A Prospective, Randomized, Double-blinded Comparison of the Use of 5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts.
Phase: PHASE2
Conditions: Ectropion, Skin Neoplasms
Sponsor: Massachusetts Eye and Ear Infirmary

Title Page 
 
April 20, 2017 
 
786680-1    
 
5-fluorouracil Versus Placebo in Periocular Full Thickness Skin Grafts    
 
 
NCT02705352 
 

 
1. CLINICAL PROTOCOL 
 
1.1 Background 
• 5-Fluorourcil (5-FU) is an antimetabolite that works by irreversible 
inhibiting the enzyme thymidylate synthetase resulting in impaired DNA 
synthesis. This reduces fibroblast proliferation, and inhibits collagen type 
1 production which is a key protein in scar formation. This medication is 
commonly used in ophthalmology after or during glaucoma filtration 
surgery. We propose a randomized controlled prospective study to 
evaluate the outcome of periocular full thickness skin grafts with or 
without the use of 5-FU injected in the post-operative period.  
• In oculofacial surgery, full thickness skin grafts are a fundamental tool 
used to restore function to the eyelid. This can be required after removal 
of skin cancer, correction of eyelid malposition such as cicatricial eyelid 
ectropion, retraction, scar formation, or trauma with loss of tissue. These 
conditions affect patients of all ages, ranging from newborns to 
nonagenarians.  Skin grafting in the periorbital area is relatively safe, 
although complications may arise.  The most common and challenging 
complication scarring and graft shrinkage. This can lead to requiring 
additional surgery to add additional skin or to improve the appearance of 
the graft.  In addition to the morbidity of another surgery, some patients 
have limited or no additional skin available (e.g. young patients, burn 
patients).  The eyelid skin is the thinnest of the body, so only thin skin 
can be used as donor material.  However, the amount of skin available for 
this purpose is very little. There are limited options for preventing graft 
shrinkage and scarring in this situation. The oldest and most commonly 
used technique is injection of steroid medication.  Steroids decrease 

proliferation of a fibroblast cells, which create collagen and 
glycosaminoglycan, two proteins created by the body that contract and 
cause graft shrinkage.  Data in literature shows that one form of steroid, 
triamcinolone, is effective for this purpose. However, there is a risk of 
embolization of this solid steroid material that can rarely cause 
blindness.  In addition, in the periocular area, steroids can elevate 
intraocular pressure causing glaucoma in some cases and accelerate the 
formation of cataracts.                                                                                            
1.2 Rationale 
• There have been two retrospective studies that have investigated the 
safety and efficacy of 5-FU injected in periorbital skin grafts with or 
without Kenalog. The first (Massry 2011) used post-operative injections 
of a 50:50 mixture of 5-FU and triamcinolone for correction of medial 
canthal webs.  In 2 patients, they found it to be safe and effective.  The 
author noted he has used it previously for other scar management cases 
and was “very pleased with the results and [had] negligible side-effect[s].”  
The same author performed another study using 5-FU for skin grafts.  
This study evaluated 19 patients who had skin grafts for various 
purposes and were injected following surgery (similar to our protocol).  
This study demonstrated safety of the injection, with no cases of 
complication.  The author concluded that the 5-FU is effective with 
“minimal scarring, high patient and surgeon satisfaction, and few 
complications 
• Medication will be injected in the periocular skin graft area 2-3 weeks 
after surgery. The medication will be injected every 2-3 weeks for a total 
of up to four injections. Concentration of medication is 50mg/ml. 
Medication will be administered using a 1cc syringe with a 30gauge 
needle. 

• Any competent patient (male or female) from the age of 18 to 89 that 
presents with any periocular pathology that requires skin graft for 
reconstruction and consents to participate will be a candidate to be 
included in the study.  
• To your knowledge 5-FU hasn’t been withdrawn from research or market 
in any country for any reason related to its safety or effectiveness.  
 
 
 
 
 
 
 
 
 
 

 
2. STUDY OBJECTIVES 
 
2.1 Primary Objective 
• Determine the effectiveness of 5-FU on the change in measured graft size. 
2.2 Secondary Objective(s) 
• Patient and surgeon satisfaction using the scar assessment scale (POSAS) 
developed and previously published by Draaijers et al.   
• Treatment related adverse events.  Examples are pain, skin thinning, 
color/texture change, atrophy, telangiectasis, infection and erythema.   
• Early post-operative complications (within 2 weeks of surgery).  Example 
of that are wound dehiscence, graft necrosis, infection, bleeding, 
partial/complete graft failure and/or ectropion.  

