Conditions: Rosacea
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 46
Healthy volunteers: no

Brief summary:
This study will evaluate the safety and tolerability of oxymetazoline HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy for participants with moderate to severe persistent facial erythema associated with rosacea.

Detailed description:

Arms:
arm 1: Participants will receive energy-based therapy (Potassium Titanyl Phosphate \[KTP\], Pulsed Dye Laser \[PDL\], or Intense Pulsed Light \[IPL\]) plus once daily application of oxymetazoline hydrochloride (HCl) cream 1.0%.

Interventions: intervention 1: Oxymetazoline HCL 1.0% Cream intervention 2: Energy-Based Therapy
Intervention descriptions: intervention 1: Oxymetazoline HCl cream 1.0% once daily application intervention 2: Energy-based therapies (Potassium Titanyl Phosphate \[KTP\], Pulsed Dye Laser \[PDL\], or Intense Pulsed Light \[IPL\])

Protocol document:
Prot_001.pdf: 
16. 
APPENDICES 
 
16.1 
Study Information 
 
16.1.1 
Protocol and Protocol Amendments 
 


 
 
CLINICAL STUDY PROTOCOL 
Multicenter, Open-Label, Interventional Study on the Safety and 
Tolerability of Oxymetazoline and Energy-Based Therapy in Subjects 
with Rosacea 
Protocol Number: 
CMO-MA-MED-0530 
 
Investigational Product: 
Rhofade (Oxymetazoline Hydrochloride [HCl] cream) 1.0% 
Phase: 
Phase 4 
Sponsor: 
Allergan 
Morris Corporate Center III 
400 Interpace Parkway 
Parsippany, NJ 07054 
United States 
 
Contract Research 
Organization: 
INC Research 
3201 Beechleaf Court 
Suite 600 
Raleigh, NC 27604 
United States 
 
Protocol Date: 
06 Feb 2018 
Protocol Version: 
Version 2 
 
 
CONFIDENTIAL 
This protocol may not be reproduced or communicated to a third party without the 
written permission of Allergan. 


 
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1 
PROTOCOL APPROVAL SIGNATURES 
Protocol Title: 
Multicenter, Open-Label, Interventional Study on the Safety and 
Tolerability of Oxymetazoline and Energy-Based Therapy in Subjects 
with Rosacea 
Protocol Number: 
CMO-MA-MED-0530 
This study will be conducted in compliance with the clinical study protocol International 
Council for Harmonisation (ICH) guidelines for current Good Clinical Practice (GCP) and 
applicable regulatory requirements. 
Sponsor Signatory 
Jai G. Parekh, MD, MBA, FAAO 
Vice-President, Eye Care & Dermatology Global Head 
Office of CMO 
Eye Care & Dermatology Medical Affairs 
Harborside Financial Center - Plaza V Suite 1900 
Jersey City, NJ 07311 
United States 
Signature 
Date 
 
DocuSign Envelope ID: 510570F1-EF3F-488E-8C07-269ED5761980

	


 
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2 
STUDY PERSONNEL 
Medical Monitor  
Name: 
Amy Chinigo, MD 
Title: 
Director, Medical Safety Physician 
Address: 
Allergan Inc. 
Global Patient Safety & Epidemiology (GPSE)  
100 Somerset Corporate Blvd 
Bridgewater, NJ 08807 
United States 
Telephone No.: 
+1 862 261 7662 
Fax No.: 
+1 908 203 2282 / +1 908 203 2285 
Digital Image Analysis  
Company Name: Canfield Scientific Inc. 
Address: 
4 Wood Hollow Road 
Parsippany, NJ 07054 
United States 
Telephone No.: 
+1 800 815 4330 
 


 
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3 
SYNOPSIS 
Protocol Number: 
CMO-MA-MED-0530 
Title: 
Multicenter, Open-Label, Interventional Study on the Safety and Tolerability of Oxymetazoline and 
Energy-Based Therapy in Subjects with Rosacea 
Investigational Product: 
Rhofade (Oxymetazoline Hydrochloride [HCl] cream) 1.0% 
Study Centers: 
4 
Phase: 
Phase 4 
Objectives: 
Primary objective: To evaluate the safety and tolerability of oxymetazoline HCl cream 1.0% when used 
as an adjunctive treatment to energy-based therapy for subjects with moderate to severe persistent facial 
erythema associated with rosacea. 
Exploratory objective: To evaluate preliminary measures of efficacy of oxymetazoline HCl cream 1.0% 
when used as an adjunctive treatment to energy-based therapy for subjects with moderate to severe 
persistent facial erythema associated with rosacea. 
Study Design: 
This is a multicenter, interventional, open-label safety and tolerability study.  
Number of Subjects:  
Approximately 45 subjects in total 
Treatment: 
All subjects will receive one of the following energy-based therapies: Potassium Titanyl Phosphate 
[KTP], Pulsed Dye Laser [PDL], or Intense Pulsed Light [IPL] twice during the study (Day 1 and Day 
29). Once-daily application of oxymetazoline HCl cream 1.0% will be initiated on Day 3 and continued 
until Day 56. Subjects will be washed out from study drug 24 hours prior to the energy-based therapy 
session on Day 29 and will recommence study drug administration on Day 31.  
Study Duration: 
The duration of the entire study for each subject is 10 weeks. This includes a screening period of up to 2 
weeks, a treatment period of 8 weeks, comprising of daily dosing of study drug and 2 energy-based 
therapy sessions, followed by a final exit visit at Week 8 (Day 56). 
Study Population: 
To be eligible for study entry subjects must satisfy all the following inclusion criteria: 
1. Subject has provided written consent prior to any study-related procedures. 
2. Male or female aged ≥ 18 years.  
3. Clinical diagnosis of rosacea. 
4. Moderate to severe persistent facial erythema associated with rosacea at baseline, as determined by 
a grade of ≥ 3 on the Clinician Erythema Assessment (CEA) scale with photonumeric guide. 


 
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5. Written informed consent prior to any study-related procedures  
6. Written Authorization for Use and Release of Health and Research Study Information  
7. Females of childbearing potential must not be lactating, must have a negative urine pregnancy test 
at screening and Day 1, and must agree to practice a reliable method of contraception throughout 
the study (See Section 5.6.9). 
8. The ability to follow study instructions and complete study assessments without assistance and 
have a willingness and ability to comply with all scheduled visits, treatment plan, and other study 
procedures.  
Subjects will be excluded from the study if 1 or more of the following criteria are applicable: 
1. Any uncontrolled systemic disease  
2. History of any of the following conditions:  Raynaud's syndrome, narrow angle glaucoma, 
orthostatic hypotension, cerebral or coronary insufficiency, thromboangiitis obliterans, 
scleroderma, Sjögren’s syndrome, severe or unstable or uncontrolled cardiovascular disease, or 
any other current uncontrolled systemic disease. 
3. Diagnosis or presence of any of the following conditions within the treatment area:  rosacea 
conglobata, rosacea fulminans, isolated rhinophyma, isolated pustulosis of the chin, peri-oral 
dermatitis, demodicidosis, facial keratosis pilaris, seborrheic dermatitis, acute lupus 
erythematosus, or chronic recurring facial acne. 
4. The presence of facial hair, tattoos, or other facial characteristics such as actinic damage (eg, 
actinic lentigines, mottled hyperpigmentation or hypopigmentation, yellowish discoloration, 
excessive telangiectasia) that could interfere with the assessments of erythema in the opinion of 
the investigator. 
5. Current treatment with monoamine oxidase (MAO) inhibitors. 
6. Current treatment with niacin ≥ 500 mg/day. 
7. Any of the following treatments occurring within the specified period prior to Day 1: 
• 
14 days: products containing oxymetazoline (eg, eye drops, nasal sprays), topical 
glucocorticosteroids applied to the face, systemic or nasal corticosteroids, any 
prescription or over-the-counter (OTC) product for the treatment of acne. 
• 
28 days: Systemic antibiotics that are known to have an effect on rosacea such as 
erythromycin or doxycycline.  
• 
180 days: isotretinoin. 
8. Prior dermal adverse reaction to using Mirvaso® (brimonidine) topical gel, 0.33% or current use of 
marketed Mirvaso® (brimonidine) topical gel, 0.33%.  
9. Previous participation in clinical trials associated with oxymetazoline cream for facial rosacea 
10. Known hypersensitivity or allergies to any component of the study drug. 
11. Greater than 3 inflammatory lesions on the face. 
12. Current enrollment in an investigational drug or device study or participation in such a study 
within 30 days of entry into this study. 
13. History or current evidence of drug or alcohol abuse within 12 months prior to the screening visit. 
14. Condition or situation that, in the investigator’s opinion, may put the subject at significant risk, 
may confound the study results, or may interfere significantly with the subject’s participation in 
the study. 
15. An employee (or a relative of an employee) of the investigators, Allergan, or representative of 
Allergan. 


 
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Primary Endpoints: 
Safety and tolerability of oxymetazoline HCl 1.0% cream as an adjunctive treatment to energy-based 
therapy as determined by: 
• 
The incidence of treatment emergent adverse events (TEAEs) and serious adverse events 
(SAEs).  
• 
The number and percentage of subjects with at least a 1-grade worsening from baseline in the 
Dermal Tolerability Assessment at any timepoint over the treatment period. 
• 
The number and percentage of subjects with at least a 1-grade worsening from baseline in the 
Clinician’s Telangiectasia Assessment (CTA) at any timepoint over the treatment period. 
Exploratory Endpoints: 
Exploratory measures of efficacy of oxymetazoline HCl 1.0% cream as an adjunctive treatment to energy-
based therapy as determined by: 
• 
The number and percentage of subjects with at least a 1-grade improvement on the CEA from 
baseline over a 6-hour period (measured at hours 1, 3, and 6) following study drug application. 
• 
Percentage change from baseline in rosacea facial redness using Digital Image Analysis (DIA) of 
standardized facial photographs during the treatment period.  
• 
Proportion of subjects indicating Satisfied or Very Satisfied with treatment on the Items from 
Satisfaction Assessment for Rosacea Facial Redness and proportion of subjects indicating 
Somewhat Satisfied or Very Satisfied with treatment on the FACE-Q Satisfaction with Skin 
Scale. 
Safety: 
The following safety assessments will be performed: 
• Adverse event (AE), TEAE, and SAE monitoring 
• Urine pregnancy test (female subjects of child bearing potential only) 
• Vital signs (blood pressure, pulse rate, and oral body temperature) 
• Physical examination 
• CTA 
• Dermal Tolerability Assessment  
Efficacy: 
 
The following assessments will be performed as preliminary measures of efficacy: 
• CEA 
• Items from Satisfaction Assessment for Rosacea Facial Redness Scale  
• FACE-Q Satisfaction with Skin Scale 
• Photography of facial treatment area for DIA 
 
Statistical Analysis: 
The following analysis populations will be used: 
• Enrolled – all subjects who signed an informed consent form (ICF) and enrolled in the study. 
• Modified intent-to-treat (mITT) – all subjects treated with both study drug and energy-based 
therapy who had at least one post-treatment efficacy assessment between Day 3 and Day 56. 
• Safety – all subjects who received at least one dose of study drug as treatment in this study. 
The enrolled population will be used for subject disposition, demographics, and baseline characteristics 
summaries; the modified intent-to-treat population will be used for the efficacy analyses, and the safety 
population will be used for safety analyses.  


 
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For safety analysis, all AEs will be coded from the verbatim text to the lower level term (LLT) and 
mapped to preferred term (PT) and primary system organ class (SOC) using the Medical Dictionary for 
Regulatory Activities (MedDRA). For pretreatment AEs (PTAEs), the number and percentage of subjects 
reporting at least 1 PTAE will be tabulated by descending order of incidence rate, by primary SOC and 
PT, and by primary SOC, PT, and severity. TEAEs regardless of causality, application-site AEs, and 
treatment-related TEAEs will be analyzed in the same manner. Maximum severity of each dermal 
tolerability measure over the treatment period will be summarized using a frequency distribution. The 
same analysis will be performed for at least a 1-grade worsening from baseline (ie, predose on day 1) over 
the treatment period for each tolerability measure. 
Physical examination data will be tabulated. Raw data and change from baseline in each vital sign 
measure will be summarized using descriptive statistics.  
The CTA will be summarized using a frequency distribution by visit.  
Concomitant medications will be recorded throughout the study and be coded to the trade or preferred 
name using the World Health Organization Drug Dictionary (WHODrug). More detailed analyses will be 
described in the analysis plan.  
For exploratory efficacy analysis the proportion of subjects with at least a 1-grade decrease 
(improvement) on the CEA from baseline (ie, predose on Day 1) will be summarized by visit and 
timepoint using frequency distributions. In addition, the raw CEA data will be summarized by visit and 
timepoint using descriptive statistics. Each item in the Items from Satisfaction Assessment for Rosacea 
Facial Redness and FACE-Q Satisfaction with Skin Scale will be summarized using frequency 
distributions by visit and timepoint. 
 
 
 
 
 


 
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TABLE OF CONTENTS 
1 
Protocol Approval Signatures ......................................................................... 2 
2 
Study Personnel ................................................................................................ 3 
3 
Synopsis ............................................................................................................. 4 
Table of Contents ............................................................................................................ 8 
LIST OF TABLES ........................................................................................................ 11 
List of Abbreviations .................................................................................................... 12 
4 
Introduction .................................................................................................... 13 
4.1 
Background ..................................................................................................... 13 
4.2 
Nonclinical Studies ......................................................................................... 13 
4.3 
Clinical Studies ............................................................................................... 14 
4.4 
Energy-Based Therapies for the Treatment of Rosacea ............................. 14 
4.5 
Rationale for Study Design ............................................................................ 15 
Study Objectives ........................................................................................................... 16 
4.6 
Primary Objective .......................................................................................... 16 
4.7 
Exploratory Objective .................................................................................... 16 
5 
Study Endpoints ............................................................................................. 16 
5.1 
Primary Endpoints ......................................................................................... 16 
5.2 
Exploratory Endpoints................................................................................... 16 
Investigational Plan ................................................................................................. 17 
5.3 
Overall Study Design and Plan: Description ............................................... 17 
5.3.1 
Study Design ................................................................................... 17 
5.4 
Discussion of Study Design ............................................................................ 19 
5.5 
Selection of Study Population ........................................................................ 19 
5.5.1 
Number of Planned Subjects ........................................................... 19 
5.5.2 
Inclusion Criteria ............................................................................. 19 
5.5.3 
Exclusion Criteria ............................................................................ 19 
5.5.4 
Removal of Subjects From Therapy or Assessments ...................... 20 
5.6 
Investigational Products and Therapies ....................................................... 21 
5.6.1 
Investigational Products Administered ........................................... 21 


 
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5.6.2 
Identity of Investigational Products ................................................ 22 
5.6.3 
Packaging and Labelling ................................................................. 22 
5.6.4 
Energy-Based Therapies.................................................................. 22 
5.6.5 
Methods of Assigning Subjects to Treatment Groups .................... 22 
5.6.6 
Selection of Doses in the Study ....................................................... 23 
5.6.7 
Selection and Timing of Energy Therapy ....................................... 23 
5.6.8 
Blinding ........................................................................................... 23 
5.6.9 
Contraceptive Requirements ........................................................... 23 
5.6.10 
Prior and Concomitant Therapy ...................................................... 24 
5.6.10.1 Prohibited Medication/Therapy ....................................................... 24 
5.6.10.2 Prohibited Treatments ..................................................................... 24 
5.6.10.3 Prohibited Activities ........................................................................ 25 
5.6.10.4 Dietary Requirements at Site ........................................................... 25 
5.6.11 
Treatment Compliance .................................................................... 25 
5.6.12 
Instructions for the Subjects ............................................................ 25 
6 
Timing of Study Procedures .......................................................................... 26 
6.1 
Pretreatment ................................................................................................... 26 
6.1.1 
Screening Visit (Day -14 to Day -1) ............................................... 26 
6.1.2 
Baseline Visit (Day 1) ..................................................................... 27 
6.1.3 
Day 3 ............................................................................................... 27 
6.1.4 
Day 29 ............................................................................................. 27 
6.1.5 
Day 31 ............................................................................................. 28 
6.1.6 
Day 56 (Exit Visit) .......................................................................... 28 
6.1.7 
Early Withdrawal (or Discontinuation) Visit .................................. 29 
6.2 
Duration of Study ........................................................................................... 29 
6.3 
Acceptable Time Window Deviations ........................................................... 29 
7 
Efficacy and Safety ASsessments .................................................................. 29 
7.1 
Efficacy and Safety and Other Measurements Assessed ............................ 29 
7.1.1 
Efficacy Assessments ...................................................................... 29 
7.1.1.1 
Clinician Erythema Assessment ...................................................... 30 
7.1.1.2 
Items From Subject Satisfaction Assessment for Rosacea 
Facial Redness ................................................................................. 30 
7.1.1.3 
FACE-Q Satisfaction With Skin Scale ............................................ 30 
7.1.1.4 
Standardized Photography ............................................................... 30 
7.1.2 
Safety Assessments ......................................................................... 31 
7.1.2.1 
Adverse Events ................................................................................ 31 
7.1.2.2 
Urine Pregnancy Test (Females of Childbearing Potential 
Only) ................................................................................................ 35 
7.1.2.3 
Vital Signs ....................................................................................... 35 
7.1.2.4 
Physical Examination ...................................................................... 35 
7.1.2.5 
Clinician’s Telangiectasia Assessment ........................................... 35 


