Light Emitting Diode-Red Light (LED-RL) Phototherapy for Skin Scarring Prevention
Phase: PHASE2
Conditions: Fibrosis, Skin Scarring, Skin Wound, Hypertrophic Scar, Scar, Keloid
Sponsor: State University of New York - Downstate Medical Center

LED-Red Light Phototherapy for Skin Scarring 
Prevention 
 
Principal Investigator: Jared Jagdeo, MD, MS 
Funded by: National Institute of General Medical Sciences 
Version Number:  v.4.2 
30 July 2019 
NCT03795116 
 

  
 
ii 
Table of Contents 
STATEMENT OF COMPLIANCE ............................................................................................................................ 1 
1 
PROTOCOL SUMMARY .............................................................................................................................. 1 
1.1 
Synopsis .............................................................................................................................................. 1 
1.2 
Schema ................................................................................................................................................ 4 
1.3 
Schedule of Activities (SoA) .............................................................................................................. 5 
2 
INTRODUCTION ........................................................................................................................................... 8 
2.1 
Study Rationale ................................................................................................................................... 8 
2.2 
Background ......................................................................................................................................... 8 
2.3 
Risk/Benefit Assessment ................................................................................................................. 10 
2.3.1 
Known Potential Risks .................................................................................................. 10 
2.3.2 
Known Potential Benefits ............................................................................................. 12 
2.3.3 
Assessment of Potential Risks and Benefits ............................................................. 12 
3 
OBJECTIVES AND ENDPOINTS ............................................................................................................. 13 
4 
STUDY DESIGN .......................................................................................................................................... 15 
4.1 
Overall Design ................................................................................................................................... 15 
4.2 
Scientific Rationale for Study Design ............................................................................................ 17 
4.3 
Justification for Dose ........................................................................................................................ 18 
4.4 
End of Study Definition .................................................................................................................... 18 
5 
STUDY POPULATION ............................................................................................................................... 19 
5.1 
Inclusion Criteria ............................................................................................................................... 19 
5.2 
Exclusion Criteria .............................................................................................................................. 19 
5.3 
Lifestyle Considerations ................................................................................................................... 20 
5.4 
Screen Failures ................................................................................................................................. 20 
5.5 
Strategies for Recruitment and Retention ..................................................................................... 20 
6 
STUDY INTERVENTION ........................................................................................................................... 22 
6.1 
Study Intervention(s) Administration .............................................................................................. 22 
6.1.1 
Study Intervention Description .................................................................................... 22 
6.1.2 
Dosing and Administration ........................................................................................... 22 
6.2 
Preparation/Handling/Storage/Accountability ............................................................................... 23 
6.2.1 
Acquisition and accountability ..................................................................................... 23 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................... 23 
6.2.3 
Product Storage and Stability ...................................................................................... 23 
6.2.4 
Preparation .................................................................................................................... 23 
6.3 
Measures to Minimize Bias: Randomization and Blinding .......................................................... 23 
6.4 
Study Intervention Compliance ....................................................................................................... 25 
6.5 
Concomitant Therapy ....................................................................................................................... 25 
6.5.1 
Rescue Medicine ........................................................................................................... 25 
7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ................................................................................................................... 26 
7.1 
Discontinuation of Study Intervention ............................................................................................ 26 
7.2 
Participant Discontinuation/Withdrawal from the Study .............................................................. 26 
7.3 
Lost to Follow-Up .............................................................................................................................. 27 
8 
STUDY ASSESSMENTS AND PROCEDURES .................................................................................... 27 
8.1 
Efficacy Assessments ...................................................................................................................... 27 
8.2 
Safety and Other Assessments ...................................................................................................... 28 
8.3 
Adverse Events and Serious Adverse Events .............................................................................. 29 

  
 
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8.3.1 
Definition of Adverse Events (AE) .............................................................................. 29 
8.3.2 
Definition of Serious Adverse Events (SAE) ............................................................. 30 
8.3.3 
Classification of an Adverse Event ............................................................................. 30 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ...................... 31 
8.3.5 
Adverse Event Reporting ............................................................................................. 32 
8.3.6 
Serious Adverse Event Reporting .............................................................................. 32 
8.3.7 
Reporting Events to Participants ................................................................................ 33 
8.3.8 
Events of Special Interest ............................................................................................ 33 
8.3.9 
Reporting of Pregnancy ............................................................................................... 33 
8.4 
Unanticipated Problems ................................................................................................................... 33 
8.4.1 
Definition of Unanticipated Problems (UP) ................................................................ 33 
8.4.2 
Unanticipated Problem Reporting ............................................................................... 34 
8.4.3 
Reporting Unanticipated Problems to Participants .................................................. 35 
9 
STATISTICAL CONSIDERATIONS ......................................................................................................... 35 
9.1 
Statistical Hypotheses ...................................................................................................................... 35 
9.2 
Sample Size Determination ............................................................................................................. 35 
9.3 
Populations for Analyses ................................................................................................................. 35 
9.4 
Statistical Analyses .......................................................................................................................... 35 
9.4.1 
General Approach ......................................................................................................... 36 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................................ 36 
9.4.3 
Analysis of the Secondary Endpoint(s) ...................................................................... 36 
9.4.4 
Safety Analyses ............................................................................................................. 36 
9.4.5 
Baseline Descriptive Statistics .................................................................................... 36 
9.4.6 
Planned Interim Analyses ............................................................................................ 37 
9.4.7 
Sub-Group Analyses .................................................................................................... 37 
9.4.8 
Tabulation of Individual participant Data ................................................................... 37 
9.4.9 
Exploratory Analyses .................................................................................................... 37 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................. 37 
10.1 
Regulatory, Ethical, and Study Oversight Considerations .......................................................... 37 
10.1.1 
Informed Consent Process .......................................................................................... 37 
10.1.2 
Study Discontinuation and Closure ............................................................................ 38 
10.1.3 
Confidentiality and Privacy .......................................................................................... 38 
10.1.4 
Future Use of Stored Specimens and Data .............................................................. 39 
10.1.5 
Key Roles and Study Governance ............................................................................. 39 
10.1.6 
Safety Oversight ............................................................................................................ 39 
10.1.7 
Clinical Monitoring ......................................................................................................... 40 
10.1.8 
Quality Assurance and Quality Control ...................................................................... 40 
10.1.9 
Data Handling and Record Keeping ........................................................................... 41 
10.1.10 
Protocol Deviations ....................................................................................................... 41 
10.1.11 
Publication and Data Sharing Policy .......................................................................... 42 
10.1.12 
Conflict of Interest Policy ............................................................................................. 42 
10.2 
Additional Considerations ................................................................................................................ 42 
10.3 
Abbreviations ..................................................................................................................................... 45 
10.4 
Protocol Amendment History .......................................................................................................... 47 
11 
REFERENCES ............................................................................................................................................ 48 
 

LED-Red Light Phototherapy for Skin Scarring Prevention 
Version 4.2 
IRB# 1304108 
30 July 2019 
 
 
1 
STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with International Conference on Harmonisation Good 
Clinical Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the 
National Institute of General Medical Sciences (NIGMS) Terms and Conditions of Award. The Principal 
Investigator (PI) will assure that no deviation from, or changes to the protocol will take place without 
prior agreement from the funding agency and documented approval from the Institutional Review 
Board (IRB), except where necessary to eliminate an immediate hazard(s) to the trial participants. All 
personnel involved in the conduct of this study have completed Human Subjects Protection and ICH 
GCP Training. 
 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval. Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled. Any amendment to the protocol will require 
review and approval by the IRB before the changes are implemented to the study. All changes to the 
consent form will be IRB approved; a determination will be made regarding whether a new consent 
needs to be obtained from participants who provided consent, using a previously approved consent 
form. 
1 
 
PROTOCOL SUMMARY 
1.1 
SYNOPSIS  
Title: 
LED-Red Light Phototherapy for Skin Scarring Prevention 
  
Study Description: 
This study will evaluate the safety and clinical efficacy of light emitting diode-
red light (LED-RL) for the treatment of skin fibrosis in subjects who have 
decided to undergo elective minimal incision facelift (mini-facelift) surgery. 
Based on our in vitro data and Phase I studies, we hypothesize that LED-RL 
phototherapy may be a safe and effective therapeutic modality to prevent or 
limit cutaneous scarring after surgery. Subjects will use commercially 
available, FDA-cleared LED-RL phototherapy devices for the treatment of 
periauricular incisions associated with the mini-facelift surgery. A total of 30 
subjects, randomly allocated to 3 treatment groups in a 1:1:1 ratio, will 
receive LED-RL at different fluences (doses) that were established as safe and 
well tolerated in Phase I studies. Using a split-face study design, each side of 
the face will be randomized to receive either LED-RL phototherapy or mock 
irradiation, allowing each subject to serve as his or her own control. The 
treatment will be administered 3 times weekly for 3 weeks, starting at 
approximately 1 week post-surgery, for a total of 9 treatment sessions. 
Efficacy assessments will include skin elasticity and induration 
measurements, tissue histology, rater-blinded photographic evaluation, 
three-dimensional skin imaging analysis, collagen measurements, optical 
coherence tomography (OCT), and subjective clinical assessments. Safety and 
adverse events will be monitored. 
  
Objectives: 
 
Using the fluences established as safe from our Phase I studies of LED-RL on 
normal human skin and hypothesized to be anti-fibrotic doses based on in 

LED-Red Light Phototherapy for Skin Scarring Prevention 
Version 4.2 
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30 July 2019 
 
 
2 
vitro data (160 J/cm2 to 480 J/cm2), we will conduct a dose-ranging, 
randomized, parallel group, split-face, single-blind, mock-controlled Phase II 
study to evaluate the efficacy of LED-RL phototherapy in preventing or 
limiting skin fibrosis in a mini-facelift surgical wound model. 
 
Primary Objective:  
To evaluate the clinical efficacy of LED-RL phototherapy in the prevention of 
skin fibrosis in subjects undergoing elective mini-facelift surgery 
 
Secondary Objectives: 
• 
To evaluate the histological, ultrastructural, and molecular changes 
that occur in vivo as a result of LED-RL phototherapy 
• 
To detect clinically meaningful changes in scar characteristics after 
LED-RL phototherapy 
• 
To continue to assess the safety of LED-RL phototherapy on human 
skin 
 
 
Endpoints: 
Primary Outcome Measure:  
Difference in quantitative scar pliability between the treated and control 
incision sites 
 
Secondary Outcome Measures:  
1) Difference in objective measurements of key scar characteristics 
(collagen and water concentration, wrinkles, texture, diameter, area, 
volume of elevation, pores, pigmentation, vascularity) between the 
treated and control incision sites 
2) Difference in the Patient and Observer Scar Assessment Scale 
(POSAS) scores between the treated and control incision sites 
3) Difference in the photograph-based Visual Analogue Scale (VAS) 
scores between the treated and control incision sites 
4) Histological and molecular analyses of treated and control skin 
specimens 
5) Incidence of adverse events 
6)  
 
Study Population: 
A total of 30 subjects will be enrolled. Individuals of any sex, race/ethnicity, 
and age who are suitable candidates for mini-facelift surgery and who do not 
meet exclusion criteria will be eligible for this study. 
  
Phase: 
2 
  
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Subjects will be enrolled at a single site, SUNY Downstate Medical Center. The 
study is not intended to include sites outside of the US. 
 
 
 
  

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Description of Study 
Intervention: 
The LED-RL source is the Omnilux new-U handheld phototherapy device 
(GlobalMed Technologies, Glen Ellen, CA), which is commercially available 
over-the-counter and FDA-cleared for the treatment of periorbital rhytides. 
The device has a 4.7 cm x 6.1 cm rectangular aperture of LED arrays and 
emits visible red light (633 nm + 6 nm) at a power density of 360.2 W/m2 at 
room temperature. Each subject will be randomly assigned to receive LED-RL 
phototherapy at doses of 160 J/cm2, 320 J/cm2, or 480 J/cm2 to one side of 
the face, with the contralateral side receiving mock treatment. 
  
Study Duration: 
24 months 
  
Participant 
Duration: 
6 months 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

LED-Red Light Phototherapy for Skin Scarring Prevention 
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1.2 
SCHEMA 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
POD: post-operative day 
Obtain informed consent. Screen subjects by inclusion and exclusion 
criteria. Administer screening photosensitivity test. 
Verify eligibility. Enroll eligible subjects who pass photosensitivity test. 
N=30 
Screening 
Group 1: 
LED-RL phototherapy at fluence 
of 160 J/cm2 
(n=10) 
Group 2: 
LED-RL phototherapy at fluence 
of 320 J/cm2 
(n=10) 
 Group 3: 
LED-RL phototherapy at fluence 
of 480 J/cm2 
(n=10) 
Administer 3 treatment sessions per week for 3 consecutive weeks, 
starting at 1 week post-surgery (POD 4-8). 
Assess outcome measures at follow-up visits on POD 30, 90, and 180. 
Refer to Section 9.4: Statistical Analyses. 
Intervention 
Treatment Dose 
Randomization 
Follow-Up 
Analysis 
Enrollment 
Baseline Visit 
Split-Face 
Randomization 
Treatment side: 
LED-RL on right 
Mock on left 
(n=5) 
Treatment side: 
LED-RL on left 
Mock on right 
(n=5) 
Treatment side: 
LED-RL on right 
Mock on left 
(n=5) 
Treatment side: 
LED-RL on left 
Mock on right 
(n=5) 
Treatment side: 
LED-RL on right 
Mock on left 
(n=5) 
Treatment side: 
LED-RL on left 
Mock on right 
(n=5) 
Subjects undergo mini-facelift surgery with periauricular incisions. 

