A Single Site Randomized, Clinical Trial Comparing the Concomitant Use of MicroMatrix® With Cytal™ Wound Matrix 2-Layer to Standard of Care in Patients With Stage 3 or 4 Pressure Injuries
Phase: NA
Conditions: Pressure Ulcers Stage III, Pressure Ulcer, Stage IV, Pressure Ulcer
Sponsor: Integra LifeSciences Corporation

 
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A single site randomized, clinical trial comparing the concomitant use 
of MicroMatrix® and CytalTM Wound Matrix 2-Layer to Standard of Care 
in patients with Stage 3 or 4 pressure injuries 
 
 
Unique Protocol ID: CA2016-001 
 
NCT03283787 
 
 
 
Version 5.0 
08 June 2018 
 
 
 
 

ACell Confidential  
 
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A single site randomized, clinical trial comparing the concomitant use of 
MicroMatrix® and CytalTM Burn  Matrix 2-Layer to Standard of Care in patients with 
Stage 3 or 4 pressure injuries 
 
 
CA2016-001 
 
 
 
 
ACell, Inc. 
6640 Eli Whitney Drive 
Columbia, MD  21046 
 
 
 
 
 
Version 5.0 
08 June 2018 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS .................................................................................................... 5 
PROTOCOL SUMMARY ....................................................................................................... 6 
1 
KEY ROLES ............................................................................................................ 13 
2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC RATIONALE ............... 15 
2.1 
Background Information ..................................................................................... 15 
2 
OBJECTIVES AND PURPOSE .................................................................................... 17 
3 
STUDY DESIGN AND ENDPOINTS ............................................................................. 18 
3.1 
Description of the Study Design ........................................................................... 18 
3.2 
Study Endpoints ............................................................................................... 19 
3.2.1 
Primary Endpoint ............................................................................... 19 
3.2.2 
Secondary Endpoints .......................................................................... 19 
3.2.3 
Tertiary Endpoints .............................................................................. 19 
4 
STUDY ENROLLMENT AND WITHDRAWAL ................................................................. 20 
4.1 
Participant Inclusion Criteria ................................................................................ 20 
4.2 
Participant Exclusion Criteria ............................................................................... 21 
4.3 
Strategies for Recruitment .................................................................................. 22 
4.4 
Participant Withdrawal or Termination ................................................................... 22 
4.4.1 
Reasons for Withdrawal or Termination .................................................. 22 
4.4.2 
Handling of Participant Withdrawals or Termination ................................... 23 
4.5 
Premature Termination or Suspension of Study ....................................................... 23 
5 
STUDY DEVICE ....................................................................................................... 24 
5.1 
Study Device Description ................................................................................... 24 
5.1.1 
Device Description ............................................................................. 24 
5.1.2 
Acquisition and accountability ............................................................... 25 
5.1.3 
Study Device Storage ......................................................................... 26 
5.1.4 
Return or Destruction of Study Device .................................................... 26 
5.2 
Potential Risks and Benefits ................................................................................ 26 
5.2.1 
Potential Risk and Product Warnings ..................................................... 26 
5.2.2 
Potential Benefits ............................................................................... 28 
6 
STUDY PROCEDURES AND SCHEDULE ..................................................................... 28 
6.1 
Study Procedures/Evaluations ............................................................................. 28 
6.1.1 
Study Schedule ................................................................................. 28 
6.1.2 
Screening Visit (Study Day -5 to 0) ........................................................ 29 
6.1.3 
Treatment Visit (Day 1) ....................................................................... 30 
6.1.4 
Follow-up Visits 1 – 13 ........................................................................ 32 
6.1.6 
Final Study Visit [± 2 weeks]) ................................................................ 35 
6.1.7 
Unscheduled Visit .............................................................................. 36 
7 
ASSESSMENT OF SAFETY ....................................................................................... 37 
7.1 
Specification of Safety Parameters ....................................................................... 37 
7.1.1 
Definition of Adverse Events (AE) .......................................................... 37 