 
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7.1.2.6 
Dermal Tolerability Assessment ..................................................... 36 
7.1.3 
Other Assessments .......................................................................... 37 
7.1.3.1 
Demographic Information and Medical History ............................. 37 
7.1.3.2 
Fitzpatrick Phototyping Scale ......................................................... 37 
8 
Statistical Methods ......................................................................................... 38 
8.1 
General Statistical Considerations................................................................ 38 
8.1.1 
Datasets or Populations Analyzed ................................................... 38 
8.1.2 
Demographic and Other Baseline Characteristics ........................... 39 
8.1.3 
Efficacy Variables and Analysis ..................................................... 39 
8.1.4 
Safety Variables and Analysis ......................................................... 39 
8.1.5 
Interim Analyses.............................................................................. 40 
8.1.6 
Handling of Missing Data ............................................................... 40 
8.2 
Determination of Sample Size ....................................................................... 40 
8.3 
Protocol Deviations......................................................................................... 40 
9 
Quality Assurance and Quality Control ....................................................... 41 
9.1 
Audit and Inspection ...................................................................................... 41 
9.2 
Monitoring ...................................................................................................... 41 
9.3 
Data Management and Coding ..................................................................... 41 
10 
Records and Supplies ..................................................................................... 42 
10.1 Drug Accountability ....................................................................................... 42 
10.2 Financing and Insurance ............................................................................... 42 
11 
Ethics ............................................................................................................... 43 
11.1 Independent Ethics Committee or Institutional Review Board ................. 43 
11.2 Regulatory Authorities................................................................................... 43 
11.3 Ethical Conduct of the Study ........................................................................ 43 
11.4 Informed Consent ........................................................................................... 43 
11.5 Subject Confidentiality .................................................................................. 44 
12 
Reporting and Publication, Including Archiving ........................................ 45 
13 
References ....................................................................................................... 46 
14 
Appendices ...................................................................................................... 48 
14.1 Clinician Erythema Assessment Photonumeric Guide ............................... 48 
14.2 Items From Satisfaction Assessment for Rosacea Facial Redness ............. 55 


 
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14.3 FACE-Q™ - Satisfaction With Skin ............................................................. 56 
Investigator Signature Page .................................................................................... 59 
 
 
LIST OF FIGURES 
Figure 1   
Overall Study Design ...................................................................... 17 
 
LIST OF TABLES 
Table 1 
Schedule of Assessments and Procedures ....................................... 18 


 
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LIST OF ABBREVIATIONS  
AE 
adverse event 
CEA 
Clinician Erythema Assessment  
CTA 
Clinician Telangiectasia Assessment 
eCRF 
electronic case report form 
EDC 
electronic data capture 
FDA 
Food and Drug Administration 
cGCP 
HCl 
current Good Clinical Practice 
Hydrochloride 
ICF 
informed consent form 
ICH 
International Conference on Harmonisation 
IEC 
independent ethics committee 
IPL 
Intense Pulsed Light  
IRB 
institutional review board 
KTP 
Potassium Titanyl Phosphate 
LLT 
lower level term 
MedDRA 
Medical Dictionary for Regulatory Activities 
MAO 
monoamine oxidase 
n 
number of subjects with an observation 
N 
NOAEL 
NOEL 
number of subjects in the dataset or population 
no observed adverse effect level 
no observed effect level 
OTC 
over-the-counter 
PP 
PDL 
per protocol 
Pulsed Dye Laser  
PT 
preferred term 
PTAE 
pretreatment AEs 
SAE 
serious adverse event 
SOC 
system organ class 
SOP 
standard operating procedure 
SUSAR 
suspected unexpected serious adverse reaction 
TEAE 
treatment emergent adverse event 
US FDA 
United States Food and Drug Administration 
WHO 
World Health Organization 
WMA 
World Medical Association 
 


 
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4 
INTRODUCTION 
4.1 
Background  
Rosacea is primarily an adult condition, with onset of symptoms generally occurring after the 
age of 30, often having a deep impact on a patient’s self-esteem and quality of life. The 
diagnosis of rosacea is made based on the presence of 1 or more primary features centrally 
distributed on the face, including flushing (transient erythema), persistent (nontransient) 
erythema, papules and pustules, and/or telangiectasia. Persistent redness is the most common 
individual sign of rosacea and is defined as stable central facial erythema that is not transient 
flushing or blushing. Various secondary features may also be present including burning or 
stinging, plaque, dry appearance, edema, phymatous changes, and ocular manifestations. 1 For 
many individuals with rosacea, symptoms are triggered or exacerbated by external stimuli 
leading to the theory that the vasodilation and immune dysregulation seen in rosacea is 
neurogenic in nature.2 Rosacea is not curable, and it generally requires long-term treatment to 
alleviate symptoms and delay or prevent disease progression. Rosacea has been classified into 4 
standard subtypes, reflecting common patterns of signs and symptoms. Many patients may 
experience characteristics of more than one subtype at the same time, and these often may 
develop in succession. In many individuals with Subtype 1 rosacea (where persistent erythema 
is the predominant symptom), small blood vessels become visible on the skin. While rosacea 
may or may not evolve from one subtype to another, each individual sign or symptom may 
progress from mild to moderate to severe. Early diagnosis and treatment are therefore 
recommended.1  
Moderately effective topical treatments such as sulfonamides, metronidazole, azelaic acid, and 
oral tetracyclines are ineffective in managing persistent erythema associated with rosacea.3,4  
Alpha agonists have been approved for topical dermal application to reduce persistent erythema 
associated with rosacea. An α2-adrenoceptor agonist, brimonidine gel 0.33%, received United 
States Food and Drug Administration (US FDA) approval in 2013 for use in facial erythema of 
rosacea; however, it has been fraught with tolerability issues.5,6 
Oxymetazoline hydrochloride (HCl) is a highly-specific α1A-adrenoceptor receptor agonist, and 
a vasoconstrictor of the cutaneous microvasculature. Oxymetazoline topical cream 1.0% has 
recently been approved by the US FDA under the name Rhofade™ for the topical treatment of 
persistent facial erythema associated with rosacea in adults.7  
4.2 
Nonclinical Studies 
Repeat-dose dermal toxicology studies, including microscopic pathology evaluation of systemic 
tissues, were conducted in rats for up to 6 months and minipigs for up to 9 months. The no 
observed adverse effect level (NOAEL) in minipigs following 9 months of treatment was 2.5%, 
which was the highest dose tested. This NOAEL is approximately 17-fold higher than that 
estimated for facial dose in human subjects at the 1.0% concentration with once-daily 
application.  
Oxymetazoline was shown to be not genotoxic, carcinogenic, nor phototoxic in nonclinical test 
systems. Maternal systemic exposures observed at the NOAEL or no observed effect level 
(NOEL) doses in reproductive and developmental toxicity studies in rats and rabbits were at 
least 2-fold higher than those observed in subjects given the 1.0% concentration once daily. 


 
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4.3 
Clinical Studies 
To date thus far there have been 4 human dermal safety studies and 10 clinical studies 
(including 3 pivotal Phase 3 studies) of topical dermal oxymetazoline for the treatment of 
persistent facial erythema associated with rosacea. All clinical studies have been conducted with 
the same cream formulation with varying concentrations of oxymetazoline.  
In the first 2 Phase 3 studies oxymetazoline HCl cream 1.0% was applied topically for 29 days, 
once daily, to the faces of patients with persistent, moderate, or severe facial erythema 
associated with rosacea, followed by a 28 day post-treatment period. The results from these 2 
pivotal studies consistently demonstrated that oxymetazoline HCl cream 1.0% was safe and well 
tolerated based upon multiple safety evaluations, and was significantly more effective than 
vehicle in reducing facial erythema associated with rosacea over a 12-hour evaluation period 
(hours 3, 6, 9, and 12) following a 29 day treatment period.  In the most recent Phase 3 study the 
long-term safety and efficacy of oxymetazoline HCl cream 1.0% (applied topically, once daily) 
was evaluated in 440 patients with moderate to severe persistent facial erythema associated with 
rosacea over a period of 52 weeks. Improvement in erythema was consistently observed 3 and 6 
hours after study drug application compared with predose assessments from Day 1 through to 
Week 52 of the treatment period.  
In the most recent Phase 3 study the most commonly reported TEAEs (reported by ≥ 2% of 
patients) were upper respiratory tract infection (3.6%), rosacea (3.2%), application site 
dermatitis (3.0%), nasopharyngitis (3.0%), hypertension (2.5%), headache (2.3%), sinusitis 
(2.3%), application site pain (2.0%), and application site pruritus (2.0%). A majority of TEAEs 
were considered to be of mild or moderate severity; severe TEAEs reported by 2 or more 
patients included application site dermatitis (0.7%, 3/440) and application site erythema, basal 
cell carcinoma, and rosacea (0.5%, 2/440 each). Treatment-related TEAEs were reported during 
the entire study period by 8.2% (36/440) of patients. The most commonly reported treatment-
related TEAEs (reported by ≥ 1% of patients) were application site dermatitis (1.8%), 
application site paresthesia (1.6%), application site pain (1.1%), and application site pruritus 
(1.1%). A majority of treatment-related TEAEs were considered to be of mild or moderate 
severity. Severe treatment-related TEAEs included application site dermatitis (0.7%, 3/440) and 
application site pain, application site erythema, and photosensitivity reaction (0.2%, 1/440 
each). 
4.4 
Energy-Based Therapies for the Treatment of Rosacea 
For more than 2 decades, lasers and non-laser light-based therapies have become increasingly 
popular in dermatology for the management of clinical conditions such as rosacea, namely 
Pulsed Dye Laser (PDL), Long-Pulsed Nd:YAG Laser, Potassium Titanyl Phosphate (KTP) 
Laser, and Intense Pulsed Light (IPL).8,9 These therapies emit wavelength of light in a range 
absorbed by the hemoglobin chromophore, resulting in targeted vessel wall destruction.10 
Moreover, these devices are able to target vascular abnormalities without significant epidermal 
and dermal dysruption.11In the most recent Cochrane review of treatments for rosacea 
(published in 2015),12 PDL was found to be more effective than Nd:YAG laser therapy (and of 
comparable effect with IPL).13 However, the evidence for the effectiveness of these therapies on 
all signs and symptoms of skin conditions were rated of low quality based on the study design 
and data. 
In an effort to address the multiple signs and symptoms of skin conditions, there has been 
increased use of a multi-modal approach with non-ablative lasers (ie, KTP, PDL) or non-laser 
light sources (ie, IPL) with pre-existing topical medications. Pharmaceutical treatments that are 


 
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routinely being used in conjunction with these devices include topical 0.33% brimonidine 
(Mirvaso®) and 0.75% metronidazole (MetroCream®, MetroLotion™) for rosacea, retinoids for 
acne and actinic damage (Differin®, Retin-A®, Avage®, Avita®, Renova®), and the prescription 
triple-combination cream (Tri-Luma®) for melasma and other pigmentary disorders.11,14,15 
Furthermore, Mirvaso® gel is an alpha adrenoceptor agonist that is in the same class as the 
topical drug product in this study.  
4.5 
Rationale for Study Design 
Oxymetazoline has been shown in 3 pivotal Phase 3 studies to be effective in treating persistent 
facial erythema in subjects with rosacea. Energy-based therapies have also been seen to be 
efficacious in reducing erythema and telangiectasia in rosacea patients.16 This Phase 4 study is 
the first to investigate the safety, tolerability, and preliminary measurements of oxymetazoline 
HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy (ie, KTP, IPL, 
and PDL) for patients with moderate to severe persistent facial erythema associated with 
rosacea.  
The side effects of energy-based therapy can include transient pupura and immediate post-
treatment erythema, which normally resolve within a day or 2.12 In a recent publication, energy-
based therapy was performed the same day as Mirvaso® application for the treatment of rosacea 
with no safety concerns reported related to concurrent treatment.14 As an additional safety 
precaution we are delaying oxymetazoline treatment for 48 hours post energy-based therapy 
(and 24 hours prior to re-treatment with energy-based device) to limit any potential interaction 
between the device and drug. Any potential AEs that may arise from the use of a device will be 
noticeable within a 48-hour window, which will alert the physician as to whether oxymetazoline 
treatment should be applied.   
There are 6 safety determinations in the current study (adverse events, urine pregnancy in 
females of childbearing potential, physical examination, vital signs, Clinician’s Telangiectasia 
Assessment [CTA], and Dermal Tolerability Assessment). Four assessments will be used as 
measures of efficacy: Clinician Erythema Assessment [CEA], Items from Satisfaction 
Assessment for Rosacea Facial Redness, FACE-Q Satisfaction with Skin Scale, and Digital 
Image Analysis [DIA] of standardized photography of the treatment area).  


 
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STUDY OBJECTIVES  
4.6 
Primary Objective 
The primary objective of the study is to evaluate the safety and tolerability of oxymetazoline 
HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy for subjects 
with moderate to severe persistent facial erythema associated with rosacea. 
4.7 
Exploratory Objective 
The exploratory objective of the study is to evaluate preliminary measures of efficacy of 
oxymetazoline HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy 
for subjects with moderate to severe persistent facial erythema associated with rosacea. 
5 
STUDY ENDPOINTS 
5.1 
Primary Endpoints 
The primary endpoints of the study are: 
• The incidence of treatment emergent adverse events (TEAEs) and serious adverse 
events (SAEs).  
• The number and percent of subjects with at least a 1-grade worsening from baseline in 
the Dermal Tolerability Assessment at any timepoint over the treatment period. 
• The number and percentage of subjects with at least a 1-grade worsening from baseline 
in the CTA at any timepoint over the treatment period. 
5.2 
Exploratory Endpoints 
The exploratory endpoints of the study are: 
• The number and percentage of subjects with at least a 1-grade improvement on the CEA 
from baseline over a 6-hour period (measured at hours 1, 3, and 6) following study drug 
application. 
• Percentage change from baseline in rosacea facial redness using DIA of standardized 
facial photographs during the treatment period.  
• Proportion of subjects indicating Satisfied or Very Satisfied with treatment on the Items 
from Satisfaction Assessment for Rosacea Facial Redness and proportion of subjects 
indicating Somewhat Satisfied or Very Satisfied with treatment on the FACE-Q 
Satisfaction with Skin Scale. 


 
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Investigational Plan 
5.3 
Overall Study Design and Plan: Description 
This is a Phase 4, multicenter, interventional, open-label study to evaluate the safety and 
tolerability of once-daily oxymetazoline HCl 1.0% cream when used as an adjunctive treatment 
to energy-based therapy for subjects with moderate to severe facial erythema associated with 
rosacea. The study will enroll approximately 45 subjects at 4 study centers within the United 
States. 
All subjects will receive 1 of the following energy-based therapies (Potassium Titanyl 
Phosphate [KTP], Pulsed Dye Laser [PDL] or Intense Pulsed Light [IPL]) on Day 1 and Day 29 
of the treatment period. Once-daily application of oxymetazoline HCl cream 1.0% will be 
initiated on Day 3 of the treatment period and will continue until the final exit visit (excluding a 
3-day washout period that begins 24 hours prior to the second energy-based therapy session on 
Day 29).  
Study Duration: 
The duration of the clinical phase is approximately 10 weeks for each subject. This includes a 
screening period of up to 2 weeks, a treatment period of 8 weeks, and a final exit visit at Week 8 
(Day 56). 
5.3.1 Study Design 
The overall study design is shown in Figure 1. The schedule of assessments for individuals is 
shown in Table 1. 
 
