Clinical trial NCT03048058
Conditions: Rosacea
Sponsor: Wake Forest University Health Sciences
Start date: 2016-05-05; Completion date: 2017-06-01
Enrollment: 20 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
An investigator-blinded, prospective, 6 month study of subjects with persistent erythema associated with active rosacea will be conducted in 20 subjects aged 18 years and older. All subjects will receive standard-of-care brimonidine topical gel, 0.33% with instructions to apply it once daily per package insert. Adherence will be assessed using weekly internet surveys to document how often the medication is being used, as well as reminders about rosacea triggers and general use of brimonidine.

Detailed description:
An investigator-blinded, prospective, 6 month study of subjects with persistent erythema associated with active rosacea will be conducted in 20 subjects aged 18 years and older. All subjects will receive standard-of-care brimonidine topical gel, 0.33% with instructions to apply it once daily per package insert. Adherence will be assessed using weekly internet surveys to document how often the medication is being used, as well as reminders about rosacea triggers and general use of brimonidine.Subjects will be randomized 1:1 to be in the weekly internet survey group or the standard care non-survey group.

At each visit, review of the internet survey use will be done to assess adherence to the medication. . Disease severity measures ((Clinician's Erythema Assessment (CEA), and Lesion counts will be obtained. QOL will be measured.

Arms: arm 1: The internet survey will ask them how often they have used their medication that week, as well as giving them treatment tips and reminders about rosacea triggers. They will be asked a variety of questions during the weekly internet survey- such as the amount of erythema they currently have (measured by VAS scale), how much burning and stinging they have, how often they have used the medication and where did they apply the medication, as well as any additional side effects they may be having from the medication. arm 2: Topical drug and standard of care follow-up, no weekly survey; only survey during 3 month and 6 month visits
Interventions: intervention 1: brimonidine topical gel 0.33% & survey intervention 2: brimonidine topical gel 0.33% & SOC
Intervention descriptions: intervention 1: The internet survey will ask them how often they have used their medication that week, as well as giving them treatment tips and reminders about rosacea triggers. They will be asked a variety of questions during the weekly internet survey- such as the amount of erythema they currently have (measured by VAS scale), how much burning and stinging they have, how often they have used the medication and where did they apply the medication, as well as any additional side effects they may be having from the medication. intervention 2: All subjects will receive standard-of-care brimonidine topical gel 0.33%

Protocol documents:
Prot_SAP_000.pdf: 
WFUHS Dept of Dermatology 
Winston-Salem, NC 
Brimonidine Adherence 
Version:  Sept 23, 2015 
 
 
 
 
 
Title: 
Internet Surveys and their Impact on Adherence to 
Brimonidine and QOL in Patients with Rosacea 
 
  Protocol Number: 
II-Rosacea Brimonidine Adherence-SF2015 
 
Principal Investigator: 
Steve Feldman, MD, PhD 
sfeldman@wakehealth.edu 
Phone Number:  (336) 716-7740 
Fax Number:  (336) 713-4255 
 
Sub-Investigator: 
Adele Clark, PA-C 
adclark@wakehealth.edu 
Phone Number:  (336) 716-7465 
Fax Number: (336) 713-4255 
 
 
Sponsor:  
 
 
Wake Forest University Health Sciences 
 
Revision Date: 
 
Version 3; April 14, 2016 
 
Version 2; December 22, 2015 
 
 
 


WFUHS Dept of Dermatology 
Winston-Salem, NC 
Brimonidine Adherence 
Version:  Sept 23, 2015 
 
 
Table of Contents 
 
1.0 
INTRODUCTION 
 
2.0 
STUDY OBJECTIVES 
 
2.1 Study Design 
 
3.0 
STUDY POPULATION 
 
3.1 Subject Population 
 
3.2 Inclusion Criteria 
 
3.3 Exclusion Criteria 
 
4.0 
STUDY DESIGN 
 
4.1 Formulations 
 
4.2 Test Drug Dosage 
 
4.3 Efficacy and Safety 
 
4.4 Power of the Study 
 
4.5 Randomization, Stratification, and Blinding 
 
5.0 
SUBJECTS RISKS AND BENEFITS 
 
5.1 Potential Risks of Study Participation 
 
5.2 Adverse Events 
 
5.3 Serious Adverse Events 
 
5.4 Adverse Event Follow-up 
 
5.5 Confidentiality 
 
5.6 Participant Benefits 


Brimonidine Adherence 
Version:  Sept 23, 2015 
WFUHS Dept of Dermatology 
Winston-Salem, NC 
 