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1.3 
SCHEDULE OF ACTIVITIES (SOA) 
 
 
Screening Visit (within 6 weeks prior to surgery) 
• 
Obtain written informed consent. 
• 
Verify that the potential subject has opted to undergo elective mini-facelift surgery. 
• 
Review medical history by interview to determine eligibility based on inclusion/exclusion 
criteria.  
• 
Review list of current medications to determine eligibility based on inclusion/exclusion 
criteria. 
Procedures 
Screening within 6 weeks 
prior to surgery 
Enrollment at 24 hours 
after screening 
Baseline/day of surgery 
(Visit 1) 
Treatment #1  
(Visit 2) 
Treatment #2 
(Visit 3) 
Treatment #3 
 (Visit 4) 
Treatment #4 
 (Visit 5) 
Treatment #5 
 (Visit 6) 
Treatment #6 
 (Visit 7) 
Treatment #7 
 (Visit 8) 
Treatment #8 
 (Visit 9) 
Treatment #9 
 (Visit 10) 
Follow-up  at POD 30 + 
1 week (Visit 11) 
Follow-up  at POD 90 + 
1 week (Visit 12) 
Final study visit at POD 
180 + 1 week (Visit 13) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Concomitant medication 
review 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Targeted physical exam of 
skin 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Conduct screening 
photosensitivity test 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Evaluate for 
photosensitivity 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse event review and 
evaluation 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Randomization 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
Mini-facelift surgery 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Administer study 
intervention (LED-RL and 
mock therapy) 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Digital photography 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Skin biopsy (optional) 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
OCT 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Skin elasticity and 
induration measurements 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Collagen and water 
concentration 
measurements 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Skin imaging analysis 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
POSAS 
 
 
 
X 
 
 
 
 
 
 
 
 
X 
X 
X 
Complete case report 
forms 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Exit questionnaire 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 

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• 
Perform targeted physical examination of skin. For this study, potential subjects must have 
excess lax facial skin that is suitable for mini-facelift surgery, as determined by the surgeon’s 
clinical assessment. Potential subjects also cannot have any open wounds, pre-existing scars, 
fibrotic skin disease, or other medical conditions affecting the periauricular skin (i.e., the site 
of the surgical incisions and of the proposed LED-RL treatment). 
• 
Conduct a screening photosensitivity test. Potential subjects will be exposed to LED-RL for 20 
minutes on the nondominant upper forearm (as recommended by the manufacturer in the 
Omnilux user guide) and evaluated either in clinic or remotely 24 hours later to assess for 
adverse reactions. 
 
Enrollment (24 hours after screening) 
• 
Evaluate for photosensitivity by examining the nondominant upper forearm. Potential 
subjects have the option to return to clinic for an in-person evaluation, or have a remote 
follow-up via a phone call. For the remote follow-up, the research team will call the subject 
and ask if he/she has experienced any adverse reactions as well as request a photograph of 
the treatment area. Criteria for photosensitivity include, but are not limited to: warmth, 
erythema, edema, blistering, rash, pain, or discomfort lasting more than 24 hours. If no 
adverse reactions occur, the potential subject is deemed "non-photosensitive" and thus 
eligible for participation in the study. 
o Definition of screen failure: Subjects who have provided consent but subsequently fail 
to meet eligibility criteria for participation in the study based on screening procedures 
o Definition of enrolled: Consented and screened, with eligibility verified 
• 
Randomize subject to treatment dose and treatment side as described in Section 6.3: 
Measures to Minimize Bias. 
• 
Schedule study visits, including the day of surgery and subsequent 9 treatment sessions, for 
participants who are eligible and available for the duration of the study.  
 
Baseline Visit and Day of Surgery (Visit 1, POD 0) 
• 
Verify inclusion and exclusion criteria, including review of medical history and concomitant 
medications.  
• 
Obtain pre-surgery photographs. 
• 
Proceed with mini-facelift surgery under tumescent local anesthesia, performed by a board-
certified dermatologic surgeon (Dr. Daniel Siegel). 
• 
Obtain optional 2 mm punch biopsies of normal periauricular skin, taken from the excess lax 
skin that is excised as part of the mini-facelift surgery. 
• 
Obtain post-surgery photographs. 
• 
Provide standard of care post-operative instructions. 
 
Treatment Sessions:  
The first treatment session will occur approximately one week after surgery, defined as POD 4 to POD 
8, a validated intervention time point for skin scar reduction therapy.1 Treatment sessions will take 
place three times weekly (for example: Monday, Wednesday, Friday) for 3 consecutive weeks, for a 
total of 9 treatment sessions. Refer to Section 6: Study Intervention for the treatment protocol.  
 
The following is a sample schedule. The specific POD of the treatment sessions in relation to the study 
visit number may vary among subjects depending on their exact date of the surgery (POD 0). Please 

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refer to Section 8.1: Efficacy Assessments for a description of all objective and subjective 
measurements that will be collected for outcome measures. 
 
Monday (Visit 2, POD 5) 
• 
Obtain pre-treatment session photographs. 
• 
Concomitant medication review: Verify that the subject is not taking any photosensitizing 
medications that would preclude treatment with LED-RL phototherapy. 
• 
Obtain baseline data for efficacy assessments: skin elasticity and induration measurements, 
collagen and water concentration measurements, optical coherence tomography (OCT), three-
dimensional skin imaging analysis, and POSAS. 
• 
Study intervention: Administer treatment with LED-RL phototherapy device and mock therapy 
device on either side of the face in accordance with the randomization and treatment 
protocol. 
• 
Safety monitoring: Record adverse events as reported by the subject or observed by the 
investigator, if applicable. 
• 
Obtain post-treatment session photographs. 
 
Wednesday (Visit 3, POD 7): Same procedures/evaluations as previous visit (except for obtaining 
baseline data for efficacy assessments), plus a review of the subject’s diary of adverse events. 
Friday (Visit 4, POD 9): Same procedures/evaluations as previous visit. 
Monday (Visit 5, POD 12): Same procedures/evaluations as previous visit. 
Wednesday (Visit 6, POD 14): Same procedures/evaluations as previous visit. 
Friday (Visit 7, POD 16): Same procedures/evaluations as previous visit. 
Monday (Visit 8, POD 19): Same procedures/evaluations as previous visit. 
Wednesday (Visit 9, POD 21): Same procedures/evaluations as previous visit. 
Friday (Visit 10, POD 23): Same procedures/evaluations as previous visit. 
 
Follow-Up Visits after Conclusion of Treatment Period:  
Follow-up visits will be scheduled on approximately POD 30 (Visit 11) and POD 90 (Visit 12). The exact 
timing of the follow-up visits is not strict and may occur up to + 1 week from the proposed POD. 
 
1 Month Follow-Up (Visit 11, approximately POD 30) and 3 Month Follow-Up (Visit 12, 
approximately POD 90) 
• 
Record adverse events since last study visit, if applicable. 
• 
Obtain standardized digital photographs of periauricular incisions/scars for visual analogue 
scale (VAS) scoring. 
• 
Measure physical scar characteristics using OCT and three-dimensional skin imaging analysis. 
• 
Measure collagen and water concentration using a spatially resolved spectroscopy probe. 
• 
Measure scar pliability using indentation instruments to quantify skin elasticity and induration. 
• 
Perform subjective scar evaluation using the Patient and Observer Scar Assessment Scale 
(POSAS). The observer assessment is done by a blinded investigator (the treating surgeon). 
 
At the 1 month follow-up visit, optional post-treatment skin biopsies will be obtained if the subject has 
provided consent. Subjects may decline biopsy and remain in the study. 
 
 

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Final Study Visit (Visit 13, approximately POD 180): Same procedures/evaluations as previous visit, 
plus an exit questionnaire to elicit the subject’s feedback. 
 
The final study visit is a 6-month follow-up at approximately POD 180. However, subjects will have the 
option to attend a 12-month follow-up (approximately POD 365) that consists of the same 
procedures/evaluations as the previous visit. While a study endpoint at 12 months would be ideal for 
long-term monitoring of clinical changes during the scar maturation process, subject attrition is a 
concern and we anticipate that subjects may have difficulty returning to clinic 1 year post-surgery. 
2 
 
INTRODUCTION 
 
2.1 
STUDY RATIONALE  
The goal of this study is to evaluate the safety and clinical efficacy of LED-RL as a treatment modality 
to reduce skin scarring after mini-facelift surgery. We hypothesize that LED-RL phototherapy has the 
potential to mitigate skin fibrosis by modulating key cellular and molecular mechanisms of fibrosis, 
including fibroblast proliferation and collagen formation.  
 
Skin fibrosis is a common complication in the wound healing process and remains a challenge in 
clinical medicine. Clinical research on post-surgical scarring indicates that early intervention on new 
wounds (i.e., in the immediate post-operative period) is more beneficial than treatment of mature 
scars, as prevention of scar formation is the key to avoidance of poor scarring.2 Despite high demand 
for early intervention to minimize scarring, there are few effective and durable treatments available. 
Skin fibrosis secondary to surgery and other trauma is due to abnormal wound healing, wherein 
fibroblasts remain pathologically active and continue to proliferate and produce collagen, resulting in 
hypertrophic scars and keloids. According to our in vitro data, LED-RL at fluences above 320 J/cm2 
demonstrates anti-fibrotic properties, limiting fibroblast proliferation and collagen deposition in the 
dermis.3,4 Furthermore, in two Phase I clinical trials, we demonstrated the safety and tolerability of 
LED-RL at fluences up to 480 J/cm2 on normal human skin (unpublished data). 
 
We propose to conduct a randomized split-face study to test the anti-fibrotic effects of LED-RL 
phototherapy in subjects who have decided to undergo elective mini-facelift surgery, using the 
periauricular skin incisions as the treatment sites. We chose this surgical wound model given that 
periauricular skin is at increased risk of scarring, yet is inconspicuous and a split-face study design 
allows subjects to serve as their own controls. 
 
2.2 
BACKGROUND  
Skin fibrosis is a significant global health problem with an estimated incidence of greater than 100 
million persons affected per annum worldwide and few effective treatment options.5 Characterized by 
excessive fibroblast proliferation and collagen deposition, skin fibrosis is involved in a variety of 
pathologic processes ranging from exuberant scar formation secondary to surgery or trauma, as in 
hypertrophic and keloidal scars, to immune-mediated processes such as scleroderma and chronic graft 
versus host disease. As highlighted by quality-of-life studies, skin fibrosis is associated with significant 
psychosocial stress and socioeconomic burden due to the functional, aesthetic, and emotional impacts 
it has on patients’ lives.5–7 Scar prevention and reduction is largely an unmet clinical need, as there is 
no universal consensus on optimal scar management. Currently, there are few non- or minimally 

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9 
invasive and effective interventions or devices shown to limit scarring,1,8–10 underscoring the impact 
and importance of therapeutic advances to achieve scarless wound healing.11 By studying the clinical 
and cellular effects of red light photobiomodulation on skin fibrosis, we aim to pioneer LED-RL as a 
paradigm changing, cost-effective, non-invasive treatment to prevent scarring and identify the 
associated molecular mechanisms using high-throughput screening arrays.12 
 
The effects of visible light, while common in our environment (visible spectrum accounts for 44% of 
total solar energy),13 remain undefined. An important safety feature of visible red light (600 nm to 700 
nm) is that it does not generate pro-carcinogenic DNA damage, unlike ultraviolet (UV) light.13 Visible 
light also has other advantages over UV light, as light of a longer wavelength can penetrate deeper 
into skin. Red light penetrates up to 4 mm in depth, reaching the entirety of the dermis where skin 
fibrosis occurs.14,15 Recently published clinical observations indicate that red light in combination with 
other modalities such as photosensitizers can lessen skin fibrosis.16–18 However, our in vitro data 
suggest that red light can function as a standalone treatment, eliminating the side effects of chemical 
photosensitizers and the potential long-term harm of UV therapy. Furthermore, commercially 
available LED units exist and are FDA-cleared for various medical and aesthetic dermatologic 
conditions.19 Thus, clinical translation for use in skin fibrosis could occur relatively quickly following 
demonstration of safety and efficacy. Developing LED-RL phototherapy as a treatment for skin fibrosis 
would represent an important therapeutic advance in scar modulation as it would offer many 
advantages over current treatment strategies. It lacks the serious systemic side effects associated with 
immunomodulatory agents (such as oral steroids); avoids the need for invasive, painful injections with 
anti-fibrotic agents (such as intralesional steroids, 5-fluorouracil and bleomycin); and eliminates the 
UV-induced DNA damage associated with skin cancer and photoaging that can result from UVA/UVA1 
and UVB/narrowband UVB phototherapy. 
 
There is limited knowledge on the mechanism(s) of red light photobiomodulation of skin fibrosis. Prior 
to our studies, in vitro data regarding the anti-fibrotic effects of LED-RL were lacking. Our studies are 
the first to indicate that LED-RL alone may modulate skin fibrosis, therefore there is a paucity of 
information in this emerging field of investigation. Based on our in vitro data, we proposed a 
mechanistic pathway demonstrating the cellular effects of red light photobiomodulation of skin 
fibrosis. Targets for modulating cutaneous fibrosis include: 1) reducing cellular fibroblast proliferation 
and migration, 2) inhibiting pro-fibrotic cytokines and growth factors such as transforming growth 
factor-beta (TGF-β), SMADs 2/3, 4, 7, connective tissue growth factor (CTGF), platelet-derived growth 
factor (PDGF), and basic fibroblast growth factor (bFGF), 3) modulating inflammatory processes 
associated with fibrosis such as free radical reactive oxygen species (ROS), and 4) decreasing 
biosynthesis of procollagen.20,21 Since red light irradiation can modulate some of these targets,22–24 it is 
an apt therapeutic candidate for anti-fibrosis evaluation. 
 
The hypothesized mechanistic pathway demonstrating the possible cellular effects and pathways of 
red light photobiomodulation of skin fibrosis is as follows: LED-RL phototherapy upregulates heme-
copper photoacceptors in cytochrome c within mitochondria, leading to an upregulation of the 
electron transport chain function resulting in intramitochondrial changes: increased generation of ATP 
and ROS, increased intramitochondrial calcium, and increased mitochondrial membrane potential.25 
Increased ROS frees bound TGF-β1 from latency binding proteins, allowing TGF-β1 to bind to TGF-β 
receptor II, initiating a pro-fibrotic cascade that modulates downstream SMADs, growth factors CTGF, 
PDGF, and bFGF, modulating proliferation and collagen biosynthesis, as low levels of TGF-β1 have 
been shown to increase fibroblast proliferation while higher concentrations inhibit fibroblast 
proliferation.26–36 Specific microRNA are associated with skin fibrosis,37 however it is unclear if LED-RL 

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modulates these microRNA (currently being researched by our laboratory). Connection of these 
intracellular signaling pathways led to our hypothesis that LED-RL phototherapy can alter cellular 
mediators of fibrosis. 
 
In addition to testing the clinical efficacy of LED-RL to prevent skin fibrosis, we aim to elucidate the 
molecular changes that occur in vivo as a result of treatment. Understanding the molecular 
mechanisms of red light photobiomodulation will allow for refinement and optimization of LED-RL 
treatment and contribute to a broader understanding of wound healing and scar formation, with 
potential for applicability in developing LED-RL based treatments to prevent pathologic scars affecting 
patients following trauma, burns, and surgery. 
 
We previously sought to address gaps in knowledge by demonstrating LED-RL anti-fibrotic effects in 
vitro and elucidating some of the underlying mechanisms involved in LED-RL photobiomodulation of 
skin fibrosis. LED-RL doses above 320 J/cm2 decrease fibroblast cell counts, DNA synthesis, and 
decrease procollagen synthesis and collagen, without increasing apoptosis or necrosis. We 
demonstrated similar findings in two keloid scar-derived fibroblast cultures.4 These effects appeared 
to be mediated by alterations in cell cycle. Furthermore, these mechanistic studies demonstrated that 
LED-RL modulates the PI3K/AKT pathway, and LY294002, a PI3K/AKT inhibitor, blocks LED-RL inhibitory 
effects on cell function (migration), suggesting that LED-RL functions in-part via this pathway. 
Additional mechanistic studies did not demonstrate LED-RL effect on ERK, an alternate pathway 
involved in fibrosis. 
 