Figure 1  Overall Study Design 
 
Screening
Treatment
Exit
-14
-1 1
3
29
31
56
Day
Energy-Based 
Therapy
Energy-Based 
Therapy
Oxy Cream - Oxymetazoline HCl Cream 1.0% once daily 
Energy-Based Therapy - Potassium Titanyl Phosphate (KTP),  Pulsed Dye Laser (PDL) or Intense Pulsed Light (IPL) Therapy
Oxy 
Cream
27
Oxy 
Cream


 
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Table 1 
Schedule of Assessments and Procedures 
Study Period 
Screening* 
Day 1/ 
Baseline* 
Day 3 
Day 29 
Day 31 
Day 56/ Exit 
Visit 
Visit Window  
Day -14 to 
Day -1 
N/A 
N/A 
± 3 Days 
+2 days from 
Day 29 
± 3 Days 
Informed Consent  
X 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
Fitzpatrick Skin Phototype 
X 
 
 
 
 
 
Inclusion/Exclusion Criteria 
X 
Xa  
 
 
 
 
Medical History 
X 
Xb 
 
 
 
 
Physical Examination 
X 
 
 
 
 
X 
Vital Sign Measurement 
X 
Xa 
Xc 
Xa 
Xc 
X 
Urine Pregnancy Test (if applicable) 
X 
Xa,b 
 
 
 
X 
Energy-Based Therapy (KTP, PDL, or IPL) 
 
X 
 
X 
 
 
Onsite Study Drug Treatment/Dispensing 
 
 
X 
 
X 
Xd 
Standardized Photography 
 
Xe  
Xf 
Xe 
Xf 
Xf 
Clinician Erythema Assessment (CEA) 
 
Xe 
Xf  
Xe 
Xf 
Xf 
Clinician’s Telangiectasia Assessment (CTA) 
X 
Xa,b 
Xa 
Xa 
Xa 
Xa 
Items From Satisfaction Assessment for Rosacea Facial Redness 
X 
Xa,b 
Xg 
 
Xg 
Xg 
FACE-Q Satisfaction With Skin Scale 
X 
X a,b 
 
Xa 
 
Xa 
Dermal Tolerability Assessment (Investigator and Subject) 
 
Xe 
Xh 
Xe 
Xh 
Xh 
Adverse Events/Reactions 
◄-------------------------------------------------------------------------------------------------------------► 
Concomitant Medications and Concurrent Procedures 
◄-------------------------------------------------------------------------------------------------------------► 
* Screening and baseline may occur on same day 
a predose (Oxymetazoline HCl)/pretreatment (Energy-based therapy [KTP, PDL, or IPL]) 
b repeated only if screening/Day1 occur on separate days 
c predose/pretreatment and 6 hr 
d Study drug application only. No study drug will be dispensed 
e predose/pretreatment and 1 hr 
f predose, 1 hr, 3 hr, and 6 hr 
g 6 hr 
h predose/pretreatment 1 hr and 6 hr 
Acceptable Time Window Deviations 
Predose – all predose assessments on Day 1 and Day 29 should occur within 90 minutes prior to energy-based treatment. All predose assessments on Day 3, Day 31, and Day 
56 should occur within 90 minutes prior to study drug administration.  
Postdose – all assessments performed at the 1 hour, 3 hour, and 6 hour postdose timepoints should be performed within 15 minutes (ie, 1 h ±15min, 3 h±15min, 6 h ±15min). 


 
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5.4 
Discussion of Study Design 
The study will take place in subjects with moderate to severe persistent facial erythema of 
rosacea in order to ascertain whether once-daily application of oxymetazoline HCl 1.0% cream 
is safe and well tolerated when used as an adjunct to energy-based therapies known to improve 
erythema and telangiectasia in rosacea subjects. For further details on study drug and energy-
based therapy dose and treatment design refer to Section 5.6. 
5.5 
Selection of Study Population 
5.5.1 Number of Planned Subjects  
The total planned number of subjects is 45.  
5.5.2 Inclusion Criteria 
To be eligible for study entry, subjects must satisfy all of the following inclusion criteria: 
1. Subject has provided written consent prior to any study-related procedures. 
2. Male or female aged ≥ 18 years.  
3. Documented clinical diagnosis of rosacea. 
4. Moderate to severe persistent facial erythema associated with rosacea at baseline, as 
determined by a grade of ≥ 3 on the CEA scale with photonumeric guide. 
5. Females of childbearing potential must not be lactating, must have a negative urine 
pregnancy test at screening and Day 1, and must agree to practice a reliable method of 
contraception throughout the study (see Section 5.6.9). 
6. The ability to follow study instructions and complete study assessments without 
assistance and have a willingness and ability to comply with all scheduled visits, 
treatment plan, and other study procedures. 
5.5.3 Exclusion Criteria 
Subjects will be excluded from the study if 1 or more of the following criteria are applicable: 
1. Any uncontrolled systemic disease. 
2. History of any of the following conditions: Raynaud's syndrome, narrow angle glaucoma, 
orthostatic hypotension, cerebral or coronary insufficiency, thromboangiitis obliterans, 
scleroderma, Sjögren’s syndrome, severe or unstable or uncontrolled cardiovascular 
disease, or any other current uncontrolled systemic disease. 
3. Diagnosis or presence of any of the following conditions within the treatment area:  
rosaceaconglobata, rosacea fulminans, isolated rhinophyma, isolated pustulosis of the 
chin, peri-oral dermatitis, demodicidosis, facial keratosis pilaris, seborrheic dermatitis, 
acute lupus erythematosus, or chronic recurring facial acne. 
4. The presence of facial hair, tattoos, or other facial characteristics such as actinic damage 
(eg, actinic lentigines, mottled hyperpigmentation or hypopigmentation, yellowish 


 
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discoloration, excessive telangiectasia) that could interfere with the assessments of 
erythema in the opinion of the investigator. 
5. Current treatment with monoamine oxidase (MAO) inhibitors. 
6. Current treatment with niacin ≥ 500 mg/day. 
7. Any of the following treatments occurring within the specified period prior to Day 1: 
• 14 days: products containing oxymetazoline (eg, eye drops, nasal sprays), 
topical glucocorticosteroids applied to the face, systemic or nasal 
corticosteroids, any prescription or over-the-counter (OTC) product for the 
treatment of acne. 
• 28 days: Systemic antibiotics that are known to have an effect on rosacea such 
as erythromycin or doxycycline. 
• 180 days: isotretinoin. 
8. Prior dermal adverse reaction to using Mirvaso® (brimonidine) topical gel, 0.33% or 
current use of marketed Mirvaso® (brimonidine) topical gel, 0.33%.  
9. Previous participation in clinical trials associated with oxymetazoline cream for facial 
rosacea 
10. Known hypersensitivity or allergies to any component of the study drug. 
11. Greater than 3 inflammatory lesions on the face. 
12. Current enrollment in an investigational drug or device study or participation in such a 
study within 30 days of entry into this study. 
13. History or current evidence of drug or alcohol abuse within 12 months prior to the 
screening visit. 
14. Condition or situation that, in the investigator’s opinion, may put the subject at significant 
risk, may confound the study results, or may interfere significantly with the subject’s 
participation in the study. 
15. An employee (or a relative of an employee) of the investigators, Allergan, or 
representative of Allergan. 
5.5.4 Removal of Subjects From Therapy or Assessments 
Subjects may stop study drug for any of the following reasons: 
• Subject request 
• Use of non-permitted concurrent therapy 
• Non-compliance with the study drug or study schedule 
• Lost to follow-up 
• Occurrence of AEs that are not compatible with the continuation of subject participation 
in the study, in the investigator’s opinion, or are unacceptable to the subject to continue 
• Investigator request 
• Intercurrent illness 
• Sponsor request 
• Treatment failure 


 
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• Pregnancy 
Subjects who do not comply with the protocol, withdraw consent, or stop study drug for any 
other reason will not be replaced. Subjects are free to withdraw from the study at any time 
without providing reason(s) for withdrawal and without prejudice to further treatment. The 
reason(s) for withdrawal will be documented in the electronic case report form (eCRF). 
Upon withdrawal from the study, any time after dosing has taken place, all efforts should be 
made to invite the subject to complete the early withdrawal visit. The same procedures should 
be performed as on the Day 56 (exit visit). The aim is to record data in the same way as for 
subjects who completed the study, particularly safety data. 
Reasonable efforts will be made to contact subjects who are lost to follow-up. These efforts 
should be documented in the subject’s file.  
The sponsor has the right to terminate the study at any time in case of SAEs or if special 
circumstances concerning the study drug/energy therapy or the company itself occur, making 
further treatment of subjects impossible. In this event, the investigators will be informed of the 
reason for study termination. 
Pregnancy 
Subjects will be instructed that known or suspected pregnancy occurring during the study, in 
subjects or female partners of male subjects, should be confirmed and reported to the 
investigator, who will then withdraw the female subject from the study without delay. Upon 
discontinuation from the study, only those procedures that would not expose the subject to 
undue risk will be performed. The investigator should also be notified of pregnancy occurring 
during the study but confirmed after completion of the study. In the event that a subject is 
subsequently found to be pregnant after inclusion in the study, any pregnancy will be followed 
to term, and the status of mother and child will be reported to the sponsor after delivery. 
Full details will be recorded on the withdrawal page of the eCRF, and a Pregnancy Data Form 
should be completed and faxed/emailed to Allergan within 24 hours of awareness of the event 
using the contact details in Section 7.1.2.1.1. 
5.6 
Investigational Products and Therapies 
5.6.1 Investigational Products Administered 
Oxymetazoline HCl cream 1.0% will be applied in a thin layer topically to the entire face 
including forehead, nose, each cheek, and chin, once daily. Subjects will be instructed to apply 
study drug to their clean, dry face in the morning, at approximately the same time each day, 
starting on Day 3 through Day 56. There will be a 3 day washout period from the study drug 
beginning 24 hours prior to the second energy-based therapy session on Day 29 (subjects will 
not apply the study drug on Day 28, Day 29, and Day 30) to ensure that energy-based therapy 
and treatment with oxymetazoline are clearly separated in the case of any treatment-related 
adverse events. The Investigator should assess if any adverse events resulting from treatment 
with the energy-based device (eg, treatment site skin irritation or wounding) would present a 
risk for treatment with oxymetazoline and either delay or discontinue treatment.  
For study visits, subjects will be instructed to apply the study drug at the study site. The dose 
will be applied after predose study assessments and procedures are completed. Site personnel 


 
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will observe subject dosing in the clinic to ensure proper study drug application technique and 
retrain if necessary. Detailed instructions on study drug application will be provided to subjects 
(see Section 5.6.12).  
5.6.2 Identity of Investigational Products 
Oxymetazoline cream 1.0% (Rhofade) contains oxymetazoline HCl, methylparaben, 
propylparaben, phenoxyethanol, sodium citrate dihydrate, citric acid anhydrous, disodium 
edetate, butylated hydroxytoluene, anhydrous lanolin, medium chain triglycerides, diisopropyl 
adipate, oleyl alcohol, polyethylene glycol (PEG)-300, PEG-6 (and) PEG-32 (and) glycol 
stearate, cetostearyl alcohol, ceteareth-6 (and) stearyl alcohol, ceteareth-25, and purified water. 
5.6.3 Packaging and Labelling 
All study drug will be supplied by Allergan. The study drug will be packaged in identically 
appearing containers consistent with all applicable regulations. The medication will be supplied 
in the approved commercial packaging. The study drug container will have a child-resistant 
feature. Labelling on the container and the carton will include the following statements: “For 
Topical Use Only” and “Keep Out of Reach of Children.” 
5.6.4 Energy-Based Therapies 
Subjects will receive one of the following 3 types of energy-based therapy at the timepoints 
indicated in Table 1 during the study: 
Pulsed Dye Laser (PDL): The following 2 PDL devices will be utilized for this study: Cynergy 
(Cynosure) and Vbeam Perfecta (Syneron-Candela). The Pulsed Dye Laser (PDL) delivers 
pulsed laser energy at a wavelength that targets hemoglobin and results in the destruction of 
superficial blood vessels, reducing both erythema and telangiectasia.17 
Potassium Titanyl Phosphate Laser (KTP): The KTP utilized for this study will be the Excel 
V (Cutera). The KTP laser has been shown to improve telangiectasia to a greater extent than 
erythema in rosacea patients.18  
Intense Pulsed Light Therapy (IPL): The IPL utilized for this study will be the Palomar Icon 
(Cynosure). IPLs emit polychromatic light and are commonly used to treat vascular lesions 
associated with rosacea.19 
Each study center will be assigned one or more devices from the list above to utilize during the 
study. Each study center will utilize only the specific devices assigned for use at their site. The 
devices will be assigned based on the current expertise and devices present at the study center.  
Approximately 11 subjects will be treated with each energy-based therapy device type. The 
method for treatment with laser at each site will be based on the Investigator’s current standard 
of practice. The details of the study treatment (ie, wavelength, pulse duration, number of pulses, 
and fluence) will be recorded in the eCRF for each subject. 
5.6.5 Methods of Assigning Subjects to Treatment Groups 
Subjects who meet all inclusion/exclusion criteria will be assigned a subject enrolment number 
that will serve as the subject identification number on all study documents.  
All eligible subjects will receive oxymetazoline HCl cream 1.0%.  


 
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There is no stratification of randomization associated with this study. Subjects will be assigned 
to 1 of 3 types of energy-based therapy, based on the assigned devices at the site they attend. 
Enrolment at each study center will be monitored to ensure that a minimum of 11 subjects will 
receive each type of energy-based therapy.  
5.6.6 Selection of Doses in the Study 
Oxymetazoline HCl cream 1.0% applied once daily for treatment of persistent facial erythema 
of rosacea has been evaluated by Allergan in 3 Phase 3 studies, with duration of application 
extending from 29 days to 52 weeks. The results from these studies consistently demonstrated 
that oxymetazoline HCl cream 1.0% was safe and well tolerated based upon multiple safety 
evaluations, and demonstrated consistent trends in efficacy, with improvements from baseline 
observed throughout the treatment period.  
5.6.7 Selection and Timing of Energy Therapy 
Laser and light therapy have been shown to reduce erythema and telangiectasia in patients with 
rosacea.17 Subjects will be allocated to one of KTP, PDL, or IPL treatments and undergo 2 
sessions (Day 1 and Day 29) during the study. The 28-day period between the 2 treatments is 
standard in current practice allowing for efficacious results. 
Subjects will begin study drug administration on Day 3 (2 days after the first energy-based 
therapy session) and will washout study drug from 24 hours prior to the second energy-based 
therapy session on Day 29, until 2 days after (Day 31). This will ensure that the study drug will 
not be present on the skin during the energy-based therapy or during the immediate recovery 
period during which there may be irritation to the skin. Any post-treatment skin irritation will be 
identified by the physician during this washout period and oxymetazoline treatment will not 
recommence until deemed safe to do so. 
5.6.8 Blinding 
This study will be an open-label study, therefore blinding of the study drug or treatments is not 
required. 
5.6.9 Contraceptive Requirements 
Females of child bearing potential are defined as any female subject post-puberty. Females that 
are postmenopausal (defined as having 12 months of consecutive spontaneous amenorrhea) or 
surgically sterile (6 months post-surgical bilateral oophorectomy with or without hysterectomy, 
6 months post-hysterectomy, or 6 months post-tubal ligation) are exempt from the contraceptive 
requirements of the study.  
Females of childbearing potential are required to use effective contraception from the time of 
signing the ICF until the end of the study. Acceptable methods of contraception are intrauterine 
devices, hormonal contraceptives (eg, oral, patch, or injectable), partner’s vasectomy (if this is 
the sole partner and vasectomy was medically confirmed), a double barrier protection method 
(eg, condom or diaphragm with spermicide cream, foam, or gel), or sexual abstinence. Periodic 
abstinence [calendar, ovulation, symptothermal, post ovulation methods] and withdrawal are not 
acceptable methods of contraception. 


 
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5.6.10 Prior and Concomitant Therapy 
Therapy considered necessary for the subject’s welfare may be given at the discretion of the 
investigator, including but not limited to medications for other conditions (ie, hypertension, 
diabetes, etc.), treatment of AEs, estrogens, androgens, anti-androgenic agents, vitamins, iron 
supplements, folate, and herbal supplements. Medications should be taken consistently 
throughout the study and at the investigator’s discretion. 
Concomitant medications as defined for this study include dietary supplements, OTC 
medications, and oral herbal preparations, as well as changes in dosages of current prescription 
medications. Concomitant medications will be documented for each subject at each scheduled 
visit. A detailed history of medications will be documented at screening. Subsequently, at each 
study visit, subjects will be asked what medication, if any, they have taken since the previous 
visit. All concomitant medications will be recorded in the eCRF. 
5.6.10.1 Prohibited Medication/Therapy 
The decision to administer a prohibited medication/treatment is done with the safety of the 
subject as the primary consideration. When possible, Allergan should be notified before the 
prohibited medication/treatment is administered. 
The following products are prohibited under this study: 
1. Products containing oxymetazoline, except for study drug. 
2. Any prescription, OTC, or herbal topical and/or systemic product that has a known effect 
on rosacea (eg, Mirvaso [brimonidine] topical gel, 0.33%, metronidazole-containing 
products, azelaic acid-containing products, systemic antibiotics such as erythromycin or 
doxycycline).  
3. Any prescription, OTC, or herbal product applied to the face that causes vasoconstriction. 
4. Any prescription, OTC, or herbal product that is primarily used to decrease facial redness. 
5. Any topical facial treatment that may affect erythema or cause skin irritation. 
6. New topical facial regimens. 
7. Topical glucocorticosteroids applied to the face. 
8. MAO inhibitors. 
9. Isotretinoin. 
10. Any new use of systemic or inhaled glucocorticosteroids, cardiac glycosides, alpha-1 
adrenergic receptor antagonists, β-adrenergic blocking agents (topical or systemic), 
β-adrenergic agonists, antihypertensive agents, or ≥ 500 mg/day niacin. 
11. Medications that the subject knows may increase their facial erythema or cause flushing. 
5.6.10.2 Prohibited Treatments 
Laser, light-source, or other energy-based therapies to the face, other than those treatments 
performed as part of the study, are not permitted during the study. 


