A Randomized, Parallel-group Autogenous ex Vivo Produced Oral Mucosa Equivalent vs. Palatal Oral Mucosa Safety and Efficacy Study in Subjects Requiring Additional Keratinized Oral Mucosa for Dental Implants
Phase: PHASE2
Conditions: Disorder of Oral Mucous Membrane
Sponsor: Stephen E. Feinberg

 NCT01834326 
Clinical Study Protocol 
 
A randomized, parallel-group (autogenous ex vivo produced oral muco- 
sa equivalent (EVPOME) vs. palatal oral mucosa (POM) safety and ef- 
ficacy study in subjects requiring additional keratinized oral mucosa for 
dental rehabilitation with endosseous dental implants or around erupted 
teeth to restore periodontal health. 
 
 
Principal Investigator: Dr. Stephen E. Feinberg, DDS, MS, PhD 
Professor & Associate Chair of Research, Department of Oral & Maxillofacial Surgery University of Michigan 
 
 
 
Supported by: 
Department of Defense 
 
Study Intervention Provided by: Clinical Tissue Manufacturing Laboratory (CTML) Uni- 
versity of Michigan 
 
Sponsor/Sponsor-Investigator: 
Stephen E. Feinberg, DDS, MS, PhD 
 
 
IND#: 10118 
 
 
 
 
 
 
 
 
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Table of Contents 
1. 
STUDY OBJECTIVES .................................................................................................................................... 6 
1.1 PRIMARY OBJECTIVE ........................................................................................................................................... 6 
2. 
BACKGROUND............................................................................................................................................... 7 
2.1 
RATIONALE ...................................................................................................................................................... 7 
2.2 
SUPPORTING DATA ........................................................................................................................................... 8 
3. 
STUDY DESIGN .............................................................................................................................................. 9 
4. 
SELECTION AND ENROLLMENT OF SUBJECTS .................................................................................. 9 
4.1 
INCLUSION CRITERIA ........................................................................................................................................ 9 
4.2 
EXCLUSION CRITERIA ..................................................................................................................................... 10 
4.3 
STUDY ENROLLMENT PROCEDURES................................................................................................................ 11 
5. 
STUDY INTERVENTIONS .......................................................................................................................... 11 
5.1 
INTERVENTIONS, ADMINISTRATION, AND DURATION...................................................................................... 11 
5.2 
HANDLING OF STUDY INTERVENTIONS ........................................................................................................... 13 
5.3 
CONCOMITANT INTERVENTIONS ..................................................................................................................... 14 
5.4 
ADHERENCE ASSESSMENT .............................................................................................................................. 15 
6. 
CLINICAL AND LABORATORY EVALUATIONS ................................................................................. 15 
6.1 
SCHEDULE OF EVALUATIONS.......................................................................................................................... 16 
6.2 
EVALUATION SCHEDULE ................................................................................................................................ 17 
6.2.1 
VISIT 1 SCREENING.................................................................................................................................... 17 
6.2.2 
VISIT 2: HARVEST BIOPSY (EVPOME GROUP ONLY) ................................................................................. 18 
6.2.3 
VISIT 3: BASELINE: INTRAORAL GRAFTING OF EVPOME OR POM GRAFTS.............................................. 18 
6.2.4 
VISIT 4: POST-OPERATIVE (POST-GRAFTING) ............................................................................................. 19 
6.2.5 
VISIT 5: POST-OPERATIVE (POST-GRAFTING) ............................................................................................. 19 
6.2.6 
VISIT 6: CLINICAL ASSESSMENT AND BIOPSY OF GRAFTS .......................................................................... 20 
6.2.7 
VISIT 7: CLINICAL ASSESSMENT ................................................................................................................ 20 
6.2.8 
VISIT 8: CLINICAL ASSESSMENT AND END OF STUDY ................................................................................ 21 
6.2.9 
LONG-TERM FOLLOW-UP ........................................................................................................................... 21 
6.2.10 
EARLY WITHDRAWAL/STUDY DISCONTINUATION EVALUATIONS ......................................................... 21 
6.2.11 
OFF-STUDY REQUIREMENTS ................................................................................................................. 21 
6.2.12 
PREGNANCY ......................................................................................................................................... 21 
6.2.13 
ADVERSE EVENTS ................................................................................................................................. 22 
6.3 
SPECIAL INSTRUCTIONS AND DEFINITIONS OF EVALUATIONS ......................................................................... 22 
7. 
MANAGEMENT OF ADVERSE EXPERIENCES .................................................................................... 23 
8. 
CRITERIA FOR INTERVENTION DISCONTINUATION...................................................................... 24 
9. 
STATISTICAL CONSIDERATIONS .......................................................................................................... 24 
9.1 
GENERAL DESIGN ISSUES ............................................................................................................................... 24 
9.2 
OUTCOMES ..................................................................................................................................................... 25 
9.3 
SAMPLE SIZE AND ACCRUAL .......................................................................................................................... 26 
9.4 
DATA MONITORING ........................................................................................................................................ 26 
9.5 
DATA ANALYSES ............................................................................................................................................ 27 
10. 
DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORTING ............ 29 

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10.1 
RECORDS TO BE KEPT/CASE REPORT FORMS ............................................................................................. 29 
10.2 
ROLE OF DATA MANAGEMENT .................................................................................................................. 30 
10.3 
QUALITY ASSURANCE ............................................................................................................................... 30 
10.4 
ADVERSE EXPERIENCE REPORTING .......................................................................................................        30 
10.5 
DATA SAFETY MONITORING BOARD (DSMB) ........................................................................................... 32 
11. 
HUMAN SUBJECTS ....................................................................................................................................... 33 
11.1 
INSTITUTIONAL REVIEW BOARD (IRB) REVIEW AND INFORMED CONSENT ................................................ 33 
11.2 
SUBJECT CONFIDENTIALITY ....................................................................................................................... 33 
11.3 
STUDY    MODIFICATION/DISCONTINUATION ........................................................................................................... 33 
12. 
PUBLICATION OF RESEARCH FINDINGS .............................................................................................. 33 
13. 
STUDY DISCONTINUATION CRITERIA .......................................................................................        33 
14. 
REFERENCES ................................................................................................................................................. 34 
15.    APPENDIX A: SCREENING AND ENROLLMENT LOG ......................................................................... 37 

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SYNOPSIS 
Study Title 
A randomized, parallel-group (autogenous ex vivo produced oral mucosa equivalent 
(EVPOME) vs. palatal oral mucosa (POM)), safety and efficacy study in subjects 
requiring additional keratinized oral mucosa for dental rehabilitation or around erupted 
teeth to restore periodontal health. 
Objectives 
The study objective is to assess the safety and efficacy for use of human EVPOME for 
soft tissue intraoral grafting procedures compared to the “gold standard” palatal oral mu- 
cosa (POM) graft. 
Design and Outcomes 
 
This is a randomized, parallel-group phase II study to assess EVPOME vs. POM to 
determine differences in the primary efficacy measure of increased keratinized mucosa; 
secondary measures of graft contracture and Wound Healing Index; and ancillary 
outcome measures of tissue perfusion measured graft color and laser Doppler flowmetry, 
and postoperative pain. 
 
Primary outcome measure: Clinical increase in zone (width) of keratinized mucosa 
(KM). For edentulous sites, KM width will be measured by determining the distance 
from the crest of the edentulous ridge to the mucogingival line to the nearest millimeter 
with a Castroviejo caliper. For patients with an existing implant, KM width will be 
measured from the implant mucosal margin to the mucogingival line. The amount of at- 
tached gingival tissue (keratinized) will be evaluated using a calibrated periodontal 
probe measured to nearest 0.5mm. 
 
Secondary outcome measures: Graft contracture will be measured in mesio-distal and 
corono-apical directions. Post-surgical measurements of the graft site will be taken at 
visits 5, 6, 7, and 8, and will be compared to the original graft size to assess percentage of 
graft contracture. Wound Healing Index (WHI) will be recorded after surgery using the 
following criteria: 
o Score 1= uneventful healing with no gingival edema, erythema, 
suppuration, patient discomfort, or flap dehiscence 
o Score 2 = uneventful healing with slight gingival edema, erythema, patient 
discomfort, or flap dehiscence, but no suppuration 
o Score 3 = poor wound healing with significant gingival edema, erythema, 
patient discomfort, flap dehiscence, or any suppuration 
 
Ancillary outcome measures: Laser Doppler flowmetry (LDF) measurements will be used 

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to assess graft blood flow (tissue perfusion of the grafts). 
 
Graft color is correlated to vascular perfusion and thus can give us an indication of graft 
vascularity. Finger pressure will be applied in the center of the graft for 15 seconds 
and/or until tissue blanching. The pressure will then be released and the time for the 
tissue to return to its previous color will be recorded. If the tissue returns to its previous 
color within 15 seconds, this will be recorded as positive graft vascularity. If not, then it 
will be recorded as negative graft vascularity. 
 
Overall postoperative pain will be assessed via a visual analog scale (VAS).  
Interventions and Duration 
The outcomes data in patients treated with experimental EVPOME soft tissue intraoral 
grafting procedure will be compared to the outcomes in patients treated with POM, which 
is the standard of care procedure. Those randomized to the experimental group will 
undergo a small 6mm palatal punch biopsy. Keratinocytes extracted from the punch 
biopsy will be harvested and expanded in vitro then seeded onto the AlloPatch®. This 
process will take approximately 30 days depending on the period of time needed for cell 
amplification. EVPOME or POM will then be grafted onto the oral defect and secured 
with absorbable sutures. At Week 4, after grafting, a 2 mm punch biopsy will be taken to 
assess degree and maturity of keratinization and microvessel ingrowth. 
 