Animal studies also demonstrate safety of LED-RL in vivo. We have tested LED-RL fluences up to 320 
J/cm2 in mice without any noticeable adverse events. However, given the anatomical differences in 
mouse skin (e.g., the epidermis and dermis measure 0.18 mm to 0.51 mm thick in mice compared to 4 
mm thick in humans),38 it is predicted that the human equivalency dose will be much higher and thus 
our LED-RL starting dose in Phase I studies was conservative. We proceeded directly to human clinical 
study based on the rationale that animal models of skin fibrosis do not recapitulate human scarring 
well, combined with the high level of importance of evaluating the safety and photobiomodulatory 
anti-fibrotic properties and mechanisms associated with LED-RL on normal human skin and human 
models of surgical scarring to yield the maximum patient benefit.  
 
While commercially available LED light therapy devices exist and are FDA-cleared for the treatment of 
various dermatological conditions such as facial wrinkles and acne, none are approved for the 
treatment of scars. To our knowledge, no clinical trials have been performed to determine the safety 
and efficacy of LED-RL for the treatment of skin fibrosis. Therefore, we intend to study LED-RL as a sole 
therapeutic modality for skin fibrosis, with the goal of pioneering LED-RL as a safe, cost-effective, 
portable, at-home therapy to reduce cutaneous scars. 
 
2.3 
RISK/BENEFIT ASSESSMENT   
 
2.3.1 KNOWN POTENTIAL RISKS  
We do not anticipate significant social, financial, legal or other risks to subjects from the proposed 
study, and the likelihood and seriousness of these risks occurring is low. Possible psychological risks 
include study boredom during longer treatment sessions and dissatisfaction or disappointment with 
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experience financial loss (e.g., transportation costs) and loss of time due to study participation. 
Although there is minimal legal risk and all appropriate safeguards are in place to prevent 
dissemination of protected health information (PHI), subjects may experience breach of data. 
 
Physical risks of the proposed mini-facelift surgery are as follows: bleeding, hematoma formation 
(bruising), infection, facial nerve injury with weakness, change in skin sensation, cutaneous or fat 
necrosis, seromas (fluid collection), scarring, poor wound healing, temporary or permanent alopecia 
(hair loss) at incisions, swelling, pain, skin sensitivity, skin contour irregularities, skin discoloration, 
facial asymmetry, irritation from sutures, wound separation, and discomfort from injection of local 
anesthesia. Any of the above risks may be immediate or long-term complications. As mentioned 
above, the subject may feel disappointed or upset by unsatisfactory results or surgical complications. 
The selection of mini-facelift surgery to serve as the surgical wound/scar model for this study is 
explained in Section 2.3.3: Assessment of Potential Risks and Benefits.  
 
Risks of the local anesthesia used during the mini-facelift surgery include: allergic reaction, bleeding, 
discomfort from the injection, injury from the needle used to inject the anesthesia, paresthesia 
(abnormal skin sensation such as burning, numbness, and tingling), and toxicity from excessive dose of 
anesthesia given. 
 
Physical risks of the proposed LED-RL phototherapy include potential toxicity and lack of efficacy. 
There is low risk of infection as we will not treat non-intact skin (since presence of open wound(s) at 
the treatment site is an exclusion criterion) and all LED-RL phototherapy devices will be cleaned with 
disinfectant before and after each treatment session. Common expected post-treatment effects 
include mild erythema (redness), warmth, and swelling that is transient (i.e., lasts less than 24 hours). 
Subjects may have tenderness or swelling at the treatment site. Since darker skin pigment absorbs 
more light energy in the epidermis, it is possible that subjects with darker skin types may experience a 
greater sensation of epidermal warmth, textural changes, or dyspigmentation. Due to the split-face 
study design (i.e., only one surgical incision receives LED-RL phototherapy), there is a possibility of 
uneven cosmetic results of the scar appearances at the conclusion of the study. That is, the scar on 
one side of the face may look better, worse, or the same as the scar on the other side. 
 
Potential serious adverse events including, but not limited to, second-degree or higher skin burning, 
blistering, persistent swelling, persistent pain, ulceration, change in sensation, mucle weakness, or 
worsening of surgical scar will be monitored and the trial will be halted early if necessary. While we 
have tested the effects of LED-RL on fibroblasts, it is not known whether LED-RL alters the function of 
other cell types in vivo. At the doses studied, there may be inhibitory effects on other cells found in 
the epidermis and dermis such as keratinocytes, melanocytes, endothelial cells, neurons and immune 
cells. Due to the location of LED-RL phototherapy on the face, there is a theoretical risk of neurological 
side effects such as headaches, malaise, fatigue, and change in hearing.  
 
We do not anticipate any physical risks of the mock irradiation since it does not generate light and 
there were no adverse events associated with the mock treatment device in the Phase I studies. 
However, due to the split-face study design, subjects may have uneven cosmetic results between the 
two periauricular incision sites. The scar on one side of the face may appear better, worse, or the 
same as the scar on the contralateral side, depending on the effects of the study intervention. 
 

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A proposed component of this study is optional skin biopsies for histological examination. Though a 
skin biopsy is a generally safe procedure, potential risks include bleeding, bruising, scarring, pain, skin 
sensitivity, and infection. 
 
2.3.2 KNOWN POTENTIAL BENEFITS  
Potential benefits of mini-facelift surgery include improvement in visible signs of aging on the face 
(e.g., improvement in wrinkles and laxity) and improved self-esteem from a good cosmetic outcome.  
 
Known potential benefits of the Omnilux new-U for LED-RL include reduction of periorbital wrinkles, 
the current FDA indication for use. The potential benefit of scar prevention is being studied in this 
protocol. 
 
Patients with post-surgical scars and skin fibrosis in general have limited treatment options. Even with 
treatment, skin fibrosis often persists and recurrence rates are high. If LED-RL phototherapy is 
effective at preventing hypertrophic or keloidal periauricular scarring, subjects will benefit from 
improved scar appearance and symptomology. This benefit by patients will in turn aid medicine and 
science.  
 
2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
Although no surgical procedure is without complications, facelift surgery is considered to be a safe 
procedure with a low incidence of major complications, with hematoma (1.1%) and infection (0.3%) 
being the most common but still occur infrequently.39 We chose mini-facelift incisions as the surgical 
wound model for the following reasons: it is considered to be a safe procedure, performed in-office 
with tumescent local anesthesia; it offers an aesthetic benefit to patients who are interested in facial 
rejuvenation; and the surgical incisions are made in relatively inconspicuous areas near the earlobes 
and are symmetrical, allowing for a split-face study. We believe that given the low incidence of 
complications of this commonly performed elective cosmetic procedure, combined with the fact that 
the procedure in this protocol is a minimal incision facelift (as opposed to the traditional full facelift 
that requires more extensive incisions and longer recovery time), the value of information to be 
gained by studying this surgical wound model outweighs the risks involved.  
 
LED-RL phototherapy is also considered to be a safe procedure that is done routinely in outpatient 
clinics and even at home. We will monitor for any unforeseen adverse events caused by LED-RL and 
follow study stopping rules, as described below. LED-RL phototherapy is completely non-invasive, does 
not cause thermal or chemical damage, and does not have post-procedure down time. The risk of side 
effects is minimal and those that do occur are usually transient and minor (e.g., mild erythema lasting 
less than 24 hours). We believe that the value of the information to be gained in this study outweighs 
the potential risks involved in LED-RL phototherapy, given that the treatment device is FDA-cleared for 
over-the-counter use on the face and has been clinically proven to be safe and well tolerated at the 
proposed treatment doses.  
 
The skin biopsies are optional and will be used for research purposes only. Minimal risk of scar will be 
incurred by subjects undergoing biopsy, as a 2 mm punch biopsy tool (the smallest sized instrument 
that can be used to obtain useful histological and molecular analysis) was selected to minimize 

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discomfort and reduce the risk of scarring. The 2 mm size is so small that the punch biopsy defect (skin 
wound) does not require suturing and heals by secondary intention. 
 
During the study, subjects are asked to refrain from using scar treatments to both periauricular 
incision sites, as to not confound the results of the study. They will be counseled on standard 
postoperative care of the incisions to optimize wound healing. Subjects are allowed to seek scar 
treatment, if desired, at the conclusion of the study (i.e., after the final study visit at 6 months post-
surgery). Facial skin is known to heal well, and thus have lower risk of abnormal scarring, compared to 
other body sites due to its rich vasculature and low tensile forces.40,41 Since most cutaneous injuries 
(such as surgical incisions) heal with a normotrophic scar over time,41,42 the study’s requirement that 
subjects wait 6 months post-surgery to seek scar treatment is not expected to cause irreversible 
health problems or extreme suffering. A normotrophic scar is defined as a flesh-colored, flat scar (as 
opposed to hypertrophic scars or keloids, pathological scars that are elevated and can be 
symptomatic).42,43 Furthermore, the remodeling phase of skin wound healing can take over a year, 
meaning that the scar maturation process is lengthy and the final scar appearance may not be known 
until 6 months to 2 years after surgery.44,45 It is important to note that should pathological scarring 
develop in a subject, it will not be evident until several months post-surgery, as this is the general 
timepoint at which a hyperplastic response (i.e., abnormal scar tissue formation) is observed.41 In 
clinical practice, it is recommended that hypertrophic scars be allowed the opportunity to regress on 
their own before initiating aggressive anti-scarring treaments such as scar revision surgery.43,46 
 
Stopping Rules: Subjects will have the ability to leave the study at any time without penalty for 
discontinuation of participation. Adverse events, serious adverse events, and unanticipated problems 
(as described in Section 8: Study Assessments and Procedures) will be monitored and the trial will be 
halted early if necessary to protect subjects. Any life threatening events and/or deaths (grade 4 and 5 
toxicity) attributable to the study protocol will result in halting the study. Toxicity data and adverse 
events will be monitored by the PI and the IRB. 
 
3 
OBJECTIVES AND ENDPOINTS 
 
 
OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
Primary 
 
 
To evaluate the 
clinical efficacy of LED-
RL phototherapy in 
the prevention of skin 
fibrosis in subjects 
undergoing elective 
mini-facelift surgery 
 
The difference in quantitative scar pliability 
between the LED-RL treated and control 
incision sites 
 
Skin elasticity (stiffness) and induration, which 
reflect scar pliability, are objectively quantified 
with two different indentation instruments, the 
ElastiMeter and the SkinFibroMeter. These 
non-invasive handheld tools measure vertical 
deformation on the skin surface; the indenter is 
pressed quickly onto the skin and the sensors 
measure the force resisting the strain. Scar 
tissue is less supple than normal skin due to 
scar thickness and inferior quality of collagen 
Various  objective scar assessment tools are 
available to assess biomechanical 
properties of the skin, including pliability, 
which correlates with degree of skin 
fibrosis.47–52 These devices have shown less 
pliability in scars as compared to normal 
controls and are commonly used to 
measure the efficacy of scar treatments.53 
The ElastiMeter demonstrates accuracy and 
reliability to assess skin elasticity.54 The 
SkinFibroMeter has good reliability 
compared with other elasticity 
measurement devices and has been applied 
in clinical studies to assess skin fibrosis.55,56 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
architecture. Elasticity and induration 
measurements are performed prior to 
treatment and at follow-up visits on POD 30, 
90, and 180. 
Secondary 
 
 
To evaluate the 
histological, 
ultrastructural, and 
molecular changes 
that occur in vivo as a 
result of LED-RL 
phototherapy 
Histological and molecular analyses of treated 
and control skin specimens 
 
Skin samples from LED-treated and mock-
treated incision sites are obtained for histology 
and molecular studies. Tissue specimens from 
POD 30 (post-treatment) are compared to 
those from POD 0 (pre-treatment). Histological 
examination includes quantification of Ki-67 
positive fibroblasts and qualitative assessment 
of collagen. Molecular testing includes RNA-
Seq, microRNA arrays, and quantitative real-
time PCR (qRT-PCR). 
 
Non-invasive tests to evaluate cellular 
features of skin fibrosis are limited. Our in 
vitro data showed that high fluence LED-RL 
decreases fibroblast cell counts in keloid 
scar-derived fibroblast cultures4 and that 
LED-RL modulates the PI3K/AKT pathway.57 
To determine the mechanism associated 
with LED-RL anti-fibrotic effects in vivo, 
biopsies of the dermis (where skin fibrosis 
occurs) are needed to conduct histological 
examination and molecular studies. 
To assess for clinically 
meaningful changes in 
scar characteristics  
after LED-RL 
phototherapy 
Difference in the Patient and Observer Scar 
Assessment Scale (POSAS) scores between the 
treated and control incision sites 
 
Subjective scar evaluation is performed using 
the POSAS, a standardized and validated tool to 
assess scar quality.58–60 The observer scar 
assessments are completed in-clinic by a 
blinded investigator in conjunction with subject 
assessments at multiple time points (follow-up 
visits on POD 30, 90, and 180). Each parameter 
on the POSAS is scored from 1 to 10, where 1 is 
“normal skin” and 10 is the “worst imaginable 
scar”. 
The POSAS is the most frequently used scar 
assessment scale for post-surgical scars61 
and is often used as a primary outcome 
measure for treatment efficacy in clinical 
trials. The POSAS was devised to quantify 
scar appearance in response to treatment 
and demonstrates internal consistency, 
inter-observer reliability, and 
agreement.53,58 Importantly, the POSAS 
incorporates the patient’s judgment of scar 
appearance and includes subjective 
symptoms of pain and pruritus, allowing for 
a more comprehensive evaluation in 
comparison to an evaluation by clinicians 
alone. 
 
 
Difference in the photograph-based Visual 
Analogue Scale (VAS) scores between the 
treated and control incision sites 
 
An independent panel of two blinded 
dermatologists will evaluate standardized split-
face scar photographs, using a validated VAS 
scoring and ranking system.53,62,63 Each scar 
dimension is rated on a 10 cm VAS such that 
The VAS has demonstrated high observer 
reliability and internal consistency in expert 
panel evaluations.53,63 The VAS has been 
used in various scar trials53 and Duncan et 
al. showed that the VAS scar scoring and 
scar ranking methods are consistent, 
reliable, valid, and feasible for assessing 
linear scars.62 

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OBJECTIVES 
ENDPOINTS 
JUSTIFICATION FOR ENDPOINTS 
higher numerical scores correlated with more 
severe scars. 
Difference in objective measurements of key 
scar characteristics between the treated and 
control incision sites 
 
A diverse set of novel, non-invasive skin 
analysis tools will be used to objectively 
measure key scar characteristics: collagen and 
water concentration, wrinkles, texture, 
diameter, area, volume of elevation, pores, 
pigmentation, and vascularity. The VivoSight 
uses multi-beam OCT technology to provide 
high-resolution cross-sectional images and 
measure scar depth, collagen density, and 
surface roughness.64 The Dermo is a 
spectroscopy probe that measures collagen and 
water concentration in the dermis. The Antera 
3D camera and Cherry3 camera use multi-
directional illumination to reconstruct three-
dimensional images of the skin surface for 
instant topographic and colorimetric analyses. 
 