 
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Dermatological treatments on the face (eg, facial peels, microdermabrasion, exfoliating 
treatments) are prohibited for the duration of the study. 
5.6.10.3 Prohibited Activities 
Twenty-four hours before all study visits, the following activities are prohibited: 
1. Consumption of any food, alcohol, or other beverage that the subject knows increases 
their facial erythema. 
2. Use of saunas, steam rooms, and hot tubs, or any other activities that the subject knows 
will increase their facial erythema.  
During all study visits, application of any facial products (eg, sunscreen, moisturizer, makeup) 
is prohibited from 2 hours before the first assessment until all assessments are complete. Facial 
cleansers are allowed; however, application of study drug and study assessments should occur at 
least 20 minutes after the cleanser is used. 
5.6.10.4 Dietary Requirements at Site 
Subjects will remain at the investigational site for at least 6.5 hours during the Day 3, Day 31, 
and Day 56 Visits. The study site will provide meals and beverages during these visits. Subjects 
may only consume the food and beverages provided by the study staff, unless they require a 
special diet that they bring from home, under study site supervision. The meals should not 
include items that may increase any of the subjects’ facial erythema, such as certain spices, 
caffeine, nicotine, hot beverages, or alcohol. Subjects may consume water at their discretion. 
5.6.11 Treatment Compliance 
At each visit after Day 1 subjects will be asked if they have used any concomitant medications, 
had any concurrent procedures, used any prohibited medications/treatments, or participated in 
any prohibited activities since the previous visit. At each visit after Day 3 subjects will also be 
asked if they have applied the study drug every day in the morning. Any breach of compliance 
will be recorded in the eCRF. 
5.6.12 Instructions for the Subjects 
Subjects will be instructed to avoid all prohibited medications, treatments, and activities, as 
described in Section 5.6.10. They will be instructed that the application of any facial products 
(eg, sunscreen, moisturizer, makeup) is prohibited during all study visits from 2 hours before the 
first assessment and until all assessments are complete. 
Use of facial products is permitted on all other dosing days; however, the products must be 
removed before study drug application and may be re-applied no sooner than 20 minutes after 
study drug application. 
If a subject routinely shaves his/her face, they will be instructed to use a consistent shaving 
habit as much as possible (eg, same time each day, use of same shaving products), and on study 
visit days they must shave at least 2 hours prior to the first assessment and refrain from shaving 
until all assessments are complete. 


 
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When the patients arrive at the study center on Days 3, 31, and 56, they will be instructed to 
wait approximately 30 minutes for acclimation to the study site environment before any 
assessments are made.  
For application of study drug, subjects will be instructed by the study staff and by an 
instructional video: 
1. To apply the study cream at approximately the same time every day (in the morning). 
2. To wash their hands before and after each application of study drug. 
3. To dispense approximately a pea size amount of study drug in the palm of the hand or 
fingertip. 
4. To dab the study drug onto each of the 5 areas of the face (ie, forehead, nose, each cheek, 
and chin). 
5. To gently spread the study drug to cover their entire face (hairline to mandibular ridge 
and from ear to ear). 
6. Care must be taken to avoid applying the study drug to the eyes, eyelids, scalp, neck, ears, 
and any membrane of the inner nose, mouth, lips, or open wounds. 
Detailed subject instructions on study drug application will be provided to subjects. Subject 
instructions will include the statements “For Topical Use Only” and “Keep Out of Reach of 
Children.” Subjects will be instructed on the proper storage of study drug and to keep it out of 
the reach of children. Subjects will be instructed to return all used and unused study drug 
containers to the site. 
Twenty-four hours before each visit, subjects should avoid any foods, beverages, or activities 
that they know trigger an increase in their facial erythema. Subjects will be asked to recall any 
missed applications of study drug. 
6 
TIMING OF STUDY PROCEDURES 
Subjects will provide written informed consent before any study-related procedures are 
performed. The planned schedule of study assessments are in Table 1. When the subjects arrive 
at the study center on Days 3, 31, and 56, they will be instructed to wait approximately 30 
minutes for acclimation to the study site environment before any assessments are made. 
6.1 
Pretreatment 
6.1.1 Screening Visit (Day -14 to Day -1) 
During the screening visit the following assessments will be performed: 
• Obtain informed consent. 
• Assess for eligibility (against inclusion and exclusion criteria). 
• Record demographic data, such as ethnic origin, date of birth, and sex.  
• Collect full medical history. 
• Record any AEs and concomitant medications or procedures. 
• Perform a physical examination.  
• Vital sign measurement (blood pressure, pulse rate, oral body temperature). 
• Urine pregnancy test (for women of childbearing potential only). 


 
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• CTA. 
• Fitzpatrick Skin Phototype. 
• Items from Satisfaction Assessment for Rosacea Facial Redness. 
• FACE-Q Satisfaction with Skin Scale. 
6.1.2 Baseline Visit (Day 1) 
The Day 1 Baseline Visit will take place up to 14 days after the Screening Visit. The screening 
and Day 1 baseline assessments may be performed on the same day. The following procedures 
will be performed at the Day 1 Baseline Visit (at the timepoints indicated in Table 1): 
• Reconfirm inclusion/exclusion criteria.* 
• Record any AEs/TEAEs and changes in concomitant medication or concomitant 
procedures. 
• Collect updated medical history.* 
• Vital sign measurement (blood pressure, pulse rate, oral body temperature). 
• Urine pregnancy test (for women of childbearing potential only).* 
• CTA.* 
• Energy-Based Therapy (KTP, PDL, or IPL). 
• Standardized photography of treatment area. 
• CEA. 
• Dermal Tolerability Assessment (investigator and subject). 
• Items from Satisfaction Assessment for Rosacea Facial Redness.* 
• FACE-Q Satisfaction with Skin Scale.* 
* only performed if screening and baseline assessments performed on separate visits. 
 
6.1.3 Day 3 
The subject will return to the site on Day 3 and the following procedures will be performed (at 
the timepoints indicated in Table 1): 
• Record any AEs/TEAEs and changes in concomitant medication or concomitant 
procedures. 
• Vital sign measurement (blood pressure, pulse rate, oral body temperature). 
• CTA.  
• Standardized photography of treatment area. 
• CEA. 
• Dermal Tolerability Assessment (investigator and subject). 
• Items from Satisfaction Assessment for Rosacea Facial Redness. 
• Application and dispensing/collection of study drug. 
The subject will be instructed how to apply the study drug at this visit and will be given a 
sufficient supply to enable once-daily application from Day 4 until Day 27. The subject will be 
instructed not to apply study drug on Day 28, Day 29, and Day 30. 
6.1.4 Day 29 
The subject will return to the site on Day 29 and the following procedures will be performed (at 
the timepoints indicated in Table 1): 


 
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• Record any AEs/TEAEs and changes in concomitant medication or concomitant 
procedures. 
• Vital sign measurement (blood pressure, pulse rate, oral body temperature). 
• CTA.  
• Standardized photography of treatment area. 
• CEA. 
• Dermal Tolerability Assessment (investigator and subject). 
• Energy-Based Therapy (KTP, PDL, or IPL). 
• FACE-Q Satisfaction with Skin Scale. 
6.1.5 Day 31 
The subject will return to the site on Day 31 and the following procedures will be performed (at 
the timepoints indicated in Table 1): 
• Record any AEs/TEAEs and changes in concomitant medication or concomitant 
procedures. 
• Vital sign measurement (blood pressure, pulse rate, oral body temperature). 
• CTA.  
• Standardized photography of treatment area. 
• CEA. 
• Dermal Tolerability Assessment (investigator and subject). 
• Items from Satisfaction Assessment for Rosacea Facial Redness. 
• Application and dispensing/collection of study drug. 
The subject will be given sufficient study drug to enable once-daily application from Day 32 to 
the Day 56 exit visit.  
 
6.1.6 Day 56 (Exit Visit) 
The subject will return to the site on Day 56 (±3 days) for the study exit visit and the following 
procedures will be performed (at the timepoints indicated in Table 1): 
• Record any AEs/TEAEs and changes in concomitant medication or concomitant 
procedures. 
• Physical Examination. 
• Urine pregnancy test (for women of childbearing potential only). 
• Vital sign measurement (blood pressure, pulse rate, oral body temperature). 
• CTA.  
• Application of study drug. 
• Standardized photography of treatment area. 
• CEA. 
• Dermal Tolerability Assessment (investigator and subject). 
• Items from Satisfaction Assessment for Rosacea Facial Redness. 
• FACE-Q Satisfaction with Skin Scale. 


 
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6.1.7 Early Withdrawal (or Discontinuation) Visit 
If a subject’s participation in the study is prematurely terminated for any reason or if the subject 
fails to return for a scheduled visit, every effort should be made to determine the reason. This 
information will be recorded in the subject’s eCRF. 
Upon withdrawal from the study, at any time after the first dose of study drug has taken place, 
all efforts should be made to invite the subject to return to the site for an early withdrawal visit 
and complete the exit visit procedures (Section 6.1.6). If for any reason the subject does not 
agree to return to the site for the exit visit, the reason and/or efforts made will be recorded.  
If the subject withdraws from the study and withdraws consent for disclosure of future 
information, no further evaluations should be performed, and no additional data should be 
collected. The Sponsor may retain and continue to use any data collected before such 
withdrawal of consent. 
6.2 
Duration of Study 
The duration of the entire study for each subject is 10 weeks. This includes a screening period of 
up to 2 weeks, a treatment period of 8 weeks, comprising of daily dosing of study drug and 2 
energy-based therapy sessions, followed by a final exit visit at Week 8 (Day 56). 
6.3 
Acceptable Time Window Deviations 
Allowed time window deviations are (assessments at screening are not described here): 
Predose – all predose assessments on Day 1 and Day 29 should occur within 90 minutes prior 
to energy-based treatment. All predose assessments on Day 3, Day 31, and Day 56 should occur 
within 90 minutes prior to study drug administration.  
Post dose – all assessments performed at the 1 hour, 3 hour, and 6 hour post dose timepoints 
should be performed within 15 minutes (ie, 1 h ±15min, 3 h ±15min, 6 h ±15min). 
7 
EFFICACY AND SAFETY ASSESSMENTS  
7.1 
Efficacy and Safety and Other Measurements Assessed  
The planned schedule of all study assessments is listed in Table 1. 
7.1.1 Efficacy Assessments  
The measures of efficacy are: 
• Investigator’s assessment of the subject’s overall severity of persistent erythema 
associated with rosacea in the treatment area as measured by a 5-point CEA scale with 
photonumeric guide (Section 7.1.1.1). 
• Patient’s self-assessment of satisfaction using patient-reported outcomes (PROs): 
o Items from Subject Satisfaction Assessment for Rosacea Facial Redness 
(Section 7.1.1.2) 
o FACE-Q Satisfaction with Skin Scale (Section 7.1.1.3). 
• Standardized photography of treatment area (Section 7.1.1.4). 


 
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7.1.1.1 Clinician Erythema Assessment 
The CEA scale is the following: 
Clinician Erythema Assessment (CEA) Scale 
Grade 
Descriptions 
0 
Clear skin with no signs of erythemaa 
1 
Almost clear of erythema, slight redness 
2 
Mild erythema, definite redness 
3 
Moderate erythema, marked redness 
4 
Severe erythema, fiery redness 
 
a Normal healthy skin color as seen in individuals without rosacea 
The CEA photonumeric guide is provided in Appendix 14.1. Prior to screening subjects, 
investigators will be trained in grading erythema severity using the CEA with photonumeric 
guide. The investigator should report the grade that best describes the average overall severity 
of persistent facial erythema associated with rosacea. All CEA and subject satisfaction 
assessments should be performed under consistent lighting conditions. The investigator may 
refer to the baseline (predose Day 1) facial photographs at each post-treatment timepoint to aid 
their assessment. The investigator must not discuss the results of the CEA with the subject, nor 
compare the results of assessments with previous assessments (other than the Day 1 predose 
assessment). 
7.1.1.2 Items From Subject Satisfaction Assessment for Rosacea Facial Redness  
The Subject Satisfaction Assessment for Rosacea Facial Redness, a PRO measure, was 
developed in accordance with the FDA PRO Guidance.20 Two questions from this assessment 
will be answered by subjects in the study at the timepoints listed in Table 1. These 2 questions 
are contained in the Items From Subject Satisfaction Assessment for Rosacea Facial Redness 
(Appendix 14.2). The subject will be allowed to view their baseline (predose Day 1) facial 
photographs during each assessment to aid their assessment. 
7.1.1.3 FACE-Q Satisfaction With Skin Scale 
The FACE-Q Satisfaction with Skin Scale (Appendix 14.3) is another PRO measure. The 
questionnaire should be completed by the subjects at the timepoints listed in Table 1. The 
subject will be allowed to view their baseline (predose Day 1) facial photographs during each 
assessment to aid their assessment. 
7.1.1.4 Standardized Photography 
Standardized photographs will be taken of the treatment area by trained study staff.  Three 
photographs will be taken for each subject’s face (right oblique, left oblique and frontal view) at 
the timepoints indicated in Table 1. Full details of the photography procedures are described in 
the Study Manual. Digital Image Analysis of the facial photographs for redness will be 
performed by a central laboratory (Canfield Scientific Inc.). The baseline (predose Day 1) 
photographs obtained can be used by the investigator and subject during post-treatment CEA 


 
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and PRO assessments (Items from Subject Satisfaction Assessment for Rosacea Facial Redness 
and FACE-Q Satisfaction with Skin Scale) to allow comparison with the current condition of 
the treatment area.    
7.1.2 Safety Assessments 
The following safety measures will be collected: 
• AEs and TEAEs (Section 7.1.2.1) 
• Urine pregnancy tests (for women of childbearing potential only, Section 7.1.2.2)  
• Vital sign measurements (blood pressure, pulse rate, and oral body temperature) 
(Section 7.1.2.3) 
• Physical examination (Section 7.1.2.4) 
• CTA (Section 7.1.2.5) 
• Dermal Tolerability Assessment (Section 7.1.2.6) 
7.1.2.1 Adverse Events 
Adverse Event Definition 
An AE is defined as any untoward medical occurrence in a clinical study subject administered a 
medicinal product that does not necessarily have a causal relationship with this treatment. An 
AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease temporally associated with the use of a medicinal 
(investigational) product, whether or not it is related to the medicinal (investigational) product. 
This includes an exacerbation of pre-existing conditions or events, intercurrent illnesses, drug 
interaction or the significant worsening of the indication under investigation that is not recorded 
elsewhere in the eCRF under specific efficacy assessments. Anticipated fluctuations of 
pre-existing conditions, including the disease under study, that do not represent a clinically 
significant exacerbation or worsening need not be considered AEs. 
Adverse event collection will commence from the time the subject signs the ICF. It is the 
responsibility of the investigator to document all AEs that occur during the study. AEs will be 
elicited by asking the subject a nonleading question, for example, “Have you experienced any 
new or changed symptoms since we last asked/since your last visit?” Adverse events should be 
reported on the appropriate page of the eCRF. 
A TEAE is any event not present prior to the initiation of the study treatments or any event 
already present that worsens in either intensity of frequency following exposure to the study 
treatments. Any AEs reported after signing the ICF and prior to study treatment are considered 
pretreatment AEs (PTAEs). 
Assessment of Severity 
Each AE will be assigned a category by the investigator as follows: 
Mild: 
An AE that is easily tolerated by the subject, causes minimal discomfort, and 
does not interfere with everyday activities. 