Throughout the duration of the study, the subject will return for subsequent study visits to 
assess oral health and graft healing, contracture, and revascularization. The subjects will 
attend 7-8 scheduled study visits, one of which will be the grafting procedure, over a 
period of approximately 30 weeks. The post-operative follow-up period will include 5 
study visits over approximately 24 weeks. 
 
Sample Size and Population 
 
Sixty (60) subjects, thirty (30) subjects per treatment group, will be randomized to 
receive either the experimental treatment, EVPOME (Group 1), or standard of care, the 
palatal oral mucosa (POM) graft (Group 2). The study population will include non- 
smoking adults (ages 18 and older) in need of additional keratinized oral mucosa.  
 
Subjects will be recruited from UMHS through clinic referrals and the UMHS clinical 
research web portal for UMClinicalStudies as well as the University of Michigan (U-M) 
School of Dentistry, and their graduate periodontics clinic. Subjects may be also be 
recruited via Clinicaltrials.gov. 

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1. STUDY OBJECTIVES 
 
1.1Primary Objective 
 
To assess the safety and efficacy for use of human EVPOME for soft tissue intraoral 
grafting procedures compared to the “gold standard” palatal oral mucosa (POM) graft. 
 
Short-term impact: 
Regeneration of oral mucosal tissue has not been previously addressed in 
craniomaxillofacial soft tissue injuries. At present, there are no successful means of 
repairing or regenerating soft tissue structures that contain mucosa, such as oral mucosa, 
or facial tissue units with a muco-cutaneous (M/C) junction, such as the lip. Damage to 
these tissues may occur in active military personnel during military operations. The lack 
of sufficient mucosal tissue is a reconstructive challenge that limits the ability of  
surgeons to reconstruct the oral cavity and other functional facial units that contain an 
M/C junction, such as the lips. This reconstructive challenge is frequently encountered by 
surgeons who treat traumatic avulsion injuries. Tissue engineering/regenerative medicine 
(TE/RM) offers a unique opportunity to address such reconstructive challenges using an 
innovative application of our proven technology and the surgical procedures proposed in 
this application. 
 
The in vitro development of a tissue-engineered human oral mucosa is important because 
it can assist in intraoral reconstruction of the oral cavity and other mucosal structures 
such as the lips, eyelid, and anterior nares. For example, in the lip, the oral mucosa 
extends onto the vermillion border to unite with the skin of the face to form an M/C 
junction and is similar to the mucosa seen in the nasal cavity and inner aspect of the 
eyelid and the conjunctiva. Skin equivalents have been developed for treatment of burns 
and chronic wounds. The development of an ex vivo produced oral mucosal equivalent 
(EVPOME) has lagged behind that developed for skin. 
 
An impediment to clinical use of TE/RM has been the lack of clinical validation trials and 
development activities. These are necessary to accelerate the transition of medical 
technologies, clinical practice guidelines, and standards of care into clinical capabilities. 
The clinical trials must be relevant to the definitive and rehabilitative care for patients. Of 
special concern are the injured war fighters who must be returned to readiness in terms of 
duty performance and quality of life. We will address the rehabilitative-reconstructive 
deficiency of contemporary options to regenerate mucosa and M/C junction. The 
proposed clinical trial is a compelling step to a solution. 
 
Long-term impact and potential to change the standard of care: 
The ultimate source of the cells to develop the soft tissue constructs will come from the 
patient, thus making the construct autochthonous (self to self). There are several 
advantages of using a TE/RM approach to reconstruct craniofacial soft tissue injuries: 

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1) Reduced donor site morbidity (we do not have to use extremities as a tissue source 
thus shortening the rehabilitation phase); 
2) Improved restoration of function (rate and degree); 
3) Reduced frequency of surgeries and operating room time; 
4) Enhanced quality and shape of the regenerated soft tissue; and 
5) Decreased hospital personnel and cost. 
 
Potential to change the standard of care: 
The results from this study will provide information to plan a Phase III clinical trial 
which will utilize larger wounds. A Phase III study will simulate the repair of major 
maxillofacial soft tissue intraoral defects that are in need of keratinized oral mucosa and 
will include medically compromised patients. The ability to assess keratinocyte 
metabolic activity and function prior to grafting is an essential component to assure a 
higher graft success rate. The potential phase III clinical trial could shift paradigms in 
surgical reconstruction of avulsion injuries to soft tissues containing oral mucosa and 
functional facial units with a mucocutaneous border (lips). The trial will also assist in the 
validation of a method to fabricate composite soft tissue grafts that will supplant facial 
transplants that require lifetime immunosuppression. 
 
This Phase II clinical trial will be the first step in a paradigm shift on how soft tissue 
reconstruction of traumatic avulsion injuries of functional facial units will eventually be 
treated. 
 
2. BACKGROUND 
 
2.1 Rationale 
 
The need for improved technology for craniofacial reconstruction is extremely relevant to 
military patients considering the high prevalence of combat-related craniomaxillofacial 
(CMF) injuries. A recent study analyzed the Joint Theatre Trauma Registry database for 
maxillofacial battle-injuries (BI) experienced by U.S. soldiers in the Iraq/Afghanistan 
conflicts to describe the type, distribution, and mechanism of injury. The study identified 
7,770 BI of which 26% had maxillofacial involvement. The primary mechanism of injury 
was due to explosive devices (84%). 
 
The study concluded that Maxillofacial BI account for a disproportionate number of 
injuries observed in Iraq and Afghanistan compared to previous American wars. Thus, 
the focus of this study on soft tissue reconstruction is especially pertinent given the 
significant number of soft tissue penetration injuries from explosive devices. 
 
Craniofacial soft tissue defects that result from explosive munitions wounds to 
unprotected regions of the body, such as the face, present unique requirements among 
tissue engineering applications. Furthermore, the nature of explosive penetration wounds 
often creates extremely complex geometric and avulsion defects. The EVPOME 
technology will address these evocative challenges. 

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We can now fabricate human tissue-engineered oral mucosa (EVPOME). By conducting 
this planned Phase II clinical trial, we will improve and advance therapeutic technology 
for soft tissue craniofacial reconstruction which is profoundly relevant to military 
patients. The knowledge gained from this study will lead to a Phase III clinical trial 
where we will focus on larger maxillofacial intraoral defects that need oral mucosa. 
 
This project will also be synergistic with another Department of Defense (DoD) project 
recently awarded, “Tissue Engineering Lips for Use in Repair of CMF Soft Tissue 
Injuries.” One of the most difficult areas of the face to reconstruct after avulsion is the 
lips because they represent a composite tissue of mucosa, skin, and muscles. Significant 
loss of these structures is an obvious functional and esthetic concern because the 
neuromuscular control of normal lip structures is required for everyday activities of 
eating, drinking, talking, and social gestures. Avulsion of the lips is a survivable injury, 
but without functional lip reconstruction, life for these injured service members is 
burdened by drooling, food spillage while eating, unintelligible speech, and social 
rejection. Success of this study will enable movement of the “lip” project into the clinical 
arena sooner, as the methodology and protocols being used are quite similar. The success 
of the lip repair/reconstruction project is predicated by the ability to bring our tissue- 
engineered human oral mucosa into the clinical arena. Thus, this Phase II clinical trial 
will be a precursor for the successful implementation of a clinical trial for soft tissue 
reconstruction of the lips which incorporates the use of oral mucosa. 
 
 
2.2 Supporting Data 
 
A previous Phase I clinical trial demonstrated the safety and efficacy of EVPOME to 
increase keratinized gingival tissue without adverse events or local complications. This 
study achieved its main objectives and informed the design of the prospective clinical trial 
described here. For the phase I clinical trial, the researchers did not receive approval to 
have a control group (i.e, AlloDerm® without cultured primary oral keratinocytes), since 
the study was done to determine safety of the EVPOME and not efficacy. Thus, no post-
operative biopsy specimens were obtained to assess vascularization of the tissue or 
persistence of the grafted cultured cells. Also note that while the previous study was 
performed using AlloDerm® as the scaffold upon which the EVPOME is constructed, this 
study will use AlloPatch® which is very similar to AlloDerm®. AlloPatch® must be used 
in this study because AlloDerm® is no longer available. 
 
Previous studies showed that the grafted EVPOMEs had a deeper red hue than 
AlloDerm® grafts at post-operative day 6. This observation suggests that the grafted 
EVPOMEs revascularized faster than AlloDerm® grafts. In addition, there was histologic 
and immunohistochemical documentation of microvessel ingrowth into the underlying 
dermal component, AlloDerm®, of the EVPOME in a study of severe combined 
immunodeficient mice. It can therefore be reasonably stated that the grafted EVPOME 
had undergone revascularization by postoperative days 7 to 14. 

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The previously mentioned completed Phase I clinical trial was distinctive from other case 
studies using tissue-engineered products because it was conducted under our 
CBER/FDA-approved, investigator-initiated IND 10118. The IND required specific and 
rigorous cell testing and monitoring of the biologic product. Glucose consumption was 
selected as the functional test because it was considered a good indicator of the number 
of viable cells present on the EVPOME. Glucose consumption could detect cellular 
variations within EVPOME grafts, even in material from the same individual. As such, 
this functional test addresses the quality assurance/control and the release criterion 
mandated by CBER/FDA. 
 
