A Multi-center Randomized Open-Label Controlled Clinical Trial Evaluating Suction Blister Grafting Utilizing a Novel Harvesting Device (CelluTome©) and Standard of Care vs. Standard of Care Alone in the Treatment of Venous Leg Ulcers
Phase: NA
Conditions: Impaired Wound Healing, Venous Insufficiency of Leg, Diabetic Ulcers
Sponsor: SerenaGroup, Inc.

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Protocol Title: A Multi-center, Randomized, Open-Label, Controlled Clinical Trial 
Evaluating 
Suction Blister Grafting Utilizing a Novel 
Harvesting Device 
(CelluTomeTM) and Standard of Care vs. Standard of Care Alone in the 
Treatment of Venous Leg Ulcers. 
 
 
 
Protocol Number: 
CELLUTOMETM-VLU-013 
Version Number: 
Version 1; Rev 3 
Version Date 
February 21, 2017  
Indication: 
Venous Leg Ulcer 
Development Phase: 
Post market 
Device under study: 
CelluTomeTM Epidermal Harvesting System 
Comparator: 
Standard of care 
Sponsor:  
Agency: 
SerenaGroup® 
Acelity (formerly KCI) 
San Antonio, TX 
Protocol Prepared By: 
Thomas E. Serena MD FACS  
90 Sherman Street 
Cambridge, MA 02140 
 
 
 
 
 
 
 
Confidentiality Statement 
This protocol is provided for conducting a clinical research study. The information contained in this 
document is confidential and except to the extent necessary to obtain informed consent or IEC/IRB 
approval, cannot be disclosed unless required by governmental regulation. Persons to whom any portion 
of the contents of this document is disclosed must be informed that the information is confidential and 
may not be further disclosed by them. 

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PROTOCOL APPROVAL PAGE 
                       
                      Protocol Number:        CELLUTOMETM-VLU-13  
             Version:                              Version 1; Rev 3 
                         Date:                                   February 21, 2017 
 
 
 
 
PROTOCOL APPROVAL FOR USE 
 
 
 
 
 
 
 
 
 
                                    Feburary 21, 2017 
                                    
Thomas E. Serena, MD, FACS 
Chief Medical Officer 
SerenaGroup®

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INVESTIGATOR’S SIGNATURE PAGE 
                       
                      Protocol Number:        CELLUTOMETM-VLU-13  
             Version:                              Version 1; Rev 3 
                         Date:                                   February 21, 2017 
 
 
 
 
 
INVESTIGATOR’S SIGNATURE 
 
 
 
I have read the protocol specified above and agree to participate in and comply with the procedures, as 
outlined herein for the conduct of this clinical trial. I also agree to comply with the applicable US Food 
and Drug Administration (FDA) regulations and Investigational Review Board (IRB) requirements for 
testing on human subjects. I agree to ensure that the requirements for obtaining informed consent are 
met. 
 
 
 
 
 
 
 
Principal Investigator’s Signature 
Date 
 
 
 
 
Print Name 
 
 
 
Site Number 

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SPONSOR INFORMATION 
 
 
Sponsor: 
SerenaGroup® Inc. 
 
 
Funding Agency: 
Acelity (formerly KCI) 
 San Antonio, TX 
 
Medical Monitor: 
Thomas E. Serena, MD, FACS 
Cell: 
814- 688-4000 
Office 
617- 945-5225 
Fax: 
617-945-5823 
E-mail: 
serena@serenagroups.com 
 
Regulatory Lead: 
Sharon McConnell, MS, CCRC 
Phone: 
814-706-3318 
E-mail: 
smcconnell@serenagroups.com 
 
Project Manager: 
Heather Connell, CCRP                   
Phone: 
617-383-3979 
E-Mail: 
hconnell@serenagroups.com 
 
Project Lead: 
Raphael Yaakov, MS 
Phone: 
617-674-1886 
E-Mail: 
ryaakov@serenagroups.com 

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LIST OF ABBREVIATIONS 
 
TERM 
DEFINITION 
ABI/ABPI 
Ankle/Brachial Index/Ankle Brachial Pressure Index 
AE 
Adverse Event 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
cm 
Centimeter 
CMO 
Chief Medical Officer 
CRF 
Case Report Form 
CV 
Curriculum vitae 
FDA 
Food and Drug Administration 
FUV 
Follow-up Visit 
GCP 
Good Clinical Practice 
HCV 
Healing Confirmation Visit 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
PBI-P 
Patient Benefit Index – Wound Version 
QOL 
Quality of Life questionnaire 
RCT 
Randomized Controlled Trial 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SD 
Standard Deviation 
SoC 
Standard of Care 
SOP 
Standard Operating Procedures 
SV 
Screening Visit 
TTO 
Time Trade-Off 
TV 
Treatment Visit 
UADE 
Unexpected Adverse Device Effects 

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Table of Contents 
1 
PROTOCOL SYNOPSIS ........................................................................................................................ 10 
2 
INTRODUCTION ................................................................................................................................. 15 
2.1 
THE PROBLEM: VENOUS LEG ULCERATION .................................................................................... 15 
2.2 
THE PATHOPHYSIOLOGY: VENOUS LEG ULCERATION .................................................................... 15 
2.3 
STANDARD OF CARE: VENOUS LEG ULCERATION .......................................................................... 17 
2.4 
EPIDERMAL BLISTER GRAFTING ..................................................................................................... 17 
2.5 
TREATMENT RATIONALE FOR THIS STUDY ..................................................................................... 18 
3 
STUDY OUTCOMES ............................................................................................................................. 18 
4 
STUDY DESIGN ................................................................................................................................... 18 
5 
STUDY POPULATION ........................................................................................................................... 21 
5.1 
NUMBER OF SUBJECTS .................................................................................................................. 21 
5.2 
INCLUSION CRITERIA ...................................................................................................................... 21 
5.3 
EXCLUSION CRITERIA ..................................................................................................................... 22 
6 
STUDY SCHEDULE ............................................................................................................................... 23 
6.1 
VISIT WINDOWS ............................................................................................................................ 23 
6.2 
SCREENING PHASE ......................................................................................................................... 25 
6.3 
TREATMENT PHASE ....................................................................................................................... 25 
6.4 
SUBJECT COMPLETION AND WITHDRAWAL .................................................................................. 29 
7 
STANDARD OF CARE AND CONCOMITANT MEDICATIONS................................................................... 31 
7.1 
CLEANING THE STUDY ULCER ........................................................................................................ 31 
7.2 
DEBRIDEMENT OF THE STUDY ULCER ............................................................................................ 31 
7.3 
COMPRESSION BANDAGING .......................................................................................................... 31 
7.4 
SUBJECT INSTRUCTIONS................................................................................................................. 31 
7.5 
CONCOMITANT MEDICATIONS ...................................................................................................... 32 
7.5.1 
EXCLUDED MEDICATIONS AND THERAPIES ............................................................................. 32 
7.5.2 
ALLOWABLE MEDICATIONS AND THERAPIES .......................................................................... 32 
8 
DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES ......................................................... 33 
8.1 
INFORMED CONSENT ..................................................................................................................... 33 
8.2 
ASSESSMENT OF ELIGIBILITY .......................................................................................................... 33 
8.3 
RE-SCREENING ............................................................................................................................... 33 
8.4 
SUBJECT DEMOGRAPHICS, MEDICAL HISTORY, ULCER HISTORY .................................................... 34 
8.4.1 
DEMOGRAPHICS .................................................................................................................... 34 

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8.4.2 
MEDICAL HISTORY .................................................................................................................. 34 
8.4.3 
LEG ULCER HISTORY ............................................................................................................... 35 
8.4.4 
PHYSICAL EXAM & VITAL SIGNS .............................................................................................. 35 
8.5 
VASCULAR ASSESSMENTS .............................................................................................................. 36 
8.5.1 
ANKLE-BRACHIAL INDEX (ABI) ................................................................................................ 36 
8.5.2 
SKIN PERFUSION PRESSURE .................................................................................................... 37 
8.6 
PAIN ASSESSMENTS ....................................................................................................................... 37 
8.7.1 
STUDY ULCER EXUDATE ASSESSMENTS .................................................................................. 37 
8.7.2 
STUDY ULCER INFECTION ASSESSMENTS ................................................................................ 38 
8.7.3 
INVESTIGATOR ASSESSMENT OF STUDY ULCER CLOSURE ........................................................ 39 
8.8 
STUDY ULCER PHOTOGRAPHS ........................................................................................................ 39 
8.9 
RANDOMIZATION .......................................................................................................................... 39 
8.10 
ASSESSMENT OF MULTI-LAYER COMPRESSION THERAPY .............................................................. 39 
9 
STATISTICAL ANALYSIS PLAN............................................................................................................... 40 
9.1 
BRIEF TRIAL DESCRIPTION .............................................................................................................. 41 
9.1.1 
GENERAL ................................................................................................................................ 42 
9.2 
RESEARCH HYPOTHESES ................................................................................................................ 42 
9.3 
SAMPLE SIZE CALCULATIONS ......................................................................................................... 44 
9.4 
RANDOMIZATION .......................................................................................................................... 44 
9.5 
INTERIM OPERATIONS (WHILE RECRUITMENT IS CONTINUING) ................................................... 44 
9.6 
INTERIM ANALYSIS ......................................................................................................................... 44 
9.7 
STATISTICAL METHODS .................................................................................................................. 46 
10 ADVERSE EVENTS (DEFINITIONS AND REPORTING) ................................................................................... 51 
10.1 
ADVERSE EVENTS ........................................................................................................................... 51 
10.2 
REPORTING OF ADVERSE EVENTS .................................................................................................. 51 
10.3 
ADVERSE EVENT SEVERITY ASSESSMENTS ..................................................................................... 52 
10.4 
ADVERSE EVENT CAUSALITY ASSESSMENTS................................................................................... 52 
11 SERIOUS ADVERSE EVENTS ....................................................................................................................... 54 
11.1 
REPORTING OF SERIOUS ADVERSE EVENTS ................................................................................... 54 
11.2 
SAE FOLLOW-UP ............................................................................................................................ 55 
12 
DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION........................................................................ 55 
13 
QUALITY CONTROL AND QUALITY ASSURANCE ................................................................................... 55 
13.1 
ACCEPTABILITY OF CASE REPORT FORMS ...................................................................................... 55 
13.2 
MODIFICATION OF PROTOCOL ...................................................................................................... 55 

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13.3 
REPORTING PROTOCOL DEVIATIONS ............................................................................................. 56 
14 
ETHICS AND REGULATORY REQUIREMENTS ....................................................................................... 56 
14.1 
INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE ........................................... 56 
14.2 
INVESTIGATOR’S RESPONSIBILITIES ............................................................................................... 57 
14.3 
SUBJECT INFORMED CONSENT REQUIREMENTS............................................................................ 57 
15 
DATA HANDLING AND RECORD KEEPING ............................................................................................ 57 
15.1 
RECORDING AND COLLECTION OF DATA ....................................................................................... 57 
15.2 
CLINICAL DATA MANAGEMENT ..................................................................................................... 58 
15.3 
ARCHIVING .................................................................................................................................... 58 
16 
PUBLICATION PLAN ............................................................................................................................ 59 
17 
MONITORING PLAN ........................................................................................................................... 61 
17.1 
SITES .............................................................................................................................................. 61 
17.1.1 
SITE SELECTION ...................................................................................................................... 61 
17.1.2 
INVESTIGATORS MEETING ..................................................................................................... 61 
17.1.3 
SITE INITIATION VISIT (SIV) ..................................................................................................... 61 
17.2 
MONITORING VISITS ...................................................................................................................... 63 
17.3 
MONITORING DOCUMENTATION .................................................................................................. 64 
17.4 
CLOSE OUT VISIT ............................................................................................................................ 64 
17.5 
SOURCE DOCUMENTATION VERIFICATION REQUIREMENTS ......................................................... 65 
17.6 
INFORMED CONSENT AND AUTHORIZATION ................................................................................. 65 
17.7 
SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS ........................................................................ 67 
17.8 
CONCOMITANT MEDICATION DOCUMENTATION ......................................................................... 67 
17.9 
INCLUSION AND EXCLUSION CRITERIA VERIFICATION ................................................................... 67 
17.10 DEVICE ACCOUNTABILITY AND RANDOMIZATION REQUIREMENTS ............................................... 67 
17.11 PHOTOGRAPHS .............................................................................................................................. 67 
17.12 PROTOCOL ADHERENCE/VIOLATIONS/DEVIATIONS/SERIOUS BREACHES ...................................... 68 
17.13 CASE REPORT FORM (CRF) COMPLETION ...................................................................................... 68 
17.14 EARLY TERMINATION DOCUMENTATION ...................................................................................... 69 
17.15 MANAGING POOR PERFORMING OR NON-COMPLIANT SITES ....................................................... 69 
17.16 FRAUD AND MISCONDUCT ............................................................................................................ 69 
18 
REFERENCES ...................................................................................................................................... 70 
19 
APPENDICES ....................................................................................................................................... 72 
19.1 
ANKLE-BRACHIAL INDEX (ABI) ........................................................................................................ 72 
19.2 
TIME TRADE OFF EVALUATION ...................................................................................................... 73 

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19.3 
MODIFIED ACTIVITY-BASED COSTING METHODOLOGY ............................................................... 104 
19.4 
DISCRETE EVENT SIMULATION MODEL TO MEASURE COST-EFFECTIVENESS AND COST-BENEFIT
 .................................................................................................................................................... 108 
19.5 
QUALITY OF LIFE QUESTIONAIRE (w-QOL) ................................................................................... 109 
19.5 
QUALITY OF LIFE QUESTIONNAIRE (w-QOL) ............................................................................... 110 
19.6 
PBI-P – PATIENT BENEFIT INDEX, WOUND VERSION .................................................................. 112 
19.7 
SWAB COLLECTION PROCEDURE ................................................................................................ 114 
19.8 
ANTIMICROBIAL DRESSING ......................................................................................................... 115 
19.9 
APPLICATION OF PRISMATM ........................................................................................................ 116 
19.10 EPIDERMAL HARVESTING PROCEDURE ....................................................................................... 117 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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PROTOCOL SYNOPSIS: CELLUTOMETM 
Study Endpoints 
a) Time to heal at 6 and 12 weeks 
b) Proportion of wounds healed at 12 weeks. 
c) Correlation between protease activity and healing at 4 and 8 weeks 
d) Incidence of adverse events at 12 weeks 
e) Difference in pain score between baseline and 12 weeks 
f) Cost-effectiveness at 12 weeks 
g) Cost-benefit at 12 weeks 
Inclusion Criteria 
Potential subjects are required to meet all of the following criteria for 
Lead Investigator 
Thomas E. Serena MD FACS FACHM MAPWCA on behalf of the 
SerenaGroup® and affiliated STRONG wound healing cooperative group 
centers. 
Title 
A Multi-center, Randomized, Open-Label, Controlled Clinical Trial 
Evaluating Suction Blister Grafting Utilizing a Novel Harvesting Device 
(CelluTomeTM) and Standard of Care vs. Standard of Care (SOC) Alone in 
the Treatment of Venous Leg Ulcers. 
Introduction 
Millions of Americans are afflicted with painful, open, draining sores 
on their lower extremities. These sores are referred to as venous leg 
ulcerations (VLUs). Under the best of circumstances these ulcers 
require weeks or months to heal. Wound care specialists often see 
patients who have suffered for years or faced amputation of the limb 
as their only option to alleviate the pain. 
 
SOC will result in healing in 50% of VLUs in 12 weeks. However, roughly 
half of patients suffering from venous ulcers will require advanced 
therapy. Epidermal grafting has been a reconstructive option for 
decades; however, to date there has not been a reliable and 
reproducible system to harvest epidermis. The CelluTomeTM Harvesting 
System permits the harvesting of epidermal blister grafts at the patient’s 
bedside without the need for anesthesia. The grafts can be easily 
transferred to the wound bed. In case studies, epidermal grafting 
appeared to be effective in reducing wound size and accelerating 
closure of VLUs. 
Objectives 
Primary Objective: 
The primary objective is time to heal in patients treated with 
epidermal grafting and SOC vs. SOC alone. 
Secondary Objectives: 
a) Proportion of wounds closed  
b) Incidence of adverse events 
c) Correlation between protease activity and healing 
d) Reduction of pain 
e) Cost-effectiveness (see Appendix 19.4) 
f) Cost-benefit (see Appendix 19.4) 
Study Centers 
The trial will be conducted at up to 30 SerenaGroup® and affiliated 
centers. 

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enrollment into the study and subsequent randomization:  
1. At least 18 years old. 
2. Adequate arterial flow (Ankle Brachial Pressure Index (ABI) > 
0.75. (Calculations will be made using measurements from both 
posterior tibial and dorsalis pedis arteries as well as both arms), 
OR Skin Perfusion Pressure (SPP) >30, OR biphasic PVR OR TBI > 
0.60 OR TCPO2 > 30mmHg OR adequate perfusion as 
demonstrated on florescent angiography, LUNA®). 
3. Presence of a VLU extending through the full thickness of the skin 
but not down to muscle, tendon or bone. The largest ulcer will be 
designated the index ulcer and the only one included in the study. If 
other ulcerations are present on the same leg they have to be more 
than 2 cm apart from the index ulcer. 
4. Study ulcer (i.e. current episode of ulceration) has been present 
for at least one month prior to the initial screening visit and is 
excluded if it has undergone 12 months of continuous high strength 
compression therapy over its duration. 
5. Study ulcer is a minimum of 2.0 cm2 and a maximum of 25 cm2 at 
the randomization visit. 
6. The target ulcer has been treated with compression therapy for at 
least 14 days prior to randomization (run-in period). 
 
7. Ulcer has a clean, granulating base with minimal adherent slough 
at the randomization visit. 
 
8. Females of childbearing potential must be willing to use 
acceptable methods of contraception (birth control pills, barriers, 
or abstinence). A urine pregnancy test must be administered 
during screening, and must be negative, for inclusion into the 
study. 
 
9. Patient understands and is willing to participate in the clinical study 
and can comply with weekly visits and the follow-up regimen. 
 
10. Patient has read and signed the IRB/IEC approved Informed 
Consent Form before screening procedures are undertaken. 
 
Exclusion Criteria 
Potential subjects meeting any of the following criteria will be 
excluded from enrollment and subsequent randomization:  
 
1. Study ulcer(s) deemed by the investigator to be caused by a 
medical condition other than venous insufficiency. These may 
include, but are not limited to: fungal ulcerations, malignant 
ulcerations, and ulcerations due to arterial insufficiency. 
 
2. Study ulcer exhibits clinical signs and symptoms of infection at the 

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SV (screening visit) or TV1 (Treatment Visit 1). 
 