 
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Moderate: 
An AE that is sufficiently discomforting to interfere with normal everyday 
activities; intervention may be needed. 
Severe: 
An AE that prevents normal everyday activities; treatment or other intervention 
usually needed. 
If there is a change in severity of an AE, it must be recorded as a separate event. 
Assessment of Causality 
Every effort will be made by the investigator to assess the relationship of the AE, if any, to the 
study drug.  Causality should be assessed using the categories presented in the following table: 
Unrelated: 
Clinical event with an incompatible time relationship to study drug 
administration, and that could be explained by underlying disease or other 
drugs or chemicals or is incontrovertibly not related to the study drug. 
Unlikely: 
Clinical event whose time relationship to study drug administration makes a 
causal connection improbable, but that could plausibly be explained by 
underlying disease or other drugs or chemicals. 
Possible: 
Clinical event with a reasonable time relationship to study drug 
administration, but that could also be explained by concurrent disease or 
other drugs or chemicals. 
Probable: 
Clinical event with a reasonable time relationship to study drug 
administration, and is unlikely to be attributed to concurrent disease or other 
drugs or chemicals. 
Very 
Likely/Certain: 
Clinical event with plausible time relationship to study drug administration, 
and that cannot be explained by concurrent disease or other drugs or 
chemicals. 
Action Taken 
The investigator will describe the action taken in the appropriate section of the eCRF, as 
follows: 
• Study drug stopped 
• Study drug temporarily interrupted 
• Energy-based therapy stopped 
• Energy-based therapy temporarily interrupted 
• Concomitant medication 
 
Follow-up of Adverse Events 
All investigators should follow up on subjects with SAEs and AEs of special interest until the 
event is resolved or until, in the opinion of the investigator, the event is stabilized or determined 
to be chronic. All other non-serious AEs will be followed until the subject exits the study. 
Details of AE resolution must be documented in the eCRF. 


 
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Documentation and Reporting of Adverse Events 
Adverse events should be reported and documented in accordance with the procedures outlined 
below. All AEs occurring during the study must be documented on the relevant eCRF pages. 
The following data should be documented for each AE: 
• Description of the symptom event 
• Classification of ‘serious’ or ‘not serious’ 
• Severity 
• Date of first occurrence and date of resolution (if applicable) 
• Action taken 
• Causal relationship 
• Outcome of event (unknown, recovered, not yet recovered, recovered with sequelae, 
death [with date and cause reported]) 
7.1.2.1.1 Serious Adverse Events 
Serious Adverse Event Definition 
An SAE is any untoward medical occurrence or effect that, at any dose, 
• Results in death. 
• Is life-threatening (an AE is life-threatening if the subject was at immediate risk of death 
from the event as it occurred, ie, it does not include a reaction that might have caused 
death if it had occurred in a more serious form). 
• Requires or prolongs inpatient hospitalization. (Complications occurring during 
hospitalization are AEs and are SAEs if they cause prolongation of the current 
hospitalization. Hospitalization for elective treatment of a pre-existing non-worsening 
condition is not, however, considered an AE. The details of such hospitalizations must be 
recorded on the medical history or physical examination page of the eCRF). 
• Results in persistent or significant disability/incapacity. An AE is incapacitating or 
disabling if it results in a substantial and/or permanent disruption of the subject’s ability 
to carry out normal life functions. 
• Results in a congenital anomaly/birth defect. 
Allergan considers all cancer AEs as SAEs. Any abortion (spontaneous or nonspontaneous) is 
also considered a SAE. 
In addition, medical and scientific judgement is required to decide if prompt notification is 
required in situations other than those defined for SAEs above. This may include any event that 
the investigator regards as serious that did not strictly meet the criteria above but may have 
jeopardized the subject or required intervention to prevent one of the outcomes listed above, or 
that would suggest any significant hazard, contraindication, side effect, or precaution that may 
be associated with the use of the study drug. 


 
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Reporting of Serious Adverse Events 
Any SAE must be reported by the investigator if it occurs during the clinical study or within 30 
days of receiving the study drug, whether or not the SAE is considered to be related to the study 
drug. An SAE report consists of the SAE form, the AE form, and the concomitant medication 
form. A copy of these forms must be faxed within 24 hours for the attention of the medical 
monitor at:  
Fax: +1 714 796 9504 
Back-Up Fax: +1 714 246 5295 
E-mail: IR-Clinical-SAE@allergan.com  
The investigator should not wait to receive additional information to document fully the event 
before notification of a SAE, though additional information may be requested. Where 
applicable, information from relevant laboratory results, hospital case records, and autopsy 
reports should be obtained. 
Instances of death, congenital abnormality, or an event that is of such clinical concern as to 
influence the overall assessment of safety, if brought to the attention of the investigator at any 
time after cessation of study drug administration and linked by the investigator to this study, 
should be reported to the study monitor. 
The sponsor and/or INC Research will promptly notify all relevant investigators and the 
regulatory authorities of findings that could adversely affect the safety of subjects, impact on the 
conduct of the study or alter the independent ethics committee (IEC)/institutional review board 
(IRB) approval/favorable opinion of the study. In addition, INC Research, on behalf of the 
sponsor, will expedite the reporting to all concerned investigators, to the IECs/IRBs, where 
required, and to the regulatory authorities of all adverse reactions that are both serious and 
unexpected. 
Details of the procedures to be followed if a pregnancy occurs are provided in Section 5.5.4. 
7.1.2.1.2 Suspected Unexpected Serious Adverse Reactions 
Suspected Unexpected Serious Adverse Reaction Definition 
An adverse event is considered “unexpected” if it is not listed in the Reference Safety 
Information (RSI), such as Investigator Brochure, Prescription Information (eg, the current 
package insert for Rhofade),7 or it is not consistent with the risk information described in any of 
the RSI. If an unexpected AE is serious and suspected, it is a suspected unexpected serious 
adverse reaction (SUSAR). 
All SUSARs will be the subject of expedited reporting. The sponsor and/or INC Research shall 
ensure that all relevant information about a SUSAR is reported to the relevant competent 
authorities and IEC/IRB within 15 days after knowledge by the sponsor of such a case. All 
investigators should follow up on SUSARs until the event is resolved or until, in the opinion of 
the investigator, the event is stabilized or determined to be chronic. Post study SUSARs that 
occur after the subject has completed the clinical study must be reported by the investigator to 
the sponsor. 


 
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7.1.2.2 Urine Pregnancy Test (Females of Childbearing Potential Only) 
Females of child bearing potential will have urine pregnancy tests performed at the timepoints 
indicated in Table 1. A negative test result must be obtained during screening and prior to 
energy-based treatment at the baseline visit. If a positive pregnancy test is obtained at any visit 
during the study the subject will be withdrawn from the study. 
Females of childbearing potential are defined as any female subject after puberty. Females that 
are postmenopausal (defined as having 12 months of consecutive spontaneous amenorrhea) or 
surgically sterile (6 months post-surgical bilateral oophorectomy with or without hysterectomy, 
6 months post-hysterectomy, or 6 months post-tubal ligation) are exempt from this requirement. 
7.1.2.3 Vital Signs 
Vital signs (blood pressure, pulse rate, and oral body temperature) will be recorded (at the 
timepoints listed in Table 1) in a standardized manner (ie, after the subject has rested in the 
sitting position for 5 minutes). 
Changes in vital signs determined by the investigator to be clinically significant will be noted as 
an AE in the eCRF. Such abnormalities will be closely monitored until stabilized or resolved. 
7.1.2.4 Physical Examination 
Physical examinations (evaluating eyes, ears, nose, mouth, throat, thyroid, lungs, heart, 
abdomen, extremities, neuromuscular system, skin, and lymph nodes) will be performed at the 
timepoints specified in Table 1.  
Significant changes from baseline examination on screening will be recorded as AEs. 
7.1.2.5 Clinician’s Telangiectasia Assessment 
The investigator will use the CTA to evaluate the average overall severity of telangiectasia on 
the subject’s face using the 5 point scale below (at the timepoints specified in Table 1). The 
investigator performing the assessment should record the results in the eCRF and should not 
compare the current assessment to previous assessments to prevent bias.  
Clinician Telangiectasia Assessment (CTA) 
Grade 
Description 
0 
Clear skin with no signs of telangiectasia 
1 
Almost clear, a few barely visible telangiectasia 
2 
Mild, a few visible telangiectasia  
3 
Moderate, with presence of clearly visible telangiectasia 
4 
Severe, with the presence of many visible telangiectasia 


 
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7.1.2.6 Dermal Tolerability Assessment 
Dermal Tolerability Assessments will be performed by both investigator and subject at the 
timepoints specified in Table 1.  
Investigator’s Assessments: Dryness and Scaling of the Treatment Area 
Investigators will assess dryness and scaling in the treatment area using the 4-point scales 
below. The results will be recorded in the eCRF and should not be discussed with the subject. 
Dryness: skin roughness 
Score 
Grade 
Description 
0 
None 
No dryness 
1 
Mild 
Slight but definite roughness 
2 
Moderate 
Moderate roughness 
3 
Severe 
Marked roughness 
 
Scaling: abnormal peeling of the stratum corneum 
Score 
Grade 
Description 
0 
None 
No peeling 
1 
Mild 
Barely perceptible peeling, noticeable only on light scratching or rubbing 
2 
Moderate 
Obvious, but not profuse peeling 
3 
Severe 
Heavy scale production 
Subject’s Assessments: Stinging/Burning and Pruritus of the Treatment Area 
The investigator will ask the subject if he/she is experiencing burning/stinging and pruritus 
(itching) using the 4-point scales below. The results will be recorded in the eCRF. 
Stinging/Burning: prickling pain sensation 
Score 
Grade 
Description 
0 
None 
No stinging/burning 
1 
Mild 
Slight warm, tingling/stinging sensation; not really bothersome 
2 
Moderate 
Definite warm, tingling/stinging sensation; somewhat bothersome 
3 
Severe 
Hot, tingling/stinging sensation that has caused definite discomfort 
 


 
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Pruritus: itching in the application area 
Score 
Grade 
Description 
0 
None 
Normal, no itching in the application area 
1 
Mild 
Noticeable discomfort causing intermittent awareness 
2 
Moderate 
Noticeable discomfort causing continuous awareness 
3 
Severe 
Definite, continuous discomfort interfering with normal daily activities 
 
7.1.3 Other Assessments 
7.1.3.1 Demographic Information and Medical History 
At the screening visit, subject demographic data will be collected. These data include date of 
birth, age, gender, race, and ethnicity. A medical history will also be obtained from each subject 
at this visit. Medical history includes a detailed history of prior cosmetic and surgical 
procedures, with start and stop dates, if applicable, as well as any discontinuations due to 
intolerability or toxicity.  
7.1.3.2 Fitzpatrick Phototyping Scale 
Each subject’s skin phototype will be assessed at screening by the investigator using the 
Fitzpatrick Phototyping Scale in the table below: 


 
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Fitzpatrick 
skin type 
Constitutive or unexposed 
skin color 
Sunburn and tanning historya 
I 
Ivory white (pale white) 
Extremely fair skin 
Burns easily, strongly; never tans 
II 
White or fair skin 
Burns easily; tans minimally with 
difficulty 
III 
Medium white skin 
Burns moderately; tans moderately and 
uniformly 
IV 
Beige or lightly tanned or olive 
skin 
Burns minimally; tans easily and 
moderately 
V 
Moderate brown or tanned brown 
skin 
Rarely burns; tans profusely (dark 
brown) 
VI 
Dark brown or black skin 
Never burns, tans profusely (dark brown 
or black) 
a Sunburn and tanning history is based on what subjects say their responses are to an initial sun 
exposure (eg, about 45 to 60 minutes of noon exposure in early summer). The subject response 
should be based on the following 2 specific questions: 
1. “How painful is your sunburn (intensity of erythema, edema, skin peeling and 
discomfort) after 24 hours?” 
2. “How much tan will you develop in a week?” 
8 
STATISTICAL METHODS 
8.1 
General Statistical Considerations 
A brief summary of the general statistical analysis methods is provided below; full details will 
be provided in a separate statistical analysis plan, which will be finalized prior to database lock.  
Data will be summarized using descriptive statistics (number of observations [n], mean, 
standard deviation, median, minimum, and maximum for continuous variables; and n and 
percentage for categorical variables). 
Two critical timepoints, baseline and end of study, will be referenced in most of statistical 
analyses for this study. Baseline is defined as the latest assessment prior to any study treatments 
for each subject (Day 1). End of study is the last clinical visit an enrolled subject has in this 
study (Day 56 exit visit). Subjects who discontinue will be asked to return for the last clinical 
visit (Day 56 exit visit) for end-of-study data collection. 
8.1.1 Datasets or Populations Analyzed 
The following analysis populations will be used: 
• Enrolled – all subjects who signed an ICF and enrolled in the study. 
• Modified intent-to-treat (mITT) – all subjects treated with both study drug and energy-based 
therapy who had at least one post-treatment efficacy assessment between Day 3 and Day 56. 
• Safety – all subjects who received at least one dose of study drug as treatment in this study. 


 
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The enrolled population will be used for subject disposition, demographics, and baseline 
characteristics summaries; the modified intent-to-treat population will be used for the efficacy 
analyses, and the safety population will be used for safety analyses.  
8.1.2 Demographic and Other Baseline Characteristics 
The number of subjects in each of the analyzed study populations will be described. Subjects 
who discontinue study drug or are removed from the study prematurely will also be reported. 
Reasons for study drug and/or energy-based therapy discontinuation, and time of withdrawal 
from the study will be described. 
Subject characteristics at entry into the study will be summarized in frequency tables and 
descriptive statistics will be provided for quantitative variables. 
Concomitant medications will be coded by means of the World Health Organization Drug 
Dictionary (WHODrug) dictionary into Anatomical Therapeutic Chemical (ATC) classification 
codes. The type and timing of use of specific concomitant medications will be listed and 
summarized. The type and duration of pre-study use will be described on the safety population. 
The type, dose, schedule, duration of use, dose modifications, dose omissions, and reasons for 
deviations from initial therapy will be described. 
8.1.3 Efficacy Variables and Analysis 
The efficacy variables are: 
• The number and percentage of subjects with at least a 1-grade decrease (improvement) 
on the CEA, from baseline over a 6-hour period following study drug application at 
each study visit and timepoint (specified in Table 1). 
• Percentage change from baseline at each visit in rosacea facial redness using DIA of 
standardized facial photographs. 
• Proportion of subjects indicating Satisfied or Very Satisfied (score of 3 or 4) with 
treatment on the Items from Subject Satisfaction Assessment for Rosacea Facial 
Redness and proportion of subjects indicating Somewhat Satisfied and Very Satisfied 
with treatment on the FACE-Q Satisfaction with Skin Scale at each visit and timepoint 
specified in Table 1. 
The proportion of subjects with at least a 1-grade decrease (improvement) on the CEA from 
baseline (ie, predose on Day 1) will be summarized by visit and timepoint using frequency 
distributions. In addition, the raw CEA data will be summarized by visit and timepoint using 
descriptive statistics. Each item from the PROs (Items from Subject Satisfaction Assessment for 
Rosacea Facial Redness and FACE-Q Satisfaction with Skin Scale) will be summarized using 
frequency distributions by visit and timepoint. 
8.1.4 Safety Variables and Analysis 
The safety variables are PTAEs, treatment emergent adverse events (TEAEs), application site 
adverse events, investigator and subject dermal tolerability assessments, physical examination, 
vital signs (blood pressure pulse rate, and oral temperature) and CTA.  
All AEs will be coded from the verbatim text to the lower level term (LLT) and mapped to 
preferred term (PT) and primary system organ class (SOC) using the Medical Dictionary for 


 
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Regulatory Activities (MedDRA). For PTAEs, the number and percentage of subjects reporting 
at least 1 PTAE will be tabulated by descending order of incidence rate, by primary SOC and 
PT, and by primary SOC, PT, and severity. TEAEs regardless of causality, application site AEs, 
and treatment-related TEAEs will be analyzed in the same manner. Maximum severity of each 
dermal tolerability measure over the treatment period will be summarized using a frequency 
distribution. The same analysis will be performed for at least a 1-grade worsening from baseline 
(ie, predose on day 1) over the treatment period for each tolerability measure. 
Physical examination and vital signs data will be tabulated. Raw data and change from baseline 
in each vital sign measure will be summarized using descriptive statistics.  
Clinician’s Telangiectasia Assessment will be summarized using a frequency distribution by 
visit. More detailed analyses will be described in the analysis plan.  
8.1.5 Interim Analyses 
No interim analysis is planned for this study. 
8.1.6 Handling of Missing Data 
Missing data strategy will be documented in the statistical analysis plan. 
8.2 
Determination of Sample Size 
Sample size for this study was calculated using estimated incidence rate of treatment-related 
AEs for daily application of oxymetazoline HCl cream 1% in conjunction with energy-based 
therapy. A conservative estimate of the empirical incidence rate of study drug related adverse 
events (p0) was 8.2% (based on the oxymetazoline arm of 3 Allergan pivotal studies). In the 
scenario of improved overall efficacy outcomes resulting from the combination of 
oxymetazoline treatment with energy-based devices, a 14% increase (less than 15%) in the 
treatment-related adverse event rate may still be tolerable or warrant further clinical 
development. Thus, we choose to use δ = 0.14 as the margin of indifference.  
Sample size calculation for this study is based on one proportion equivalence test for testing (2-
sided) the null hypothesis H0: |p – p0| > δ against the alternative hypothesis H1:  |p – p0| < δ.   A 
sample size of N = 43 is required for attaining a power of 80% while controlling Type-I error 
rate of the test at 5%. To allow for a small percentage of potential subject withdrawal, 
approximately 45 subjects will be enrolled into this study. 
8.3 
Protocol Deviations 
Major protocol deviations may include, but are not limited to: 
• Inclusion/Exclusion criteria violations. 
• Inadequate compliance with study drug. 
• Prohibited medications taken. 
• Significant deviations from the study drug administration schedule. 
• Other protocol deviations that could affect subjects' outcomes. 
The final list of major protocol deviations will be defined during the data review meeting.  