Overall, the cell culture protocols used in this clinical trial proved to be acceptable, since 
all EVPOMEs were successfully grafted into subjects with no signs of morbidity and/or 
contamination. The release criterion of glucose consumption correlated well with 
histologic examination of the EVPOME. Results showed a direct correlation between 
glucose consumption and the presence of a well-stratified oral mucosa epithelial layer. 
Therefore, the glucose consumption testing for this protocol will be similar to that of the 
earlier phase I study under IND 10118. 
 
3. STUDY DESIGN 
 
This safety and efficacy study will be a single site, randomized, parallel-group 
autogenous ex vivo produced oral mucosa equivalent (EVPOME) vs. the “gold standard” 
palatal oral mucosa (POM), in subjects requiring additional keratinized oral mucosa.  
 
A total of sixty subjects will be randomized in a 1:1 ratio to autogeneous EVPOME vs. 
POM. If randomized to EVPOME, the subjects will be scheduled for a harvest biopsy 
(Visit 2 procedure). If randomized to the POM group, the subjects will be scheduled for 
the graft (Visit 3 procedure). See Table 1(Section 6.1) for the Schedule of Evaluations. 
Subjects will be non-smoking adults (18 years and older) needing increased keratinized 
oral mucosa. 
 
 
4. SELECTION AND ENROLLMENT OF SUBJECTS 
 
4.1 Inclusion Criteria 
 
4.1.1 Adults ages 18 years and older 
 
4.1.2 Deficient band (≤ 3 mm) of keratinized mucosa. 
 
4.1.3 Surgery to increase width of keratinized mucosa is clinically indicated or request- 
ed by the patient to facilitate oral hygiene procedures or to improve esthetics. 

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4.1.4 Patients must be able to understand and provide informed consent for participa- 
tion in the protocol. 
 
4.1.5 Patients in need of a graft measuring up to approximately 15 x 10 x 20 mm in di- 
mension. 
 
4.1.6 Women who test negative on a urine pregnancy test. 
 
4.2 Exclusion Criteria 
4.1.1. Subjects with a known sensitivity to agents used in AlloPatch® production 
including: Gentamicin, Cefoxitin, Lincomycin, Polymyxin B, and Vancomycin 
 
4.1.2. Subjects with potential medical complications such as evidence of clinically sig- 
nificant (as defined by investigators) renal, hepatic, cardiac, endocrine, hematologic, 
autoimmune, or any systemic disease which may complicate execution of the proto- 
col and/or interpretation of results, i.e. interfere with wound healing or be a poor 
candidate for general anesthesia, uncontrolled diabetic, renal failure etc. 
 
4.1.3. Documented history of syphilis, HIV, Hepatitis B or C virus 
 
4.1.4. Pregnant women or women planning to become pregnant or unwilling to abstain 
or use double barrier contraceptives during the course of the study 
 
4.1.5. Known or suspected allergy to bovine (cow) protein or iodine 
 
4.1.6. Current radiation therapy or history of radiation therapy treatment to the intraoral 
donor biopsy site or recipient site for graft placement. 
 
4.1.7. Smoking or use of tobacco products within 6 months prior to screening (subjects 
who quit smoking > 6 months prior to screening will be considered former smokers) 
 
4.1.8. History of either alcohol or drug abuse in the past 5 years 
 
4.1.9. Participation in another clinical trial within 30 days of screening 
 
4.1.10. Subjects taking medications that can result in gingival enlargement/overgrowth 
(Cyclosporine, Dilantin, calcium channel blockers) 
 
4.1.11. Current use of a medication used to treat a thyroid disease. 
 
4.1.12. Current use of intravenous anti-resorptive therapies or a history of intravenous 
antiresorptive therapies during the past 5 years 
 
4.1.13. Prior successful or attempted graft placement at the study defect site 
 
4.1.14. Any physical or mental condition which in the opinion of the Investigator or 
Medical Monitor may interfere with the subject’s ability to comply with the study 
procedures 

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4.3 Study Enrollment Procedures 
 
The clinical treatment site will maintain a screening and enrollment log to track screen 
failures and enrollment (See Appendix A). A subject will not be screened until an 
Informed Consent Form has been signed. A subject’s reason for ineligibility and reasons 
for nonparticipation or withdrawal from the study will be documented for inclusion in the 
Trial Master File (TMF). 
 
Subjects who appear to meet the criteria for study participation will be informed of the 
study and, if interested, will review the study consent(s) with a qualified individual 
(approved by the PI to administer consent and listed on the Delegation of Authority Log). 
 
During the informed consent process, study staff will detail the study procedures to ensure 
that the subject understands the study procedures and what is involved prior to signing   
the informed consent document. Subjects will be informed that they can withdraw      
from the study at any time and receive alternative care outside of the study.            
Subjects will be afforded as much time as needed to make an informed decision regarding 
willingness to participate in the study. Additionally, the study staff will provide contact 
information and will be available to discuss any questions or concerns potential subjects 
may have. 
 
At the time of enrollment, immediately after written informed consent is obtained and 
before performing any study-related procedures, each subject will be assigned a unique 
sequential subject number for identification throughout the study by the study staff. This 
subject number will not be reused for any other participant in the study. 
 
Once a subject has successfully met all inclusion and exclusion criteria, the subject will 
be randomized using the random number generator in a 1:1 ratio to EVPOME or POM 
via the web-based Treatment Assignment Tool U-M (TATUM) to obtain the subject’s 
treatment assignment. The randomization schedule will begin with block sizes of 2, 4, or 
6. 
 
Upon randomization, an email will be sent to the Co-Investigator and/or any appropriate 
study staff. Randomization numbers will be assigned in the order in which subjects 
qualify for treatment, not in the order of study enrollment. 
 
 
5. STUDY INTERVENTIONS 
 
5.1 Interventions, Administration, and Duration 
 
5.1.1 Oral Examination 
 
Study investigators will examine the subject as part of a comprehensive oral 
examination to evaluate the mouth, jaw, and teeth to assure that there is no cancer 

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recurrence and to verify the absence of other pathology that would mitigate 
subject study inclusion (i.e. dental infection). 
 
5.1.2 Intraoral Photographs 
 
Study staff, or medical residents aiding study staff will collect intraoral 
photographs for each subject randomized. Photographs will be taken of the graft 
site at a standard magnification (1:1 ratio) so that they can be compared from visit 
to visit to assess percent keratinization and contracture. 
 
5.1.3 Laser Doppler Flowmetry (LDF) 
LDF measurements will be taken at post-grafting for assessment of tissue perfu- 
sion. 
 
Details of use and measurement of the LDF is described in Section 6.2.5. 
 
5.1.4 Dental Impressions of Maxilla 
 
All subjects will have an upper, maxillary, impression taken for a healing palatal 
stent that will be protective for the patient post-surgery at the graft donor site. 
 
5.1.5 Harvest Biopsy 
 
For subjects randomized to the EVPOME arm of the study, during visit 2, surgeon 
co-investigators will extract a single 6 mm circular punch biopsy for EVPOME 
manufacturing. Detailed handling of the EVPOME is described in Section 5.2. 
 
5.1.6 Biopsy and Specimen Handling 
 
All subjects will be prepped and draped in a sterile fashion prior to intraoral 
biopsies. Anesthesia will be obtained by local infiltrations and/or blocks, and 
tissue will be harvested using a 6 mm punch. If bleeding is not controlled under 
gauze tamponade, a hemostatic collagen sponge will be placed and a cyanoacrylic 
dressing will be applied topically over the wound. Subjects will be given routine 
post-operative instructions to include a prescription for analgesia. The 6 mm 
biopsy specimen will be placed in a specifically prepared transport medium 
containing 500.0 ml DPBS (Dulbecco’s Phosphate Buffered Saline) w/o Ca2+ or 
Mg2+ and containing 0.54 g D-Glucose, 62.5 mg Gentamicin and 500.0 µg 
Fungizone. The biopsy will be immediately delivered to the Clinical Tissue 
Manufacturing Laboratory (CTML) for oral keratinocyte dispersion and culture. 
The specimen will be labeled with pre-printed labels from the CTML with 
protocol number and subject study number. 

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5.1.5 Grafting 
 
After the subject is anesthetized, the surgical site will be prepared leaving the 
underlying periosteum intact. The EVPOME or POM grafts (harvested from the 
palate at this same visit) will be sutured and assessed to assure they are immobile. 
Patients will be given standard post-operative instructions, analgesics, and 
antibiotics per standard of care. 
 
5.1.6 Assessment of Graft Contracture 
 
At each follow-up visit, the percent (%) graft contracture will be determined by 
linear measurements taken from the periphery of the standardized size graft. 
 
5.1.7 Study Laboratory Evaluations 
 
Histology and immunohistochemistry will be performed on each 2 mm circular 
graft biopsy taken at Week 4 at the site after laser Doppler measurement has been 
taken. Histology will consist of standard hematoxylin and eosin stain, while im- 
munohistochemistry will be used to assess microvessels within the dermal matrix. 
 
5.1.8 Observation 
 
At each follow-up visit, the percent (%) epithelial coverage will be determined by 
linear measurements taken from the periphery of the graft. 
 
5.1.9 Postoperative pain 
 
Pain following the grafting procedure will be evaluated using a visual analog 
scale (VAS) at the time of palatal biopsy for the EVPOME and at the time of har- 
vesting and grafting of the POM grafts. 
 
5.1.10 X-rays/radiographs 
 
If a current panoramic radiograph or full mouth series of periapical radiographs 
are not available, new ones will be obtained. Close proximity of the mental nerve 
canal, periapical (endodontic) lesions or other pathologies to the anticipated sur- 
gical site may contradict surgery. Radiographs taken in the past two years are suf- 
ficient to determine if surgery is contradictory. 
 
