSMENT ..........................................................................................69 
7.7.1 Analysis of primary endpoint .....................................................................69 
8 ETHICS ....................................................................................................................... 70 
8.1 
INFORMED CONSENT ...............................................................................................70 
8.2 
INSTITUTIONAL REVIEW BOARD .............................................................................70 
8.3 
STUDY SUBJECT CONFIDENTIALITY ........................................................................71 
9 DOCUMENTATION ................................................................................................. 72 
9.1 
SITE REGULATORY DOCUMENTS REQUIRED FOR INITIATION ..................................72 
9.2 
MAINTENANCE AND RETENTION OF RECORDS ........................................................72 
9.3 
CASE REPORT FORMS (CRFS) .................................................................................73 
9.4 
PRIMARY SOURCE DOCUMENTS ..............................................................................73 


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9.5 
STUDY MONITORING ...............................................................................................74 
9.6 
AUDITS AND INSPECTIONS ......................................................................................74 
9.7 
MODIFICATIONS TO THE PROTOCOL ........................................................................75 
9.8 
COMPLETION OF STUDY ..........................................................................................75 
10 
STUDY SUBJECT INSURANCE ....................................................................... 76 
11 
CONFIDENTIALITY, USE OF INFORMATION, AND PUBLICATION ... 77 
12 
PREMATURE TERMINATION OF STUDY/SUBJECT ............................... 78 
13 
REFERENCES ..................................................................................................... 79 
14 
LIST OF APPENDICES ...................................................................................... 80 
FULL PRESCRIBING INFORMATION .................................................................. 88 
2 DOSAGE AND ADMINISTRATION ...................................................................... 88 
3 DOSAGE FORMS AND STRENGTHS .................................................................. 88 
4 CONTRAINDICATIONS ......................................................................................... 88 
5 WARNINGS AND PRECAUTIONS ....................................................................... 88 
5.2 POTENTIATION OF VASCULAR INSUFFICIENCY .................................. 88 
5.3 RISK OF ANGLE CLOSURE GLAUCOMA ................................................... 88 
6 ADVERSE REACTIONS .......................................................................................... 88 
TABLE 1: ADVERSE REACTIONS REPORTED BY > 1% OF SUBJECTS 
THROUGH 4 WEEKS OF TREATMENT IN CONTROLLED CLINICAL 
TRIALS ....................................................................................................................... 89 
7 DRUG INTERACTIONS .......................................................................................... 89 
7.2 MONOAMINE OXIDASE INHIBITORS ......................................................... 89 
8 USE IN SPECIFIC POPULATIONS ....................................................................... 89 
8.2 LACTATION ........................................................................................................ 91 
8.4 PEDIATRIC USE ................................................................................................. 91 
8.5 GERIATRIC USE ................................................................................................ 91 
10 
OVERDOSAGE .................................................................................................... 91 
11 
DESCRIPTION .................................................................................................... 91 
12 
CLINICAL PHARMACOLOGY ....................................................................... 92 
12.2 PHARMACODYNAMICS .................................................................................. 92 
12.3 PHARMACOKINETICS .................................................................................... 92 
13 
NONCLINICAL TOXICOLOGY ...................................................................... 92 
14 
CLINICAL STUDIES .......................................................................................... 93 
TABLE 2: PROPORTION OF SUBJECTS ACHIEVING COMPOSITE 
SUCCESS*  ON DAY 29 ........................................................................................... 93 


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16 
HOW SUPPLIED/STORAGE AND HANDLING ............................................ 93 
17 
PATIENT COUNSELING INFORMATION .................................................... 94 
 


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LIST OF ABBREVIATIONS 
°C 
Degree Celsius 
AE 
Adverse event 
ALP 
Alkaline phosphatase 
ALT 
ANOVA 
Alanine aminotransferase 
Analysis of variance 
AST 
 
Aspartate aminotransferase 
 
 
BA/BE 
Bioavailability/Bioequivalence 
BMI 
Body mass index 
Bpm 
Beats per minute 
CEA 
Clinician Erythema Assessment 
CFR 
Code of Federal Regulations 
CRF 
Case Report Form 
CRO 
Contract Research Organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
EC 
Ethics Committee 
eCRF 
Electronic Case Report Form 
EDC 
 
 
Electronic Data Capture 
 
 
EoS 
End of Study 
EoT 
End of Treatment 
FDA 
Food and Drug Administration 
GCP 
Good Clinical Practice 
HIPAA 
Health Insurance Portability and Accountability Act 
ICF 
Informed Consent Form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
ID 
Identification 
IND 
Investigational New Drug 
INR 
International normalized ratio 
IP 
Investigational Product 


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IRB 
Institutional Review Board 
IUD 
Intra-uterine device 
ITT 
Intent-to-treat 
IWRS 
Interactive Web Response System 
LOCF 
Last observation carried forward 
MAO 
Monoamine oxidase 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified intent-to-treat 
mmHg 
Millimeters of mercury 
NA 
NDA 
Not applicable 
New Drug Application 
OTC 
Over-the-counter 
PhV 
Pharmacovigilance 
PP 
Per-protocol 
RLD 
Reference Listed Drug 
SAE 
Serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
Standard deviation 
SOC 
System Organ Class 
SOP 
Standard Operating Procedure 
SSA 
Subject Self-Assessment 
TEAE 
Treatment-emergent adverse event 
TESAE 
Treatment-emergent serious adverse event 
ULN 
Upper limit of normal 
US/USA 
United States/United States of America 
WOCBP 
Females of child bearing potential 


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1 INTRODUCTION AND BACKGROUND 
1.1 Rationale for the Study 
This therapeutic equivalence study with clinical endpoint is designed to determine the 
therapeutic equivalence of “Oxymetazoline hydrochloride Cream, 1%” (manufactured by 
Actavis Laboratories, Salt Lake City, UT) with the reference listed drug (RLD) 
RHOFADETM (Oxymetazoline hydrochloride Cream, 1%) marketed by Allergan, in healthy 
males and non-pregnant females diagnosed with moderate to severe persistent facial 
erythema of rosacea. 
1.2 Overview of Study Indication 
Rosacea is a common, chronic dermatological condition of uncertain etiology that is 
characterized by a myriad of clinical manifestations, including persistent erythema (which 
may be accompanied by facial stinging and burning), facial edema, superficial 
telangiectasias, recurrent papules and pustules, facial phymas (most commonly rhinophyma), 
and ocular manifestations.[1,2] In a recent meta-analysis, the global prevalence of rosacea was 
found to affect 5.46% of the adult population.[3] It is estimated to affect more than 16 million 
Americans, yet only a small fraction is being treated.[4] Its onset is typically between the ages 
of 30 and 50, and women are affected 2 to 3 times more often than men.[5] Of all the clinical 
manifestations of rosacea, facial flushing and persistent erythema are among the most 
common and are often associated with psychological distress.[6,7,8] Although the precise 
etiology and pathogenesis of erythematous rosacea remain uncertain, it is hypothesized that 
abnormal flushing and persistent erythema result from a progressive dysregulation in the 
cutaneous vasomotor response (i.e., persistently dilated facial blood vessels).[9] 
While rosacea is not curable, it is a treatable condition; treatment goals include alleviation of 
signs and symptoms, improvement of appearance, and delay or prevention of advancement of 
the condition. Effective treatments have been developed to treat papulopustular rosacea using 
topical anti-infective agents such as sulfonamides, metronidazole, azelaic acid, ivermectin 
and tetracyclines.[2,10] 
Conspicuous facial redness may have a deep impact on a patient's self-esteem and quality of 
life. Surveys of rosacea patients conducted by the National Rosacea Society indicate that 
more than 90% had lowered self-esteem and self-confidence; of rosacea patients with severe 
symptoms, 88% said the condition had adversely affected their professional interactions. 
Nearly 51% said they had even missed work because of their condition.[4] 
Most topical pharmacologic agents approved by the United States Food and Drug 
Administration (US FDA) for treatment of papules and pustules of rosacea have no effect on 
persistent facial erythema. Oxymetazoline, an alpha1A-adrenoceptor agonist, is approved by 
the US FDA to treat persistent facial erythema of rosacea. A long-term safety and dermal 
tolerability of once daily application of oxymetazoline over 52 weeks has been established. 
No clinically relevant rebound effect was observed; efficacy was observed at day 1 through 
52 weeks and response rates increased throughout the study.[11] 
1.3 Reference Product Information (RHOFADETM)[12] 
Oxymetazoline is an alpha1A-adrenoceptor agonist and vasoconstrictor of the cutaneous 
microvasculature that is US FDA approved for the topical treatment of persistent facial 
erythema associated with rosacea in adults. [12] 
 
1.3.1 Dosage and administration 


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Oxymetazoline cream is for topical use only. A pea-sized amount of oxymetazoline cream, 
once daily should be applied in a thin layer to cover the entire face (forehead, nose, each 
cheek, and chin) while avoiding the eyes and lips. Hands should be washed immediately after 
applying the cream. [12] 
1.3.2 Pharmacokinetics 
Absorption  
The pharmacokinetics of oxymetazoline cream was evaluated following topical 
administration in a thin layer to cover the entire face in adult subjects with erythema 
associated with rosacea. The median weight of cream for each dose administration was 0.3 g. 
Plasma oxymetazoline concentrations were measurable in most of the subjects. Following the 
first dose application, the mean ± standard deviation (SD) peak concentrations (Cmax) and 
area under the concentration-time curves from time 0 to 24 hours (AUC0-24h) were 60.5 ± 
53.9 pg/mL and 895 ±798 pg*hr/mL, respectively. Following once daily applications for 28 
days, the mean ± SD Cmax and AUC0-24h were 66.4 ± 67.1 pg/mL and 1050 ± 992 pg*hr/mL, 
respectively. [12] 
 Distribution  
An in vitro study demonstrated that oxymetazoline is 56.7% to 57.5% bound to human 
plasma proteins. [12]  
 Metabolism  
In vitro studies using human liver microsomes showed that oxymetazoline was minimally 
metabolized, generating mono-oxygenated and dehydrogenated products of oxymetazoline. 
The percentage of parent drug oxymetazoline remaining was 95.9% after a 120-minute 
incubation with human liver microsomes. [12]  
 Excretion  
The excretion of oxymetazoline following administration of oxymetazoline hydrochloride 
cream has not been characterized in humans. [12]  
Pharmacokinetic Interactions 
In vitro studies using human liver microsomes demonstrated that oxymetazoline up to the 
tested concentration of 100 nM had no inhibition on the activities of the cytochrome P450 
(CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 3A4/5. Treatment of cultured 
human hepatocytes with up to 100 nM oxymetazoline did not induce CYP1A2, CYP2B6, or 
CYP3A4. [12]  
1.3.3 Drug interactions 
Anti-hypertensives/Cardiac Glycosides  
Alpha-adrenergic agonists, as a class, may impact blood pressure. Caution should be taken in 
using drugs such as beta-blockers, anti-hypertensives and/or cardiac glycosides. 
Caution should also be exercised in subjects receiving alpha 1 adrenergic receptor antagonists 
such as in the treatment of cardiovascular disease, benign prostatic hypertrophy, or Raynaud's 
disease. [12]  
Monoamine Oxidase (MAO) Inhibitors 
Caution should be taken with subjects taking MAO inhibitors that can affect the metabolism 
and uptake of circulating amines. [12] 


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1.3.4 Adverse effects 
Clinical Studies Experience  
A total of 489 subjects with persistent facial erythema associated with rosacea were treated 
with oxymetazoline cream once daily for 4 weeks in 3 controlled clinical trials. An additional 
440 subjects with persistent facial erythema associated with rosacea were also treated with 
oxymetazoline cream once daily for up to one year in a long-term (open-label) clinical trial. 
Adverse reactions that occurred in at least 1% of subjects treated with oxymetazoline cream 
through 4 weeks of treatment are presented below. [12] 
 
Table 1-1: Adverse reactions reported by ≥1% of subjects through 4 weeks of treatment in 
controlled clinical trials 
Adverse Reaction 
Pooled controlled 
clinical trials 
 
Oxymetazoline 
hydrochloride 
cream 
(N=489) 
Vehicle 
cream 
(N=483) 
Application site dermatitis 
9 (2%) 
0 
Worsening inflammatory lesions of rosacea 
7 (1%) 
1 (<1%) 
Application site pruritus 
5 (1%) 
4 (1%) 
Application site erythema 
5 (1%) 
2 (<1%) 
Application site pain 
4 (1%) 
1 (<1%) 
 
In the long-term (open-label) clinical trial, the rates of adverse reactions over a one-year 
treatment period were as follows: worsening inflammatory lesions of rosacea (3%), 
application site dermatitis (3%), application site pruritis (2%), application site pain (2%), and 
application site erythema (2%). Subjects with persistent erythema along with inflammatory 
lesions were allowed to use additional therapy for the inflammatory lesions of rosacea. [12] 
 
1.3.5 Contraindications 
None [12] 
1.3.6 Warnings and precautions 
Potential Impacts on Cardiovascular Disease  
Alpha-adrenergic agonists may impact blood pressure. Oxymetazoline cream should be used 
with caution in subjects with severe or unstable or uncontrolled cardiovascular disease, 
orthostatic hypotension, and uncontrolled hypertension or hypotension. Subjects with 
cardiovascular 
disease, 
orthostatic 
hypotension, 
and/or 
uncontrolled 
hypertension/hypotension should be advised to seek immediate medical care if their condition 
worsens. [12]  
 Potentiation of Vascular Insufficiency  


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Oxymetazoline cream should be used with caution in subjects with cerebral or coronary 
insufficiency, Raynaud’s phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren’s 
syndrome. Subjects should be advised to seek immediate medical care if signs and symptoms 
of potentiation of vascular insufficiency develop. [12]  
 Risk of Angle Closure Glaucoma  
Oxymetazoline cream may increase the risk of angle closure glaucoma in subjects with 
narrow-angle glaucoma. Subjects should be advised to seek immediate medical care if signs 
and symptoms of acute angle closure glaucoma develop. [12] 
1.3.7 Use in specific populations 
Pregnancy 
Risk Summary  
There are no available data on oxymetazoline cream use in pregnant women to inform a drug 
associated risk for major birth defects and miscarriage. A literature article describing 
intranasal decongestant use in pregnant women identified a potential association between 
second-trimester exposure to oxymetazoline (with no decongestant exposure in the first 
trimester) and renal collecting system anomalies. In animal reproduction studies, there were 
no adverse developmental effects observed after oral administration of oxymetazoline 
hydrochloride in pregnant rats and rabbits at systemic exposures up to 3 times and 73 times, 
respectively, the exposure associated with the maximum recommended human dose. The 
estimated background risks of major birth defects and miscarriage for the indicated 
population are unknown. All pregnancies have a background risk of birth defect, loss, or 
other adverse outcomes. In the U.S. general population, the estimated background risk of 
major birth defects and miscarriage in clinically recognized pregnancies is 2-4% and 15-20%, 
respectively. [12] 
Fetal/Neonatal Adverse Reactions  
Following repeated use of oxymetazoline hydrochloride solution nasal spray for the treatment 
of nasal congestion at a dose 5 times higher than recommended, one case of fetal distress was 
reported in a 41-week pregnant patient. The fetal distress resolved hours later, prior to the 
delivery of the healthy infant. The anticipated exposures for the case are 8- to18-fold higher 
than plasma exposures after topical administration of oxymetazoline cream. [12] 
Human Data  
No adequate and well-controlled trials of oxymetazoline cream have been conducted in 
pregnant women. Across all clinical trials of oxymetazoline cream, two pregnancies were 
reported. One pregnancy resulted in the delivery of a healthy child. One pregnancy resulted in 
a spontaneous abortion, which was considered to be unrelated to the trial medication. A 
literature article summarizing the results of exploratory analyses of intranasal decongestant 
use during pregnancy identified a potential association between second-trimester exposure to 
oxymetazoline hydrochloride solution (with no decongestant exposure in the first trimester) 
and renal collecting system anomalies. [12] 
Lactation 
No clinical data are available to assess the effects of oxymetazoline on the quantity or rate of 
breastmilk production, or to establish the level of oxymetazoline present in human breastmilk 
post-dose. Oxymetazoline was detected in the milk of lactating rats. The developmental and 
health benefits of breastfeeding should be considered along with the mother’s clinical need 


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for oxymetazoline cream and any potential adverse effects on the breastfed child from 
oxymetazoline cream or from the underlying maternal condition. [12] 
Pediatric Use 
Safety and effectiveness of oxymetazoline cream have not been established in pediatric 
subjects below the age of 18 years. [12] 
Geriatric Use 
One hundred and ninety-three subjects aged 65 years and older received treatment with 
oxymetazoline cream (n = 135) or vehicle (n = 58) in clinical trials. No overall differences in 
safety or effectiveness were observed between subjects > 65 years of age and younger 
subjects, based on available data. Clinical studies of oxymetazoline cream did not include 
sufficient numbers of subjects aged 65 and over to determine whether they respond 
differently from younger subjects. [12] 
 


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2 OBJECTIVES 
2.1 Primary Objective 
The primary objective of this clinical study is to establish the therapeutic equivalence 
between Test Product (Oxymetazoline hydrochloride Cream, 1%, manufactured by Actavis 
Laboratories, Salt Lake City, UT) and Reference Product (RHOFADETM Cream, 1%, 
Allergan) using the primary endpoint (proportion of subjects with treatment success at all 
time-points 3, 6, 9, and 12 hours post application on Day 29) , in subjects with moderate to 
severe persistent facial erythema of rosacea. 
(1) To evaluate study sensitivity, the Test and Reference products will be statistically 
evaluated with regard to their superiority (P < 0.05) over placebo for the primary 
endpoints 
2.2 Safety Objectives 
 
(1) To monitor adverse events (AEs) and assess the safety and tolerability of Test Product 
and Reference Product in subjects with moderate to severe persistent facial erythema of 
rosacea. 
3 STUDY DESIGN 
3.1 Design Overview  
This is a multi-center, randomized, double-blind, parallel-group, three-arm, placebo-
controlled, therapeutic equivalence study with clinical end-point. The study will compare the 
efficacy and safety of Test Product “Oxymetazoline hydrochloride Cream, 1%” 
(manufactured by Actavis Laboratories, Salt Lake City, UT) with that of an approved topical 
formulation RHOFADETM (Oxymetazoline hydrochloride Cream, 1%) marketed by Allergan, 
in healthy males and non-pregnant females diagnosed with moderate to severe persistent 
facial erythema of rosacea. Both the test and the reference formulations will also be 
compared to a placebo (vehicle) formulation to test for superiority. 
Subjects with a conﬁrmed diagnosis of moderate to severe persistent facial erythema of 
rosacea will be randomized to one of the three treatment groups as follows: 
Test Group: Oxymetazoline hydrochloride Cream, 1%, to be applied once daily preferably, 
and at the same time each day, for 29 days. 
Reference Group: RHOFADETM (Oxymetazoline hydrochloride Cream, 1%), to be applied 
once daily preferably, and at the same time each day, for 29 days. 
Placebo Group: Vehicle Cream, to be applied once daily preferably, and at the same time 
each day, for 29 days. 
Planned sample size 
 
 
 
 
 
Methodology 


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The study subject will receive treatment for approximately 29 days from the Baseline visit to 
the End of Treatment (EoT) visit. There will be 4 study visits, 3 to the study site and 1 
telephone follow-up: Screening 
 visit (Visit 1), Baseline (Day 1
) visit (Visit 
2), Telephone Follow-up (Day 14
) visit (Visit 3), and EoT (Day 29
) visit (Visit 4).  
At screening, a written Informed Consent Form (ICF) has to be signed by the subject and the 
eligibility criteria of the subject will be evaluated by clinical assessments. If necessary, 
subjects will be allowed to conduct screening procedures on two separate days in order to 
allow for enough time to complete the adequate washout period required for medications, 
makeup use, etc. Subjects should sign ICF (prior to the start of any study procedures), 
complete washout, and return to the clinic to conduct the remainder of the screening 
procedures. 
After the screening visit, each qualified subject will return to the clinic on Day 1 for 
confirmation of eligibility. Eligible subjects will be assigned to one of the three study 
treatment groups as per the computer-generated randomization schedule, and the assigned 
study medication will be dispensed by the study site staff.  Since this is a double-blind study, 
neither the study team at the site nor the subjects will know the treatment the subject is 
assigned. 
Treatment will be initiated at the clinic on Day 1 after collecting baseline measurements for 
both CEA and SSA for facial erythema as per the scales defined (Table 3-1). 
The subject will be instructed to apply a pea-size amount of the study treatment to cover the 
entire face (forehead, chin, nose, and each cheek [avoiding the eyes and lips]), once daily 
preferably, at the same time each day, for 29 days. On Day 1 visit and Day 29 visit, the 
subject will apply the assigned medication at the clinic under the supervision of an 
Independent Dispenser, unblinded to the treatment the subject is receiving. 
 