3. Known allergy to the components of the multi-layer compression 
bandaging, or who cannot tolerate multi-layer compression therapy. 
 
4. Study ulcer, in the opinion of the investigator, is suspicious for 
cancer should undergo an ulcer biopsy to rule out a carcinoma 
of the ulcer. The patient may be enrolled after a negative biopsy. 
 
5. Patients with a history of more than two weeks treatment with 
immunosuppressants (including systemic corticosteroids), cytotoxic 
chemotherapy, or application of topical steroids to the ulcer 
surface within one month prior to initial screening, or who 
receive such medications during the screening period, or who are 
anticipated to require such medications during the course of the 
study. 
 
6. Study ulcer has been previously treated with tissue engineered 
materials (e.g. Apligraf® or Dermagraft®) or other scaffold 
materials (e.g. Oasis, Matristem) within the last 30 days. 
 
7. Study ulcer requiring negative pressure wound therapy or 
hyperbaric oxygen during the course of the trial. 
 
8. Ulcers on the dorsum of the foot or with more than 50% of the 
ulcer below the malleolus are excluded. 
 
9. Pregnant or breast feeding. 
 
10. Known history of having Acquired Immunodeficiency Syndrome 
(AIDS) or with a history known to be infected with Human 
Immunodeficiency Virus (HIV). 
 
11. Known uncontrolled Diabetes Mellitus, as measured by an 
HbA1c > 10%. 
 
12. Ulcers that have healed more than 40% during the screening 
phase (run-in period) are excluded. 
 
13. Patients on any investigational drug(s) or therapeutic device(s) 
within 30 days preceding screening (i.e. S1); or patient or 
physician anticipates use of any of these therapies by the 
subject during the course of the study. 
14. History of radiation at the ulcer site. 
15. Presence of one or more medical conditions, as determined by 
medical history, including renal, hepatic, hematologic, active 
auto-immune or immune diseases that, in the opinion of the 
Investigator, would make the subject an inappropriate candidate 

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for this ulcer healing study. 
16. Patients who are unable to understand the aims and objectives 
of the trial. 
17. Presence of any condition(s) which seriously compromises the 
subject's ability to complete this study, or has a known history 
of poor adherence with medical treatment. 
Trial Design 
This study is a multi-center, randomized, open-label trial designed to 
evaluate the safety and effectiveness of Epidermal grafting plus SOC 
versus SOC alone in the healing of venous leg ulcers. The SOC therapy 
in this  study  is  multi-layer  compression therapy. A number of 
compression bandaging systems are commercially available.  
 
The Screening Phase (1-14 days) consists of a series of screening 
assessments designed to determine eligibility followed by, for those 
who meet the eligibility criteria (described in more detail below). 
 
At or up to 14 days before the first Screening Period Visit (S1), 
written informed consent from the subject will be obtained by the 
Investigator or suitably qualified designee before the performance of 
any other protocol- specific procedure. 
 
Patients who have not been treated with documented full 
compression therapy for the target ulcer must receive a minimum of 
14 days of compression prior to enrollment. 
 
At the first Screening Period Visit (S1), the Investigator will select the 
study (target) ulcer. Each subject will have only one VLU selected as 
the study (target) ulcer. In the situation where a subject has more 
than one VLU at the S1 visit, the Investigator will select the largest 
VLU that meets the eligibility criteria of the protocol as the study 
(target) ulcer (no more than 2 ulcers on target limb). During the 
screening phase, the wound will be swabbed for protease activity prior 
to the application of PrismaTM Matrix Wound Dressing (Systagenix, San 
Antonio, TX). 
 
PrismaTM is to be used during the 2 week screening phase. PrismaTM 
provides a moist environment at the wound surface and provides an 
effective barrier against common pathogens. The rationale for 
permitting the use of PrismaTM in subjects is to reduce the risk of 
infection. For subjects who are allergic to PrismaTM, any of the allowed 
antimicrobial dressings should be used (Appendix 19.8).  
 
The Screening Period is designed to determine whether subjects are 
eligible to proceed to the Treatment Period of the study. 
 
The Treatment Phase begins with a series of assessments designed to 
confirm the subjects’ continued eligibility. Subjects who continue to 
meet eligibility criteria will be randomized to one of two groups: 
(1) Up to 3 applications of Epidermal grafting harvested utilizing the 

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CelluTomeTM system at TV1, TV5 and TV9, visits plus SOC (multi-layer 
compression) (Group 1A) (2) SOC alone (Group 2A). 
 
At TV 7, wound assessment will be carried out to evaluate wound 
healing in Group  2A . Subjects in Group 2A , whose percentage area 
reduction (PAR) is <40% will be allowed to have CelluTomeTM treatment 
in addition to continuation of SOC and will constitute Group 2C. Group 
2C subjects will receive a graft at TV7 and TV11. The remainder of Group 
2A subjects will be termed Group 2B subjects. Patient codes will still 
remain the same to enable tracking continuity. 
 
During the Treatment Phase, the wound will be swabbed for protease 
activity for Group 1A and 2A/B subjects: TV1 (In Group 1A this will be 
prior to CelluTomeTM application), TV5 and TV9 visits.  
 
Subjects will be evaluated on a weekly basis during the Treatment 
Phase. Effectiveness evaluations each week will include Investigator 
assessment of wound healing and measurements of ulcer size using 
digital planimetry. At TV4 and TV8, PrismaTM is to be applied to the study 
ulcer for Group 1A, 2A, and 2B subjects. Group 2C subjects will receive 
PrismaTM at TV10. Safety evaluations during the Treatment Phase will 
consist of adverse event assessments at each visit. 
Dosage and Frequency of 
Administration 
Epidermal grafting will be applied up to three times in Group 1A: 
TV1, TV5 and TV9. Group 2C subjects will receive up to two grafts: 
TV7 and TV11. 
Duration of Study 
A run-in period of 2 weeks followed by 12 weeks of active treatment. 
Statistical Methods, Power, 
and Sample Size Calculations 
Please see the Statistical Analysis Plan in the protocol. 
Protease Levels 
Absolute values of inflammatory proteases (Neutrophil elastase, 
MMP 8 and 9) will be measured at S1 before application of PrismaTM, 
day 0 before application of Epidermal grafts and week 4 and 8 visits 
thereafter to determine the effect of protease levels on graft success 
for Group 1A and 2A/B subjects. The results will be blinded to the 
Investigators. 
Key Words 
Epidermal 
Grafts 
Chronic 
Wounds 
Clinical 
Trial 
Venous 
Leg ulcer 
Protease levels in chronic wounds 
 
 
 
 

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2 
INTRODUCTION 
 
2.1 
THE PROBLEM: VENOUS LEG ULCERATION 
 
Lower extremity ulcers pose significant clinical and economic burdens on society. Millions of Americans 
are afflicted with painful, open, draining sores on their lower extremities. These ulcers, referred to as 
venous leg ulcerations (VLUs) 1, 2,3,4,5, require weeks or months to heal under the best of circumstances. 
Physicians often see patients who have suffered for years or faced amputation of the limb as their only 
option to alleviate the pain. In fact, pain is a common feature of VLUs. A study by Phillips in 1994 
found that 65% of patients with VLU complained of severe pain and 68% of patients stated that their 
ulcer created a negative emotional and psychological impact including feelings of fear, social isolation, 
anger, depression, anxiety and negative self-image6. 
 
VLUs are the end result of chronic venous insufficiency caused by an abnormality of the veins in the 
lower extremity. The venous system of the lower extremity consists of a superficial and a deep system 
connected by a series of perforating veins. In the normal state, valves within these veins direct blood 
from the superficial into the deep system which then carries the blood back to the heart. The flow in 
the deep system is facilitated by the pumping action of the musculature of the lower extremity 
during physical activity. A variety of illnesses and disease states may interrupt the normal function 
of the venous system. For example, patients who in the past have suffered from an episode of deep 
venous thrombosis may not have functioning valves within their veins. The blood then flows in a 
reverse fashion from the deep system to the superficial system. This reversal of flow leads to pooling of 
blood and fluid in the legs. The patient may first experience swelling or edema of the lower extremities 
followed by the hallmark signs of hyper-pigmentation, venous stasis dermatitis, hemosiderin deposits, 
loss of hair, thickened nails, atrophy blanch and lipodermatosclerosis. Eventually the skin ulcerates 
typically in the gaiter region of the leg. 
2.2 
THE PATHOPHYSIOLOGY: VENOUS LEG ULCERATION 
 
The venous system in the leg is made up of two networks, the superficial and the deep venous 
systems.2,3 The superficial system is composed of the axial superficial veins (the long and short 
saphenous veins) and their tributaries, which drain blood from the microcirculatory bed. The deep 
venous system is composed of the main axial veins between the muscle compartments and the venous 
sinuses within the calf muscles. The superficial and deep venous systems connect at the sapheno-
popliteal and sapheno- femoral junctions, as well as communicating through the perforator veins. 
Perforator veins either connect directly to the main axial veins or link to the veins and venous sinuses 
within the muscles, thus indirectly draining into the main axial veins.2,3 
 
Bicuspid valves in veins ensure that venous return is unidirectional towards the heart.3,4 Valves in the 
perforator veins also serve to protect the superficial venous system from the high compartmental 
pressures present in the deep veins during contraction of the calf muscle pump. This muscle pump 
assists the return of blood against gravity.5 In a leg with normal venous return, the hydrostatic pressures 
within the superficial and deep venous systems are both approximately 80 mmHg when a person is  
upright at rest.4   However, during exercise such as walking or plantar flexion of the venous, calf muscle 
contraction increases pressure within the deep veins, closing the valves in the perforator veins and 

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propelling blood in the deep veins towards the heart.2 Subsequent muscle relaxation following 
contraction causes pressure in the deep venous system to fall abruptly to a level lower than that in the 
perforator veins. This sudden pressure drop to between 0 and 10 mmHg ensures the valves in the 
superficial system open to refill the deep venous system.4 Proper functioning of venous return is 
dependent on competent valves within the veins to prevent retrograde flow or reflux from the deep to 
the superficial venous system.2,4 
 
Dysfunction in venous return occurs through: 
1. Incompetent valves in the superficial, perforating or deep veins giving rise to venous reflux, 
2. Outflow obstructions in the deep veins also giving rise to venous reflux, or 
3. Calf muscle pump failure because of diseases influencing lower limb mobility. 
The reflux resulting from valvular incompetency or outflow obstructions leads to sustained increases in 
venous pressure in the superficial system. This venous hypertension is the hallmark of chronic venous 
insufficiency (CVI).8,9,10   Clinical manifestations of CVI include: 
 
Telangiectasia or spider veins 
 
Varicose veins, ranging in severity from submalleolar venous flare to tortuous dilatations of the 
axial superficial veins 
 
Dependent edema in the lower leg 
 
Atrophic blanche or smooth white scar tissue 
 
Hyperpigmentation caused by deposition of red blood cells into the dermis, with subsequent 
reddish-purple to brown discoloration of the tissue 
 
Eczematous skin changes, such as scaling, flaky skin 
 
Induration of the lower leg caused by fibrosis of subcutaneous fat, giving the appearance of an 
inverted bottle in its most severe presentations (so called “champagne legs”) 
 
Leg ulceration on the lower third of the leg, but not excluding presentations on the dorsum of 
the venous. 
The microcirculatory cascade from venous hypertension to leg ulceration has not been fully described 
and understanding of the pathogenesis of VLU is incomplete. Various hypotheses have been 
proposed to explain experimental observations. These hypotheses include pericapillary fibrin cuff 
formation presenting a barrier to oxygen diffusion11.12, white cells plugging capillaries causing tissue 
anoxia13,14, and fibrin cuffs trapping growth factors.15 More recently, ulcer pathogenesis is thought to be 
an inflammatory chain brought about by a chronic ischemia-reperfusion cycle.9,16 An inflammatory 
cascade involving cytokines, oxygen-derived free radicals, and activated polymorphonuclear neutrophils 
promote the deposition of capillary cuffs trapping growth factors and cell adhesion molecules. These 
matrix cuffs attract and activate more white cells. The repeated activation of this cascade eventually 
overwhelms compensatory capacity, with balance tipped in favor of tissue destruction.17 Although the 
observed cause of ulceration may in many cases be mechanical, for instance minor trauma, healing is 
arrested or counteracted by the ischemic-reperfusion cycle until the underlying venous hypertension is 
corrected. 

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2.3 
STANDARD OF CARE: VENOUS LEG ULCERATION 
 
The therapeutic mainstay in management of VLUs is graduated compression bandaging. Healing rates in 
VLUs are significantly improved by the application of compression therapy18, but generally only 
approximately 45% of subjects will be healed by 12 weeks even with compression19. High compression 
(40 mmHg at the ankle) is more effective at healing venous leg ulcers than low compression.20 High 
compression can be achieved using a variety of multilayer bandaging systems or compression 
hosiery. 
 
Currently there are a couple of advanced products which are approved for use in VLUs. Apligraf®, a 
bioengineered skin product composed of living neonatal foreskin derived skin was shown to heal VLU 
more rapidly than compression.21 However, even though more wounds healed than SOC, only 57% of 
ulcers were healed at 24 weeks. Similarly, Oasis® derived from the submucosal lining of porcine small 
intestine healed wounds more rapidly than SOC, but only 55% were healed at 12 weeks.22 There are 
numerous other products utilized in the treatment of VLUs that do not have randomized controlled 
trial evidence. The goal of epidermal grafting is to accelerate this healing beyond standard care and 
currently available advanced products. 
 
Compression should only be applied in the absence of significant arterial disease.  The threshold 
normally employed for the use of compression is an ankle brachial pressure (ABI) index of greater than 
0.75. An ABI is the ratio of the systolic blood pressure in the leg over the systolic blood pressure in the 
arm. Normal adult values range between 0.9 and 1.2. Levels lower than 0.75 are thought to indicate 
the presence of moderate arterial disease. 
2.4 
EPIDERMAL BLISTER GRAFTING 
 
Epidermal grafts have been used to treat acute and chronic wounds for decades. However, in the past 
epidermal micrografts were created using a free hand blade or syringes which applied negative pressure 
to produce an epidermal blister.23,24,25,26,27,28,29 However, these procedures are difficult to perform, can 
remove dermis resulting in patient discomfort and can be time consuming. The CelluTomeTM epidermal 
harvesting system (Acelity,  San Antonio, TX) is cleared by the FDA and commercially available in the 
United States. It harvests up to 120 epidermal blister grafts from a donor site usually on the inner 
thigh. The grafts are collected in a dressing that can easily be transferred to another area of the body. 
To date, this system has been used to treat acute and chronic wounds in Haiti and across the United 
States.30,31 The results from these case series suggest that epidermal grafting is effective in accelerating 
the healing in VLUs. In fact, the principal investigator’s experience suggests that epidermal grafting may 
be far superior to current advanced therapies. The epidermal harvesting procedure is described in 
section 19.7. 
 
Epidermal results in minimal or no discomfort to the patient. Anesthesia is not required. The donor site 
heals in 3 to 4 days. In the principal investigators case series experience the only adverse event seen was 
irritation of the donor site secondary to the Tegaderm® dressing.31 These adverse events resolved with 

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removal of the Tegaderm® There were no problems with donor site healing. Epidermal grafting is 
associated with a low risk of complications and potentially can accelerate closure of venous ulcers. 
 
2.5 
TREATMENT RATIONALE FOR THIS STUDY 
 
The primary goal in treating a VLU is to obtain wound closure as rapidly as possible which in turn 
decreases patient discomfort, reduces the risk of infection and improves the patient’s quality of life. 
Healing can be a lengthy and painful process for ulcers of lower extremity requiring greater than 12 
weeks to achieve closure in many cases. Epidermal grafts are believed to promote healing by two 
mechanisms: graft take and the promotion of wound healing through the delivery of growth factors and 
the essential elements of tissue repair and wound healing.30 This study is intended to establish the 
superior effectiveness of epidermal grafting and multi-layer compression over that of multi-layer 
compression alone, in the treatment of venous leg ulcers. In addition, case studies suggest that 
epidermal grafting may be more effective than currently approved advanced therapies. 
 
3 
STUDY OUTCOMES 
 
Primary outcome measure is time to heal in patients treated with epidermal grafting and SOC 
vs. SOC alone (Group 1A versus Group 2A at 6 weeks; and Group 1A versus Group 2B at 12 
weeks).  
 
Secondary outcomes include: 
1. Percentage of wounds closed at 6 and 12 weeks. 
2. Correlation between protease activity and healing at 4 and 8 weeks. 
3. Incidence of adverse events at 12 weeks. 
4. Pain reduction between baseline and 12 weeks. 
5. Cost-effectiveness (see Appendix 19.4) 
6. Cost-benefit (see Appendix 19.4) 
 
4 
STUDY DESIGN 
This study is a multi-center, randomized, controlled open-label study designed to evaluate the safety 
and effectiveness of epidermal grafting using the CelluTomeTM system plus SOC (multi-layer 
compression) versus SOC alone in the treatment of VLUs. 
 
The study will have two phases: Screening and Treatment. 
 
The Screening Phase (1 -14 days) is designed to determine whether subjects are eligible to proceed to 
the Treatment Phase of the study and consists of a series of screening assessments designed to 
determine eligibility. 

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At or up to 14 days before the first Screening Phase Visit (S1), written informed consent from the subject 
will be obtained by the Investigator or suitably qualified designee before the performance of any other 
protocol-specific procedure. 
 
At the first Screening Phase Visit (S1), the Investigator will select the study (target) ulcer. Each subject 
will have only one VLU selected as the study (target) ulcer. In the situation where a subject has more 
than one VLU at the S1 visit, the Investigator will select the largest VLU that meets the eligibility criteria 
of the protocol as the study (target) ulcer.  
 
The wound will be swabbed for protease activity to measure the absolute values of inflammatory 
proteases (Neutrophil elastase, MMP 8 and 9) before the application of PrismaTM Matrix Wound 
Dressing (Systagenix, San Antonio, TX). 
 
PrismaTM is to be used during the 2 week screening phase. PrismaTM provides a moist environment at the 
wound surface and provides an effective barrier against common pathogens. The rationale for permitting 
the use of PrismaTM in subjects is to reduce the risk of infection. For subjects who are allergic to PrismaTM, 
any of the allowed antimicrobial dressings should be used (see Appendix 19.8). 
 
Patients whose target ulcer has been treated with compression therapy for the previous two weeks are 
eligible to enter the treatment phase once all of the inclusion and exclusion criteria are met. If the ulcer 
has not received compression, the patient should be placed in compression and enrolled in the study 
after 14 days of compression therapy. Ulcers that have decreased in size by more than 40% during the 
screening period will be excluded as a “rapid healer.” 
The Treatment Phase (TV1 to TV13) Begins with a series of assessments designed to confirm the 
subjects’ continued eligibility. Investigators will debride the ulcer. Subjects whose ulcers continue to 
meet eligibility criteria will then be randomized to one of two groups: (1) One application of epidermal 
microdomes at day zero and standard of care (Group 1A) OR (2) standard of care: multi-layer compression 
(Group 2A) (see figure on next page). 
 