 
5.2 Handling of Study Interventions 
All of the AlloPatch® used in this study will be procured and stored by UM 
Clinical Tissue Manufacturing Laboratory (CTML) for use on this study. When 
subjects are randomized to EVPOME arm, AlloPatch® will be available to the 
study team in the Clinical Tissue Manufacturing Laboratory where EVPOME 
manufacturing will take place. 

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For subjects randomized to the EVPOME arm of the study, during Visit 2, 
surgeon co-investigators will extract a single 6 mm circular palatal punch biopsy 
for EVPOME manufacturing. I n  t h e  c a s e  i n  w h i c h  t h e  s u b j e c t  
w e a r s  a n  u p p e r  p r o s t h e s i s  t h e  h a r v e s t  b i o p s y  w i l l  b e  
t a k e n  f r o m  t h e  r e t r o m a n d i b u l a r  t r i g o n e  r e g i o n  i n  t h e  
m a n d i b l e .  A member of the EVPOME manufacturing team will provide 
pre-labeled transportation vessels, a primary vessel containing transportation 
media in which the biopsy will be placed, and a secondary containment vessel 
into which the primary transportation vessel will be placed. 
 
The surgeon and the EVPOME manufacturing technician will document the chain 
of custody by completing the transportation of punch biopsy record. The 
manufacturing technician will transport the biopsy and record to the Clinical 
Tissue Manufacturing Laboratory and begin EVPOME manufacturing. EVPOME 
manufacturing procedures provide detailed instructions for the manufacture, 
control, and release of the EVPOME product. 
 
On the day that the EVPOME engraftment is to occur, the Principal Investigator, 
Dr. Feinberg, or the Clinical Tissue Manufacturing Laboratory Manager will 
review the EVPOME manufacturing records and determine if the EVPOME 
meets required specifications (passing the sterility tests and satisfying the release 
criterion of glucose consumption over the last 24 hours) for engraftment. If the 
EVPOME is released by the Principal Investigator or the CTML Manager, the 
certificate of analysis is signed. The manufacturing staff will then transport the 
EVPOME to the surgeon in the surgical suite and attain site staff signature of 
receipt. If the EVPOME is determined to be unsuitable for engraftment, then 
there are two paths of accountability for the unused EVPOME. One of the 
following two paths will be used and documented on the EVPOME certificate of 
analysis: 
 
1. The informed consent document allows research subjects to opt-in or opt- 
out of allowing excess tissues and EVPOME devices to be transferred to a 
University of Michigan tissue repository held by Dr. Feinberg (IRB 
approved HUM00035831). If a subject opts-in, then their unused cells 
and EVPOMEs will be de-identified, labeled, and transferred from the 
Clinical Tissue Manufacturing Laboratory to the Medical Science 
Research Building II where the PI, Dr. Stephen Feinberg, has a research 
laboratory and the oral mucosa bank is housed. 
 
2. If a subject opts-out, then their excess cells and EVPOMEs will be 
destroyed as biohazard waste by processing in an autoclave. 
 
 
 
5.3 Concomitant Interventions 
 
5.3.1 Required Interventions 

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All standard surgical and post-operative standard medications and therapies will 
be performed. 
 
5.3.2 Prohibited Interventions 
 Consumption of alcohol or use of alcohol-containing products 
 Smoking 
 Other interventions which may be questionable for use should be dis- 
cussed with the Principal Investigator and/or surgeon prior to use, if able. 
 
5.4 Adherence Assessment 
 
During each post-surgery visit, study subjects will be questioned on adherence to post- 
operative guidelines including dental hygiene, alcohol consumption, and smoking 
abstinence to assess correlation of these factors with graft contracture and 
revascularization. 
 
 
6. CLINICAL AND LABORATORY EVALUATIONS 
 
A defined table of study procedures by visit is listed in section 6.1. A narrative of these 
evaluations is described in section 6.2. 

 
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6.1 Schedule of Evaluations 
 
Procedure 
Visit 1 
Screening 
Visit 2 
Harvest 
Biopsy 
Visit 3 Base- 
line 
Intra-oral 
Graft 
Visit 4 Post- 
Op 
Visit 5 
Follow-up 
Visit 6 
Biopsy and 
Follow-up 
Visit 7 
Follow-up 
Visit 8 
End of Study 
Timeline (in reference to baseline) 
-1 to 
-90 days 
-2 to 
-40 days 
Day 0 
Week 1 +/- 
3 days 
Week 2 +/- 3 
days 
Week 4 +/- 1 
week 
Week 8 +/- 1 
week 
Week 24 +/- 
1 week 
Informed Consent and 
Inclusion/Exclusion 
X 
Urine Pregnancy Test 
*females of child bearing potential only 
X 
Randomization 
X 
Medical/Dental History 
X 
X-rays (if none have been taken in the 
past two years) 
X 
Oral Examination 
X 
X 
X 
X 
X 
X 
Pain Visual Analog Scale (VAS) 
X 
X 
X 
X 
X 
X 
X 
X 
Clinic Assessments* 
X 
X 
X 
X 
X 
Intraoral Photographs 
X 
X~ 
X 
X 
X 
X 
X 
X 
Dental Impressions 
X 
Tissue Harvest Biopsy~ 
X~ 
Graft Placement 
X∞ 
Graft Biopsy 
X 
Laser Doppler Flowmetry (LDF) 
X 
X 
X 
X 
Laboratory Evaluations+ 
X 
Assess Adverse Events 
X 
X 
X 
X 
X 
X 
X 
Follow-up phone calls will occur at 9 and 12 months post-grafting. 
*Clinic assessments may include: PPD, CAL, BOP, Mobility, keratinization, graft contracture, graft color, wound healing index, 
~Harvest biopsy will be performed only on subjects randomized to the experimental EVPOME arm of the study 
+Laboratory evaluations include: histology, immunohistochemistry 
∞ At this time the POM graft will be harvested from the donor palatal site and grafted to the recipient site 

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6.2 Evaluation Schedule 
 
6.2.1 Visit 1 Screening 
Subjects will be recruited through the Patient Admitting and Emergency Services 
(PAES) clinic in the U-M School of Dentistry in conjunction with MCOHR. All 
new patients are routed through PAES and assigned to specialty or undergraduate 
clinics. Most patients do not return to the PAES clinic, so we are not likely to have 
redundancy. PAES had 13,100 visits in 2003. It is estimated that 40% of the 
western population is missing 1 or more teeth (50% to be restored with implants 
for our purposes). Approximately 1/3 of them are in need of soft tissue oral 
mucosa grafts which is a very common procedure. This will give us a population 
from which to draw approximately 865 new patients per year. Of this group we 
need to recruit 60 subjects over two years from a potential pool of 1,730 patients. 
With an estimated enrollment of 1 out of 4 screened patients, we should have a 
pool of over 400 patients per year from which to select 30 subjects. Subjects will 
be recruited by full-time faculty members in the Department of Periodontics at the 
U-M School of Dentistry. 
 
Informed consent will be obtained from each subject before any study-related 
procedures are performed. Screening and consenting procedures will be 
performed by the study staff on site at the clinic. 
 
During the consenting process, the study staff will allow time for the subject to 
review the Informed Consent Form, ask questions, and make an informed 
decision (i.e. allow the subject to discuss with family etc.). 
 
If the subject is willing and able to consent, the study staff will perform the study- 
specific procedures and evaluations to determine eligibility. Determination of 
eligibility will include review of subject-reported medical and dental history, an 
oral examination, and x-rays, if necessary. Subject weight will also be collected. 
 
Medical and dental history will be questioned to determine any history of special 
conditions that may affect the subject during the study and its associated 
procedures. Potential study contraindications may include history of heart disease, 
relevant allergies, or the use of medications such as blood thinners. Concomitant 
medications will be updated throughout the trial. A visual analog scale of pain 
will be taken at this time for both group I and II, 
 
Women of childbearing potential must agree to use a medically acceptable means 
of birth control and test negative on the Screening Visit urine pregnancy test. 
Intraoral photographs will also be taken. 
 
Lastly, upper and lower jaw impressions will be taken for stent fabrication to 
protect the donor site and for use in LDF measurements 

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Subjects randomized to Group 1 (EVPOME), will be scheduled for Visit 2 to 
undergo a palatal punch biopsy/tissue harvesting which will be the source of 
autogenous cells used to make the cellular component of the EVPOME, within 14 
days of determination. Subjects randomized to Group 2 (POM) will bypass Visit 2 
and proceed to scheduling of harvesting of palatal donor tissue graft and intra-oral 
grafting at recipient site (Visit 3) upon completion of screening procedures. 
 
 
6.2.2 Visit 2: Harvest Biopsy (EVPOME group only) 
At this time, a 6 mm in diameter supra-periosteal circular  biopsy will be 
harvested for fabrication of the EVPOME from Group 1 subjects. Co- 
Investigators will perform the biopsy procedure. This biopsy will be performed at 
the school of dentistry research clinic. Intraoral photographs will also be taken at 
this time. A stent will be placed at this time if needed. 
 
Biopsy procedures: All subjects will be prepped and draped in a sterile fashion 
prior to intraoral biopsies. Anesthesia will be obtained by local infiltrations and/or 
blocks. Tissue will be harvested using a 6mm punch. If bleeding is not controlled 
under gauze tamponade, a hemostatic collagen sponge will be placed and a 
cyanoacrylic dressing will be topically applied over the wound. Subjects will be 
given routine post-operative instructions to include a prescription for analgesia. 
 