 
From Day 2 to Day 28, the subject will be asked to apply the assigned 
medication once daily preferably, at the same time each day, and complete the subject diary, 
handed over by the study site staff at Baseline visit. The subject will note the date and time of 
application of the study medication, any AE experienced, and any concomitant medication 
taken or changes from the existing ones, in the subject diary from Day 1 to Day 29. 
A phone call will be made by the site to the subject around Day 14 to follow up for any  
change in concomitant medications, adherence to study restrictions, overall well-being of the 
subject, and check on compliance of study medication usage.  
Key assessments 
The schedule of visits and the assessments to be performed at each visit are presented in 
Table 6-1. Assessments should be performed by the same evaluator throughout the study 
whenever possible. 
Efficacy Measurements  
Efficacy measurements include Investigator’s assessment of the severity of facial erythema 
using the CEA scale and subject’s assessment of the severity of facial erythema using the 
SSA scale, at Pre-dose, 3, 6, 9, and 12 hours on Day 1 and Day 29. The CEA and SSA scales 
are shown in Table 3-1. 
 
 
 


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Table 3-1: Sample CEA and SSA Scale for Rosacea 
Grade 
CEA scale description 
SSA scale description 
0 
Clear skin with no signs of erythemaa 
No sign of unwanted redness 
1 
Almost clear; slight redness 
Almost clear of unwanted redness 
2 
Mild erythema; definite redness 
Mild redness 
3 
Moderate erythema; marked redness 
Moderate redness 
4 
Severe erythema; fiery redness 
Severe redness 
aNormal healthy skin color as observed in individuals without rosacea 
CEA: Clinician Erythema Assessment; SSA: Subject Self-Assessment 
Source: Draelos et al., 2018 
 
Safety/Tolerability 
Safety of the subject will be monitored and evaluated continuously throughout the study, after 
application of the first dose of assigned study treatment. Safety will be assessed by close 
monitoring and timely assessment of: 
Vital signs: Blood pressure, heart rate and body temperature will be recorded at screening; at 
pre-dose and 12 hours on Day 1; and at pre-dose and 12 hours on Day 29. 
Adverse event monitoring: Subjects will be questioned about any adverse events along with 
investigator evaluation of any application site reactions (including application site dermatitis, 
application site pruritis, application site erythema, and application site pain, scaling or 
burning) at, Day 1 and Day 29. 
Pregnancy tests: A urine pregnancy test at screening visit and on Day 1 and Day 29 visits will 
be done for women of childbearing potential.  
Physical examination: The Investigator will examine the subject for any physical 
abnormalities at screening and Day 29 for the following body systems: general appearance, 
head, eyes, ears, nose, throat, heart/cardiovascular, lungs, abdomen, neurologic, extremities, 
back, musculoskeletal, lymphatic, skin, and other findings. The subject’s height and weight 
will be recorded at screening only. 
3.2 
Primary Endpoints 
The primary efficacy endpoint will be used to address the primary objective, which aims at 
demonstrating therapeutic equivalence between Test Product and Reference products. 
The primary efficacy endpoint is the proportion of subjects with treatment success at all time-
points 3, 6, 9, and 12 hours post application on Day 29,which will be calculated for each 
subject as described in Section 6.4.2. 
 
3.3 
Safety Endpoints 
x Incidence of AEs. 
 


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4 STUDY POPULATION 
This multi-center study will enroll approximately 
 male or female subjects ≥18 years-of-
age presenting with a clinical diagnosis of persistent facial erythema of rosacea. 
 
4.1 Inclusion Criteria 
Subjects must meet all of the following criteria to be eligible for the study. 
1. Study subjects must have provided IRB approved written informed consent using the 
latest version of the IRB informed consent form, (or assent in applicable state). In 
addition, study subjects must sign a HIPAA authorization, if applicable. 
2. Healthy male or non-pregnant females, ≥18 years-of-age with a clinical diagnosis of 
rosacea with persistent (non-transient) facial erythema 
3. Ability to follow study instructions and complete subject diary without assistance. 
4. Females of child bearing potential (WOCBP*) must not be pregnant or lactating at 
screening visit (as documented by a negative urine pregnancy test) and at baseline visit 
(as documented by a negative urine pregnancy test).  
*All female subjects will be considered to be of childbearing potential unless they are 
postmenopausal. Female subjects of childbearing potential (WOCBP) are defined as 
sexually mature women without prior hysterectomy, or who have had any evidence of 
menses in the past 12 months. However, women who have been amenorrheic for the past 
12 or more months are still considered to be of childbearing potential, if the amenorrhea 
is possibly due to other causes, including prior chemotherapy, anti- estrogens, or ovarian 
suppression. Postmenopausal women (defined as women who have been amenorrheic for 
at least 12 consecutive months, in the appropriate age group, without other known or 
suspected primary cause) or women who have been sterilized surgically or who are 
otherwise proven sterile (i.e., total hysterectomy, or bilateral oophorectomy with surgery 
at least 4 weeks prior to randomization) are not considered WOCBP. Subjects who have 
undergone tubal ligation are NOT considered as surgically sterile. 
5. Female subjects of childbearing potential must be willing to use an acceptable form of 
birth control from the day of the first dose administration to 30 days after the last 
administration of IP. For the purpose of this study the following are considered acceptable 
methods of birth control: oral or injectable contraceptives, contraceptive patches, 
Depo-Provera® (medroxyprogesterone acetate-stabilized for at least 3 months); vaginal 
contraceptive; contraceptive implant; double barrier methods (e.g. condom and 
spermicide); Nuvaring vaginal hormonal birth control, intra-uterine device (IUD), or 
abstinence with a second method of birth control should the subject become sexually 
active.  
6. Moderate to severe persistent facial erythema associated with rosacea, defined as a grade 
of ≥3 on the CEA scale as assessed by the Investigator at Screening and on Baseline 
(Day 1) visit prior to study drug application (Table 3-1). 
7. Moderate to severe persistent facial erythema associated with rosacea, defined as a grade 
of ≥3 on the Subject SSA scale as assessed by the subject at Screening and on Baseline 
(Day 1) visit prior to study drug application (Table 3-1). 
8. Stable erythema (for at least 3 months prior to screening) associated with rosacea, with 
minimal variation from day to day and within each day, in the opinion of the subject. 


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9. Willingness to complete the required visits including short stay for at least 12 hours at the 
investigational site for 2 separate visits. 
10. Subjects who use make-up, facial moisturizers, creams, lotions, cleansers and/or 
sunscreens must have used the same product brands/types for a minimum period of 4 
weeks prior to Baseline, must agree not to change brand/type or frequency of use 
throughout the study and must agree not to use make-up, facial moisturizers, creams, 
lotions and/or sunscreens on the scheduled clinic visit day before the visit. 
11. Subject must be willing to avoid the use of abrasive cleansers or washes (e.g., exfoliating 
facial scrubs), adhesive cleansing strips (e.g., Bioré® Pore Strips) and wax epilation on 
the face, during the entire duration of their study participation. 
12. Subject’s willingness to minimize external factors that might trigger rosacea flare-ups 
(e.g., spicy foods, thermally hot foods and drinks, hot environments, prolonged sun 
exposure, strong winds, alcoholic beverages). 
13. Subject must be in good health and free from any systemic or dermatological disorder 
(other than rosacea) that, in the opinion of the Investigator, will interfere with the study 
evaluations or increase the risk of AEs. 
14. Any skin type or race, providing the skin pigmentation will allow discernment of 
erythema. 
4.2 Exclusion Criteria 
Subjects are to be excluded from the study if they display any of the following criteria: 
1. Any of the following conditions: severe or unstable or uncontrolled cardiovascular 
disease, clinically unstable hypertension, orthostatic hypotension, and uncontrolled 
hypertension or hypotension, cerebral or coronary insufficiency, Raynaud’s Syndrome, 
thromboangiitis obliterans, scleroderma, Sjögren’s syndrome, renal or hepatic 
impairment. 
2. Subjects with narrow angle glaucoma. 
3. Females who are pregnant, breast feeding, or planning a pregnancy during the study. 
4. Females of childbearing potential who do not agree to utilize an adequate form of 
contraception during their participation in the study. 
5. Clinical signs of particular forms of rosacea (rosacea conglobata, rosacea fulminans, 
isolated rhinophyma, isolated pustulosis of the chin) on the face or other concomitant 
facial dermatoses that are similar to rosacea such as peri-oral dermatitis, demodicidosis, 
facial keratosis pilaris, seborrheic dermatitis, acute lupus erythematosus, or actinic 
telangiectasia that may interfere with the study evaluations, in the opinion of the 
Investigator. 
6. Presence of ≥3 facial inflammatory lesions of rosacea at screening and baseline 
7. Presence of any skin condition on the face that would interfere with the diagnosis or 
assessment of rosacea, as determined by the Investigator. 
8. Excessive facial hair (e.g., beards, sideburns, moustaches, etc.) that would interfere with 
the study treatments or study assessments. 
9. History of drug or alcohol abuse within 12 months prior to the Screening visit. 


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10. Known hypersensitivity or allergies to any component of the study treatment. 
11. Use within 12 hours prior to baseline of any topical products including, but not limited to, 
lotions, creams, ointments, and cosmetics applied to the face (facial cleanser is 
acceptable). 
12. Use 1 week prior to baseline of niacin ≥500 mg/day. 
13. Use within 2 weeks prior to baseline of products containing topical corticosteroids, 
topical retinoids, topical antibiotics, topical anti-inflammatory, topical treatment for 
rosacea, or topical treatment for acne.  
14. Use within 4 weeks prior to baseline of topical immunomodulators, systemic antibiotics, 
systemic corticosteroids, systemic anti-inflammatory agents, systemic treatment for 
rosacea, or systemic treatment for acne (other than oral retinoids, which require a 6-
month washout).  
15. Undergone 4 weeks prior to baseline any dermatologic or surgical procedure on the face. 
16. Use within 3 months prior to baseline of any systemic immunomodulators known to have 
an effect on rosacea. 
17. Use within 6 months prior to baseline of any oral retinoids (e.g., isotretinoin) or 
therapeutic vitamin A supplements of greater than 10,000 units/day (multivitamins are 
allowed). 
18. Undergone 6 months prior to baseline any laser, light-source (e.g. intense pulsed light, 
photodynamic therapy) or other energy-based therapy to the face. 
19. Exposed to excessive UV radiation within 1 week before Screening  
visit and/or subject is unwilling to refrain from excessive exposure to UV radiation during 
the course of the study. 
 
20. Current use of monoamine oxidase (MAO) inhibitors, barbiturates, opiates, sedatives, 
systemic anesthetics, or oxymetazoline (e.g., eye drops, nasal sprays). 
21. Subject has participated in a clinical trial within 30 days or in a biologics study within 6 
months preceding admission of this study. 
22. Previous participation in this study.  
23. Inability to communicate well (i.e., language problem, poor mental development, 
psychiatric illness or poor cerebral function), that may impair the ability to provide 
written informed consent. 
24. Subject has any evidence of organ dysfunction, chronic infectious disease, system 
disorder or has a condition or is in a situation that, in the Investigator’s opinion, that may 
put the subject at significant risk, may confound the study results, or may significantly 
interferes with the subject’s participation in the study. 
25. Employees or family members of the research center or Investigator. 
 
 


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4.3 
Restrictions and Prohibitions 
The following treatments/applications will not be allowed before or during study participation as per the below schedule:  


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1. Niacin ≤500 mg/day if not at a stable dose or if it is known to cause flushing. 
2. Vitamins in quantities above the recommended daily dose (e.g., Vitamin A above about 10,000 IU).  
3. The use of anti-inflammatory medications (e.g., NSAIDs). NSAID use allowed on as needed basis for conditions such as headache, menstrual cramps, 
and minor injuries; Low dose aspirin is also allowed); Subjects will also be allowed to use acetaminophen for pain relief, as needed. The acceptable 
maximum dosage of acetaminophen should be 3,000mg/day.  
4. Subject has to refrain from changing the use of any concomitant therapies after the screening visit until study completion. 


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4.4 Subject Withdrawal / Dropout 
Study subjects will be discontinued from the study for any of the following reasons: 
1. If the study subject withdraws his or her consent for any reason. 
2. Subjects who discontinue treatment early due to insufficient or lack of treatment effect or 
whose condition worsens and require alternate or supplemental therapy for the treatment 
of moderate to severe persistent facial erythema of rosacea, the subjects should be 
discontinued, but included in the PP population analysis as treatment failures and 
provided with effective treatment. 
3. Subjects that withdraw or discontinue early for reasons other than lack of treatment effect 
should be excluded from the PP population, but included in the mITT population, using 
last observation carried forward (LOCF). 
4. If the study subject’s drug code is un-blinded. 
5. If an AE occurs for which the study subject desires to discontinue treatment or the 
Investigator determines that it is in the study subject’s best interest to be discontinued. 
6. If the subject experiences an SAE.  
7. If there is a protocol violation.  
8. If a concomitant therapy is reported or required which is prohibited or may interfere with 
the results of the study. 
9. If the study subject is lost to follow-up. 
10. If the study subject becomes pregnant (refer to Section 6.5.4) 
11. 
 
 
  
12. Administrative reasons. 
13. Any other reason that may affect the outcome of the study or the safety of study subjects. 
*A protocol violation is defined as any study subject or Investigator activity that could have 
possibly interfered with the therapeutic administration of the treatment or the precise 
evaluation of treatment efficacy that affects the rights, well-being or safety of the subject or 
the scientific integrity of the study data. 
If a subject discontinues participation in the study, every attempt will be made to complete 
the EoT as indicated in Table 6-1, and any outstanding data and study medication will be 
collected if possible. The reasons for a discontinuation and the date of removal from the study 
will be documented on the electronic Case Report Form (eCRF) and Sponsor will be notified. 
Before a study subject is considered lost to follow-up, the Investigator will document all 
attempts to reach the study subject twice by telephone and will send a follow-up letter. 
In the event of discontinuation of a subject from the study at any time due to an AE, the 
reason for discontinuation, the nature of the event and its clinical course must be fully 
documented. For such a study subject, the Investigator must strive to follow the study subject 
until the AE has resolved, become clinically insignificant, is stabilized or the study subject is 


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lost to follow-up. Should an SAE be noted, procedures stated in Section 6.5.1 must be 
followed. 
When a study subject discontinues the study due to any of the above reasons, the study 
subjects should be prescribed appropriate treatment that he/she can continue to use as per the 
Investigator’s clinical judgment. 


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5 TREATMENTS 
5.1 Treatments to be Administered 
The IPs supplied by the Sponsor will consist of the following: 
Test Product 
Name of the product 
: Oxymetazoline hydrochloride Cream, 1% 
Active ingredient(s) 
: Oxymetazoline hydrochloride 
Pharmaceutical dosage form 
: Cream 
Strength 
: 1% (each gram of cream contains 10 mg [1%] 
oxymetazoline hydrochloride, equivalent to 8.8 mg 
[0.88%] of oxymetazoline free base) 
Route of administration 
: Topical 
Manufacturer 
: Actavis Laboratories, Salt Lake City, UT (a subsidiary of 
Teva Pharmaceuticals, USA)  
Reference (R) 
Name of the product 
: RHOFADE™ (Oxymetazoline hydrochloride Cream, 
1%) 
Active ingredient(s) 
: Oxymetazoline hydrochloride 
Pharmaceutical dosage form 
: Cream 
Strength 
: 1% (each gram of cream contains 10 mg [1%] 
oxymetazoline hydrochloride, equivalent to 8.8 mg 
[0.88%] of oxymetazoline free base) 
Route of administration 
: Topical 
Manufacturer/Marketed by 
: Manufactured by DPT Laboratories Ltd, for Allergan 
Placebo (Vehicle) 
Name of the product 
: Vehicle to Oxymetazoline hydrochloride Cream 
Active ingredient(s) 
: NA 
Pharmaceutical dosage form 
: Cream 
Strength 
: NA 
Route of administration 
: Topical 
Manufacturer 
: Actavis Laboratories, Salt Lake City, UT (a subsidiary of 
Teva Pharmaceuticals, USA) 
 


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5.2 Treatment Assignment (Randomization) 
The kit number will correspond to a computer-generated randomization schedule assigning 
that number to one of the three study treatment groups.
 
The study subject numbers will be assigned to study subjects sequentially in the order in 
which study subjects are enrolled into the study. 
 
5.3 Dosage and Administration 
The study medication will be dispensed to the subjects on Day 1 at the study site. Subjects 
will gently wash their face with a mild, non-medicated cleanser 
), rinse 
with warm water and pat dry. The subjects will be asked to apply a pea-size amount of the 
assigned study treatment cream to cover the entire face [forehead, chin, nose, and each cheek 
(avoiding the eyes and lips)], once daily, preferably at the same time each day, for 29 days. 
Subjects will be instructed to avoid applying the study medication to the eyes, eyelids, lips, 
mouth, scalp, neck, ears, and any membrane of the inner nose, or open wounds. Subjects will 
be required to wash their hands before and after each application of study treatment. 
On Day 1 and Day 29, the dose will be applied in the morning after completion of pre-dose 
study assessments and procedures. 
 
 
 
 
 
 
 
5.4 Receipt and Storage 
Investigational Products (IPs) should be stored at 20°C-25°C (68°F-77°F), excursions 
permitted to 15°C-30°C (59°F-86°F) [see USP Controlled Room Temperature]; in a secured, 
authorized access area at the investigative site. 
 
5.5 Packaging and Labeling 
 
 The randomization will be pre-planned according 
to a computer-generated randomization schedule. The study medication will be blinded, 
packaged and delivered to the site in bulk. The study medication will be labeled and 
packaged such that neither the study subject nor the Investigator can identify the treatment. 
The labeling and packaging scheme will be outlined in a separate document by the Sponsor. 
The study medications will be shipped to the Investigator’s site from a centralized location. 
The Principal Investigator will be responsible for ensuring that all study products are stored 
in a locked, secure location, with access limited to the Investigator and his/her designee(s). 
An accurate inventory of the study medication will be maintained in accordance with federal 
regulations. 
 
 


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5.6 Blinding 
This is a double-blinded clinical end point bioequivalence study. Study medications will be 
provided in similar cartons to maintain study blinding.  
If necessary, for the safety and proper treatment of the subjects, the Investigator can unblind 
the subject’s treatment assignment to conduct appropriate follow-up care. Whenever possible, 
the Sponsor or medical monitor will be notified before unblinding the study medication. The 
date and signature of the person breaking the code as well as the reason for breaking the code 
and any associated AEs will be recorded in the subject’s source documentation. 
The Investigator, staff at the study site, study monitors, and data analysis/management 
personnel will be blinded to the treatment assigned to the subject. The study site will have at 
least one Independent Dispenser. The role of the unblinded Independent Dispenser will be to 
dispense and collect study medication to/from the subjects, maintain dispensing records, and 
ensure the study medication logs are complete and accurate. The Independent Dispenser will 
also be responsible for observing and supervising the administration of the study medication 
by the subject on clinic visits, Day 1 and Day 29.  The subject will be requested not to discuss 
the appearance of the study medication with the Investigator or study staff outside of the 
Independent Dispenser. Independent dispenser should not participate in any activities other 
than the activities defined in this section. To ensure that information that could potentially 
bias handling of data is not disclosed, the packaging team will hold the randomization 
scheme until after database lock.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
At the conclusion of the study, after the database has been locked, each site will be sent the 
study randomization scheme (respective to their site) that should be retained with the study 
documents in the event of an FDA inspection along with evidence of when the randomization 
scheme was provided. 
 
 
 


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5.7 Assessment of Compliance 
A subject diary will be provided to all subjects on Day 1 where it is required to document the 
date and time of application of the study medication. In the subject diary, subjects will also 
note any AE observed and any concomitant medication taken or changes. 
Compliance will be determined from the subject diary, which the subject will be trained and 
instructed to use to record the application of study medication each day, as well as all missed 
applications. The number of missed and additional applications will be captured on the 
compliance page of the CRF. 
 
 
 
 
 
 
5.8 Study Medication Replacement 
In the event of loss/spillage, extra tubes of study medication may need to be dispensed.  See 
IMP manual for details. 
Before dispensing the replacement study medication, the information will be recorded on the 
Study Medication Accountability Log. 
5.9 Accountability of Study Medication 
It is the responsibility of the Investigator to ensure that the accountability of the IP is 
maintained at the study site where study medication is stored and dispensed.  
A Drug Accountability Log will assist study site staff in maintaining inventory records of 
study medication.  
The study medications will be dispensed only by an appropriately Independent dispenser. 
Study subjects must return used/unused IP to the Independent Dispenser. Any remaining drug 
supplies can be accounted for and noted in the Drug Accountability Log. The original Drug 
Accountability Log must remain at the study site and a copy should be provided to the study 
monitor after the study. See IMP manual for details. 
5.10 Retention of Study Medication Samples 
Retention samples should be randomly selected from the drug supplies received prior to 
dispensing to subjects. 
 
  
 
 
 
 
 
 
 
 
 


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5.11 Return of Drug Supplies 
With the exception of the retention samples, all remaining IP will be returned by the 
Investigator or designee to the designated drug depot for storage and / or destruction after the 
close-out visit, 
. 


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6 STUDY PROCEDURES 
6.1 Schedule of Events 
The study will include the following scheduled visits: Screening visit 
 
Baseline visit (Day 1
), Telephone Follow-up visit (Day 14
) and EoT visit (Day 29
). 
The schedule of visits and the study assessments at each visit are presented in Table 6-1. The 
assessments will be performed by, or under the supervision of, an Investigator or a qualified 
delegate. Evaluations should be performed by the same evaluator throughout the study 
whenever possible. Additional examinations may be performed as necessary to ensure the 
safety and well-being of subjects during the study. 
 