During the Treatment Phase, subjects will be evaluated on a weekly basis. Effectiveness evaluations 
each week will include Investigator assessment of wound healing and measurements of ulcer size using 
digital photos.  
 
At TV 7, wound assessment will be carried out to evaluate wound healing in Group  2A . Subjects in Group 
2A , whose percentage area reduction (PAR) is <40% will be allowed to have CelluTomeTM treatment in 
addition to continuation of SOC and will constitute Group 2C. Group 2C will receive a graft at TV7 and TV11. 
The remainder of Group 2A subjects will be termed Group 2B subjects. Patient codes will still remain the 
same to enable tracking continuity. 
 
During the Treatment Phase, the wound will be swabbed for protease activity for Group 1A and 2A/B 
subjects: TV1 (In Group 1A this will be prior to CelluTomeTM application), TV5 and TV9 visits.  
 
Subjects will be evaluated on a weekly basis during the Treatment Phase. Effectiveness evaluations each 
week will include Investigator assessment of wound healing and measurements of ulcer size using 
digital planimetry. At TV4 and TV8, PrismaTM is to be applied to the study ulcer for Groups 1A, 2A, and 2B 
subjects. Group 2C subjects will receive PrismaTM at TV10. Safety evaluations during the Treatment 

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Phase will consist of adverse event assessments at each visit. 
 
Diagram showing progress of trial and the different subjects groups. Up to 6 weeks from randomization only 
Groups 1A and 2A exist; after 6 weeks, Groups 1A, 2B, and 2C exist.  
 
 
 
 
 
 
 
Randomization 
Group 1A: 
CelluTomeTM 
Group 2A: SOC 
PAR analysis 
TV7 (week 6) 
Group 2B: SOC 
Group 2C:  
SOC + 
CelluTomeTM 
PAR > 40% 
PAR < 40% 

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5 
STUDY POPULATION 
 
5.1 
NUMBER OF SUBJECTS 
 
The study will consist of up to 30 centers in the United States each contributing about 10 subjects per 
center in order to obtain 300 evaluable subjects. We anticipate a 10% drop out rate during the trial for 
both Groups 1A and Group 2A, and 30% of subjects in Group 2A will switch to Group 2C and therefore a 
total of 225 subjects will be recruited. This trial employs an adaptive design therefore the enrollment 
numbers may be reduced or increased based on planned interim analysis. 
5.2 
INCLUSION CRITERIA 
 
Potential subjects are required to meet all of the following criteria for enrollment into the study and 
subsequent randomization. 
 
1. At least 18 years old. 
 
2. Ankle Brachial Pressure Index (ABI) > 0.75. Calculations will be made using measurements from 
both posterior tibial and dorsalis pedis arteries as well as both arms AND/OR Skin Perfusion 
Pressures (SPP) greater than 30 mmHg OR Biphasic PVR OR TBI > 0.60 OR TCPO2> 30mmHg. 
 
3. Presence of a VLU extending through the full thickness of the skin but not down to muscle, 
tendon, or bone. The largest ulcer will be designated the index ulcer and the only one 
included in the Study. If other ulcerations are present on the same leg the index ulcer must be 2 
cm or greater in distance from the wound edge of the other ulcers. 
 
4. Study ulcer (i.e. current episode of ulceration) had been present for at least one month (30 
days) prior to the initial screening visit, and is excluded if it has undergone 12 month of 
continuous high strength compression therapy over its duration. 
 
5. Study ulcer is a minimum of 2.0 cm2 and a maximum of 25 cm2 at the TV1 Randomization visit. 
 
6. The target ulcer has been treated with documented full compression for at least 14 days prior to 
randomization. 
7. Ulcer has a clean, granulating base with minimal adherent slough at the TV1 Randomization 
visit. 
8. Females of childbearing potential must be willing to use acceptable methods of contraception 
(birth control pills, barriers, or abstinence). A urine pregnancy test must be administered during 
screening, and must be negative, for inclusion into the study. 
 
9. Patient understands and is willing to participate in the clinical study and can comply with weekly 
visits and the follow-up regimen. 
 
10. Patient has read and signed the IRB/IEC approved Informed Consent Form before screening 
procedures are undertaken. 

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5.3 
EXCLUSION CRITERIA 
 
Potential subjects meeting any of the following criteria will be excluded from enrollment and 
subsequent randomization: 
1. Study ulcer(s) deemed by the Investigator to be caused by a medical condition other than 
Venous Insufficiency. These may include, but are not limited to: fungal ulcerations, malignant 
ulcerations, diabetic ulcerations, and ulcerations due to arterial insufficiency. 
 
2. Study ulcer exhibits clinical signs of symptoms of infection at S1 or TV1. 
3. Known allergy to the components of the multi-layer compression bandaging, or who cannot 
tolerate multi-layer compression therapy. 
 
4. Study ulcer, in the opinion of the investigator, is suspicious for cancer should undergo an ulcer 
biopsy to rule out a carcinoma of the ulcer. The patient may be enrolled after a negative 
biopsy. 
 
5. Patients with a history of more than two weeks treatment with immunosuppressants (including 
systemic corticosteroids), cytotoxic chemotherapy, or application of topical steroids to the ulcer 
surface within one month prior to initial screening, or who receive such medications during the 
screening period, or who are anticipated to require such medications during the course of the 
study. 
 
6. Patients on any investigational drug(s) or therapeutic device(s) within 30 days preceding 
screening (i.e. S1); or patient or physician anticipates use of any of these therapies by the 
subject during the course of the study. 
 
7. History of radiation at the ulcer site. 
8. Presence of one or more medical conditions, as determined by medical history, including renal, 
hepatic, hematologic, active auto-immune or immune diseases that, in the opinion of the 
Investigator, would make the subject an inappropriate candidate for this ulcer healing study. 
 
9. Study ulcer has been previously treated with tissue engineered materials (e.g. Apligraf® or 
Dermagraft®) or other scaffold materials (e.g. Oasis, Matristem) within the last 30 days. 
 
 
10. Study ulcer requiring negative pressure wound therapy or hyperbaric oxygen during the course 
of the trial. 
 
11. Ulcers on the dorsum of the foot or with more than 50% of the ulcer below the malleolus are 
excluded. 
 
12. Ulcers that have healed more than 40% during the screening phase (run-in period) are excluded. 
13. Pregnant or breast feeding. 

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14. Known history of having Acquired Immunodeficiency Syndrome (AIDS) or with a history known 
to be infected with Human Immunodeficiency Virus (HIV). 
 
15. Known uncontrolled Diabetes Mellitus, as measured by an HbA1c > 10%. 
16. Patients who are unable to understand the aims and objectives of the trial. 
17. Presence of any condition(s) which seriously compromises the subject's ability to complete this 
study, or has a known history of poor adherence with medical treatment. 
 
6 
STUDY SCHEDULE 
 
The study is divided into two phases: Screening and Treatment Phases. The schedules for the protocol- 
specified assessments and procedures in each phase are detailed below in the following sections. The 
Schedule of Events tables are presented on the next pages. 
 
6.1 
VISIT WINDOWS 
Subject visit dates must be scheduled within the visit windows detailed on the Schedule of Events tables. 
One week equals 7 days. 
During the Screening Phase, each visit is scheduled from the S1 visit date, with reference to the allowed 
visit window. 
During the Treatment Phase, each visit is scheduled from the TV1 visit date, with reference to the 
allowed visit window.  For example, the TV2 visit is scheduled for 1 week ± 2 days after the TV1 visit. 
TV3 is scheduled for 2 weeks ± 2 days after the TV1 visit. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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SCHEDULE OF EVENTS 
 
 
 
Visit 
SVs 
(14 days) 
TV1 
(rand) 
T
V
TV3 
TV4 
TV5 
TV6 
TV7 
TV8 
TV9 
TV10 
TV11 
TV12-
13 
Weeks from 
Randomization Date 
 
+1 
 
+2 
+3 
+4 
+5 
+6 
+7 
+8 
+9 
+10 
 
+11-12 
Window Period 
0 
±2 
da
±2 
days 
±2 
days 
±2 
days 
±2 
days 
±2 
day
±2 
days 
±2 
days 
±2 
days 
±2 
days 
±2 
days 
Assessment of eligibility 
√ 
Medical history 
√ 
Apply PrismaTM 
√ 
√ 
√ 
√[B] 
Randomization 
√ 
Ulcer assessments 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Physical exam 
√ 
Vital signs 
√ 
Pain assessment 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Study ulcer 
photographs 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Study ulcer cleaning 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Study ulcer 
debridement 
√[A] 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Study ulcer swab 
√ 
√ 
 
 
√ 
 
 
√ 
Assessment of 
compression 
bandaging 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Epidermal graft 
application 
√ 
 
 
√ 
√[B] 
 
√ 
√[B] 
Study ulcer dressings 
and compression 
therapy 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Study ulcer closure 
assessment 
√ 
√ 
√ 
√ 
√ 
√[C] 
√ 
√ 
√ 
√ 
√ 
Assess for 
concomitant 
medications 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Assess for AEs and 
SAEs 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
√ 
Quality of Life, PBI-P 
and Time-trade off 
questionnaires 
√ 
 
 
√ 
 
 
√ 
 
 
√[D] 
 
[A] – If required per the Investigator’s judgment. 
[B] – Group 2C subjects only 
[C] – Evaluation of wound area reduction since TV1. Subjects in Group 2A (SOC), whose study ulcer PAR is < 40%, will 
become Group 2C; the remainder of Group 2A subjects will become Group 2B  
[D]- Questionnaires are to be completed for TV13 only 

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6.2 
SCREENING PHASE 
 
The subject will sign and date the ICF and HIPAA authorization (according to site practices) prior to 
any study-related procedures. A screening number will be assigned to each subject in successive 
order of entering the study after signing the ICF at each center, beginning with 001 at each site. 
 
SCREENING VISIT – S1 
The following procedures must be performed: 
 
 
Informed consent will be obtained prior to any study related procedures and the subject will 
sign a written Informed Consent Form 
 
Demographic information will be collected. 
 
Medical history obtained. 
 
Concomitant medications assessed. 
 
Vital signs taken. 
 
Physical examination performed. 
 
Pain assessment. 
 
Ulcer history recorded. 
 
Study Ulcer Assessments will be recorded. 
 
Assess signs and symptoms of clinical infection of the study ulcer. 
 
Vascular assessment. 
 
Clean the study ulcer using saline. 
 
Digital photo of the study ulcer. 
 
Perform swab on study ulcer. 
 
Debridement of the study ulcer if applicable. 
 
Application of PrismaTM or allowed antimicrobial dressing (Appendix 19.8). 
 
Apply multi-layer compression bandaging therapy. 
 
Assessment of subject’s eligibility to continue on in the study. 
 
Schedule the next visit (S2 or TV1) in one week, if they are still eligible. 
 
 
6.3 
TREATMENT PHASE 
 
TREATMENT VISIT 1 (TV1) – PRIOR TO RANDOMIZATION 
The following procedures must be performed: 
 
Pain assessment 

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 
Assess effectiveness of compression bandaging 
 
Check for any changes in the subject’s health and update the Medical History with any changes 
 
Assess concomitant medications 
 
Assessment of study ulcer 
 
Check for signs of clinical infection of the study ulcer. 
 
Clean the study ulcer with saline. 
 
Digital photo of the study ulcer 
 
Debridement, if required to remove non-viable tissue 
 
If the subject is eligible, perform the following procedures (TV1) immediately. 
 
If the subject is not eligible, discharge the subject from the study as a screen failure. 
 
TREATMENT VISIT (TV1) – RANDOMIZATION 
 
Randomize the subject 
 
Perform swab on study ulcer 
 
If randomized to the epidermal grafting arm: Harvest epidermal grafts using the CelluTomeTM 
device then apply the grafts to the wound bed. (Procedure detailed in Appendix 10). 
 
If randomized to standard of care apply provided foam to the ulcer. 
 
Apply multi-layer compression therapy 
 
Complete Quality of Life, PBI-P, and Time trade off questionnaires (see Appendices 19.5, 19.6, and 
19.2) 
 
Schedule the next study visit one week later 
 
TREATMENT PHASE VISITS TV2-4, 6, 8, 10, 12 
The following procedures must be performed: 
 
 
Pain assessment 
 
Assess compression bandaging 
 
Assess concomitant medications 
 
Check for any changes in the subject’s health and update the Adverse Events or Serious Adverse 
Events pages with any events 
 
Study ulcer closure assessment will be determined by a blinded observer 
o If the study ulcer is 100% re-epithelialized, the subject will be scheduled for a Pre-Healing 
Confirmation Visit (HCV) one week later 
o If the study ulcer is healed, no other study procedures need to be completed at this visit 
 
Check for signs of clinical infection. If clinical diagnosis of infection has been made, then the 
subject can be treated with topical antimicrobials or oral antibiotics, but topical antibiotics 
CANNOT be used on the study ulcer. During the time that an infection is being treated, 

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treatment with the IP will be stopped. 
 
Digital photo of the study ulcer 
 
Apply PrismaTM or approved antimicrobial dressing at TV4, TV8 for both Groups 1A/2A,2B; and at 
TV10 for Group 2C.  
 
Apply provided foam and multi-layer compression bandaging therapy. 
 
 
The next visit will be scheduled for one week. 
 
 
TREATMENT PHASE VISIT TV5 AND TV9 
The following procedures must be performed: 
 
Pain assessment 
 
Assess compression bandaging 
 
Assess concomitant medications 
 
Check for any changes in the subject’s health and update the Adverse Events or Serious Adverse 
Events pages with any events 
 
Study ulcer closure assessment will be determined by a blinded observer 
o If the study ulcer is 100% re-epithelialized, the subject will be scheduled for a Pre-Healing 
Confirmation Visit (HCV) one week later 
o If the study ulcer is healed, no other study procedures need to be completed at this visit 
 
Check for signs of clinical infection. If clinical diagnosis of infection has been made, then the 
subject can be treated with topical antimicrobials or oral antibiotics, but topical antibiotics 
CANNOT be used on the study ulcer. During the time that an infection is being treated, 
treatment with the IP will be stopped. 
 
Digital photo of the study ulcer 
 
Perform swab on study ulcer 
 
If in the epidermal grafting arm: Harvest epidermal grafts using the CelluTomeTM device and 
then apply the grafts to the wound bed. (Procedure detailed in Appendix 10). 
 
If randomized to standard of care apply the provided foam to the wound. 
 
Apply multi-layer compression bandaging therapy 
 
Complete Quality of Life, PBI-P, and Time trade off questionnaires (see Appendices 19.5, 19.6, and 
19.2) 
 
The next visit will be scheduled for one week 
 
TREATMENT PHASE VISIT TV7 
The following procedures must be performed: 
 
Pain assessment 
 
Assess compression bandaging 

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 
Assess concomitant medications 
 
Check for any changes in the subject’s health and update the Adverse Events or Serious Adverse 
Events pages with any events 
 
Study ulcer closure assessment will be determined by a blinded observer 
o If the study ulcer is 100% re-epithelialized, the subject will be scheduled for a Pre-Healing 
Confirmation Visit (HCV) one week later 
o If the study ulcer is healed, no other study procedures need to be completed at this visit 
 
Check for signs of clinical infection. If clinical diagnosis of infection has been made, then the 
subject can be treated with topical antimicrobials or oral antibiotics, but topical antibiotics 
CANNOT be used on the study ulcer. During the time that an infection is being treated, 
treatment with the IP will be stopped. 
 
Digital photo of the study ulcer 
 
Wound will be assessed for percentage area reduction (PAR) since TV1. Subjects in Group 2A 
whose wounds are < 40% will become Group 2C subjects and receive a graft at TV 7 and TV 11. 
 
For Group 2C subjects: Harvest epidermal grafts using the CelluTomeTM device and then apply the 
grafts to the wound bed. (Procedure detailed in Appendix 10). 
 
Apply multi-layer compression bandaging therapy 
 
The next visit will be scheduled for one week 
 
TREATMENT PHASE VISIT TV11 
The following procedures must be performed: 
 
Pain assessment 
 
Assess compression bandaging 
 
Assess concomitant medications 
 
Check for any changes in the subject’s health and update the Adverse Events or Serious Adverse 
Events pages with any events 
 
Study ulcer closure assessment will be determined by a blinded observer 
o If the study ulcer is 100% re-epithelialized, the subject will be scheduled for a Pre-Healing 
Confirmation Visit (HCV) one week later 
o If the study ulcer is healed, no other study procedures need to be completed at this visit 
 
Check for signs of clinical infection. If clinical diagnosis of infection has been made, then the 
subject can be treated with topical antimicrobials or oral antibiotics, but topical antibiotics 
CANNOT be used on the study ulcer. During the time that an infection is being treated, 
treatment with the IP will be stopped. 
 
Digital photo of the study ulcer 
 
Group 2C subjects will receive a graft. Harvest epidermal grafts using the CelluTomeTM device and 
then apply the grafts to the wound bed. (Procedure detailed in appendix). 
 
Apply multi-layer compression bandaging therapy 

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 
Complete Quality of Life, PBI-P, and Time trade off questionnaires (see Appendices 19.5, 19.6, and 
19.2) 
 
The next visit will be scheduled for one week 
 
FINAL TREATMENT PHASE VISIT (TV13) 
The procedures must be performed: 
 
Pain assessment 
 
Assess compression bandaging 
 
Assess concomitant medications 
 
Check for any changes in the subject’s health and update the Adverse Events or Serious Adverse 
Events pages with any events 
 
Study ulcer closure assessment will be determined by a blinded observer 
 
Clean the study ulcer with saline 
 
Digital photo of the study ulcer 
 
Complete Quality of Life, PBI-P, and Time trade off questionnaires (see Appendices 19.5, 19.6, and 
19.2) 
 
UNSCHEDULED VISITS 
Unscheduled visits may be required in addition to the visits detailed above. Additional visits are at the 
discretion of the investigator. An example of an unscheduled visit is when a change in compression 
bandaging is required between scheduled visits. The details of these unscheduled visits with subjects 
will be recorded in the medical records/source documents and on the CRF. 
 
MISSED VISITS 
If a subject misses a visit, the site is to make every effort to have the subject return as soon as possible 
to make up the visit. Once the subject is seen, he/she is to return to his/her original weekly visit 
schedule. For example, if a subject was seen regularly on Mondays but missed a scheduled Monday visit 
and came in on Wednesday, he/she should return the next Monday to maintain his/her weekly Monday 
visit schedule. 
 
