Randomized Controlled Clinical Trial Pilot Study: Patient Outcomes and Gingival Blood Flow Using Laser Doppler Flowmetry Following the Use of Episil on Free Gingival Graft Donor Sites
Phase: NA
Conditions: Pain From Free Gingival Graft
Sponsor: The University of Texas Health Science Center, Houston

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
 
 
 
 
 
 
 
 
 
 
Patient Outcomes and Gingival Blood Flow using Laser Doppler Flowmetry 
Following the use of episil on Free Gingival Graft Donor Sites 
 
NCT03350724 
 
Version Date: 10/06/2015 
 
 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
Protocol Title 
Patient Outcomes and Gingival Blood Flow using Laser Doppler Flowmetry 
Following the use of episil on Free Gingival Graft Donor Sites 
 
Principal Investigator 
Jennifer D. James M.B.A., D.M.D. 
 
Co-Investigators 
Robin Weltman D.D.S., M.S. 
Sridhar V.K. Eswaran B.D.S, M.S., M.S.D. 
 
Population 
The population will consist of 40 subjects, 18 years of age and over, females (non- 
pregnant or non-breast feeding) and males, with a general health status of ASA 1 or 
2, and patients of record at UTHealth School of Dentistry in Houston, Texas requiring 
the gingival augmentation procedure, the free gingival graft. [Augmentation of 
gingival tissues may be considered an elective procedure. Elective 
surgical procedures are not routinely performed on pregnant and lactating women. 
Such procedures can be performed after childbirth and/or completion of lactation.] 
A total of 60 subjects will be consented to account for some subject’s unwillingness 
or inability to continue in the study and non-compliance with study procedures and 
appointments. 
 
Number of Sites 
This will be a single site study at UTHealth School of Dentistry in Houston, Texas. 
 
Study Duration 
The duration of the study will be two years. 
 
Subject Duration 
The duration per subject will be three weeks. 
 