These objective efficacy assessments will be 
done prior to treatment initiation and at 
follow-up visits. 
OCT has been used to non-invasively 
evaluate skin fibrosis at high resolution 
without discernible effect on tissue.65 This 
imaging technique is highly suited to 
fibrosis assessment and may represent a 
diagnostic alternative to punch biopsies.66  
 
Three-dimensional skin imaging analysis 
provides quantitative measurements of 
various scar tissue indicators such as 
pigmentation, vascularity, texture, and 
volume of depressions and elevations. 
Because it is an objective analysis tool, it 
provides quantitative evidence of 
therapeutic results, avoiding the influence 
of subjective evaluation that most scar 
assessments are based on.67–69 It has been 
used to assess therapeutic efficacy of 
various interventions on keloids and burn 
scars.  
 
 
To continue to assess 
the safety of LED-RL 
phototherapy on 
human skin 
The safety profile is determined by the 
incidence of common expected post-treatment 
effects, adverse events, serious adverse events, 
and unanticipated problems throughout the 
study. Special attention will be paid to the 
identification of any differential safety findings 
based upon skin type (i.e., race and ethnicity), 
given the findings of our previous Phase I trials. 
While two phase I studies demonstrated 
the safety of LED-RL in healthy subjects, the 
safety of LED-RL in a mini-facelift surgical 
wound model may differ from the safety on 
normal human skin. In addition, differential 
safety effects of LED-RL on different skin 
types have not been described previously, 
but our previous research suggest that 
darker skin types may be more 
photosensitive to LED-RL. 
 
 
 
 
 
4 
STUDY DESIGN  
 
4.1 
OVERALL DESIGN 
This is a Phase II clinical trial, following two previous Phase I studies of LED-RL on human skin in 
healthy subjects (STARS 1 and STARS 2). We will conduct a dose-ranging, randomized, parallel group, 
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undergo elective minimal incision facelift (i.e., mini-facelift) surgery. We hypothesize that LED-RL 
phototherapy may be a safe, well tolerated, and effective treatment for skin fibrosis. 
 
The trial will be conducted at a single site: the Laser, Aesthetics and Body (LAB) Institute at SUNY 
Downstate Medical Center. The LAB Institute is part of the Center for Photomedicine, Department of 
Dermatology, and is located at University Hospital of Brooklyn. The mini-facelift surgery is a simple 
excision of redundant skin (i.e., excess lax facial skin) with wound closure. The surgery is done in-office 
in a procedure room within the LAB Institute, which is equipped with LED surgical lighting and stocked 
with standard care supplies, medications, and surgical instruments needed for dermatologic surgical 
procedures done in an ambulatory setting. The surgery is performed under tumescent local anesthesia 
by a board-certified dermatologic surgeon (Dr. Daniel Siegel) at the baseline visit, referred to as post-
operative day (POD) 0. Following the mini-facelift surgery, subjects will be counseled on standard 
postoperative wound care and be provided with a handout of instructions. Subjects are asked to 
adhere to the postoperative care instructions to optimize skin wound healing and to refrain from using 
scar treatments at the incision sites during the study. 
 
 
Subjects will use commercially available, FDA-cleared LED-RL phototherapy treatment devices 
(Omnilux new-U; GlobalMed Technologies, Glen Ellen, CA) aimed at the periauricular skin (i.e., the site 
of incisions from mini-facelift surgery). The Omnilux new-U will be held in place using a provided hair 
net that has been used by other researchers to stabilize facial positioning of LED-RL phototherapy 
units. The maximum recommended starting dose (MRSD) of 160 J/cm2 is based on previously 
published maximum doses of LED-RL that demonstrated safety with no adverse events in clinical 
studies.70,71 The highest dose to be tested is 480 J/cm2, which was found to be the maximum tolerated 
dose (MTD) in our Phase I studies (unpublished data). The MTD is defined as the dose level below the 
dose producing unacceptable but reversible toxicity and is considered to be the upper limit of subject 
tolerance. 
 
A total of 30 subjects will be randomly allocated into three treatment groups of 10 subjects to receive 
LED-RL phototherapy at the following doses: 160 J/cm2, 320 J/cm2, or 480 J/cm2. Based on safety data 
obtained in our Phase I studies, we concluded that skin of color individuals (as determined by race and 
ethnicity) may be more photosensitive to LED-RL compared to Caucasian non-Hispanic individuals. 
This novel description of possible differential cellular effects of red light on skin is based on findings 
that LED-RL doses up to 320 J/cm2 was safe in all skin types, but one African-American subject had an 
adverse event of a blister with LED-RL at 480 J/cm2. Because no definitive conclusions may be drawn 
due to the limited sample size (1 subject who developed a blister out of 3 subjects who received the 
same treatment in that group), and the dose-escalation study design precluded continued 
administration of LED-RL at 480 J/cm2 (i.e., no further subjects were enrolled in that treatment group 
due to the adverse event), this trial will test the MTD of 480 J/cm2 in all subjects regardless of skin 
type. 
 
In this study, skin type is determined by the National Institute of Health’s definitions for racial and 
ethnic categories.72 For the purposes of monitoring safety in relation to skin type, any individual who 
self-identifies with a race/ethnicity (or any combination thereof) other than “Caucasian, not Hispanic 
or Latino” will be considered to have skin of color. 
 
The treatment side (right face versus left face) will also be randomized to control for effects of uneven 
sun exposure. The untreated side will receive mock therapy with sham irradiation via a mock device 
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be blinded to the LED-RL device versus mock device as the treatment site is outside of their range of 
view and they will wear safety goggles.  
 
Beginning scar reduction therapy at 1 week after surgery (defined as POD 4 to POD 8) is a validated 
intervention time point for limiting surgical scars.1 Subjects will receive their treatment sessions in-
office three times weekly, a standard phototherapy regimen,73–75 starting at 1 week post-surgery for a 
total of nine treatment sessions. This treatment schedule (frequency and duration) is identical to the 
schedules used in our Phase I studies. Each treatment session will be observed by an investigator to 
monitor for any adverse events and to ensure safety and adherence. 
 
During the study, subjects will be asked to avoid scar treatments to both periauricular incision sites. 
Scar treatment options include, but are not limited to, silicone gels/sheets, intralesional 
corticosteroids, 5-fluorouracil, laser therapy, radiotherapy, cryotherapy, bleomycin, mitomycin C, 
imiquimod, pressure therapy, adhesive microporous hypoallergenic paper tape, onion extract, 
massage therapy, over-the-counter topical emollients for scars, laser therapy, and surgical revision.76 
As described above, subjects will be counseled on proper wound care during the postoperative period 
to facilitate appropriate wound healing. Refer to Section 10.2: Additional Considerations for a 
discussion of available scar treatments at the conclusion of the study. 
 
Following the study intervention period, subjects will have follow-up assessments on approximately 
POD 30, 90, and 180. At each follow-up visit, scar characteristics will be recorded objectively and 
subjectively through skin elasticity and induration measurements, tissue histology, photographic 
evaluation, skin imaging analysis, collagen and water concentration measurements, OCT, and 
standardized patient and observer assessments as described in Section 3: Objectives and Endpoints 
and Section 8: Study Assessments and Procedures. 
 
Skin specimens will be obtained via elective 2 mm punch biopsy on POD 0 (prior to surgery) and POD 
30 (first follow-up visit after completion of LED-RL treatment). Skin specimens will be used for 
histological examination and molecular studies via RNA sequencing, microRNA analysis, and qRT-PCR. 
 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The methodology of a dose-ranging, randomized, parallel group, split-face, single-blind, mock-
controlled study offers several advantages. 
 
A dose-ranging study design is implemented as the safety of LED-RL phototherapy in a surgical wound 
model may differ from the safety in normal skin. For example, higher fluences determined to be safe 
in normal skin may potentially cause problems in post-surgical/scarred skin, such as dehiscence. Thus, 
the MTD established in our Phase I studies serves as the upper limit of treatment dose in this study. 
 
The split-face study design allows each subject to serve as his or her own control, allowing for a 
within-subject comparison of clinical efficacy between the treated side and mock-treated side. That is, 
any observed improvements in scar characteristics can be attributed to the treatment. The split-face 
design also eliminates the need to consider inter-individual differences in wound healing as a 
confounding factor when comparing different treatment arms. It is important to note that in the 
prospective evaluation of scar reduction therapy, it is assumed that if left untreated, the wounds on 
the treated side and untreated side would heal with identical scars. Since wound healing and scar 

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formation are influenced by many variables, the selection of a self-controlled study design is favored 
to allow detection of true treatment effects. 
 
There are no known problems associated with the control (sham irradiation), since the mock device is 
designed to simulate the treatment device without actually producing light. 
 
The mini-facelift with periauricular incisions is an ideal model for studying wound healing and skin 
fibrosis because: patients are motivated to have the best wound healing outcomes and aesthetic 
results (i.e., minimal or imperceptible scarring), hence will likely be compliant with therapy and have a 
low attrition rate; patients are usually healthy in order to be suitable candidates for the surgery; and 
the periauricular skin is at risk of pathological scar development, yet has low skin tension and robust 
blood circulation to allow for optimal wound healing. 
 
4.3 
JUSTIFICATION FOR DOSE 
As discussed in Section 4.1: Overall Design, the MRSD of 160 J/cm2 is based on maximum doses of LED-
RL that demonstrated safety with no adverse events in clinical studies.49,50 The planned maximum 
dose is 480 J/cm2, which was found to be the MTD for Caucasian non-Hispanic individuals in our Phase 
I studies.  
Based on safety data generated by our Phase I studies, we had established a MTD of 320 J/cm2 in 
individuals with darker skin color based on an adverse event of a skin blister in an African-American 
subject following administration of LED-RL at 480 J/cm2. Because the occurrence of a skin blister was 
pre-defined as an unacceptable toxicity, further treatment sessions for subjects enrolled in the LED-RL 
480 J/cm2 treatment group were halted. That subject was the only one out of 3 subjects of different 
skin types (1 African American, 2 Caucasian non-Hispanic) in that particular treatment group who had 
experienced a blister. Therefore, while no definitive conclusions may be drawn about differential 
safety of LED-RL based on race/ethnicity due to the limited sample size, we hypothesized that skin of 
color individuals may be more photosensitive to LED-RL compared to Caucasian non-Hispanic 
individuals. This observation of possible differential safety of visible red light on different skin types 
had not been described previously. To further evaluate safety of LED-RL on skin and to explore this 
hypothesis, this Phase II trial is designed to allow subjects of any skin type to be randomized to the 
highest intensity treatment dose of 480 J/cm2. In a joint discussion with research colleagues and the 
IRB, the study team decided that the adverse event of a blister, which is more likely to occur at higher 
fluences, is an acceptable risk since treatment-related cutaneous blistering is expected to be mild and 
resolve without permanent sequelae. During the informed consent process, subjects will be counseled 
on the potential risk of blistering and be informed that darker skin individuals may be more prone to 
this risk.  
 
Please refer to Section 2.3.3: Assessment and Potential Risks and Benefits and Section 7.1: 
Discontinuation of Study Intervention for a discussion and description of stopping rules. 
 
The thrice weekly treatment regimen is a standard phototherapy protocol,52-54 which is based on 
guidelines for UVB phototherapy for psoriasis and is applicable to this study of LED-RL phototherapy. 
 
 
4.4 
END OF STUDY DEFINITION 

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A participant is considered to have completed the study if he or she has completed all phases of the 
study including the last visit shown in Section 1.3, Schedule of Activities (SOA). 
 
The end of the study is defined as completion of the last visit or procedure shown in the SOA in the 
trial globally. The end of the study is the point at which all required data has been collected to answer 
the research questions in the protocol. 
 
 
5 
STUDY POPULATION 
 
5.1 
INCLUSION CRITERIA 
 
Individuals of any sex, ethnicity, and age may potentially be eligible to participate in this study. In 
order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Provision of signed and dated informed consent form 
2. Stated willingness to comply with all study procedures and availability for the duration of the 
study  
3. Desire to undergo elective mini-facelift surgery and is a suitable surgical candidate, as 
determined by the surgeon’s clinical assessment 
4. Pass a screening photosensitivity test 
 
 
5.2 
EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Concomitant use of any photosensitizing medications (e.g., lithium, melatonin, phenothiazine 
antipsychotics, tetracycline antibiotics, quinolone derivative antibiotics)† 
2. Light-sensitive conditions 
3. Diabetes mellitus 
4. Systemic lupus erythematosus  
5. Current tobacco use 
6. History of bleeding or coagulation disorder 
7. Lax skin associated with genetic disorders (e.g., Ehlers-Danlos, cutis laxa) 
8. Open wounds on the face or neck 
9. Fibrotic skin disease, pre-existing scar(s), or other skin conditions affecting the periauricular 
skin 
10. History of surgery or procedure involving or affecting the periauricular facial skin within the 
past 6 months (e.g., facial plastic surgery, dermal fillers, physician-strength chemical peels, 
neuromodulator treatment, laser skin resurfacing), or plan to have such procedures during the 
study period 
11. Tattoos that cover the proposed treatment sites on the periauricular skin  
12. Any other medical condition(s) that could be compromised by exposure to the proposed 
treatment 
† Refer to Section 6.5: Concomitant Therapy for the full list of prohibited medications to be reviewed 
on case report forms. 

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5.3 
LIFESTYLE CONSIDERATIONS 
During this study, participants are asked to: 
• 
Abstain from smoking 
• 
Refrain from use of any scar treatments (e.g., silicone gel/sheets, intralesional corticosteroids, 
massage therapy, topical emollients, laser therapy, surgical revision) on the periauricular 
incision sites 
• 
Avoid any elective cosmetic procedure that would affect the facial skin 
 
If a prohibited medications, treatments, or procedures are indicated for standard of care, the 
participant will be withdrawn early from the study. Exceptions include, but are not limited to, use of a 
photosensitizing medication after the conclusion of the intervention period (i.e., after all LED-RL 
phototherapy sessions are completed).  
 
5.4 
SCREEN FAILURES 
 
 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently randomly assigned to the study intervention or entered in the study. A minimal set of 
screen failure information is required to ensure transparent reporting of screen failure participants, to 
meet the Consolidated Standards of Reporting Trials (CONSORT) publishing requirements and to 
respond to queries from regulatory authorities. Minimal information includes demography, screen 
failure details, eligibility criteria, and any serious adverse event (SAE). 
 