Specimen handling: The 6 mm biopsy specimen will be placed in a specifically 
prepared transport medium, containing 500.0ml DPBS (Dulbecco’s Phosphate 
Buffered Saline) w/o Ca2+ & Mg2+ containing 0.54 g D-Glucose, 62.5 mg 
Gentamicin and 500.0 µg Fungizone. The biopsy is immediately delivered to the 
CTML for oral keratinocyte dispersion and culture. The specimen will be labeled 
with pre-printed labels from the CTML with protocol number and subject study 
number. 
 
A visual analog scale of pain will be taken at this time for group I and subjects 
will also be questioned about any adverse events. 
 
 
6.2.3 Visit 3: Baseline: Intraoral Grafting of EVPOME or POM Grafts 
Grafts will be applied as determined by the randomization schedule. Group 1 
subjects will undergo intraoral grafting of EVPOME and Group 2 subjects will 
receive POM that will be harvested at this time from the donor site, palate. For 
Group 1 subjects, before release of the EVPOME for grafting from the CTML, 
glucose utilization will be measured and determined as percent of glucose utilized 
by the EVPOME during the final days of laboratory incubation. Gram stain 
analysis will be performed on culture media that the EVPOME was grown in 
during the final day of incubation. Preliminary results of in-process sampling to 
determine the sterility (aerobic, anaerobic, and fungal cultures) of the product will 

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be reviewed. Results of in-process mycoplasma testing will be 
reviewed. Analysis of in-process sampling for endotoxin will also be reviewed. If 
the device fabrication is unsuccessful, the subject will be given the opportunity to 
have a second palatal or retromandibular trigone (location is at the discretion of 
the principal investigator and the surgeon) biopsy taken for production of another 
EVPOME device. 
Every effort will be made to maintain contact with the subject for safety data 
should the subject decline a second biopsy and withdraw from the study to pursue 
standard of care treatment. It is important to note that in our completed Phase I 
clinical trial we did not have to abort any procedure because of in-processing 
difficulties in not achieving our release criteria of passing the sterility tests and 
satisfying glucose consumption over the last 24 hours. Samples of spent media 
that the EVPOME was grown in may be stored and analyzed for proteins or other 
cell secretions in order to better understand graft success or failure. 
 
EVPOME and POM grafts will be sutured and assessed to assure they are 
immobile. Subjects will be given standard post-operative instructions which may 
include analgesics and antibiotics per standard of care. 
 
Intraoral photographs will also be taken at this time. A maxillary stent will be 
placed at this time for the POM subjects. 
 
A visual analog scale of pain will be taken at this time for both group I and II and 
subjects will also be questioned about any adverse events. 
 
 
 
6.2.4 Visit 4: Post-operative (Post-grafting) 
Routine post-operative visits at Week 1 +/- 3 days post-grafting will include an 
oral examination.  Intraoral photographs will also be taken at this time. A visual 
analog scale of pain will be taken, and subjects will also be questioned about any 
adverse events. 
 
 
6.2.5 Visit 5: Post-operative (Post-grafting) 
Routine post-operative visits at Week 2 +/- 3 days post-grafting will include an 
oral examination and clinical assessments, including degree of epithelialization 
and percent contracture. 
 
Measurement of the maximum distance between the peripheral borders of the 
graft in both the x and y axis will be taken to assess percent of graft contracture. 
Laser Doppler flowmetry measurements will be taken with the pre-fabricated 
template at the approximate geometric center of the graft and on the contralateral 
side of the jaw as the graft placement. This will be done after stent removal.per 
this protocol: 
 
LDF measurements will be with the subject resting in supine position, and at a 

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room temperature. A flexible probe (PR407, Perimed) will be used to obtain the 
measurements. The flowmeter will be calibrated before taking any measure- 
ments. Gingival blood-flow data will be reported in perfusion units (PU) and col- 
lected on the wideband setting. Voltage output values will be stored on an en- 
crypted PC computer for storage and subsequent analysis. 
 
Intraoral photographs will be taken. A visual analog scale of pain will be taken, 
and subjects will also be questioned about any adverse events. 
 
 
6.2.6 Visit 6: Clinical Assessment and Biopsy of Grafts 
Visit 6 will occur 4 weeks after the graft procedure +/- 3 days. Grafted sites of all 
subjects will be evaluated through clinical observation and photographs. 
Measurement of the maximum distance between peripheral margins of the grafts 
will be taken to assess degree of contracture as performed previously in Visit 5. 
Three variables of keratinization, contracture and micro-vascularization will be 
evaluated to assess outcomes 
 
A 2 mm biopsy of the central portion of the surface of the graft will be obtained 
for evaluation, under local anesthesia, after the LDF measurements have been 
completed. Histology and immunohistochemistry evaluations will be performed 
on the biopsied tissue. Intraoral photographs will be taken. We expect that the 
EVPOME will have a higher number of microvessel ingrowth at the early stages 
after grafting compared to the POM. We also expect that epithelium will be 
present and will mature at an earlier stage after grafting compared to the POM. 
 
Rationale for selection of 4 weeks for timing of biopsy: The first 2 weeks after 
grafting, a pressure dressing (surgical stent) is in place. At 3 weeks, the overlying 
mucosa is immature and friable. Based on previous experience, four weeks is the 
earliest time period we can detect a mature graft. If a graft fails, it will do so 
within the first 4 weeks. This supports the rationale for selection of this time 
period. Previous clinical studies took the biopsy at 6 months. We believe this time 
period is too far beyond the surgery date and would diminish the differences seen 
between the two types of grafts. The EVPOME graft is approximately 0.75- 
1.0 mm thick. It has been previously shown that it takes 10-11 weeks for a free 
mucosal graft of this thickness to reach maturity. Others showed that in 4 weeks, 
free grafts are keratinized. 
 
Intraoral photographs will also be taken at this time. A visual analog scale of pain 
will be taken, and subjects will also be questioned about any adverse events. 
 
 
 
6.2.7 Visit 7: Clinical Assessment 
A clinical assessment and oral examination visit to measure subject comfort and 

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progress will be scheduled at Week 8 +/- 1 week. This visit will also include 
measurements for degree of graft contracture, as well as other periodontal 
measures for adjacent teeth and implant (if present). Intraoral photographs will be 
taken. A visual analog scale of pain will be taken, and subjects will also be 
questioned about any adverse events. 
 
 
 
 
6.2.8 Visit 8: Clinical Assessment and End of Study 
A clinical assessment and oral examination visit will be performed to measure 
subject progress at Week 24 +/- 1 week (6 months). This visit will also include 
measurements for degree of graft contracture, as well as periodontal measures for 
adjacent teeth and implants (if present).  Intraoral photographs may be taken at 
the investigator’s discretion. A visual analog scale of pain will be taken, and 
subjects will also be questioned about any adverse events. At this time point, the 
subject’s participation in this study will be completed. 
 
6.2.9 Long-term Follow-up 
 
At 9 and 12 months, the subject will be phoned to discuss any Adverse Events or 
concerns with the graft site. At approximately 12 months, the subject will return 
for a standard of care visit and clinical examination with their primary oral sur- 
geon/restorative dentist for further dental rehabilitation. Any issues with the study 
graft will be recorded in the patient dental records. 
 
 
6.2.10 Early Withdrawal/Study Discontinuation Evaluations 
 
Upon discontinuation, subjects will be evaluated following the Visit 8/ End of 
Study procedures listed in the Schedule of Evaluations (Table 1, Section 6.1). 
 
 
6.2.11 Off-Study Requirements 
Subjects who discontinue early from the study for any reason after Visit 3 will be 
asked to return to perform study procedures as described in Visit 8/End of Study 
All subjects who discontinue or complete the study will also be asked to report 
any Serious Adverse Events that occur within 30 days of completion/withdrawal 
from the study. 
 
6.2.12 Pregnancy 
Subjects who become pregnant will be followed until pregnancy completion and 
reported as per FDA reporting guidelines. 

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6.2.13 Adverse Events 
Adverse Events will be assessed during all On-Study/On-Intervention Evaluation 
visits. 
 
 
6.3 Special Instructions and Definitions of Evaluations 
 
 
6.3.1 Informed Consent 
 
The subject will be provided and allowed time to review the study informed 
consent form as outlined in the study Manual of Procedures and as described in 
section 6.2.1. 
 
6.3.2 Documentation of Degree of Inefficient Zone of Keratinized Oral Mucosa 
 
The study subject source documents will document the need for additional zone of 
keratinized oral mucosa for each subject. We will use a standard trapezoidal graft 
measuring up to approximately 15 x 10 x 20 mm for both arms of the study. 
 
6.3.3 Medical History 
 
The subject Medical and Dental history will be questioned and documented by the 
subject’s recollection of history. Source documentation from hospital records may 
be collected and reviewed to determine subject eligibility or for 
inclusion/exclusion criteria. 
 
6.3.4 Study Intervention Modifications 
 
Any Study Intervention Modifications must be discussed with the Medical 
Monitor prior to implementation unless changes are required due to emergency 
needs of the subject. All modifications must be reported to the Medical Monitor 
within 24 hours of occurrence if not prior to the event. All study intervention 
modifications will also need to be reported to the IRB and FDA (if required per 
21 CFR 312.30) prior to the change being made unless the change is intended to 
eliminate an apparent immediate hazard to the subjects. 
 