 
Signs and symptoms that existed before signing informed consent should be recorded as 
medical history findings. Signs and symptoms that worsen after the informed consent is 
signed as well as any sign or symptom that begins after the ICF is signed (even if before start 
of study treatment) should be recorded on an AE page of the eCRF using Common 
Terminology Criteria for Adverse Events (CTCAE), version 4.03 (see Section 6.5.1). 
 
 


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Table 6-1: Schedule of Events 
Procedures 
 
Visit 
Screening 
A 
[
  
 
Screening B 
  
 
Day 1 
(Baseline) 
 
Day 14  
(Telephone 
Follow-up)a  
 
Day 29  
(EoT)  
 
Written informed consent 
X 
 
 
 
 
Demographics (height, weight, body mass index (BMI), 
gender, race, ethnicity) 
X 
 
 
 
 
 
 
 
 
 
Pregnancy test (Urine) 
X 
X 
X 
 
X 
X 
 
 
 
 
Medical and surgical history 
X 
X 
 
 
 
Prior and concomitant medications and concurrent 
procedures 
X 
X 
X 
X  
X 
 
 
 
 
 
 
 
 
 
 
Vital signs measurements (blood pressure, heart rate, body 
temperature) 
X 
X 
Pre-dose and 12 hrs 
 
Pre-dose and 12 hrs 
 
 
 
 
 
 
 
 
 
 
Clinician Erythema Assessment (CEA) 
X 
X 
Pre-dose, 3, 6, 9, and 
 
Pre-dose, 3, 6, 9, and 


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12 hrs 
12 hrs 
Subject Self-Assessment (SSA) for rosacea facial redness 
X 
X 
Pre-dose, 3, 6, 9, and 
12 hrs 
 
Pre-dose, 3, 6, 9, and 
12 hrs 
Physical examination 
X 
 
 
 
X 
Review of Inclusion/Exclusion 
X 
 
X 
Pre-dose (confirm 
eligibility) 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
Dispense study medication tube and subject diary  
 
 
X 
 
 
Dosing (Days 1-29)b 
 
 
X 
 
X 
Adverse event monitoringc 
X 
X 
X 
X 
X 
Subject diary review 
 
 
X 
 
X 
Confinement in study clinic 
 
 
≥12 hrs in clinic 
 
≥12 hrs in clinic 
Collection of study medication tube 
 
 
 
 
X 
a14 days after the first dose of study drug, a phone call will be made to follow-up on any changes in concomitant medications and check on compliance of study 
medication usage. 
bSubject will apply study medication once daily, preferably at the same time each day, from Day 2 to Day 28 at home, as instructed. 
cIncluding application site dermatitis, application site pruritis, application site erythema, and application site pain, scaling, burning at Visit 2 and Visit 4.  
 


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6.2 
Visit Description 
Screening visit 
 
The following is a list of all tests and procedures at the screening visit: (If necessary, subjects 
will be allowed to conduct screening procedures on two separate days in order to allow for 
enough time to complete the adequate washout period required for medications, makeup use, 
etc. Subjects should sign ICF, complete washout, and return to the clinic to conduct the 
remainder of the screening procedures.) 
x Signed informed consent must be obtained prior to performing any study-specific tests or 
assessments.  
Note: A unique study subject number will be assigned to the subject at the time of the 
screening visit and will serve as subject identification on all study documents throughout 
the study. 
x Obtain demographic information (age, gender, height, weight, BMI, race and ethnicity). 
x Conduct urine pregnancy test (subjects of childbearing potential only). 
x Document primary clinical diagnosis of facial rosacea   
x Obtain current and past medical and surgical history including drug and alcohol use. 
x Collect information on all prior (within 6 months of screening visit) and current 
medications.  
x Record vital signs (blood pressure, heart rate and oral body temperature).  
x Investigator’s assessment of the severity of facial erythema using the CEA scale. 
x Subject’s assessment of the severity of facial erythema using the SSA scale. 
x Complete physical examination. 
x Screen the subject for protocol inclusion and exclusion criteria.  
x Adverse event monitoring 
If necessary, subjects will be allowed to conduct screening procedures on two separate 
days in order to allow for enough time to complete the adequate washout period required 
for medications, makeup use, etc. 
 
Screening B visit 
 
In the event that the subject requires a Screening B visit, the following procedures should be 
performed: 
x Conduct urine pregnancy test (subjects of childbearing potential only). 
 
x Review of Medical and Surgical History 
 
x Review of Prior and concomitant medications and concurrent procedures 
 
x Record vital signs (blood pressure, heart rate and oral body temperature). 
x Investigator’s assessment of the severity of facial erythema using the CEA scale  
 


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x Subject’s assessment of the severity of facial erythema using the SSA scale 
 
x Screen the subject for protocol inclusion and exclusion criteria.  
 
x Adverse event monitoring 
 
Day 1 (Baseline) visit  
The following is a list of all tests and procedures at Day 1
: 
Pre-dose procedures 
x Confirm subject’s eligibility (check of inclusion / exclusion criteria) and randomize to 
treatment.  
x Record vital signs (blood pressure, heart rate and oral body temperature). 
x Investigator’s assessment of the severity of facial erythema using the CEA scale at 
pre-dose. 
x Subject’s assessment of the severity of facial erythema using the SSA scale at pre-dose. 
x Conduct urine pregnancy test (subjects of childbearing potential only). 
Review of Prior and concomitant medications and concurrent procedures 
x Dispense the assigned study medication tube (to be done by Independent Dispenser). 
x Hand over subject diary (to be done by study site staff). 
Dosing 
x Subjects will gently wash their face with a mild, non-medicated cleanser 
 
, rinse with warm water and pat dry.  
x Subject should wash their hands with soap and water before and after applying treatment 
and to avoid contact of the study product with the eye or lips. 
x Subject will apply a pea-size amount of the assigned study medication to cover the entire 
face (forehead, chin, nose, and each cheek [avoiding the eyes and lips]), under the 
supervision of the unblinded Independent Dispenser. The Independent Dispenser will be a 
designated site staff; unblinded to the treatment and will not be involved in any other 
clinical assessment activities.  
x Subject will note the date and time of application of the study medication in the subject 
diary. 
Post-dose procedures 
x 
 
 
 
 
 


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x Subjects will be questioned about how they are feeling and if any AE experienced this 
will be recorded in the subject diary. 
x Subject will be advised to apply a pea-size amount of the assigned study medication to 
cover the entire face (forehead, chin, nose, and each cheek [avoiding the eyes and lips]), 
once daily preferably, at the same time each day, from Day 2 to Day 28 at home. 
x 
Subject will be instructed to wash his/her hands before and after each application of study 
treatment and to avoid applying the study medication to the eyes, eyelids, lips, mouth, 
scalp, neck, ears, and any membrane of the inner nose, or open wounds. 
 
x Subject will be instructed to refrain from using restricted/prohibited medications. 
x Subjects who use make-up, facial moisturizers, creams, lotions, cleansers and/or 
sunscreens, will be instructed to use the same product brands/types, and not change the 
brand/type or frequency of use throughout the study, and not to use make-up, facial 
moisturizers, creams, lotions, and sunscreens on the scheduled clinic visit day before the 
visit. However, the use of facial cleanser will be acceptable. 
x Subjects will be instructed to minimize external factors that might trigger rosacea flare-
ups (e.g., spicy foods, thermally hot foods and drinks, hot environments, prolonged sun 
exposure, strong winds, alcoholic beverages) throughout the study. 
x Subject will be asked to return to the study site on the morning of Day 29 without 
applying the assigned study medication and to refrain from using restricted/prohibited 
medications prior to the clinic visit. 
 
 
 
Day 2 to Day 28 (At home) 
The following is a list of procedures subject should follow at home. 
x Subject will apply study medication once daily, preferably, at the same time each day, as 
instructed. 
x Subject will note the date and time of application of the study medication daily in the 
subject diary. The subject will also note any AE observed and any concomitant 
medication taken or changes. 
 
Telephone Follow-up (Day 14
) visit 
x The follow-up visit will be performed via a phone call contact at Day 14 
 after 
the first dose of study drug, to follow-up for any changes in concomitant medications and 
concurrent procedures and check on compliance of study medication usage.  
 
Day 29
 (End-of-Treatment) visit  
The following is a list of the tests and procedures to be performed at Day 29
: 
Pre-dose procedures 
x Review of subject diary for compliance, AEs and concomitant medication. 


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x 
 
x Investigator’s assessment of the severity of facial erythema using the CEA scale at 
pre-dose. 
x Subject’s assessment of the severity of facial erythema using the SSA scale at pre-dose. 
x Record vital signs (blood pressure, heart rate and body temperature). 
x Conduct urine pregnancy test (subjects of childbearing potential only). 
Dosing 
x Subjects will gently wash their face with a mild, non-medicated cleanser 
 
 rinse with warm water and pat dry. 
x Subject should wash their hands with soap and water before and after applying treatment 
and to avoid contact of the study product with the eye or lips. 
x Subject will apply a pea-size amount of the assigned study medication to cover the entire 
face [forehead, chin, nose, and each cheek (avoiding the eyes and lips)], under the 
supervision of designated staff (who is not involved in any other clinical assessment 
activities).  
x Subject will note the date and time of application of the study medication in the subject 
diary. 
Post-dose procedures 
x The study medication tube will be collected by the study site staff. 
x 
 
 
 
 
 
x Perform complete physical examination. 
 
Unscheduled Visit and Early Discontinuation Visit 
Unscheduled visit may occur as necessary, for any reason, if in the Investigator’s opinion it is 
warranted. If the Unscheduled Visit is due to an AE, the Investigator will determine whether 
additional visits are needed. Relevant and clinically significant laboratory data and AEs 
obtained at the unscheduled visits should be entered into the eCRF and recorded in the source 
documentation as necessary.  
If a study subject is discontinued from the study during an Unscheduled Visit, the 
Unscheduled Visit will be referred to as an Early Discontinuation Visit and all procedures 
scheduled for Day 29 Visit will be performed. If the Unscheduled Visit is not an Early 
Discontinuation Visit (i.e., the study subject will continue to take part in the study), then the 
reason for unscheduled visit is documented and required procedures at the discretion of 
Investigator considering the reason for visit, will be performed. 


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If the study subject’s condition has worsened to the degree that it is unsafe to continue in the 
study, the study subject may be discontinued from the study as treatment failure and a 
standard of care treatment may be advised at the Investigator’s discretion. 
 
6.3 Population Characteristics 
6.3.1 Demographics 
For demographic assessment, the following parameters will be recorded: year of birth (for 
age), sex, ethnicity/race, weight, height and BMI. 
6.3.2 Medical history 
Medical history findings (i.e., previous diagnoses, diseases or surgeries) meeting all criteria 
listed below will be collected as available to the Investigator: 
x Not pertaining to the study indication; 
x Start before signing of the informed consent; 
x Considered relevant for the subject’s study eligibility. 
Complete medical history includes prior surgeries (including dermal surgeries), prior and 
concomitant medications, concomitant diseases and allergy history. 
 
6.4 Efficacy 
The primary efficacy variable will be derived from the efficacy measures: the Investigator’s 
assessment of the severity of facial erythema using the 5-point CEA scale (Table 3-1). 
6.4.1 Efficacy variables 
The efficacy variable will be the following: 
- 
Score on the Clinical Erythema Assessment (CEA) scale 
 
6.4.2 Primary Efficacy Endpoints 
The primary efficacy endpoint will be used to address the primary objectives, which aims at 
demonstrating therapeutic equivalence between Test Product and Reference Product. 
The primary efficacy endpoint is the proportion of subjects with treatment success at all 
time-points 3, 6, 9, and 12 hours post application on Day 29. Treatment success is defined 
as having CEA score at least 2 grades lower than the baseline (Day 1 pre-dose) value.. 
-  
6.5 Safety 
6.5.1 Safety Variables 
The safety variables will be as follows: 
- 
Serious Adverse Events (SAEs)  
- 
Non-SAEs 


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6.5.2 Adverse events 
Incidence of all AEs reported during the study will be summarized using the current version 
of Medical Dictionary for Regulatory Activities (MedDRA) dictionary by treatment group, 
body system, severity, and relationship to the study drug. No inferential statistical analyses 
are planned. 
6.5.2.1 Definitions 
Adverse event (AE) 
An AE is any untoward medical occurrence in a subject, regardless of whether it has a causal 
relationship with this treatment. 
In this study, any AE occurring after the subject has signed the ICF until the end of follow-up 
period should be recorded and reported as an AE. 
An AE can, therefore, be any unfavorable and unintended physical sign, symptom, or 
laboratory parameter that develops or worsens in severity during the course of this study, or 
significant worsening of the disease under study or of any concurrent disease, whether or not 
considered related to the study drug. A new condition or the worsening of a pre-existing 
condition will be considered an AE. Stable chronic conditions (such as arthritis) that are 
present before study entry and do not worsen during this study will not be considered AEs. 
Accordingly, an AE can include any of the following: 
x intercurrent illnesses 
x physical injuries 
x events possibly related to concomitant medication 
x significant worsening (change in nature, severity, or frequency) of the disease under study 
or other preexisting conditions drug interactions 
x events occurring during diagnostic procedures or during any washout phase of this study 
 
Worsening of the disease under study will be measured by evaluation of pain, inflammation 
lesions of rosacea, dermatitis, pruritus and erythema at the application site. The evaluation of 
pain and inflammation should be recorded as an AE only if the presentation and/or outcome 
is more severe than would normally be expected from the normal course of the disease in a 
particular subject. 
A treatment-emergent AE (TEAE) is any AE that occurs after initiation of study medication, 
or any event already present that worsens in either intensity or frequency following exposure 
to study medication. 
Serious adverse event (SAE) 
A SAE is an AE occurring at any dose that results in any of the following outcomes or 
actions: 
x death 
x a life-threatening AE (i.e., the subject was at immediate risk of death from the event as it 
occurred; does not include an event that, had it occurred in a more severe form, might 
have caused death) 


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x in-subject hospitalization or prolongation of existing hospitalization means that hospital 
in-subject admission and/or prolongation of hospital stay were required for treatment of 
an AE, or that they occurred as a consequence of the event. Hospitalizations scheduled 
prior to study entry will not be considered SAEs, unless there was worsening of the 
preexisting condition during the subject’s participation in this study. 
x persistent or significant disability or incapacity (refers to a substantial disruption of one’s 
ability to conduct normal life functions) 
x a congenital anomaly/birth defect 
x an important medical event that may not result in death, be life-threatening, or require 
hospitalization, but may jeopardize the subject and may require medical intervention to 
prevent one of the outcomes listed in this definition. Examples of such events are 
intensive treatment in an emergency room or at home for allergic bronchospasm; blood 
dyscrasias or convulsions that do not result in hospitalization; or the development of drug 
dependency or drug abuse. Note: Any suspected transmission of an infectious agent via a 
medicinal product is considered an important medical event. 
x An AE that does not meet any of the criteria for seriousness listed above will be regarded 
as a non-SAE. 
Other significant adverse events 
When tested, marked hematological and other laboratory abnormalities (other than those 
meeting the definition of serious) and any events that led to an intervention, including 
withdrawal of test drug/IP treatment, dose reduction, or significant additional concomitant 
therapy, other than those reported as SAEs, should be collected in the CRF and summarized 
in the Clinical Study Report (CSR). 
6.5.2.2 Classifications for adverse event assessment 
All AEs will be assessed and documented by the Investigator according to the categories 
detailed below. 
Seriousness 
For each AE, the seriousness must be determined according to the criteria given in Section 
6.5.2.1. 
Intensity 
The severity of each adverse event must be recorded as 1 of the choices on the following 
scales. 
Mild: No limitation of usual activities 
Moderate: Some limitation of usual activities 
Severe: Inability to carry out usual activities 
Causal relationship 
The assessment of the causal relationship between an AE and the administration of treatment 
is a decision to be made by the investigator, who is a qualified physician, based on all 
information available at the time of the completion of the eCRF.  


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Causality should be assessed separately for each study treatment as detailed in the eCRF. If 
the investigator feels that the event cannot be firmly attributed to one of the study treatments 
(e.g., owing to a suspected underlying interaction), the same assessment will be documented 
for each study treatment. 
Adverse events will be assessed for the relationship to the study drug (causality) according to 
the following scale: 
 
TERM 
DEFINITION 
CLARIFICATION 
No 
Reasonable 
Possibility 
(not related) 
This category applies to those 
adverse events which, after careful 
consideration, are clearly due to 
extraneous 
causes 
(disease, 
environment, etc.) or to those 
adverse events, which after careful 
medical consideration at the time 
they are evaluated, are judged to 
be unrelated to the test drug. 
An adverse experience may be considered “No 
Reasonable 
Possibility” 
if it is 
clearly due to 
extraneous causes or when (must have two): 
• 
It does not follow a reasonable temporal sequence 
from the administration of the test drug. 
• 
It could readily have been produced by the 
subject’s clinical state, environmental or toxic 
factors, or other modes of therapy administered to 
the subject. 
• 
It does not follow a known pattern of response to 
the test drug. 
• 
It does not reappear or worsen when the drug is re-
administered.  
Reasonable 
Possibility 
(related) 
This category applies to those 
adverse events for which, after 
careful medical consideration at 
the time they are evaluated, a 
connection with the test drug 
administration cannot be ruled out 
with certainty or felt with a high 
degree of certainty to be related to 
the test drug. 
An adverse experience may be considered “Reasonable 
Possibility related” if or when (at least two of the 
following): 
• 
It follows a reasonable temporal sequence from 
administration of the drug. 
• 
It could not be reasonably explained by the known 
characteristics of the subject’s clinical state, 
environmental or toxic factors, or other modes of 
therapy administered to the subject. 
• 
It disappears or decreases on cessation or reduction 
in dose. There are important exceptions when an 
adverse 
event 
does 
not 
disappear 
upon 
discontinuation of the drug, yet drug relatedness 
clearly exists. 
• 
It follows a known pattern of response to the test 
drug. 
 
 
Expectedness 
An AE which is not included in the adverse events section of the relevant Safety Information 
Reference by its specificity, severity, outcome or frequency is considered an unexpected 
adverse event. 
The reference safety information for this study is to be found in Appendix II. 


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When applicable, the sponsor’s Pharmacovigilance Department will determine the 
expectedness for all serious adverse events. CRO and investigators will not determine the 
expectedness. 
 
Action taken with study treatment 
Any action on study treatment to resolve the AE is to be documented using the categories 
listed below. 
The study treatment action should be recorded separately for each study treatment as detailed 
in the eCRF. 
x Drug withdrawn 
x Drug interrupted 
x Dose reduced 
x Dose not changed 
x Not applicable 
x Unknown 
 
Other specific treatment(s) of adverse events 
x None 
x Remedial drug therapy 
x Other 
 
Outcome 
The outcome of the AE is to be documented as follows: 
x Recovered / resolved 
x Recovering / resolving 
x Recovered / resolved with sequelae 
x Not recovered / not resolved 
x Fatal 
x Unknown 
 
6.5.2.3 
Recording and Reporting of adverse events 
In this study, safety will be assessed by qualified study personnel by evaluating reported AEs, 
vital signs measurements, physical examination findings (including body weight and height 
measurements) and use of concomitant medication.  


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For AE recording, the study period is defined for each subject as that time period from 
signature of the ICF through the end of the study.  
All AEs that occur during the defined study period must be recorded on the source 
documentation, regardless of the severity of the event or judged relationship to the study 
drug. For SAEs, the SAE Form must also be completed, and the SAE must be reported 
immediately (see Section 12). The Investigator does not need to actively monitor subjects for 
AEs once the study has ended. However, SAEs occurring in a subject after the treatment of 
that subject has ended should be reported to the Sponsor if the Investigator becomes aware of 
them. 
At each contact with the subject, the Investigator or designee must question the subject about 
AEs by asking an open-ended question such as, “Have you had any unusual symptoms or 
medical problems since the last visit? If yes, please describe.” All reported or observed signs 
and symptoms will be recorded individually, except when considered manifestations of a 
medical condition or disease state. A precise diagnosis will be recorded whenever possible. 
When such a diagnosis is made, all related signs, symptoms, and any test findings may be 
recorded collectively as a single diagnosis on the CRF and, if it is a SAE, on the SAE Form. 
The onset and end dates and times, action taken regarding study drug, treatment administered, 
and outcome for each AE must be recorded on the source documentation. 
The relationship of each AE to study drug treatment and study procedures, and the severity 
and seriousness of each AE, as judged by the Investigator, must be recorded as described 
above. 
Subjects will be evaluated at each site visit for any signs/symptoms of application site 
dermatitis, application site pruritus, application site erythema, application site pain, and 
application site scaling or burning.  The Investigator’s assessment of Application Site 
Reactions will be captured in the following format within the source documents: 
 


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The clinical course of each AE will be monitored at suitable intervals until resolved or 
stabilized or returned to baseline, until the subject is referred for continued care to a health 
care professional or until a determination of a cause unrelated to the study drug or study 
procedure is made. 
Adverse events will be coded according to MedDRA and reported with respect to severity, 
duration, relationship to study medication(s), seriousness and action taken. 
6.5.2.4 Reporting of serious adverse events 
To satisfy regulatory requirements, all SAEs (as described in Section 6.5.2.1) that occur 
during the study period, regardless of judged relationship to treatment with the study drug, 
must be reported to the Sponsor or CRO by the Investigator. The event must be reported 
within 24 hours of when the Investigator learns about it. Completing the SAE form and 
reporting the event must not be delayed, even if not all the information is available. 
 