 
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9 
QUALITY ASSURANCE AND QUALITY CONTROL 
9.1 
Audit and Inspection 
Study centers and study documentation may be subject to Quality Assurance audit during the 
course of the study by the sponsor or its nominated representative. In addition, inspections may 
be conducted by regulatory authorities at their discretion. 
9.2 
Monitoring 
Data for each subject will be recorded on an eCRF. Data collection must be completed for each 
subject who signs an ICF and is administered study drug. 
In accordance with current Good Clinical Practice (cGCP) and ICH guidelines, the study 
monitor will carry out source document verification at regular intervals to ensure that the data 
collected in the eCRF are accurate and reliable. Monitoring will be performed both on site and 
remotely, for further details, refer to the Monitoring Plan. 
The investigator must permit the monitor, the IEC/IRB, the sponsor’s internal auditors, and 
representatives from regulatory authorities direct access to all study-related documents and 
pertinent hospital or medical records for confirmation of data contained within the eCRFs.  
9.3 
Data Management and Coding 
INC Research will be responsible for activities associated with the data management of this 
study. This will include setting up a relevant database and data transfer mechanisms, along with 
appropriate validation of data and resolution of queries. Data generated within this clinical study 
will be handled according to the relevant standard operating procedures (SOPs) of the data 
management and biostatistics departments of INC Research. 
Study centers will enter data directly into an electronic data capture (EDC) system by 
completing the eCRF via a secure internet connection. Data entered into the eCRF must be 
verifiable against source documents at the study center. Data to be recorded directly on the 
eCRF will be identified and the eCRF will be considered the source document. Any changes to 
the data entered into the EDC system will be recorded in the audit trail and will be FDA Code of 
Federal Regulations (CFR) 21 Part 11 compliant. 
Medical coding will use Medical Dictionary for Regulatory Activities (MedDRA) for 
concomitant diseases and AEs and WHODrug for medications. 
Missing or inconsistent data will be queried in writing to the investigator for clarification. 
Subsequent modifications to the database will be documented. 


 
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10 RECORDS AND SUPPLIES 
10.1 Drug Accountability 
On receipt of the study drug, the investigator (or deputy) will conduct an inventory of the 
supplies and verify that study drug supplies are received intact and in the correct amounts before 
completing a supplies receipt. The investigator will retain a copy of this receipt at the study 
center and return the original receipt to the study monitor. The monitor may check the study 
supplies at each study center at any time during the study. 
It is the responsibility of the study monitor to ensure that the investigator (or deputy) has 
correctly documented the amount of the study drug received, dispensed, and returned on the 
dispensing log that will be provided. A full drug accountability log will be maintained at the 
study center at all times. The study monitor will arrange collection of unused study drug 
returned by the subject. The study monitor will also perform an inventory of study drug at the 
end of the study. Accountability may be performed remotely (refer to Monitoring Plan for 
further detail). All discrepancies must be accounted for and documented. 
10.2 Financing and Insurance 
Financing and insurance of this study will be outlined in a separate agreement between INC 
Research and the sponsor. 


 
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11 ETHICS 
11.1 Independent Ethics Committee or Institutional Review Board 
Before initiation of the study at each study center, the protocol, the ICF, other written material 
given to the subjects, and any other relevant study documentation will be submitted to the 
appropriate IEC/IRB. Written approval of the study and all relevant study information must be 
obtained before the study center can be initiated or the study drug is released to the investigator. 
Any necessary extensions or renewals of IEC/IRB approval must be obtained for changes to the 
study such as amendments to the protocol, the ICF, or other study documentation. The written 
approval of the IEC/IRB together with the approved ICF must be filed in the study files. 
The investigator will report promptly to the IEC/IRB any new information that may adversely 
affect the safety of the subjects or the conduct of the study. The investigator will submit written 
summaries of the study status to the IEC/IRB as required. On completion of the study, the 
IEC/IRB will be notified that the study has ended. 
11.2 Regulatory Authorities 
Relevant study documentation will be submitted to the regulatory authorities of the participating 
countries, according to local/national requirements, for review and approval before the 
beginning of the study. On completion of the study, the regulatory authorities will be notified 
that the study has ended. 
11.3 Ethical Conduct of the Study 
The investigator(s) and all parties involved in this study should conduct the study in adherence 
to the ethical principles based on the Declaration of Helsinki, GCP, ICH guidelines, and the 
applicable national and local laws and regulatory requirements. 
11.4 Informed Consent 
The process of obtaining informed consent must be in accordance with applicable regulatory 
requirement(s) and must adhere to GCP. 
The investigator is responsible for ensuring that no subject undergoes any study-related 
examination or activity before that subject has given written informed consent to participate in 
the study. 
The investigator or designated personnel will inform the subject of the objectives, methods, 
anticipated benefits, and potential risks and inconveniences of the study. The subject should be 
given every opportunity to ask for clarification of any points s/he does not understand and, if 
necessary, ask for more information. At the end of the interview, the subject will be given ample 
time to consider the study. Subjects will be required to sign and date the ICF. After signatures 
are obtained, the ICF will be kept and archived by the investigator in the investigator’s study 
file. A signed and dated copy of the subject ICF will be provided to the subject. 
Photographs of the subject’s face will be taken as part of this study. If a subject does not consent 
to have the photographs taken, they cannot participate in the study. Subjects will also have the 
option of indicating whether or not they give permission for the use of their study photographs 
for advertising, publicity, and promotional purposes. If subjects do not consent to their 
photographs being used, they will be excluded from participating in the study. 


 
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It should be emphasized that the subject may refuse to enter the study or to withdraw from the 
study at any time, without consequences for their further care or penalty or loss of benefits to 
which the subject is otherwise entitled. Subjects who refuse to give or who withdraw written 
informed consent should not be included or continue in the study. 
If new information becomes available that may be relevant to the subject’s willingness to 
continue participation in the study, a new ICF will be approved by the IEC(s)/IRB(s) (and 
regulatory authorities, if required). The study subjects will be informed about this new 
information and reconsent will be obtained. 
11.5 Subject Confidentiality 
Monitors, auditors, and other authorized agents of the sponsor and/or its designee, the 
IEC(s)/IRB(s) approving this research, and the US FDA, as well as that of any other applicable 
agency(ies), will be granted direct access to the study subjects’ original medical records for 
verification of clinical study procedures and/or data, without violating the confidentiality of the 
subjects to the extent permitted by the law and regulations. In any presentations of the results of 
this study or in publications, the subjects’ identity will remain confidential. 
All personal data collected and processed for the purposes of this study should be managed by 
the investigator and his/her staff with adequate precautions to ensure confidentiality of those 
data, and in accordance with the Health Insurance Portability and Accountability Act,21 
applicable to national and/or local laws and regulations on personal data protection. 


 
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12 REPORTING AND PUBLICATION, INCLUDING ARCHIVING 
Essential documents are those documents that individually and collectively permit evaluation of 
the study and quality of the data produced. After completion of the study (end of study defined 
as the date of the last visit of the last subject), all documents and data relating to the study will 
be kept in an orderly manner by the investigator in a secure study file. This file will be available 
for inspection by the sponsor or its representatives. Essential documents should be retained for 2 
years after the final marketing approval in an ICH region or for at least 2 years since the 
discontinuation of clinical development of the study drug. It is the responsibility of the sponsor 
to inform the study center when these documents no longer need to be retained. The investigator 
must contact the sponsor before destroying any study-related documentation. In addition, all 
subject medical records and other source documentation will be kept for the maximum time 
permitted by the hospital, institution, or medical practice. 
The sponsor must review and approve any results of the study or abstracts for professional 
meetings prepared by the investigator(s). Published data must not compromise the objectives of 
the study. Data from individual study centers in multicenter studies must not be published 
separately. 


 
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13 REFERENCES 
1. Wilkin J, Dahl M, Detmar M, Drake L, Feinstein A, Odom R, et al. Standard 
classification of rosacea: Report of the National Rosacea Society Expert Committee on 
the Classification and Staging of Rosacea. J Am Acad Dermatol. 2002;46(4): 584-587. 
2. Del Rosso JQ. Advances in understanding and managing rosacea: part 1: connecting 
the dots between pathophysiological mechanisms and the common clinical features of 
rosacea with emphasis on vascular changes and facial erythema. J Clin Aesthet 
Dermatol. 2012;5(3):16-25. 
3. Elewski BE, Draelos Z, Dreno 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;25(2):188-200. 
4. Blount BW, Pelletier AL. Rosacea: A common, yet commonly overlooked, condition. 
Am Fam Physician. 2002;66(3):435-440. 
5. Mirvaso® (brimonidine gel, 0.33%) [package insert]. Fort Worth, TX: Galderma 
Laboratories, LP; 2013. 
6. Routt ET, Levitt JO. Rebound erythema and burning sensation from a new topical 
brimonidine tartrate gel 0.33%. J Amer Acad Dermatol.2014;70(2):e37-e38. 
7. RHOFADE® (oxymetazoline HCl 1% cream) [package Insert]. Irvine CA: Allergan; 
2017. 
8. Nestor MS, Goldberg DJ, Goldman P, Weiss RA, Rigel DS. New Perspectives on 
Photorejuvenation. Skin & Aging 2003; 11(5):68-74. 
9. Nestor MS. Results of procedural and prescription therapy for medical and cosmetic 
conditions in dermatology. Poster presented at the 62nd Annual Meeting of the 
American Academy of Dermatology. February 6-11, 2004. Washington, D.C 
10. Patil UA, Dhami LD. Overview of lasers. Indian J Plast Surg. 
2008;41(Suppl):S101-S113. 
11. Nestor MS. Combination therapy in clinical and cosmetic dermatology: the marriage 
of device and drug. J Drugs Dermatol. 2004;3(5 suppl):S4-S11. 
12. van Zuuren EJ, Fedorowicz Z, Carter B, van der Linden MMD, Charland L. 
Interventions for rosacea. Cochrane Database Syst Rev.  2015;4: CD003262. 
13. Karsai S, Roos S, Raulin C. Treatment of facial telangiectasia using a dual-wavelength 
laser system (595 and 1,064 nm): a randomized controlled trial with blinded response 
evaluation. Dermatol Surg. 2008;34(5):702-708. 
14. Micali G, Dall’Oglio F, Verzi AE, Luppino I, Bhatt K, Lacarubba F. Treatment of 
erythemato-telangiectatic rosacea with brimonidine alone or combined with vascular 
laser based on preliminary instrumental evaluation of the vascular component. Lasers 
Med Sci. 2017. Epub ahead of print. 
15. Micali G, Gerber PA, Labarubba F, Schäfer G. Improving Treatment of 
Erythematotelangiectatic Rosacea with Laser and/or Topical Therapy Through 
Enhanced Discrimination of its Clinical Features. J Clin Aesthet Dermatol. 2016 Jul; 
9(7): 30-39. 
16. Shim TN, Abdullah A. The effect of pulsed dye laser on the dermatology life quality 
index in erythematotelangiectatic rosacea patients: an assessment. J Clin Aesthet 
Dermatol. 2013;6(4):30-32.  


 
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17. Jasim ZF, Woo WK, Handley JM: Long-pulsed (6-ms) pulsed dye laser treatment of 
rosacea-associated telangiectasia using subpurpuric clinical threshold. Dermatol Surg. 
2004;30(1):37-40. 
18. Maxwell EL, Ellis DA, Manis H. Acne rosacea: Effectiveness of 532 nm laser on the 
cosmetic appearance of the skin. J Otolaryngol Head Neck Surg. 2010;39(3):292-296. 
19. Hoffman MA, Lehmann P. Physical modalities for the treatment of rosacea. J Dtsch 
Dermatol Ges. 2016;14Suppl. 6:38-43. 
20. US Department of Health and Human Services. Guidance for Industry: Patient-
Reported Outcome Measures: Use in Medical Product Development to Support 
Labeling Claims. December 2009 
https://www.fda.gov/downloads/drugs/guidances/ucm193282.pdf  
21. US Department of Health and Human Services.  The Health Insurance Portability and 
Accountability Act (HIPAA) of 1996 (P.L.104-191) [HIPAA].  
http://aspe.hhs.gov/admnsimp/pl104191.htm. Effective August 21, 1996. 
 


 
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14 APPENDICES 
14.1 Clinician Erythema Assessment Photonumeric Guide 


 
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14.2 Items From Satisfaction Assessment for Rosacea Facial Redness 
 
INSTRUCTIONS 
This questionnaire includes two questions about how satisfied you are with the facial 
redness caused by your rosacea.   
 
Before answering each question, please look in the mirror and think about the redness 
on your whole face caused by your rosacea.  Please mark ONE “X” in the box (
) 
that best describes your satisfaction right now.   
 
There are no right or wrong answers to any of the questions. 
 
1. Right now, how satisfied are you with the appearance of your facial redness? 
Very 
dissatisfied 
Dissatisfied 
Neither 
satisfied nor 
dissatisfied 
Satisfied 
Very satisfied 
▼ 
▼ 
▼ 
▼ 
▼ 
0 
1 
2 
3 
4 
 
 
2. Right now, how satisfied are you with the amount of redness on your face? 
Very 
dissatisfied 
Dissatisfied 
Neither 
satisfied nor 
dissatisfied 
Satisfied 
Very satisfied 
▼ 
▼ 
▼ 
▼ 
▼ 
0 
1 
2 
3 
4 
 
 


 
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14.3 FACE-Q™ - Satisfaction With Skin 


 
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FACE-QTM - SATISFACTION WITH SKIN 
For each question, circle only one answer. With your facial skin (complexion) in mind, in 
the past week, how satisfied or dissatisfied have you been with: 
 
Very 
Dissatisfied 
Somewhat 
Dissatisfied 
Somewhat 
Satisfied 
Very 
Satisfied 
a. How your facial skin looks at the end 
of your day? 
1 
2 
3 
4 
b. How healthy your facial skin looks? 
1 
2 
3 
4 
c. 
How attractive your facial skin makes 
you look? 
1 
2 
3 
4 
d. How smooth your facial skin looks? 
1 
2 
3 
4 
e. How clear your facial skin 
(complexion) looks? 
1 
2 
3 
4 
f. 
How refreshed your facial skin makes 
you look? 
1 
2 
3 
4 
g. 
How hydrated your facial skin looks? 
1 
2 
3 
4 
h. How your facial skin looks when you 
first wake up? 
1 
2 
3 
4 
i. 
How radiant your facial skin looks? 
1 
2 
3 
4 
j. 
How the tone (color) of your facial 
skin looks? 
1 
2 
3 
4 
k. 
How your pores look? 
1 
2 
3 
4 
l. 
How even-colored your facial skin 
looks? 
1 
2 
3 
4 
Copyright©2013 Memorial Sloan-Kettering Cancer Center, New York, USA. All rights reserved.  
 
The FACE-Q, authored by Drs. Andrea Pusic, Anne Klassen and Stefan Cano, is the copyright of Memorial Sloan-Kettering Cancer 
Center (Copyright ©2013, Memorial Sloan-Kettering Cancer Center). The FACE-Q has been provided under license from 
Memorial Sloan-Kettering Cancer Center and must not be copied, distributed or used in any way without the prior written 
consent of Memorial Sloan-Kettering Cancer Center.  
 