Background, Aim, & Hypothesis 
The free gingival graft (FGG) is a commonly used periodontal plastic surgery 
procedure for the augmentation of keratinized gingiva around teeth and implants. 
The FGG procedure uses a harvesting technique from the palate that leaves an open 
wound that heals by secondary intention, which can take 2 to 4 weeks. Mucogingival 
surgery has been shown to cause postoperative pain 3.5 times as much pain as 
osseous surgery and 6 times as much pain as soft tissue surgery2. When bone is left 
exposed it tends to exaggerate the inadvertent postsurgical inflammatory response 
and increase postoperative pain. Wessel and Tatakis1 compared patient outcomes 
following subepithelial connective tissue graft (SCTG) and FGG procedures and 
indicated that FGG was associated with a greater incidence of donor site pain 
compared to SCTG donor site during the early postoperative period. There were 
significant differences between early (3-day) and late (3-week) pain levels for FGG 
donor sites. Pain in the palatal donor site at 3 days postoperatively was reported by 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
50% of SCTG subjects and 90% of FGG subjects; this difference was statistically 
significant. A previous study4 found similar results and attributed the poorer patient 
outcomes following FGG to differences in donor site harvesting techniques. In an 8- 
week observational study using a verbal descriptor scale to assess postoperative 
discomfort, Del Pizzo et al.4 reported postoperative discomfort at palatal donor sites 
during the first postoperative week in 100% of subjects treated with an FGG 
harvesting technique and in only 50% of subjects treated with a single-incision 
harvesting technique. Additionally, in a study on 228 subjects using questionnaires 
to assess postoperative pain, Griffin et al.3 reported FGG subjects were three times 
more likely than SCTG subjects to develop post-surgical pain during the first 
postoperative week. 
Improving patient outcomes is important in clinical practice. Wessel and 
Tatakis1 found that even with the use of palatal stents to protect FGG donor sites, a 
greater incidence of donor site pain was found during the early healing period 
compared to SCTG. The results of their study suggested that there is opportunity to 
improve the postoperative protocols of commonly used soft tissue grafting 
procedures with more effective donor wound protection schemes. 
At the present time, some type of wound covering over the palatal donor 
tissue site is considered a standard of post-operative care.   While palatal stents are 
one option for protection of the palatal wound, other techniques have been utilized 
to aid in hemostasis and post-operative discomfort. Another technique utilizes a 
hemostatic agent such as Gelfoam® (absorbable gelatin compressed sponge) or 
Surgicel® covered with a wound dressing such as PeriAcryl®90 (a cyanoacrylate 
tissue adhesive). 
A new wound dressing material, episil, has shown to give rapid extended 
reduction of pain in cancer patients suffering from Oral Mucositis/Stomatitis (may 
be caused by chemotherapy or radiotherapy). The intended use of episil is for the 
management of pain and relief of pain, by adhering to the mucosal surface of the 
mouth, soothing oral lesions of various etiologies. episil has obtained 501(k) 
market clearance by the US FDA, in June 2011. episil is an oromucosal liquid in a 
multi-dose container and is without active pharmaceutical ingredients and without 
systemic side effects demonstrated in clinical and pre-clinical studies. episil is 
intended for use in the oral cavity as far as the pharynx but it is not dangerous to 
swallow.  The oromucosal liquid transforms in situ to a bioadhesive oromucosal gel 
by uptake of small amounts of aqueous fluid. episil contains six ingredients 
glycerol dioleate, soy phosphatidyl choline (lecithin), ethanol, propylene glycol, 
polysorbate 80 and peppermint oil which are all generally recognized as safe. No 
side effects have been reported. episil® contains small amounts of ethanol (alcohol), 
less than 100 mg per dose, which may cause a burning sensation when applied to 
sore mucosal surfaces. episil® contains also small amounts of propylene glycol 
which may cause skin irritation and peppermint oil which may cause allergic 
reaction. episil should not be used on patients allergic to any of the ingredients, 
including peanuts, soy (soya) or peppermint oil. Currently there are no known 
concerns of use of episil in human pregnancy or breast-feeding. 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
episil is contained within an amber glass bottle with a manual metering 
pump filled with 10 mL of oral liquid. It is applied to the oral cavity by spraying 1 – 3 
times. Distributed to affected areas in the mouth and within a few minutes the liquid 
converts to a gel and the protective film is formed. It is intended for use 2 – 3 times 
a day or as needed and is normally intended for continuous use for not more than 
30 days. 
Oral mucositis in advanced stages, similar to a FGG donor site, can be 
extremely painful, preventing a patient from eating and even disrupting the 
patient’s daily functions. The aim of this study will be to compare patient-based 
outcomes, specifically postoperative pain, at the FGG donor sites, using an 
interventional parallel-group design, whereby a hemostatic gauze, Surgicel®, will be 
placed within all of the palatal donor sites and covered with either episil (test) or a 
cyanoacrylate dressing, PeriAcryl®90 (control). The secondary aim of this study 
will be to compare gingival healing via measurement of the gingival blood flow at 
the FGG donor sites by the laser Doppler flowmetry (LDF) technique, by monitoring 
blood perfusion. The hypothesis for the present study is that patient-based 
outcomes and gingival blood flow will be more favorable for the FGG donor sites 
being covered by the test wound dressing material episil compared to the control 
dressing. 
 