 
6.0 
METHODOLOGY 
 
6.1 Study Visits 
 
6.2 Visit Schedule 
 
6.3 Termination of Study 
 
7.0 
CONCOMITANT THERAPY 
 
 
8.0 
STUDY MANAGEMENT AND MATERIALS 
 
8.1 Study Materials 
 
 
8.2 Study Documentation 
 
8.2.1 Case Report Forms (CRFs) and Source Document Completion 
and Transfer of Study Data 
 
8.2.2 Transfer of Essential Study Documents  
 
 
8.2.3 Archiving of Study Documentation 
 
8.3 Monitoring and Quality Assurance 
 
9.0 
DATA ANAYLSIS 
 
9.1 Sample Size 
 
10.0 REFERENCES 
 
11.0 APPENDICES 


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SUMMARY 
 
 
 
 
Title: Internet Surveys and their Impact on Adherence to Brimonidine topical gel and 
QOL in Patients with Rosacea 
 
  Source of Funding: Wake Forest University Health Sciences 
 
Objective: 
Primary Objective: To assess adherence to topical brimonidine topical gel, 0.33% for the 
treatment of rosacea.  
Secondary Objectives: To determine the impact of reported adherence on rosacea 
outcomes, to identify factors that affect adherence to rosacea treatment and to assess QOL. 
 
Study Design: 
 
An investigator-blinded, prospective, 6 month study of subjects with persistent erythema 
associated with active rosacea will be conducted in 20 subjects aged 18 years and older. 
All subjects will receive standard-of-care brimonidine topical gel, 0.33% with instructions 
to apply it once daily per package insert. Adherence will be assessed using weekly internet 
surveys to document how often the medication is being used, as well as reminders about 
rosacea triggers and general use of brimonidine. 
 
Patients with persistent erythema associated with rosacea will be recruited from the 
Wake Forest Baptist Health Dermatology Clinics and IRB approved advertising. At the 
baseline screening visit, subjects will have the diagnosis of rosacea confirmed by an 
investigator. Patients will be classified as having erythematotelangiectatic or a 
combination erythematotelangiectatic and papulopustular. We will evaluate whether patients 
believe they have constant erythema or more intermittent flushing and blushing. Subjects 
will be informed of the benefits and risks of treatment. If they agree to participate, the 
subjects will give written consent approved by the Institutional Review Board and will be 
seen in follow up at 3 months and 6 months. 
 
Subjects will be randomized 1:1 to be in the weekly internet survey group (appendix) or 
the standard care non-survey group. The internet survey will ask them how often they 
have used their medication that week, as well as giving them treatment tips and reminders 
about rosacea triggers. They will be asked a variety of questions during the weekly internet 
survey- such as the amount of erythema they currently have (measured by VAS scale), 
how much burning and stinging they have, how often they have used the medication 
and where did they apply the medication, as well as any additional side effects they 


WFUHS Dept of Dermatology 
Winston-Salem, NC 
 
5 
 
may be having from the medication. 
 
Subjects in the non-internet survey group will just get these identical surveys at the Month 3 
and Month 6 visits. We are also interested in learning through the adherence surveys if 
subjects begin using the medication on an as needed basis, and if this affects the side 
effect profile and satisfaction with the medication. 
 
 
 
At each visit, review of the internet survey use and medication weights will be 
done. Disease severity measures ((Clinician’s Erythema Assessment (CEA), 
Patient Severity Assessment (PSA, Lesion counts)) will be obtained. Investigator 
and subject Visual Analog Scale (VAS) to measure facial erythema will be 
obtained. Adverse events will be logged at every visit. Attention will be paid 
to any symptoms of rebound erythema and more detailed information 
concerning location and timing will be collected. QOL surveys will be completed 
at the end of study visit. 
 


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1.0     
INTRODUCTION 
 
Rosacea is a chronic disease with great psychosocial and emotional impact. 
Topical therapies are the mainstay of rosacea treatment; however patients often 
continue to suffer from rosacea after being prescribed a treatment; poor adherence 
likely plays a role in poor treatment outcomes. Non-adherence is a patient’s 
failure to follow a medication regimen as directed by the physician. In many 
cases, non-adherence, rather than non- response, is the underlying cause of 
treatment failure. 
 
 
 
 
Brimonidine is a topical treatment for the persistent erythema associated with 
rosacea. Some patients have noticed some rebound flushing when using the 
medication. This raises the question about adherence to the medication in the 
setting of adverse effects. The general thought is that there is a relationship 
between adverse effects from medications and treatment adherence- the more often 
side effects occur the less often a medication may be taken. However that is not 
always the case. Many patients take medications such as isotretinoin and topical 
fluorouracil with well documented side effects. Yet adherence to these medications 
is often very good. So do any adverse effects from brimonidine affect patient 
adherence? 
 
