Ablative Fractional Laser Treatment for the Improvement of Hypertrophic Scars and Scleroderma: a Prospective Cohort Study
Phase: NA
Conditions: Scars, Scleroderma
Sponsor: Massachusetts General Hospital

Ablative Fractional Laser Treatment for the Clinical Improvement of 
Hypertrophic Scars and Scleroderma: a prospective cohort study 
 
 
PRINCIPAL INVESTIGATORS: 
 
 
 
Dieter Manstein, MD, PhD 
Assistant Professor of Dermatology 
Cutaneous Biology Research Center  
Massachusetts General Hospital  
Harvard Medical School 
 (617) 726-4893 
e-mail: DMANSTEIN@mgh.harvard.edu 
 
 
VERSION DATE 
November 20, 2023 
 
NCT04567537 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

 
 
TABLE OF CONTENTS 
 
Page 
I. OBJECTIVE …………………………………………………………………………..3 
 
II. BACKGROUND……………………………………………………………………………..3 
 
III. AIMS……………………………………………………………………………….…………5 
 
IV.  SUBJECT SELECTION 
 
a.  
Inclusion Criteria ................................................................................ 5 
 
b.  
Exclusion Criteria ............................................................................... 6 
 
c.  
Source and recruitment of subjects .................................................. 6 
 
V.  SUBJECT ENROLLMENT 
 
a.  
Method of enrollment ......................................................................... 6 
 
b.  
Informed consent form (ICF) .............................................................. 6 
 
VI. STUDY PROCEDURES .................................................................................. 7 
 
VII. BIOSTATISTICAL ANALYSIS ..................................................................... 11 
 
 
VIII. RISKS AND DISCOMFORTS ..................................................................... 11 
 
 
IX. POTENTIAL BENEFITS 
 
a.   
Potential benefits to subjects .......................................................... 11 
 
b.   
Potential benefits to society….. ....................................................... 11 
 
X. MONITORING AND QUALITY ASSURANCE 
 
a.   
Independent monitoring of source data ......................................... 11 
 
b.   
Safety monitoring  ............................................................................ 12 
 
c.   
Outcome monitoring ......................................................................... 12 
 
d.   
Adverse Event reporting….. ............................................................. 12 
 
XII. Data Management 
      a.       Data collection .................................................................................. 13 
      b.       Record retention ............................................................................... 14 
 
XIII. IRB Review and Approval ......................................................................... 14 
 
XIV. References ................................................................................................. 14 
 
Appendix A (Physician’s Global Assessment of Clinical Condition) ........... 16 
 
 
 
 
 
 

 
 
I. 
Objective 
 
The objective of this study is to evaluate the efficacy of ablative fractional CO2 laser 
treatment on the clinical improvement of skin conditions including hypertrophic 
scars and scleroderma. 
 
II. 
Background 
 
Skin conditions such as hypertrophic scars and scleroderma (morphea) are all 
linked to abnormal collagen production and distribution throughout the skin.  
 
Hypertrophic scars are the result of abnormal wound healing and while poorly 
understood, they are believed to be triggered by the inflammatory cascade through 
cytokine dysregulation. The resulting phenotype is a haphazard increase in 
collagen and abnormal vasculature. TGF-B and PDGF-1 have both been 
implicated in hypertrophic scar pathogenesis. The second condition, scleroderma 
(also known as morphea), is an autoimmune disease that causes the formation of 
stiff scar-like skin lesions that can restrict motion across joints in addition to its 
aesthetic implications. Scleroderma is characterized by excessive collagen 
deposition leading to the thickening of the dermis, subcutaneous tissues, or both. 
The disease is progressive and can often worsen, despite treatment. There is 
currently no cure to the autoimmune disease and little relief for those suffering from 
lesional contracture. 
 
Ablative fractional carbon dioxide (CO2) lasers are commonly used to improve 
the appearance of both conditions, either alone or through laser-assisted drug 
delivery.9-11 While the mechanism is not completely understood, ablative 
fractional laser alone may induce MMPs to help remodel and normalize both 
collagen and elastin.11  
 
In this study, we seek to evaluate the effects of ablative fractional CO2 laser 
treatment on the redistribution/regeneration of collagen on the clinical, 
microscopic, and molecular profiles hypertrophic scars and scleroderma. 
Study design  
A prospective cohort study of 10 subjects with hypertrophic scars and 10 subjects 
with scleroderma.  
Analysis of Skin Samples 
Optional skin samples will be used to test the hypothesis that fractional laser 
treatment can improve the clinical appearance of scars and scleroderma.  