6.4 
SUBJECT COMPLETION AND WITHDRAWAL 
 
SUBJECT COMPLETION 
 
A subject whose study ulcer has closed will be considered as having completed the study. 
 
A subject who completes the Treatment Phase will be considered as having completed the 
study. 
 
 

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SUBJECT PREMATURE WITHDRAWAL FROM THE STUDY 
A subject who is randomized into the Treatment Period of the study but who does not complete the 
study through TV4 has prematurely discontinued. 
 
All subjects have the right to withdraw at any point during treatment without prejudice. It will be 
documented whether or not each subject completed the clinical study. If for any subject, study 
treatment or observations were discontinued, the reason(s) will be recorded. 
 
The Investigator can discontinue a subject at any time if it is considered medically necessary. 
In addition, subjects WILL be withdrawn from the study, in consultation with the Medical Monitor and 
the Investigator, if any of the following are met: 
 
A subject is significantly non-compliant with the requirements of the protocol. 
 
A subject becomes pregnant (Note: the pregnancy will be followed up to term for safety 
follow-up. Relevant safety information collected after the study has completed will be 
reported as supplemental information.) 
 
A subject has revascularization surgery on the leg with the study (target) ulcer. 
 
A subject has a target ulcer wound bed that has exposed bone, tendon or fascia. 
 
The subject’s study ulcer cannot be dressed with multi-layer compression. 
 
Two separate infections with no response to allowable treatments 
 
The subject’s ulcer merges with an adjacent ulcer. 
 
 
Premature withdrawal from the study MAY occur if: 
 
A subject is treated with a prohibited medication. This decision will be made by the Medical 
Monitor in conjunction with the Investigator as to whether premature withdrawal is 
warranted. 
 
 
Every attempt should be made to collect follow-up information. The reason for treatment 
discontinuation or withdrawal from the study will be recorded in the source documents and on the 
appropriate page of the CRF. 
Before a subject is identified as lost-to-follow up, the site should make all reasonable efforts to contact 
the subject. These attempts must be documented and should include at a minimum one phone call and 
one certified letter. 
In the event that a subject is prematurely discontinued from the study at any time due to an adverse 
event of SAE, SAE procedures must be followed. 
 
 
SCREEN FAILURES 
A subject who has signed a consent form, has been assigned a screening number, but is not randomized 
is classified as a screen failure. Subject number, demography, and reason for screen failure will be 
collected. 
 

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7 
STANDARD OF CARE AND CONCOMITANT MEDICATIONS 
Beginning at the S1 visit, ALL subjects must have their study ulcer managed using the SOC procedures 
noted below. 
 
 
7.1 
CLEANING THE STUDY ULCER 
 
Remove the bandage and wash the leg. At any time when the bandage is removed, the leg should be 
elevated for as much time as possible. 
Wash the leg with potable saline or tap water. Gently irrigate the study ulcer prior to each dressing 
change with warm tap water or saline.  Strict aseptic technique is not needed. 
During the Treatment Phase, the washing and cleaning of the VLU must be done with great care on the 
patients receiving epidermal grafting. 
 
 
7.2 
DEBRIDEMENT OF THE STUDY ULCER 
 
It is important to remove all non-viable and necrotic material from the target ulcer prior to enrolling the 
patient. Extensive debridement is not permitted during the treatment phase. Care must be taken not to 
remove the graft by debriding the ulcer. Briefly, the following procedures should be followed, 
1. The target ulcer and the surrounding skin are prepped with saline solution. 
2. Anesthesia, topical or injected, is applied to the ulcer as necessary to reduce patient discomfort. 
3. Using clean technique. All non-viable tissue in the wound bed is to be removed from the wound 
bed. 
4. Ideally hemostasis is achieved using direct pressure. Cautery may be employed if necessary. 
 
 
7.3 
COMPRESSION BANDAGING 
 
Multi-layer compression is applied at every visit following the manufacturer’s suggested procedure 
technique. Patients cannot be enrolled until they have received at least 14 days of compression 
therapy. Training in compression wrapping will be provided. 
 
 
7.4 
SUBJECT INSTRUCTIONS 
 
Subjects will be instructed to elevate the study ulcer limb above their heart as much  as  possible. 
Subjects will be instructed to keep the bandaging dry and to call or visit the study site if the bandaging 
becomes soiled or is removed. 

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7.5 
CONCOMITANT MEDICATIONS 
 
The subject may be administered any necessary medications, at the discretion of the Investigator, 
provided such medications are not applied topically to the ulcer surface (topical medication can be 
applied to other surfaces around the ulcer). 
 
All medications and therapies administered or taken by the subject beginning 30 days prior to signing 
the ICF and throughout the study will be recorded in the source documents and, for randomized 
subjects, on the appropriate page of the Case Report Form (CRF). 
 
 
7.5.1 EXCLUDED MEDICATIONS AND THERAPIES 
 
The following treatments and medications are prohibited within 30 days prior to randomized treatment 
and throughout the study: 
 
Heat lamps 
 
UV lights 
 
Whirlpool baths 
 
Water Piks
 
Hyperbaric Oxygen 
 
Jet water streams (other than gentle saline irrigation) 
 
Wound dressings that include growth factors, engineered tissues or skin substitutes (e.g., 
Regranex®, Dermagraft®, Apligraf®, GraftJacket®, OASIS®, Primatrix®, Matristem®,etc.) 
 
Revascularization surgery on the leg with study (target) ulcer within 3 months 
 
Radiation therapy to the foot 
 
Topical antibiotics or other non-approved topical agents (with the exception of 
anesthetics used during debridement). 
 
Patients on Trental may remain on the medication but patients should not be started on 
Trental during the trial. 
 
Systemic steroids/oral corticosteroids (note: inhaled steroids are acceptable) 
 
Other Immunosuppressive agents 
 
Autoimmune disease therapies 
 
Cytostatic drugs 
 
Any investigational treatment/medications 
 
 
7.5.2 ALLOWABLE MEDICATIONS AND THERAPIES 
 

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The following treatments are allowed during the study, if in the opinion of the Investigator, they are 
required for proper care of the research subject: 
 
 
Use of anesthetics for debridement. 
 
Treatment with systemic antibiotics for acute or chronic infection; however, prophylactic 
use of systemic antibiotics is not allowed. 
 
Topical antimicrobials as listed for use to treat an infection to the reference ulcer or at the 
scheduled treatment weeks. 
 
Use of Hibiclens Skin Cleanser for cleansing of general skin, wound and the harvest site. 
Alternatively, chlorhexidine soap may also be used.  
 
Other medications/therapies that are not otherwise prohibited and, in the opinion of the 
Investigator, are required for proper medical care. 
 
 
8 
DESCRIPTION OF PROTOCOL ASSESSMENTS AND PROCEDURES 
 
8.1 
INFORMED CONSENT 
 
Written informed consent will be obtained for this study by the Investigator or suitably qualified 
designee from all subjects before the performance of any protocol-specific procedure. This study will be 
conducted in accordance with the provisions of the Declaration of Helsinki. 
 
In obtaining and documenting informed consent the Investigator must comply with applicable 
regulatory requirements and must adhere to Good Clinical Practice (GCP). Evidence of GCP training is 
required for all investigators. The Investigator, or designee, must fully inform subjects of all pertinent 
aspects of the study. Before informed consent may be obtained, the Investigator, or a person 
designated by the Investigator, must provide the subject ample time and opportunity to inquire about 
details of the study and to decide whether or not to participate in the trial. All questions about the trial 
must be answered to the satisfaction of the subject. Prior to the subject’s participation in the trial, the 
written informed consent must be signed and personally dated by the subject and by the person who 
conducted the informed consent discussion. 
 
 
8.2 
ASSESSMENT OF ELIGIBILITY 
 
At each visit during the Screening Period, the Investigator must assess a subject’s continued suitability 
and eligibility for the trial, especially with regards to the Inclusion and Exclusion criteria. If the subject is 
not suitable or eligible for the trial, then the subject will be a screen failure. Screen failure subjects may 
be re-entered into the study at a later time and re-screened. 
 
 
8.3 
RE-SCREENING 

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If a subject initially fails to meet inclusion/exclusion criteria and is later reconsidered for 
participation, the subject will be re-consented and assigned a new screening number at the time 
of re-screening. Subjects who fail their first screening attempt may be re-screened again (i.e., up to 
three screenings) and may be enrolled if they are found to meet ALL inclusion and NO exclusion 
criteria at the second screening visit. 
 
 
8.4 
SUBJECT DEMOGRAPHICS, MEDICAL HISTORY, ULCER HISTORY 
 
8.4.1 DEMOGRAPHICS 
 
For the purposes of this study, demographic information will include: 
 
Dates of Informed Consent Form signature 
 
Date of birth 
 
Gender 
 
Race 
(American 
Indian/Alaskan 
Native, 
Asian, 
Black/African 
American, 
Native 
Hawaiian/Pacific Islander, Caucasian, or other) 
 
Ethnicity (Hispanic/Latino or Not Hispanic/Latino) 
 
Use of tobacco products 
 
 
8.4.2 MEDICAL HISTORY 
 
A medical history will be recorded during the Screening Period and will include: 
 
ALL ongoing medical conditions 
 
ALL previously  resolved  medical  conditions  related  to  Venous  Insufficiency  or  Leg 
Ulceration or which are relevant in the opinion of the Investigator 
 
ANY prior medical conditions that have resolved within the last year 
 
Events that emerge prior to the randomization visit (TV1) will be recorded in the medical history and not 
as Adverse Events. Aside from being used to determine subject eligibility, this information will permit 
the Investigator to record the nature, duration and severity of any ongoing baseline medical conditions 
prior to receiving investigational product treatment. 
 
Medical histories will be recorded using the body system categories outlined below: 
 
 
Cardiovascular 
 
Lymphatic 
 
Respiratory 
 
Hematologic 
 
Gastrointestinal 
 
Immunologic 
 
Renal 
 
Dermatologic 
 
Hepatic 
 
Psychiatric 

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 
Neurological 
 
Genitourinary 
 
Endocrine 
 
Other 
For each relevant history, the following will be documented: 
 
Disease/disorder/condition 
 
Date of diagnosis 
 
History status (resolved or ongoing) 
8.4.3 LEG ULCER HISTORY 
 
Duration of the current VLU 
Note: ‘Duration’ is defined as the length of time that the study ulcer has been open at this 
location since the last time it was fully closed. 
 
Current bandaging system used for the VLU and length of time that this has been used 
 
Prior treatments that have been used on the VLU 
 
Age when the subject developed his/her first VLU 
 
Total number of previous VLUs 
 
Location of the current VLU 
Note: ‘Study ulcer location’ is defined by the ulcer being on the left or right leg, by the 
location of the ulcer on the malleolus, low gaiter or high calf, and by the positioning of the 
ulcer as lateral, medial, anterior or posterior. 
 
Number of additional VLUs and location of each present at the screening visits 
 
History of VLU recurrence 
Note: ‘Recurrence’ is defined as the re-opening of the study ulcer after complete healing. 
 
History of a DVT (deep vein thrombosis) in the study leg 
 
Presence of hyper-pigmentation, edema, varicosities, lipodermatosclerosis, thickened nails 
and dermatitis. 
 
 
8.4.4 PHYSICAL EXAM & VITAL SIGNS 
 
PHYSICAL EXAMINATION 
 
The physical examination will include routine examinations for the following: 
 
 
HEENT 
 
Abnormalities of the extremities 
 
Neurologic abnormalities 
 
Heart/cardiovascular abnormalities 
 
Musculoskeletal abnormalities 

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 
Dermatologic abnormalities 
 
Any other body system for which an abnormality is noted and which, in the opinion of the 
Investigator, is relevant to the safety of the subject or could impact safety or efficacy 
results for the subject; i.e., the abnormality is clinically significant. 
 
Each abnormality will be recorded and the Investigator will record an assessment of its clinical 
significance. 
 
VITAL SIGNS 
The following vital signs will be collected at S1 visit only: 
 
Height  
 
Weight 
 
BMI calculated. 
 
Seated blood pressure (take after the subject has been seated for at least 5 minutes) 
 
Pulse 
 
Temperature 
 
 
8.5 
VASCULAR ASSESSMENTS 
 
8.5.1 ANKLE-BRACHIAL INDEX (ABI) 
 
Ankle Brachial Index (ABI) is the ratio of blood pressure measured at the ankle to that measured at the 
arm. An ABI < 0.75 indicates that there is a high probability that arterial insufficiency is present (positive 
predictive value 95% in a general practice population). 
 
It should be noted that incompressible, calcified arteries may occur in diabetes causing a falsely elevated 
ABI, so if the subject has other signs or symptoms that could suggest peripheral arterial disease, further 
investigations to determine vascular status may be warranted. 
 
A documented record of an ABI test performed using the study ulcer (target) leg, within 3 months of the 
first Screening visit (S1) is acceptable for the purposes of this study otherwise this must be completed in 
the Screening Period. 
 
NOTE: Compression bandaging must not be applied to subjects entered onto this study unless the ABI is 
confirmed to be greater than 0.75. 
 
The technique for measuring ABI explained in Appendix 19.1. 

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8.5.2 SKIN PERFUSION PRESSURE 
 
Skin perfusion pressure (SPP) can also be employed to evaluate the patient’s vascular status. SPP is 
obtained using a Laser Doppler. Patients with SPP less than 30 mmHg have Arterial Insufficiency and are 
not candidates for enrollment. 
 
 
8.6 
PAIN ASSESSMENTS 
 
Pain intensity of the VLU is to be assessed before any dressing changes or other wound manipulations at 
all screening visits, treatment visits, and at follow-up period visits. 
 
Subject will be asked to rate his/her pain on a scale of 0 to 10 with 0 being “no pain” and 10 being the 
“worst pain possible”. 
 
8.7 
ULCER ASSESSMENTS 
 
8.7.1 STUDY ULCER EXUDATE ASSESSMENTS 
 
The Investigator will determine the amount and type, if any, of study ulcer exudate. In determining the 
amount of study ulcer exudate, the Investigator must take into account the amount of exudate 
absorbed into the study ulcer dressing. The following categories will be used to quantify the amount & 
describe the type of ulcer exudate: 
 
 
 
Study Ulcer Exudate Assessment 
Volume 
 
No exudate 
 
Minimal amount 
 
Light (scant) or small amount 
 
Moderate amount 
 
Heavy/large/copious amounts 
Type 
 
Not applicable: no exudate present 
 
Serous: clear or light yellow watery plasma 
 
Serosanguinous: pink to light-red watery plasma 
 
Sanguineous: red with fresh bleeding 
 
Opaque exudate: green or tan 

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8.7.2 STUDY ULCER INFECTION ASSESSMENTS 
 
The presence/absence of the following signs of infection at the study ulcer site will be documented at 
each visit. Infection of the index wound will be assessed using the STONES method developed by Woo 
and Sibbald.29 The wound can be considered infected when: 
 
 
 
 
INFECTION AT STUDY ULCER SITE PRIOR TO RANDOMIZATION 
If the infection occurs prior to randomization i.e., prior to the first Treatment Phase visit (TV1), then the 
subject will be ineligible to be randomized. 
 
INFECTION AT STUDY ULCER SITE AFTER RANDOMIZATION 
If infection of the study ulcer site occurs after randomization i.e., after the Randomization visit (TV1), 
record the infection as an adverse event, and treat as appropriate with topical antimicrobial (e.g. topical 
silver antimicrobial) and/or oral (but not topical) antibiotics at the discretion of the investigator. 
Note: topical antibiotics to the study ulcer site are prohibited 
 
A subject with an infected ulcer that is being treated by the Investigator will remain in the study unless 
the situation requires an alternative methodology that violates the protocol. Antibiotic interventions will 
be recorded on the Concomitant Medications Form and the event will be categorized as an Adverse 
Event, serious if it meets the definition of that category. All subjects who show evidence of an ulcer 
infection must have it reported on an Adverse Event Form. 
 
All subjects will be instructed to contact the Investigator if signs or symptoms of infection develop prior 
to their next scheduled visit. 
Study Ulcer Infection Assessment 
Three of the following signs or symptoms: 

Increased surface area 

Increased  periwound  margin  temperature  by  more  than  3⁰F  difference  between  2 
mirror image sites 

Exposed bone or can be probed to the bone 

New areas of breakdown or satellite lesions 

Presence of swelling or reddened skin in periwound area 

Increased wound drainage 

Unpleasant, sweet, or sickening odor present 
NOTE: A wound  that  can  be  probed  to  the  bone  should warrant  work-up  to  eliminate 
osteomyelitis even if other factors are absent. 

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During an episode of infection, the Investigator can continue multi-layer compression.   However, the 
dressings should be changed at least every 72 hours until infection is resolved. 
 
8.7.3 INVESTIGATOR ASSESSMENT OF STUDY ULCER CLOSURE 
 
“Complete healing” of the study ulcer is defined as 100% re-epithelialization without drainage.  At each 
visit, the investigator will assess the wound by answering the following questions: 
 
Study ulcer 100% re-epithelialized? 
 
Drainage is absent? 
 
Both questions must be answered “yes” for the study ulcer to be considering having reached “complete 
closure”. 
 
The date of complete healing is defined as the date of the first assessment of 100% re-epithelialization. 
 
8.8 
STUDY ULCER PHOTOGRAPHS 
 
The study ulcer will be digitally photographed according to the schedules in this protocol.  The digital 
photographic measurements will be used for surface area measurements to determine eligibility. 
 
8.9 
RANDOMIZATION 
 
Subjects who are eligible to participate in the trial will be randomized by computer to one treatment 
group at the TV1 visit. 
 