 
 
 
Return office visits are used to follow treatment compliance and adherence. An 
online survey may provide an effective and more practical alternative to an extra 
office visit as a method to measure and promote improved adherence. Internet 
surveys may improve intrinsic motivation to take medication by making the patient 
feel cared for, enhancing a trusting patient-physician relationship. A good deal of 
real time information can be obtained through an internet survey. 
 
 
 
2.0     STUDY OBJECTIVES 
Primary Objective: To assess adherence to topical brimonidine for the 
treatment of rosacea. 
 
Secondary Objectives: To determine the impact of reported adherence on 
rosacea outcomes, To identify factors that affect adherence to rosacea 
treatment and to assess QOL. 
 
2.1       Study Design 
 
An investigator-blinded, prospective, 6 month study of subjects with 


WFUHS Dept of Dermatology 
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persistent erythema associated with active rosacea will be conducted 
in 20 subjects aged 18 years and older. All subjects will receive standard-
of-care brimonidine topical gel 0.33% with instructions to apply it once 
daily per package insert. Adherence will be assessed using weekly 
internet surveys to document how often the medication is being used, as 
well as reminders about rosacea triggers and general use of brimonidine. 
Before starting treatment, subjects will be reminded that bromonidine is 
indicated for persistent, not transient, erythema. They will be given a copy of 
the product package insert and a copy of the American Academy of 
Dermatology website (www.aad.org) information on rosacea that contains 
standardized information about the diagnosis and triggers. 
 
 
 
 
Patients with persistent erythema due to rosacea will be recruited from 
the Wake Forest Baptist Health Dermatology Clinic and IRB approved 
advertising. At the baseline screening visit, subjects will have the diagnosis 
of rosacea confirmed by an investigator. Patients will be classified as having 
erythematotelangiectatic or a combination erythematotelangiectatic and 
papulopustular. We will evaluate whether patients believe they have 
constant erythema or more intermittent flushing and blushing. Subjects 
will be informed of the benefits and risks of treatment as indicated in the 
package insert. If they agree to participate, the subjects will give written 
consent approved by the Institutional Review Board and will be seen in 
follow up at 3 months and 6 months. 
 
 
 
 
Subjects will be randomized (according to standard randomization tables)1:1 
to be in the weekly internet survey group (appendix) or the standard care 
non-survey group. The internet survey will ask them how often they have 
used their medication that week, as well as giving them treatment tips and 
reminders about rosacea triggers. They will be asked a variety of 
questions during the weekly internet survey- such as the amount of erythema 
they currently have (measured by VAS scale), how much burning and 
stinging they have, how often they have used the medication and where did 
they apply it, as well as any additional side effects they may be having 
from the medication. Subjects in the non-internet survey group will just 
get these identical surveys at the Month 3 and Month 6 visits. We are also 
interested in learning through the adherence surveys if subjects begin 
using the medication on an as needed basis, and if this affects the side 
effect profile and satisfaction with the medication. 
 
At each visit, review of the internet survey use and medication weights 
will be done. Disease severity measures (CEA, PSA, lesion counts) will 
be obtained. Investigator and subject VAS scales to measure facial erythema 


WFUHS Dept of Dermatology 
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will be obtained. Adverse events will be logged at every visit. Attention will 
be paid to any symptoms of rebound erythema and more detailed 
information concerning location and timing will be collected.  The lesion 
counts will also measure any papules or telangiectasia that may 
become more readily visible with the improvement in background 
erythema. Telangiectasia will be counted individually by facial 
quadrant as noted in the Lesion Count Appendix. Measuring 
individual visible telangiectasia is important as subjects may 
confuse these with underlying erythema of rosacea, thus affecting 
subject assessment of their disease. QOL surveys will be completed at 
the end of study visit. 
 
 
Descriptive statistics will be generated with mean ± standard deviation 
(S.D.) or median (interquartile range) for continuous measures depending on 
the distribution of the data and frequency distribution for categorical 
variables. Estimate for adherence rates will be obtained as the mean 
adherence rate along with the corresponding 95% confidence interval. 
 
 
 
 
3.0     STUDY POPULATION 
 
3.1 
Subject Population 
 
The study population will consist of 20 subjects aged 18 years and older with the 
diagnosis of persistent erythema associated with rosacea. Subjects will be recruited from 
Wake Forest University Department of Dermatology Clinics and IRB approved 
advertising. 
 
3.2 
Inclusion Criteria 
 
• 
Male or female subject with persistent erythema associated with 
rosacea, age greater than 18, who agrees to participate and provide 
written consent. 
 
• 
Have an Investigator Global Assessment of mild to moderate 
rosacea (IGA rating between 2 and 5 in the Investigator Global 
Assessment score which includes erythema in the assessment). 
 
• 
Access to a computer and the internet. 
 
