Epidermal Permeability Barrier Function and Stratum Corneum Hydration of Rosacea Following Application of Ivermectin
Phase: PHASE2
Conditions: Rosacea
Sponsor: Wake Forest University Health Sciences

 
Study Protocol and Statistical Analysis Plan Cover sheet:  
 
 
Title: Epidermal Permeability Barrier Function and Stratum Corneum Hydration of 
Rosacea Following Application of Ivermectin 
 
NCT Number: NCT04275999 
 
Date of document: 02/19/2021 
 
 
 

Title: Epidermal Permeability Barrier Function and Stratum Corneum Hydration of Rosacea 
Following Application of Ivermectin  
 
Principle Investigator: Steven R. Feldman, MD, PhD 
 
Sponsor or funding source: Galderma 
 
Study Rationale: 
Facial erythema is the hallmark of rosacea and the mandatory criterion for its 
diagnosis.(1) It is estimated that rosacea-related erythema affects more than 40 million people 
worldwide. The repair and maintenance of the epidermal barrier are critically important in the 
treatment of rosacea. Rosacea lesions can have a defective barrier, characterized by elevated 
transepidermal water loss (TEWL) rates and reduced levels of stratum corneum (SC) 
hydration.(2) The skin barrier function is a critical factor for assessing the severity of rosacea. 
The precise mechanisms underlying the relationship between rosacea and skin barrier function 
are not yet known. Some argue that impaired skin barrier function is a consequence of 
inflammation and continuous stimulation, while others attribute it to infection with follicle 
mites.(3) 
Ivermectin possesses anti-inflammatory by effecting cytokines and neutrophils, and anti-
parasitic properties by effecting Demodex mites. (4, 5) Ivermectin offers a potential treatment 
option in maintenance therapy. (6) Recent attention has been directed toward the maintenance 
and prevention of relapse of rosacea. Treatment with ivermectin may decrease follicle mites, 
thereby decreasing rosacea flares, improving epidermal barrier dysfunction, reduces TEWL, and 
improves SC hydration.(7) However, topical application of medications can be complicated, 
time-consuming, and often frustrating. Poor adherence to therapy can lead to treatment failure 
and poor health outcomes.(8, 9)  
Frequent office visits improve adherence, but are rarely feasible in everyday practice.(10, 
11) Reminders are helpful for patients who are strongly motivated to take the medication but 
sometimes forget. For the majority of patients, who have not completely bought into the 
regimen, a subtler approach appears better. This approach aims at building intrinsic motivation, 
trust, feelings of being cared for, and accountability through frequent contact. In a pilot study of 
teenagers with acne, sending weekly surveys querying subjects about perceived burden of 
treatment, perceived usefulness of the medication, current disease severity, and side effects 
raised mean adherence to 89%, compared to 33% in the control group.(12) The present study 
aims to validate a very similar tool for patients at risk for low adherence to ivermectin. 
Another limitation to improving patients’ adherence to topical treatments is that there has 
not been a practical way to give patients feedback on the state of their skin barrier.  Measuring 
TEWL rates and SC hydration levels could be a valuable tool to give patients this feedback.  We 
propose to test whether we can improve patients’ use of topical ivermectin in subjects with 
rosacea by using a portable hydration measurement device that simultaneously measures both the 
TEWL rates and SC hydration levels in a study in which we would objectively measuring 
adherence to daily ivermectin.(13)  
Our primary hypothesis is that weekly digital interactions and routine measurement of 
TEWL rates and SC hydration levels will promote patient adherence to maintenance ivermectin 
therapy and prevent disease relapse. The project will consist of a trial in which thirty subjects 
with rosacea receive ivermectin therapy and are randomized to receive either no intervention, a 

weekly digital survey to assess patient’s attitudes towards ivermectin therapy, or a portal 
hydration measurement device that measures TEWL rates and SC hydration levels. We will 
measure adherence objectively in all groups with electronic monitors attached to the containers 
of the ivermectin, which all subjects will be told to use daily for maintenance therapy. 
Additionally, the hydration measurement device can transmit data to an Internet server via a 
smartphone using Bluetooth technology, thereby allowing providers to monitor a patient’s 
TEWL rate and SC levels.  
 
 
Objectives: 
 Determine the effect of the portable hydration measurement device on treatment 
adherence to daily ivermectin therapy  
 Determine the effect of weekly digital survey on treatment adherence to daily 
ivermectin therapy  
 Determine the effect of daily ivermectin therapy on TEWL rate, SC levels, and 
rosacea treatment outcomes 
 
 
Methods and Measures: 
 