Study Population and Design 
Forty subjects will be recruited from the Periodontics and Dental Hygiene 
Clinic and the UTDentists Practice, located at the UTHealth School of Dentistry in 
Houston, Texas, where the study will be performed. Only subjects who have already 
formally agreed to receive a FGG as part of their overall periodontal treatment plan 
will be recruited. Inclusion criteria will be 18 years of age or older, patient of record 
at UTHealth School of Dentistry Houston Texas, signed treatment plan for a FGG, and 
the ability to provide research informed consent. Exclusion criteria will be any 
allergies to any of the ingredients in episil including allergies to peanuts, soy or 
peppermint oil, smokers, pregnant or breast feeding women, and inability or 
unwillingness to provide informed consent. As stated above, elective surgical 
procedures are not routinely performed on pregnant or lactating women and are 
postponed until after childbirth and or completion of lactation.  Exit criteria will be 
unwillingness or inability to continue in the study and non-compliance with study 
procedures and appointments. The Institutional Review Board of The University of 
Texas will approve the study protocol, questionnaires and informed consent form. 
The study will be of an interventional parallel-group design. A computer 
generated randomization scheme will assign the subjects to one of the two 
treatment groups.  All subjects will have the gingival grafting procedure, the free 
gingival graft, performed at sites lacking attached keratinized gingival tissues. The 
palatal donor site in subjects assigned to the control group will receive the 
hemostatic agent, Surgicel®, covered by the cyanoacrylate dressing, PeriAcryl®90. 
The palatal donor site in the subjects assigned to the test group will receive the 
hemostatic agent, Surgicel®, covered by episil®. Additionally, the subjects in the 
test group will be given the remainder of the bottle of episil® to take home with 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
instructions for self-application as needed 3 times daily for pain relief. A sufficient 
supply of the episil® will be provided to the test subjects for the study duration. 
The total duration of the study per subject will be 21 days from the day of the 
surgical procedure. The primary outcome of postoperative pain will be determined 
by the subjects recording their postoperative pain threshold using a Visual Analog 
Scale Form/Questionnaire and the number of analgesic pills taken each day at 1, 2, 
3, 5, 7, 10, 14 and 21 days postoperatively. The Visual Analog Scale Form/ 
Questionnaire for post-operative days 1, 2, 5 and 10 will be completed at the 
subject’s place of residence, while the Visual Analog Scale Form/Questionnaire for 
days 3, 7, 14 and 21 will be completed at the subject’s post-operative appointments 
at the dental clinic. The Visual Analog Scale Form/Questionnaire will evaluate the 
subjects’ postoperative pain using a visual analog scale (VAS) scores from 1 to 10, 
with 1 indicating minimal pain and 10 indicating severe pain. If no pain is present, a 
score of 0 will be given. The levels of postoperative pain will be classified as none to 
minimum if the score is “0 to 3,” moderate for “4 to 6,” and severe for “7 to 10.” None 
to minimal pain will mean little or no discomfort; moderate is any pain that bothers 
the subject and mildly affects normal function; and severe will be considered any 
pain that will not be tolerated and may even disrupt the subject’s daily functions. 
One of the secondary outcomes, gingival blood flow, will be determined with 
the laser Doppler flowmetry (LDF) technique to measure the blood perfusion of the 
FGG donor site and as well as the contralateral side of the palate, as a positive 
control, at baseline prior to surgery, immediately after harvesting of the FGG from 
donor site, and on post-operative days 3, 7, 14 and 21. The LDF technique is an 
unbiased non-invasive method of monitoring the response to periodontal therapy. It 
is adequate for recording changes in gingival blood flow following periodontal 
surgery presenting different patterns of microvascular blood flow alterations during 
the would-healing period.18 The LDF technique is based on the Doppler principle. A 
laser beam will be emitted by an optical fibre onto the FGG donor site. The light 
hitting moving erythrocytes is scattered back in shifting frequency, which is the 
Doppler effect, and is captured by one or more optical fibers. The light signals are 
then converted into electric signals and the resulting photocurrent is processed to 
provide a recording of the blood flow.19 The term used to describe blood flow is flux 
– a quantity proportional to the average speed of the blood cells and their 
concentration. This is expressed in arbitrary perfusion units (PU), which are linearly 
related to flux. The PeriFlux System 5000 (Laser Doppler Blood Perfusion Monitoring 
and tcpO2/tcpCO2) along with the Laser Doppler Probes for the PeriFlux 
System 5000 will be used to perform the LDF technique. 
The other secondary outcome will be the time needed to obtain a complete 
re-epithelialization of the FGG donor site, and will be performed by a non-invasive 
peroxide test.20, 21 This test is based on the principle that if the epithelium is 
discontinuous, the H2O2 diffuses into the connective tissue; the enzyme catalase acts 
on H2O2 to release water and oxygen: this is clinically shown by the production of 
bubbles on the wound. 3% H2O2 will be applied to the FGG donor site with a syringe 
and the appearance of bubbles will be recorded as a dichotomous variable (yes/no) 
at the post-operative days 3, 7, 14, and 21 until a subject’s FGG donor site has 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
completely epithelialized (no bubbles observed), when they will not be measured 
again at future post-operative visits. 
 