 
 
 
 
 


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3.3 
Exclusion Criteria 
 
• 
Initiation or change in dose within 4 weeks of baseline of 
systemic anti‐inflammatory medication which may influence study 
outcome. 
• 
Use of topical therapy for rosacea within 2 weeks of baseline. 
• 
Use of systemic corticosteroids within 4 weeks of baseline. 
Presence of  a  concurrent  medical  condition  or  skin  
condition,  which  is determined  by  the  investigator  to  
potentially  interfere  with  study outcomes or patient assessments. 
• 
Subjects with known allergy or sensitivity to bromonidine 
topical gel, 0.33% or components therein. 
• 
Female subjects who are not postmenopausal for at least 1 year, 
surgically sterile, or willing to practice effective contraception 
during the study. Nursing mothers, pregnant women and women 
planning to become pregnant while on study are to be excluded. 
• 
Subjects 
with 
severe cardiovascular disease or vascular 
insufficiency.  
 
 
 
 
4.0 
STUDY DESIGN 
 
4.1 
Formulations 
 
Brimonidine Topical Gel, 0.33%, 30 gram tubes, three tubes per 
patient per each 3 month period, total of 6 tubes per patient.  
 
4.2 
Test Drug Dosage 
 
Subjects will use topical bromonidine once daily 
 
4.3 
Efficacy and Safety 
Evaluation for efficacy will include:  
Objective Clinical Efficacy: 
- 
Clinician’s Erythema Assessment (CEA) 
- 
Lesion counts 
- 
Investigator VAS scale ratings of erythema 
 
 
 
 
Subjective Clinical Efficacy: 
- 
Patient  Severity  Assessment  (PSA)Subject  VAS  scale  


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ratings  of erythema 
 
Subjective Symptom Improvement: 
 
- 
Quality of life will be measured with the DLQIi 
- 
Subject survey to identify factors that affect adherence to rosacea 
treatment such adverse effects of medication (erythema, burning, 
stinging) 
 
Safety will be based on adverse events reported by the patient or 
observed by the investigator. 
 
 
4.4 
Power of the Study 
 
The sample size of 20 subjects is designed to give us an estimate 
of the adherence rate and to provide adequate sampling to assess 
common patterns of adherence. 
 
4.5 
Randomization, Stratification, and Blinding 
 
Subjects will be randomized 1:1 to be in the weekly internet survey 
group (appendix) or the standard care non-survey group. 
 
Principal Investigator will be blinded to randomization and study group 
assignments for all study participants for the duration of the study.  The 
study coordinator will perform randomization.  All assessments at sub-
sequential visits will be performed prior to review of survey inquiries.  
 
 
5.0 
SUBJECTS RISKS AND BENEFITS 
 
5.1 
Potential Risks of Study Participation 
 
The risks of this study are minimal. Subjects would have the same 
risk of using bromonidine whether they were in the study or not. 
 
Alternative treatments will be discussed with all subjects prior to 
enrolling in the study. Alternative treatments for rosacea include, but 
are not limited to, topical (applied to the skin) antibiotic treatments, 
such as clindamycin, oral antibiotics such as cephalexin, and the use 
of antibacterial soaps. 
 
Answering questions on the QOL surveys may make the subject feel 
uncomfortable. Subjects will answer these surveys in the privacy of 


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the exam room and results will be kept confidential as part of the 
study data. 
 
5.2 
Adverse Events 
 
An adverse event in this study of approved medications is considered 
any unfavorable, harmful, or pathological change in a research subject 
as indicated by physical signs, symptoms, and/or clinically 
significant laboratory abnormalities that are considered product-
related. This definition includes: intercurrent illness; injuries; 
exacerbation of pre- existing conditions (excluding rosacea); adverse 
events occurring as a result of product withdrawal, abuse, or 
overdose; and a change in a laboratory variable if considered by the 
attending physician to be clinically significant or if it caused (or 
should have caused) the clinician to reduce or discontinue the use of 
the product or institute therapy.  This definition does not include 
inpatient or outpatient elective surgery for a condition that was 
present prior to the start of the trial and which has not worsened 
unexpectedly during the trial. 
  
To capture any adverse events related to rosacea, changes in lesion 
counts, papules and telangiectasia will be captured in the lesion count 
assessments. If a subject has an increase in visible papules (once the 
erythema is improved with the study drug), then this will be captured 
as an AE if a concomitant medication is added. 
 
The investigator will monitor the occurrence of adverse events 
during the course of the study. The investigator must provide to the 
Sponsor appropriate information concerning any findings that 
suggest significant hazards, contraindications, side effects or 
precautions pertinent to the safety of the study. 
 