 
3. STUDY DESIGN 
 
3.1 Study Design Description 
• Randomized double blinded study comparing  5-FU versus placebo. 
o Patients will be randomized between treatment and control group. 
Double-masked study, neither patient nor physician providing 
treatment will know which group they are participating. Pharmacy 
will provide medication (5-FU versus saline). 
o Subject will be evaluated on first visit for the periocular pathology 
referred to our clinic requiring a full thickness skin graft to 
reconstruct the affected area. On that same visit patient will be 
schedule to have surgery and research study will be presented. 
Whether or not patients decide to participate on study, surgery will 
be performed as normal. Then patient will be seen one week post-
op as all surgical patients are normally seen. If patients decide to 
participate, 1-2 weeks later will start injecting medication (5-FU 
versus saline) on affected area. Injections will be repeated three 
more times, for a total of up to four, in a period of 2-3 weeks 
between each injection. After last injection is placed, patient will be 
seen 2-3 weeks after, and then 6 and 12 months after original 
surgery date. During each visit after surgery patient will be 
required to fill a scar assessment questionnaire. 
3.2 Allocation to Treatment 
• Patients will be randomly allocated between the two arms: treatment or 
control group by the MEEI Pharmacy Department.  
 

 
3.2.1 Randomization Procedures 
• Randomization will be performed by the research pharmacy per their 
protocol. The study will be conducted in a double-blind manner.  
3.2.2 Masking Procedures 
• Pharmacy will provide medication on the same syringe, no matter the 
group, with only patient’s information.  
3.2.3 Breaking the Mask (only if proposed study is masked) 
• If any of the study participants suffer a serious adverse event, the 
identity of the study drug received by the subject will be given by the 
pharmacy for effective emergency treatment of the event. 

 
4. SUBJECT SELECTION 
 
4.1 Subject Inclusion Criteria 
• Competent patient (male or female) 
• Between ages of 18 and 89 
Present with any ocular pathology requiring a full thickness skin graft4.2 
Subject Exclusion Criteria 
• Women lactating, pregnant or planning to get pregnant 
• Minors (<18 years old) or patients over 89 years old 
• Immunosuppressed or immunocompromised 
• Serious and active infection 
• Dihydropyrimidine dehydrogenase enzyme deficiency 
• Severe hepatic or renal failure 
• Patient unable to consent 

 
5. STUDY DRUG(S)/DEVICE(S)  
 
5.1 Study Drug Information 
• Study drug that will be administered to  fifteen of our patients is 5-
Fluorouracil, FDA-approved systemic chemotherapy medication to treat 
certain cancers, the concentration 50 mg/ml and will inject less than 1cc 
total in the subcutaneous tissue of the affected area.  
• Study placebo that will be administered to the other fifteen of our 
patients is sodium chloride 0.9% (PF). 
• Medications will be given every 2 to 3 weeks for a total of 4 injections.   
• The amount of medication injected will depend on the 
extension/dimension of the periocular area affected with a maximum 
dose of 1cc total. 
5.2 Study Drug Compliance/Adherence  
• Drug will be injected in office by the physician. Medication will be 
administered every 2 to 3 weeks.  
• Patient will be withdrawn from study if patient doesn’t follow post-
operative instructions or is non-compliant with follow up appointments.  
• 
If a subject is withdrawn from study participation due to 
noncompliance/adherence will be replaced for another patient and will 
receive the corresponding medication. 
5.3 Study Drug Supplies 
• Formulation and Packaging 
Medication will be received directly from MEEI Pharmacy department. 
Medication will come on a syringe with only patient’s information on it. 

• Preparing and Dispensing 
Medication will be prepared on-site by the MEEI Pharmacy. 
• Administration 
Medication will be administered in the Ophthalmic Plastic and 
Reconstructive Surgery clinic on the main MEEI building. Injection will be 
place on the corresponding affected area of each patient.  
5.4 Study Drug/Device Storage and Accountability 
• Medication will be prepared and stored by MEEI Pharmacy Department as 
by their protocol. 
• Medication disposable or destruction upon completion as per MEEI 
Pharmacy Department. 
5.5 Other Medications 
• Administration 
No limitation in concomitant medication use prior or during the clinical 
study participation. 
• Rescue Medication or Therapy 
No identifiable rescue medication or therapy that can be used during the 
participation in the clinical study.  