Study Design: 
Adult subjects will be offered an opportunity to participate in the study. Subjects will 
either have a diagnosis of rosacea. A total of 30 subjects will be enrolled. After consent and basic 
demographics, a study team member will use the GPSkin Barrier® to measure the baseline 
moisture level of the face of all subjects. Subjects will also fill out questionnaires pertaining to 
quality of life, accountability, patient-physician relationship, and severity of rosacea.   
Subjects will be randomized into one of three arms: the control group (n= 10), the digital 
interaction group (n=10), or the GPSkin group (n=10). All patients will receive ivermectin 
equipped with an electronic monitor to measure adherence for daily treatment of rosacea. The 
digital interaction group will receive a survey by email each week asking about their use 
ivermectin generated by Causa Research. The patients in the GPSkin group will receive the 
GPSkin Barrier® to measure their moisture level of their face daily. Subjects will be instructed 
to use the ivermectin once daily. Subjects will return at 3 Months. At this visit, the data from the 
electronic adherence monitoring will be downloaded, the ivermectin will be weighed, and the 
patient will fill out the same questionnaires (quality of life, accountability, patient-physician 
relationship, and severity of rosacea). The intervention subjects will be evaluated on their use of 
the GPSkin Barrier® to measure their stratum corneum hydration. Participants not randomized to 
the email intervention group will receive an accountability questionnaire at the beginning and 
end of the study.  
 
Setting 
The study will be conducted at Department of Dermatology at Wake Forest School of 
Medicine. Data will also be analyzed at Department of Dermatology at Wake Forest School of 
Medicine. 
 
Subject Selection 

 
 
Inclusion Criteria 
- 
Subject is 18 years of age or older. 
- 
Subject has a working knowledge of English. 
- 
Subject with a diagnosis of Rosacea 
- 
Subjects without a known allergy to ivermectin 
- 
Subjects with access to a smart phone  
 
Exclusion Criteria 
- 
Subjects under 18 years of age.  
- 
Subject does not have a working knowledge of English.  
- 
Subject with a diagnosed skin condition other than rosacea 
- 
Subjects with a known allergy to ivermectin  
- 
Subjects without access to a smart phone  
 
Intervention and Interactions 
Patients will be recruited from the Dermatology Clinic or from the Dermatology Clinic 
Database. Team members can recruit in-person with patients in the Dermatology Clinic, or by 
calling patients with a diagnosis of Rosacea (ICD 10: L71.9). Patients will then be brought to the 
Center for Dermatology Research for their initial screening visit. Demographic data collected 
from the patient includes sex, age, and ethnicity.  
 
Outcome Measure 
Outcomes include adherence (as measured by electronic monitoring), weight of the 
ivermectin, rosacea severity, quality of life, reporting of adverse effects, accountability 
questionnaire, and use of the GPSkin Barrier® in the GPSkin group. Data from the clinical study 
will be analyzed by a biostatistics software. Correlation between demographics will be measured.  
 
Analytical Plan 
Data will be analyzed using descriptive statistics on a biostatistics software.  
 
Human Subjects Protection 
 
Subject Recruitment Methods 
Subjects who meet the inclusion and exclusion eligibility criteria will be able to 
participate in the study. Subjects are recruited at a clinic in the Department of Dermatology at 
Wake Forest School of Medicine or through the Department of Dermatology Database.   
 
Informed Consent 
Informed consent will be acquired for this study. The risk of harm or discomfort is not 
expected to be more than a daily life or routine physical or psychological exam or test. Rights 
and welfare of subjects will be protected through the use of measures to maintain the 
confidentiality of study information. No identifying information will be taken from the patient. 
The only information taken from the patient includes age, gender, ethnicity, location of the skin 
lesion, and email addresses. The information collected for this research study includes quality of 

life, accountability, and severity of rosacea information. Results of the study will be published or 
presented in lieu of providing individual subjects additional information regarding the study.  
 
Confidentiality and Privacy 
Confidentiality will be protected by collecting information needed to assess study 
outcomes, minimizing to the fullest extent possible the collection of any information that could 
directly identify subjects, and maintaining all study information in a secure manner. To help 
ensure subject privacy and confidentiality, no subject identifiers will be used. The results of the 
survey will be presented as an anonymous data set. Data access will be limited to study staff. 
Data will be kept locked and secured, with computer data password protection. No references to 
any individual participant will appear in reports, presentations, or publications that may arise 
from the study.  
 
Data and Safety Monitoring 
The principal investigator will be responsible for monitoring data and safety of subjects. 
The principal investigator will be assisted by other members of study staff.  
 
Report of Unanticipated Problems, Adverse Events, or Deviations 
All unanticipated problems, serious or unexpected adverse events, deviations or protocol 
amendments will be reported by the principle investigator or designated member of the research 
team to IRB or appropriate government agency if appropriate.   
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
 
 
 
 
Appendix 
I. 
Demographic Questions 
II. 
Dermatology Quality of Life Index 
III. 
Weekly Accountability Questionnaire for Digital Interaction Group 
IV. 
Rosacea Severity Indices  
V. 
Accountability Measurement Tool (AMT) 
VI. 
Patient-Doctor Relationship Questionnaire (PDRQ-9) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix I: Demographic Questions for Patients 
 