Skin will be sampled using  four 3 mm-punch biopsies. Biopsies will be obtained 
from the treated lesion (1)  and perilesional healthy skin   (1) during the first and 
during the post-procedural visit. Skin biopsies will be optional for scleroderma 
subjects.  
Using histopathological analysis, microscopic and immunohistochemical tissue 
effects between treatment arms will be compared.   
The study will take place at MGH’s Clinical Unit for Research Trials & Outcomes 
in Skin (CURTIS) at 50 Staniford Street, Suite 240 Boston, MA  02114 or 
Translational Clinical Research Center (TCRC) on the 12th floor of the White 
Building. 
III. 
Aims 
 
The aims of this study are:  
 
• To determine the efficacy of ablative fractional laser in clinical improvement 
of hypertrophic scars and scleroderma. 
 
IV. 
Subject selection 
 
Subjects will be screened to determine if they meet all the eligibility criteria 
specified below. 
 
a. 
Inclusion Criteria 
1. Subject must be able and willing to provide written informed consent 
and comply with the requirements of the study protocol; 
2. In good general health, based on answers provided during the 
screening visit; 
3. Any gender and any Fitzpatrick skin type;  
4. Age equal to or greater than 18 years old; 
5. Subjects in the hypertrophic scar branch must have at least one 
extragenital hypertrophic scar (defined as abnormal proliferation of 
scar tissue that forms at the site of cutaneous injury and does not 
regress and grows beyond the original margins of the scar) at least 
4cm in length for scar treatment; 
6. Subjects in the scleroderma branch must have eligible extragenital 
lesions; large enough to treat; 
7. Willing to sun protect treated area for the duration of enrollment in 
the study and 1 year after treatment. 
 
 
 
b. 
Exclusion Criteria 

1. Participation in another investigational drug or device clinical trial in 
the past 30 days;   
2. Are pregnant or lactating; 
3. Use of any prescription or in-clinic medications or treatments, such 
as intralesional corticosteroids or excision, on the eligible 
scars/scleroderma in the previous 3 months; 
4. History of allergic reaction to topical or local anesthesia; 
5. Regular intake of high doses of anti-inflammatory drugs (aspirin >81 
mg/day, ibuprofen, corticosteroids, etc.) or high and/or  non 
stabilized doses of immunosuppressive drugs; 
6. Clinically significant abnormal findings or conditions which might, in 
the opinion of the Investigator, interfere with study evaluations or 
pose a risk to subject safety during the study; 
7. Laser treatment in past six months; 
8. History of poor wound healing.  
 
           c.  Source and Recruitment of Subjects 
 
The study will be posted on the Partner’s clinical research web page (Rally), 
around the hospital, and outpatient clinics (treating scars, scleroderma, or 
morphea) to reach an economically and socially diverse population.  
 
V.  Subject Enrollment 
 
a. Method of Enrollment 
All subjects who electronically sign an informed consent form (ICF) and are 
screened will be documented on a screening log. All subjects who qualify 
at the screening visit and who are enrolled in the study will be documented 
on the enrollment log. A note will be made in the source documentation 
verifying that the subject has willingly signed the ICF prior to participation in 
any study procedures. All randomized subjects will receive a subject 
number. 
 
b. Informed Consent Form (ICF) 
 
A licensed physician investigator or sub-investigator will inform the potential 
study subject of all aspects of the study and answer their questions. If the 
subject agrees to be a study subject, they will document consent in 
electronic form by signing an online ICF via Adobe eSign. Subjects who 
need more time to decide whether they would like to participate will have 
access to the electronic consent form and will call if they are interested in 
participating in the study.  
 
The investigator is responsible for using a consent form that has been 

approved by the IRB/Partner’s HRC and is the most current version. If a 
new version of the consent form is approved by the IRB/Partner’s HRC 
while a subject is still participating in the study, then the Investigator will 
inform the subject of the changes and, if the subject agrees to continue 
study participation, they should sign the updated form. 
 