Data and Safety Monitoring 
Subjects will be informed that if they experience any adverse events with the 
use of episil, that they should discontinue the use of the product immediately. 
Depending on the severity of the adverse event the patient will be advised to either 
call 911 or Dr. Jennifer D. James to report the event. An Unanticipated Problems 
Tracking Log Form will be used to report adverse events to report them to CPHS. 
Any adverse event will then be immediately reported to Camurus AB, the 
manufacture of episil. 
An Unanticipated Problems Tracking Log Form will be used to record and 
report any adverse events that are unexpected, related and put the subjects or 
others at harm, meet the definition of Unanticipated Problems Involving Risks to 
Subjects or Others and will be reported to the Committee for the Protection of 
Human Subjects. 
 
Surgical Procedures & Postoperative Care 
As stated above, periodontal residents under the direct supervision of 
periodontal faculty will perform the FGG procedure in all subjects. The FGG 
procedure will be performed following the surgical technique of Sullivan and 
Atkins15,16 or Miller17. The donor tissue for the FGG procedure will be retrieved from 
either the right or left side of the palate. The FGG donor sites will be of a 
standardized size of 10 mm x 10 mm.  As stated above, subjects in the control group 
will receive a hemostatic gauze, Surgicel®, covered by a cyanoacrylate dressing, 
PeriAcryl®90, at the donor site while the subjects in the test group will receive the 
same brand of hemostatic gauze, Surgicel, but covered with episil®. Subjects in 
the test group will be given the remainder of the bottle of episil® with instructions 
for home application up to 3 times daily.  Postoperative instructions will include 
discontinuing tooth brushing and flossing around the surgical site for the first 3 
post-operative weeks. Subjects will be provided with a prescription for ibuprofen 
(600 mg) to take as needed for analgesia, unless contraindicated. Acetaminophen 
with 30mg of codeine will be prescribed to subjects unable to ingest ibuprofen. 
The LDF measurements in the FGG donor site and on the contralateral side of 
the palate will be recorded in four sites. A clear acrylic stent will be fabricated for 
each subject from individual subjects’ dental casts.  Holes will be made in the stent 
in four locations on each the right and left sides of the palate.  One site located 
centrally, one close to the mesial, one close to the distal and one close to the apical of 
the FGG donor site and in the same locations on the contralateral side of the palate 
will be measured at each of the specified postoperative appointments. The LDF 
measurement will be performed at baseline prior to surgery, immediately after 
harvesting of the FGG donor site, and on post-operative days 3, 7, 14 and 21. The 
LDF measurements will be performed with the tip of the fibre optic probe inserted 
into the holes of the individual acrylic stent.20 The LDF probe will be placed at a 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
standardized location perpendicularly to the tissues and at a distance of 0.5 mm 
from the tissues and will remain motionless during the LDF measurements. 
 