1. What is your gender?  
- 
Male  
- 
Female 
- 
Other 
 
2. What is your ethnicity? 
- 
Caucasian  
- 
African American 
- 
Asian 
- 
Native American  
- 
Other 
 
3. What is your age?  
- 
Open ended question. 
 
4. Do you regularly use a moisturizer on your skin? 
- 
Yes 
- 
No 
- 
Intermittently 
 
5. If you use a moisturizer, what is the name of the moisturizer? 
- 
Open ended question.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix II: Dermatology Quality of Life Index 
 
 

Appendix III: Accountability Questionnaire – email survey that subjects in digital 
intervention group will receive weekly  
 
Hi {PARTICIPANT NAME}!  Time for a {diagnosis} check in!   
1. Do you feel the medication is helping your rosacea?  
a. Yes, my {diagnosis} is much better 
b. Yes, my {diagnosis} is somewhat better 
c. I haven’t noticed a change in my {diagnosis} 
d. No, my {diagnosis} is moderately worse 
e. No, my {diagnosis} is much worse 
2. How many days were you able to use the {medication} this week?  
a. Every day 
b. I missed 1 or 2 days 
c. I missed the majority of this week  
3. Did you have any difficulty using the {medication}?  
a. No- it was very easy to use 
b. It was OK 
c. I found it inconvenient to use 
d. It was difficult to use 
e. It was very difficult to use 
4. Have you had any side effects from using the {medication}? 
a. Yes 
i. If yes, what side effects did you experience? 
ii. Open data entry field for responses 
____________________________________________________________
_____ 
b. No 
5. Do you use a reminder system of any kind to help you remember to use your 
{medication}? For example, some of our patients use reminders or applications on a 
smart phone. Others have told us they keep their medicine somewhere in their home 
that they can’t miss. 
a. Yes 
i. Please list the methods you use to help you keep track of your 
medications: 
____________________________________________________________
__________________________ 
b. No 
6. Thinking ahead to next week, how many days do you think you will be able to use 
your {medication}? We will check in again next week through your weekly survey to 
see how you’re doing.  
a. Every day 
b. 5-6 days per week 
c. Other, please list: _________________________ 
 
Thanks! We’ll reach out to you again next week!  
 

 
 
Open text field 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix IV: Rosacea Indices  
 
 
 
 
 

 
 
 
 
 
Investigator Global Assessment 
 
Scores
0
Clear
No inflammatory lesions present, no erythema
1
Almost Clear
Very few small papules/pustules present, very mild erythema
2
Mild
Few small papules/pustules, mild erythema
3
Moderate
Several small or large papules/pustules, moderate erythema
4
Severe
Numerous small and/or large papules/pustules, severe erythema
 
 
 
 
Patient Self-Assessment 
 
Scores
0
Clear
No Redness
1
Almost Clear
Very Mild Redness
2
Mild
Mild Redness
3
Moderate
Moderate Redness
4
Severe
Severe Redness
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix V: Accountability Measurement Tool (AMT) 
 
Accountability Measurement Tool  
 
Please circle one option for each question. 
 
1 = Strongly disagree 
2 = Disagree 
3 = Neutral 
4 = Agree 
5 = Strongly agree 
 
1) I feel guilty if I do not follow my doctor’s recommendations.  
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
2) I am afraid of disappointing my doctor by not following his/her recommendations.  
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
3) I am concerned that my doctor may be disappointed if I do not follow his/her 
recommendations.  
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
4) I feel proud showing my doctor how well my condition has improved. 
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
5) I am pleased letting my doctor know how well I have taken my medication.  
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 

 
6) I look forward to letting my doctor know how well I have taken my medication. 
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
7) All in all, I feel accountable towards my doctor. 
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
8) An upcoming office visit with my doctor motivates me to follow my doctor’s 
recommendations. 
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
9) I would feel guilty if [I thought] the doctor believed I wasn’t following his/her 
directions. 
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
10) I don’t want to let my doctor down by not taking my medicine well. 
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
11) I am concerned of how I would be perceived if my doctor thought I didn’t do a 
good job taking my medication.  
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 

12) I try to take my medication regularly because I have a doctor’s visit coming up. 
a. 1 = Strongly disagree 
b. 2 = Disagree 
c. 3 = Neutral 
d. 4 = Agree 
e. 5 = Strongly agree 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

Appendix VI: Patient-Doctor Relationship Questionnaire (PDRQ-9) 
 
PDRQ-9 
Instruction: 
You will read nine statements that a person can make about his/her physician. Please choose the 
appropriateness of each statement for your physician by marking one number per statement. The 
meaning of the numbers is as follows: 
1 = not at all appropriate 
2 = somewhat appropriate 
3 = appropriate 
4 = mostly appropriate 
5 = totally appropriate  
1 My physician helps me
1 2 3 4 5
2 My physician has enough time for me
1 2 3 4 5
3 I trust my physician
1 2 3 4 5
4 My physician understands me
1 2 3 4 5
5 My physician is dedicated to help me
1 2 3 4 5
6 My physician and I agree on the nature of my medical symptoms 1 2 3 4 5
7 I can talk to my physician
1 2 3 4 5
8 I feel content with my physician’s treatment
1 2 3 4 5
9 I find my physician easily accessible
1 2 3 4 5
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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