Electronic informed consent will be obtained prior to performance of any 
protocol-specific procedures. 
 
c. Subject selection 
 
Ten subjects with one or more hypertrophic scars and ten subjects with 
scleroderma will be recruited for this study. Each subject will undergo an 
biopsy of perilesional normal-appearing skin adjacent to lesion to be 
treated (scar or scleroderma) and an optional biopsy of the treated side at 
their final visit.  Biopsies will only be optional for scleroderma subjects.   
 
 
IV. 
Study Procedures 
 
a. Study Visits and Procedures  
 
Baseline Assessment (Phone Call/In-Person Visit) 
The baseline/consent assessment will be done in-person or phone call upon 
physicians discretion. At the baseline visit, eligibility criteria, including a review of 
medical history and medications, and detailed information about the study will be 
reviewed. Informed consent will be obtained, if the subject desires to proceed 
with the study.  
 
Trial treatment Visit 1  
Once consented, range of motion assessment (non-facial scleroderma), Mouth 
Handicap in Systemic Sclerosis scale (facial scleroderma) and Modified 
Vancouver Scar Scale (hypertrophic scars)(Appendix 2 )  will be used to assess 
lesions. Medical photography of the lesions and urine pregnancy test (for female 
subjects of childbearing potential) will be obtained prior to treatment. OCT 
imaging and three-dimensional imaging (Cherry Imaging) may also be performed 
on select consented subjects.  The subject will be questioned about itch and pain 
in the area that will be treated.   
 
Two 3 mm-punch biopsies will be obtained, one from perilesional normal-
appearing skin adjacent to treated lesion (scar or scleroderma), and one from 
skin treated with laser. Biopsies will be optional for scleroderma subjects. 
 
 
The subject will be anesthetized with 23% lidocaine, 7% tetracaine topical 
numbing for 30 minutes to one hour, which is standard of care in laser clinic. 

Once the subject has been anesthetized, they will undergo laser treatment. The 
entire lesion will be treated with Ultrapulse CO2 laser DeepFX an energy level 
between 20 mJ-50 mJ and 5%-10% density, 1-2 passes. The area to be treated 
will not exceed 20cm. Vaseline will be applied evenly with a gloved hand on the 
entire lesion following the procedure.   
 
Trial treatment Visit 2 (1 month after treatment visit 1) 
The treated lesion(s) will be evaluated clinically for any potential adverse events 
and urine pregnancy test (for female subjects of childbearing potential) will be 
obtained prior to treatment. Each area of scar or scleroderma will be marked with 
a surgical marker based on photographs from the previous visit to ensure the 
treatment area is consistent. Medical photography of the lesion and urine 
pregnancy test (for female subjects of childbearing potential) will be obtained 
prior to treatment. OCT imaging may also be performed on select consented 
subjects. 
 
The subject will be anesthetized with 23% lidocaine, 7% tetracaine topical 
numbing for 30 minutes to one hour, which is standard of care in laser clinic. 
Once the subject has been anesthetized, they will undergo laser treatment. the 
lesion will be treated with Ultrapulse CO2 laser DeepFX, an energy level of 20 
mJ-50 mJ and 5%-10% density, 1-2 passes. The area to be treated will not 
exceed 20cm.Vaseline will be applied evenly with a gloved hand on the entire 
lesion following the procedure.   
 
 
Trial treatment Visit 3 (1 month after treatment visit 2) 
The treated lesion(s) will be evaluated clinically for any potential adverse events 
and urine pregnancy test (for female subjects of childbearing potential) will be 
obtained prior to treatment. Each area of scar or scleroderma will be marked with 
a surgical marker based on photographs from the previous visit to ensure the 
treatment area is consistent. Medical photography of the lesion and urine 
pregnancy test (for female subjects of childbearing potential) will be obtained 
prior to treatment. OCT imaging may also be performed on select consented 
subjects. 
 