Individuals who do not meet the criteria for participation in this trial (screen failure) because of use of 
prohibited medications that have subsequently been discontinued may be rescreened. Rescreened 
participants should be assigned the same participant number as for the initial screening. 
 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 
Potential subjects who are interested in elective mini-facelift surgery will be recruited through IRB-
approved flyers on bulletin boards, physician referrals, websites (SUNY Downstate Department of 
Dermatology webpage, SUNY Downstate Clinical and Translational Science Center “Clinical Trials List”, 
StudyPages.com, and ClinicalTrials.gov), social media, website ads, radio ads, and/or newspaper ads. 
Potential participants will be identified by their expressed interest in a mini-facelift or perceived 
suitability for the surgery (i.e., they have excess lax facial skin and desire a mini-facelift). Aside from 
physician referrals and direct recruitment from clinic, recruitment materials will be distributed or 
made available to the general public. That is, potential participants may learn about the study and 
approach or contact the research team directly. We anticipate screening up to 150 potential 
participants and ultimately enrolling 30 subjects. 
 
At the initial screening visit, investigators will explain the study, provide relevant literature and 
information, and answer all questions. Written informed consent will be obtained prior to any study-
related procedures or interventions. We will indicate that the subjects will receive the same standard 
of clinical care options regardless of whether they decide to participate in the study. Subjects will be 
informed that the costs of the surgery are covered by the research study and that participation is 
voluntary, allowing them to withdraw from the study at any time. 
 

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Measures to minimize undue influence: Due to the nature of this research study, specifically the 
provision of an elective cosmetic procedure at no cost to the subject, measures are in place to 
minimize undue influence. The fact that the cost of the surgery is covered by the Department of 
Dermatology will not be advertised in recruitment materials. That is, we are not emphasizing “free 
surgery” as a way to gain the attention of potential subjects. In the recruitment materials, we call for 
volunteers who are considering or interested in a mini-facelift, without commenting on whether the 
surgery itself is part of the study. The fact that the surgery will be provided at no cost for enrolled 
subjects is disclosed during the informed consent process (i.e., after a potential subject makes contact 
with the research team to express interest in the study and comes in-person for the screening visit). 
With this recruitment strategy, we will be able to screen potential subjects who are already 
aesthetically motivated and inclined to undergo cosmetic surgery such as a mini-facelift, regardless of 
the opportunity provided by this study. During the informed consent process, the individual’s 
comprehension of risks, benefits, and outcome expectations are of paramount concern when 
determining appropriate candidates for the mini-facelift. In this study, there is an ethical concern that 
an offer of no-cost surgery may impair an individual’s judgment such that they do not fully consider 
risks and thus engage in activities that contravene their interests. To minimize this risk, we will 
conduct an assessment of the individual’s understanding and appreciation of the surgery’s 
risks/benefits and alternative options to ensure that they demonstrate decision-making capacity. We 
will emphasize that research participation is voluntary, that the subject can withdraw at any time, and 
that the decision whether or not to participate will have no impact on the availability of care. Known 
benefits of the mini-facelift and the study intervention will be stated accurately but not exaggerated; 
potential or uncertain benefits will also be stated as such, with clear language indicating how much is 
known about the uncertainty or likelihood of these potential benefits. For example, we will ensure 
that the potential subject has reasonable expectations about the cosmetic outcome of the mini-
facelift; they should understand what the mini-facelift can and cannot do to change physical 
appearance. We will seek consent only under circumstances that provide the prospective subject 
sufficient opportunity to consider participation and that minimize the possibility of undue influence.  
 
To minimize potential for drop-out due to scheduling conflicts, subjects will be directly asked prior to 
enrollment if they are willing and able to be compliant with therapy (i.e., be able to attend all 
proposed study visits on the schedule). We will educate subjects regarding the benefits and risks of 
the study, as well as importance of attending all treatment sessions and follow-up visits for subject 
safety. We will guard against drop out by confirming study visits with subjects in advance to ensure no 
scheduling conflicts via multiple methods of communication including phone calls, email, and text 
message reminders. To minimize subject burden and enhance retention, we will make every attempt 
to accommodate subject preferences in scheduling time (e.g., treatment sessions in the mornings 
only). All treatment sessions and follow-up visits will be in the same location. 
 
We hypothesize that drop-out will be low, as we hope that subjects are interested in and motivated to 
limit post-surgical scarring for functional and aesthetic reasons. 
 
Subjects will be compensated for study participation. A total amount of $375 will be given in the form 
of gift cards and/or checks. Subjects will receive $100 at the end of each week during the 3-week 
treatment period, plus $25 for each of the 3 follow-up visits. In the event that a subject withdraws 
early from the study, the payment will be prorated based on the number of study visits completed 
prior to withdrawal.  
 
 

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6 
STUDY INTERVENTION 
 
6.1 
STUDY INTERVENTION(S) ADMINISTRATION 
 
6.1.1 STUDY INTERVENTION DESCRIPTION 
 
The LED light source is the Omnilux new-U handheld LED phototherapy device, which is commercially 
available and FDA-cleared for the treatment of periorbital wrinkles. This device has not been approved 
or cleared for the indications the protocol is designed to investigate (skin fibrosis). The device has a 3-
position switch that allows the user to select the red light output (switch down).  
 
The mock therapy device emits no irradiation. The mock therapy device has a ventilation fan and 
functional resistors designed to sound, look, and feel (i.e., temperature matched) similar to the 
phototherapy treatment device, but does not emit LED-RL.   
6.1.2 DOSING AND ADMINISTRATION 
Randomization: 
A computer-based randomization algorithm will be used to assign subjects to three different 
treatment groups to receive LED-RL at the following doses: 160 J/cm2, 320 J/cm2, or 480 J/cm2. The 
treatment side (right face versus left face) will also be randomized using the same algorithm. The 
same dose will be maintained throughout all treatment sessions for each individual subject, with no 
dose escalation. Refer to Section 6.3: Measures to Minimize Bias for a detailed description of the 
randomization protocol. 
 
Treatment Protocol:  
The subject will be inside a private clinic examination room. The subject’s periauricular skin on both 
sides of the face will be cleaned with alcohol pads. A surgical marking pen will be used to outline the 
treatment area at the start and completion of every treatment. The Omnilux new-U device and mock 
therapy device will be aimed at the periauricular skin and positioned in close contact with the skin 
(maximum of 1 cm from the skin surface), held in place by a hair net throughout the duration of the 
treatment. LED-RL phototherapy and mock therapy are administered simultaneously. Subjects will be 
allowed to receive the treatment sitting up or laying down, per personal preference for a comfortable 
position. 
 
Duration of the treatment administration for each group is as follows:  
• 
Group 1: LED-RL 160 J/cm2 and mock therapy – 30 minutes 
• 
Group 2: LED-RL 320 J/cm2 and mock therapy – 60 minutes 
• 
Group 3: LED-RL 480 J/cm2 and mock therapy – 90 minutes 
Dr. Julie Nguyen (research coordinator) will perform the phototherapy, observe the treatment session, 
and assess for any safety issues that may arise. Any adverse events reported by the subject or 
observed by the investigator will be recorded. Common expected post-treatment effects include mild 
erythema, warmth, and swelling, which are expected to resolve within 24 hours. 
 

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Subjects will receive LED-RL phototherapy and mock therapy sessions in-office three times weekly, 
starting at approximately 1 week post-surgery, for a total of nine treatment sessions. The duration of 
treatment administration is controlled by the investigator (i.e., the investigator will take responsibility 
for timing the treatment and determining when the devices are turned off to end treatment). 
 
The Omnilux new-U has been tested to international standards to ensure that its outputs are safe for 
the eyes. However, subjects will wear safety goggles during the treatment sessions, as recommended 
by the manufacturer for patient comfort. 
 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
 
The study intervention and control products were originally purchased from Photo Therapeutics. 
There is no distribution plan as the treatment and mock devices are already in the possession of the 
research team (previously purchased for the Phase I studies). Disposal of unused product is not 
applicable to this protocol. 
 
 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
 
The LED light source is the Omnilux new-U (GlobalMed Technologies, Glen Ellen, CA) handheld LED 
phototherapy device, which is commercially available and FDA cleared for treatment of periorbital 
wrinkles. The device contains an array of LEDs with a transparent lens cover, a ventilation fan, a three-
position switch, and a connection socket. The LED has a 4.7 cm x 6.1 cm rectangular aperture and 
emits visible red light (633 nm + 6 nm) at a power density of 360.2 W/m2 at room temperature.  
 
The mock therapy device has a ventilation fan and functional resistors designed to sound, look, and 
feel similar to the phototherapy treatment device, but emits no irradiation.   
 
6.2.3 PRODUCT STORAGE AND STABILITY 
The phototherapy treatment and mock therapy devices will be stored at room temperature in a 
secured private clinic examination room, avoiding extreme temperatures and direct sunlight. 
 
6.2.4 PREPARATION 
The treatment and mock devices are powered by wall power supply plugged into an AC electrical 
outlet. The operator (i.e., investigators) will flip the selector switch to turn on the red LEDs and place 
the transparent lens in close contact with the treatment area, at a maximum of 1 cm from the skin 
surface. 
 
6.3 
MEASURES TO MINIMIZE BIAS: RANDOMIZATION AND BLINDING 
Treatment Dose Randomization 
A block randomization scheme will be used for balanced allocation of subjects to study arms, such that 
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(i.e., sequentially in blocks of three). Study enrollment concludes when a total of 30 subjects have 
been randomized. 
 
For the first subject who enrolls, Arabic numeral “1”, “2”, or “3” will be generated at random using a 
computer-based randomization tool (www.randomizer.org). This subject has a 1 in 3 chance of being 
assigned to any of the three treatment groups: “1” for Group 1 (LED-RL 160 J/cm2), “2” for Group 2 
(LED-RL 320 J/cm2), or “3” for Group 3 (LED-RL 480 J/cm2). The next subject who enrolls is then 
similarly randomized to one of the remaining two treatment groups, and the following subject who 
enrolls is automatically assigned to the last treatment group. This block randomization process 
continues until each treatment group is filled with 10 subjects. 
 
Split-Face Randomization 
Within each treatment group, the treatment side (right face versus left face) will be determined using 
a computer-generated randomization tool (www.randomizer.org). The assignment to a treatment 
dose and a treatment side of the face occurs simultaneously. Within each treatment group, a single 
set of Arabic numerals “0” to “9” will be generated, resulting in a random sequence of 10 numerals for 
sampling without replacement. As subjects are allocated to a treatment group, they are assigned to a 
numeral in this set based upon their order of enrollment. In other words, the first subject to enroll in a 
treatment group is assigned to the first random numeral, the second subject to the second random 
numeral, etc. Subjects assigned to even numerals will receive LED-RL phototherapy on the right side of 
the face, making the left face the control. Subjects assigned to odd numerals will receive LED-RL 
phototherapy on the left side of the face, making the right face the control. Within each treatment 
group (n=10), 5 subjects will receive treatment on the right face and the other 5 subjects will receive 
treatment on the left face. 
 
Blinding 
This is a single-blind study wherein the subjects are blinded to the treatment side. From the subject’s 
perspective, the LED-RL phototherapy device and the mock therapy device are indistinguishable since 
1) the treatment area is outside of their range of view and 2) the mock therapy device was designed to 
simulate the actual treatment device in terms of appearance, sound, and feel. 
 
Clinicians involved in evaluating certain outcome measures (e.g., histology, POSAS, evaluation of 
digital photography) will be also be blinded to the treatment side. This includes the following 
clinicians. 
• 
The investigator who will perform the POSAS, a subjective scar assessment scale that is scored 
based on clinical judgment – Dr. Daniel Siegel 
• 
The expert panel of two independent dermatologists charged with photographic evaluation of 
the scars – Dr. Edward Heilman and Dr. Jeannette Jakus 
• 
The dermatopathologist examining the skin specimen slides – Dr. Edward Heilman 
 
The PI and research coordinator will be aware of the trial randomization codes. Unblinding may occur 
at the discretion of the PI. For example, the occurrence of a SAE may necessitate knowledge of the 
treatment side so that the subject may receive appropriate medical care. In the event of inadvertent 
unblinding of blinded investigators or collaborators, the data point for the outcome measure affected 
by the unblinding will be considered invalid. For example, if the investigator performing the POSAS 
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statistical analyses due to potential bias. Intentional and unintentional breaking of the blind should be 
reported to the PI. 
 
 
6.4 
STUDY INTERVENTION COMPLIANCE 
Subjects will be closely monitored during each treatment session to ensure appropriate dosing of the 
phototherapy device (as determined by length of treatment time) and subject’s adherence to the 
protocol (i.e., the subject remains with both treatment and mock-treatment devices in the correct 
position). The exact start time and end time of each treatment session will be recorded in the case 
report forms. 
 
6.5 
CONCOMITANT THERAPY 
For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications, and supplements.  
 
A review of concomitant medications will be performed at each study visit during the treatment 
period. Subjects will be asked to state all concomitant medications as well as to deny use of all of the 
prohibited medications. 
 
Treatment with the following medications that are known to have photosensitizing properties will not 
be permitted, as they are relatively or absolutely contraindicated with concomitant phototherapy 
(adapted from Appendix 1 in the Omnilux Treatment Protocols manual), unless discussed with and 
approved by the investigators: 
• 
Amiodarone 
• 
Azathioprine 
• 
Chlorpromazine 
• 
Gold 
• 
Griseofulvin 
• 
Isotretinoin  
• 
Lithium 
• 
Melatonin  
• 
Methotrexate 
• 
Phenothiazine antipsychotics 
• 
Tetracycline antibiotics (e.g., demecocycline, doxycycline, lymecycline, minocycline, 
oxytetracycline) 
• 
Quinolone derivative antibiotics 
 
6.5.1 RESCUE MEDICINE 
 
N/A 
 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL 
 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from LED-RL phototherapy does not mean discontinuation from the study, and 
remaining study procedures should be completed as indicated by the study protocol. If a clinically 
significant finding is identified (including, but not limited to changes from baseline) after enrollment, 
the investigator or qualified designee will determine if any change in participant management is 
needed. Any new clinically relevant finding will be reported as an adverse event (AE). 
 
The data to be collected at the time of study intervention discontinuation will include the following: 
• 
Details of any adverse events (e.g., nature, severity, relationship to study intervention, and 
expectedness) will be documented in the CRFs 
• 
Digital photography of the affected site(s), if applicable 
 
Stopping Rules: Adverse events, serious adverse events, and unanticipated problems (as described in 
Section 8: Study Assessments and Procedures) will be monitored and the trial will be halted early if 
necessary to protect subjects. Any life threatening events and/or deaths (grade 4 and 5 toxicity) 
attributable to the study protocol will result in halting the study. 
 