8.10 ASSESSMENT OF MULTI-LAYER COMPRESSION THERAPY 
 
The following measurements will be taken to assess the performance of the compression bandaging 
during the Screening and Treatment Phase visits and at selected Follow-up visits: 
1. Whether the bandage was in place at each visit (Yes/No). 
2. If the bandage was not in place, the date it was removed and the reason for removal 
(slippage, strikethrough or other). 
3. If the bandage is in place but needs to be changed at an unscheduled visit, the reason 
for removal/change must be recorded from the following: 
a.   Maximum wear time 
e.  Primary dressing change needed 
b.   Subject withdrawn 
f. Soiled 
c. Adverse event 
g.  Subject request 
d.   Slippage 
h. Other 

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9 
STATISTICAL ANALYSIS PLAN 
 
 
 
SerenaGroup® 
Statistical Analysis Plan (SAP): CelluTomeTM-VLU-013 
A Multi-center Randomized Open-Label Controlled Clinical Trial Evaluating 
Suction Blister Grafting utilizing a Novel Harvesting Device (CelluTomeTM) and 
Standard of Care vs. Standard of Care alone in the Treatment of Venous Leg 
Ulcers. 
Sponsor: SerenaGroup® 
CONFIDENTIAL 
The information contained herein is confidential and proprietary.  
It is intended for the use of the SerenaGroup® and Strategic 
Solutions, and others directly involved in this clinical investigation. No 
unpublished information presented in this document may be 
reproduced or referred to in publications or public presentations 
without the expressed written consent of SerenaGroup®. 
Version 2 

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9.1 
BRIEF TRIAL DESCRIPTION 
 
THIS TRIAL IS A RANDOMIZED CONTROLLED TRIAL (RCT) IN WHICH SUBJECTS WITH VENOUS LEG 
ULCERS (VLUS) WILL BE RANDOMIZED 1:1 TO A MAXIMUM OF 3 TREATMENTS OF CELLUTOMETM 4 
WEEKS (GROUP 1A) OR STANDARD OF CARE (SOC; GROUP 2A) AND FOLLOWED FOR 12 WEEKS. 
PRIMARY ENDPOINT IS TIME TO HEAL WITHIN 6 AND 12 WEEKS.  IF WOUNDS IN GROUP 2A HAVE NOT 
BEEN REDUCED IN AREA BY AT LEAST 40% BY 6 WEEKS, PATIENTS WILL BE ALLOWED TO RECEIVE 
CELLUTOMETM TREATMENT (GROUP 2C; 2 TREATMENTS WITHIN THE REMAINING 6 WEEKS). THE 
REMAINDER OF THE SOC PATIENTS WILL BECOME GROUP 2B.
Trial Statistician: 
Marissa J. Carter PhD MA MAPWCA 
President 
Strategic Solutions, Inc 
307-587-5352 
mcarter@strategic-solutions-inc.com 

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9.1.1 
GENERAL 
Descriptive statistical methods will be used to summarize the data from this study with hypothesis 
testing performed for primary and secondary endpoints. These include number of subjects (n), mean, 
median, standard deviation, minimum, and maximum for continuous data, and frequencies and 
percentages for categorical data. All data collected during the study will be reported and analyzed. 
Unless specified otherwise, all statistical testing will be two-sided and performed using a significance 
(alpha) level of 0.05. 
All statistical analyses will be conducted using PASW 19. 
 
 
9.2 
RESEARCH HYPOTHESES 
Primary endpoints 
H1: Time to heal 
 
Time to heal after 12 weeks of CelluTomeTM + SOC (Group 1A; maximum of 3 CelluTomeTM applications) 
versus 12 weeks of SOC (Group 2B) will be equal for both groups or time to heal after 6 weeks of 
CelluTomeTM + SOC (Group 1A; maximum of 2 CelluTomeTM applications) versus 6 weeks of SOC (Group 
2A) will be equal for both groups. Formally, H0: T1–T2=0; HA: T1–T2=D1 ≠ 0, where T1 is the time to 
heal for Group 1A, T2 is the time to heal for Group 2A or 2B depending whether T2 is 12 or 6 weeks, D1 
is the difference (T1–T2) assuming the alternative hypothesis, and statistical test used is log rank applied 
to a Kaplan-Meier analysis. If either result is statistically significant, results will be adjusted using Cox 
regression and appropriate covariates. 
 
Secondary endpoints 
H2: Proportion of wounds healed 
 
The proportion of wounds healed at 12 weeks after 12 weeks of CelluTomeTM + SOC (Group 1A; 
maximum of 3 CelluTomeTM applications) versus 12 weeks of SOC (Group 2B) will be equal for both 
groups. Formally, H0: P1–P2=0; HA: P1– P2=D1≠0, where P1 is the proportion of wounds healed for 
Group 1A, P2 is the proportion of wounds healed for Group 2B, D1 is the difference (P1–P2) assuming 
the alternative hypothesis, and statistical test used is chi square. 
 
H3: Incidence of Adverse Events (AEs) 
 
The incidence of adverse events (AEs) by 12 weeks after 12 weeks of CelluTomeTM + SOC (Group 1A; 
maximum of 3 CelluTomeTM applications) 12 weeks of versus SOC (Group 2B) will be equal for both 
groups. Formally, H0: I1–I2=0; HA: I1– I2=D1≠0, where I1 is the incidence of AEs for Group 1A on a 
per subject basis , I2 is same metric for Group 2B, D1 is the difference (I1–I2) assuming the alternative 
hypothesis, and statistical test used is the Mann-Whitney test. 
 
H4: Correlation of wound area with protease activity at 4 weeks 
 
The Pearson correlation coefficient (or Spearman’s rho in the case of severe non-normality) calculated 

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from the mean change in wound area and protease activity between baseline and 4 weeks after 4 weeks 
of CelluTomeTM + SOC (Group 1A) versus 4 weeks of SOC (Group 2A) will be equal for both groups. 
Formally, H0: r1–r2=0; H1: r1–r2=D1 ≠ 0, where r1 is the Pearson correlation coefficient for subjects in 
Group 1A calculated  from difference in mean wound area and difference in mean protease activity 
between baseline and 4 weeks, r2 is the is the same specified metric for subjects Group 2A, D1 is the 
difference (r1–r2) assuming the alternative hypothesis, and the statistical test used is Steiger’s Z test 
with the assumption that r will have the same sign for both groups. 
 
H5: Correlation of wound area with protease activity at 8 weeks 
 
The Pearson correlation coefficient (or Spearman’s rho in the case of severe non-normality) calculated 
from the mean change in wound area and protease activity between baseline and 8 weeks after 8 weeks 
of CelluTomeTM + SOC (Group 1A) versus 8 weeks of SOC (Group 2B) will be equal for both groups. 
Formally, H0: r1–r2=0; H1: r1–r2=D1 ≠ 0, where r1 is the Pearson correlation coefficient for subjects in 
Group 1A calculated  from difference in mean wound area and difference in mean protease activity 
between baseline and 8 weeks, r2 is the is the same specified metric for subjects in Group 2B, D1 is the 
difference (r1–r2) assuming the alternative hypothesis, and the statistical test used is Steiger’s Z test 
with the assumption that r will have the same sign for both groups. 
 
H6: Reduction in pain score at 12 weeks 
 
The change in mean pain score between baseline and at 12 weeks after 12 weeks of CelluTomeTM + 
SOC (Group 1A) versus 12 weeks of SOC (Group 2B) will be equal for both groups. Formally, H0: μ1–
μ2=0; H1: μ1–μ2=D1 ≠ 0, where μ1 is the mean difference in pain score for subjects in Group 1A 
between baseline and 12 weeks, μ2 is the is the same specified metric in Group 2B, D1 is the 
difference (μ1–μ2) assuming the alternative hypothesis, and the statistical test used is the paired t 
test if data are normal and the Mann-Whitney test on a non-paired basis if data are non-normal. 
 
H7: Proportion of wounds healed at 12 weeks (Groups 2B versus 2C) 
The first hypothesis to be tested is that the proportion of wounds healed in Group 2C (12 weeks of SOC + 2 
CelluTomeTM applications ) is no more than 15% lower than the proportion of wound healed in Group 2B 
(12 weeks of SOC).  Noninferiority is established if the lower limit of the (1-2α) x 100% CI (confidence 
interval) for the difference (Group 2C – Group 2B) is above -15% where the equivalence margin, δ, is 15%. 
If non-inferiority is not established because the proportion of wounds healed in Group 2C is much higher 
than in Group 2B, the superiority hypothesis testing used in H2 will be utilized. 
 
H8: Incidence of Adverse Events (AEs) (Groups 2B versus 2C) 
 
The incidence of adverse events (AEs) by 12 weeks after 12 weeks of CelluTomeTM + SOC (Group 2C; 
maximum of 2 CelluTomeTM applications) versus 12 weeks of SOC (Group 2B) will be equal for both 
groups. Formally, H0: I1–I2=0; HA: I1– I2=D1≠0, where I1 is the incidence of AEs for Group 2C on a 
per subject basis , I2 is same metric for Group 2B, D1 is the difference (I1–I2) assuming the alternative 
hypothesis, and statistical test used is the Mann-Whitney test. 

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9.3 
SAMPLE SIZE CALCULATIONS 
A two-sided logrank test with an overall sample size of 225 subjects (113 in the control group and 112 in 
the treatment group) achieves 86.1% power at a 0.05 significance level to detect a hazard ratio of 1.74 
when the proportion of wounds healed in the control group is 0.5. The study lasts for 12 weeks with all 
subjects beginning the study together (no accrual periods). The proportion dropping out of the control 
group is 0.033 per week. The proportion dropping out of the treatment group is 0.0083 per week. The 
proportion switching from the control group to another group with a hazard ratio equal to that of the 
treatment group is 0. 
9.4 
RANDOMIZATION 
Randomization will be stratified by age of wound at the first screening visit (1-6 months and > 6 
months). 
The randomization algorithm will employ blocks of 2 and 4, with random selection of block sizes (Pass 
11). 
 
9.5 
INTERIM OPERATIONS (WHILE RECRUITMENT IS CONTINUING) 
Safety 
The following variables will be analyzed for the first 40 subjects after each subject has completed the 
study (or been withdrawn): 
 
Initial assignment (Group 1A or 2A) 
 
Subsequent assignments (Groups 2B and 2C) 
 
Site 
 
Ulcer area at randomization (TV1) through TV13  
 
Patients withdrawn 
 
Patients who experience infection (and visit number(s)) 
 
The report should show accrued data in aggregate and by site. The report should be available in 
Excel format. 
If for some reason severe imbalances develop between groups or at sites, a new randomization scheme 
will be implemented with additional or modified stratification based on the most affected variables. 
 
 
9.6 
INTERIM ANALYSIS 

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One interim safety and efficacy analysis will be performed when approximately 110 subjects have been 
enrolled (approximately 50% of subjects). The total number of AEs and SAEs will be calculated, and the 
proportion of healed wounds tabulated for all groups (at 12 weeks). New sample size calculations will 
be performed based on the proportion of healed wound data (time to heal). No statistical analysis will 
be conducted. 
 
 
TRIAL STOPPING RULES 
The Medical Monitor may unblind, or appoint an independent assessor to unblind interim data analyses 
to determine whether the study should be stopped if any of the following occur: 
 
 
 
If the primary outcome likely has reached statistical significance and there is agreement to 
analyze the secondary outcomes regardless of whether they are likely to achieve statistical 
significance or not. 
 
If the primary outcome has likely not reached statistical significance and based on futility 
boundary analysis, the numbers of additional subjects needed to reach significance based on the 
rate data are too high to realistically extend the trial. 
 
> 25% of ulcers have deteriorated (meaning an increase in area from baseline to 12 weeks). 
 
A significant proportion of patients (> 25%) in either group continue to experience infections 
despite Prisma/antimicrobial treatment or other measures 
 
Excessive non-planned withdrawal of subjects 
 
 
List of variables for interim analysis 
 
Site ID 
 
Subject ID 
 
Treatment assignment 
 
Gender 
 
Pain score at baseline and 12 weeks 
 
Wound healed (Y/N) by 12 weeks (after 12 weeks have elapsed from date of randomization) 
 
When wound healed (days from randomization) 
 
Ulcer area at baseline and 6/12 weeks 
 
AEs (by category; have separate category for infected wounds) and SAEs at 12 weeks 
(count by subject, and description/category where applicable) 
 
Withdrawn subjects or subjects that have been lost to follow-up (count and by assignment with 
reason where applicable) 
 
Number of subjects in Groups 2B and 2C. 
 
 
PATIENT POPULATIONS 
The populations defined for the final analysis will include the intent-to-treat (ITT), per protocol (PP), and 
safety populations. 

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INTENT-TO-TREAT POPULATION 
 
The ITT population will be analyzed for primary and secondary endpoints up to 12 weeks; however, 
Index Ulcers that have been healed are still subject to confirmed wound closure for 2 weeks later (up to 
14 weeks for ulcers initially healed in the 12th week). 
 
 
PRE PROTOCOL POPULATION 
The PP population for the 12-week study will comprise all subjects for which no protocol violations 
occurred and in which for both groups’ complete data are available for all primary and secondary 
endpoints, and all covariates needed to conduct adjusted analyses. 
 
 
SAFETY POPULATION 
The safety population will be all subjects who have received at least CelluTomeTM treatment or have 
completed the first visit (randomization, TV1). 
 
 
9.7 
STATISTICAL METHODS 
 
MISSING DATA 
Missing data may be the result of missed visits, subjects lost to follow-up or who have died, or data not 
available (e.g., smoking status). 
 
 
Missing primary endpoint data within 12 weeks from start of study will not be imputed for ITT 
populations as these will constitute right-censored data in the time to heal analysis. The last visit for 
which data are available will constitute the start of censoring (healing outcome). For secondary 
endpoints within 12 weeks from start of study, the last observation carried forward (LOCF) principle will 
be used for ITT populations. 
 
 
For adjusted analyses of primary and secondary endpoints, missing data for covariates used to adjust 
analyses may be imputed in separate models when the missing data for each covariate is ≤ 30% and it 
can be reasonably demonstrated that the missing data for each covariate are MCAR. 
 
 
FINAL ANALYSIS 
Analysis can be started when database lock for the trial is initiated. In regard to statistical modeling, the 
initial list of independent variables will be examined for correlation between pairs. In the event that 

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correlation (however calculated) exceeds 0.7, a selection will be made between the 2 variables to avoid 
possible issues of co linearity and variance inflation. 
The following analysis will be conducted: 
1. Flow chart (subjects) 
2. Overall trial statistics (enrollment dates, site numbers, numbers of subjects) 
3. Demographics between groups at baseline (no statistical testing but identification of likely trial 
imbalances) 
4. Count of subjects in each group 
5. Primary endpoints within 6 and 12 weeks (time to heal; previously defined by groups) will be 
analyzed by Kaplan-Meier and log rank test (unadjusted); and then Cox regression to adjust for 
the following variables (with and without covariate imputation): 
 
 
Site 
 
Year enrolled (if trial lasts 2 years or more) 
 
Treatment group 
 
Initial area at randomization (cm2) 
 
Initial wound depth (cm) 
 
Age of wound at enrollment (days) 
 
Smoking status 
 
Prior VLU 
 
Pain score at randomization 
 
Patient age 
 
Gender 
 
Ethnicity/race 
 
VCS score 
 
Diabetes 
 
Patient on pain medications 
 
Smoking status 
 
BMI 
 
Infection episodes 
 
6. Secondary endpoints will be analyzed as follows: 
 
 
Proportion of wounds healed at 12 weeks will be analyzed by chi square (unadjusted); 
this endpoint may also be analyzed using logistic regression to adjust for the following 
variables (with and without covariate imputation) if needed: 
 
o Site 
o Year enrolled (if trial lasts 2 years or more) 
o Treatment group 
o Initial area at randomization (cm2) 
o Initial wound depth (cm) 
o Age of wound at enrollment (days) 
o Smoking status 
o Prior VLU 
o Pain score at randomization 

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o Patient age 
o Gender 
o Ethnicity/race 
o VCS score 
o Diabetes 
o Patient on pain medications 
o Smoking status 
o BMI 
o Infection episodes 
Note: unadjusted testing for Group 2C versus 2B will be non-inferiority, followed 
by superiority testing if the former fails and proportion of wounds healed in 
Group 2C is much higher than in Group 2B. 
 
 
A summary of the incidence of adverse events (count by patient): 
 
o AE (category) 
o SAE (category; brief description; resolution; should include death) 
o When event happened in relation to start of treatment (days) 
o Associated patient ID, site ID 
 
Incidence of AEs will be analyzed by Mann-Whitney test on a per subject basis.  
 
 
Correlation of changes in wound area with changes in protease activity will be first 
analyzed by calculating the Pearson correlation coefficient for each group or 
Spearman’s rho if data are grossly non-normal. For each subject the change in protease 
activity is calculated by subtraction of the value at 4 or 8 weeks from the value at 
baseline; reduction in wound area is calculated similarly. Differences in r will be 
analyzed using Steiger’s Z test with the assumption that r will have the same sign for 
both groups. If significant differences are found between groups, further analysis using 
GLM doubly multivariate repeated measures (change in wound area and protease 
activity between baseline and 4 and 8 weeks) to adjust for the following variables (with 
and without covariate imputation) may be undertaken (ordinal re-categorization will be 
done if data are severely non-normal): 
 
o Site 
o Year enrolled (if trial lasts 2 years or more) 
o Treatment group 
o Initial area at randomization (cm2) 
o Initial wound depth (cm) 
o Age of wound at enrollment (days) 
o Smoking status 
o Prior VLU 
o Pain score at randomization 
o Patient age 
o Gender 
o Ethnicity/race 
o VCS score 

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o Diabetes 
o Patient on pain medications 
o Smoking status 
o BMI 
o Infection episodes 
 
 
Reduction in pain score (baseline – Week 12) will be analyzed by paired t test if the 
dependent variable data are not grossly non-normal or the Mann-Whitney test if they are 
grossly non-normal (unadjusted). 
To create the flow chart, the following numbers will be required for each group: eligible (n), screened 
(n), screen failure (n, with categorical reasons), randomized (n), completed 12 weeks study (n), 
withdrawals or lost to follow-up after randomization (n, with categorical reasons). 
These variables are required for the final analysis: 
 
Site ID (alphanumeric) 
 
Patient ID (alphanumeric) 
 
Year enrolled (numeric; date, year only) 
 
Group assignment (nominal factor, [1A, 2A, 2B, 2C]; note: subjects in 2A can also have 2B or 2C 
assignments as well) 
 
Lost to follow up (binomial factor [1,0; 1 = yes]; estimated date lost to follow-up; associated 
patient ID; categorical reason for lost to follow-up) 
 
Death during study (binomial factor [1,0; 1 = yes]; estimated date when death occurred) 
 
Gender (nominal factor [1, 0; male = 1]) 
 
Subject age at S1 (continuous variable with breakpoint at > 90 years if > 90) 
 
Ethnicity/race (multinomial factor) 
 
Smoking status at S1 (ordinal factor: [1, 2, 3; never, ever, current]) 
 
Wound count (Poisson distribution variable; count of VLUs at patient level at randomization) 
 
Index Ulcer location (multinomial factor) 
 
Prior VLU at S1 (binomial factor [1,0; 1 = yes]) 
 
Wound age at S1 (continuous variable, days; S1) 
 
Pain score (continuous variable, 0-10, TV1 and 13) 
 
VCS score at S1 (continuous variable, 0-24) 
 
BMI at S1 (continuous variable) 
 
Diabetes at S1 (nominal factor [1, 0; yes = 1]) 
 
Subject on pain medication at S1 (nominal factor [1, 0; yes = 1]) 
 
Wound area (continuous variable, cm2; weekly, weeks TV1-13) 
 
Wound depth (continuous variable, cm; weekly, weeks TV1-13) 
 
Outcome healed at 12 weeks (binomial factor, [1,0; 1 = yes]) 
 
Time to heal (continuous variable, 0-84, days after randomization for healed wounds) 
 
Initial wound healed within 12 weeks and confirmed closed about 2 weeks later (binomial, [1,0; 
1 = yes]) 
 
Ulcer recurrence by 12 weeks (binomial factor, [1,0; 1 = yes]; estimated days after 
randomization when event occurred) 
 
Infection episode (Poisson variable, weeks TV1-13) 
 
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 
TEAE (Poisson distribution variable, count at patient level for each of 4 categories; date of onset) 
 
SAE (Poisson distribution variable, count at patient level; date of onset; resolution; brief 
description) 
 
ADJUSTMENT FOR FEWR 
 
Adjustment to control for the family wise error rate (FEWR) (also known as multiplicity of testing) will 
use the Hochberg step-up procedure thus: Let p1 ≥ p2 ≥ … pK be the ordered p-values and H1, H2, …, 
HK be the corresponding null hypotheses. Reject Hk and all Hj for j ≤ k if pk ≤ α/k. The adjusted p-values 
are pak = min {p1, 2p2, …kpk} for k = 1, 2, …, K. 
 