Below is a summary of the timeline of the study: 
First clinic visit (Screening visit): Discussion of study and attain informed 
consult for participation in the study; medical history will be updated, vital signs 
will be taken, and an upper arch alginate impression will be taken in order to create 
a plastic stent, which will be worn during the laser Doppler flow measurements. 
Second clinic visit (Day of Surgery): The day of surgery, the laser Doppler 
flowmetry readings will be performed before the surgery and then again 
immediately after harvesting of the FGG donor site. Subjects will receive 4 copies of 
the Visual Analog Scale Form/Questionnaire to be completed at their homes on days 
1, 2, 5, and 10 postoperatively, which will be labeled accordingly. Subjects assigned 
to the test group will receive a manual-metering pump containing sufficient episil® 
for the duration of the study. Subjects in the test group will be instructed to use the 
pump up to 3 times a day. Instructions for home application of the episil® will be 
given orally and in writing at this appointment. 
Day 1 post-operative: All subjects will complete at home the Day 1 Post- 
Operative Visual Analog Scale Form/Questionnaire. 
Day 2 post-operative: All subjects will complete at home the Day 2 Post- 
Operative Visual Analog Scale Form/Questionnaire. 
Day 3 post-operative (3rd clinic visit): All subjects will bring the 2 
completed Visual Analog Scale Forms/Questionnaires to the day 3 post-operative 
clinic appointment and will complete the Day 3 Post-Operative Visual Analog Scale 
Form/Questionnaire during this appointment. The laser Doppler flowmetry 
readings will be performed on the free gingival graft donor site and on the 
contralateral side of the palate utilizing the fabricated stent with holes for the 
Doppler probe positioning for repeatability of readings. 3% H2O2 will be applied to 
the FGG donor site with a syringe and the appearance of bubbles will be recorded as 
a dichotomous variable. 
Day 5 post-operative:  All subjects will complete at home the Day 5 Post- 
Operative Visual Analog Scale Form/Questionnaire. 
Day 7 post-operative (4th clinic visit): All subjects will bring completed 
Visual Analog Scale Form/Questionnaire to the day 7 post-operative appointment 
and will complete a Day 7 Post-Operative Visual Analog Scale Form/Questionnaire 
during that appointment and laser Doppler flowmetry readings will be performed 
on the free gingival graft donor site and on the contralateral side of the palate. 3% 
H2O2 will be applied to the FGG donor site with a syringe and the appearance of 
bubbles will be recorded as a dichotomous variable. 
Day 10 post-operative: All subjects will complete at home the Day 10 Post- 
Operative Visual Analog Scale Form/Questionnaire. 
Day 14 post-operative (5th clinic visit): All subjects will bring completed 
Visual Analog Scale Form/Questionnaire to the day 14 post-operative appointment 
and will complete a Day 14 Post-Operative Visual Analog Scale Form/Questionnaire 
and laser Doppler flowmetry readings will be performed on the free gingival graft 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
donor site and on the contralateral side of the palate. 3% H2O2 will be applied to the 
FGG donor site with a syringe and the appearance of bubbles will be recorded as a 
dichotomous variable. 
Day 21 post-operative (6th clinic visit): All subjects will attend the day 21 
post-operative appointment and will complete a Day 21 Post-Operative Visual 
Analog Scale Form/Questionnaire and laser Doppler flowmetry readings will be 
performed on the free gingival graft donor site and on the contralateral side of the 
palate. 3% H2O2 will be applied to the FGG donor site with a syringe and the 
appearance of bubbles will be recorded as a dichotomous variable. 
 