 
PLEASE NOTE THAT EMAIL IS THE PREFERRED MEANS OF COMMUNICATION. 
The CRO should inform the Pharmacovigilance (PhV) unit if the whole study is early 
discontinued due to safety reasons. 
It is the responsibility of the CRO to report a SAE to the FDA within proper time constraints 
as per the Guidance for Industry and Investigator’s Safety Reporting Requirements for 
Investigational New Drugs (INDs) and Bioavailability/Bioequivalence (BA/BE) Studies – 
DEC 2012. Confirmation of submission of this report must then be provided to Actavis, Inc. 
(Teva)’s study representative as well as their Pharmacovigilance department (contact info 
below). 
The timeliness for submission of expedite reports should be 15 days or 7 days (death cases) 
or as otherwise specified in local regulations. 
All SAE of the study due to safety reasons must be reported in parallel to the following 
persons: 
 
 
 
 
Sponsor’s Contact person for this Biostudy (copy of the SAE details for information purposes 
only)  
 
 
 
  
These SAE reports must contain the following information, preferably using the template 
provided by the Sponsor: 


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A. Study name/number 
B. Study Drug 
C. Investigator details (name, phone, fax, e-mail) 
D. Subject Number 
E. Subject Initials when appropriate 
F. Subject Demographics 
G. Clinical Event 
1) Description 
2) Date of onset 
3) Treatment (drug, dose, dosage form) 
4) AE Relationship to study drug 
5) Action taken regarding study drug in direct relationship to the AE 
H. If the AE was Fatal: 
1) Cause of death (whether or not the death was related to study drug) 
2) Autopsy findings (if available) 
The SAE form and supportive documents should be filled/ written in English. The SAE form 
completion and reporting must not be delayed even if all of the information is not available at 
the time of the initial contact. Additional information (follow-up) about any SAE unavailable 
at the initial reporting should be forwarded within 24 hours of the information becoming 
available to the same address as the initial report. Subjects who have had an SAE during the 
treatment period must be followed clinically until all parameters (including laboratory) have 
either returned to normal or have stabilized or are otherwise explained. 
Each report of an SAE will be reviewed and evaluated by the Investigator and the Sponsor 
pharmacovigilance to assess the nature of the event and the relationship of the event to the 
study drug, study procedures, and to underlying disease.  
The CRO will take on the responsibility of reporting SAEs to the Investigators and/or to the 
IRB/Ethics Committee (EC). 
The Investigator does not need to actively monitor subjects for AEs once the study has ended. 
Serious adverse events occurring to a subject after the treatment of that subject has ended 
should be reported to the Sponsor if the Investigator becomes aware of them. 
Submission of SAEs 
Any SAE will be reported to competent authority and EC according to the country specific 
requirements and the responsibilities defined in the abovementioned section. All AEs will be 
reported in the CSR with the complete information named above according to the 
requirements of the Note for Guidance on Structure and Content of CSRs 
(CPMP/ICH/137/95).  
Investigator Reporting of SAEs 


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Adverse events which are evaluated by the Investigator as "Serious" will be reported to the 
CRO designated below and IRB within 24 hours of notice whether or not they are considered 
expected or drug-related. All SAEs will be reported as per the FDA regulations.  
Any SAEs should be reported to 
 within 24 hours to: 
 
 
 
 
 
 
 
 
 
 
 
 
 
The Investigator or the Investigator’s designee must be prepared to supply minimum details 
needed in the SAE reporting with the following information: 
a. Investigator Name and Site Number 
b. Subject ID Number 
c. Subject initials and date of birth 
d. Subject Demographics 
e. Clinical Event 
1) Description 
2) Date of onset 
3) Severity 
4) Treatment (including hospitalization) 
5) Relationship to study drug 
6) Action taken regarding study drug 
f. If the AE was Fatal or Life-threatening 
1) Cause of death (whether or not the death was related to study drug) 
2) Autopsy findings (if available) 
3) Death Certificate 
g. Concomitant medication log 
h. AE log 
i. Relevant tests with dates 
j. IP Unblinding information, if applicable 
CRO Reporting of SAEs  
TCTM will report any SAE to Actavis Inc. drug safety team and the medical monitor within 
1 business day. 


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Drug Safety Department:  
 
 
 
 
Sponsor Study Manager:  
 
 
 
 
 
 
  
 
Medical Monitor: 
 
 
 
 
 
 
 
 
6.5.2.5 Submission of SAEs 
The Principal Investigator or the Principal Investigator’s designee must complete the 
provided SAE Form (Appendix III). 
 
 
 
 
6.5.3 Follow-up of subjects after AE 
The staff of the clinical facility has to monitor the clinical trial subject’s safety from the 
occurrence of an AE until satisfactory recovery. 
Any AE which remains unresolved at the time point of subject’s last visit requires detailed 
evaluation and follow-up until the AE has been resolved or a reasonable explanation for its 
persistence is found; in case of AEs related to the IPs every effort has to be made to follow-


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up clinical trial subjects in order to determine the final outcome. If follow-up cannot be 
completed until release of CRF by the Investigator the individual CRF will be released and 
transferred to the Clinical Data Management. In this case, follow-up information will be 
documented separately in the subject’s record and outcome including a short description on 
follow-up procedures performed must be sent to the Sponsor. 
It is the Investigator’s responsibility to assure that subjects experiencing adverse reactions 
will receive definitive treatment for any adverse reaction, if required. Details of follow-up 
care are to be provided (i.e., if treatment or hospitalization is required).  
 
6.5.4 Pregnancy 
If a subject becomes pregnant during the study, the Investigator will notify the Sponsor 
immediately after the pregnancy is confirmed and the subject exits from the study after 
appropriate safety follow-up. 
All pregnancies of women participating in the study that occur during the study, or within 30 
days of completion of the study, are to be reported immediately to the individual identified in 
the clinical study personnel contact information section of this protocol, and the Investigator 
must provide the Sponsor with the pregnancy form. The process for reporting a pregnancy is 
the same as that for reporting a SAE (also see Section 6.5.2.4).  
Any female subject becoming pregnant during the study will discontinue treatment. The 
Investigator will notify the subject’s physician that the subject may have been treated with an 
investigational medication (oxymetazoline or vehicle), follow the progress of the pregnancy 
to term, and document the outcome of the pregnancy (including spontaneous or voluntary 
termination). 
If the pregnancy continues to term, the outcome (health of the infant up to 8 weeks of age), 
including details of birth and presence or absence of any birth defect, congenital 
abnormalities, or maternal and newborn complications, will be reported to the Sponsor. Any 
complication of pregnancy during the study and any complication of pregnancy that the 
Investigator becomes aware of after termination from the study will be reported as an AE or 
SAE, as appropriate. 
If the pregnancy does not continue to term, one of the following actions will be taken: 
x For a spontaneous abortion, report as an SAE. 
x For an elective abortion due to developmental anomalies, report as an SAE. 
x For an elective abortion not due to developmental anomalies, report on the pregnancy 
form; do not report as an AE. 
 
6.6 
Other Procedures and Variables 
6.6.1 Physical examination 
The physical examination (by means of inspection, palpation, auscultation) will be performed 
by the Investigator or the designated physician at the study site on the day of screening and 
Day 29. All clinical signs and symptoms that can be brought into context with the underlying 


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disease, the treatment to be administered or any relevant comorbidities (if present) should be 
assessed during the physical examination. 
At a minimum, the subject will be examined for the following aspects/symptoms but will not 
be commented on, unless there is an issue: 
x General appearance 
x Skin (paleness, jaundice, redness / rash, acneiform changes) 
x Hand and feet (signs of hand-foot syndrome / palmar-plantar erythrodysesthesia) 
x Eyes (accommodation, double images, abnormal sensitivity to light, jaundice) 
x Ears, nose, throat (presence of petechial bleedings, gingiva bleeding) 
x Head and neck 
x Lungs 
x Heart/ cardiovascular 
x Abdomen (pain, tenderness, peristaltic, ascites, organomegaly) 
x Lymph nodes 
x Musculoskeletal system and spine 
x Arms and legs (petechial bleedings, ulcer, signs of thrombosis) 
x Neurological examination  
Other clinical signs and symptoms may be investigated as well if clinically indicated. The 
subject’s height and weight will be recorded at screening only.  
 
6.6.2 Vital signs 
Blood pressure, heart rate and body temperature will be recorded by a member of the 
Investigator’s team at screening; at pre-dose and 12 hours on Day 1; and at pre-dose and 12 
hours on Day 29.  
Blood pressure (millimeters of mercury [mmHg]) and heart rate (beats per minute [bpm]) will 
be measured during the physical examination after 5 minutes rest in sitting position. Blood 
pressure and heart rate will be obtained preferably using the same arm and same equipment 
each time. If one arm has higher blood pressure than the other, that arm should be used for 
further blood pressure measurements (all further blood pressure measurements should be 
done in the same arm). 
Body temperature will be measured using the oral or tympanic thermometer with digital 
display and recorded in the eCRF in degree Celsius (°C). Preferably the same method will be 
used each time.  
If clinically indicated at the Investigator’s discretion, additional vital sign assessments may 
be performed at unscheduled time points. 
 


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6.6.3 Laboratory evaluations 
Urine pregnancy testing at Screening and Day 1 and Day 29 visits will be done for women of 
childbearing potential. A negative result will be required prior to receiving assigned study 
treatment. Further urinary pregnancy tests could be performed at any time during the study at 
the discretion of the Investigator. 
 
6.7 Medication Error and Special Situations 
Any administration of medication that is not in accordance with the study protocol should be 
reported on the eCRF, regardless of whether an AE occurs as a result.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
x 
 
 
 
 
 
 
6.8 
Follow up of Subjects after AE 
The staff of the clinical facility has to monitor the clinical trial subject's safety from the 
occurrence of an AE until satisfactory recovery. 
Any AE which remains unresolved at the time point of subject’s last visit requires detailed 
evaluation and follow-up until the AE has been resolved or a reasonable explanation for its 
persistence is found; in case of AEs related to the IPs every effort has to be made to follow-
up clinical trial subjects in order to determine the final outcome. If follow-up cannot be 
completed until release of CRF by the investigator the individual CRF will be released and 
transferred to the Clinical Data Management. In this case, follow-up information will be 
documented separately in the subjects’ record and outcome including a short description on 
follow-up procedures performed must be sent to the sponsor. 
 


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It is the investigator’s responsibility to assure that subjects experiencing adverse reactions 
will receive definitive treatment for any adverse reaction, if required. Details of follow-up 
care are to be provided (i.e. if treatment or hospitalization is required). The responsibility to 
provide adequate follow-up for AEs includes periodically repeating laboratory tests (if 
required) yielding clinically abnormal results at the end of study evaluation. 
6.9 
Reconciliation of SAEs 
Upon completion of the study, it is the responsibility of 
to perform a reconciliation of 
the SAEs in the study with those in the Pharmacovigilance database. An email with this 
confirmation should be sent to 
 
6.10 
Appropriateness of Procedures / Measurements 
All efficacy and safety parameters, as well as the methods to measure them are standard 
variables/methods in clinical studies and/or clinical practice. They are widely used and 
generally recognized as reliable, accurate, and relevant for this therapeutic area. 
 
 


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7 STATISTICAL AND ANALYTICAL PLANS 
The sections described here highlight the sample size determinations and planned analyses 
for this study. SAS Version 9.4 or higher will be used to perform all the statistical analyses. A 
Statistical Analysis Plan (SAP) that expands the statistical section of the protocol will be 
approved prior to locking the database. The SAP will provide descriptions of the statistical 
methods, hypotheses, analysis populations to be analyzed, and text with table and listing 
shells. The SAP will serve as a companion to the protocol and will serve as the de facto 
documentation of the proposed statistical evaluation. 
The continuous data will be summarized by treatment groups using descriptive statistics 
(number of subjects (n), mean, standard deviation (SD), median, minimum, and maximum). 
Categorical data will be summarized by treatment groups using frequency count (n) and 
percentages (%). 
All statistical tests will be conducted at the 5% significance level, unless indicated otherwise. 
7.1 Sample Size Rationale 
 
 
 
 
 
 
The assumptions used to estimate this sample size were based on the efficacy data presented 
in the 
 were as follows: 
x 
 
 
 
 
 
 
  
 
x 
 
 
 
 
 
 
 
 
 
 
 
 
7.2 Randomization Procedures 


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7.3 Significance Level 
All statistical tests will be carried out at a significance level of α = 0.05, unless otherwise 
indicated. No adjustment will be made for multiplicity. 
7.4 Datasets to be Analyzed 
Three analysis populations will be used in the analysis of the clinical data and they are 
defined as follows: 
x 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
7.5 Comparability of Study Groups at Baseline 
The number and percentage of all the subjects entering and completing the study will be 
provided across treatment groups. Similarly, summarization of the primary reasons for 
discontinuation will be provided. The listing of subjects who discontinued from analysis 
population along with reasons of discontinuation will be presented. Descriptive statistics for 
various continuous demographic variables age (in years), height (in cm) and weight (in kg) 
will be provided. The frequency count (n) and percentages (%) for categorical variables will 
be provided by treatment groups for intent-to-treat (ITT) population. Other baseline data will 
be tabulated and listed appropriately. Medical history will be coded using MedDRA terms. 
The frequency count and percentage of subjects will be summarized according to the coded 
terms of System Organ Class (SOC) and preferred term across all the treatment groups for 


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safety population. Listing for all the demographic and baseline characteristics will be 
provided. No inferential analyses are planned. 
7.6 Safety Assessment 
Safety analyses will be performed on the safety population. No inferential analyses are 
planned. 
The extent of exposure will be summarized using descriptive statistics. Subject exposure to 
the study medication will be characterized by study duration and treatment duration. Study 
duration will be defined as number of days from the date of first dosing to the date of EoT 
visit (Day 29); if the date of EoT visit is missing, the date of the last visit will be used (i.e., 
date of study visit minus date of first dosing plus 1). Treatment duration will be defined as 
number of days from the date of first dosing to last dose (i.e., date of last dose minus date of 
first dose plus 1). Study duration and  treatment duration will be summarized using 
descriptive statistics by treatment group. 
Adverse events will be coded using preferred terms and primary SOC from the current 
version of MedDRA. The AEs and SAEs are considered to be treatment-emergent if they 
have started or worsened after first application of any study drug up until the EoT visit. The 
incidence of TEAEs, treatment-emergent SAEs (TESAEs) and drug-related TEAEs and 
TESAEs will be summarized by treatment group in frequency tables. The maximum severity 
of a TEAE/TESAE experienced by a subject will be determined by the most severe rating 
recorded on the eCRF for the subject’s given TEAE. TEAEs leading to study discontinuation 
and treatment-related TEAEs leading to study discontinuation will be summarized by 
preferred term within primary SOC. Individual subject listings will be generated for TEAEs 
and TESAEs, including subject age, sex, and race, sorted by primary SOC, preferred term, 
onset and stop date, onset day relative to the most recent dose, relationship, and severity.
Adverse events will also be collected both for the screening and baseline period (which will 
be referred to as pretreatment AEs). A listing of pretreatment AEs (including any SAEs) will 
be presented. 
Incidence of concomitant medications will be summarized by treatment group. A listing by 
subject of all abnormal physical examination values will be provided. The vital signs (body 
temperature, systolic blood pressure, diastolic blood pressure and heart rate), will be 
reviewed by the Investigator or qualified delegate and will be summarized by descriptive 
statistics. 
7.7 Efficacy Assessment  
The efficacy analysis will be performed on all the subjects in mITT and PP population. Analyses will 
be conducted with the PP population for equivalence determination, and analyses with the mITT 
population will be for supportive superiority purposes. The SAP will provide descriptions of the 
statistical methods, hypotheses, and analysis populations to be analyzed. 
7.7.1 Analysis of primary endpoint  
x Equivalence testing  
Therapeutic equivalence will be concluded if 90% continuity-corrected confidence interval 
for the difference between test and reference products (πT – πR) of the treatment success 
rates at all timepoints 3, 6, 9, and 12 hours post-application on Day 29 falls within the 
acceptance range of [-0.20, +0.20] using PP population. 


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x Superiority testing 
A frequency distribution of subjects with at least a 2-grade decrease (improvement) on CEA 
scores by time point on Day 1 and Day 29 and by treatment group will be tabulated. A two-
sided exact Cochran-Mantel-Haenszel test, stratified by clinical site, will be applied to test 
the difference between treatment success rates at all post-application timepoints on Day 29 
of Test or Reference Product and Placebo. The sensitivity of the equivalence analysis 
(superiority of Test Product and Reference Product over Placebo) will be established if 
active treatment success rate is higher than and statistically significantly different from (p-
value < 0.05) that of the Placebo group for each active treatment, using the mITT 
population. No adjustment will be made for multiplicity. 
Detailed statistical methods will be explained in SAP.  
8 ETHICS 
This study will be performed in accordance with the ethical principles that have their origin 
in the current Declaration of Helsinki (Appendix I) and will be consistent with International 
Council on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for 
Human Use Good Clinical Practice (ICH-GCP) and applicable regulatory requirements. The 
study will be conducted in compliance with the protocol. 
The rights, safety and well-being of the study subjects are the most important considerations 
and should prevail over interests of society and science. 
8.1 Informed Consent 
The Investigator must ensure that study subjects are clearly and fully informed about the 
purpose, potential risks and other critical issues regarding clinical studies in which they 
volunteer to participate. The principles of Informed Consent, according to FDA Regulations 
and ICH-GCP will be followed. A copy of the proposed consent form must be submitted to 
the IRB, together with the protocol, for approval. Prior to beginning of the study, the 
Investigator must have the IRB’s written approval of the written ICF and any other 
information to be provided to study subjects. 
Informed consent will be obtained from all study subjects using the following procedure: 
Study subjects must have provided IRB approved written informed consent. Each study 
subject’s signed informed consent must be kept on file by the Investigator. A copy of the 
signed consent form will be given to the study subject. A notation will be made in the study 
subject’s medical record indicating the date the informed consent was obtained. In addition, 
the Investigator or the Investigator’s designee will provide a HIPAA authorization form (if 
applicable) for the study subject to review and sign. Both the ICF and the HIPAA form (if 
applicable) must be signed by the study subject before any protocol assessments can be 
undertaken. 
8.2 Institutional Review Board 
Before study initiation, the Investigator must have, including but not only, written and dated 
approval from the IRB for the protocol, consent form, study subject recruitment materials and 
any other written information to be provided to study subjects. The Investigator or Sponsor 
name/CRO will also provide the IRB with a copy of the package insert. 
Any changes to the protocol as well as a change of the Investigator, which is approved by the 
Sponsor, must also be approved by the site’s IRB and documentation of this approval 
provided to the Sponsor/designee. Records of the IRB review and approval of all documents 


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pertaining to this study must be kept on file by the Investigator and are study subject to 
inspection during or after completion of the study. All SAEs must also be reported to the 
IRB. 
Periodic status reports must be submitted to the IRB at least annually, as well as notification 
of completion of the study and a final report within one (1) month of study completion or 
discontinuation. A copy of all reports submitted to the IRB must be sent to the 
Sponsor/designee. 
8.3 Study Subject Confidentiality 
As of 14 APR 2003, the federal medical Privacy Rule authorized by the HIPAA requires 
most health care providers to take new measures to protect the privacy of individually 
identifiable health information. The Privacy Rule’s requirements extend to identifiable health 
information used or disclosed in research. 
The HIPAA Privacy Rule reinforces clinical Investigator’s existing obligations to protect the 
privacy of identifiable health information under state law, codes of medical ethics and the 
federal regulations governing research. 
Please be advised that the Privacy Rule compliance obligations include the following: 
1. Treating individually identifiable health information as confidential in accordance with 
HIPAA and other federal, state and local laws and regulations governing the 
confidentiality and privacy of such information 
2. Using or disclosing individually identifiable health information for study subject 
recruitment purposes only as permitted by HIPAA, applicable laws and regulations and 
institutional policies 
3. Obtaining each study subject’s written authorization for the use or disclosure of 
individually identifiable health information in research, where applicable, in a form that 
meets the requirements of HIPAA and identifies all uses, disclosures and data recipients 
4. Disclosing identifiable health information created or maintained in connection with the 
research only for the purposes and to the parties described in the authorization form or as 
necessary to communicate with the FDA and other regulatory authorities or as otherwise 
permitted or required by law 
5. Employing appropriate physical and technical safeguards to protect the privacy of 
individually identifiable health information 
6. Obtaining a HIPAA waiver of authorization, or where applicable, providing 
representations and/or entering data use agreements as required under the HIPAA Privacy 
Rule for any secondary data analyses or activities preparatory to research and referencing 
these and other research uses and disclosures in your HIPAA notice of privacy practices.
Also, in compliance with federal guidelines regarding the monitoring of clinical studies and 
in fulfillment of his/her obligations to the Sponsor, it is required that the Investigator permit 
the study monitor, Sponsor auditor, IRB and/or FDA representative to review that portion of 
the study subject’s medical record that is directly related to the study. This shall include all 
study relevant documentation including study subject medical histories to verify eligibility, 
admission/discharge summaries for hospital stays occurring while the study subject is 
enrolled in the study and autopsy reports for deaths occurring during the study. 