 
 

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10 ADVERSE EVENTS (DEFINITIONS AND REPORTING) 
The Investigator is responsible for the detection and documentation of events meeting the criteria and 
definition of an AE or SAE, as provided in this protocol. During the study when there is a safety 
evaluation, the Investigator or site staff will be responsible for detecting, documenting and reporting 
AEs and SAEs as detailed in this Section of the protocol. 
 
10.1 ADVERSE EVENTS 
 
An adverse event (AE) is defined as any unfavorable or unintended sign, symptom, or disease that 
occurs or is reported by the patient to have occurred, or a worsening of a pre-existing condition. An 
adverse event may or may not be related to the treatment regimen. All AEs and intercurrent illnesses 
must be recorded in the subject’s medical records and on the CRF. 
 
Adverse events will be defined as those events that occur after signing the informed consent until the 
final study visit. A description of the AE along with the onset date, end date, severity, action taken, 
treatment, outcome, likely cause, and relationship to the study products will be recorded in the CRF. 
 
Local and systemic AEs associated with each treatment arm will be tabulated and compared. AEs will be 
elicited through direct questioning, subject reports, and physical examination. 
 
An abnormal laboratory test result is not by itself considered to be an AE unless the Investigator 
considers the finding of clinical significance that should be reported in such a manner. 
 
 
10.2 REPORTING OF ADVERSE EVENTS 
 
The Investigator is responsible for assessing the relationship of the adverse event to the treatment, and 
the seriousness and expectedness of the adverse event at the time of occurrence. A medically qualified 
person appointed by the Sponsor will also assess this, once the Sponsor has been notified of an AE. All 
adverse events that occur during the trial will be documented on the supplied adverse event forms. 
 
AEs/SAEs reported during the study, or SAEs reported within 30 days of the end of the study, should be 
followed to resolution of the AE/SAE or, within thirty days from the end of the study. A final assessment 
of the outcome will be made at that time. 
Each AE will be categorized as “serious” or “not serious” based on the definition of an SAE. An SAE is 
defined as an AE resulting in at least one of the outcomes: 
 
 
Results in death 
 
 
Is life threatening (the subject is at immediate risk of dying from the adverse experience) 
 

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 
Requires subject hospitalization or prolongs existing hospitalization 
 
 
Results in persistent or significant disability/incapacity 
 
 
Is a congenital anomaly/birth defect 
 
Important medical events that may not result  in death,  be  life-threatening,  or  require 
hospitalization  may  be  considered  a  serious  adverse  device  effect  when,  based  upon 
appropriate medical judgment, they may jeopardize the subject or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
 
10.3 ADVERSE EVENT SEVERITY ASSESSMENTS 
 
The guidelines outlined in CTCAE v4 will be used for severity assessments. Note: the term “severe” is a 
measure of intensity and that a severe AE is not necessarily serious. 
 
AE SEVERITY GRADING SCALE 
 
Severity Grade 
Description 
Mild (1) 
Awareness of sign, symptom, or event, but easily tolerated; does not 
interfere with usual daily activities or tasks. 
Moderate (2) 
Discomfort enough to cause interference with usual daily activity. It may 
warrant therapeutic intervention. 
Severe (3) 
Incapacitating; inability to perform  usual  activities  and  daily  tasks; 
significantly affects clinical status; requires therapeutic intervention. 
Life-threatening (4) 
Emergency treatment required life-threatening, death. 
 
 
10.4 ADVERSE EVENT CAUSALITY ASSESSMENTS 
 
Adverse events will be assigned a relationship (causality) to the treatments. The Investigator will be 
responsible for determining the relationship between an AE and the treatment. The type of event, 
organ system affected, and timing of onset of the event will be factors in assessing the likelihood that an 
AE is related to the treatment. Relationship of AEs to study products will be classified as follows: 
 
Not Related: No relationship exists between the AE and the treatment. The event is 
attributed to a pre-existing medical condition or an intercurrent event unrelated to the 
study product. 
 
Possibly Related: Follows the treatment, but may have developed as a result of an 
underlying clinical condition or treatments/interventions unrelated to the study product. 
 
Probably Related: Follows the treatment, but is unlikely to have developed as a result of the 
subject’s underlying clinical condition or other treatment or other interventions. 
 
Definitely Related: Follows the treatment and physical evidence shows a convincing 
relationship to the treatment. 

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 
Unknown: Follows the treatment, but unable to determine the relationship to the 
treatment. 

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11 SERIOUS ADVERSE EVENTS 
A Serious Adverse Event (SAE) is any untoward medical incident that occurs during the course of the trial 
beginning after informed consent has been executed and extending until 30 days after the final study 
visit. 
 
A SAE is defined as any AE that: 
 
 
Results in death 
 
 
Is life threatening (the subject is at immediate risk of dying from the adverse experience) 
 
 
Requires subject hospitalization or prolongs existing hospitalization 
 
 
Results in persistent or significant disability/incapacity 
 
 
Is a congenital anomaly/birth defect 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse device effect when, based upon 
appropriate medical judgment, they may jeopardize the subject or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
 
 
11.1 REPORTING OF SERIOUS ADVERSE EVENTS 
 
The Investigator is required to report all SAEs that occur during the study. Once the Investigator 
becomes aware of an SAE, he/she must report the SAE to SerenaGroup® and the Project Lead within 24 
hours of discovery: 
 
 
 
 
 
A written SAE report must follow and must include a full description of the event and all supporting 
documentation available at the time (e.g., lab reports, electrocardiogram [ECG] reports, etc.). Additional 
follow-up information as it becomes available must be reported to the Sponsor. 
 
The Investigator is also responsible for reporting all SAEs to the appropriate Institutional Review Board 
(IRB) in accordance with local laws and regulations. The Investigator is responsible for maintaining 
documentation in the study file that indicates the IRB has been properly notified. 
Medical Monitor 
Thomas E. Serena MD FACS (814) 688-4000 

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11.2 SAE FOLLOW-UP 
 
All SAEs will be monitored for a minimum of 30 days until they are resolved, have stabilized, or are 
clearly determined to be due to a subject’s stable or chronic condition or intercurrent illness(es). 
 
 
12 DIRECT ACCESS TO SOURCE DATA/DOCUMENTATION 
Subjects will be identified on CRFs by a unique subject identification number and on source documents 
by name and date of birth. No personal identifier will be used in any publication or communication used 
to support this research study. The subject identification number will be used if it becomes necessary to 
identify data specific to a single subject. 
 
The monitors, auditors, personnel authorized by the Sponsor, the local IRB, and the FDA are eligible to 
review medical and research records related to this study as a part of their responsibility to protect 
human subjects in clinical research and will be given direct access to source data and documentation 
(e.g., medical charts/records, printouts etc.) for source data verification, provided that subject 
confidentiality is maintained in accordance with local requirements. Access to electronic medical records 
may be governed by institution policy and each site will be required ensure access while remaining 
compliant with institutional requirements. 
 
 
 
13 QUALITY CONTROL AND QUALITY ASSURANCE 
 
13.1 ACCEPTABILITY OF CASE REPORT FORMS 
 
CRF must be completed for each subject who has signed an informed consent form. For subjects who 
are screen failures, this would be limited to the screen failure CRF page. All source documents and CRFs 
will be completed as soon as possible after the subject’s visit. 
 
 
13.2 MODIFICATION OF PROTOCOL 
 
The Investigator will not modify or alter this protocol without first obtaining the concurrence of the 
Sponsor. Approval by the Investigator’s IRB must also be obtained prior to implementation of  the 
change, with two exceptions: 
 
1. When necessary to eliminate apparent immediate hazard to the subject; or 
 
2. When the modification does not involve the subject’s participation in the trial. 

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An amendment may also require modification of the informed consent form. The Investigator  will 
provide an approval letter for the amendment and revised informed consent form, if applicable, to the 
Sponsor. An amendment must be in writing and it must be dated by both the Sponsor and the 
Investigator. If necessary, the Sponsor will submit protocol amendments to FDA and other appropriate 
regulatory authorities and notify other Investigators using this protocol. 
 
 
13.3 REPORTING PROTOCOL DEVIATIONS 
 
The Investigator is obligated to follow the protocol without departure from the requirements written in 
the protocol. If the Investigator deviates from the protocol requirements, the Sponsor will make the 
determination as to whether the subject will continue in the study. The Sponsor also has the right to 
discontinue the subject for protocol violations. The IRB may also have to contacted if safety to the 
subject or if the scientific soundness of the study is involved. All protocol deviations must be 
documented in the CRFs. 
 
 
14 ETHICS AND REGULATORY REQUIREMENTS 
This study is to be conducted in accordance with the specifications of this protocol and in accordance 
with principles consistent with Declaration of Helsinki, Good Clinical Practice (GCP), 21 CFR 312, ICH E6, 
HIPAA regulations in 45 CFR Part 164, and the Belmont Principles of respect for persons, beneficence, 
and justice. No protocol changes will be implemented without the prior review and approval of the IRB, 
except where it may be necessary to eliminate an immediate hazard to a research subject. In such a 
case, the change will be reported to the IRB as soon as possible, according to IRB regulations. 
Additionally, all study products used in this study are manufactured, handled and stored in accordance 
with applicable Good Manufacturing Practices (GMP) and the products provided for this study will be 
used only in accordance with this protocol. 
 
 
14.1 INSTITUTIONAL REVIEW BOARD/INDEPENDENT ETHICS COMMITTEE 
 
The Principal Investigator will provide the Institutional Review Board/Independent Ethics Committee 
(IRB/IEC) with all appropriate materials as required by their IRB, including but not limited to the clinical 
study protocol, informed consent form, and any advertising materials. The study will not be initiated 
until the IRB provides written approval of the aforementioned documents and until approval documents 
have been obtained by the Principal Investigator and Sponsor or Sponsor designee. The Investigator will 
not participate in the decision. If the Investigator is an IRB or IEC member, documentation must be 
provided indicating recusal from the approval process. Appropriate reports on the progress of this study 
by the Principal Investigator will be made to the IRB/IEC as required by local and applicable government 
regulations and in agreement with policy established by the Sponsor. The Investigator is required to 

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maintain an accurate and complete record of all written correspondence to and received from the 
IRB/IEC, and must agree to share all such documents and reports with the Sponsor. 
 
No changes from the final approved protocol will be initiated without the IRB/IEC’s prior written 
approval or favorable opinion of a written amendment, except when necessary to eliminate immediate 
hazards to the subjects or when the change involves only logistics or administration. 
 
 
14.2 INVESTIGATOR’S RESPONSIBILITIES 
 
The Investigators are responsible for performing the study in full accordance with the protocol and the 
current revision of the Declaration of Helsinki, the Good Clinical Practice: Consolidated Guideline, 
approved by the ICH, and any applicable national and local laws and regulations. Information regarding 
any study centers participating in this study that cannot comply with these standards will be 
documented. 
 
 
14.3 SUBJECT INFORMED CONSENT REQUIREMENTS 
 
Written and oral information about the study in a language understandable by the subject will be given 
to all subjects by the Investigator and/or designee. Written informed consent will be obtained from each 
subject before any procedures or assessments that would not otherwise be required for the care of the 
subject are done and after the aims, methods, anticipated benefits, potential hazards, and insurance 
arrangements in force are explained and the subject has been given sufficient time to ask questions and 
consider participation in the study. It will also be explained to the subjects that they are free to refuse 
entry into the study and free to withdraw from the study at any time without prejudice to future 
treatment. It is permissible for a third person (e.g., a family member) to be present during the 
explanation of the study. 
 
The written Informed Consent Form (ICF) is to be in compliance with Code of Federal Regulations (CFR) 
21 Part 50.27 and Good Clinical Practice (GCP) guidelines. The Sponsor and/or designated CRO will 
approve the ICF and all amendments to the ICF prior to submission to the IRB/IEC. A copy of the ICF to 
be used will be submitted by the Investigator to the IRB/IEC for review and approval prior to the start of 
the study. Each study site must provide the Sponsor with an unsigned copy of IRB/IEC-approved ICF 
along with applicable documentation to support this approval. The original signed ICF is retained in the 
subject's study records, and a copy is provided to the subject. A second copy may be filed in the 
subject’s medical record, if allowed by institutional policy. 
 
 
15 DATA HANDLING AND RECORD KEEPING 
 
15.1 RECORDING AND COLLECTION OF DATA 
 

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The primary source document for this study will be the subject's medical record. If separate research 
records are maintained by the investigator(s), the medical record and  the research records will be 
considered the source documents for the purposes of auditing the study. 
 
Applicable source data will be manually transcribed to approved case report forms (CRF). The 
investigator is ultimately responsible for the accuracy of the data transcribed on the forms. All source 
documents and CRFs will be completed as soon as possible after the subject's visit. 
 
The Investigator will review CRFs to indicate that, to his/her knowledge, they are complete and 
accurate. If further changes are made after this, the Investigator will need to again sign the Investigator 
signature page. Designated source documents will be signed and dated by the appropriate study 
personnel. The Investigator must agree to complete and maintain source documents and CRFs for each 
subject participating in the study. 
 
All research data will be entered, either electronically or manually, into a computerized database, 
designed in accordance with 21 CFR Part 11 and based on protocol requirements defined by the Sponsor 
in association with the PI and clinical data manager. 
 
The Investigator will maintain a confidential list of study subjects which will include each subject’s study 
number, name, date of birth and unique hospital identification number if applicable. This list will be kept 
by the Investigator and will not be collected by the Sponsor. A notation will be made in the subject’s 
case history/medical chart that he/she is participating in a clinical study and has provided a signed and 
dated informed consent form (ICF) as well as the required site HIPAA authorization (if separate from the 
ICF). The Investigator must also maintain a separate screening log of all the subjects screened for 
participation in the study; it should include gender; age; eligibility status; reason for ineligibility, if 
applicable; and study allocated subject number, if applicable. 
 
 
15.2 CLINICAL DATA MANAGEMENT 
 
The Sponsor will be responsible for the processing and quality control of the data. Data management 
will be carried out as described in the Sponsor’s standard operating procedures (SOPs) for clinical 
studies. 
 
 
15.3 ARCHIVING 
 
All study documentation at the Investigator site and Sponsor site will be archived in accordance with ICH 
GCP E6 and the Sponsor’s quality standards and SOPs. 
 
In accordance with new Medical Device Directive [MDD 2007/47/EC], study records must be retained by 
the Investigator for 15 years following the conclusion or termination of the study. Study records should 

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not be destroyed without prior written agreement between the Sponsor and the study Investigator. At 
the completion of the study, details of the archival process must be provided to the Sponsor. Study 
records are subject to inspection by applicable health and regulatory agencies at any time. 
 
Records to be retained by the Investigator include, but are not restricted to: 
 
Source data and the primary records upon which they are based (e.g., subject’s progress notes, 
adverse event data, test results, and any other diagnostic procedures required to evaluate the 
progress of the study). 
 
Signed protocols and protocol amendments 
 
Laboratory results, ranges and certifications 
 
Product (e.g., Investigational product, Standard of Care supplies) and accountability records 
 
Study personnel signature log 
 
Monitoring logs 
 
Correspondence to and from the Sponsor, designee and IRB 
 
Investigator and sub-investigator CVs 
 
Signed informed consent and HIPAA consent forms 
 
Subject screening and randomization log 
 
Serious adverse event reports 
 
Institutional Review Board approval and re-approval letters 
 
Wound tracings and images 
 
Subject diary pages 
 
Completed quality of life questionnaire 
 
Other documents pertaining to the conduct of the study 
 
These documents must be maintained and kept on file by the Investigator so that the conduct of the 
study can be fully documented and monitored. 
 
 
16 PUBLICATION PLAN 
Manuscripts and abstracts will be prepared by both the Sponsor. The results of the study may be 
published in scientific literature and may also be used in submissions to regulatory authorities. It is the 
intent of the Sponsor, and the Principal Investigator to publish or present the study results together with 
the other sites, unless specific permission is obtained in advance from the Sponsor to publish separate 
results. Co-authorship with any of the Sponsor’s personnel will be discussed and mutually accepted 
upon submission of a manuscript or publication. 

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All information concerning the Sponsor’s operations (such as patent applications, formulae, 
manufacturing processes, basic scientific data, or formulation information supplied to the Investigator 
and not previously published) is considered confidential by the Sponsor and shall remain the sole 
property of the Sponsor. The Investigator agrees not to use it for other purposes without written 
consent. 
 
 
PUBLICIATION AND DISCLOSURE 
 
Because this is a multi-center trial, site and investigator shall not independently publish,  publicly 
disclose, present or discuss any results of or information pertaining to site’s and Investigator’s activities 
conducted under this agreement until such a multi-center publication is released under Sponsor’s 
direction; provided, however, that if a publication is not released within eighteen (18) months after 
completion of analysis of all study data from all studies conducted within the multi-center trial, site and 
Investigator shall have the right to publish the results of and information pertaining to site’s and 
Investigator’s activities conducted under this protocol and the clinical trial agreement. Site and 
Investigator agree to submit any proposed manuscript, presentation or other public disclosure regarding 
the study to Sponsor for review at least thirty (30) days prior to submitting such proposed manuscript to 
a publisher or delivering or making such presentation or other public disclosure to  any third party. 
Within thirty (30) days of its receipt, Sponsor shall advise site and/or Investigator, as the case may be, in 
writing of any information contained therein that is confidential information (other than research results 
included in a proposed manuscript) or that may impair sponsor’s ability to obtain patent protection. 
Sponsor shall have the right to require site and/or Investigator, as applicable, to remove specifically 
identified confidential information (but may not require removal of research results from a proposed 
manuscript) and/or to delay the proposed submission or delivery of the proposed manuscript or 
presentation, or other public disclosure, for an additional sixty (60) days to enable Sponsor to seek 
patent protection. Site and Investigator shall not publish, publicly disclose, present or discuss any results 
of or information pertaining to site’s and Investigator’s activities prior to completion of the trial, even if 
the multi-center trial or the study is terminated before its completion and the final clinical study report 
is signed off, or (b) with respect to any endpoints or analyses other than those specified in this protocol. 
 