All adverse events occurring after the Baseline visit must be 
recorded on the Adverse Event Case Report Form page. 
 
 
 
 
5.3 
Serious Adverse Events 
 
1. Definition An adverse event is considered a serious adverse 
event (SAE) if it: 
 
1. Is fatal  
2. is life threatening (i.e., results in an immediate risk of 
death); 
3. is persistently or significantly disabling/incapacitating; 


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4. results in, or prolongs, hospitalization; 
 
5. results in a congenital anomaly; 
 
6. is an event which, in the opinion of the investigator/Medical 
Monitor, may jeopardize the subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in 
this section. 
 
The definition of an SAE encompasses both known and 
unexpected events. 
 
2. Recording and Reporting Obligations for SAEs 
 
The investigator will provide the IRB appropriate information 
concerning any findings that suggest there has been an SAE 
related to the study drug. Any adverse event that is considered 
serious 
must 
be 
reported 
within 
one 
working 
day 
(IMMEDIATELY) to the IRB.  Serious adverse events 
(regardless of relationship) must also be reported to FDA. Clinical 
judgment should be exercised in deciding whether expedited 
reporting is appropriate in other situations. Important medical 
events that may not be immediately life- threatening, results in 
death, or hospitalization but may jeopardize the patient or may 
require intervention to prevent one of the outcomes listed 
above, should also be considered serious and reported to the 
sponsors. 
 
 
 
 
5.4 
Adverse Event Follow-up 
 
After the completion of the Screening visit, all untoward medical 
events (as defined in Section 5.2 above) will be documented as 
Adverse Events through the 6 Mo visit. Any adverse events not 
resolved by the 6 Mo visit and considered to be potentially related 
to the study medication will be followed as clinically indicated until 
their resolution or, if non-resolving, until considered stable. 
 
5.5 
Confidentiality 
 
All information provided by study participants will be kept 
confidential and identification numbers/initial will replace participant 
names once enrolled and at data entry. All study materials (including 
completed questionnaires, medical histories, severity scores and 


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adherence measures) will be kept in locked files accessible only to 
key study personnel. If the results of this study are written about in a 
journal article or presented at a professional meeting, individual 
participant names will not be used. 
 
5.6 
Participant Benefits 
 
Subjects will be given bromonidine gel at no cost to them. Subjects 
may have disease improvement resulting from participation in the 
study. Subjects will also be seen frequently in the dermatology clinic 
with the opportunity to have questions about their disease answered. 
Subjects may withdraw from the study at any time without prejudice 
or impact on their future health care. 
 
Subjects will not be compensated for participation in 
the study.  Study medication and study visits are 
provided at no cost. 
 
 
 
 
6.0 
METHODOLOGY 
 
6.1a 
Study Visits- 
 
Visit 1-Screening/Baseline 
 
The following procedures are required at the Screening visit: 
 
1. 
Written informed consent. 
2. 
Inclusion/Exclusion criteria must be met. 
3. 
Demographics, medical history, current medications 
4. 
Vital signs, weight and height 
5. 
Urine pregnancy test if applicable 
6. 
Clinician’s Erythema Assessment (CEA) 
7. 
IGA (for inclusion) 
8. 
Lesion counts 
9. 
Investigator VAS scale ratings of erythema 
10. 
Patient Severity Assessment (PSA) 
11 
Subject VAS scale ratings of erythema 
12. 
QOL survey (DLQI) 
13. 
Weigh and dispense study medication 
14. 
Internet randomization 
15. 
Subjects will be asked to return in 3 months 
 
Visit 2- Month 3 
 


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1. Review concomitant medications and adverse events 
2. Clinician’s Erythema Assessment (CEA) 
3. Lesion counts 
4. Investigator VAS scale ratings of erythema 
5. Patient Severity Assessment (PSA) 
6. Subject VAS scale ratings of erythema 
7. Subject QoL questionnaire and Internet survey, 
8. Weigh and collect/dispense study medication 
 
Visit 3- Month 6 
 
1. 
Review concomitant medications and adverse events 
2. 
Clinician’s Erythema Assessment (CEA) 
3. 
Lesion counts 
4. 
Investigator VAS scale ratings of erythema 
5. 
Patient Severity Assessment (PSA) 
6. 
Subject VAS scale ratings of erythema 
7. 
Subject QoL questionnaire and Internet Survey 
8. 
Weigh and collect study medication 


WFUHS Dept of Dermatology 
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6.2 Brimonidine Study Flow Chart 
 
 
 
 
 
 
 
 
 
 
Baseline 
  Month 3 
     Month 6 
Inc/Exc, Demographics Medical Hx/Con meds  
X 
Vital signs/weight/height  
 
 
 
X 
Urine pregnancy test   
 
 
 