6.3.5 Clinical Assessments 
 
Clinical assessments include width of keratinized mucosa (KM) as determined by 
the distance between the crest of the edentulous ridge,  the gingival margin of the 
tooth, or the implant mucosal margin and the mucogingival line to the nearest 
millimeter, graft contracture, graft color as determined by assessing tissue 
perfusion, postoperative pain, Wound Healing Index (WHI), color of graft tissue 
compared to surrounding 

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non-grafted tissue, and oral care follow-up. These assessments will be performed 
at post-operative visits 5, 6, 7 and 8. Periodontal measures include Periodontal 
Pocket Depth (PPD – measured from gingival margin to base of periodontal 
pocket to nearest millimeter ), gingival recession measured from cemento-enamel 
junction on tooth to gingival margin, Clinical Attachment Level (CAL- 
determined by subtracting the gingival recession from PPD), and bleeding on 
probing (BOP) determined as present (1) or absent (0), 
 
Visual analog scale for pain will be assessed for groups, I (at time of harvest of 
biopsy and EVPOME placement) and group II at time of harvesting of palatal 
donor graft and grafting at recipient site. 
 
6.3.6 Laboratory Evaluations 
Histology and immunohistochemistry evaluations will be performed on tissue 
collected via the Visit 6 biopsy. Histology will consist of standard hematoxylin 
and eosin stains to assess presence and maturity of the epithelial layer, while 
immunohistochemistry will assess the endothelial cells in microvessels within the 
dermal component. 
 
6.3.7 Intraoral Photographs 
 
Standardized intraoral photographs will be taken at each visit. 
 
6.3.8 X-rays 
 
If a current panoramic radiograph or full mouth series of periapical radiographs 
are not available, new ones should be obtained. Close proximity of the mental 
nerve canal, periapical (endodontic) lesions or other pathologies to the anticipated 
surgical site may contradict surgery. Radiographs taken in the past two years are 
sufficient to determine if surgery is contradictory. 
 
 
7. MANAGEMENT OF ADVERSE EXPERIENCES 
Expected, mild and routine adverse experiences including swelling, bruising, bleeding at 
the site, numbness at the site, lack of sensation, pain associated with the grafting site and 
lack of adherence of the graft after stent removal will not be considered adverse events, 
unless the magnitude or duration is greater than what is routinely expected. These events, 
however, will be documented in the medical record.  If the magnitude or duration is 
greater than what is routinely expected, the experience will be considered an adverse event 
and will be recorded on the Case Report Form. Serious, expected and unexpected  
(serious or not serious) adverse events will be collected at every study visit and recorded 
on the Case Report Forms.” 
Quality Control procedures at the CTML will be in place to reduce the likelihood of 
EVPOME contamination. Comprehensive post-operative oral care instructions will be 

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distributed to study subjects. Adverse events will be reported as described in Section 
10.4. 
 
Possible risks to the subjects participating in this study include: 
 Pain, swelling, numbness or discomfort from the biopsy of the roof of the mouth 
 Contamination of the graft 
 Graft failure 
 Pain at the surgical site 
 Possible unforeseeable harm to pregnant women, the embryo, or fetus 
 Allergic reaction to the reagents used in the development of the EVPOME 
 
 
8. CRITERIA FOR INTERVENTION DISCONTINUATION 
 
Subjects who are diagnosed with HIV, cancer requiring radiation therapy, etc. will be 
discontinued from the study. 
 
Those subjects who are discontinued will be asked to return for a final End of Study sub- 
ject visit as described in Visit 8 study procedures. 
 
9. STATISTICAL CONSIDERATIONS 
 
9.1 General Design Issues 
 
This is a randomized, parallel-group (autogenous ex vivo produced oral mucosa 
equivalent (EVPOME) vs. palatal oral mucosa (POM)) safety and efficacy study in 
subjects requiring additional keratinized oral mucosa for dental rehabilitation. The 
primary hypothesis is that EVPOME is an equivalent intraoral grafting material when 
compared to POM in regards to keratinized tissue and graft contracture, but is superior to 
POM in regards to pain, color rendition, and microvessel infiltration. 
 
The comparison will be done using primary efficacy measures of enhanced keratinization, 
and secondary measures of graft contracture and wound healing index, and ancillary 
measures of increased microvessel ingrowth. Clinical assessments will include 
postoperative pain. Intraoral photographs will be done at screening and at biopsy, 2, 4, 8, 
and 24 weeks after intra-oral grafting. Tissue biopsy will be conducted at week 4 and 
laser Doppler flowmetry at weeks 2, 4, 8, and 24. Primary assessment time will be at 
week 4, and final assessments for all subjects will be at week 24. 
 
Subjects will be screened until we have the necessary 60 enrolled. It is likely there will be 
4 screened subjects to 1 enrolled subject. All subjects will undergo informed consent prior 
to any screening procedures. It is expected that it will take 2.5 years to successfully enroll 
60 patients. Subjects will be recruited through the Patient Admitting and Emergency 
Services (PAES) clinic in the U-M School of Dentistry in conjunction with          
MCOHR. All new patients are routed through PAES and assigned to specialty or 

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undergraduate clinics. Most patients do not return to the PAES clinic, so we are not likely 
to have redundancy. PAES had 13,100 visits in 2003. It is estimated that 40% of the 
western population is missing 1 or more teeth (50% to be restored with implants for our 
purposes). Approximately 1/3 of them are in need of soft tissue oral mucosa grafts which 
is a very common procedure. This will give us a population from which to draw 
approximately 865 new patients per year. Of this group we need to recruit 60 subjects 
over two years from a potential pool of 1,730 patients. With an estimated enrollment of 1 
out of 4 screened patients, we should have a pool of over 400 patients per year from which 
to select 30 subjects. Subjects will be recruited by full-time faculty members in the 
Department of Periodontics at the U-M School of Dentistry. 
 
9.2 Outcomes 
 
9.2.1 Primary outcome 
 
The primary outcome will be clinical increase in zone (width) of keratinized mu- 
cosa (KM). For edentulous sites, KM width will be measured by determining the 
distance from the crest of the edentulous ridge to the mucogingival line to the 
nearest millimeter with a Castroviejo caliper. For patients with an existing im- 
plant or tooth, KM width will be measured from the implant mucosal or tooth 
margin to the mucogingival line. 
 
 
 
9.2.2 Secondary outcomes 
The secondary outcome will include percent graft contracture and wound healing 
index. Graft contracture will be measured in mesio-distal and corono-apical 
directions. Post-surgical measurements of the graft site will be taken at visits 5, 6, 
7, and 8 (Weeks 2, 4, 8, and 24), and will be compared to the original graft size to 
assess percentage of graft contracture. Photographs of the surgical site will be 
taken. 
 
Wound Healing Index (WHI) will be recorded after surgery using the following 
criteria: 
o Score 1= uneventful healing with no gingival edema, erythema, 
suppuration, patient discomfort, or flap dehiscence 
o Score 2 = uneventful healing with slight gingival edema, erythema, patient 
discomfort, or flap dehiscence, but no suppuration 
o Score 3 = poor wound healing with significant gingival edema, erythema, 
patient discomfort, flap dehiscence, or any suppuration 
 
 
9.2.3 
Ancillary outcomes 
Ancillary outcome will include assessment of blood flow (tissue perfusion of the 
grafts) via laser Doppler flowmetry (LDF) evaluation, graft color, postoperative 

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pain, histology, and immunohistochemistry (IHC) to evaluate graft 
revascularization. 
 
Graft color is correlated to vascular perfusion and thus can give us an indication 
of graft vascularity. Finger pressure will be applied in the center of the graft for 
15 seconds and/or until tissue blanching. The pressure will them be released and 
the time for the tissue to return to its previous color will be timed. If the tissue 
returns to its previous color within 15 seconds, this will be recorded as positive 
graft vascularity. If not, then it will be recorded as negative graft vascularity. 
 
Overall postoperative pain will be assessed via a visual analog scale (VAS). 
 
9.3 Sample Size and Accrual 
 
We propose to have 60 subjects to give clinical and histological endpoints of interest at 
the primary assessment time of 4 weeks post graft. We expect no more than 6 subjects to 
potentially drop out of the study before providing Week 4 data, and thus will enroll 66 
patients in total. With an estimated enrollment of 1 out of 5 screened patients, we expect 
to have a pool of over 330 patients over two years from which to select 66 subjects (33 
subjects per group over two years) that will be randomized equally to one of the two 
groups - EVPOME and POM grafts. The randomization list will be prepared 
electronically in advance by the biostatistician and transferred to the MICHR statistics 
group for incorporation into the TATUM system. Randomization will be stratified by 
smoking status. 
 
The primary clinical endpoint is the degrees of keratinized tissue. Secondary outcomes 
are contracture and wound healing index. Ancillary endpoints include the presence or 
absence of a continuous epithelial layer, the degree of vascular ingrowth, the LDF meas- 
urement of gingival blood flow. The main aim is to show that EVPOME treatment give 
comparable clinical and histological results when compared with POM treatment. It is 
also expected that the EVPOME will cause less patient discomfort and pain, and have a 
better color rendition to the surrounding tissue than the POM. Hence, we expect 
EVPOME to show better outcomes for pain, color rendition, and microvessel infiltration 
than POM, while showing comparable outcomes on primary endpoints of keratinized tis- 
sue and graft contracture or histological endpoints compared with POM. Sample size is 
calculated to show near equivalence of the two groups for primary and secondary out- 
comes. Sample size calculation and power consideration are provided following the data 
analytic plan described for each outcome. 
 