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
 
Participants are free to withdraw from participation in the study at any time upon request, without 
penalty. For example, the participant may withdraw after receiving the mini-facelift surgery but before 
starting treatment without being penalized for the procedure-related costs of the mini-facelift 
surgery. 
 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
 
• 
Significant study intervention non-compliance  
• 
Any clinical adverse event (e.g., second-degree or higher skin burning, blistering, swelling, 
pain, ulceration, change in sensation, muscle weakness, worsening of surgical scar) or other 
medical condition or situation occurs such that continued participation in the study would not 
be in the best interest of the participant 
• 
The participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Unforeseen serious adverse event (e.g., neurological symptoms lasting more than 24 hours) 
occurs 
The reason for participant discontinuation or withdrawal from the study will be recorded on the CRF. 
Subjects who sign the informed consent form and are randomized but do not receive the study 
intervention may be replaced. Subjects who sign the informed consent form, and are randomized and 
receive the study intervention, and subsequently withdraw, or are withdrawn or discontinued from 
the study, will be replaced only if the enrollment period is still open. 
 

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7.3 
LOST TO FOLLOW-UP 
 
A participant will be considered lost to follow-up if he or she fails to report to at least one scheduled 
study visit and is unable to be contacted by the study site staff to complete all protocol-required study 
procedures.  
 
The following actions must be taken if a participant fails to return to the clinic for a required study 
visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within a 
reasonable time window as determined by the PI (taking into consideration the time-sensitive 
nature of the treatment regimen and the relative flexibility of timing of the long-term follow-
up visits) and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
effort to regain contact with the participant (where possible, 3 telephone calls and, if 
necessary, a certified letter to the participant’s last known mailing address or local equivalent 
methods). These contact attempts should be documented in the participant’s medical record 
or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 
 
8 
STUDY ASSESSMENTS AND PROCEDURES 
 
8.1 
EFFICACY ASSESSMENTS  
Refer to Section 1.3: Schedule of Activities, for the specific timing of procedures and evaluations to be 
done at each study visit. All procedures and evaluations will be performed by qualified personnel. 
 
Study Specific Procedures and Evaluations for Efficacy 
• 
Digital photographs of the treatment sites will be taken immediately before and after each 
treatment session, as well as at each follow-up visit, to track the appearance of the 
incisions/scars for outcome measures. During the analysis phase, the standardized 
photographs will be rated in a blinded fashion by an independent panel of expert 
dermatologists using a visual analogue scale (VAS). 
o The VAS is a validated photograph-based scale that is presented as a 10 cm horizontal 
line, with the extreme ends of 0 indicating normal skin and 10 corresponding to the 
worst possible scar. Duncan et al. demonstrated that a VAS with scar ranking is a 
consistent, reliable, and valid method for linear scar assessment.62 Micomonaco et al. 
further developed a VAS-based instrument that incorporates the dimensions of 
pigmentation, vascularity, observer comfort, contour, and overall severity for the 
assessment of area scars.63 
• 
Objective scar characteristics will be recorded at follow-up visits using the following tools: 
o ElastiMeter and SkinFibroMeter (Delfin Technologies, Kuopio, Findland) are two non-
invasive instruments used to measure skin elasticity and induration, respectively, 
using the same indentation principle. They each have an indenter, reference plate, 

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and built-in force sensors. The probe is pressed against the skin surface while the 
indenter imposes a constant deformation, instantly measuring the skin’s elasticity. 
o VivoSight (Michelson Diagnostics, Maidstone, UK) is a high-resolution imaging 
technology based on multi-beam OCT that produces two-dimensional, cross-sectional, 
real-time imaging of the skin and provides objective measurements of tissue 
microstructure, including scar depth and collagen density. The scanning procedure is 
quick and non-invasive.  
o Dermo (Connected Physics, Orsay, France) is a novel spectroscopy probe that instantly 
measures both collagen and water concentration in the dermis. 
o Antera 3D (Miravex, Dublin, Ireland) is a novel skin imaging analysis device that uses 
reflectance mapping of different wavelengths to acquire three-dimensional images of 
the skin surface and objectively measures multiple skin dimensions. It accurately 
measures wrinkles, texture, scars, skin color, redness, and pigmentation. The software 
also compares images to enable progress tracking and assess therapeutic efficacy. 67,68 
§ 
Alternatively, the Cherry3 camera (Cherry Imaging, Yokneam, Israel) is a new 
stereoscopic optical and high-resolution 3D imaging system that is specifically 
designed to objectively measure changes in above-surface scar volume after 
various interventions. It has been shown to be valid, accurate, and practical 
for assessing scar volume and for monitoring treatment response.69 
• 
Skin specimens will be obtained via optional 2 mm punch biopsy on POD 0 (prior to surgery) 
and POD 30 (first follow-up visit after completion of LED-RL treatment). All optional skin 
biopsies will be perform by Dr. Daniel Siegel or Dr. Jared Jagdeo. Skin specimens will be used 
for histological analysis and molecular studies. 
o After skin biopsy, the sample will be placed in fixative (10% neutral buffered formalin) 
for routine tissue processing and embedding. Paraffin embedded sections will be 
mounted on glass slides and stained with hematoxylin and eosin (H&E) and either 
Masson’s trichrome or picrosirius red for evaluation of collagen. Histological 
examination of skin specimens will be conducted to quantify the number of Ki-67 
positive fibroblasts and to qualify collagen content.77 
o High-throughput assays will be performed using subject biopsy specimens to screen 
for molecular effects associated with LED-RL treatment. Molecular testing will include 
RNA-Seq, microRNA arrays, and quantitative real-time PCR (RT-PCR).  
• 
Subjective scar evaluations using the Patient and Observer Scar Assessment Scale (POSAS) will 
be performed by the same blinded investigator (the treating surgeon) in conjunction with the 
subject at follow-up visits on POD 30, 90, and 180. 
o The POSAS was designed for a subjective evaluation of various types of scars. Van de 
Kar et al. critically tested the POSAS on linear scars and found it to have good internal 
consistency, reliability, and agreement.58 Each subscale of the POSAS consists of six 
items rated on a numerical 10-point scale, with 10 indicating the “worst imaginable 
scar”. The observer rates scar vascularity, pigmentation, thickness, relief, pliability, 
and surface area while the patient assesses pain, itching, color, stiffness, thickness, 
and relief. The scores of each of the six items are summed for a total score (range 6 to 
60). 
 
 
8.2 
SAFETY AND OTHER ASSESSMENTS 

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Refer to Section 1.3: Schedule of Activities, for the sequence of events that should occur during the 
screening process. 
 
Study Specific Procedures and Evaluations for Safety or Other Purposes 
• 
The subject’s medical history will be obtained by interview at the screening visit to screen for 
exclusion criteria. 
• 
The subject’s concomitant medication list will be reviewed at each study visit to screen for 
prohibited medications. 
• 
A screening photosensitivity test will be conducted prior to enrollment, wherein the potential 
subject will be exposed to LED-RL for 20 minutes on the non-dominant upper forearm (as 
recommended by the manufacturer in the Omnilux new-U user guide), and then evaluated 24 
hours later for evidence of photosensitivity. Criteria for photosensitivity include, but are not 
limited to: warmth, erythema, edema, blistering, rash, pain, or discomfort lasting more than 
24 hours. If no adverse events occurred, the potential subject is deemed "non-photosensitive" 
and thus eligible for participation in the study. 
• 
At the screening visit, the mini-facelift surgery will be discussed with the subject, including 
details of the procedure, risks, benefits, alternative options, expected outcomes, and pre- and 
post-operative instructions.  
• 
The mini-facelift surgery will be performed in-office under local anesthesia by Dr. Daniel Siegel 
(co-investigator and board-certified dermatologic surgeon). 
• 
A targeted physical examination of the treatment sites (i.e., the periauricular skin and 
surrounding areas) will be performed at each study visit. 
• 
Each treatment session will be monitored for any safety issues or adverse events, either 
reported by the subject or observed by the investigator. 
• 
Subjects will be provided with a daily diary to record any adverse events experienced at home 
during the 3-week treatment period. Investigators will call subjects on a weekly basis to 
monitor for adverse events during the same time period. 
o Common expected post-treatment effects of transient (i.e., lasts less than 24 hours) 
erythema, warmth, or edema at the treated sites will be recorded. However, any 
occurrence of these expected effects will not be considered an adverse event in safety 
data reports, unless the effect lasts more than 24 hours or is considered serious. 
• 
An exit questionnaire will be administered at the final study visit to assess for patient-reported 
outcomes and elicit other feedback. 
 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 
 
8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). 
 
In this study, there are predefined “common expected post-treatment effects” that should be 
transient (i.e., lasts less than 24 hours): erythema, warmth, and edema at the treated sites. These 
effects will be recorded on CRFs on safety monitoring, but will not be considered AEs unless the effect 

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persists longer than expected (i.e., does not resolve within 24 hours of treatment administration) or 
meets the definition of a serious AE. 
 
Close attention will be paid to any incidences of cutaneous blistering at the treated sites, either within 
the incision sites or on the peri-incisional skin. 
 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
 
An adverse event (AE) or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or sponsor, it results in any of the following outcomes: death, a life-threatening 
adverse event, inpatient hospitalization or prolongation of existing hospitalization, or a persistent or 
significant incapacity or substantial disruption of the ability to conduct normal life functions. 
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition.  
 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
For AEs not included in the protocol defined grading system, the following guidelines will be used to 
describe severity.  
 
• 
Mild – Events require minimal or no treatment and do not interfere with the participant’s 
daily activities.  
• 
Moderate – Events result in a low level of inconvenience or concern with the therapeutic 
measures. Moderate events may cause some interference with functioning. 
• 
Severe – Events interrupt a participant’s usual daily activity and may require systemic drug 
therapy or other treatment. Severe events are usually potentially life-threatening or 
incapacitating.  Of note, the term “severe” does not necessarily equate to “serious”. 
 
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
 
All AEs must have their relationship to study intervention assessed by the clinician who examines and 
evaluates the participant based on temporal relationship and his/her clinical judgment. The degree of 
certainty about causality will be graded using the categories below. In a clinical trial, the study product 
must always be suspect.  
 
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other 
possible contributing factors can be ruled out. The clinical event occurs in a plausible time 
relationship to study intervention administration and cannot be explained by concurrent 
disease or other drugs or chemicals. The response to withdrawal of the study intervention 
(dechallenge) should be clinically plausible. The event must be pharmacologically or 
phenomenologically definitive, with use of a satisfactory rechallenge procedure if necessary. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of 
other factors is unlikely. The clinical event occurs within a reasonable time after 
administration of the study intervention, is unlikely to be attributed to concurrent disease or 

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other drugs or chemicals, and follows a clinically reasonable response on withdrawal 
(dechallenge). Rechallenge information is not required to fulfill this definition. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, 
other factors may have contributed to the event (e.g., the subject’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, 
it can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event whose temporal relationship to study intervention 
administration makes a causal relationship improbable (e.g., the event did not occur within a 
reasonable time after administration of the study intervention) and in which other drugs or 
chemicals or underlying disease provides plausible explanations (e.g., the subject’s clinical 
condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology. There must be an 
alternative, definitive etiology documented by the clinician. 
 
If there is any doubt as to whether a clinical observation is an AE, the event will be reported. 
Evaluation of relatedness will consider etiologies such as natural history of the underlying disease, 
concurrent illness, concomitant therapy, study-related procedures, accidents, and other external 
factors. 
 
8.3.3.3 EXPECTEDNESS  
 
The PI will be responsible for determining whether an AE is expected or unexpected.  An AE will be 
considered unexpected if the nature, severity, or frequency of the event is not consistent with the risk 
information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during study visits and 
interviews of a study participant presenting for medical care, or upon review by a study monitor. 
 
All AEs including local and systemic reactions not meeting the criteria for SAEs will be captured on the 
appropriate CRF. Information to be collected includes event description, time of onset, clinician’s 
assessment of severity, relationship to the study intervention (assessed only by those with the training 
and authority to make a diagnosis), and time of resolution/stabilization of the event. All AEs occurring 
while on study must be documented appropriately regardless of relationship. All AEs will be followed 
to adequate resolution. 
 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any 
time during the study, it will be recorded as an AE.  
 
Changes in the severity of an AE will be documented to allow an assessment of the duration of the 
event at each level of severity to be performed. AEs characterized as intermittent require 
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The investigators will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day of study 
participation. At each study visit, the investigator will inquire about the occurrence of AE/SAEs since 
the last visit. Events will be followed for outcome information until resolution or stabilization. 
 
8.3.5 ADVERSE EVENT REPORTING  
 
All required reportable events must be reported to the IRB within the deadlines specified in the SUNY 
Downstate Medical Center Policy IRB-01: Human Research Protections Program. Unanticipated 
adverse device effects (UADEs) will be reported as soon as possible, but no later than 10 days. 
Any AEs that occur in-office during or immediately after treatment sessions, or reported by the subject 
in the AE diary or in weekly phone calls, will be captured on the appropriate CRF. Information to be 
collected includes a description of the AE, time of onset, severity, relationship to the study 
intervention, and time of resolution/stabilization. 
 
Subjects will be counseled regarding the expected outcome of skin erythema and warmth, found to 
resolve within 24 hours in other clinical studies and occurs in 10% of participants.70,71 For this study, 
the common expected post-treatment side effects of transient erythema, warmth, and swelling at the 
treated sites will be recorded, but will not be considered an AE for the purposes of safety reports. 
 
All AEs will be reported to the designated medical monitor (Dr. Neil Brody), independent safety 
monitor (Dr. Jeannette Jakus), and internal faculty committee at monthly meetings. Please refer to 
Section 10.1.6: Safety Oversight for the composition of the internal committee. Dr. Jakus is the 
Director of Clinical Trials & Research in the Department of Dermatology at SUNY Downstate whose 
responsibilities include: managing and ensuring research compliance; monitoring all departmental 
clinical trials for AEs; and overseeing appropriate reporting of AEs to the IRB. AEs will be reported to 
the IRB, NIH, and FDA on a quarterly basis. The PI is responsible for completing and signing off on the 
AE reports. 
                  Each Study Visit                                            Monthly                                         Quarterly 
 
 
 
 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
 
The study clinician will immediately report to the sponsor any SAE, whether or not considered study 
intervention related, including those listed in the protocol and must include an assessment of whether 
there is a reasonable possibility that the study intervention caused the event. Study endpoints that are 
SAEs must be reported in accordance with the protocol unless there is evidence suggesting a causal 
relationship between the study intervention and the event. In that case, the investigator must 
immediately report the event to the sponsor. 
 