 
7. STUDY PROCEDURES 
 
7.1 Screening Procedures 
• Every patient that comes to the clinic requiring a full thickness skin graft 
to reconstruct the periocular area (meets the inclusion and exclusion 
criteria) will be offered the opportunity to participate on the clinical trial 
study.  
7.2 Enrollment/Baseline Procedures 
• Every patient will undergo periocular reconstructive surgery with the use 
of a skin graft. Afterwards (2-3 weeks later) will start receiving the 
injections. 
7.3 Study Drug or Device Procedures 
• Every patient that participates on the study will obtain a physical 
examination with emphasis on the affected area in every visit. Plus 
patient will be required to fill out a scar assessment questionnaire. Also a 
photograph will be taken to monitor changes objectively. 
7.4 Standard of Care Procedures 
• No matter the patient’s enrollment in the study, all patients will obtain 
the appropriate surgical procedure without deviation of the normal 
surgical routine. Follow up will be kept the same.  
7.5 Follow-up Procedures  
• After patient receives last injection, he will be followed 3 more times (2-3 
week after last injection, and 6 and 12 month post-op from original 
surgery date). During those visits, patient will be required to fill out a 
questionnaire and will obtain a physical examination by the physician 
and photos will be taken. 

7.6 Unscheduled Visits 
• If patient needs to be seen sooner for any reason, it will be allowed and 
documented in the study. 
7.7 Early Termination 
• If early results show that medication have serious adverse reaction, not 
seen in any of the previous published studies, then study will be stopped 
and patients will be informed of the event. Study physician may withhold 
any injections if there is an adverse event like infection. 
7.8 Schedule of Activities (Study Table) 
 
Intervention 
(injection) 
Physical 
examination 
Questionnaire Photograph 
Initial evaluation 
(screening) 
 
x 
 
x 
Surgery 
 
 
 
x 
First post-
operative visit 
 
x 
 
x 
2-3 weeks after 
surgery (1st 
injection) 
x 
x 
x 
x 
2-3 weeks after 
1st injection (2nd 
injection) 
x 
x 
x 
x 
2-3 weeks after 
2nd injection (3rd 
injection) 
x 
x 
x 
x 

2-3 weeks after 
3rd injection (4th 
injection) 
x 
x 
x 
x 
2-3 weeks after 
4th injection 
 
x 
x 
x 
6 months after 
initial surgery 
 
x 
x 
x 
12 months after 
initial surgery 
 
x 
x 
x 
 

 
8. SAFETY AND EFFECTIVENESS ASSESSMENTS 
 
8.1 Safety Assessments 
• Patients will be ask in each visit after surgery for any adverse events or 
complain from surgery or injection. It will be documented in the record 
as normally done with any patient.   
• The PI will be responsible for safety review. Physician may withhold any 
injection if there is an adverse event like infection 
8.2 Effectiveness Assessments 
• Effectiveness of the study medication will be evaluated by measuring skin 
graft in each visit after surgery. The measurements will be recorded and 
analyzed at the end of the study to evaluate the graft size change during 
the whole study and compare the two groups. Photos will be taken also to 
objectively observe and document changes. Scar assessment will be 
evaluated with the use of a questionnaire completed by the 
observer/surgeon and patient. Questionnaire will be stored and at the 
end of the study values will be analyzed. 

 
9. ADVERSE EVENT RECORDING AND REPORTING 
 
9.1 Recording Requirements 
• Research subjects will be routinely questioned about treatment related 
adverse events at each study visit. All possible, if any, non-serious 
examples are pain, erythema/redness, skin thinning/atrophy, infection, 
color/texture change, swelling, telangiectasia, graft shrinkage/rejection 
and need for additional surgery. Serious adverse events are not expected 
to be seen at any moment of the study since medication has been shown 
to be safe to the patient. In addition, patients will be evaluated for early 
post-operative complications (within 2 weeks of surgery) not related to 
study drug treatment.  Example of that are wound dehiscence, graft 
necrosis, infection, bleeding, partial/complete graft failure and/or 
ectropion. Events will be followed until it resolves or stabilizes; if needed 
other treatment (eg. antibiotics) will be added to manage adverse event. 
9.2 REPORTING PROCEDURES 
Ø Reporting Adverse Events to the Human Studies Committee (HSC) 
• Will follow HSC Policy for “Reporting Adverse Events and Unanticipated 
Problem”. As follows, any adverse events that are serious, unexpected 
and related or possibly related to the study will be reported to the HSC 
within 7 days from the time the PI becomes aware of the event. Any 
unexpected and study-related death will be reported to HSC within 24 
hours of the PI’s knowledge of the event by e-mail or telephone. A 
completed AE report form will be submitted to HSC within 7 calendar 
days of initial HSC notification. If the PI becomes aware more than 30 
days after the conclusion of a subject’s participation of a serious adverse 
event that is both related to the research and unexpected, the PI will 