 
9.4 Data Monitoring 
 
No interim data analysis is planned, but accrual rates and dropout rates will be monitored 
every 6 months. On-site data monitoring will occur at least annually. 

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9.5 Data Analyses 
 
The main aim of the study is to determine by quantitative outcome measures that 
EVPOME will function as well as POM in terms of increased epithelialized tissue, 
decreased contracture, and increased microvessel infiltration. It is also expected that the 
EVPOME will have a closer adaptation in color rendition to the surrounding tissue. Our 
primary comparisons will be based on the observations at four weeks post-graft. 
 
AIM 1 - Keratinized Tissue: Primary comparison will be based on week 4 assessment us- 
ing an equivalence test of means. Background data on measurements of keratinized tis- 
sue for POM (standard of care) gave a mean measurement of 3.70 mm with an SD of 0.65 
mm. The mean and SD were relatively constant over the follow up period from 3 to 12 
months. If, in this study, both EVPOME and POM give comparable results, the distribu- 
tion of the mean difference in keratinized tissue with 30 subjects in each arm will be ap- 
proximately normal with a mean of 0 and standard error of 0.17, and a 95% confidence 
interval for the true mean difference between the two procedures will have a margin of 
error of about 0.33 mm. This confidence interval will exclude a value for the mean dif- 
ference of 0.55mm or larger with probability at least 80%. Therefore sample size will be 
adequate to show near equivalence of the two treatments if the degree of keratinized tis- 
sue measurement of EVPOME is within ±0.55mm of POM. Statistical power will be 
even larger if non-inferiority of EVPOME to POM is desired, where true increase in ke- 
ratinized zone in EVPOME group is no less than 0.55 mm compared with the increase of 
zone of keratinized tissue in POM. 
 
AIM 2 - Shrinkage in Graft: The percent shrinkage (contracture) in graft will be ex- 
pressed as 100*(1- (Area final/Area Day0)), and the comparison will be based on week 4 
assessment using an equivalence test of means (with log transformation if the data are 
highly skewed upon visualization). Prior data for POM gave a mean shrinkage of 25% at 
4 weeks post-op with a standard deviation (SD) of about 13%. If shrinkage is about the 
same for both EVPOME and POM, with a sample size of 30 subjects in each group, this 
translates into an estimate of the mean difference with standard error of about 3.4%. This 
gives a margin of error of 6.6% for a 95% confidence interval, and the 95% confidence 
interval excluding a value for the mean difference in shrinkage as large as 11% with 
probability of 80%. 
 
Wound Healing Index (WHI): WHI will be analyzed via the following chart, and the in- 
dex will be tabulated by treatment group at follow-up visits 5, 6, 7, and 8. Depending on 
the observed distribution of the index, the data will either be dichotomized or considered 
as an ordinal data. 
 
Scores 
Criteria 
1 
Uneventful healing with no gingival edema, erythema, suppuration, 
patient discomfort, or flap dehiscence 
2 
Uneventful healing with slight gingival edema, erythema, patient dis- 
comfort, or flap dehiscence but no suppuration 

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Ancillary Outcomes: 
Histological Epithelial Coverage: The presence/absence of a continuous epithelialized 
tissue will be determined from the Week 4 biopsy using routine histology and staining. 
The percent of subjects with complete epithelialized layer between the two groups will be 
compared using non-equivalence of the two proportion test. If the EVPOME and POM 
groups give a common proportion of about 75% epithelial coverage, then the standard er- 
ror of the estimate of the difference between the EVPOME and POM groups is about  
11% based on 30 subjects per group. This gives a margin of error of about 22% for a 
95% confidence interval. The primary test will be based on a two-proportion test where a 
lower bound for the power can be determined by the power associated with binomial 
comparisons with n = 30 in each group. If the true epithelial coverage of 75% is assumed 
at 4 weeks, and if we consider that a difference in epithelial coverage as large as 36.5% in 
favor of POM would still allow the EVPOME to be non-inferior, the proposed sample size 
of 30 per group would give 80% power to confirm non-inferiority and a one-sided 
confidence level of 97.5%. 
 
Vascular Ingrowth: The degree of vascular in growth noted on the Week 4 biopsy 
specimen will be compared based on ordinal microvessel vascular in-growth from the 
IHC data. It is expected there will be utilization of the full range of the four point scale 
(labeled 1 through 4) and that a standard deviation of 1 unit might conservatively be 
expected. The margin of error for a 95% confidence interval will be 0.51 based on two 
sample sizes of 30 each. For the comparison between EVPOME and POM, the sample 
size will allow us to detect a difference as large as 0.72 units with 80% power using a 
0.05 level test. 
 
Laser Doppler Flow (LDF): LDF data will be compared based on gingival blood flow at 
Week 4 post-surgery at the graft site between the EVPOME and POM groups. One as- 
pect of this study will be to examine and explore the usefulness of this measure. In par- 
ticular, we will explore the use of control measures taken on normal tissue to help adjust 
for intra subject factors contributing to the variability. The primary investigation will 
compare gingival blood flow at the graft site at two weeks, four weeks, eight weeks, and 
24 weeks post-surgery to the values in an analysis of covariance (ANCOVA) model. 
The corresponding differences at the control site will also be incorporated as a covariate 
to partially adjust for intra-individual variability.  More detailed analyses will utilize 
ANCOVA methods for repeated measures. There is relatively little background data on 
the use of LDF to measure perfusion in the context being studied here though some pre- 
liminary data on measuring gingival blood flow can be found in Justus et al. where 
change in gingival blood flow from baseline to post surgery (over the period 7 to 
24 .days) was found to have a mean of about -25 perfusion units (PU) with an SD of 
about 60 PU. The measurement is highly variable. 
 
For repeatedly measured data such as pain and wound healing index, data will be 
3 
Poor wound healing with significant gingival edema, erythema, patient 
discomfort, flap dehiscence, or any suppuration 

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summarized by treatment groups at each follow-up time. In addition, linear mixed- 
effects models will be used to make the between group comparison while adjusting for 
potential within person correlation of the outcome variables. By using the modeling 
approach, it will be possible to incorporate all observations from both treatment groups 
and make between treatment group comparisons efficiently using a treatment dummy 
indicator. The model will allow us to not only compare the time-averaged means, but also 
allows us to explore the rate of decline between the EVPOME and POM groups such as 
the rate of decline in pain, using appropriate interactions terms. When appropriate, 
comparisons between treatments will be adjusted for surface area of the graft as well as 
measures of its geometry, and other variables including age, general health and alcohol 
use. 
 
 
10. DATA COLLECTION, SITE MONITORING, AND ADVERSE EXPERIENCE REPORT-  
ING 
 
10.1 Records to Be Kept/Case Report Forms 
 
Data for this study will include subject source data for all clinical data assessments as 
described in the protocol and subject safety and efficacy data. 
 Data will be stored in the study database and will be password 
protected. All research staff requiring access will be assigned a unique 
login name and password. 
 Data for subjects, including documentation of informed consent, will be stored 
in a locked area accessible only by study research personnel. 
 
The research team will develop paper Case Report Forms based on data collection 
requirements outlined in the protocol. These paper forms will serve as back-up to the 
electronic data entry screens that are created during development of the project database. 
The site coordinator will be responsible for completing paper forms and entering the 
results into the data management system. Alternatively, results may be entered directly 
into the project database via the data management system’s web-based interface. The data 
collection instruments will undergo internal quality checks, and review and acceptance 
testing prior to their release for use. Paper Case Report Forms will be maintained at the 
study site and stored in compliance with Good Clinical Practice and relevant institutional 
policies. 
Once completed, the study data will be archived in a secure location and documented by 
the Study Investigator. An Electronic Trial Master File (TMF) will be retained. All 
expected research data must be entered into the data management system and any data 
discrepancies resolved before the database is locked. Edit access to the study database will 
be restricted to read-only at this time. A read-only, time-stamped snapshot of the data will 
be created for analysis. Following data analysis, the database is frozen and access      
rights to the database are revoked. Only approved changes that significantly affect data 

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analysis are permitted once the database has been frozen. A snapshot of the frozen 
database is archived. Both the lock and freeze snapshots will be transmitted to the study 
team as password-protected files or via MiShare, a secure file transfer system supported 
by Medical Center Information Technology (MCIT). 
 
10.2 Role of Data Management 
The data management group will create a validated, 21CFR part 11 compliant database 
using the OpenClinica system. To ensure quality data, logic checks will be incorporated 
into the database. Discrepancy management will also be performed both manually and 
through the use of programmed validation checks within the system to ensure high 
quality data. Data extracts in the form of tables and reports will be exported from the 
database routinely to assess study progress, enrollment, safety, and efficacy. These 
reports are made available to the Investigator and the Statistician, as needed. 
 
10.3 Quality Assurance 
To ensure the highest level of data integrity and quality assurance, the study will be 
monitored by a qualified clinical trial monitor. 
The purpose of monitoring is to ensure that the rights and safety of the participants are 
protected and the study is implemented in accordance with the protocol, Good Clinical 
Practice, applicable federal and local regulations, and the quality and integrity of the 
study data are maintained. 
The clinical site monitoring plan will specify the frequency, procedures, levels of 
monitoring activities, and a monitoring communication plan. Monitoring activities will 
include the site initiation (pre-investigation) visit, interim site monitoring visits, and a 
close-out visit. The plan may also include for-cause visits. During the interim monitoring 
visits, the monitor will review participant medical and research records, consent 
documents, unanticipated problems, serious adverse events, site regulatory documents, 
etc. A summary of findings will be documented in a monitoring report and action items 
will be reviewed and followed until closed. Complete monitoring visit documentation 
will be provided to the study PI/Site PI and sponsor. 
A site initiation visit will be scheduled prior to site activation and enrollment, and interim 
site visits will occur at least annually. 
The sponsor or other regulatory officials may perform an audit or may accompany the 
clinical monitor on a monitoring visit. 
The Medical Monitor, Dr. Christos Skouteris, will be available to review significant 
protocol deviations and AEs/SAEs on a scheduled and as needed basis. 
 