The subject will be anesthetized with 23% lidocaine, 7% tetracaine topical 
numbing for 30 minutes to one hour, which is standard of care in laser clinic. 
Once the subject has been anesthetized, they will undergo laser treatment. The 
entire lesion will be treated with Ultrapulse CO2 laser DeepFX, an energy 20 mJ-
50 mJ and 5%-10% density, 1-2 passes. The area to be treated will not exceed 
20cm. Vaseline will be applied evenly with a gloved hand on the entire lesion 
following the procedure.   
 
Post-procedural visit (final visit, 1 month after treatment visit 3) 
One-month after the last treatment The subject will be questioned about itch and 
pain in the treated area.  Range of motion assessment (non-facial scleroderma), 

Mouth Handicap in Systemic Sclerosis scale (facial scleroderma) and Modified 
Vancouver Scar Scale (hypertrophic scars) (Appendix 2) will be used to assess 
lesions. Lesion marked with surgical marker. Additional medical photography and 
two  3 mm-punch biopsies will be obtained, one from perilesional normal-
appearing skin adjacent to treated lesion (scar or scleroderma), and one from 
lesional skin treated with laser. Biopsies are optional for scleroderma subjects 
only. OCT imaging and three-dimensional imaging (Cherry Imaging) may also be 
performed on select subjects.  
 
Clinical assessment  
Clinical photographs taken pre-treatment and post-treatment will be complied 
and reviewed in blinded fashion by at least one dermatologist using the 
Physician’s Global Assessment, a widely used scale from the existing literature 
to determine clinical change from baseline. We will use the Mouth Handicap in 
Systemic Sclerosis1 scale for assessing facial scleroderma. For non-facial 
scleroderma, we will evaluate range of motion of the joint by assessing flexion, 
extension, supination, and pronation using a goniometer2. All scars, facial and 
non-facial, will be assessed using the Modified Vancouver Scar Scale3. 
 
Cherry Imaging Photography 
The Cherry Imaging system is a 3-dimensional photographic imaging system 
designed to accurately measure aesthetic treatments to deliver objective subject 
data before and after aesthetic treatments. The handheld camera captures 
thousands of three-dimensional images of the face and/or body from multiple 
field views and angles that are analyzed to provide 100-micron accuracy level 
data of the body and/or face for real-time evaluation of treatment results and 
traceability over time. The Cherry Imaging device will be used to take images of 
the scars before the laser treatment takes place and during each subsequent 
study visit. No special lighting is needed for the imaging device, so the images 
will be taken and processed directly in the room where the laser procedure will 
take place. 
 
Lumenis® Ultrapulse® C02 laser with DeepFX™  
The Lumenis Ultrapulse C02 laser is approved by the U.S. Food and Drug 
Administration (FDA) for several treatments in dermatology & plastic surgery, 
podiatry, otolaryngology (ENT), gynecology, and surgery. However, the Lumenis 
Ultrapulse C02 laser is not FDA approved for scleroderma.The subject will be 
 
1 Mouthon L, Rannou F, Bérezné A, et al. Development and validation of a scale for mouth 
handicap in systemic sclerosis: the Mouth Handicap in Systemic Sclerosis scale. Ann Rheum Dis. 
2007;66(12):1651-1655. doi:10.1136/ard.2007.070532 
2 Micheletti RG, Chansky PB, Haun PL, et al. Ablative fractional laser resurfacing for treatment of 
sclerosis and contractures in chronic graft-versushost disease: A pilot study. J Am Acad 
Dermatol. 2020;82(4):984-986. doi:10.1016/j.jaad.2019.07.084 
3 Baryza, M. J., & Baryza, G. A. (1995). The Vancouver Scar Scale: an administration tool and its 
interrater reliability. The Journal of burn care & rehabilitation, 16(5), 535-538. 
 

anesthetized with 23% lidocaine, 7% tetracaine topical numbing for 30 minutes to 
one hour, which is standard of care in laser clinic. Once the subject has been 
anesthetized, they will undergo laser treatment. The lesion(s) will be treated with 
the laser at an energy level of 20 mJ-50 mJ and 5%-10% density, 1-2 passes. 
Protective eyewear will be worn by subjects and study staff in accordance with 
standard laser safety procedures. Subjects will then be instructed to perform post-
procedural care. 
 