Record AEs observed by 
investigator or reported by subject 
Report AEs to medical 
monitor and safety officer 
Report AEs to IRB, 
NIH, and FDA 

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All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to 
be chronic or the participant is stable. Other supporting documentation of the event may be 
requested by the study sponsor and should be provided as soon as possible. 
 
If applicable, the study investigator shall complete an Unanticipated Adverse Device Effect Form and 
submit to the study sponsor and to the reviewing IRB as soon as possible, but in no event later than 10 
working days after the investigator first learns of the effect. The study sponsor is responsible for 
conducting an evaluation of an unanticipated adverse device effect and shall report the results of such 
evaluation to the FDA and to all reviewing IRBs and participating investigators within 10 working days 
after the sponsor first receives notice of the effect. Thereafter, the sponsor shall submit such 
additional reports concerning the effect as FDA requests. 
 
Per SUNY Downstate policy for clinical trials, SAEs must be reported within 24 hours if an internal AE is 
serious, unanticipated, and would have implications for the conduct of the study. For this study, SAEs 
will be reported to the designated medical monitor (Dr. Neil Brody), safety officer (Dr. Jeannette 
Jakus) and the reviewing IRB on the same day of learning of the event. SAEs will be reported to the 
FDA and the NIH within 48 hours by express mail. The PI is responsible for completing and signing off 
on the SAE reports. 
 
                Each Study Visit                                               Same Day                                         Within 48 Hours 
 
 
 
 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
 
N/A 
 
8.3.8 EVENTS OF SPECIAL INTEREST  
 
N/A 
 
8.3.9 REPORTING OF PREGNANCY  
 
N/A 
 
8.4 
UNANTICIPATED PROBLEMS 
 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
 
The Office for Human Research Protections (OHRP) considers unanticipated problems (UPs) involving 
risks to participants or others to include, in general, any incident, experience, or outcome that meets 
all of the following criteria: 
 
Record SAEs observed by 
investigator or reported by subject 
Report SAEs to medical 
monitor, safety officer, and IRB 
Report SAEs to NIH 
and FDA 

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• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that 
are described in the protocol-related documents, such as IRB-approved research protocol and 
informed consent document; and (b) the characteristics of the participant population being 
studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
 
This definition could include an unanticipated adverse device effect, any SAE on health or safety or 
any life-threatening problem or death caused by, or associated with, a device, if that effect, problem, 
or death was not previously identified in nature, severity, or degree of incidence in the investigational 
plan or application (including a supplementary plan or application), or any other unanticipated serious 
problem associated with a device that relates to the rights, safety, or welfare of subjects (21 CFR 
812.3(s)). 
 
8.4.2  UNANTICIPATED PROBLEM REPORTING  
 
The investigator will report UPs to the reviewing IRB and to the PI. The UP report will include the 
following information: 
 
• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken 
or are proposed in response to the UP. 
 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
 
• 
UPs that are SAEs will be reported to the IRB on the same day of the investigator becoming 
aware of the event and to the study sponsor within 48 hours.  
• 
Any other UP will be reported to the IRB and to the study sponsor within 10 working days of 
the investigator becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the OHRP 
within 10 working days of the IRB’s receipt of the report of the problem from the investigator. 
 
An investigator shall submit to the sponsor and to the reviewing IRB a report of any unanticipated 
adverse device effect occurring during an investigation as soon as possible, but in no event later than 
10 working days after the investigator first learns of the effect (21 CFR 812.150(a)(1)). A sponsor who 
conducts an evaluation of an unanticipated adverse device effect under 812.46(b) shall report the 
results of such evaluation to the FDA and to all reviewing IRB’s and participating investigators within 
10 working days after the sponsor first receives notice of the effect. Thereafter the sponsor shall 
submit such additional reports concerning the effect as FDA requests (21 CFR 812.150(b)(1)).    
 

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8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
 
N/A 
 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL HYPOTHESES 
 
• 
Hypothesis for Primary Efficacy Endpoint: There is a statistically significant difference in scar 
pliability between a LED-RL-treated incision and a mock-treated incision.  
o Skin elasticity and induration (an index of scar pliability) are measured pre-treatment 
at the first treatment session and post-treatment on follow-up visits at POD 30, 90, 
and 180. 
 
• 
Hypothesis for Secondary Efficacy Endpoint(s): LED-RL phototherapy treatment results in a 
statistically significant improvement in POSAS score and VAS score compared to mock 
treatment. 
 
9.2 
SAMPLE SIZE DETERMINATION 
The study will have three treatment arms (LED-RL 160 J/cm2, LED-RL 320 J/cm2, and LED-RL 480 J/cm2) 
with 10 subjects each. The primary outcome measure is the difference in pliability between a treated 
incision site and the contralateral mock-treated incision site.  
 
To calculate the sample size for this study, we anticipate that the minimal clinically important 
difference in scar pliability is 15%, based on minimum decrease in fibroblast cell number after LED-RL 
treatment from our in vitro data. A power analysis plan predicted that with 9 subjects, the study 
would have greater than 80% power to detect a 15% difference in pliability by using a two-sided 
paired t-test. To take into account a dropout rate of 10%, 10 subjects will be enrolled in each 
treatment arm. Up to 150 potential participants will be screened and a total of 30 subjects will be 
enrolled in the study. 
 
9.3 
POPULATIONS FOR ANALYSES 
• 
Intention-to-treat (ITT) analysis dataset: all participants who are enrolled and randomly 
allocated to treatment, regardless of treatment actually receive 
 
• 
Per-protocol analysis dataset: participants who adhered to the protocol and completed the 
treatment originally allocated (i.e., attended all treatment sessions) 
 
• 
Safety analysis dataset: participants who received at least one dose of the study intervention 
 
 
9.4 
STATISTICAL ANALYSES 
 

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9.4.1 GENERAL APPROACH 
In initial intention-to-treat analyses, all available data will be included. Multiple imputation will be 
used where dependent variable values are missing. In subsequent per-protocol analyses, only subjects 
with complete data will be included. 
SAS (SAS Institute, Cary NC) 9.4 statistical software will be used. 
 
 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The two principal outcomes (scar pliability measurements of skin elasticity and skin induration) will be 
used separately as dependent variables (DVs) in mixed linear models. Fixed factors in each model will 
be treatment group, whether treated, side of face (left versus right), and time (3 points post-baseline). 
Baseline DV measure will be introduced as a scored covariate; subject ID as a random factor. The 
Akaike information criterion will be used to assess what intra-subject covariance structure might be 
optimal. Tests of Interaction among fixed factors will be conducted, and the utility of polynomial terms 
in the baseline DV investigated. Model residuals will be examined for skew and for outliers; the DV will 
be power-transformed if necessary to maximize normality of residuals. 
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
Secondary outcomes will be presented as descriptives tabulated by whether treated, treatment group 
and time, showing medians and ranges. No inferential analyses will be conducted, in order to 
minimize the multiple testing problem. 
 
9.4.4 SAFETY ANALYSES 
AEs, SAEs, and UPs will be recorded and reported as described in the protocol. The information 
documented about each event or problem includes onset, duration, severity, relationship to the study 
intervention, and outcome. Summary statistics of safety data will be presented as number of subjects 
who experienced AEs in each treatment group and a breakdown of the event types. AEs will be coded 
according to the terminology in the Medical Dictionary for Regulatory Activities (MeDRA). AEs leading 
to premature discontinuation from the study and serious treatment-emergent AEs will also be 
presented. 
 
9.4.5 BASELINE DESCRIPTIVE STATISTICS 
Descriptives of relevant subject characteristics (age, gender, race, and ethnicity) of the entire study 
population (i.e., intent-to-treat population) will be tabulated by treatment group. Continuous 
variables will be presented as median and range. Categorical variables will be presented as 
proportions. Significance tests will not be applied. 

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9.4.6 PLANNED INTERIM ANALYSES  
 
N/A 
 
9.4.7 SUB-GROUP ANALYSES 
To determine if any differential effects of LED-RL are associated with demographics (race, ethnicity, 
age, and gender), a linear regression or robust linear regression with adjustment for treatment group 
effect on pliability will be performed. 
 
9.4.8 TABULATION OF INDIVIDUAL PARTICIPANT DATA 
 
Individual participant data will be listed by measure and time point for raw data analyses. 
 
9.4.9 EXPLORATORY ANALYSES 
 
N/A 
 
10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
 
10.1.1 INFORMED CONSENT PROCESS 
 
10.1.1.1 CONSENT/ASSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO 
PARTICIPANTS 
 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.  The following consent materials are submitted with 
this protocol: 
• 
LED-Red Light Phototherapy for Skin Scarring Prevention Informed Consent for Research Study 
• 
Consent to Invasive Procedure (Optional Skin Biopsy) 
• 
Research Study Summary for Potential Participants 
 
 
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the 
study and continues throughout the individual’s study participation. Consent forms will be IRB-
approved and the participant will be asked to read and review the document. The investigator will 
explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
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will have the opportunity to carefully review the written consent form and ask questions prior to 
signing. The participants should have the opportunity to discuss the study with their family or 
surrogates or think about it prior to agreeing to participate. The participant will sign the informed 
consent document prior to any procedures being done specifically for the study. Participants must be 
informed that participation is voluntary and that they may withdraw from the study at any time, 
without prejudice. A copy of the informed consent document will be given to the participants for their 
records. The informed consent process will be conducted and documented in the source document 
(including the date), and the form signed, before the participant undergoes any study-specific 
procedures. The rights and welfare of the participants will be protected by emphasizing to them that 
the quality of their medical care will not be adversely affected if they decline to participate in this 
study.  
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be 
provided by the suspending or terminating party to the NIH. If the study is prematurely terminated or 
suspended, the PI will promptly inform study participants, the IRB, and sponsor and will provide the 
reason(s) for the termination or suspension. Study participants will be contacted, as applicable, and be 
informed of changes to study visit schedule. 
  
Circumstances that may warrant termination or suspension include, but are not limited to: 
• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, 
and satisfy the sponsor, IRB and/or FDA. 
 
10.1.3 CONFIDENTIALITY AND PRIVACY  
 
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their 
staff, and the sponsors and their interventions. This confidentiality is extended to cover testing of 
biological samples and genetic tests in addition to the clinical information relating to participants. 
Therefore, the study protocol, documentation, data, and all other information generated will be held 
in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the sponsor.  
 
All research activities will be conducted in as private a setting as possible. 
 
The study monitor, other authorized representatives of the sponsor, representatives of the IRB, or 
regulatory agencies may inspect all documents and records required to be maintained by the 
investigator, including but not limited to, medical records (office, clinic, or hospital) and pharmacy 
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The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, 
will be managed and protected in accordance with SUNY Downstate Medical Center Human Research 
Protections Program. This will not include the participant’s contact or identifying information. Rather, 
individual participants and their research data will be identified by a unique study identification 
number. Written study subject individual or aggregate data from the study will be secured in a locked 
cabinet, in a locked room. Computerized data will be stored on the HIPAA-compliant SUNY Downstate 
Department of Dermatology desktop computers that are connected to the SUNY Downstate Medical 
Center’s secure network behind a firewall, complete with 128-bit data encryption. Storage of any PHI 
on a laptop or portable device (e.g., external drive, flash drive, CD/DVD, USB drive or similar) will be 
encrypted and used only for temporary storage. In addition to being encrypted, removable storage 
devices will be stored in a locked cabinet or drawer when not in use. 
 
Certificate of Confidentiality 
To further protect the privacy of study participants, a Certificate of Confidentiality will be issued by the 
NIH.  This certificate protects identifiable research information from forced disclosure. It allows the 
investigator and others who have access to research records to refuse to disclose identifying 
information on research participation in any civil, criminal, administrative, legislative, or other 
proceeding, whether at the federal, state, or local level. By protecting researchers and institutions 
from being compelled to disclose information that would identify research participants, Certificates of 
Confidentiality help achieve the research objectives and promote participation in studies by helping 
assure confidentiality and privacy to participants. 
 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
 
Biological samples and data collected for this study will not be stored for future research after the 
study is completed. 
 
10.1.5 KEY ROLES AND STUDY GOVERNANCE 
 
Principal Investigator 
Medical Monitor 
Jared Jagedo, MD, MS 
Neil Brody, MD, PhD 
SUNY Downstate Medical Center 
SUNY Downstate Medical Center 
Department of Dermatology 
450 Clarkson Avenue 
Brooklyn, NY, 11203 
Department of Dermatology 
450 Clarkson Avenue 
Brooklyn, NY, 11203 
917-837-9796 
516-779-2377 
jrjagdeo@gmail.com 
neil.brody@downstate.edu  
 
 
10.1.6 SAFETY OVERSIGHT 
 

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Safety oversight will be under the direction of an Independent Safety Monitor (ISM) with the 
appropriate expertise. For this study, the ISM is Dr. Jeannette Jakus, the Director of Clinical Research 
in the Department of Dermatology at SUNY Downstate. The ISM is independent from the study 
conduct and free of conflict of interest. The ISM will meet at least semiannually to assess safety and 
efficacy data on each arm of the study. The primary responsibility of the ISM is to provide 
independent safety monitoring in a timely fashion, including by review of AEs, immediately after they 
occur or are reported, with follow-up through resolution. The ISM will provide her input to the PI and 
study sponsor. 
 
For this study, monitoring will be performed on a quarterly basis by the following entities: 
a. PI: Jared Jagdeo, MD, MS 
b. SUNY Downstate IRB 
c. Independent Safety Monitor: Jeannette Jakus, MD 
d. Designated Medical Monitor: Neil Brody, MD, PhD 
e. SUNY Downstate Department of Dermatology Clinical Research Faculty Committee: Neil 
Brody, MD, PhD; Edward Heilman, MD; Jeannette Jakus, MD 
 
10.1.7 CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of 
the trial is in compliance with the currently approved protocol/amendment(s), with ICH GCP, and with 
applicable regulatory requirement(s).  
 
• 
Monitoring for this study will be performed by the designated ISM. Monitoring will be on-site 
throughout the study and includes targeted data verification of endpoint, safety and other 
key data variables.  
• 
Each clinical site will perform internal quality management of study conduct, data collection, 
documentation and completion.  
 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
 
Each clinical site will perform internal quality management of study conduct, data and biological 
specimen collection, documentation and completion. 
 
Quality control (QC) procedures will be implemented beginning with the data entry system and data 
QC checks that will be run on the database will be generated. Any missing data or data anomalies will 
be communicated to the site(s) for clarification/resolution. 
 
Following written Standard Operating Procedures (SOPs), the monitors will verify that the clinical trial 
is conducted and data are generated and biological specimens are collected, documented (recorded), 
and reported in compliance with the protocol, ICH GCP, and applicable regulatory requirements (e.g., 
Good Laboratory Practices (GLP), Good Manufacturing Practices (GMP)).  
 