Note to Investigators: This scale can be used independently of the other scales. A REDCap Data Dictionary file is 
available (http://projectredcap.org/). 
Psychometric Paper: Klassen AF, Cano SJ, Schwitzer J, Baker SB, Carruthers A, Carruthers J, Chapas A, Pusic AL. 
Development and Psychometric Validation of the FACE-Q Skin, Lips and Facial Rhytides Appearance Scales and 
Adverse Effect Checklists for Cosmetic Procedures. JAMA Dermatol. 2016 Apr 1;152(4):443-51. 
 


 
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FACE-QTM - SATISFACTION WITH SKIN CONVERSION TABLE 
Instructions: Higher scores reflect a better outcome. If missing data is less than 50% of the scale’s items, 
insert the mean of the completed items. Use the Conversion Table below to convert the raw scale 
summed score into a score from 0 (worst) to 100 (best).
 
SUM SCORE 
EQUIVALENT RASCH TRANSFORMED SCORE (0-100) 
12 
0 
13 
3 
14 
9 
15 
14 
16 
18 
17 
21 
18 
24 
19 
26 
20 
29 
21 
32 
22 
34 
23 
36 
24 
39 
25 
41 
26 
43 
27 
45 
28 
47 
29 
49 
30 
51 
31 
53 
32 
55 
33 
57 
34 
59 
35 
61 
36 
63 
37 
65 
38 
67 
39 
69 
40 
72 
41 
74 
42 
76 
43 
79 
44 
81 
45 
84 
46 
88 
47 
93 
48 
100 


 
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CONFIDENTIAL 
Investigator Signature Page 
Protocol Title: 
Multicenter, Open-Label, Interventional Study on the Safety and 
Tolerability of Oxymetazoline and Energy-Based Therapy in Subjects 
with Rosacea 
 
Protocol Number: 
CMO-MA-MED-0530 
Confidentiality and cGCP Compliance Statement 
I, the undersigned, have reviewed this protocol (and amendments), including appendices, and I 
will conduct the study as described in compliance with this protocol (and amendments), GCP, 
and relevant ICH guidelines. 
Once the protocol has been approved by the IEC/IRB, I will not modify this protocol without 
obtaining prior approval of Allergan and of the IEC/IRB. I will submit the protocol amendments 
and/or any ICF modifications to Allergan and IEC/IRB, and approval will be obtained before 
any amendments are implemented. 
I understand that all information obtained during the conduct of the study with regard to the 
subjects’ state of health will be regarded as confidential. No subjects’ names will be disclosed. 
All subjects will be identified by assigned numbers on all eCRFs, laboratory samples, or source 
documents forwarded to the sponsor. Clinical information may be reviewed by the sponsor or its 
agents or regulatory agencies. Agreement must be obtained from the subject before disclosure of 
subject information to a third party. 
Information developed in this clinical study may be disclosed by Allergan, to other clinical 
investigators, regulatory agencies, or other health authority or government agencies as required. 
 
 
 
Investigator Signature 
 
Date 
 
 
 
Printed Name 
 
 
 
 
 
Institution 
 
 
 

SAP_000.pdf: 
16.1.9 
Documentation of Statistical Methods 
 


StudyID: CMO-MA
Study Title: Multicen
Tolerabil$ of Ox)mretazo
Rosacea
StudyPhase: IV
Version 1 .1
Date: June 28, 2018
Prepared bY: YiYong Fu,
Biostatistics,
Date ofApproval:
Approved bY: \bu4g Zhu, PhD
Safety and
:cts with
Associate Vicb Presidont,
Biostatistics, Allergan Plo'


 
1 
 
Contents 
1. 
Introduction ........................................................................................................................ 3 
1.1 
Primary Study Objectives and Design ..................................................................... 3 
1.1.1 Study Design ................................................................................................ 3 
1.1.2 Primary Objectives ....................................................................................... 4 
1.1.3 Secondary and Other Objectives .................................................................. 4 
2. 
Analysis Populations and Data Conventions ..................................................................... 4 
2.1 
Analysis Populations ................................................................................................ 4 
2.2 
Visit and Timepoint Windows .................................................................................. 5 
2.3 
Data Conventions ..................................................................................................... 5 
3. 
Disposition and Exit Status ................................................................................................ 7 
3.1 
Screening Log Data .................................................................................................. 7 
3.2 
Disposition and Exit Status ...................................................................................... 7 
4. 
Demographics and Baseline Characteristics ...................................................................... 7 
4.1 
Demographics .......................................................................................................... 7 
4.2 
Prior Medications ..................................................................................................... 8 
4.3 
Concomitant Medications ........................................................................................ 8 
4.4 
Medical History ........................................................................................................ 9 
5. 
Efficacy Analyses ............................................................................................................ 10 
5.1 
Collection of Efficacy Measurements and Derivation of Efficacy Variables ........ 10 
5.2 
Analyses of Efficacy Variable(s) ............................................................................ 10 
5.3 
Other Analyses of Efficacy Variable(s) .................................................................. 11 
5.4 
Subgroup Analyses for Efficacy Variables ............................................................. 11 
6. 
Safety Analyses ................................................................................................................ 12 
6.1 
Exposure to Study Treatment(s) ............................................................................. 12 
6.2 
Adverse Events....................................................................................................... 12 
6.3 
Serious Adverse Events .......................................................................................... 14 
6.4 
Dermal Tolerability Assessments ........................................................................... 16 
6.5 
Clinician’s Telangiectasia Assessments (CTA) ...................................................... 16 
6.6 
Vital Signs .............................................................................................................. 17 
6.7 
Other Safety Analyses ............................................................................................ 17 


 
2 
 
6.8 
Subgroup Analyses for Safety Variables ................................................................ 17 
7. 
Pharmacokinetic, Biomarker, Genomic, or Immunogenicity Data Analyses .................. 17 
8. 
Health Outcomes Data Analyses ..................................................................................... 17 
9. 
Interim Analyses .............................................................................................................. 17 
10. Data Collected but not Analyzed ..................................................................................... 17 
11. Deviations from Protocol ................................................................................................. 17 
12. References ........................................................................................................................ 18 
13. Amendment(s) ................................................................................................................. 18 
 
 


 
3 
 
1. 
Introduction 
The purpose of this statistical analysis plan (SAP) is to provide details of the statistical 
analyses and reporting that are outlined in the study protocol, which is dated on Oct 12, 2017 
and titled “Multicenter, Open-Label, Interventional Study on the Safety and Tolerability of 
Oxymetazoline and Energy-Based Therapy in Subjects with Rosacea”.  This SAP should be 
reviewed in conjunction with the study protocol. Information contained in the protocol will 
not be restated unless it is essential for the descriptions in this SAP. In case of any 
discrepancies (for example, the definition of the Safety Analysis Population) between the 
protocol and the SAP, the SAP will supersede the protocol, as the SAP is intended to be more 
specific and precise with respect to statistical analysis and reporting.  Any amendments to the 
SAP will be made prior to database lock. Any additional analyses not described in the final 
SAP or deviations from the final SAP will be documented in the clinical study report.  
This study is a Phase 4 study sponsored by Allergan Plc. This study is a multicenter, 
interventional, open-label safety and tolerability study to evaluate the safety and tolerability 
of oxymetazoline HCl cream 1.0% when used as an adjunctive treatment to energy-based 
therapy for subjects with moderate to severe persistent facial erythema associated with 
rosacea. 
 
Approximately 45 subjects will be enrolled into this study at 4 clinical sites in the United 
States. The duration of the study for each subject is 10 weeks. This includes a screening 
period of up to 2 weeks, a treatment period of 8 weeks, comprising of daily dosing of study 
drug and 2 energy-based therapy sessions, followed by a final exit visit at Week 8 (Day 56). 
 
There will be no interim analysis. One final analysis is planned for this study. The final 
analysis will be performed at the completion of the study. Database lock will be executed for 
the final analysis.  
 
 
1.1 
Primary Study Objectives and Design 
1.1.1 Study Design 
This is a multicenter, interventional, single-arm, open-label safety and tolerability study. 
 
Sample size calculation and power consideration are discussed in Section 8.2 of the study 
protocol. A total of 45 subjects with rosacea-associated moderate to severe persistent facial 
erythema will be enrolled into this study. Subjects will be screened for eligibility, and will be 
consented for the study entry. 


 
4 
 
 
On Day 1, all subjects will receive one of the following energy-based therapies: Potassium 
Titanyl Phosphate (KTP), Pulsed Dye Laser (PDL) or Intense Pulsed Light (IPL). After a 2-
day washout, oxymetazoline HCl cream 1.0% will be applied once-daily starting from Day 3 
up through Day 27. On Day 29, all subjects will receive a second energy-based therapy, 
followed by a 2-day washout and then once daily application of oxymetazoline HC1 cream 
1.0% up through Day 56. 
 
1.1.2 Primary Objectives 
The primary objective is to evaluate the safety and tolerability of oxymetazoline HCl cream 
1.0% when used as an adjunctive treatment to energy-based therapy for subjects with 
moderate to severe persistent facial erythema associated with rosacea.    
 
1.1.3 Secondary and Other Objectives 
The secondary objective is to evaluate preliminary measures of efficacy of oxymetazoline 
HCl cream 1.0% when used as an adjunctive treatment to energy-based therapy for subjects 
with moderate to severe persistent facial erythema associated with rosacea. 
 
 
2. 
Analysis Populations and Data Conventions 
2.1 
Analysis Populations 
To adequately describe the appropriate statistical analyses, four analysis populations are 
defined as follows: 
• 
Enrolled Population: consists of all subjects who signed an informed consent form 
(ICF), thus deemed as enrolled for the study. 
• 
Safety Analysis Population: consists of all enrolled subjects who met the eligibility 
criteria and had an energy-based therapy and received at least one dose of study drug as 
treatment in this study.  
• 
Evaluable Population: consists of all safety subjects who had at least one baseline 
efficacy assessments at Day 1 or prior to Day 1 and had at least one post-treatment efficacy 
assessments between Day 3 and Day 56, inclusive. 
• 
      Per Protocol Population: consists of all evaluable subjects who have not had any 
significant violations of the protocol, including but not limiting to significant deviations 
from the scheduled visit windows.  


 
5 
 
 
Unless specified otherwise, the enrolled population will be used for subject disposition, 
demographics, and baseline characteristics summaries; the safety analysis population will be 
used for safety analyses, and the evaluable population will be used for the efficacy analyses. 
Efficacy analyses may be repeated on the per protocol population if significant protocol 
violations are found prevalent in the evaluable population.  
 
Note that in the context of this analysis plan (including the Table/Listing/Figure mockup 
shells), the terms safety analysis population and safety population are interchangeably used, 
and subjects in the safety population can be called safety subjects and subjects in the 
evaluable population can be called evaluable subjects.   
 
 
2.2 
Visit and Timepoint Windows 
There is no plan to programmatically derive visit/timepoint windows. The scheduled 
visits/timepoints as recorded on the electronic Case Report Form (CRF) will be directly taken 
as the analysis visits/timepoints and will be used in reporting and analyses. The analysis 
visits include the Screening Visit, the Baseline (Day 1) Visit, the Day 3 Visit, the Day 29 
Visit, the Day 31 Visit and the Day 56 (Exit Visit). The analysis timepoints corresponding to 
each visit on and after Day 1 include the Pre-Dose and the Post-Dose.  Also refer to Table 1 
Schedule of Assessments and Procedures (page 18) of the Protocol (Oct 12, 2017) for 
scheduled visits/timepoints.     
 
If there are multiple observations of same assessment within the same scheduled 
visit/timepoint window, all values of multiple observations will be included for listing, but 
only the mean value of multiple observations will be used for the by-visit/timepoint summary 
or analysis.  Assessment outside the scheduled visit/timepoint window will be marked as 
unscheduled assessment, and will be used for listing only.  
 
 
2.3 
Data Conventions 
 
2.3.1   Study day 
For each subject, the reference start date (also referred to as Day 1) is the date when the 
subject had an energy-based therapy. Study day will be calculated using visit date and the 


 
6 
 
reference start date as follows: (1) study day = visit date – reference start date + 1, for any 
visit date ≥ reference start date.  (2) study day = visit date – reference start date, for any visit 
date < reference start date. 
 
2.3.2   Imputation for missing measurement or assessment data 
On some certain parameters, a subject has multiple assessments prior to the initiation of the 
energy-based therapy at Day 1. Specifically, those parameters include vital sign 
measurements, urine pregnancy tests, Clinician’s Telangiectasia Assessments (CTA), 
Satisfaction assessments for Rosacea facial redness, FACE-Q satisfaction with skin scale.  
The baseline values for subjects on those parameters will be derived using the rule of Last 
Observation Carried Forward (LOCF) as follows: The value immediately prior to the 
initiation of energy-based therapy at Day 1 will be used as the baseline value; if that value is 
missing or does not exist, then the value at screening will be used.  On other parameters, a 
subject has one single assessment or measurement during screening or prior to the initiation 
of the energy-based therapy at Day 1, then the single value will simply be used as the 
baseline value for the subject.    
 
There is no imputation of missing values for any post-baseline measurements or assessments. 
All data summaries and analyses of post-baseline data will be conducted using observed 
cases. 
 
2.3.3   Study end date for patient 
Study end date for each individual patient is defined as the date of completion of last 
assessment on the Day 56 visit or the date of the early withdrawal visit in case of earlier 
discontinuation from treatment.  Note that subjects who are discontinued earlier from 
treatment for whatever reasons will be invited to attend the early withdrawal visit for the end-
of-study data collection.   
 
2.3.4   Study completer 
Study completers are defined as those evaluable subjects who have completed the last 
assessment on the Day 56 visit.   
 
2.3.5   Other conventions 
Summary statistics (used interchangeably with the term descriptive statistics) for continuous 
data include sample size (N), mean, standard deviation (SD), median, minimum, and 
maximum. Categorical variables will be summarized using sample size (N), frequency and 
percentages of patients. In calculating the percentage, unless specified otherwise, the count of 


 
7 
 
subjects “at risk” will be used as denominator.   Ordinal variables will be handled as 
categorical variables when presenting summary statistics using ordinal variables.    
 
Change from baseline is calculated as follow-up minus baseline. Percentage change from 
baseline is calculated as change from baseline divided by baseline value, then multiplied by 
100. If baseline value is zero, percentage change from baseline will be undefined. If baseline 
value is missing, percentage change from baseline will be missing. 
 
Data will be pooled across clinical sites/centers for analyses with an exception of one patient 
enrollment table.  
 
The International System of Units (Système international d'unités or SI) is the current 
international standard metric system. The SI units will be used for the reporting in all 
Tables/Figures/Listings for this study.   
 
All statistical analysis and reporting will be performed using SAS® version 9.3 or higher. 
 
    
3. 
Disposition and Exit Status 
3.1 
Screening Log Data 
Subject eligibility criteria (including both inclusion and exclusion criteria) and date of 
informed consent will be listed for the enrolled population. Note that date of informed 
consent will be included in the subject disposition listing.  
 
3.2 
Disposition and Exit Status 
Reasons for exclusion from safety population will summarized and will be listed for the 
enrolled population. Subject disposition will be listed for the enrolled population.  
 
 
4. 
Demographics and Baseline Characteristics 
4.1 
Demographics 
All patient demographic and baseline characteristic data will be summarized using 
descriptive statistics for the enrolled population and the safety population. 


 
8 
 
 
Age (years) captured at enrollment will be summarized as a continuous variable. Other 
continuous variables to be presented include weight, height and body mass index (BMI) and 
baseline vital signs (i.e., blood pressure, pulse rate, and oral body temperature).  Categorical 
or ordinal variables to be presented include sex, race, ethnicity, the type of energy-based 
therapy on Day 1 and Fitzpatrick skin phototype. 
 
Demographic tables will also be presented for the safety population stratified by the presence 
or absence of Treatment-Emergent Adverse Events (TEAE) during the study, and by whether 
having had at least 1-grade worsening from baseline in Clinician’s Telangiectasia 
Assessments (CTA) at any timepoint in the study. 
 
All demographic data will be listed.  
 
4.2 
Prior Medications 
Prior medications are defined as any medication which is administered any time prior to the 
initiation of the energy-based therapy treatment at Day 1 regardless when the medication 
stops. 
 
Prior medications will be coded by the Anatomical Therapeutic Chemical (ATC) 
classification system according to the World Health Organization (WHO) Drug WHODDE 
March 2016 or later. Medications will be summarized by ATC class (level 2) and subclass 
preferred term (PT) for all patients in the safety analysis cohort.  
 
The summary tables will show the frequency count and percentage of patients with at least 
1 usage of medications on the subclass level within each ATC class, sorted alphabetically. 
Percentages will be calculated using the number of patients in the safety population as the 
denominator. 
 
All prior medications will be listed. 
 