X 
CEA, PSA 
 
 
 
 
 
X 
 
      X  
 
X 
 
Lesion Counts  
 
 
 
 
X 
 
      X  
 
X 
VAS scales for erythema (Subject and investigator) X 
 
      X  
 
X  
Weigh/Dispense Med  
 
 
 
X 
 
      X  
 
 
Weigh/Collect study med  
 
 
 
 
 
 
 
 
X 
QOL and Internet survey  
 
 
 
X 
 
     X  
 
X 
Internet Randomization  
 
 
 
X 
 
      
 
 
 
Con meds/ AEs 
 
 
 
 
 
 
     X  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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6.3 
Termination of Study 
 
Any subject may be discontinued from the study at any time at 
the discretion of the investigator if he/she feels it is in the best 
interest of that subject. 
 
A discontinuation occurs when an enrolled subject ceases 
participation in the study prior to completion of the 6 month 
visit, regardless of reason. The investigator must determine the 
reason for discontinuation of the study. If the subject 
discontinues from the study because of a serious adverse 
event, the event must be reported immediately to the IRB and 
be recorded in the case report form. 
 
Discontinuation 
 
A subject must be discontinued from the study if he or 
she: 
1. Uses any medications used in the exclusion 
criteria 
2. Has an allergic reaction to the study 
medication 
3. The investigator decides it is in the subject’s best interest 
to discontinue 
4. Study is cancelled by PI or by the Institutional Review Board 
 
7.0 
CONCOMITANT THERAPY 
 
Concomitant medication is defined as any medication the subject takes that is not 
specified in the treatment protocol. All such medications must be recorded in the 
subject’s medical record. The patient must not use any of the medications listed in 
the exclusion criteria, with one exception. If the subject complains of increased papules 
once baseline erythema has cleared and the patient desires treatment for the papules, a 
topical therapy (such as metronidazole) may be added per standard of care. This should 
help with subject retention over the course of the study while not interfering with the 
overall objective of the study to measure adherence to brimonidine. 
 
 


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The subject is not allowed to undergo radiation therapy, use cytostatic drugs, or 
any investigational agents for the duration of the study. 
 
 
 
8.0 
STUDY MANAGEMENT AND MATERIALS 
 
8.1 
Study Materials 
 
Study medication will be provided to the subject by the 
sponsor.. 
 
8.2 
Study Documentation 
 
8.2.1 Case Report Forms (CRFs) and Source Document Completion 
and Transfer of Study Data  
 
The investigator is required to prepare and maintain adequate and 
accurate case histories (i.e. medical records) designed to record all 
observations and other data pertinent to the study for each study 
participant. The medical records must contain adequate information 
to allow for verification of subject identity throughout the study. 
Investigators must retain a subject identification code list, should they 
need to contact the subjects after the study. This list should contain 
subject’s name, study ID number and telephone number and/or 
address, and will be held in confidentially at the investigator’s site after 
completion of the study. 
 
A Source Document will be completed for each subject enrolled in 
the study. Each subject’s source document will incorporate the safety 
and efficacy data points. 
 
8.2.2 Transfer of Essential Study Documents  
 
All essential documents (such as IRB approval, acknowledgements) are 
to be kept on site. 
 
8.2.3 Archiving of Study Documentation 
Study data and other essential documents should be retained for a 
minimum of two years after the last approval of a marketing application in 
an International Conference on Harmonization (ICH) region 
and until there are no pending or contemplated marketing applications in 
an ICH region. However, these documents should be retained for a 
longer period if required by the applicable legal requirements. 
 
8.3 Monitoring and Quality Assurance 


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The review of the subjects’ medical records will be performed in a 
manner 
to 
ensure 
that 
subject 
confidentiality 
is 
maintained. 
Inspections/audits, of the study date, will be carried out giving due 
consideration to data protection and subject confidentiality. 
 
 
 
 
 
 
9.0 
DATA ANALYSIS 
 
Descriptive statistics (SAS Statistical System, Cary NC) will be utilized to provide 
an overview of efficacy and safety parameters, Baseline characteristics and QoL 
responses of study participants will be compared between the two groups. 
Descriptive statistics consisting of frequency tables and percents for categorical 
variables and means, medians, standard deviations, ranges, etc. for continuous variables 
will be tabulated. Simple comparisons of baseline characteristics between treatment 
groups will be made using the Chi-square tests for categorical variables and the two-
sample t-tests or the Wilcoxon test for continuous variables. 
 
10.1 REFERENCES 
 
Balkrishnan R, Dugan E, Camacho FT, Hall MA. Trust and satisfaction with 
physicians, insurers, and the medical profession. Med Care 2003;41(9):1058-1064. 
 