Optical coherence tomography (OCT) imaging 
This device is not FDA approved. However, it’s been safely used in over 1000 
research participants so far. OCT imaging is performed spectral-domain OCT 
scanner TELESTO II (Thorlabs Inc., Newton, New Jersey). It operates at a 
central wavelength of 1,300 nm with an output power of 2.2 mW with continuous 
wave exposure of approximately 30 seconds per image, non-pulsed. Using a 
lens with an optical lateral resolution of 13 μm (LSM03, Thorlabs Inc.), we 
acquire images with an oversampling factor of 2× leading to voxel sizes of 6.5 × 
6.5 × 3.5 μm3 and a field-of-view (FOV) of 6 × 6 × 3.5 mm3 (length × width × 
depth), acquired at an A-Scan rate of 76 kHz. 
 
The imaging data is further processed and analyzed by custom made software 
tools implemented in MATLAB 2016b (MathWorks Inc). All OCT image data files 
will be labeled with the study subject number assigned to each subject upon 
consent. No identifying information will be used in labeling the image data files and 
the files will be stored on Partners OneDrive. 
 
The OCT imaging system will be cleansed with 70% isopropyl alcohol wipe in the 
subject’s presence prior to perform any imaging procedure. The subject’s lesion 
at the intended OCT imaging sites will be cleansed with 70% isopropyl alcohol 
prep and allowed air dry thoroughly. A z-spacer (OCT-Imm03, ThorLabs, Inc., 
Newton, NJ) will be attached to the OCT probe and glycerol will be utilized for 
optical coupling (immersion) between the OCT spacer and the skin. The 
acquisition and saving time per image will be less than 1 minute.  If study staff 
operating the OCT imaging device decide the images are of too low quality or 
contain artifacts that would affect analysis, this procedure may be repeated on an 
area of the skin within close proximity to the original imaging location but at least 
2-3 cm away from the original location. After finishing the OCT imaging 
procedures, the z-spacer will be detached and cleansed with 70% isopropyl 
alcohol wipe then allowed to air dry thoroughly prior to next use. 
 
Skin biopsies 
 
Two skin biopsies will be obtained at visit 1 and at the post-procedural visit of 
perilesional normal-appearing skin adjacent to treated lesion (scar or 
scleroderma) and laser treated lesional skin. This will result in up to four biopsies 
per subject over the course of this study. Biopsies are optional for scleroderma 
patients only.  

 
The areas to be biopsied will be cleansed with a 70% isopropyl alcohol prep. The 
area will then be anesthetized with lidocaine HCl 1% and Epinephrine 1:100,000 
(approximately 1 cc to each site). 3 mm punch biopsies will be performed similar 
to that performed in the dermatology clinic. Biopsy sites will be closed with two 
absorbable sutures (5.0 or 6.0 fast absorbing gut) or with gel foam.  Vaseline and 
band-aid will be applied.   
 
Tissue handling  
 
All specimens will be manually bisected with a 15-blade. One-half of each 
specimen will be placed in formalin and sent for pathological analysis for H/E and 
immunohistochemical staining. The other half of the specimen will be evaluated 
using electron microscopy.  
 
Histopathological analysis 
 
Specimens be will be fixed in zamboni and sectioned. Immunohistochemical 
staining to using Masson’s trichrome stain, elastin and CD31 will be used to 
evaluate 
collagen, elastic 
fibers 
and vasculature 
in 
each 
specimen. 
Immunohistochemical staining  for nerve fiber density will be done as well.  
 
b. Remuneration  
Subjects will be reimbursed up to $ 500 dollars for participation and completion of 
this study. They will receive, $50 for each second and third treatment visit (visit 2-
3) and $200 for completing the first and the  final visit if biopsies are taken(visit 1 
and 4) .If biopsies are not taken, subjects will be paid $50 for completing the first 
and the  final visit each. If the subject does not complete the study, they will be 
paid in accordance to the number of visits ($50 per treatment visit, $50 per 
biopsy). We will also provide a parking voucher at MGH main campus for each 
visit upon request. 
 
We may use subject samples and information to develop a new product or 
medical test to be sold.  The Sponsor, hospital, and researchers may benefit if 
this happens.  There are no plans to pay subjects if samples or information are 
used for this purpose. 
 