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As part of the required content of the informed consent, the study subjects must be informed 
that his/her medical chart may be reviewed by the Sponsor, the Sponsor’s authorized 
representatives, FDA officials. Should access to the medical record require a separate waiver 
or authorization, it is the Investigator’s responsibility to obtain such permission from the 
study subject in writing before the study subject is entered into the study. 
 
9 DOCUMENTATION 
9.1 Site Regulatory Documents Required for Initiation 
A minimum of the following set of documents will be received by 
prior to the 
initiation of the study: 
1. Fully executed protocol 
2. Completed and signed FDA Form 1572 
3. Current curricula vitae, signed and dated for the Investigator and each Sub- Investigator 
named in the FDA Form 1572 (current within 2 years) 
4. Current medical licenses of the Investigator and Sub-Investigators named in FDA Form 
1572 
5. Documentation of “No Objection” to proceed from the local regulatory agency, wherever 
applicable. 
6. Documentation of IRB approval of this study protocol, Investigator, and ICFs 
7. Current IRB membership list or roster and EC Standard Operating Procedures (SOPs) 
8. Original Non-disclosure Agreements for the Investigator and Sub-Investigators named in 
FDA Form 1572 
9. Financial Disclosure Statement for the Investigator and each Sub-Investigator named in 
FDA Form 1572 
9.2 Maintenance and Retention of Records 
It is the responsibility of the Investigator to maintain a comprehensive and centralized filing 
system of all relevant documentation. 
Copies of all pertinent records will be retained by the Investigator for at least two years 
following final approval of the drug and/or notification from the Sponsor. These regulatory 
documents should be retained for a longer period if required by local regulatory authorities. 
These records include documents pertaining to the receipt and return of drug supplies, IRB, 
informed consent, source documents, as well as CRFs (paper or electronic files). No 
documents shall be transferred from the site or destroyed without first notifying the Sponsor. 
The Sponsor will archive the data for the lifetime of the product. If the Investigator 
withdraws from the study, the records shall be transferred to a mutually agreed upon 
designee. Notice of such transfer will be given in writing to the Sponsor. 
The Investigator is required to prepare and maintain adequate and accurate case histories 
designed to document all observations and other data pertinent to the investigation on each 
individual treated with the IP or entered as a control in the investigation. Data reported on the 
eCRF, which are derived from source documents, must be consistent with the source 
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9.3 Case Report Forms (CRFs) 
Electronic Data Capture (EDC) technology will be utilized. Electronic CRFs (eCRFs) will be 
prepared for all data collection fields. Study subjects will be identified by initials, birth date 
and subject number, if applicable. Corrections to the CRF will generate an automated audit 
trail including date and timestamp, full name of the person making the correction and original 
entry. The user will document the reason for the change which is also maintained in the audit 
trail. CRFs may be reviewed and signed manually / electronically by properly trained and 
authorized individuals. The EDC platform will be compliant with 21 CFR (Code of Federal 
Regulations) part 11 security and audit trail requirements. 
CRFs must be kept current to reflect the study subject’s status at each phase during the course 
of the study. Study subjects are not to be identified on CRFs by name; appropriately coded 
identification (i.e., study subject study number) and the study subject’s initials must be used. 
The Investigator must keep a separate log of the study subject’s names and addresses. 
Source documents such as the clinic chart are to be maintained separately from the eCRF (in 
order to allow data verification. Due to the potential for errors and inaccuracies in entering 
data into CRFs, originals of laboratory and other test results must be kept on file with the 
study subject’s source document. Source documents and copies of test results must be 
available at all times for inspection by the study monitor. 
9.4 Primary Source Documents 
The Investigator must maintain primary source documents supporting significant data for 
each study subject’s medical notes. These documents, which are considered “source data”, 
should include documentation of: 
x Demographic information 
x Evidence supporting the diagnosis/condition for which the study subject is being studied 
x General information supporting the study subject’s participation in the study 
x General history and physical findings 
x Hospitalization or Emergency Room records (if applicable) 
x Each study visit by date, including any evaluations, relevant findings/notes by the 
Investigator(s), occurrence (or lack) of AEs and changes in medication usage, including 
the date the study drug commenced and completed. 
x Any additional visits during the study 
x Any relevant telephone conversations with the study subject regarding the study or 
possible AEs 
x An original, signed ICF for study participation 
x Subject’s diary 
The Investigator must also retain all study subject specific printouts/reports of 
tests/procedures performed as a requirement of the study. During monitoring visits, the 
monitor will need to validate data in the CRFs against these sources of data. 
 


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9.5 Study Monitoring 
 will be responsible for monitoring the study according to GCP and 
applicable regulations. Monitoring visits are for the purpose of confirming adherence to the 
protocol and to verify complete and accurate data collection. The clinical site will make all 
records associated with the study available to 
 representative during such visits and 
audits. 
The study may be subject to audit by the Sponsor, Sponsor Representative or by regulatory 
authorities. If such an audit occurs the Investigator must agree to allow access to required 
subject records. By signing this protocol, the Investigator grants permission to personnel from 
the Sponsor, its representatives and appropriate regulatory authorities for on-site monitoring 
of all appropriate study documentation, as well as on-site review of study procedures. 
The following should also be available for review: 
1. Study Subject Screening/Enrollment Log – reflecting the reason any study subject 
screened for the study was found to be ineligible and start and end dates for all study 
subjects  
2. Delegation of Authority / Study Personnel Signature Log – all site personnel will be listed 
along with their responsibilities and signatures; to be maintained at the site throughout the 
study 
3. Monitoring Log – the date and purpose of all monitoring visits by the Sponsor/designee 
will be documented 
4. Drug Inventory/Packing Slip – reflecting the total amount of drug shipped to the site and 
received and signed for by the Investigator 
5. Drug Accountability Log – reflecting the total amount of IP dispensed to and returned by 
each study subject 
6. Informed Consent Form – which must be available for each study subject and be verified 
for proper documentation 
7. All correspondence 
Monitoring visits will be arranged in advance at a mutually acceptable time with site 
personnel. Sufficient time must be allowed by the site personnel for the monitoring of CRFs 
and relevant source documents. The Study Coordinator and/or Investigator should be 
available to answer questions or resolve data clarifications. Adequate time and space for these 
visits should be made available by the Investigator. 
At the end of the study, a closeout monitoring visit will be performed. 
9.6 Audits and Inspections 
During the course of the study and/or after it has been completed, one or more site visits may 
be undertaken by auditors as authorized representatives of the Sponsor. The purpose of the 
audit is to determine whether or not the study is being conducted and monitored in 
compliance with the protocol, recognized GCP guidelines and all applicable regulations. 
Additionally, the study may be inspected by regulatory agencies. These inspections may take 
place at any time during the study or after the study. 
 


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9.7 Modifications to the Protocol 
The procedures defined in the protocol and in the eCRF/paper CRF will be carefully 
reviewed to ensure that all parties involved with the study fully understand the protocol. In 
order to ensure the validity of the data, no deviations from the protocol, with minimal 
exceptions, may be made unless the issue is broad enough to warrant revision of the protocol. 
Such revisions must be submitted to and have documented approval from the Sponsor and the 
IRB prior to implementation. All amendments to the protocol, which involve substantial 
changes in study design, procedure or analyses, will be submitted to appropriate regulatory 
authority for prior approval. 
The only circumstance in which an amendment may be initiated without prior IRB approval 
is to eliminate apparent immediate hazards to a study subject or study subjects. However, the 
Investigator must notify the Sponsor and the IRB as soon as possible. 
9.8 Completion of Study 
The Investigator is required to forward CRFs and all other relevant data and records to CRO. 
The Investigator will complete and report (submission of CRFs) his/her study in satisfactory 
compliance with the protocol as soon as possible after the completion of the study. 
The Investigator must submit a final report to the IRB and CRO within one (1) month of 
study completion or discontinuation. 
A CSR will be prepared in accordance with ICH-GCP and Sponsor requirements. In the event 
the study is prematurely terminated for medical reasons, the principal Investigator or his/her 
authorized designee will produce an abbreviated safety report.  


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10 STUDY SUBJECT INSURANCE 
All study subjects will be covered by adequate insurance for any trial related injuries. This 
insurance covers cost of medical treatment, discomfort or injury to the study subject as a 
result of drug administration or any of the procedures carried out during the study. 


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11 CONFIDENTIALITY, 
USE 
OF 
INFORMATION, 
AND 
PUBLICATION 
All information supplied by the Sponsor in connection with this study and not previously 
published, is considered confidential information. This information includes, but is not 
limited to, data, materials (i.e., the clinical protocol, CRFs), equipment, experience (whether 
of a scientific, technical, engineering, operational or commercial nature), designs, 
specifications, know-how, product uses, processes, formulae, costs, financial data, marketing 
plans and direct selling systems, customer lists and technical and commercial information 
relating to customers or business projections used by the Sponsor in its business. Any data, 
inventions or discoveries collected or developed, as a result of this study is considered 
confidential. This confidential information shall remain the sole property of the Sponsor, 
shall not be disclosed to any unauthorized person or used in any unauthorized manner without 
written consent of the Sponsor and shall not be used except in the performance of the study. 
The information developed during the course of this clinical study is also considered 
confidential and will be used by the Sponsor in connection with the development of the drug. 
The information may be disclosed as deemed necessary by the Sponsor. To allow the use of 
the information derived from this clinical study, the Investigator is obliged to provide the 
Sponsor with complete test results and all data developed in the study. The information 
obtained during this study may be made available to other Investigators who are conducting 
similar studies. 
 


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12 PREMATURE TERMINATION OF STUDY/SUBJECT 
A subject may terminate from the study early for any reason at any time without any 
disadvantages. In this case, the Investigator should make every effort to have the subject 
return to the next scheduled visit to perform all required Study Completion/Early Termination 
visit activities and to collect and reconcile all test articles. If the subject does not return for 
the Study Completion/Early Termination visit, the site should fully document the reason for 
early termination. All data, including the date and primary reason for termination, must be 
recorded on the Study Completion/Early Termination CRF, and source document. 
Any subject who experiences an AE may be terminated from the study or from study 
treatment at any time at the discretion of the Investigator. In this case, the subject should be 
followed at the discretion of the Investigator until the resolution or stabilization of the AE. 
All applicable data should be recorded in the AEs section of the CRF. If a subject terminates 
from the study early for multiple reasons that include AEs, the Study Completion/Early 
Termination CRF should indicate that early termination was related to an AE.  
An exception to this requirement will be the occurrence of an AE that in the opinion of the 
Investigator is not severe enough to warrant early termination but that requires the use of a 
prohibited medication, thereby requiring discontinuation of the subject. In such a case, the 
reason for discontinuation would be the need to take a prohibited medication, not the AE. 
The Investigator must inform the clinical project physician/clinical leader/Principal 
Investigator as soon as possible of all subjects who are being considered for early termination 
due to AEs. Additional reports must be provided when requested. 
The Sponsor reserves the right to terminate the study at any time for administrative reasons. 
The study may also be terminated by regulatory authorities or by the Investigator for his/her 
site following consultation with the Sponsor. Following a decision to discontinue the trial, the 
Investigator will immediately inform both the study subjects and the IRB responsible for this 
trial within 10 working days, stating the reasons for discontinuation of the study and, 
furthermore, advise them in writing of any potential risks to the health of study subjects or 
other persons. It is Sponsor’s responsibility to report the premature termination of the study 
to the regulatory agencies within 15 days providing them with the reasons for the trial 
discontinuation and advising them in writing of any potential risks to the health of study 
subjects or other persons. The CRO may notify the regulatory agency on behalf of the 
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13 REFERENCES 
1. Culp B, Scheinfeld N. Rosacea: a review. Pharmacy and Therapeutics. 2009 Jan;34(1):38. 
2. McGregor SP, Alinia H, Snyder A, Tuchayi SM, Fleischer A Jr, Feldman SR. A Review 
of the Current Modalities for the Treatment of Papulopustular Rosacea. Dermatol Clin. 
2018 Apr;36(2):135-150. 
3. Gether L, Overgaard LK, Egeberg A, Thyssen JP. Incidence and prevalence of rosacea: a 
systematic review and meta-analysis. Br J Dermatol. 2018 Aug;179(2):282-289. 
4. National Rosacea Society, 2018; URL: https://www.rosacea.org/ 
5. Mikkelsen CS, Bjerring P, Holmgren HR. Rosacea: Time for a New Approach. InForum 
for Nord Derm Ven 2017 (Vol. 22, No. 1). 
6. Breneman D, Savin R, VandePol C, Vamvakias G, Levy S, Leyden J. Double-blind, 
randomized, vehicle-controlled clinical trial of once-daily benzoyl peroxide/clindamycin 
topical gel in the treatment of patients with moderate to severe rosacea. Int J Dermatol. 
2004 May;43(5):381-7. 
7. Drummond PD, Su D. Blushing in rosacea sufferers. J Psychosom Res. 2012 
Feb;72(2):153-8. 
8. Reinholz M, Ruzicka T, Steinhoff M, Schaller M, Gieler U, Schöfer H, Homey B, 
Lehmann P, Luger TA. Pathogenesis and clinical presentation of rosacea as a key for a 
symptom-oriented therapy. J Dtsch Dermatol Ges. 2016 Dec;14 Suppl 6:4-15. 
9. Crawford GH, Pelle MT, James WD. Rosacea: I. Etiology, pathogenesis, and subtype 
classification. J Am Acad Dermatol. 2004 Sep;51(3):327-41. 
10. Elewski BE, Draelos Z, Dréno B, Jansen T, Layton A, Picardo M. Rosacea - global 
diversity and optimized outcome: proposed international consensus from the Rosacea 
International Expert Group. J Eur Acad Dermatol Venereol. 2011 Feb;25(2):188-200. 
11. Draelos ZD, Gold MH, Weiss RA, Baumann L, Grekin SK, Robinson DM, Kempers SE, 
Alvandi N, Weng E, Berk DR, Ahluwalia G. Efficacy and safety of oxymetazoline cream 
1.0% for treatment of persistent facial erythema associated with rosacea: Findings from 
the 52-week open label REVEAL trial. J Am Acad Dermatol. 2018 Jun;78(6):1156-1163. 
12. Prescribing information, RHOFADE™ topical cream, Allergan. Revised: 01/2017. 
13. Fox L, Csongradi C, Aucamp M, du Plessis J, Gerber M. Treatment Modalities for Acne. 
Molecules. 2016 Aug 13;21(8). 
14. Cline A, McGregor SP, Feldman SR. Medical Management of Facial Redness in Rosacea. 
Dermatol Clin. 2018 Apr;36(2):151-159. 
15. Sharma R, Abrol S, Wani M. Misuse of topical corticosteroids on facial skin. A study of 
200 patients. J Dermatol Case Rep. 2017;11(1):5-8. 
 
 


 
 
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14 LIST OF APPENDICES 
Appendix-I: Declaration of Helsinki 
Appendix-II: Reference Safety Information (Prescribing Information: RHOFADE™) 
Appendix-III: SAE Form 
Appendix-IV: Pregnancy Form 
 
 
 


 
 
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APPENDIX – 1   DECLARATION OF HELSINKI – ETHICAL PRINCIPLES FOR 
MEDICAL RESEARCH INVOLVING HUMAN   SUBJECTS 
 
Adopted by the 18th WMA General Assembly, Helsinki, Finland, June 1964 and 
amended by the: 
29th WMA General Assembly, Tokyo, Japan, October 1975 35th WMA General 
Assembly, Venice, Italy, October 1983 41st WMA General Assembly, Hong Kong, 
September 1989 
48th WMA General Assembly, Somerset West, Republic of South Africa, October 
1996  
52nd WMA General Assembly, Edinburgh, Scotland, October 2000 
53rd WMA General Assembly, Washington DC, USA, October 2002 (Note of 
Clarification added)  
55th WMA General Assembly, Tokyo, Japan, October 2004 (Note of Clarification 
added) 
59th WMA General Assembly, Seoul, Republic of Korea, October 2008  
64th WMA General Assembly, Fortaleza, Brazil, October 2013 
Preamble 
1. 
The World Medical Association (WMA) has developed the Declaration of Helsinki as a statement of 
ethical principles for medical research involving human subjects, including research on identifiable human 
material   and data. 
The Declaration is intended to be read as a whole and each of its constituent paragraphs should be applied with 
consideration of all other relevant paragraphs. 
2. 
Consistent with the mandate of the WMA, the Declaration is addressed primarily to physicians. The WMA 
encourages others who are involved in medical research involving human subjects to adopt these principles. 
General Principles 
3. 
The Declaration of Geneva of the WMA binds the physician with the words, “The health of my patient 
will    be my first consideration,” and the International Code of Medical Ethics declares that, “A physician shall 
act in        the patient’s best interest when providing medical    care.” 
4. 
It is the duty of the physician to promote and safeguard the health, well-being and rights of patients, 
including those who are involved in medical research. The physician’s knowledge and conscience are dedicated to 
the fulfilment of this duty. 
5. 
Medical progress is based on research that ultimately must include studies involving human subjects. 
6. 
The primary purpose of medical research involving human subjects is to understand the causes, 
development and effects of diseases and improve preventive, diagnostic and therapeutic interventions (methods, 
procedures and treatments). Even the best proven interventions must be evaluated continually through research for 
their safety, effectiveness, efficiency, accessibility and quality. 
7. 
Medical research is subject to ethical standards that promote and ensure respect for all human subjects and 
protect their health and rights. 


 
 
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8. 
While the primary purpose of medical research is to generate new knowledge, this goal can never take 
precedence over the rights and interests of individual research subjects. 
9. 
It is the duty of physicians who are involved in medical research to protect the life, health, dignity, 
integrity, right to self-determination, privacy, and confidentiality of personal information of research subjects. The 
responsibility for the protection of research subjects must always rest with the physician or other health care 
professionals and never with the research subjects, even though they have given consent. 
10. 
Physicians must consider the ethical, legal and regulatory norms and standards for research involving 
human subjects in their own countries as well as applicable international norms and standards. No national or 
international ethical, legal or regulatory requirement should reduce or eliminate any of the protections for research 
subjects set forth in this Declaration. 
11. 
Medical research should be conducted in a manner that minimises possible harm to the environment. 
12. 
Medical research involving human subjects must be conducted only by individuals with the appropriate 
ethics and scientific education, training and qualifications. Research on patients or healthy volunteers requires the 
supervision of a competent and appropriately qualified physician or other health care professional. 
13. 
Groups that are underrepresented in medical research should be provided appropriate access to 
participation in research. 
14. 
Physicians who combine medical research with medical care should involve their patients in research only 
to the extent that this is justified by its potential preventive, diagnostic or therapeutic value and if the physician 
has good reason to believe that participation in the research study will not adversely affect the health of the 
patients who serve as research subjects. 
15. 
Appropriate compensation and treatment for subjects who are harmed as a result of participating in 
research must be ensured. 
Risks, Burdens and Benefits 
16. 
In medical practice and in medical research, most interventions involve risks and burdens. 
Medical research involving human subjects may only be conducted if the importance of the objective outweighs 
the risks and burdens to the research subjects. 
17. 
All medical research involving human subjects must be preceded by careful assessment of predictable 
risks and burdens to the individuals and groups involved in the research in comparison with foreseeable benefits 
to them and to other individuals or groups affected by the condition under investigation. 
Measures to minimise the risks must be implemented. The risks must be continuously monitored, assessed and 
documented by the researcher. 
18. 
Physicians may not be involved in a research study involving human subjects unless they are confident 
that the risks have been adequately assessed and can be satisfactorily managed. 
When the risks are found to outweigh the potential benefits or when there is conclusive proof of definitive 
outcomes, physicians must assess whether to continue, modify or immediately stop the study. 
Vulnerable Groups and Individuals 
19. 
Some groups and individuals are particularly vulnerable and may have an increased likelihood of being 
wronged or of incurring additional harm. 