 
 
Below is a chart of the timeline of the study: 
 
Procedure 
Visit 
1 
Screening 
Visit 
2 
Day of 
Surgery 
Visit 
3 
3 Day 
Post-op 
Visit 
4 
7 Day 
Post-op 
Visit 
5 
14 Day 
Post-op 
Visit 
6 
21 Day 
Post-op 
Medical History 
√ 
√ 
√ 
√ 
√ 
√ 
Vital Signs 
√ 
√ 
√ 
√ 
√ 
√ 
Complete Visual 
Analog Scale/ 
Questionnaire 
√ 
√ 
√ 
√ 
Doppler Flowmetry 
(FGG donor site) 
√ 
√ 
√ 
√ 
√ 
Doppler Flowmetry 
(Contralateral side) 
√ 
√ 
√ 
√ 
√ 
3% H2O2 
(FGG donor site) 
√ 
√ 
√ 
√ 
 
Statistical Analysis 
Descriptive statistics will be expressed as means+/- SD and frequency 
distributions. Intergroup (FFG donor site using episil and Surgicel (test) and FGG 
donor site with PeriAcryl90 and Surgicel (control)) comparisons at 1, 2, 3, 5, 7, 
10, 14 and 21 days will be analyzed by the Mann-Whitney U test. The Wilcoxon 
signed-rank test will be used for intragroup comparisons between 1, 2, 3, 5, 7, 10, 14 
and 21 days. Differences in frequency distributions between the episil group and 
the PeriAcryl90 group will be analyzed by the Fisher exact test. Associations 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
between pain VAS scores and the number of analgesic pills or number of days 
analgesics were taken will be examined by the Pearson correlation coefficient. The 
significance level for rejection of the null hypothesis will be set at  = 0.05. 
All LDF recordings, which may be impaired by artifacts caused by the relative 
motion of the probe, will be excluded. An average of the 2-minute period of each 
individual recording will be calculated. Changes of blood flux values in the FGG 
donor site will be expressed as the difference (PU) between the PU value at a 
specific site at a specific observation time point (PUt) and the individual baseline 
value of the same site (PU0):PUt – PU0. 
Descriptive statistics will be performed using the SPSS statistical software. 
The PU values in the FGG donor site will be analyzed using the general linear 
model (GLM) univariate test, after verification of the assumptions of homogeneity of 
variance and normality of the residual distribution. The observation time and point 
and the position (mesial, center, distal and apical to the FGG donor site) will be 
modeled as fixed factors and the patient as a random factor with the PU as the 
dependent variable. The Dunett two-sided t-test will be used, in order to evaluate 
the differences between baseline and subsequent time points and between different 
positions in the FGG donor site during the overall observational period. Data will be 
presented as mean SE. Statistical significance will be accepted at p<0.05. 
The outcome analysis of the time needed to obtain complete re- 
epithelialization of the FGG donor site will be made by comparing experimental 
groups on the frequency distribution of patients experiencing complete re- 
epithelization in each of the 4 post-operative visits. The Williams-adjusted log- 
likelihood ratio was performed, followed by post-hoc tests using Bonferroni- 
corrected Fisher’s exact test (2-tailed). 
Based on a sample size of n = 40 (20 per group), a repeated measures 
analysis will have 80% power to detect an effect size of f = .57. For a sample size of n 
= 30 (15 per group), the same analysis will have 80% power to detect an effect size 
of f = .67, while a sample size of n = 20 (10 per group) will have 80% power to 
detect an effect size of f = .83. All of these effect sizes are classified as large effects 
by Cohen’s guidelines (1988), or large differences in the change in pain score 
between the two groups22. 
 
Ethics 
 
 
The Committee For the Protection of Human Subjects will seek IRB approval. 
Subjects will be required to sign the Informed Consent Form, which includes the 
following sections, invitation to take part in the research project, purpose, 
procedures, time commitment, benefits, risks and/or discomforts, alternatives, 
study withdrawal, in case of injury, costs, reimbursement and compensation, 
confidentiality, new information, and questions. 
 
Data Handling & Record Keeping 
Subjects will not be identifiable directly or through identifying information. 
The data will not be able to be linked to the subjects during the study. The Post- 

IRB NUMBER: HSC-DB-15-0658 
IRB APPROVAL DATE: 10/06/2015 
 
Operative Visual Analog Scale Form / Questionnaire will be collected from the 
patient and stored by the principal investigator, Dr. Jennifer D. James. 
 
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