We will be using an approved, outside vendor (Forte Research) to make these 
payments via a reloadable credit card-based system, called Forte Payments. 
This secure system is similar to a gift card or credit card. If subjects are paid by 
this system, they will be given a Forte Payments Via card (which is just like a 
debit card) when subjects enroll in the study. Once the card is activated, the 
study team will add a payment after each paid visit completed by the subjects. 
The payment should be available within one (1) business day. Research staff will 
not know where subjects spend the money. Subjects may use the card anywhere 
Visa cards are accepted, such as at a grocery store. 

  
We will need to collects subjects’ Social Security number in order to make these 
payments, and it will be shared securely with the company that runs the card-
based system. Payments like this are considered taxable income. If subjects 
receive more than $600, the payment will be reported to the IRS as income by the 
hospital. 
 
VII. Biostatistical Analysis 
 
In order to detect a difference of one point assuming a standard deviation of one 
point on the primary clinical outcome measure, Physician’s Global Assessment of 
Clinical Condition (PGA) scale (a numerical scale from 0-6), a sample size of 10 
subjects per condition (10 for scars, 10 for scleroderma, 20 total) is required to 
achieve a power of 0.8. A student’s t test, one sample, two-sided, will be used to 
determine if any significant statistical difference is present between the clinical 
response of each treatment arm using the absolute difference between the pre- 
and post-treatment PGA. A p-value of less than 0.05 is considered statistically 
significant.  
 
VIII. Risks and Discomforts 
 
There is a potential risk of loss of privacy.  We will protect privacy by labeling 
samples and information only with a code, and keeping the key to the code in a 
password protected database.   
 
Potential risks of the skin punch biopsy include allergic reaction to the anesthetic, 
bleeding, infection, poor wound healing, pain, hyper or hypopigmentation and 
scarring. 
 
Possible risks of fractional laser surgery include pain, scarring, infection, abnormal 
wound healing, hyper or hypopigmentation. 
 
Possible side effects of topical 23% lidocaine, 7% tetracaine include redness, mild 
burning sensation, tingling, itching or swelling. Rare side effects include an allergic 
reaction, which may manifest as dizziness or drowsiness.  
 
IX.  Potential Benefits 
  
a.  Potential Benefits to subjects 
Subjects who participate in this study may benefit by having 
improvement in the appearance of their skin lesions.  
 
b.  Potential Benefits to Society 
Information gathered from this study may improve the understanding of 
disorders of collagen metabolism.   
 

 
X.  Monitoring and Quality Assurance 
 
a.  Independent monitoring of source data 
 
Experienced study personnel (study monitor) who are not assigned to complete 
procedures of this study will conduct monitoring after the first subject is enrolled 
and periodically thereafter. The monitor will be responsible for confirming the 
completion and correctness of the study procedures as well as record collection 
and keeping. 
    
b.  Safety monitoring 
 
Prior to enrollment, subjects will be screened for eligibility; at which time a 
complete medical history, including a baseline assessment of the subject’s skin in 
the area of interest will be done. Evaluations will be ongoing throughout the study 
to detect adverse events and changes in existing medical conditions. 
At any time after enrollment, a subject may be discontinued. Reasons for 
discontinuation of a subject from the study will include, but may not be limited to, 
the following: 
1. Subject is found to be intolerant to a required study procedure at any time 
point. 
2. Subject is noncompliant with protocol restrictions and requirements. 
3. Subject develops an intercurrent illness that would, in the judgment of the 
investigator, affect assessments of clinical status to a significant degree.  
4. Subject becomes pregnant while participating in the study. 
5. Subject enrolls in another investigational study. 
6. Subject requests to withdraw from the study. 
7. The study Sponsor decides to suspend or terminate the study. 
 
 
If possible, a final set of assessments will be performed on all subjects who end 
their participation prior to study completion. 
 
d. Outcome monitoring 
 
The study will be conducted in accordance with applicable regulations and Good 
Clinical Practice Guidelines. Keeping files locked with access limited to study staff 
will ensure confidentiality and data integrity. 
 
e. Adverse Event Reporting 
 
Definition 

 
Adverse Event (AE) is any untoward medical occurrence in a subject that does not 
necessarily have a causal relationship with this treatment. An AE can therefore be 
any unfavorable and unintended sign, symptom, or disease temporally associated 
with the use of an investigational product, whether or not related to the 
investigational product. 
 