 
4.3 
Concomitant Medications 
Concomitant medications encompass any medication that is administered any time after the 
initiation of the energy-based therapy, regardless of when the medication starts or stops. Note 
that concomitant medication includes on-going prior medications. i.e., medicinal products 


 
9 
 
that are administered prior to the initiation of the energy-based therapy at Day 1 and is still 
being used during the study.  
 
Any concomitant medication will be recorded at each visit, including the medication name, 
dose, unit, frequency, route of administration, indication, and medication start and end dates. 
 
Concomitant medications will be coded by the ATC classification system according to the 
WHO Drug WHODDE March 2016 or later. Medications will be summarized by ATC class 
(level 2) and subclass (PT) for all patients in the safety analysis cohort.  
 
The summary tables will show the frequency count and percentage of patients with at least 
1 usage of medication on the subclass level within each ATC class, sorted alphabetically. 
Percentages will be calculated using the number of patients in the safety population as the 
denominator. 
 
All concomitant medications will be listed. 
 
Prohibited Medications are listed in Section 5.6.10.1 of the Protocol.  Prohibited concomitant 
medications that were inadvertently administered will be summarized similarly as that for 
concomitant medications.  Listing will also be provided for prohibited medications that were 
inadvertently administered.  
 
Per Section 5.6.10.2 of the Protocol, treatments by laser, light-source, or other energy based 
therapies to the face, other than those treatments performed as part of the study, are not 
permitted during the study. Dermatological treatments on the face (e.g., facial peels, 
microdermabrasion, exfoliating treatments) are prohibited for the duration of the study.  The 
use of any of such treatments is considered as a deviation (violation) of protocol per this SAP.  
Listing of protocol deviation (violation) will be provided. 
 
 
4.4 
Medical History 
Descriptions of medical history findings will be coded using Medical Dictionary for 
Regulatory Activities (MedDRA) version 20.1 or later. Medical history will be summarized 
for the safety population by the number and percentage of patients within each system organ 
class (SOC) and PT, sorted descending overall frequency. 
 


 
10 
 
Medical history will be listed for all patients in the safety population. Medical history data 
listings will be sorted by patient number, start date, SOC, PT and verbatim term. 
 
 
5. 
Efficacy Analyses 
For this study, efficacy analyses will be exploratory in nature.  Certain efficacy analyses will 
be conducted to evaluate the effect of daily application of oxymetazoline 1.0% cream 
adjunctive to energy-based therapy on Clinician Erythema Assessment (CEA), rosacea facial 
redness and subject’s satisfaction rating.  These analyses as described below will be based on 
the evaluable population.  
  
5.1 
Collection of Efficacy Measurements and Derivation of 
Efficacy Variables 
The following measurements and variables are of the primary interest. 
 
• Measurement: CEA;  
Variable: Improvement on CEA from baseline.  An improvement is defined by a 
negative change from baseline.   
 
• Measurement: Satisfaction rating per the Satisfaction Assessment for Rosacea Facial 
Redness; 
Variable: Proportion of subjects who rate “Satisfied” or “Very Satisfied”.    
 
• Measurement: Satisfaction rating per the FACE-Q Satisfaction with Skin Scale; 
Variable: Proportion of subjects who rate “Somewhat Satisfied” or “Very Satisfied”.   
  
• Measurement: Rosacea facial redness using DIA of standardized facial photographs;  
Variable: Percentage change from baseline in rosacea facial redness. 
 
5.2 
Analyses of Efficacy Variable(s) 
There is no statistical testing of hypotheses pertaining to efficacy variables. Statistical 
inference will be limited to the construction of distribution-free 95% CI for the median 
percentage change from baseline variables, since these percentage change variables are 
known for the deviation from normality in distribution.  The distribution-free 95% CI for the 


 
11 
 
median will be calculated using SAS® procedure Proc Univariate.  In this section, summary 
tables mainly in the forms of descriptive statistics will be presented for the above-specified 
efficacy and patient reported outcomes (PRO) variables.  
 
• The number and percentage of subjects with at least a 1-grade improvement on the 
CEA from baseline, by visit/timepoint. 
• Summary statistics of CEA by visit/timepoint. 
• Proportion of subjects indicating Satisfied or Very Satisfied with treatment on the 
Items of Satisfaction Assessment for Rosacea Facial Redness, by visit.  There are two 
items (questions). See Appendix 14.2 of the Protocol.  Item 1 (Question 1) is: Right 
now, how satisfied are you with the appearance of your facial redness?  Item 2 
(Question 2) is: Right now, how satisfied are you with the appearance of the amount 
of redness on your face?  This summary will be repeated for each of the two items. 
• Proportion of subjects indicating Somewhat Satisfied or Very Satisfied with treatment 
on the FACE-Q Satisfaction with Skin Scale, by visit. There are 12 questions on the 
FACE-Q Satisfaction assessments regarding the subjects’ rating of their satisfaction 
with skin. See Appendix 14.3 of the Protocol. This summary will be repeated for the 
response to each of the 12 questions, and for the average response to the 12 questions.  
• Percentage change from baseline in rosacea facial redness using Digital Image 
Analysis (DIA) of standardized facial photographs, by visit/timepoint. This summary 
table will be presented if the rosacea facial redness data are obtained and such facial 
redness can be quantified.  This summary table for the percentage change from 
baseline in rosacea facial redness will be provided.  
 
5.3 
Other Analyses of Efficacy Variable(s) 
Not applicable. 
 
5.4 
Subgroup Analyses for Efficacy Variables 
Not applicable. 
 
 
 


 
12 
 
6. 
Safety Analyses 
All safety analyses will be based on the safety population. Safety will be assessed primarily 
in terms of the frequency count and the binominal incidence proportion of the adverse events 
of interest. The binomial incidence proportion for a given event of interest during a certain 
period is defined as the number of unique patients who have experienced the event of interest 
in the period divided by the number of patients in the safety population, then multiplied by 
100.  Note that, for the calculation of the incidence proportion, the numerator is counted at 
subject level. Specifically, if a subject has experienced the event(s) of interest (at a given 
summarization level) more than once during the period, he/she is counted only once into the 
numerator. The binomial incidence proportion of an event is also called the percentage of 
subjects who have had such an event. The two terms are used interchangeably.  The 95% CIs 
for binomial incidence proportion will also be calculated using the Clopper and Pearson 
exact method (via SAS® procedure Proc Freq).     
 
 
6.1 
Exposure to Study Treatment(s) 
Treatment duration in days will be calculated as:  Date of last dose of study medication - 
Date of the initiation of the energy-based therapy + 1.  Treatment duration will be 
summarized using descriptive statistics. Number of energy-based therapies administered and 
number of days in which Oxymetazoline 1.0% cream had been applied over the study period 
will be summarized using descriptive statistics.   
 
Partial or missing start/end dates will be handled as per Section 2.3.3. 
 
All treatment data will be listed. 
 
 
6.2 
Adverse Events 
Adverse events will be coded using MedDRA version 20.1 or later to give a PT and a SOC 
term for each event. 
 
An adverse event (AE) is defined as any untoward medical occurrence in a clinical 
investigational patient administered a pharmaceutical (investigational) product and which 
does not necessarily have to have a causal relationship with this treatment.     
 


 
13 
 
All AEs will be included in by-subject AE listings. A separate listing will be created with all 
the distinct levels of SOC and PT, and the verbatim investigator description reported in the 
study. Sorting will be by earliest observed SOC, PT within SOC and then verbatim 
description. 
 
A treatment-emergent adverse event (TEAE) is a post-baseline AE where (i) there is no pre-
treatment AE of the same MedDRA primary SOC and PT; or (ii) the maximum severity 
during the post-baseline period is greater than the maximal severity of any pre-treatment AE 
of the same MedDRA primary SOC and PT during the screening/baseline period.  Note that 
the post-baseline period of the study starts upon the initiation of the energy-based therapy at 
Day 1.  
 
Any AEs reported after signing of the Informed Consent Form and prior to the energy-based 
therapy on Day 1 are considered pretreatment AEs (PTAEs) 
 
Relationship to study drug is categorized as ‘related’, ‘possibly related’, ‘unlikely related’, 
‘not related’, and ‘not assessable’. Relationship to trial medication as per investigator is not 
expected to be missing after data cleaning. However, if relationship is confirmed as missing, 
the AE will be considered as treatment related as per PI.  
 
An overall summary of frequency count and the binomial incidence proportion with 
associated 95% CIs will be presented to describe the incidents of TEAEs. Note that 95% CIs 
of the binomial incidence proportion will be presented for the overall summary analyses of 
TEAEs, but not for the by-visit/timepoint analyses.  Percentages and corresponding 95% CIs 
will be displayed to 1 decimal place.  
 
Each type of AE will be tabulated by SOC and PT within SOC.  The SOC and PT within 
SOC will be sorted by descending frequency. If a subject has multiple occurrences (start and 
stop) of an event associated with a specific SOC and PT, a patient will only be counted once 
in the incidence count for the SOC level and once at each PT within the SOC level.  
 
The incidence of all TEAEs by SOC and PT will be presented for the following categories: 
• 
Any TEAE 
• 
Any TEAE related to energy-based therapy and leading to discontinuation of study 
medication 
• 
Any TEAE related to treatment (i.e., study medication or energy-based therapy or 
both)  


 
14 
 
• 
Any TEAE by maximum severity 
• 
Any PTAE 
 
 
The following listings will be provided: 
• 
Listing of all TEAE 
• 
Listing of patients with TEAEs related to energy-based therapy and leading to 
            discontinuation of study medication 
• 
Listing of patients with TEAEs leading to discontinuation of treatment 
 
6.3 
Serious Adverse Events 
A serious adverse event (SAE) is any AE occurring at any dose that results in any of the 
following outcomes: death, a life-threatening AE, inpatient hospitalization or prolongation of 
existing hospitalization, a persistent or significant disability/incapacity, or a congenital 
anomaly/birth defect. Important medical events that may not result in death, be life-
threatening, or require hospitalization may be considered a SAE when, based upon 
appropriate medical judgment, they may jeopardize the patient and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition. Allergan 
considers all cancer AEs as SAEs. In addition, an abortion (spontaneous or non-spontaneous) 
is also considered a SAE. Any pre-planned surgery or procedure should be clearly 
documented in the source documents at the center by the medically qualified investigator at 
the time of the patient’s entry into the study. If it has not been documented at the time of the 
patient’s entry into the study, then it should be documented as a SAE and reported to Allergan.  
 
If an unexpected AE is serious and suspected, it is a suspected “unexpected” serious adverse 
reactions (SUSAR). See Section of 7.1.2.1.2 of the Protocol for details, such as what is 
considered as “unexpected”.    
 
An overall summary of frequency count and the binomial incidence proportion with the 
associated 95% CIs will be presented to describe the incidents of treatment emergent 
SAEs. Note that 95% CIs of the binomial incidence proportion will be presented for the 
overall summary analyses of SAE, but not for the by-visit/timepoint analyses.  Percentages 
and corresponding 95% CIs will be displayed to 1 decimal place.   
 
The incidence of all treatment-emergent SAEs by SOC and PT within SOC will be presented 
for the following categories: 


 
15 
 
• 
Any SAE 
• 
Any SAE related to energy-based therapy and leading to discontinuation of study 
medication 
• 
Any SAE related to treatment (i.e., study medication or energy-based therapy or both) 
• 
Any SAE by maximum severity 
• 
Any SUSAR 
 
 
 
The following listings will be provided: 
• 
Listing of subjects who died 
• 
Listing of subjects with treatment-emergent SAEs 
• 
Listing of subjects with treatment-emergent SAEs related to energy-based therapy 
            and leading to discontinuation of study medication          
• 
Listing of patients with treatment-emergent SAEs leading to discontinuation of 
treatment 
• 
Listing of patients with any SUSAR 
 
 
 


 
16 
 
6.4 
Dermal Tolerability Assessments 
Subject-assessed pruritus (itching), stinging/burning and dermatologist-assessed 
dryness and scaling will be summarized and displayed in terms of frequency count and 
proportion of subjects who reported at least a 1-grade worsening in severity from baseline at 
any time points over the study period.  
 
For all dermal tolerability assessments, the scale (grade) was:  0 = none, 1 = mild, 2 = 
moderate, 3 = severe. A subject is classified as having had a at least 1-grade worsening from 
baseline for a timepoint if his change from baseline value ≥ 1 for the timepoint.  The 
denominator used for calculating the proportion is the number of safety subjects who have 
baseline and at least one data of post-baseline dermal tolerability assessments.  
 
There is no testing of any hypothesis or interval estimation of proportions with respect to 
dermal tolerability assessments.   
 
Frequency count and proportion of subjects having had at least 1-grade worsening from 
baseline in dermal tolerability assessment parameters will be repeated and displayed by 
visit/timepoint. Summary statistics of dermal tolerability assessment parameters will also be 
presented by visit/timepoint.  
 
6.5 
Clinician’s Telangiectasia Assessments (CTA) 
Clinician’s Telangiectasia Assessments (CTA) will be summarized and displayed in terms of 
frequency count and proportion of subjects who report at least a 1-grade worsening in 
severity from baseline at any time point over the study period.  
 
For CTA, the scale was:  0 = clear skin, 1= almost clear, 2 = mild, 3 = moderate, 4 = severe. 
A subject is classified as having had a at least 1-grade worsening from baseline for a 
timepoint if his change from baseline value ≥ 1 for the timepoint.  The denominator used for 
calculating the proportion is the number of safety subjects who have baseline and at least one 
data of post-baseline CTA.  
 
There is no testing of any hypothesis or interval estimation of the proportions with respect to 
CTA.   
 
Frequency count and proportion of subjects having had at least a 1-grade worsening from 
baseline in CTA will also be presented by visit/timepoint. Summary statistics of CTA will 
also be presented by visit/timepoint.  
 
 


 
17 
 
 
 
6.6 
Vital Signs 
Vital signs (e.g., systolic/diastolic blood pressure, heart rate, respiration rate, and body 
temperature) will be summarized by visit/timepoint using descriptive statistics.   
 
6.7 
Other Safety Analyses 
All positive results of pregnancy tests will be listed.  
6.8 
Subgroup Analyses for Safety Variables 
Not applicable. 
 
7. 
Pharmacokinetic, Biomarker, Genomic, or Immunogenicity Data 
Analyses 
Not applicable. 
 
8. 
Health Outcomes Data Analyses 
Analyses of certain patient reported outcome (PRO) measurements are described in Section 
5.2.  No other health outcomes data analyses will be conducted.  
 
9. 
Interim Analyses 
There is no interim analysis planned for this study. 
 
10. 
Data Collected but not Analyzed 
Not Applicable. 
 
11. 
Deviations from Protocol  
The modified Intent-to-Treat Population as defined in the Protocol (Oct 12, 2017) will not be 
used for reporting and analyses, since the intent-to-treat principle is commonly confined to 
randomized trials.  Instead, an evaluable population, which is applicable for non-randomized 
trials, is defined in the SAP (See Section 2.1) and will be used for efficacy summaries.  


 
18 
 
Another deviation from the Protocol is that per protocol analysis population is defined and 
added into the SAP, and efficacy analyses will be repeated on the per protocol population if 
more than 20% of the evaluable subjects have had major protocol violations.  
 
 
 
12. 
References 
 
Journals or Software 
SAS Institute Inc., Cary, NC (2013): SAS version 9.3 
 
 
Allergan’s Study Protocol 
STUDY NUMBER 
STUDY TITLE 
CMO-MA-MED-0530 
Multicenter, Open-Label, Interventional Study on the Safety and 
Tolerability of Oxymetazoline and Energy-Based Therapy in Subjects with 
Rosacea 
 
 
 
 
 
 
 
13. 
Amendment(s) 
Per protocol analysis population is defined and added to the SAP of Version 1.1.  The per 
protocol population consists of all evaluable subjects who have not had any significant 
violations of the study protocol.  Patients who have had significant violations of the study 
protocol will be identified before the analyses on the per protocol population being 
performed. Efficacy analyses will be repeated on the per protocol population if more than 
20% of the evaluable subjects have had major protocol violations.  
 
As those specified in the study protocol, major protocol violations (deviations) may include, 
but are not limited to: 


 
19 
 
(1) Inclusion/Exclusion criteria violations. 
(2) Inadequate compliance with study drug. 
(3) Prohibited medications and treatments taken. Refer to the Protocol sub-sections 5.6.10.1 
and 5.6.10.2 for the list of prohibited medications and treatments.  
 (4) Significant deviations from the study drug administration schedule. Specifically, if a 
subject had ever deviated by more than 7 days from the scheduled visit windows, the subject 
will be considered as having had a major protocol violation. 
 
The final list of the major protocol deviations will be defined during the data review meeting 
and before the final study database lock day.