10.4 Adverse Experience Reporting 
Adverse Events (AEs) other than routine, mild and expected experiences, either observed 
by the Investigator or one of his/her medical collaborators, or reported by the subject, will 
be documented.. These AEs will be followed until the event is resolved, until the event is 
deemed chronic, or until 30 days after the subject’s participation in the study has ended. 

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Expected, routine, mild adverse experiences include: lack of sensation, numbness, swell- 
ing, bleeding, and pain associated with the grafting site and lack of adherence of the graft. 
These adverse experiences will be documented in the medical record. 
Any Serious Adverse Event (SAE) that occurs must be reported to the University of 
Michigan IRB (IRBMED) according to the IRBMED reporting guidelines. Information 
about all SAEs is collected and recorded on the Serious Adverse Event Report Form. All 
pertinent medical records and information collected during the treatment and follow-up  
of the subject should be maintained. The Investigator must assess the SAE relationship to 
investigational product. All SAEs will be reported to the FDA in compliance with the 
FDA reporting requirements as found under 21 CFR 312.32. This includes reporting to 
the FDA all unexpected, fatal or life-threatening adverse events assessed as related to the 
product by telephone or fax within seven days and the reporting in writing of unexpected 
serious adverse events assessed as related to the product within 15 days. 
Expected Serious Adverse Events include allergic reaction, uncontrollable bleeding 
and/or pain or an infection requiring hospitalization. 
Any death occurring through the end of the study (30 days following the intervention), 
regardless of the degree of relationship to study, must be reported as a Serious Adverse 
Event. 
The investigator will submit an attribution for the relatedness of the adverse event to the 
test article or procedure. As far as possible, each AE should be evaluated to determine: 
 the severity grade (mild, moderate, severe); 
 its relationship to the study investigational product(s); 
 its duration (start and end dates or, if ongoing, at final exam); 
 action taken; and 
 seriousness (yes/no) 
The severity grade should be determined by the Investigator using the definitions below: 
 Mild: Discomfort noticed but no disruption of normal daily activity; 
 Moderate: Discomfort sufficient to reduce or affect normal daily activity; or 
 Severe: Inability to work or perform daily activity. 
The relationship of AEs to the investigational product should be determined by the Inves- 
tigator using the definitions below: 
 Definitely related: clearly associated with study drug/treatment; 
 Probably related: likely associated with study drug/treatment; 
 Possibly related: may be associated with study drug or other treatment; 
 Unlikely to be related; or 
 Definitely not related to the study drug/treatment. 

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For reporting purposes, an AE should be regarded as definitely or probably related to the 
regimen if the investigator believes that at least one of the following criteria are met: 
a. There is a clinically plausible time sequence between onset of the AE and 
the administration of the study drug or treatment; 
b. There is a biologically plausible mechanism for the study drug or 
treatment causing or contributing to the AE; 
c. The AE cannot be attributed solely to concurrent/underlying illness, other 
drugs, or procedures; or 
d. A potential alternative cause does not exist. 
Expected adverse events are those adverse events that are listed in the study informed 
consent documents. 
Unexpected adverse events are those that are not described in the study informed consent. 
This includes adverse events for which the specificity or severity is not consistent with the 
description in the informed consent. 
Should an unanticipated problem occur during the investigation, the investigator will 
report them to IRBMED, the FDA, and DOD according to the reporting requirements of 
each entity. 
An unanticipated problem is any incident, experience, or outcome that meets ALL three 
of the following conditions: 
1. Is unexpected (in terms of nature, severity, or frequency) given the procedures 
described in the research protocol documents (e.g., the IRB-approved research 
protocol and informed consent document) and the characteristics of the human 
subject population being studied; 
2. Is 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 
3. Suggests that the research places human subjects or others at a greater risk of harm 
(including physical, psychological, economic, or social harm) than was previously 
known or recognized, even if no harm has actually occurred. 
 
10.5 Data Safety Monitoring Board (DSMB) 
A DSMB will be chartered to assure adequate protection of research subjects. The 
board will review Serious Adverse Events and other pertinent data according to the 
DSMB charter on a regular basis throughout the study. The DSMB will be comprised 
of at least three members with expertise in the dental/medical field and experience in 
the conduct of clinical trials or statistical knowledge. DSMB members will not have 
any conflicts of interest with the study. 

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11. HUMAN SUBJECTS 
 
 
11.1 Institutional Review Board (IRB) Review and Informed Consent 
 
This protocol, the Informed Consent Form, and any subsequent modifications will be 
reviewed and approved by the IRB or ethics committee responsible for study oversight. 
A signed consent form will be obtained from the subject.  For subjects who cannot 
consent for themselves, such as those below the legal age, a parent, legal guardian, or 
person with power of attorney must sign the consent form. Additionally, the subject's 
assent must also be obtained if he or she is able to understand the nature, significance, 
and risks associated with the study. The consent form will describe the purpose of the 
study, the procedures to be followed, and the risks and benefits of participation. A copy 
of the consent form will be given to the subject, parent, or legal guardian, and this fact 
will be documented in the subject’s record. 
 
 
 
11.2 Subject Confidentiality 
 
All laboratory specimens, evaluation forms, reports, and other records that leave the site 
will be identified only by the Study Identification Number (SID) to maintain subject 
confidentiality. All records will be kept in a locked file cabinet. All computer entry and 
networking programs will be done using SIDs only. Clinical information will not be 
released without written permission of the subject, except as necessary for monitoring by 
IRB, the FDA, the OHRP, the sponsor, or the sponsor’s designee. 
 
11.3 Study Modification/Discontinuation 
 
The study may be modified or discontinued at any time by the IRB, the sponsor, the 
OHRP, the FDA, or other government agencies as part of their duties to ensure that 
research subjects are protected. 
 
12. PUBLICATION OF RESEARCH FINDINGS 
 
Publication of the results of this trial will be governed by the policies and procedures 
developed by the Executive Committee. Any presentation, abstract, or manuscript will 
be made available for review by the sponsor prior to submission. 
 
13. STUDY DISCONTINUATION CRITERIA 
 
Stopping Rules for Safety reasons: The Data Safety Monitoring Board (DSMB) will review all 
Serious Adverse Events (SAEs) and make recommendations regarding the continuation or dis- 

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continuation of the study, as appropriate. SAEs that may necessitate possible discontinuation in- 
clude: 
 Infection of the graft site reported in 5 experimental subjects. Subjects will be treated 
with antibiotics and followed until resolution of the infection. 
 Complete loss of the experimental graft occurring in 5 subjects 
 Severe or excessive oral bleeding in 5 experimental arm subjects requiring transfusion 
 Reported uncontrollable oral pain in 5 experimental arm subjects 
 
All subjects will be followed until resolution of the adverse event and will also be contacted 9 
and 12 months post-surgery to assess any possible long term safety issues. 
 
Should the study be stopped because of safety concerns, the FDA and IRB will be promptly noti- 
fied, and a comprehensive safety review will be initiated. 
 
 
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31. Sato M, Harada K, Okada Y and Omura K: Blood-Flow Change and Recovery of 
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Patent Application for an Invention Entitled: “Mucosal Cell Composites and Meth- 
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35. McGuire MK, Nunn ME: Evaluation of the safety and efficacy of periodontal appli- 
cations of a living tissue engineered human fibroblast-derived dermal substitute. I. 
Comparison to the gingival autograft: A randomized controlled pilot study. J Perio- 
dontol 76:867-880, 2005, 2005. 
 
36. Wei PC, Laurell L, Geivelis M, Lingen MW, Maddalozzo D: Acellular dermal matrix 
allografts to achieve increased attached gingiva. Part I. A clinical study. J Periodontol 
71:1297-1305, 2000. 
 
37. Yan JJ, Tsai AYM, Wong MY, Hou LT; Comparison of Acellular Dermal Graft and 
Palatal Autograft in the Reconstruction of Keratinized Gingiva Around Dental Im- 
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Keratinocyte-Derived Interleukin-8 Which is Chemotactic for Neutrophils and T 
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40. Dale BA, Kimball JR, Krisanaprakornkit S, Roberts F, Robinovitch M et al: Local- 
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41. Hata K, Kagami H, Ueda M, Torii S,Matsuyama M: The characteristics of cultured 
mucosal cell sheet as a material for grafting; comparison with cultured epidermal cell 
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Factor and Angiogenesis. Pharmacol Rev 56: 549-580, 2004. 

 
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Protocol Number: 
Investigator Name: 
Study Coordinator Name: 
 
Screening 
Number 
Date 
Screened 
(MM/DD/YY) 
Eligibility 
Criteria 
Met 
(Yes/No) 
Subject 
Initials 
Informed 
Consent 
Signed 
(Date or N/A) 
Copy to subject 
Version 
of 
Consent 
Surgeon 
Reason for 
Exclusion 
(Screen fail, refused to participate, etc.) 
Randomization 
Number 
Assigned 
Treatment 
 
Appendix A: SUBJECT SCREENING & ENROLLMENT LOG