 
Serious Adverse Event (SAE) is any untoward medical occurrence 
that: 
• Results in death 
• Is life-threatening 
• Requires inpatient hospitalization or prolongation of existing 
hospitalization 
• Results in persistent or significant disability or incapacity 
• Is a congenital anomaly/birth defect 
• Is another medically important condition 
 
Reporting and Documenting Adverse Events 
All untoward medical occurrences that occur after the subject signs a consent form 
will be documented as an AE. The Investigator will ensure that all events that occur 
during the study period are recorded on an Adverse Events Tracking Log. We will 
report any adverse events that are experienced by subjects during their 
participation, even those determined to be unrelated to the study. All AEs will be 
followed until resolution or until, in the Investigator’s judgment, they are chronic 
and stable. If an emergency situation should occur, appropriate medical measures 
should be taken to stabilize the subject. 
 
Documentation of AEs includes: date and time of onset and resolution of AE, 
intensity, frequency, seriousness, related interventions and outcome. The 
Investigator will also evaluate the probability of a causal relationship of the AE to 
the study treatment as being: “definite, probable, possible, unlikely, or unrelated.” 
Intensity of adverse events will be graded as mild, moderate, or severe according 
to the following criteria: 
 
• Mild: symptoms that are easily tolerated and transient in nature 
with minimal or no impairment of normal activity 
• Moderate: symptoms that are poorly tolerated, are sustained, 
and interfere with normal activity 
• Severe: symptoms that are incapacitating and render the 
subject unable to work or participate in many or all usual 
activities 
 

All SAEs will be reported to the IRB according to the IRB’s requirements. They will 
also be reported to the study Sponsor. 
 
Adverse events will be reported to the PHRC as described in the PHRC policy on 
Unanticipated Problems Involving Risks to Subjects or Others Including Adverse 
Events, which can be found on the Research Navigator website. 
 
 
 
XII.  Data Management 
 
a. Data collection 
 
Study data will be collected during all visits.  Study data to be collected includes 
clinical photography, OCT imaging, biological analysis of skin biopsies, cherry 
imaging, PGA, range of motion assessment, Mouth Handicap in Systemic 
Sclerosis scale and Modified Vancouver Scar Scale (Appendix 2) assessments, 
and qualitative subject responses to treatment. All physical documentation and IRB 
correspondence will be stored in study binders maintained in restricted lab space 
only accessible by study staff and members of the Manstein Lab. Digital data 
including photographs will deidentified and stored on Partners computers and 
EPIC. All study documents containing PHI will be password encrypted, including 
the enrollment log and identification key. An encrypted external hard drive will be 
used to store the data as a backup. 
 
c.  Record retention 
 
The Investigator or designees will retain all study records in accordance with MGB 
Human Subject Research Recordkeeping and Record Retention Requirements 
Policy and clinical trials regulations. 
 
XIII.  IRB Review and Approval 
   
The study will not begin prior to the receipt of written confirmation of approval by 
the IRB and any relevant regulatory authority.  It is the responsibility of the 
Investigator to obtain the IRB approval (per the U.S. Code of Federal 
Regulations, Title 21, Part 56 and applicable ICH guidelines) for the protocol, 
amendments, informed consent, subject information sheet, questionnaires, and 
advertising materials used to recruit study subjects, if appropriate.    
  

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Appendix 1: Physician’s Global Assessment (PGA) of Clinical Condition  
 
 
 
Score 
Description 
0 
Completely 
Clear  
No evidence of disease, 100% improvement  
1 
Almost Clear 
Very significant clearance (≥90% to 100%); only traces of disease remain  
2 
Marked 
Improvement 
Significant improvement(≥75% to < 90%); some evidence of disease remains  
3 
Moderate 
Improvement  
Intermediate between slight and marked improvement (≥50% to <75%) 
4 
Slight 
Improvement  
Some improvement (≥25% to <50%); significant evidence of disease remains  
5 
No Change 
Disease has not changed from baseline (+ or - <25%) 
6 
Worse 
Disease is worse than at baseline by ≥25% or more  

 
 
 
 
 
 
 
 
 
 
 
 
 
Appendix 2 : Vancouver Scar Scale