Atkinson MJ, Sinha A, Hass SL et al. Validation of a general measure of treatment 
satisfaction, the Treatment Satisfaction Questionnaire for Medication (TSQM), using a 
national panel study of chronic disease. Health Qual Life Outcomes 2004;2:12.:12. 
 
Yentzer BA, Wood AA, Sagransky MJ, et al. An Internet-based survey and 
improvement of acne treatment outcomes. Arch Dermatol. 2011 Oct;147(10):1223-4. 
 
Tanghetti EA, Jackson JM, Belasco KT, et al. Optimizing the use of topical brimonidine in 
rosaacea management: panel recommendations. J Drugs Dermatol. 2015: 14(1):33-40. 


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11.0  APPENDICES 
 
 
 
 
 
Sample Internet Survey: 
The above is a sample of the appearance of the internet survey sent to subjects. For this 
Rosacea study we would ask the following questions: 
How many days did you apply the Brimonidine this week?  
How well did it control the redness: 
Completely, moderately, slightly, not at all, redness is worse 
If worse, are the areas of worsening: 
 check at that apply: new areas, old areas that were already red.  
When did the worsening occur:  
           When the medication was applied? After missing one or more doses? 
 
Are you using the medication regularly or only as needed? 
Have you had any side effects: If so what? 
Have you been exposed to any of the following rosacea triggers this week?  (Check all that 
apply) 
Spicy food, hot food or drink, sun exposure, extreme hot or cold weather, alcohol 


WFUHS Dept of Dermatology 
Winston-Salem, NC 
 
20 
 
 
 
 
Appendix- Clinician Erythema Assessment scale 
 
Date  
 Visit (circle one)   Screen   Baseline,   Mo 3 Mo 6 
 
 
CEA 
0 = Clear 
Clear skin with no signs of erythema 
1 = Almost clear Almost clear; slight redness 
2 = Mild 
Mild erythema, definite redness 
3 = Moderate 
Moderate erythema; marked redness 
4 = Severe 
Severe erythema; fiery redness 
 
 
 
 
Appendix - Investigator Global Assessment 
 
Date_  
 
 
Visit (circle one) Screen 
 
 
 
For Face Check One: 
0 
Virtually no rosacea, i.e., no papules and/or pustules; no or residual 
erythema 
1 
Rare papules and/or pustules; residual to mild erythema 
2 
Few papules and/or pustules; mild erythema 
3 
Distinct number of papules and/or pustules; mild to moderate erythema 
4 
Pronounced number of papules and/or pustules; moderate erythema 
5 
Many papules and/or pustules, occasionally with large inflamed lesions; 
moderate erythema 
6 
Numerous papules and/or pustules, occasionally with confluent areas of 
inflamed lesions; moderate or severe erythema 
 
 
 
 
Investigator Signature: 
_Date:  
 


WFUHS Dept of Dermatology 
Winston-Salem, NC 
 
21 
 
 
Appendix 
Lesion Count (Performed by investigator) 
 
Visit (Circle one): 
Screening/Baseline 
Month 3   Month 6 
 
 
Instructions: Count lesions in each area on face (Forehead, L. cheek, R. Cheek, and chin) and record. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Forehead  
Left Cheek 
Right Cheek Chin 
Total 
# of Inflammatory Papules 
# of Inflammatory Pustules 
Telangiectasias 
 
Total Number of Papules and Pustules   
 
 
Investigator Signature: 
 
Date:    
 


WFUHS Dept of Dermatology 
Winston-Salem, NC 
 
22 
 
 
 Investigator Visual Analogue Scale 
 
Please mark on the line below to indicate on a scale of 0-10 how much redness the subject 
has: 
 
 
 
 
No 
Slight 
Moderate 
Excessive 
Severe 
redness 
redness 
redness 
redness 
redness 
 
 
 
 
0 
5 
10 
 
 
 
 
 
 
 
Investigator Signature 
Date 


WFUHS Dept of Dermatology 
Winston-Salem, NC 
 
23 
 
 
SUBJECT-ASSESSED LOCAL TOLERABILITY 
 
 
ITCHING and BURNING/STINGING 
 
Date 
Visit (circle one)  Screen  Baseline, Mo 3 Mo 6 
 
 
(Mark one box for Itching and one box for Burning/Stinging) 
 
 
Grade 
Itching 
Burning/Stinging 
0 
None 
None 
1 
Slight 
Slight 
2 
Moderate 
Moderate 
3 
Severe 
Severe 
 
 
 
 
 
Subject Visual Analogue Scale 
 
Please mark on the line below to indicate on a scale of 0-10 how much redness that you have 
 
 
 
 
No 
Slight 
Moderate 
Excessive 
Severe 
redness 
redness 
redness 
redness 
redness 
 