 

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17 MONITORING PLAN 
 
17.1 SITES 
 
17.1.1 SITE SELECTION 
 
SerenaGroup® will be responsible for site selection. 
 
17.1.2 INVESTIGATORS MEETING 
 
The purpose of the Investigator’s meeting is to review the salient features of the study and what will be 
required of the investigators. In addition, the need for strict adherence to the research protocol and 
research principles in general will be discussed. The meeting will be conducted by the Lead or Principal 
Investigator and other personnel as necessary. Regional meetings may be held in place of a national 
meeting if a large number of sites are expected for the study. 
 
At the end of the meeting, if the site investigator still wishes to continue, a site initiation visit will be 
scheduled. 
 
17.1.3 SITE INITIATION VISIT (SIV) 
 
The purpose of the visit is to ensure that all the required study documentation is in place and that study 
site personnel are sufficiently prepared to conduct the clinical trial according to the study protocol, and 
ICH-GCP. The visit will include review of the study protocol, subject recruitment, informed consent 
procedures, case report form (CRF) completion, investigational device (ID), study specific procedures, 
monitoring and source documentation, adverse event reporting and review of essential documents 
maintained in the Investigator Site File. 
 
SIV 
The following topics will be reviewed with key site personnel during the SIV: 
Study Specific introductory information 
 
Background 
 
Standard treatments 
 
Study design 
 
Rationale for study 
 
Study objectives 
 
Investigational Products 
 
Presentation, use, ordering, delivery, dispensing, handling, storage and disposal of CelluTomeTM 
units and harvesters. 
 
Physician training on use of the CelluTomeTM epidermal harvesting system. 

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Study design and schedule of events 
 
CelluTomeTM manufacturers suggested use. 
 
Review of protocol and procedures 
 
Inclusion/exclusion criteria, including study eligibility after the 2-week screening period 
 
Efficacy and safety endpoints 
 
SAE and Adverse Event documentation and reporting 
 
Subject Recruitment 
 
Informed consent procedure and documentation 
 
Screening and enrolment procedures 
 
Procedure for randomization 
 
Procedure for follow up / withdrawal and criteria for withdrawal 
 
Case Report Form 
 
Methods of completion of trial documentation 
 
Data Clarification 
 
Monitoring queries 
 
Resolution process 
 
Study specific procedures 
 
Preparation of ulcer area 
 
Wound measurement. 
 
ABI measurement AND/OR SPP measurement 
 
Photography 
 
Swab collection for proteases/ 
 
Protease collection procedure (Serena Technique®) 
 
Dressing application / Compression wrapping 
 
Investigator Site File (ISF) 
 
Signed protocol 
 
Signed letter of agreement 
 
Regulatory approvals 
 
ICH-GCP 
 
Confirmation that all staff have completed GCP training 
 
Investigator responsibilities 
 
Sponsor responsibilities 
 
Source Documentation 
 
Protocol Compliance 
 
Protocol Deviations/Violations 

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STUDY SPECIFIC MATERIALS 
 
The site will be provided with study specific materials: 
 
Protocol 
 
Source documentation 
 
Protease swabs 
 
Camera and Memory Card 
 
Measuring grids, if applicable. 
 
 
SIV DOCUMENTATION 
 
All attendees must sign the SIV “Local Site and Trial Personnel Training Form” attendee log. SIV training 
will be documented in the monitor’s visit report and filed in the trial master file (TMF). A pre-visit letter 
listing the agenda items and a post-visit letter will be sent to the principle investigator (PI) at the site 
and filed in the ISF, copies will be filed in the TMF. 
An “Initiation Checklist” will be completed at the SIV to confirm that all essential study related procedures, 
trial products and responsibilities have been discussed at the visit. The PI will sign and date the Initiation 
Checklist, and “Protocol receipt.” 
Following the SIV the medical monitor or designee will notify the site that it is ready to start recruiting. 
 
17.2 MONITORING VISITS 
 
FREQUENCY OF MONITORING VISITS 
CRFs will be accessed and monitored remotely through a secure server. The monitor will schedule 
at least one on-site routine monitoring visit during the active phase of the study. This will be arranged 
as soon as practical. This visit is intended to ensure that the study is conducted according to the 
protocol, verifies subject’s eligibility and, if applicable, SAE forms have been completed appropriately. 
This may be adjusted should there be concerns with the site such as significant number of protocol 
violations or non-compliance with GCP, in such circumstances further on site monitoring visits may be 
required. 
Telephone contact may also take place to discuss the status of the site. These must be recorded in a 
telephone contact report and filed in both ISF and TMF. 
The frequency of on-site monitoring visits may increase due to any of the following, including but not 
limited to: 
 
Detection of significant protocol violations. 
 
Protocol non-compliance. 
 
Change in site staff requiring training. 
 
Significant and persistent non-compliance with GCP. 
 
Protocol amendment that introduces a significant change requiring training. 

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 
Rapid enrolment. 
 
Poor enrolment. 
 
Unusually high AE or SAE counts 
 
Improper standard of care 
 
Poor data management. 
 
17.3 MONITORING DOCUMENTATION 
 
 
Documents Created with Regard to the Monitoring Visit 
o Pre-visit Letter 
o Monitor Visit Report 
o Post Visit Follow Up Letter 
o Any other Site Correspondence 
 
 
Monitoring Logs 
o Informed Consent Log 
o CV checklist Log 
o GCP checklist Log 
o Adverse Event Log 
o Protocol Violation/Deviation Log 
o SAE Log 
o Termination / Withdrawal Log 
 
 
Monitoring Reports 
o Study Initiation Visit Report 
o Routine Monitoring Visit Report 
o Close Out Monitoring Visit Report 
 
 
Site Logs and Tracking Forms 
o Investigational Device Accountability Log 
o Screening / Enrolment Log 
o Delegation of Staff Duties Log 
17.4 CLOSE OUT VISIT 
 
Each site will receive a close out visit.  During the visit, the monitor shall perform the following activities 
including but not limited to: 
 
 
Review and address unresolved action items from previous monitoring visit(s). 
 
Review regulatory documents for completeness including a final review of signed informed 
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 
Verify that all general and ethics/regulations/R&D correspondence is present in the ISF. 
 
Dispose of all unused investigational devices  (if  applicable)  in  accordance  with  standard 
procedures for the site. 
 
Verify that all queries have been resolved and copies are filed in the appropriate CRF binder. 
 
Sign the Monitoring Visit Log. 
 
Review Investigator Responsibilities with the Principal Investigator; including archive. 
 
Discuss trial publication. 
 
The ISF will be thoroughly reviewed at the close out visit. The monitor will use the ISF checklist to verify 
that all essential documents are filed at the site and with the Sponsor in the TMF. Updated documents 
will be collected for inclusion in the TMF. Any document(s) that the site does not have will be sent to the 
site with the close out visit follow-up letter. A follow-up letter will be sent to the site by the monitor, 
which summarizes the visit, addresses protocol violations, highlights site action items, and provides 
information about study material retention. 
 
17.5 SOURCE DOCUMENTATION VERIFICATION REQUIREMENTS 
 
Source Data Verification will be performed through-out the study. 
 
Definition: 
Source documents are the ORIGINAL documents or records where raw/source data concerning a patient 
(subject) have been first recorded. These documents include but are not limited to the following: 
 
 
Patient (subject) files (e.g. medical notes, physician’s notes, nurse’s notes, dictations, death 
certificates, etc). 
 
Clinical laboratory reports and other laboratory  reports  (e.g.  chest x-ray, haematology, 
microbiology, urinalysis, ultrasounds, etc). 
 
ID related records, signed and dated informed consent documents, parts of the case report 
form, and contact report forms (e.g. telephone logs, appointment books, etc). 
 
17.6 INFORMED CONSENT AND AUTHORIZATION 
 
The following points will be validated for all screened and enrolled subjects: 
 
 
The informed consent document has been personally signed and dated by the subject. 
 
The informed consent has been taken by a physician / PI / Research nurse who is delegated to 
perform this procedure on the delegation of duties log. 
 
The informed consent process is documented in the source notes. 
 
The correct approved informed consent document was used for consenting. 
 
The original signed and dated consent document is maintained with the subject’s file notes. 

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 
A copy of the signed consent document has been provided to the subject and a copy has been 
filed in the subjects medical / source data notes. 
 
The informed consent was obtained prior to any study related procedures being performed. 
 
Validation of the above procedures will be documented on the consent form log. 

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17.7 SERIOUS ADVERSE EVENTS AND ADVERSE EVENTS 
 
At each monitoring visit the site monitor will verify the following: 
 
 
Serious and non-serious adverse events are recorded in the source document and accurately 
reflected on the case report form. 
 
All participant withdrawals due to an adverse event are accurately reflected on the case report 
form. 
 
That the investigator site has reported any serious adverse events (SAEs) to SerenaGroup® in 
accordance with the protocol. 
 
17.8 CONCOMITANT MEDICATION DOCUMENTATION 
 
At each monitoring visit the site monitor will verify the following: 
 
 
All medication usage including over-the-counter products and products related to the 
administration of general anaesthesia, regional block or local anaesthesia are documented in 
the source document and accurately reflected in the CRF. 
 
Use of any exclusionary medications per protocol are documented in the source document and 
accurately reflected in the CRF. 
 
17.9 INCLUSION AND EXCLUSION CRITERIA VERIFICATION 
 
At each monitoring visit the site monitor will verify the following: 
 
That each participant (subject) was eligible to enter the study by checking specific inclusion / 
exclusion criteria against medical history and source documents. 
 
All inclusion criteria must be checked “yes” and all exclusion criteria must be checked “no”. 
 
17.10 DEVICE ACCOUNTABILITY AND RANDOMIZATION REQUIREMENTS 
 
At each monitoring visit the site monitor will verify the following: 
 
 
The CelluTomeTM has been used according to the study schedule and administered in accordance 
with the protocol 
 
17.11 PHOTOGRAPHS 
 

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At each monitoring visit the site monitor will verify the following: 
 
That the site staff has been trained to use the camera. 
 
Ensure that the photographs are of a suitable quality and include the following: 
o In-focus. 
o Study specific information with the subject’s initials, visit number, visit date. 
o A measurement scale is visible in the photograph. 
 
 
 
17.12 PROTOCOL ADHERENCE/VIOLATIONS/DEVIATIONS/SERIOUS BREACHES 
 
A breach of GCP and/or protocol is defined as serious when it is likely to affect to a significant degree: 
 
 
The safety or physical or mental integrity of the subjects of the trial; or the scientific value of the 
trial. 
A protocol violation is a serious failure to comply with the study protocol and may result in the exclusion 
of the subject from the study. 
 
SerenaGroup® (sponsor) shall review all protocol violations/deviations submitted by the site and/or 
monitor and documented in the monitoring report. At each monitoring visit the site monitor will verify 
the following: 
 
 
Protocol Adherence. 
 
Protocol violations/deviations (e.g. missing procedures or evaluations outside of  scheduled 
visits) – these should be recorded in the source document and discussed with the site to prevent 
future occurrence. 
 
Document protocol violations and deviations in the monitoring report (which is filed in the TMF) 
and Investigator Follow-up Visit letter (which is filed in the TMF and ISF). 
 
Verify the Independent Ethics Committee (IEC) reporting requirements on Protocol Violations 
and document such requirements in the monitoring report and follow up visit letter and file in 
TMF and ISF. 
 
 
17.13 CASE REPORT FORM (CRF) COMPLETION 
 
All CRFs must be completed as per training. The header information at the top of each CRF must be 
complete and accurate. The monitor will check the visit schedule to ensure that the required CRFs have 
been completed.  The monitor shall check all CRFs for appropriate initials and/or signatures and verify 
that they can be found on the delegation of duties log. The site and monitor should refer to the CRF 
completion instructions, to assist them in decreasing queries and the manner in which the CRF forms 
should be completed. 

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17.14 EARLY TERMINATION DOCUMENTATION 
 
Any subject who discontinues study treatment early must have the reason documented in the source 
document and a termination form must be completed. 
 
 
17.15 MANAGING POOR PERFORMING OR NON-COMPLIANT SITES 
 
If a site is not conducting the study per protocol or Clinical Trial Directive, ICH guidelines or GCP 
regulations, the monitor should discuss this with SerenaGroup®. If the non-compliance impacts directly 
on the safety of subjects, study endpoints or timelines, the medical monitor should be involved in the 
discussion. Corrective action (e.g. extra training,) should be considered. Repeated poor performance may 
result in the site being shut down. 
 
 
17.16 FRAUD AND MISCONDUCT 
 
Suspicion that any data provided may not be valid should be reported immediately to SerenaGroup® 
and the medical monitor. 
 
Examples of trends that may cause suspicion of fraud include but are not limited to: 
 
 
Similar handwriting on CRF/source documentation to documentation completed by subjects 
such as consent forms or quality of life questionnaires. 
 
No original source documents only copies. 
 
No adverse events. 
 
Perfect data with no issues such as missed visits etc. 
 
A pattern of data for a given site which does not match the pattern of data generated at other 
sites (adverse events, trends in lab data, repetition of data, and frequency of withdrawals). 
 
Visit adherence schedule too exact for all subjects. 
 
 

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18 REFERENCES 
1. Vowden K, Goulding V, Vowden P. Hand-held Doppler assessment for peripheral arterial disease. J 
Wound Care 1996;5(3):125-127. 
 
2. Nelzen O, Bergqvist D, Lindhagen A. Leg ulcer etiology - a cross sectional  population  study.  J 
VascSurg 1991;14(4):557-64. 
 
3. Baker SR, Stacey MC, Jopp-McKay AG, Hoskin SE, Thompson PJ. Epidemiology of chronic venous 
ulcers. Br J Surg 1991;78(7):864-7. 
 
4. Schmid-Schobein GW, Takase S, Bergan JJ. New advances in the understanding of the 
pathophysiology of chronic venous insufficiency. Angiology 2001;52(Suppl 1):S27-S34. 
 
5. Cullum N, Fletcher AW, Nelson EA, Sheldon TA. Compression bandages and stockings in the 
treatment of venous ulcers. Cochrane Database Syst Rev 2000;CD000265:DOI: 10.1002/14651858. 
 
6. Antignani PL. Classification of chronic venous insufficiency: a review. Angiology 2001;52(Suppl 
1):S17-S26. 
 
7. Negus D. Leg ulcers: A practical approach to management. 2nd ed. Oxford: Butterworth Heinemann, 
1995. 
 
8. Ballard JL, Bergan JJ, editors. Chronic venous insufficiency. Diagnosis and treatment. London: 
Springer-Verlag, 2000. 
 
9. Olivencia JF. Pathophysiology of venous ulcers: surgical implications, review and update. 
DermatolSurg 1999;25:880-885. 
 
10. Nelzen O, Bergqvist D, Lindhagen A, Hallbook T. Chronic leg ulcers: an underestimated problem 
Nelzen O, Bergqvist D, Lindhagen A. Venous and non-venous leg ulcers: clinical history and 
appearance in a population study. Br J Surg 1994;81(2):182-7. 
 
11. Callam MJ, Ruckley CV, Harper DR, Dale JJ. Chronic ulceration of the leg: extent of the problem and 
provision of care. Br Med J (Clin Res Ed) 1985;290(6485):1855-66. 
 
12. Coleridge Smith PD, Thomas P, Scurr JH, Dormandy JA. Causes of venous ulceration: a new 
hypothesis. BMJ 1988;296:1726-1727. 
 
13. Bergan JJ, Schmid-Schonbein GW, Coleridge Smith PD, Nicolaides AN, Boisseau MR, Eklof B. Chronic 
venous disease. New Engl J Med 2006;355:488-498. 
 
14. Browse NL, Burnand KG. The cause of venous ulceration. Lancet 1982;ii:243-245. 
 
15. Coleridge Smith PD. Pathogenesis of chronic venous insufficiency and possible effects of 
compression and pentoxifylline. Yale J Biol Med 1993;66:47-59. 

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16. Agren MS, Eaglstein WH, Ferguson MW, Harding KG, Moore K, Saarialho-Kere UK, et al. Causes and 
effects of the chronic inflammation in venous leg ulcers. ActaDermVenereolSuppl (Stockh) 
2000;210(Suppl):3-17. 
 
17. Browse NL. The cause of venous ulceration. Lancet 1982;2(8292):243-5. 
 
18. Browse NL. Venous ulceration. BMJ 1983;286:1920-1922. 
 
19. Cornwall JV, Dore CJ, Lewis JD. Leg ulcers: epidemiology and aetiology. Br J Surg 1986;73(9):693-6. 
 
20. Cullum N, Fletcher AW, Nelson EA, Sheldon TA. Compression bandages and stockings in the 
treatment of venous ulcers. Cochrane Database Syst Rev 2000;CD000265:DOI: 10.1002/14651858. 
 
21. Falanga V, Et al Rapid healing of venous ulcers and lack of clinical rejection with an 
allogeneic cultured human skin equivalent. Arch Dermatol 1998 134(3) 293-300. 
 
22. Mustoe EN, Haraway GD, HoddeJP, King D. Effectiveness of an extracellular matrix graft (Oasis 
Wound Matrix) in the treatment of venous leg ulcers: a randomized clinical trial. J Vasc Surg 2005 
May 41(5);837-43. 
23. Biswas A, et al. The micrograft concept for wound healing: strategies and application. J 
Diabetes Sci Technol. 2010;4(4):808-819. 
24. Hsieh CS, et al. Five years’ experience of the modified Meek technique in the management of 
extensive burns. Burns. 2008;34(3):350-354. 
25. Ichiki Y, et al. Successful treatment of scleroderma-related cutaneous ulcer with suction blister 
grafting. Rheumatol Int. 2008;28(3):299-301. 
26. Costanzo U, et al. Autologous suction blister grafting for chronic leg ulcers. J 
EurAcadDermatolVenereol.    2008;22(1):7-10. 
27. Njoo MD, et al. A systematic review of autologous transplantation methods in vitiligo. Arch 
Dermatol.   1998;134(12):1543-1549. 
28. Patel NS, et al. Advanced treatment modalities for vitiligo. Dermatol Surg. 2012;38(3):381- 391. 
29. Li J, et al. Suction blister epidermal grafting using a modified suction method in the treatment 
of stable vitiligo: a retrospective study. Dermatol Surg. 2011;37(7):999-1006. 
30. Serena T, et al. Experience with a novel epidermal harvesting device in Haiti. Manuscript in 
progress. 
31. Serena T. et. al. Case studies utilizing CelluTomeTM a novel epidermal harvesting device in 
chr onic wounds. Manuscript in progress.