 
 
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All vulnerable groups and individuals should receive specifically considered protection. 
20. 
Medical research with a vulnerable group is only justified if the research is responsive to the health needs 
or priorities of this group and the research cannot be carried out in a non-vulnerable group. In addition, this group 
should stand to benefit from the knowledge, practices or interventions that result from the research. 
Scientific Requirements and Research Protocols 
21. 
Medical research involving human subjects must conform to generally accepted scientific principles, be 
based on a thorough knowledge of the scientific literature, other relevant sources of information, and adequate 
laboratory and, as appropriate, animal experimentation. The welfare of animals used for research must be 
respected. 
22. 
The design and performance of each research study involving human subjects must be clearly described 
and justified in a research protocol. 
The protocol should contain a statement of the ethical considerations involved and should indicate how the 
principles in this Declaration have been addressed. The protocol should include information regarding funding, 
sponsors, institutional affiliations, potential conflicts of interest, incentives for subjects and information regarding 
provisions for treating and/or compensating subjects who are harmed as a consequence of participation in the 
research study. 
In clinical trials, the protocol must also describe appropriate arrangements for post-trial provisions. 
Research Ethics Committees 
23. 
The research protocol must be submitted for consideration, comment, guidance and approval to the 
concerned research ethics committee before the study begins. This committee must be transparent in its 
functioning, must be independent of the researcher, the sponsor and any other undue influence and must be duly 
qualified. It must take into consideration the laws and regulations of the country or countries in which the research 
is to be performed as well as applicable international norms and standards but these must not be allowed to reduce 
or eliminate any of the protections for research subjects set forth in this Declaration. 
The committee must have the right to monitor ongoing studies. The researcher must provide monitoring 
information to the committee, especially information about any serious adverse events. No amendment to the 
protocol may be made without consideration and approval by the committee. After the end of the study, the 
researchers must submit a final report to the committee containing a summary of the study’s findings and 
conclusions. 
Privacy and Confidentiality 
24. 
Every precaution must be taken to protect the privacy of research subjects and the confidentiality of their 
personal information. 
Informed Consent 
25. 
Participation by individuals capable of giving informed consent as subjects in medical research must be 
voluntary. Although it may be appropriate to consult family members or community leaders, no individual 
capable of giving informed consent may be enrolled in a research study unless he or she freely  agrees. 
26. 
In medical research involving human subjects capable of giving informed consent, each potential subject 
must be adequately informed of the aims, methods, sources of funding, any possible conflicts of interest, 


 
 
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institutional affiliations of the researcher, the anticipated benefits and potential risks of the study and the 
discomfort it may entail, post-study provisions and any other relevant aspects of the study. The potential subject 
must be informed of the right to refuse to participate in the study or to withdraw consent to participate at any time 
without reprisal. Special attention should be given to the specific information needs of individual potential 
subjects as well as to the methods used to deliver the information. 
After ensuring that the potential subject has understood the information, the physician or another appropriately 
qualified individual must then seek the potential subject’s freely-given informed consent, preferably in writing. If 
the consent cannot be expressed in writing, the non-written consent must be formally documented and witnessed. 
All medical research subjects should be given the option of being informed about the general outcome and results 
of the study. 
27. 
When seeking informed consent for participation in a research study the physician must be particularly 
cautious if the potential subject is in a dependent relationship with the physician or may consent under duress. In 
such situations the informed consent must be sought by an appropriately qualified individual who is completely 
independent of this relationship. 
28. 
For a potential research subject who is incapable of giving informed consent, the physician must seek 
informed consent from the legally authorised representative. These individuals must not be included in a research 
study that has no likelihood of benefit for them unless it is intended to promote the health of the group represented 
by the potential subject, the research cannot instead be performed with persons capable of providing informed 
consent, and the research entails only minimal risk and minimal burden. 
29. 
When a potential research subject who is deemed incapable of giving informed consent is able to give 
assent to decisions about participation in research, the physician must seek that assent in addition to the consent of 
the legally authorised representative. The potential subject’s dissent should be respected. 
30. 
Research involving subjects who are physically or mentally incapable of giving consent, for example, 
unconscious patients, may be done only if the physical or mental condition that prevents giving informed consent 
is a necessary characteristic of the research group. In such circumstances the physician must seek informed 
consent from the legally authorised representative. If no such representative is available and if the research cannot 
be delayed, the study may proceed without informed consent provided that the specific reasons for involving 
subjects with a condition that renders them unable to give informed consent have been stated in the research 
protocol and the study has been approved by a research ethics committee. Consent to remain in the research must 
be obtained as soon as possible from the subject or a legally authorised representative. 
31. 
The physician must fully inform the patient which aspects of their care are related to the research. The 
refusal of a patient to participate in a study or the patient’s decision to withdraw from the study must never 
adversely affect the patient-physician relationship. 
32. 
For medical research using identifiable human material or data, such as research on material or data 
contained in biobanks or similar repositories, physicians must seek informed consent for its collection, storage 
and/or reuse. There may be exceptional situations where consent would be impossible or impracticable to obtain 
for such research. In such situations the research may be done only after consideration and approval of a research 
ethics committee. 
Use of Placebo 
33. 
The benefits, risks, burdens and effectiveness of a new intervention must be tested against those of the best 
proven intervention(s), except in the following circumstances: 


 
 
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Where no proven intervention exists, the use of placebo, or no intervention, is acceptable; or 
Where for compelling and scientifically sound methodological reasons the use of any intervention less effective 
than the best proven one, the use of placebo, or no intervention is necessary to determine the efficacy or safety of 
an intervention 
and the patients who receive any intervention less effective than the best proven one, placebo, or no intervention 
will not be subject to additional risks of serious or irreversible harm as a result of not receiving the best proven 
intervention. 
Extreme care must be taken to avoid abuse of this option. 
Post-Trial Provisions 
34. 
In advance of a clinical trial, sponsors, researchers and host country governments should make provisions 
for post-trial access for all participants who still need an intervention identified as beneficial in the trial. This 
information must also be disclosed to participants during the informed consent process. 
Research Registration and Publication and Dissemination of Results 
35. 
Every research study involving human subjects must be registered in a publicly accessible database before 
recruitment of the first subject. 
36. 
Researchers, authors, sponsors, editors and publishers all have ethical obligations with regard to the 
publication and dissemination of the results of research. Researchers have a duty to make publicly available the 
results of their research on human subjects and are accountable for the completeness and accuracy of their reports. 
All parties should adhere to accepted guidelines for ethical reporting. Negative and inconclusive as well as 
positive results must be published or otherwise made publicly available. Sources of funding, institutional 
affiliations and conflicts of interest must be declared in the publication. Reports of research not in accordance 
with the principles of this Declaration should not be accepted for publication. 
Unproven Interventions in Clinical Practice 
37. 
In the treatment of an individual patient, where proven interventions do not exist or other known 
interventions have been ineffective, the physician, after seeking expert advice, with informed consent from the 
patient or a legally authorised representative, may use an unproven intervention if in the physician’s judgement it 
offers hope of saving life, re-establishing health or alleviating suffering. This intervention should subsequently be 
made the object of research, designed to evaluate its safety and efficacy. In all cases, new information must be 
recorded and, where appropriate, made publicly available. 
 
 


 
 
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Appendix-II: Reference Safety Information (Prescribing Information: RHOFADE™) 
HIGHLIGHTS OF PRESCRIBING INFORMATION 
These highlights do not include all the information needed to use RHOFADE™ topical cream safely 
and effectively. See full prescribing information for RHOFADE™ topical cream. 
RHOFADE™ (oxymetazoline hydrochloride) cream, for topical use 
Initial U.S. Approval: 1964 
 
------------------INDICATIONS AND USAGE------------------ 
RHOFADE™ is an alpha1A adrenoceptor agonist indicated for the topical treatment of persistent facial 
erythema associated with rosacea in adults. (1) 
 
---------------DOSAGE AND ADMINISTRATION------------ 
x Not for oral, ophthalmic, or intravaginal use. (2) 
x Prime pump bottle before initial use and discard product from first three pumps. (2) 
x Apply a pea-sized amount once daily in a thin layer to cover the entire face (forehead, nose, each cheek, 
and chin) avoiding the eyes and lips. (2) 
x Wash hands after application. (2) 
 
------------DOSAGE FORMS AND STRENGTHS------------- 
Cream, 1%. Each gram of cream contains 10 mg (1%) oxymetazoline hydrochloride, equivalent to 8.8 mg 
(0.88%) of oxymetazoline free base. (3) 
--------------------CONTRAINDICATIONS--------------------- 
x None. (4) 
 
--------------WARNINGS AND PRECAUTIONS-------------- 
x Alpha-adrenergic agonists as a class may impact blood pressure. Advise patients with cardiovascular 
disease, orthostatic hypotension, and/or uncontrolled hypertension or hypotension to seek medical care 
if their condition worsens. (5.1) 
x Use with caution in patients with cerebral or coronary insufficiency, Raynaud’s phenomenon, 
thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome and advise patients to seek medical 
care if signs and symptoms of potentiation of vascular insufficiency develop. (5.2) 
x Advise patients to seek immediate medical care if signs and symptoms of acute narrow-angle glaucoma 
develop. (5.3) 


 
 
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--------------------ADVERSE REACTIONS---------------------- 
Most common adverse reactions (incidence > 1%) are application site dermatitis, worsening inflammatory 
lesions of rosacea, application site pruritis, application site erythema, and application site pain. (6.1) 
To report SUSPECTED ADVERSE REACTIONS, contact Allergan at 1-800-433-8871 or FDA at 1-
800-FDA-1088 or www.fda.gov/medwatch. 
See 17 for PATIENT COUNSELING INFORMATION and FDA-approved patient labeling. 
 
Revised: 01/2017 
 
 
 
 
 
FULL PRESCRIBING INFORMATION: CONTENTS* 
1 INDICATIONS AND USAGE 
2 DOSAGE AND ADMINISTRATION 
3 DOSAGE FORMS AND STRENGTHS 
4 CONTRAINDICATIONS 
5 WARNINGS AND PRECAUTIONS 
5.1 Potential Impacts on Cardiovascular Disease 
5.2 Potentiation of Vascular Insufficiency 
5.3 Risk of Angle Closure Glaucoma 
6 ADVERSE REACTIONS 
6.1 Clinical Studies Experience 
7 DRUG INTERACTIONS 
7.1 Anti-hypertensives/Cardiac Glycosides 
7.2 Monoamine Oxidase Inhibitors 
8 USE IN SPECIFIC POPULATIONS 
8.1 Pregnancy 
8.2  Lactation 
8.4 Pediatric Use 
8.5 Geriatric Use 
10 OVERDOSAGE 
11 DESCRIPTION 
12 CLINICAL PHARMACOLOGY 
12.1 Mechanism of Action 
12.2 Pharmacodynamics 
12.3 Pharmacokinetics 
13 NONCLINICAL TOXICOLOGY 
13.1 Carcinogenesis, Mutagenesis, Impairment of Fertility 
14 CLINICAL STUDIES 
16 HOW SUPPLIED/STORAGE AND HANDLING 
17 PATIENT COUNSELING INFORMATION 
*Sections or subsections omitted from the full prescribing 
information are not listed. 


 
 
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FULL PRESCRIBING INFORMATION 
 
1 
INDICATIONS AND USAGE 
RHOFADE™ cream is indicated for the topical treatment of persistent facial erythema associated with rosacea in adults. 
 
2 
DOSAGE AND ADMINISTRATION 
For topical use only.  RHOFADE is not for oral, ophthalmic, or intravaginal use. 
Prime the RHOFADE pump before using for the first time. To do so, with the pump in the upright position, repeatedly 
depress the actuator until cream is dispensed and then pump three times. Discard the cream from priming actuations. 
It is only necessary to prime the pump before the first dose. 
RHOFADE tubes do not require priming. 
Apply a pea-sized amount of RHOFADE cream, once daily in a thin layer to cover the entire face (forehead, nose, 
each cheek, and chin) avoiding the eyes and lips. Wash hands immediately after applying RHOFADE cream. 
 
3 
DOSAGE FORMS AND STRENGTHS 
RHOFADE (oxymetazoline hydrochloride) cream, 1% is a white to off-white cream. Each gram of cream contains 10 mg 
(1%) oxymetazoline hydrochloride, equivalent to 8.8 mg (0.88%) of oxymetazoline free base. 
 
4 
CONTRAINDICATIONS 
None. 
 
5 
WARNINGS AND PRECAUTIONS 
5.1 
Potential Impacts on Cardiovascular Disease 
Alpha-adrenergic agonists may impact blood pressure. RHOFADE should be used with caution in patients with severe or 
unstable or uncontrolled cardiovascular disease, orthostatic hypotension, and uncontrolled hypertension or hypotension. 
Advise patients with cardiovascular disease, orthostatic hypotension, and/or uncontrolled hypertension/hypotension to 
seek immediate medical care if their condition worsens. 
 
5.2 
Potentiation of Vascular Insufficiency 
RHOFADE should be used with caution in patients with cerebral or coronary insufficiency, Raynaud’s 
phenomenon, thromboangiitis obliterans, scleroderma, or Sjögren’s syndrome. Advise patients to seek 
immediate medical care if signs and symptoms of potentiation of vascular insufficiency develop. 
 
5.3 
Risk of Angle Closure Glaucoma 
RHOFADE may increase the risk of angle closure glaucoma in patients with narrow-angle glaucoma. Advise patients to 
seek immediate medical care if signs and symptoms of acute angle closure glaucoma develop. 
 
6 
ADVERSE REACTIONS 
6.1 
Clinical Studies Experience 


 
 
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Because clinical trials are conducted under varying conditions, adverse reaction rates observed in the clinical trials of a 
drug cannot be directly compared to rates in the clinical trials of another drug and may not reflect the rates observed in 
practice. 
A total of 489 subjects with persistent facial erythema associated with rosacea were treated with RHOFADE once daily 
for 4 weeks in 3 controlled clinical trials. An additional 440 subjects with persistent facial erythema associated with 
rosacea were also treated with RHOFADE once daily for up to one year in a long-term (open- label) clinical trial. Adverse 
reactions that occurred in at least 1% of subjects treated with RHOFADE through 4 weeks of treatment are presented in 
Table 1 below. 
 
Table 1: Adverse Reactions Reported by > 1% of Subjects through 4 Weeks of Treatment 
in Controlled Clinical Trials 
 
 
Adverse Reaction 
Pooled Controlled 
Clinical Trials 
RHOFADE Cream 
(N = 489) 
Vehicle Cream 
(N = 483) 
Application site dermatitis 
9 (2%) 
0 
Worsening inflammatory 
lesions of rosacea 
7 (1%) 
1 (<1%) 
Application site pruritus 
5 (1%) 
4 (1%) 
Application site erythema 
5 (1%) 
2 (<1%) 
Application site pain 
4 (1%) 
1 (<1%) 
 
In the long-term (open-label) clinical trial, the rates of adverse reactions over a one-year treatment period were as follows: 
worsening inflammatory lesions of rosacea (3%), application site dermatitis (3%), application site pruritis (2%), application 
site pain (2%), and application site erythema (2%). Subjects with persistent erythema along with inflammatory lesions 
were allowed to use additional therapy for the inflammatory lesions of rosacea. 
 
7 
DRUG INTERACTIONS 
7.1 
Anti-hypertensives/Cardiac Glycosides 
Alpha-adrenergic agonists, as a class, may impact blood pressure. Caution in using drugs such as beta-blockers, anti-
hypertensives and/or cardiac glycosides is advised. 
Caution should also be exercised in patients receiving alpha1 adrenergic receptor antagonists such as in the treatment of 
cardiovascular disease, benign prostatic hypertrophy, or Raynaud's disease. 
 
7.2 
Monoamine Oxidase Inhibitors 
Caution is advised in patients taking MAO inhibitors which can affect the metabolism and uptake of circulating amines. 
8 
USE IN SPECIFIC POPULATIONS 
8.1 
Pregnancy 


 
 
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Risk Summary 
There are no available data on RHOFADE use in pregnant women to inform a drug-associated risk for major birth 
defects and miscarriage. A literature article describing intranasal decongestant use in pregnant women identified a 
potential association between second-trimester exposure to oxymetazoline (with no decongestant exposure in the first 
trimester) and renal collecting system anomalies [see Data]. In animal reproduction studies, there were no adverse 
developmental effects observed after oral administration of oxymetazoline hydrochloride in pregnant rats and rabbits at 
systemic exposures up to 3 times and 73 times, respectively, the exposure associated with the maximum 
recommended human dose (MRHD) [see Data]. The estimated background risks of major birth defects and miscarriage 
for the indicated population are unknown. All pregnancies have a background risk of birth defect, loss, or other adverse 
outcomes. In the U.S. general population, the estimated background risk of major birth defects and miscarriage in 
clinically recognized pregnancies is 2-4% and 15-20%, respectively. 
 
Clinical Considerations 
Fetal/Neonatal Adverse Reactions 
Following repeated use of oxymetazoline hydrochloride solution nasal spray for the treatment of nasal congestion at a 
dose 5 times higher than recommended, one case of fetal distress was reported in a 41-week pregnant patient. The fetal 
distress resolved hours later, prior to the delivery of the healthy infant. The anticipated exposures for the case are 8- 
to18-fold higher than plasma exposures after topical administration of RHOFADE. 
Data 
Human Data 
No adequate and well-controlled trials of RHOFADE have been conducted in pregnant women. Across all clinical trials of 
RHOFADE, two pregnancies were reported. One pregnancy resulted in the delivery of a healthy child. One pregnancy 
resulted in a spontaneous abortion, which was considered to be unrelated to the trial medication. A literature article 
summarizing the results of exploratory analyses of intranasal decongestant use during pregnancy identified a potential 
association between second-trimester exposure to oxymetazoline hydrochloride solution (with no decongestant exposure 
in the first trimester) and renal collecting system anomalies. 
 
Animal Data 
Effects on embryo-fetal development were evaluated in rats and rabbits following oral administration of oxymetazoline 
hydrochloride during the period of organogenesis. Oxymetazoline hydrochloride did not cause adverse effects to the fetus 
at oral doses up to 0.2 mg/kg/day in pregnant rats during the period of organogeneisis (3 times the MRHD on an AUC 
comparison basis). Oxymetazoline hydrochloride did not cause adverse effects to the fetus at oral doses up to 1 
mg/kg/day in pregnant rabbits during the period of organogeneisis (73 times the MRHD on an AUC comparison basis). 
Maternal toxicity, such as decreased maternal body weight, was produced at the high dose of 1 mg/kg/day in pregnant 
rabbits and was associated with findings of delayed skeletal ossification. 
 
In a rat perinatal and postnatal development study, oxymetazoline hydrochloride was orally administered to pregnant rats 
once daily from gestation day 6 through lactation day 20. Maternal toxicity was produced at the high dose of 0.2 
mg/kg/day (3 times the MRHD on an AUC comparison basis) in pregnant rats and was associated with an increase in 
pup mortality and reduced pup body weights. Delayed sexual maturation was noted at 0.1 and 0.2 mg/kg/day (2 times the 
MRHD and 3 times the MRHD on an AUC comparison basis, respectively). Oxymetazoline hydrochloride did not have 
any adverse effects on fetal development at a dose of 
0.05 mg/kg/day (one-half of the MRHD on an AUC comparison basis). 


 
 
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8.2
Lactation 
No clinical data are available to assess the effects of oxymetazoline on the quantity or rate of breastmilk production, or 
to establish the level of oxymetazoline present in human breastmilk post-dose. Oxymetazoline was detected in the 
milk of lactating rats. The developmental and health benefits of breastfeeding should be considered along with the 
mother’s clinical need for RHOFADE and any potential adverse effects on the breastfed child from RHOFADE or from 
the underlying maternal condition. 
 
8.4 
Pediatric Use 
Safety and effectiveness of RHOFADE have not been established in pediatric patients below the age of 18 years. 
 
8.5 
Geriatric Use 
One hundred and ninety-three subjects aged 65 years and older received treatment with RHOFADE (n = 135) or vehicle 
(n = 58) in clinical trials. No overall differences in safety or effectiveness were observed between subjects > 65 years of 
age and younger subjects, based on available data. Clinical studies of RHOFADE did not include sufficient numbers of 
subjects aged 65 and over to determine whether they respond differently from younger subjects. 
 
10 
OVERDOSAGE 
RHOFADE is not for oral use. If oral ingestion occurs, seek medical advice. Monitor patient closely and administer 
appropriate supportive measures as necessary. Accidental ingestion of topical solutions (nasal sprays) containing 
imidazoline derivatives (e.g., oxymetazoline) in children has resulted in serious adverse events requiring hospitalization, 
including nausea, vomiting, lethargy, tachycardia, decreased respiration, bradycardia, hypotension, hypertension, 
sedation, somnolence, mydriasis, stupor, hypothermia, drooling, and coma. Keep RHOFADE out of reach of children. 
 
11 
DESCRIPTION 
RHOFADE (oxymetazoline hydrochloride) cream 1% contains oxymetazoline hydrochloride, an alpha1A adrenoceptor 
agonist. RHOFADE is a white to off-white cream. It has a chemical name of 3-[(4,5-Dihydro- 1H-imidazol-2-yl)methyl]-6-
(1,1-dimethylethyl)-2,4-dimethyl-phenol hydrochloride and a molecular weight of 
296.8. It is freely soluble in water and ethanol and has a partition coefficient of 0.1 in 1-octanol/water. The molecular 
formula of oxymetazoline HCl is C16H25ClN2O and its structural formula is: 
 
 
Each gram of RHOFADE (oxymetazoline hydrochloride) cream contains 10 mg (1%) oxymetazoline hydrochloride, 
equivalent to 8.8 mg (0.88%) of oxymetazoline free base. The cream contains the following inactive ingredients: sodium 
citrate dihydrate, citric acid anhydrous, disodium edetate dihydrate, butylated hydroxytoluene, anhydrous lanolin, medium 
chain triglycerides, diisopropyl adipate, oleyl alcohol, polyethylene glycol 300, PEG-6 stearate, glycol stearate, PEG-32 
stearate, cetostearyl alcohol, ceteareth-6, stearyl alcohol, ceteareth-25, methylparaben, propylparaben, phenoxyethanol, 
and purified water. 