 
 
 
0 
5 
10 
 
 
 
 
 
 
 
 
 Subject’s Initials: 
Date:  
 


WFUHS Dept of 
Dermatology 
 
24 
 
 PATIENT SEVERITY  ASSESSMENT (PSA)  
 
Date 
Visit (circle one)  Screen  Baseline, Mo 3 Mo 6 
 
(Mark one box) 
 
0 
= My face is basically free of rosacea, with only an occasional erythema 
1 
= My face has occasional small red bumps, but there are no tender deep-seated 
bumps or cysts. My face may have mild redness. 
2 
= My face has several to many red inflamed bumps and may have one deep seated 
bump or cyst. My face has mild to moderate redness 
3 
= My face has many red inflamed bumps or pustules and may have several deep 
seated bumps or cysts. My face has moderate redness 
4 
= My face has severe medium to large sized red inflamed bumps or pustules, My 
face has severe redness 
 
 
 
 
My Redness is: 
 
(Circle one) 
 
Constant 
Intermittent (Comes and Goes) 
 
 
 
 
Subject’s Initials: 
Date: 
  
 


WFUHS Dept of 
Dermatology 
 
25 
 
 
QUALITY OF LIFE SURVEY 
The questions in this section are about your rosacea and its treatment. 
 
1. How long have you had rosacea? 
 
  
years(s) and 
month(s) 
 
2. 
Do you have attacks of facial redness and feeling hot which last for a few minutes? 
Yes 
No (Skip to question 5) 
 
3. How often do you have these attacks? 
Rarely (not every month) 
A few per month A 
few per week A few 
per day 
More than 10 attacks per day 
 
4. How long do these attacks last? 
Less than a few seconds 
More than a few seconds but less than 1 minute 1 
to 15 minutes 
More than 15 minutes 
 
5. How many small red blood vessels are visible on your face? 
I do not have visible vessels 
A few A 
lot 
 
6. 
How mild or severe is your burning and stinging sensation on your face? 
I do not have burning and stinging 
Mild Moderate 
Severe 
7. 
How mild or severe is your skin dryness or flaking on your face? 
I do not have dryness or flaking skin. 
Mild Moderate 
Severe 
 
8. Do you have any skin changes in places other than your face due to rosacea? 
 
Yes 
No 


WFUHS Dept of 
Dermatology 
 
26 
 
 
 
9. Which rosacea skin change do you suffer from most? ( Choose one) 
Redness 
Dryness 
Flaking skin 
Bumpiness 
Sensitivity 
Attacks of facial redness and warmth 
Swollen nose 
 
10. 
Which of the following problems do you have with your eyes (check all that apply)? 
Gritty feeling 
Burning and stinging 
Dryness 
Itching 
Redness 
Sensitivity to light 
Blurred vision 
Small bumps on the edges of your eyelids (a stye) 
Swollen/puffy eyelids 
 
 
 
11. When was the last time you went to a doctor or clinic for treatment of your rosacea? (This 
includes all visits during which your rosacea was talked about) 
 
Within the past month 
1 to 3 months ago 
3 to 6 months ago 
6 months to 1 year ago 
Over 1 year ago 
 
12. Are you a member of the National Rosacea Society? 
Yes 
No 
 
 
 
13. Have you used any topical treatments for your rosacea (other than the study medication)? 
 
Yes 
No 


 
 
Wake Forest University Health Sciences 
Department of Dermatology 
Winston-Salem, NC 
 
 
This section is about the impact of rosacea and its treatment on your life.  Below are listed 
everyday activities.  Check the box that best describes how much your rosacea or its 
treatment has interfered with each activity during the past four weeks. 
 
Has not 
interfered 
at all 
Has 
interfered a 
little 
Has 
interfered a 
lot 
1.   Working around the house or yard 
2.   Choosing which cosmetics to wear 
3.   Shopping 
4.   How often you wash your face 
5.   How often you bathe or shower 
6.   Being at work (or school) 
7.   Maintaining employment (or studies) 
8.   Being promoted or advancing in your job (studies) 
9.   Having new employment opportunities 
10. Having a good relationship with your co-workers (fellow 
students) 
11. Shaking hands with others 
12. Going out in public 
13. Going to parties 
14. Being with family members 
15. Making new friends 
16. Dating 
17. Kissing or hugging 
18. Having intimate sexual relations 
19. Doing your hobbies 
20. Going out socially or to a special event 
21. Participating in sports or recreation activities 
22. Using public bathing facilities (pools, beach) or changing 
facilities (locker rooms) 
23. Traveling or vacationing 
24. Getting enough sleep 
25. Sleeping where you want 
26. Exercising as much as you want 
27. Making plans for the future 
28. Other ( please explain):