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and 
regulatory authorities. 

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10.1.9 DATA HANDLING AND RECORD KEEPING  
 
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation 
of data.   
 
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data recorded in the electronic case report 
form (eCRF) derived from source documents should be consistent with the data recorded on the 
source documents.  
 
Clinical data (including AEs, concomitant medications, and expected adverse reactions data) and 
clinical laboratory data will be entered into REDCap (Research Electronic Data Capture), a 21 CFR Part 
11-compliant data capture system provided by the SUNY Downstate Clinical & Translational Science 
Center. The data system includes password protection and internal quality checks, such as automatic 
range checks, to identify data that appear inconsistent, incomplete, or inaccurate. Clinical data will be 
entered directly from the source documents. 
 
10.1.9.2 STUDY RECORDS RETENTION  
 
Study documents will be securely maintained to protect confidentiality and privacy in accordance with 
Downstate policies. According to the minimum retention periods required by Downstate, research 
records collected by investigators will be maintained for at least three years, and up to 10 years as 
practicable, after completion of the research. Research participants’ signed HIPAA Research 
Authorization forms will be kept for a minimum of six years after such authorization last was in effect. 
Research records will not be destroyed unless in conformity with Downstate policies and 
requirements of the NIH. 
 
10.1.10 
PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol, ICH GCP, or Manual of 
Procedures (MOP) requirements. The noncompliance may be either on the part of the participant, the 
investigator, or the study site staff. As a result of deviations, corrective actions are to be developed by 
the site and implemented promptly.  
 
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
 

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It is the responsibility of the site investigator to use continuous vigilance to identify and report 
deviations within 10 working days of identification of the protocol deviation, or within 10 working 
days of the scheduled protocol-required activity. All deviations must be addressed in study source 
documents, reported to the NIGMS Program Official. Protocol deviations must be sent to the 
reviewing IRB per their policies. The site investigator is responsible for knowing and adhering to the 
reviewing IRB requirements.  
 
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
 
This study will be conducted in accordance with the following publication and data sharing policies and 
regulations: 
 
NIH Public Access Policy, which ensures that the public has access to the published results of NIH 
funded research. It requires scientists to submit final peer-reviewed journal manuscripts that arise 
from NIH funds to the digital archive PubMed Central upon acceptance for publication. 
 
This study will comply with the NIH Data Sharing Policy and Policy on the Dissemination of NIH-Funded 
Clinical Trial Information and the Clinical Trials Registration and Results Information Submission rule. 
As such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-
reviewed journals.   
 
 
10.1.12 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical. Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a 
way that is appropriate to their participation in the design and conduct of this trial. The study 
leadership in conjunction with the NIGMS has established policies and procedures for all study group 
members to disclose all conflicts of interest and will establish a mechanism for the management of all 
reported dualities of interest. 
 
10.2 ADDITIONAL CONSIDERATIONS 
 
Scar Treatment 
During the study, subjects are asked to refrain from using scar treatments to both periauricular 
incision sites, as to not confound the results of the study given that the objective is to evaluate clinical 
efficacy of LED-RL on scar reduction. Refer to Section 2.3.3: Assessment of Potential Risks and Benefits 
for a discussion of how prohibition of scar treatment during the study period does not pose significant 
harm to subjects. Briefly, patients undergoing facelift tend to have favorable wound healing outcomes 
(i.e., minimal scarring) since facial skin heals well after injury, and most surgical incisions ultimately 
heal with a normal scar.41 Furthermore, the scar maturation process is lengthy (up to 2 years to 
produce the final scar result) and the vast majority of scars improve aesthetically over time as the 
fibrous scar tissue undergoes remodeling.43 In other words, scars are not considered to be fully 
mature until 6 months-2 years after the injury. At 6 months post-surgery (coinciding with the final 

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study visit), scars will be evaluated to determine if they are pathological (e.g., hypertrophic scars or 
keloids) or appear consistent with normal healing. While scars can be associated with symptoms of 
pain and pruritus, scar treatment is considered cosmetic and elective in nature. Thus, prohibition of 
concomitant scar treatment or prophylaxis during the study is not expected to cause irreversible harm 
or suffering to subjects. 
 
It is important to note that this stipulation should not be construed as subjects being “denied standard 
scar treatment” as 1) most scar treatments are not medically necessary, 2) it may take several months 
for pathological scarring to become evident (and the type of pathological scar guides clinical 
management), and 3) in clinical practice, many scars are observed during maturation and only treated 
if they become problematic to the patient. Also, in the postoperative period, the most important 
strategy to promote skin healing is proper wound care (i.e., maintenance of a clean and moist wound 
environment), which the subjects will be counseled on. 
 
Subjects will be able to seek and receive elective scar treatments, if desired, at the conclusion of the 
study (i.e., after completion of the final study visit at approximately 6 months post-surgery). All 
subjects will be offered fractionated carbon dioxide (CO2) laser treatment to the surgical incision sites 
for scar reduction. If a subject opts to have CO2 laser resurfacing of the treated and/or untreated 
incision sites, the cost of the treatment will be covered by the Center for Photomedicine, Department 
of Dermatology. Laser resurfacing is an accepted therapeutic modality for scar revision that is 
commonly offered by dermatologists and has been shown to be effective in improving the appearance 
of various types of scars (e.g., traumatic, surgical, pathologic).78–80 For management of post-facelift 
hypertrophic scars, it is preferred to wait at least 6 months following surgery to perform any scar 
revision procedures such as surgical revision, dermabrasion, and laser skin resurfacing.46 
 
There is no “gold standard” for scar management and existing treatment options for scar reduction 
have variable efficacy in the evidence base. Current treatment options include silicone gels or sheets, 
intralesional corticosteroids, 5-fluorouracil, laser therapy, radiotherapy, cryotherapy, bleomycin, 
mitomycin C, imiquimod, pressure therapy, adhesive microporous hypoallergenic paper tape, onion 
extract, massage therapy, over-the-counter topical emollients for scars, laser therapy, and surgical 
revision.76 No scar treatment can completely remove or eliminate scarring, only minimize its visibility 
and associated symptoms. 
 
Limitations 
There are limitations in this study due to the study design. In theoriginal study design, subjects are 
differentially randomized based on race and ethnicity, making skin color a confounding variable that 
cannot be controlled in the statistical analysis phase. That is, any observed clinical effects would have 
been difficult to interpret due to the possibility of differential effects of LED-RL phototherapy on 
different skin types. In the Phase I studies, our finding of differential safety profile of LED-RL based on 
skin type (i.e., skin of color individuals were more photosensitive and possibly at increased risk of 
blistering) was unexpected and not described previously. 
 
In a joint discussion with Dr. Jeremy Weedon (biostatistician and Associate Director of the Scientific 
Computing Center at SUNY Downstate), we considered the following methodology changes and 
describe their advantages and disadvantages below. 
 
1) Have two treatment groups, using only the low and medium intensity doses (Group 1 LED-RL 
160 J/cm2 and Group 2 LED-RL 320 J/cm2).  

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a. Advantages: Since the stratification of treatment dose based on skin type is removed, 
all subjects can be randomized to Group 1 or Group 2. The groups may be more 
balanced in terms of baseline characteristics. With a larger sample size of n=15 in each 
group, there is greater power to the study. 
b. Disadvantages: Based on in vitro data, LED-RL phototherapy as antifibrotic effects on 
skin fibroblasts at fluences of 320 J/cm2 and above. The clinical efficacy of LED-RL to 
treat skin fibrosis is unknown and a wide dose-ranging study is necessary to discern 
any therapeutic effects at different fluences. Exclusion of Group 3 (LED-RL 480 J/cm2) 
from the study may limit our ability to detect these effects. For example, there may be 
no clinical difference between the treated and untreated scars at 320 J/cm2, but a 
difference may be apparent at 480 J/cm2. 
 
2) Enroll only Caucasian non-Hispanic subjects and keep all three treatment groups. 
a. Advantages: The block randomization process will be simplified since there is no need 
to consider skin type and safety of certain LED-RL fluences. Also, since the subject 
population is homogeneous in terms of race and ethnicity, any observed clinical 
effects of LED-RL (e.g., significant difference in primary outcome between a treated 
and untreated scar at a certain treatment dose) can be interpreted as an effect of the 
study treatment without the confounding variable of skin type. 
b. Disadvantages: Under the current inclusion criteria, individuals of any race and 
ethnicity may be eligible to enroll in the study. We do not want to exclude any 
potential subjects based on skin color. Racial and ethnic minorities are 
underrepresented in clinical trials and the NIH Revitalization Act of 1993 mandates the 
appropriate inclusion of minorities in all NIH-funded research.81,82 In addition, given 
the demographics of the patient population at SUNY Downstate, a targeted study with 
only Caucasian non-Hispanic individuals would exclude many potential study 
participants from this population. 
 
3) Enroll subjects of any race/ethnicity and randomize them to all three treatment groups, with 
the understanding that safety data from Phase I studies suggest that skin of color subjects are 
more susceptible to blistering at higher fluences.  
a. Advantages: The block randomization process will be simplified if skin of color subjects 
are not excluded from the highest intensity treatment group. The groups may be more 
balanced in terms of baseline characteristics. 
b. Disadvantages: Based upon safety data generated from our two Phase I studies, we 
concluded that the maximum tolerated dose (MTD) of LED-RL phototherapy is 320 
J/cm2 for skin of color subjects. This MTD was established as a precaution after one 
African-American subject developed a small skin blister at the treatment site after a 
LED-RL phototherapy session administered at 480 J/cm2. While we cannot make any 
inferences about the true rate of this adverse event in the skin of color population, we 
do not want to enroll these subjects into the highest intensity treatment group 
knowing that the risk of blistering may be greater. 
 
4) Conduct two separate clinical trials – one with skin of color subjects only and the other one 
with Caucasian non-Hispanic subjects only. 
a. Advantages: The block randomization process will be simplified in each trial. Any 
observed clinical effects of LED-RL can be interpreted in the context of skin type, 

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without having to consider the possibility of differential therapeutic efficacy based on 
race and ethnicity. 
b. Disadvantages: This approach has the same limitations as option #3, plus would be 
challenging to implement in terms of logistics and feasibility. Conducting two clinical 
trials would require doubling the sample size (i.e., enroll a total of 60 subjects) to 
achieve statistical power, and it would be logistically difficult to recruit for a study of 
this size.  
 
In a joint discussion with the IRB, this version of the protocol was modified to reflect a change in the 
study design to reflect option #3 above. It was agreed that the unequal randomization scheme of the 
original study design (i.e., participants would undergo different randomization algorithms based on 
race/ethnicity, as skin of color individuals are restricted from receiving the highest intensity dose) 
would be a major potential confounding factor during data analysis. In this protocol, all subjects of any 
race/ethnicity will undergo a single randomization process to be allocated to any 1 of the 3 treatment 
groups. That is, subjects are randomized equally without regard to skin type. This change in the study 
design was made after carefully considering the risks and benefits of allowing skin of color subjects to 
receive the highest treatment intensity dose. 
 
Based on the safety data from the Phase I trials described above, we believe skin of color individuals 
are more photosensitive to LED-RL phototherapy and are therefore at increased risk of adverse events 
such as blister formation at higher intensity doses. However, this hypothesis is based on a single 
observation that one African-American subject developed a small skin blister at the treatment site 
after a LED-RL phototherapy session administered at 480 J/cm2. Therefore, the MTD of 320 J/cm2 for 
skin of color individuals is a precautionary determination, as no definitive conclusions can be made 
about LED-RL safety from a limited sample size. Further evaluation of safety is required, especially in 
regards to skin of color subjects who receive LED-RL at a fluence of 480 J/cm2. By allowing skin of color 
subjects to be enrolled in the highest treatment intensity group, we will be able to generate more 
safety data with a larger sample size, as well as interpret any statistically significant clinical effects 
more accurately (without skin type as a confounding variable). 
 
During the informed consent process, potential subjects will be counseled extensively on the known 
potential risks of LED-RL phototherapy. All potential subjects will be informed verbally and in writing 
(included in the consent form) that previous safety data suggest a higher risk of blistering in 
individuals with skin of color. 
 
10.3 ABBREVIATIONS 
 
AE 
Adverse Event 
ANOVA 
Analysis of Variance 
bFGF 
Basic Fibroblast Growth Factor 
CFR 
Code of Federal Regulations 
CLIA 
Clinical Laboratory Improvement Amendments 
CMP 
Clinical Monitoring Plan 
COC 
Certificate of Confidentiality 
CONSORT 
Consolidated Standards of Reporting Trials 
CRF 
Case Report Form 
CTGF 
Connective Tissue Growth Factor 
DHHS 
Department of Health and Human Services 

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DSMB 
Data Safety Monitoring Board 
DV 
Dependent Variable 
eCRF 
Electronic Case Report Forms 
FDA 
Food and Drug Administration 
FDAAA 
Food and Drug Administration Amendments Act of 2007 
GCP 
Good Clinical Practice 
GLP 
Good Laboratory Practices 
GMP 
Good Manufacturing Practices 
H&E 
Hematoxylin and Eosin 
HIPAA 
Health Insurance Portability and Accountability Act  
ICC 
Intraclass Correlation Coefficient 
ICH 
International Conference on Harmonisation  
IRB 
Institutional Review Board 
ISM 
Independent Safety Monitor 
ITT 
Intention-To-Treat 
LED-RL 
Light Emitting Diode-Red Light 
MedDRA 
Medical Dictionary for Regulatory Activities 
MOP 
Manual of Procedures 
MRSD 
Maximum Recommended Starting Dose 
MTD 
Maximum Tolerated Dose 
MSDS 
Material Safety Data Sheet 
NIGMS 
National Institute of General Medical Sciences 
NIH  
National Institutes of Health 
OCT 
Optical Coherence Tomography 
OHRP 
Office for Human Research Protections 
OSAS 
Observer Scar Assessment Scale 
PDGF 
Platelet-Derived Growth Factor 
PHI 
Protected Health Information 
PI 
Principal Investigator 
POSAS 
Patient and Observer Scar Assessment Scale 
PSAS 
Patient Scar Assessment Scale 
qRT-PCR 
Quantitative Reverse Transcription Polymerase Chain Reaction 
QC 
Quality Control 
REDCap 
Research Electronic Data Capture 
ROS 
Reactive Oxygen Species 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMAS 
Superficial Musculoaponeurotic System 
SMC 
Safety Monitoring Committee 
SOA 
Schedule of Activities 
SOP 
Standard Operating Procedure 
TGF-β 
Transforming Growth Factor-Beta 
UP 
Unanticipated Problem 
US 
United States 
UV 
Ultraviolet 
VAS 
Visual Analogue Scale 
 
 
 

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10.4 PROTOCOL AMENDMENT HISTORY 
 
Version 
Date 
Description of Change  
Brief Rationale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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