report the event to HSC at the time he becomes aware of it. PI will report 
to the HSC all non-serious adverse events that are unexpected and related 
or possibly related to the research within 30 calendar days from the time 
the PI becomes aware of the event. All unanticipated problems (UAP) 
involving risks to subjects or others will be reported in writing to the HSC 
within 7 calendar days from the time the PI becomes aware of the event. 
If a UAP or an unexpected serious adverse event results in a subject’s 
death or was potentially life-threatening, the PI will notify HSC through e-
mail or phone within 24 hours from the time the event is identified. A 
follow-up report will be submitted at a later date when more information 
is available. The PI will notify HSC through e-mail or phone within 24 
hours from the time the event is identified for UAPs that take the form of 
a data loss. 
9.3 Withdrawal of Subjects due to Adverse Events 
• If subject presents with a serious event from intervention, he(she) will be 
withdrawn from further study intervention and the investigators will 
evaluate the reason for event. If patient states a minor adverse event 
patient will continue unless patient wishes to voluntary withdrawn.  
• A serious event includes a severe allergic reaction to medication causing 
systemic symptoms of anaphylaxis.  
• Data will continue to be collected from the withdrawn subjects, until 12 
months after original surgery date, but without further intervention (no 
more injections) and patient will not be included in the analysis. 
Withdrawn subjects from study participation due to an adverse event 
will not be replaced for a new patient. 

 
11. DATA AND SAFETY MONITORING  
 
11.1 Data and Safety Monitoring Plan  
• Safety review will take place on site on every follow up visit by the 
examining physician that will monitor all patients for any complication or 
side effect from treatment; if serious treatment will be stopped.  All 
adverse events and unanticipated problems will be reported to the 
Human Studies Committee as previously explained. Every examining 
physician has the expertise and knowledge to identify any complication 
from the treatment each patient is receiving. Each physician and member 
of the study has completed MEEI training. Each month, the study will be 
assessed by the PI and study coordinator to evaluate for significant 
adverse or treatment effects. All data collected will be stored in a locked 
cabinet inside the oculoplastics administrative office. 

 
12. DATA HANDLING, RECORD-KEEPING AND MONITORING 
 
12.1 Data Recording, Record-Keeping and Monitoring  
• A Case Report Form (CRF) will be completed for each subject enrolled 
into the clinical study.  The Sponsor-Investigator will review, approve and 
sign/date each completed CRF; the Sponsor-Investigator’s signature 
serving as attestation of the Sponsor-Investigator’s responsibility for 
ensuring that all clinical data entered on the CRF are complete, accurate 
and authentic. The physician will review the informed consent, confirm 
subject eligibility and verify the accuracy of data transfer from the source 
document to CRF. Data monitoring will occur monthly if new patients 
have been recruited during that specific time. Data review will be done by 
PI and study coordinator.  
• Source Data are the clinical findings and observations, and test 
data/measurements, and other information contained in Source 
Documents.  Source Documents are the original records (and certified 
copies of original records); including, but not limited to, hospital medical 
records,  physician or office charts, physician or nursing notes, pharmacy 
dispensing records, recorded data from automated instruments, x-rays, 
etc.  When applicable, information recorded on the CRF shall match the 
Source Data recorded on the Source Documents.   
• The electronic data recording data system being used for this clinical 
research study has not been fully certified as being compliant with the 
FDA regulations at 21 CFR Part 11 due to the limited scope of this clinical 
research study.  
 

 
13. STUDY DISCONTINUATION CRITERIA 
 
13.1 Discontinuation of Individual Research Subjects 
• Discontinuation criteria for individual research subjects has been 
previously addressed under section 5.2 (Withdrawal of subjects due to 
non-compliance/adherence) and section 9.3 (Withdrawal of subjects due 
to adverse events) of the clinical protocol. Decision will be done by PI. 
Data will be collected until subjects are withdrawn. If subjects have 
already received part of the treatment or withdrawn before treatment has 
been started then subjects will be replaced using the same eligibility 
criteria.  
13.2 Sponsor-Investigator Discontinuation of the Clinical Research Study 
• Clinical research study will be discontinued if treatment is showed during 
the course of the study to be harmful to the patient or graft. The rest of 
subjects will be notified and evaluated to make sure harmful side effects 
have not occurred to them.    
• The HSC and the FDA will be notified promptly of discontinuation of the 
entire clinical study.