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19 APPENDICES 
 
19.1 ANKLE-BRACHIAL INDEX (ABI) 
 
Technique: Place the  patient in the supine position, with the arms and legs at the same level as the 
heart, for a minimum of 10 minutes before measurement 
 
Select an appropriately sized blood pressure cuff for both the ankle and the arms (figure 1); the cuff 
width should be, at a minimum, 20% greater than the diameter of the extremity. The ankle cuff should 
be placed on the leg between the malleolus and the calf. Enough room should be left below both cuffs 
to permit placement of the ultrasound gel, so that the Doppler device can adequately detect the 
brachial, dorsalis pedis, and posterior tibial arteries. 
 
Obtain the brachial systolic pressures of both arms. Use the higher of the arm pressures in the ABI 
calculation. Obtain the pressure in the dorsalis pedis and posterior tibial arteries for the extremity with 
the target ulcer. Use the highest pressure for the ABI calculation. 
 
Ankle-Brachial Index = Highest ankle pressure/Highest brachial pressure. 
 
Care should be taken to cover the ulcer during the ABI measurement. In addition, patients should be 
informed that they may experience discomfort during the test secondary to the pressure exerted by the 
cuff in the area of skin breakdown. 
 
 
 
 

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19.2 TIME TRADE OFF EVALUATION 
 
A time-tradeoff (TTO) measurement using an electronic system called Wound-Trade© will be elicited 
from patients to facilitate the assessment of cost-effectiveness (cost-utility). Value for improving patient 
quality of life is typically quantified using cost-utility analysis. A cost-utility analysis is defined as a type 
of cost-effective analysis that compares different procedures and outcomes relative to a person's quality 
of life. It is the most sophisticated form of economic analysis and typically incorporates utility values. 
Utility values measure the preference for a health state and range from 0.0 (death) to 1.0 (perfect 
health). When the change in utility measures conferred by a health care intervention is multiplied by the 
duration of the benefit, the number of quality-adjusted life-years (QALYs) gained from the intervention 
is ascertained. This methodology incorporates either the improvement in quality of life and/or length of 
life, or the value, occurring as a result of the intervention. In wound care, patients’ experiences of living 
with wounds are dominated by symptom management, with all studies showing that the wound and its 
treatment have a profound effect on quality of life. 
 
WOUND-TRADE© 
 
Wound-Trade© is a system developed and created by Dr. Walton Sumner, MD, Associate Professor, 
Department of Medicine, Washington University School of Medicine, St. Louis, Missouri and Mr. Ronald 
Shannon, MPH, Health Economist and Epidemiologist, Global Health Economic Projects, LLC,  Clifton 
Park, New York. Dr. Wound-Trade© is implemented on a laptop computer, which facilitates the 
development of customized utility interviews. The automated format facilitates a consistent 
presentation of questions and enables a discounted, risk-adjusted, quality of life health utility index 
score through classic time-trade-off methodology. An individual is given a hypothetical choice: he/she 
can live for x-years in perfect health followed by death, or he/she can live y years with a particular 
chronic condition such as a chronic wound, where y > x. The number of healthy years x is then varied 
until the person is indifferent between the two outcomes. The health utility index in this example 
equals x/y. For example, suppose that an individual feels that fifteen years of perfect health is worth 
twenty years of life with a chronic wound. Using the time trade-off approach, this individual is giving a 
chronic wound a health utility index of0.75. The health utility index can be used in a cost-utility 
equation (cost-effectiveness based on quality-adjusted life years) from a new medical treatment or 
technology: 
 
 
RISKS 
There are no risks to the patient related to their health or well-being. The scenarios in Wound-Trade© 
are imaginary and do not interfere with their current therapy as guided by the hospital wound center. 

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INTERVIEW TIME 
The interview process can take as little as a few minutes to 15 minutes to complete. A research assistant 
will be available to assist the patient with process but will not influence the decisions made by the 
patient. 
 
WOUND-TRADE SCREEN SHOTS AND INTERVIEW PROCESS 
 
A. 
Introductory Screen 
Researcher will enter the following information: 
1. 
Enter a patient number in subject identifier field; 
2. 
Enter birth date as month/day/ year exactly like this: 06/25/1955; 
3. 
Select either M for Male or F for Female; 
4. 
For the remainder of information it is not necessary to enter it but you can if you wish; 
5. 
Hit continue button to go to next page 
 
 

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B. 
Comorbidities 
6. 
Check all that apply and hit continue: 
 
 
 
 
6.  Check all that apply and hit continue: 

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C. 
Value Check 
This page reflects the calculation used to determine the number of years of life expectancy for a person 
of their current age and existing comorbidities. The adjusted life expectancy is used in the forthcoming 
time trade-off questions. This page is for the research assistant. 
 
 

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D. 
Introductory Patient Screens 
1. 
Hit continue button; 
 
 
 
 
 
 
1. Patient will read and then hit continue button; 

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1. Patient will read and then hit continue button; 

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1. Patient will read and then hit continue button; 

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2. Patient will read and then select their choice; 
 
3. Hit continue; 
 
 

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4. Patient will read and then hit continue. Questions may be answered by research 
assistant; 
 
 

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5. Patient will read, ask questions to research assistant if necessary and then choose yes 
or no; 
6. If they hit yes then they will go on to trade questions; 
 
7. If no, then patient will go to next section focusing on their wound and not their 
general health; 
8. Either way they hit continue; 
 
 

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9. Assuming they choose yes, the patient will click on the box of their preference. In this 
scenario the patient may choose “No treatment” which indicates they would rather 
live 5 years in their current overall health condition including their wounds rather 
than live 4 years completely cured of all health problems but die 1 year early (The 
screen will transition to new scenario - goto next page); 
 
 
 
 

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10. The trade questions continue after the patient chooses “No treatment”.  A new 
scenario evolves whereby the patient will make another choice.  For sake of 
demonstration the patient selects “Treatment”.  Their preference is 2 years completely 
cured of all health problems but die 3 years early over “No treatment”. A new screen 
comes forward (next page); 
 
 
 
 

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11. The trade continues until patient cannot decide between Treatment or No treatment. 
They click on Choice C which is hard to choose. This trade is done for general health 
but with a wound. A new scree will will evolve (next page); 
 
 
 
 

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12. Status of interview; 
 
13. Hit continue to go to wound focus; 
 
 

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14. Patient answers question related to their wound; 
 
15. Hit continue; 
 
 

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16. Patient will read the text; 
 
17. Hit continue; 
 
 

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18. Patient will read and choose either yes or no.  If no then this trade stops and goes into 
ricky treatment section; 
19. Check yes it will go to trade section where patient will choose preferences again; 
 
20. Hit continue either way; 
 
 

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21. Patient will select their preferences related to their wound. Screens will change based 
on their selection; 
 
 

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22. Another example of screen change.  If they click on Choice C then this trade is done 
(Next screen); 
 
 

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23. Status of interview; 
 
24. Hit continue; 
 
 

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25. The next set of trades require a basic understanding of survival curves.  This one slide 
gives a general overview that is enough to complete next sections of trades. The 
research assistant can also guide the patient here; 
26. Hit continue after review; 
 
 

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27. This section focuses on risky treatment that may decrease early survival but if they 
survive their prognosis for longer survival becomes better.  In the example below, the 
patient will most likely choose the green box as it gives better probability of survival 
over 5 years. Once they select their preference the trades begin – go to next page; 
 
 
 
 

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28. Notice that the survival curve changes with their selection in previous section. 
Patient now will most likely click on option B.  Page transitions to next preference 
trade – go to next page; 
 
 
 
 

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29. The scenario changes in this section with new trade preference options. Also notice 
the survival curve changes based on choices. Patient selects Option B and a new 
trade appears on next page; 
 
 
 
 

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30. Choose Option B. New section comes open on next page. Survival curve changes 
with selections; 
 
 

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31. Patient chooses Option C and the trade stops. Next section automatically appears; 
 
 

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32. Status page; 
 
33. Hit continue; 
 
 

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34. The next section is similar to the previous risky treatment scenario except it focuses 
on wounds only. Patient will select accordingly until they hit Option C when the 
survey is over. The next section gives quality of life utility measurements with 
discounted numbers; 
 
 

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35. This screen shows current health condition utility measure between 0 and 1 (0.77). A 
discounted rate of 0.07 was subtracted from the utility measure giving the above 
answer 0.77. 
36. Hit continue; 
 
 

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37. Wound quality of life utility measurement that is discounted; 
 
38. Hit continue; 
 
 

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39. The interview is complete; 
 
40. The researcher can save and quit or do another interview. 
 
 
 

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19.3 MODIFIED ACTIVITY-BASED COSTING METHODOLOGY 
 
Introduction 
Modified activity-based costing methodology will be used in this study to document direct costs (direct 
reimbursable medical cost, direct non-reimbursable medical costs, direct non-medical costs) and indirect 
costs related to each treatment group.    Modified activity-based costing (ABC) is an accounting technique 
that allows healthcare organizations to determine actual costs associated with their services based on the 
resources they consume.   
 
Direct medical costs related to care of venous leg ulcers include 1) labor for office visits, diagnostics, 
laboratory tests, debridement, application of treatment to the wound, applying compression bandages 
etc.  This may be accomplished through a physician, nurse or other qualified healthcare professional; 2) 
materials such as wound dressings, compression bandages and medical supplies (gloves, saline, gauze 
etc.); 3) medications for pain, infection etc. and 4) the treatment under investigation.  Indirect costs will 
be estimated by results from the Patient Benefit Index questionnaire (Appendix 19.6). 
 
Sampling Institutions for Direct Human Clinical Resource, Medical Supplies and Diagnostics Costing 
Analysis 
Wound clinics participating in the study will be randomly selected and given 5 costing worksheets (5 
patients) for CelluTomeTM group (see figures on next 3 pages) and 5 costing worksheets (5 patients) for 
the control group in each institution to document the weekly direct human clinical resource time for each 
group.  This involves clinical contact within the wound clinic and during the week with non-wound clinic 
staff (e.g., primary care physicians, home care nurse, RN etc.). An assigned clinician or research assistant 
will collect the information contained within the costing worksheet for each patient randomly selected 
within each wound clinic. This data will be used to estimate direct human clinical resource consumption 
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Patient Consumption of Drugs, Skin Care, Medical Supplies and CelluTomeTM 
The patients randomly selected at the eight wound clinics will have their consumption of medical supplies 
(e.g., dressings, compression bandages, debridement, tape, gloves, saline and, gauze etc.), drugs (e.g., 
antibiotics, pain meds, antimicrobials etc.) and CelluTomeTM documented in the patient record (CRF) over 
the course of their assigned therapy.  A research assistant or assigned nurse will pull the records for each 
patient and document the consumption and costs of medical supplies and CelluTomeTM for health 
economic analysis.   
 
Laboratory and Miscellaneous Diagnostics 
A record of diagnostics used within the treatment process is contained in the randomly assigned patient 
medical record and case report form.  A research assistant or assigned nurse will pull the records for each 
patient and document the consumption and costs of diagnostics for health economic analysis.   
 
Cost Analysis 
Multiple costing perspectives are considered in the health economic analysis:  
  
Hospital/Outpatient Perspective: Direct institutional medical costs for the treatment and control group 
will be collected through modified activity-based costing methodology. Hourly payment rates will be 
collected directly from the institutions where care is provided for each care provider involved in the 
treatment for each cohort.  An average hourly payment rate per resource will be determined across the 

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institutions participating in the study.  For resource consumption outside of the wound clinic national 
hourly wage rates will be determined for home care visits, nursing home staff, family caregiver etc. as 
detected in modified activity-based costing data collection forms.  All direct medical costs from the 
hospital/outpatient sector will be compiled for each cohort and compared between groups as the 
patients flow through the study/system.  This allows a pragmatic view of costs and cost savings from the 
hospital/outpatient perspective in relation to their charges and reimbursement.  
 
Payer Perspective: Reimbursement from Medicare, Medicaid and Private payers during the course of the 
study for each group are compiled from each institution participating in the study. Average 
reimbursement for each product/procedure/stay for each cohort and patient will be determined across 
the institutions.  This information will come from data sources within each institution as compiled by an 
internal research assistant. Cost effectiveness analysis from the payer perspective is expected to show 
reduced reimbursement costs for CelluTome group in respect to expedited healing and reduction in 
complications. 
 
Patient Perspective:  Patient costs will be determined from the patient or proxy related to the direct care 
(medicine, hospital, therapy etc.) that are out-of-pocket, indirect work loss, worker replacement, and 
reduced productivity from the ulcer.     
 
A comparative cost-benefit, cost-utility and cost-effectiveness analysis will be derived from a discrete-
event simulation model with a time-frame conducive to each perspective above (Appendix 19.4).  For the 
hospital/outpatient clinic a return-on-investment (cost-benefit) is determined over 6 to 12 treatment 
weeks which is standard length-of-time patient is engaged with that sector.  From a payer perspective, 
the model will highlight costs from 1 to 3 years as VLU patients that do not heal within 6 months continue 
with treatment expenses.  Fortunately, patients that do not heal within 6 months are few (~10 percent) 
but still costly.  Reduction in patient out-of-pocket expenses will be compared over the entire span of the 
model (3 years). 
 
19.4 DISCRETE EVENT SIMULATION MODEL TO MEASURE COST-EFFECTIVENESS 
AND COST-BENEFIT 
 
A discrete event simulation model (see figure this page) is used to measure the costs (e.g., clinical human 
resources, medical supplies, drugs, diagnostics, investigations and CelluTome) and consequences (e.g., 
healing, clinical infection, hospitalization and death) over the course of the study time period from the 
perspective of the hospital/outpatient, payer and patient.  The model will contain health states (e.g., 
healed ulcer, infected ulcer, severely infected ulcer, hospitalization (e.g., cellulitis, amputation), 
uncomplicated ulcer and death. The 
patient and respective ulcer will 
travel over time in the model for 
three years accumulating costs and 
consequences.  Cost analysis for 
differing perspectives and time-
horizons are completed using the 
advantages of the model framework. 
 
In particular, average quality of life 
utility score values will be assigned to 

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each health state from the use of Wound-Trade©, time trade-off assessment (Appendix 19.2) matched to 
the health states in a separate matching analysis between scores and health state of the ulcer/patient 
measured in the case report form.  As the patient/ulcer traverses through the model over time weekly 
assigned utility values in each health state will be compiled and totaled for each patient and respective 
group at years end.  This will facilitate the determination of cost per quality adjusted life year comparison 
between groups. 
 
A cost-benefit (return-on-investment) measurement will also be completed from the hospital/outpatient 
perspective to show value to the institution. Average direct medical costs attributed to resource 
utilization, medical supplies, drugs, diagnostics and CelluTomeTM will be estimated during the trial for 
each group.  Financial benefits include averted costs of complications from rapid healing that may be 
consequential to the hospital/outpatient clinic. 
 
Cost-effectiveness is used to demonstrate the value of CelluTomeTM for rapid healing, reduced 
complications and therefore reduced financial impact for the payer.  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Return-on Investment Metrics: 
 
 
 
19.5 QUALITY OF LIFE QUESTIONAIRE (w-QOL) 
 
 
 
 
 

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19.5 QUALITY OF LIFE QUESTIONNAIRE (w-QOL) 
 

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19.6 PBI-P – PATIENT BENEFIT INDEX, WOUND VERSION 
 
At the beginning of treatment for each group a patient benefit index questionnaire is given to the patient for 
completion.  It is intended to give the patient a chance to give their goals of treatment: 
  
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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At the end of treatment, the patient will complete the form below indicating if the respective treatment met their 
goals: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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19.7 SWAB COLLECTION PROCEDURE 
 
1. Ensure that complete haemostasis has been achieved before obtaining the specimen. 
 
2. Moisten wound area to be swabbed with saline. Care should be taken not to flood the wound 
with excessive saline. 
 
3. Use the swabs provided by the Sponsor(s). 
 
4. Avoid swabbing areas that contain blood, necrotic material or thick slough. 
 
5. Press the head of the swab flat against the base of the wound and gently rotate it back and forth 
several times while applying pressure. Continue rotating the swab head until it is fully coated with 
wound fluid.  The head of the swab should turn a tan color. 
 
6. Collect additional swabs using the same procedure described in step 5 above. Apply additional 
saline drops to remoisten the wound between swabs. 
 
7. Label the swabs with Subject ID#, date, and study visit number. 
 
 
 

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19.8 ANTIMICROBIAL DRESSING 
 
In order to reduce the risk of infection, any of the following dressing may be used during the 2 week 
screening period and during TV4, TV8, and TV10 (for patients crossing over): 
 
Prisma 
Silver Alginate 
Silver Hydrogel 
Honey 
Hydrofera blue 
 
 
 
 

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19.9 APPLICATION OF PRISMATM 
1. Clean wound with saline; dry peri-wound skin 
2. Cut PrismTM to cover the wound bed 
3. Apply PrismaTM directly on the wound if it is moist. Normal saline may be used for dry 
wounds before PrismaTM is applied. 
4. Apply appropriate cover dressing to maintain a moisture balanced wound environment. 
PrismaTM will be absorbed over 3 days. PrismaTM may need replacing more frequently if 
wound is exudating heavily. 
 
 
 

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19.10 EPIDERMAL HARVESTING PROCEDURE 
 
 
Select donor site (inner thigh). 
 
Using clippers to remove any hair from the skin. (Do not use a razor to shave the patient) 
 
Prep the site with isopropyl alcohol. 
 
Anesthesia is not required. 
 
Apply the harvester and affix in place using the Velcro strap. 
 
 
Attach the vacuum hood. Press on the opposite sides of the hood until you here a 
click. This ensures that you have a seal. 
 
 
Turn the machine on. The vacuum head will apply 200 mmHg negative pressure and 
heat the skin to 40 C. The patient may experience a warm feeling.  
 
The epidermal microdomes are ready for harvesting when the epidermis has formed 
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 
Turn off the power. 
 
Remove the vacuum hood. 
 
Place the foam dressing provided in the harvester. 
 
 
 
 
Pull the blue handle back until you hear a “click.”  
 
Place the foam dressing provided in the harvester. Activate the blades cutting the 
epidermal microdomes by advancing the blue handle back onto the harvester. 
 
 
 
 
 
 
                                   
 
 
 
 
 

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 Examine the foam and record the percentage of microdomes harvested. 
 
                          
 
 Transfer the foam to the wound and secure using the 3M Coban-2 
compression wrap. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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 
 Cover the donor site with Tegaderm® provided.