 
 
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12 
CLINICAL PHARMACOLOGY 
12.1 
Mechanism of Action 
Oxymetazoline is an alpha1A adrenoceptor agonist.  Oxymetazoline acts as a vasoconstrictor. 
 
12.2 
Pharmacodynamics 
The pharmacodynamics of RHOFADE has not been studied. 
 
12.3 
Pharmacokinetics 
Absorption 
The pharmacokinetics of oxymetazoline was evaluated following topical administration of RHOFADE in a thin layer to 
cover the entire face in adult subjects with erythema associated with rosacea. The median weight of cream for each dose 
administration was 0.3 g. Plasma oxymetazoline concentrations were measurable in most of the subjects. Following the 
first dose application, the mean ± standard deviation (SD) peak concentrations (Cmax) and area under the concentration-
time curves from time 0 to 24 hours (AUC0-24hr) were 60.5 ± 53.9 pg/mL and 895 ±798 pg*hr/mL, respectively. Following 
once daily applications for 28 days, the mean ± SD Cmax and AUC0-24hr were 66.4 ± 67.1 pg/mL and 1050 ± 992 
pg*hr/mL, respectively. Following twice daily applications (twice the recommended frequency of application) for 28 days, 
the mean ± SD Cmax and AUC0-24hr were 68.8 ± 61.1 pg/mL and 1530 ± 922 pg*hr/mL, respectively. 
Distribution 
An in vitro study demonstrated that oxymetazoline is 56.7% to 57.5% bound to human plasma proteins. 
Metabolism 
In vitro studies using human liver microsomes showed that oxymetazoline was minimally metabolized, generating 
mono-oxygenated and dehydrogenated products of oxymetazoline. The percentage of parent drug oxymetazoline 
remaining was 95.9% after a 120-minute incubation with human liver microsomes. 
Excretion 
The excretion of oxymetazoline following administration of RHOFADE has not been characterized in humans. 
Drug Interaction 
In vitro studies using human liver microsomes demonstrated that oxymetazoline up to the tested concentration of 100 
nM had no inhibition on the activities of the cytochrome P450 (CYP) isoenzymes 1A2, 2B6, 2C8, 2C9, 2C19, 2D6, and 
3A4/5. Treatment of cultured human hepatocytes with up to 100 nM oxymetazoline did not induce CYP1A2, CYP2B6, or 
CYP3A4. 
 
13 
NONCLINICAL TOXICOLOGY 
13.1 
Carcinogenesis, Mutagenesis, Impairment of Fertility 
Oxymetazoline hydrochloride was not associated with an increased incidence of neoplastic or proliferative changes in 
transgenic mice given oral doses of 0.5, 1.0, or 2.5 mg/kg/day oxymetazoline hydrochloride for 6 months. 
Oxymetazoline hydrochloride revealed no evidence of mutagenic or clastogenic potential based on the results of two in 
vitro genotoxicity tests (Ames assay and human lymphocyte chromosomal aberration assay) and one in vivo gentoxicity 
test (mouse micronucleus assay). 


 
 
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Effects on fertility and early embryonic development were evaluated in rats following oral administration of 0.05, 0.1, or 0.2 
mg/kg/day oxymetazoline hydrochloride prior to and during mating and through early pregnancy. Decreased number of 
corpora lutea and increased post-implantation losses were noted at 0.2 mg/kg/day oxymetazoline hydrochloride (3 times 
the MRHD on an AUC comparison basis). However, no treatment related effects on fertility or mating parameters were 
noted at 0.2 mg/kg/day oxymetazoline hydrochloride (3 times the MRHD on an AUC comparison basis). 
 
14 
CLINICAL STUDIES 
RHOFADE was evaluated for the treatment of persistent erythema associated with rosacea in two identical, 
randomized, double-blind, vehicle-controlled, parallel-group clinical trials. The trials enrolled 885 subjects aged 18 
years and older. Overall, 90% of subjects were Caucasian and 79% were female. Subjects applied either RHOFADE 
or vehicle once daily for 29 days. 
Disease severity was graded by the clinician using a 5-point clinician erythema assessment (CEA) scale and by the 
subject on a similar 5-point subject self-assessment (SSA) scale, on which subjects scored either “moderate” or “severe” 
on both scales. 
CEA and SSA were measured over a 12-hour period at equally-spaced timepoints (hours 3, 6, 9, and 12) post- dose on 
Days 1, 15, and 29. The primary efficacy endpoint was defined as the proportion of subjects with at least a 2-grade 
reduction in erythema (improvement) from baseline (pre-dose on Day 1) on both the CEA and SSA measured at hours 
3, 6, 9, and 12 on Day 29. The results from both trials on the composite endpoint for Day 29 are presented in Table 2. 
 
Table 2: Proportion of Subjects Achieving Composite Success*  on Day 29 
 
Time-point 
(Hour) 
Trial 1 
Trial 2 
RHOFADE Cream 
Vehicle Cream 
RHOFADE Cream 
Vehicle Cream 
(N=222) 
(N=218) 
(N = 224) 
(N=221) 
3 
12% 
6% 
14% 
7% 
6 
16% 
8% 
13% 
5% 
9 
18% 
6% 
16% 
9% 
12 
15% 
6% 
12% 
6% 
*Composite success is defined as the proportion of subjects achieving at least a 2-grade improvement on both CEA 
and SSA. 
 
16 
HOW SUPPLIED/STORAGE AND HANDLING 
RHOFADE (oxymetazoline hydrochloride) cream, 1%, is a white to off-white cream. The product is available in a 
laminated tube and an airless pump polypropylene bottle in the following packaging configurations, each with a child-
resistant closure: 
 
NDC 0023-5300-30 
30 gram tube 
NDC 0023-5300-60 
60 gram tube 
NDC 0023-5300-35 
30 gram pump 
NDC 0023-5300-65 
60 gram pump 
Storage: Store at 20°C-25°C (68°F-77°F); excursions permitted to 15°C-30ºC (59°F-86ºF) [see USP Controlled Room 
Temperature]. 


 
 
TEVA Pharmaceuticals USA,Inc. 
Protocol No.: OXY2018-01 
 
 
 
Version No.: 3.0;  
 
 
 
29 JAN 2020
 
Confidential 
 
Page 94 of 102
 
17 
PATIENT COUNSELING INFORMATION 
Advise the patient and/or caregiver to read the FDA-approved patient labeling (Patient Information and 
Instructions for Use). 
Important 
Administration 
Instructions 
Advise patients of the following: 
x RHOFADE is for topical use only. 
x RHOFADE pumps require priming before initial use and discard product from the first three pumps. 
x Do not to apply RHOFADE to irritated skin or open wounds. 
x Avoid contact with the eyes and lips. 
x Wash hands immediately after application. 
x Keep RHOFADE out of reach of children. 
 
Manufactured for Allergan, Irvine, CA 92612, U.S.A. by 
DPT Laboratories, Ltd, San Antonio, TX 78215 
 
© 2017 Allergan. All rights reserved. 
Irvine, CA 92612 
All trademarks are the property of their respective owners. Patented. See 
www.allergan.com/patents 
Made in the U.S.A. 
 
73141US10 


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PATIENT 
INFORMATION 
RHOFADE™ (roe' fayd) 
(oxymetazoline hydrochloride) 
Important: RHOFADE cream is for skin (topical) use on the face only. Do not use RHOFADE cream in your eyes, mouth, or 
vagina. 
Keep RHOFADE cream out of the reach of children. 
Get medical help right away if you, a child, or anyone else swallows RHOFADE cream. 
What is RHOFADE cream? 
RHOFADE cream is a prescription medicine used on the skin (topical) to treat facial redness due to rosacea that does not go away 
(persistent) in adults. 
It is not known if RHOFADE cream is safe and effective in children under 18 years of age. 
Before you use RHOFADE cream, tell your healthcare provider about all of your medical conditions, including if you: 
x 
have heart, blood vessel, or blood pressure problems. Call your healthcare provider or get medical help if these conditions 
worsen. 
x 
have problems with blood circulation or have had a stroke 
x 
have Sjögren’s Syndrome 
x 
have scleroderma 
x 
have Raynaud’s phenomenon 
x 
have thromboangiitis obliterans 
x 
have narrow-angle glaucoma. Call your healthcare provider or get medical help if your glaucoma worsens. 
x 
have irritated skin or open sores on the face 
x 
are pregnant or plan to become pregnant. It is not known if RHOFADE cream will harm your unborn baby. 
x 
are breastfeeding. It is not known if RHOFADE cream passes into your breast milk. Talk to your healthcare provider about the 
best way to feed your baby if you use RHOFADE cream. 
Tell your healthcare provider about all the medicines you take, including prescription and over-the-counter medicines, skin 
products, vitamins, and herbal supplements. Using RHOFADE cream with certain other medicines may affect each other and can 
cause serious side effects. 
How should I use RHOFADE cream? 
x 
See the detailed Instructions for Use that comes with your RHOFADE cream tube or pump for information about how to 
apply RHOFADE cream correctly. 
x 
Use RHOFADE cream exactly as your healthcare provider tells you. Do not use more RHOFADE cream than 
prescribed. 
x 
RHOFADE cream is for use on your skin only. Do not use RHOFADE cream in your eyes, mouth, or vagina. Avoid contact 
with your lips and eyes. 
x 
Do not apply RHOFADE cream to irritated skin or open wounds. 
What are the possible side effects of RHOFADE cream? 
The most common side effects of RHOFADE cream include application site reactions of: 
x 
skin reactions (dermatitis) 
x 
itching 
x 
pain 
x 
worsening of rosacea pimples 
x 
redness 
These are not all the possible side effects of RHOFADE cream. 
Call your doctor for medical advice about side effects. You may report side effects to FDA at 1-800-FDA-1088. 
How should I store RHOFADE cream? 
x 
Store RHOFADE cream at room temperature between 68°F to 77°F (20°C to 25°C). 
Keep RHOFADE cream and all medicines out of the reach of children. 


TEVA Pharmaceuticals USA,Inc. 
Protocol No.: OXY2018-01 
 
 
 
Version No.: 3.0;  
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General information about the safe and effective use of RHOFADE cream 
Medicines are sometimes prescribed for purposes other than those listed in a Patient Information leaflet. Do not use RHOFADE 
cream for a condition for which it was not prescribed. Do not give RHOFADE cream to other people, even if they have the same 
symptoms that you have. It may harm them. You can ask your pharmacist or healthcare provider for information about RHOFADE 
cream that is written for health professionals. 
 
This Patient Information has been approved by the U.S. Food and Drug Administration                                                 Approved: 01/2017 
73141US10 
 
 
What are the ingredients in RHOFADE cream? Active 
ingredient: oxymetazoline hydrochloride 
Inactive ingredients: sodium citrate dihydrate, citric acid anhydrous, disodium edetate dihydrate, butylated 
hydroxytoluene, anhydrous lanolin, medium chain triglycerides, diisopropyl adipate, oleyl alcohol, polyethylene glycol 300, PEG-
6 stearate, glycol stearate, PEG-32 stearate, cetostearyl alcohol, ceteareth-6, stearyl alcohol, ceteareth-25, methylparaben, 
propylparaben, phenoxyethanol, and purified water 
Manufactured for Allergan, Irvine, CA 92612, U.S.A. by 
DPT Laboratories, Ltd, San Antonio, TX 78215 
© 2017 Allergan. All rights reserved. Irvine, CA 92612, U.S.A. 
All trademarks are the property of their respective owners. Patented. See www.allergan.com/patents. Made in 
the U.S.A. 


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Appendix-III: SAE Form 
 


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Version No.: 3.0;  
29 JAN 2020
 
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Version No.: 3.0;  
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Protocol No.: OXY2018-01 
 
 
 
Version No.: 3.0;  
29 JAN 2020
 
Confidential 
 
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Appendix-IV: Pregnancy Form 
 


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29 JAN 2020
 
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SAP_001.pdf: 
 
Statistical Analysis Plan 
 
Study code 
OXY2018-01 
 
Version 
Amendment 1 Final 
 
Date 
Feb18, 2020 
 
 
 
 
 
 
 
 
 
 
 
 
A RANDOMIZED, DOUBLE-BLIND, PARALLEL-GROUP, THREE-
ARM, PLACEBO-CONTROLLED, MULTI-SITE THERAPEUTIC 
EQUIVALENCE STUDY WITH CLINICAL END-POINTS 
COMPARING TEST PRODUCT “OXYMETAZOLINE 
HYDROCHLORIDE CREAM, 1%” TO REFERENCE PRODUCT 
“RHOFADE™ CREAM, 1%” IN THE TREATMENT OF MODERATE 
TO SEVERE PERSISTENT FACIAL ERYTHEMA OF ROSACEA 
 
 
 
 
Study Statistician 
 
 
 
 
   
 
Date  
 
 
Sponsor Representative 
 
 
 
   
   
 
Date 
 
 
 
 
 
 
 
 
 
 
 
 


Statistical Analysis Plan  
Study Code OXY2018-01 
Version Amendment 1 Final  
Date Feb18, 2020 
2 
TABLE OF CONTENTS 
PAGE 
TITLE PAGE ............................................................................................................................ 1 
TABLE OF CONTENTS ......................................................................................................... 2 
LIST OF ABBREVIATIONS .................................................................................................. 4 
1. 
INTRODUCTION ................................................................................................... 5 
2. 
OBJECTIVES .......................................................................................................... 5 
3. 
STUDY OVERVIEW .............................................................................................. 6 
3.1 
Study Design ............................................................................................................ 6 
3.2 
Sample Size .............................................................................................................. 7 
3.3 
Randomization and Unblinding Procedures ............................................................ 8 
4. 
STUDY ENDPOINTS/OUTCOMES ...................................................................... 9 
5. 
HYPOTHESES TESTING ...................................................................................... 9 
6. 
ANALYSIS SUBSETS .......................................................................................... 10 
6.1 
Safety Population ................................................................................................... 10 
6.2 
Modified Intent to Treat Population (mITT Population) ....................................... 10 
6.3 
Per Protocol Population (PP Population) ............................................................... 10 
7. 
STATISTICAL METHODS OF ANALYSIS ....................................................... 11 
7.1 
General Principles .................................................................................................. 11 
7.2 
Subject Disposition ................................................................................................ 12 
7.3 
Demographic and Baseline Characteristics............................................................ 12 
7.4 
Medical History ..................................................................................................... 13 
7.5 
Protocol Deviations ................................................................................................ 14 
7.6 
Efficacy Analyses .................................................................................................. 14 
7.6.1 
Site Pooling ............................................................................................................ 14 
7.6.2 
Derivation of the Primary Endpoint ....................................................................... 15 
7.6.3 
Analyses of Primary Endpoints ............................................................................. 15 
7.7 
Safety Analyses ...................................................................................................... 16 
7.7.1 
Adverse Events ...................................................................................................... 16 
7.7.2 
Application Site Reactions ..................................................................................... 17 
7.7.3 
Vital Signs .............................................................................................................. 17 
7.7.4 
Physical Examination ............................................................................................. 18 
7.7.5 
Exposure to Product ............................................................................................... 18 
7.7.6 
Exposure to Concomitant Medication ................................................................... 19 


Statistical Analysis Plan  
Study Code OXY2018-01 
Version Amendment 1 Final  
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3 
8. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES ............................... 20 
9. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS ............................. 21 
10. 
LITERATURE CITATIONS  REFERENCES ..................................................... 21 
11. 
APPENDICES ....................................................................................................... 22 
11.1 
Study visit Schedule ............................................................................................... 22 
11.2 
Code Fragments ..................................................................................................... 23 
 


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4 
LIST OF ABBREVIATIONS 
Abbreviation or 
special term 
Explanation 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
ATC 
Anatomic-therapeutic-chemical 
BMI 
Body Mass Index 
CEA 
Clinical Erythema Assessment 
CI 
Confidence Interval 
CMH 
Cochran-Mantel-Haenszel 
eCRF 
Electronic Case Report Form 
EoT 
End of Treatment 
FDA 
Food and Drug Administration 
HEENT 
Head, eyes, ears, nose, throat 
ICF 
Informed Consent Form 
IWRS 
Interactive Web Response System 
LS 
Least Squares 
MedDRA 
Medical Dictionary for Regulatory Activities 
mITT 
Modified Intent to Treat 
NDA 
New Drug Application 
PP 
Per Protocol 
PT 
Preferred Term 
RLD 
Reference Listed Drug 
SAP 
Statistical Analysis Plan 
SD 
Standard Deviation 
SOC 
System Organ Class 
SSA 
Subject Self-Assessment 
TEAE 
Treatment-Emergent Adverse Event 
WHODRUG 
World Health Organization Drug Dictionary 
 


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5 
1. 
INTRODUCTION 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses that have been outlined within the protocol "A Randomized, Double-blind, Parallel-
group, Three-arm, Placebo-controlled, Multi-Site Therapeutic Equivalence Study with 
Clinical End-points Comparing Test Product “Oxymetazoline hydrochloride Cream, 1%” to 
Reference Product “RHOFADE™ Cream, 1%” in the Treatment of Moderate to Severe 
Persistent Facial Erythema of Rosacea", version 3.0, dated January 29, 2020. 
This therapeutic equivalence study with clinical endpoint is designed to determine the 
therapeutic equivalence of Oxymetazoline hydrochloride Cream, 1% (manufactured by 
Actavis Laboratories, Salt Lake City, UT) with the reference listed drug (RLD) RHOFADE™ 
(Oxymetazoline hydrochloride Cream, 1%) marketed by Allergan, in healthy males and non-
pregnant females diagnosed with moderate to severe persistent facial erythema of rosacea. 
This document will give a description of the planned methods of the analysis. 
2. 
OBJECTIVES 
The primary objectives of this study are: 
- 
To establish the therapeutic equivalence between Test Product (Oxymetazoline 
hydrochloride Cream, 1%, manufactured by Actavis Laboratories, Salt Lake City, UT) 
and Reference Product (RHOFADE™ Cream, 1%, Allergan) on Day 29, in subjects 
with moderate to severe persistent facial erythema of rosacea. 
- 
To demonstrate superiority of the efficacy of the two active treatments over the 
placebo control.  
The secondary (safety) objective of this study is: 
- 
To monitor adverse events (AEs) and assess the safety and tolerability of Test Product 
and Reference Product in subjects with moderate to severe persistent facial erythema 
of rosacea. 


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3. 
STUDY OVERVIEW 
3.1 
Study Design 
This is a multi-center, randomized, double-blind, parallel-group, three-arm, placebo-
controlled, therapeutic equivalence study with clinical endpoints. The study will compare the 
efficacy and safety of test product “Oxymetazoline hydrochloride Cream, 1%” (manufactured 
by Actavis Laboratories, Salt Lake City, UT) with that of an approved topical formulation 
RHOFADE™ (Oxymetazoline hydrochloride Cream, 1%) marketed by Allergan, in healthy 
males and non-pregnant females diagnosed with moderate to severe persistent facial erythema 
of rosacea. Both the test and the reference formulations will also be compared to a placebo 
(vehicle) formulation to test for superiority. 
Subjects with a confirmed diagnosis of moderate to severe persistent facial erythema of 
rosacea will be randomized to either Test Group (Oxymetazoline hydrochloride Cream, 1%); 
Reference Group (RHOFADE™, Oxymetazoline hydrochloride Cream, 1%); or Placebo 
Group (Vehicle Cream).  
The study subjects will receive treatment for approximately 29
 days from the Baseline visit 
to the End of Treatment (EoT) visit. There will be 4 study visits, 3 to the study site and 1 
telephone follow-up: 
- 
Screening 
  
- 
Baseline (Day 1
) 
- 
Telephone Follow-up (Day 14
) 
- 
End of Treatment (Day 29
) 
At screening a written Informed Consent Form (ICF) has to be signed by the subject and the 
eligibility criteria of the subject will be evaluated by clinical assessments. 
 
 
 
. Subjects should sign ICF prior to start of any study procedures, complete 
washout, and return to the clinic to conduct the remainder of the screening procedures. 


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Study subject numbers will be assigned to study subjects sequentially in the order in which 
study subjects are enrolled into the study.  
After the screening visit, each qualified subject will return to the clinic on Day 1 for 
confirmation of eligibility. Eligible subjects will be assigned to one of the three study 
treatment groups as per the computer-generated randomization schedule, and the assigned 
study medication will be dispensed by the study site staff. Since this is a double-blind study, 
neither the study team at the site nor the subjects will know the treatment the subject is 
assigned. 
The subject will be instructed to apply a pea-size amount of the study treatment to cover the 
entire face (forehead, chin, nose, and each cheek [avoiding the eyes and lips]), once daily 
preferably, at the same time each day, up to and including the day before scheduled Visit 4 
(Day 29±2). 
 
. On Day 1 visit and Day 29±2 visit, the 
subject will apply the assigned medication at the clinic under the supervision of an 
Independent Dispenser (unblinded to the treatment the subject is receiving). 
 
 
). From Day 2 up to and including the day before scheduled 
Visit 4 (Day 29
), the subject will be asked to self-apply the assigned medication once daily 
and complete the subject diary, handed over by the study site staff at Baseline visit. The 
subject will note the date and time of application of the study medication, any AE 
experienced, and any concomitant medication taken or changes from the existing ones, in the 
subject diary from Visit 2 (Day 1) to Visit 4 (Day 29
). A phone call will be made around 
Day 14 to follow up for any change in concomitant medications, and check on compliance of 
study medication usage. 
3.2 
Sample Size  
 
 
 
 


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8 
 
 
 
 
 
• 
 
 
 
 
 
 
 
• 
 
 
 
 
 
 
 
 
 
 
. 
3.3 
Randomization and Unblinding Procedures  
Subjects will be randomly assigned in a treatment allocation ratio of 1:1:1 to receive the Test 
product or the Reference Product or the Placebo control, respectively. The randomization 
schedule for this study will be generated by a third-party vendor such that a non-study-
assigned independent expert will allocate the subjects to one of the three treatment arms using 
a computer-generated automated process, 
. A copy of the randomization scheme 


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(respective to that site) will be retained at the study site following the completion of the study 
and should be available to regulatory authority inspectors at the time of site inspection to 
allow for verification of the treatment identity of each subject. 
The Investigator, staff at the study site, study monitors, and data analysis/management 
personnel will be blinded to the treatment assigned to the subject. Only the Independent 
Dispenser will have access to the study medication, but their primary responsibilities will be 
limited to dispensing, collecting and observing and supervising the administration of the study 
medication by the subject on clinical visits. They will not participate in any activities.  
In case of an emergency, if the details of the study drug are required for management of an 
emergency as per the opinion of Investigator, the Investigator can unblind the product that is 
received by the subject during the study. 
At the conclusion of the study, after the database has been locked, each site will be sent the 
study randomization scheme (respective to their site) that should be retained with the study 
documents in the event of an FDA inspection along with evidence of when the randomization 
scheme was provided. 
4. 
STUDY ENDPOINTS/OUTCOMES 
Primary Efficacy Endpoint 
The primary efficacy endpoint is the proportion of subjects with treatment success at all time-
points 3, 6, 9, and 12 hours post application on Day 29. Treatment success is defined as 
having CEA score at least 2 grades lower than the baseline (Day 1 pre-dose) value.  
Safety Endpoints 
Safety endpoints include incidence of AEs. 
5. 
HYPOTHESES TESTING 
Hypothesis of Equivalence 
A two-sided, continuity-corrected 90% confidence intervals on the Test-vs-Reference 
difference for the proportion of subjects with treatment success at all timepoints (3, 6, 9 and 
12 hours post-application on Day 29) will be constructed. Therapeutic equivalence will be 


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Study Code OXY2018-01 
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10 
established if the 90% confidence interval for the difference is contained within the interval [-
0.20, +0.20] for the PP population. 
Hypothesis of Superiority 
The null hypotheses to be tested are that there is no difference in the proportions of subjects 
with treatment success at all time-points (3, 6, 9 and 12 hours post-application on Day 29).  
The evaluation of superiority will be conducted separately for the Test treatment versus the 
Placebo treatment and for the Reference treatment versus the Placebo treatment.  The analysis 
will be conducted using two-sided, α = 0.05, exact CMH test stratified by study site.  
Superiority will be established if the success proportion for each active treatment is greater 
than, and statistically different from, that of the Placebo for the mITT population. 
6. 
ANALYSIS SUBSETS 
6.1 
Safety Population 
The safety population includes all randomized subjects who applied at least 1 dose of study 
medication in the study, as recorded in the subject diary.  
The safety population will be the primary population for the safety analysis. 
6.2 
Modified Intent to Treat Population (mITT Population) 
The mITT population includes all randomized subjects who met all the inclusion and none of 
the exclusion criteria, have a CEA measurement at baseline (i.e. pre-dose on Day 1), applied 
at least one dose of study treatment, and have at least one post-baseline measurement for CEA 
or discontinue due to lack of treatment effect after completing 2 days of treatment. 
This population will be used for analyses of superiority. 
6.3 
Per Protocol Population (PP Population) 
The PP population includes all subjects in the mITT population who have no major protocol 
deviations/violations that would affect the treatment evaluation.  
See section 7.5 for more details on protocol deviations and how they affect exclusion from the 
PP population. 


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The PP population will be used for analyses of therapeutic equivalence. 
7. 
STATISTICAL METHODS OF ANALYSIS 
7.1 
General Principles 
 
 
  
In general, all data will be listed by treatment group, subject and visit/time-point where 
appropriate.  The summary tables will also be stratified by, or have columns corresponding to, 
treatment groups. 
All subjects will be identified by their unique subject numbers.  Data from the screen failures 
will not be included in tables, listings, or figures. 
The total number of subjects in the study group (N) under the stated population will be 
displayed in the header of summary tables. 
Data will be summarized using descriptive statistics for continuous variables.  Unless 
otherwise specified, descriptive statistics will include number of subjects, mean, standard 
deviation (SD), minimum, median, and maximum.  The minimum and maximum statistics 
will be presented to the same number of decimal places as the original data.  The mean and 
median will be presented to one more decimal place than the original data.  The standard 
deviation will be presented to two more decimal places than the original data.  The number of 
missing observations will be presented only if non-zero. 
In summary tables of categorical variables, counts, and percentages will be used.  The count 
[n] indicates the actual number of subjects in a particular category, which should always be 
less than or equal to the total number of subjects in the respective study group with known 
(non-missing) category [M].  Percentage will be obtained by: % = n/M*100.  Unless otherwise 
specified, all percentages will be expressed to one decimal place. 
All statistical tests will be two-sided at a significance level of α = 0.05, unless otherwise 
indicated.  No adjustment will be made for multiplicity. 


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Unless otherwise specified below, baseline for an assessment will be defined as the last 
available assessment obtained prior to the first application of the study drug. 
 
 
 
In by-visit summaries only scheduled visits/time-points will be presented. Unscheduled 
assessments will not be included in by-visits summaries, however, will be shown in listings 
and may be used in selecting the baseline, if applicable. 
Relative days will be calculated relative to the date of the first dose of the study medication.  
Relative days will be calculated as follows only when the full assessment date is known (i.e., 
partial dates will have missing relative days). 
For assessment on or after the day of the first dose of the study drug: 
Relative Day = Date of Assessment – Date of First Dose of Study Drug+1. 
For assessment before the day of the first dose of the study drug: 
Relative Day = Date of Assessment – Date of First Dose of Study Drug. 
All dates will be displayed in DDMMMYYYY format. 
7.2 
Subject Disposition 
The number of subjects screened in the study, randomized to treatment, included in the Safety, 
PP, mITT populations, prematurely discontinued from the study (along with the reasons for 
discontinuation) will be calculated.  The percentages will be based on the number of subjects 
randomized to each treatment group.  Percentages for discontinuation reasons will be based on 
the sub-population of subjects who discontinued from the study. 
Number and percentage of subjects enrolled by site will be tabulated for all enrolled subjects, 
Safety, mITT, and PP populations. 
7.3 
Demographic and Baseline Characteristics 
Demographic characteristics will include: 
• age;  


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• gender;  
• race;  
• ethnicity; 
Baseline characteristics include: 
• Height, weight and BMI; 
• Time since rosacea diagnosis (years). 
• Baseline CEA score; 
• Baseline SSA score; 
Descriptive statistics will be presented for age (years), height, weight, BMI and time since 
diagnosis (years).  Frequency counts and percentages will be presented for race, ethnicity, and 
baseline CEA and SSA score. Height will be reported in centimeters and weight in kilograms. 
Age will be derived from Informed Consent Signed Date and Date of Birth as the number of 
whole years between those two dates. 
Demographic and baseline/randomization characteristics will be evaluated for comparability 
across treatment groups in the following manner.  Continuous variables (age, height, weight, 
BMI, time since diagnosis) will be analyzed with an ANOVA with factors of treatment and 
investigational site.  Overall p-value for the global null hypothesis of all groups being equal 
will be displayed.  Categorical variables (gender, ethnicity, race, CEA and SSA scores) will be 
analyzed with a Cochran-Mantel-Haenszel, stratified by investigational site. For gender, 
ethnicity, race, CMH general association statistic will be used. For CEA and SSA scores, 
“mean scores differ” statistic will be used. 
All parameters reported during screening or baseline phase (including informed consent 
information, inclusion/exclusion criteria, randomization information, method of contraception, 
etc.) will be presented in by-subject listings. 
7.4 
Medical History 
Medical history terms will be coded using MedDRA version 22.0. 
Medical and surgical history other than rosacea history will be summarized by MedDRA 
system organ class, preferred term and treatment group.  One subject will be counted only 


Statistical Analysis Plan  
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14 
once under each applicable system organ class and preferred term. System organ classes and 
preferred terms will be presented alphabetically. 
7.5 
Protocol Deviations 
 
 
 
 
 
 
Specific deviations and their severities are defined in the separate Protocol Deviations List 
document. 
Protocol deviations will be summarized by deviation type and treatment group.  This analysis 
will be performed for all randomized subjects. 
7.6 
Efficacy Analyses  
7.6.1 
Site Pooling 
To eliminate potential effect of random fluctuations at a small site on the primary endpoint 
small sites will be pooled.  
 
 
 
 
 
 
 
 
 
Pooled sites will be used in all the efficacy analyses. 


Statistical Analysis Plan  
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15 
7.6.2 
Derivation of the Primary Endpoint 
A subject is defined as achieving treatment success at a time-point if the CEA score is at least 
2 grades lower than the baseline value of the score. In this case baseline is defined as the pre-
dose assessment on Day 1. To achieve the primary endpoint, the subject needs to have 
treatment success at all 4 post-application timepoints (3, 6, 9 and 12 hours) on Day 29. 
The CEA score at all post-application time-points on Day 29 as well as the pre-treatment 
assessment on Day 1 are required to determine the primary endpoint. 
 
 
 
 
 
7.6.3 
Analyses of Primary Endpoints  
Proportion of subjects achieving the primary endpoint will be presented by treatment. 
Also, proportions of subjects with treatment success will be presented by visit (Day 1 or Day 
29), time-points and treatment. 
7.6.3.1 
Analysis of Therapeutic Equivalence of Test and Reference Treatments 
Two-sided, continuity-corrected, 90% confidence intervals on the Test-vs-Reference 
difference for the proportion of subjects with treatment success at all timepoints on Day 29 
will be constructed.  Therapeutic equivalence will be established if the 90% confidence 
interval for the difference is contained within the interval [-0.20, +0.20] for the PP population. 
7.6.3.2 
Analysis of Superiority to Placebo Control 
The evaluation of superiority will be conducted separately for the Test treatment versus the 
Placebo treatment and for the Reference treatment versus the Placebo treatment, comparing 
the proportions of subjects with treatment success at all time-points on Day 29.  The analysis 
will be conducted using two-sided exact CMH test stratified by site.  
Superiority will be established if the success proportion for each active treatment is greater 
than, and statistically significantly different from (p < 0.05 for the exact CMH test) that of the 


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Placebo for the mITT population.  Analysis of superiority will be performed on the mITT 
population.   
7.7 
Safety Analyses 
7.7.1 
Adverse Events  
Adverse Events will be coded using the MedDRA Version 22.0 AE coding system for 
purposes of summarization. 
Only Treatment Emergent Events (TEAEs) will be used for the summary analysis.  An AE 
will be considered as treatment-emergent if the time of onset is after the time of the first study 
drug administration or if it increased in severity during the study period.  AEs with unknown 
start dates will be counted as treatment-emergent unless the AE resolution date is prior to the 
study drug start date.  If the start date is partially missing, then month and year (when 
available) will be used to determine if the event occurred prior to or post dosing. 
Pre-treatment AEs will be listed only. 
A TEAE is defined as treatment-related if it is recorded as related to the study medication on 
the eCRF.  In case the relatedness was not assessed, the most conservative result (related) will 
be chosen for the analysis.  
An overall summary will include, by treatment group and overall, the number of TEAEs and 
the number and percentage of subjects reporting at least 1 TEAE in the following categories: 
- 
Any TEAE 
- 
Treatment-related TEAE 
- 
Serious TEAE 
- 
TEAE leading to discontinuation of the study medication 
- 
TEAE leading to death. 
The following TEAE frequency tables will be prepared summarizing the overall number of 
TEAEs, the number and percentage of subjects reporting at least one TEAE by MedDRA SOC 
and PT: 
- 
All TEAEs, 
- 
Serious TEAEs 


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- 
AEs leading to discontinuation of the study drug 
- 
TEAEs by Severity 
- 
TEAEs by Relationship to Study Drug. 
A subject experiencing the same AE (the same preferred term) multiple times will only be 
counted once for that preferred term.  Similarly, if a subject experiences multiple AEs within 
the same system organ class, that subject will be counted only once in that system organ class.  
AEs summaries will be presented in alphabetical order of SOC and preferred terms. When 
summarizing AEs by severity, only the most severe occurrence within the preferred term or 
system organ class will be used. Similarly, when summarizing AEs by relationship to study 
drug, only the most related occurrence within the preferred term or system organ class will be 
selected for displays in summary tables. 
Additionally, TEAEs will be summarized by the preferred terms in the descending order of 
frequency in the total treatment group.  In this table a p-value from Fisher's exact test 
comparing event rates between the Test and the Reference treatment groups will be provided 
for those preferred terms that have frequency > 1% in either Test or Reference group. 
All information pertaining to adverse events noted during the study will be listed by subject, 
detailing verbatim, preferred term, system organ class, start date, stop date, intensity, outcome, 
action taken, and causal relationship to the study drug.   
7.7.2 
Application Site Reactions 
At Baseline Visit (Day 1) and End of Treatment visit (Day 29) subjects will be evaluated for 
signs and symptoms of application site reactions, 
 
  
  
Number and percentage of subjects with each severity will be presented by visit, 
sign/symptom and treatment. 
7.7.3 
Vital Signs 
Vital signs, including blood pressure, heart rate and body temperature will be recorded at 
screening; at pre-dose and 12 hours post-dose on Day 1; and at pre-dose and 12 post-dose 


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hours on Day 29. Overall interpretation (normal, abnormal not clinically significant or 
abnormal clinically significant) will also be recorded. 
Vital sign measurements can be repeated. Repeats will be handled as follows. At the screening 
visit the latest repeat will be used for analysis. On Day 1 and Day 29 the latest repeat obtained 
prior to dosing will be used for analysis at the pre-dose time-point and the latest repeat 
obtained after dosing will be used for analysis at the 12-hour post-dose time-point. 
Vital signs and their changes from baseline will be summarized descriptively by visit and 
treatment. Overall interpretation will also be summarized. All results will be listed. 
7.7.4 
Physical Examination 
Physical examination will be performed at screening and Day 29 visit. The following body 
systems will be examined: General Appearance; Skin; HEENT; Heart; Lungs; Muscular-
Skeletal; Lymph nodes; Neurological; Gastrointestinal; Genitourinary; Extremities as well as 
other if necessary. Each system will be classified as normal, abnormal not clinically 
significant or abnormal clinically significant. 
Number and percentage of subjects with each classification will be presented by body system, 
visit and treatment. All results will be listed. 
7.7.5 
Exposure to Product 
The subjects will be instructed to use the diary to document all doses taken. Dosing 
information will be summarized on the eCRF. 
Compliance with scheduled application of the study drug will be determined as [Actual 
number of applications] / [Planned number of applications] * 100%, where 
- 
Actual number of applications will be taken from the eCRF (“Total number of doses 
applied” field in the “Investigational Product Use Compliance” form)  
- 
Planned number of applications is 29. 
Number of missed doses will be calculated as follows.  The number of doses missed in the 
dosing period (between the first and the last study drug application) will be taken directly 
from the eCRF. 
 


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Duration of exposure will be calculated as Date of last use of study medication – Date of first 
use of study medication + 1.  Duration of exposure will be summarized descriptively by 
treatment group. 
Compliance and duration of exposure will be summarized for the Safety and mITT 
populations. 
7.7.6 
Exposure to Concomitant Medication 
Prior and concomitant medications and concomitant non-drug therapies will be assessed at 
baseline and at each subsequent study visit.  The start and stop date of concomitant medication 
use during the study will be provided in the data set, in addition to the reason for the 
medication use.  
Medication or non-drug therapy will be classified as prior, if the end date is known and is 
prior to the first use of the study medication.  Medications and non-drug therapies that are 
ongoing or ended after the first use of the study medication will be classified as concomitant.  
If the end date of the medication or non-drug therapy is unknown, it will also be considered 
concomitant. 


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Concomitant medications will be summarized by ATC class (the highest available level) and 
preferred name for each treatment group as coded by the World Health Organization Drug 
(WHODRUG) dictionary March-2019 B3. Each subject will be counted only once for each 
applicable preferred name and ATC class. Concomitant medications will also be listed in a by-
subject listing.  Prior medications will be listed only. 
8. 
CHANGES FROM PROTOCOL-SPECIFIED ANALYSES  
There are no changes from the protocol-specified analyses. 


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9. 
LIST OF PLANNED TABLES, FIGURES, AND LISTINGS 
See separate document with the table, figure and listing shells. 
10. 
LITERATURE CITATIONS  REFERENCES 
1. Study Protocol: "A Randomized, Double-blind, Parallel-group, Three-arm, Placebo-
controlled, Multi-Site Therapeutic Equivalence Study with Clinical End-points 
Comparing Test Product “Oxymetazoline hydrochloride Cream, 1%” to Reference 
Product “RHOFADE™ Cream, 1%” in the Treatment of Moderate to Severe Persistent 
Facial Erythema of Rosacea", version 3.0, dated January 29, 2020 
2. Draft Guidance on Oxymetazoline Hydrochloride. FDA, November 2019. 
 


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11. 
APPENDICES 
11.1 
Study visit Schedule 
 
 
Visit 1a 
Visit 1b 
Visit 2 
Visit 3 
Visit 4 
Procedures 
Screening 
 
Screening 
 
Day 1 
(Baseline) 
Day 14 
(Telephone 
follow-up)a 
) 
Day 29 (EoT) 
) 
Written informed consent  
X 
 
 
 
 
Demographics (height, 
weight, body mass index 
(BMI), gender, race, 
ethnicity) 
X 
 
 
 
 
Pregnancy test (Urine)  
X 
X 
X 
 
X 
Medical and surgical 
history  
X 
X 
 
 
 
Prior and concomitant 
medications and 
concurrent procedures 
X 
X 
X 
X 
X 
Vital signs measurements 
(blood pressure, heart 
rate, body temperature) 
X 
X 
Pre-dose and 
12 hrs 
 
Pre-dose and 
12 hrs 
Clinician Erythema 
Assessment (CEA)  
X 
X 
Pre-dose, 3, 6, 
9, and 12 hrs 
(± 30 minutes 
at each 
timepoint) 
 
Pre-dose, 3, 6, 
9, and 12 hrs 
(± 30 minutes 
at each 
timepoint) 
Subject Self-Assessment 
(SSA) for rosacea facial 
redness  
X 
X 
Pre-dose, 3, 6, 
9, and 12 hrs 
(± 30 minutes 
at each 
timepoint) 
 
Pre-dose, 3, 6, 
9, and 12 hrs 
(± 30 minutes 
at each 
timepoint) 
Physical examination  
X 
 
 
 
X 
Review of 
Inclusion/Exclusion 
X 
X 
Pre-dose 
(confirm 
eligibility) 
 
 
Randomization  
 
 
X 
 
 
Dispense study 
medication tube  
 
 
X 
 
 
Dosing (Days 1-29)b  
 
 
X 
 
X 
Adverse event 
monitoringc  
X 
X 
X 
X 
X 
Subject diary review 
 
 
X 
 
X 
Confinement in study 
clinic 
 
 
≥12 hrs in 
clinic 
 
≥12 hrs in 
clinic 
Collection of study 
medication tube 
 
 
 
 
X 


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a 14 days after the first dose of study drug, a phone call will be made to follow-up on any 
changes in concomitant medications and check on compliance of study medication usage. 
b Subject will apply study medication once daily preferably at the same time each day from 
Day 2 to Day 28 at home, as instructed. 
c Including monitoring of application site dermatitis, application site pruritus, application site 
erythema, and application site pain, scaling or burning at Visit 2 and Visit 4. 
11.2 
Code Fragments  
Therapeutic equivalence analysis in the primary endpoint 
proc freq data=<dataset> 
tables <treatment>*<success> / riskdiffc; 
run; 
Note: this analysis needs to be performed on a dataset containing test and reference treatment 
subjects only. 
Superiority analysis in the primary endpoint 
ods output ExactTests=ExactTests; 
proc logistic data=<dataset>; 
  class <treatment> / param=ref; 
  model <success> = <treatment>; 
  strata <pooled site>; 
  exact <treatment>; 
run; 
 
Note: p-value from exact CMH test is found in ExactTests dataset, variable ExactPValue. 
Reference for exact CMH test: http://support.sas.com/kb/32/711.html. 
This analysis needs to be performed separately for test and reference treatments on a dataset 
containing only test and placebo or reference and placebo treatment subjects.