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7.1.2 
Definition of Serious Adverse Events (SAE) ............................................. 38 
7.1.3 
Definition of Unanticipated Adverse Device Effect (UADE) .......................... 39 
7.2 
Classification of an Adverse Event ....................................................................... 39 
7.2.1 
Severity of Event ............................................................................... 39 
7.2.2 
Relationship to Study Agent ................................................................. 39 
7.2.3 
Expectedness ................................................................................... 40 
7.3 
Time Period and Frequency for Event Assessment and Follow-Up .............................. 40 
7.4 
Reporting Procedures ........................................................................................ 41 
7.4.1 
Adverse Event Reporting ..................................................................... 41 
7.4.2 
SAE Reporting .................................................................................. 41 
7.4.3 
UADE Reporting ................................................................................ 41 
7.4.4 
Reporting of Pregnancy ....................................................................... 41 
8 
CLINICAL MONITORING ........................................................................................... 42 
9 
STATISTICAL CONSIDERATIONS .............................................................................. 42 
9.1 
Statistical and Analytical Plans ............................................................................ 42 
9.2 
Statistical Hypotheses ....................................................................................... 42 
9.3 
Analysis Datasets ............................................................................................. 43 
9.4 
Description of Statistical Methods ......................................................................... 43 
9.4.1 
General Approach .............................................................................. 43 
9.4.2 
Analysis of the Primary Efficacy Endpoint(s) ............................................ 44 
9.4.3 Analysis of the Secondary Endpoint(s) ...................................................................... 44 
9.4.4 Safety Analyses 
 .......................................................................................... 45 
9.4.5 Adherence and Retention Analyses .......................................................................... 45 
9.4.6 Baseline Descriptive Statistics ................................................................................. 45 
9.4.7 Planned Interim Analyses ....................................................................................... 46 
9.4.8 Additional Sub-Group Analyses ............................................................................... 46 
9.4.9 Multiple Comparison/Multiplicity ............................................................................... 46 
9.4.10 Tabulation of Individual Response Data ................................................................... 46 
9.4.11 Exploratory Analyses  .......................................................................................... 46 
9.5 
Sample Size .................................................................................................... 46 
9.6 
Measures to Minimize Bias ................................................................................. 47 
9.6.1 
Enrollment/ Randomization .................................................................. 47 
10 
SOURCE DOCUMENTS AND CASE REPORT FORMS ................................................... 48 
11 
QUALITY CONTROL AND ASSURANCE ...................................................................... 48 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS ............................................................ 49 
12.1 
Ethical Standard ............................................................................................... 49 
12.2 
Laws and Regulations ....................................................................................... 49 
12.3 
Institutional Review Board .................................................................................. 49 
12.4 
Informed Consent Process ................................................................................. 49 
12.5 
Participant and Data Confidentiality ...................................................................... 50 
13 
DATA HANDLING AND RECORD KEEPING .................................................................. 50 

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13.1 
Study Records Retention .................................................................................... 50 
13.2 
Protocol Deviations ........................................................................................... 51 
13.3 
Publication and Data Sharing Policy ..................................................................... 51 
14 
CONFLICT OF INTEREST POLICY .............................................................................. 51 
15  
LITERATURE REFERENCES ..................................................................................... 52 
APPENDIX I: SCHEDULE OF EVENTS .................................................................................. 54 
APPENDIX II: STATEMENT OF COMPLIANCE ....................................................................... 57 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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LIST OF ABBREVIATIONS 
 
ABI 
Ankle Brachial Index 
ADL 
Activities of Daily Living 
AE 
Adverse Event 
BMI 
Body Mass Index 
CFR 
Code of Federal Regulations 
CMS 
Centers for Medicare and Medicaid Services 
CRF 
Case Report Form 
eCRF 
Electronic Case Report Form  
GCP 
Good Clinical Practice 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonisation 
IRB 
Institutional Review Board 
NPUAP 
National Pressure Ulcer Advisory Panel 
NPWT 
Negative Pressure Wound Therapy  
PUSH 
Pressure Ulcer Scale for Healing  
QC 
Quality Control 
SAE 
Serious Adverse Event  
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
SF 
Short Form  
SID 
Subject Identification Number  
SNF 
Skilled Nursing Facility 
SOC 
Standard of Care 
UADE 
Unanticipated Adverse Device Effect 
VPS 
Visual Pain Scale 
 
 
 
 
 
 

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PROTOCOL SUMMARY 
Title: 
A single site randomized, clinical trial comparing: 
 Concomitant use of MicroMatrix® and CytalTM Burn Matrix 
2-Layer 
 MicroMatrix® and CytalTM Burn Matrix 2-Layer with a 
negative pressure wound therapy (NPWT) system  
 A NPWT alone 
in the management of Stage 3 or 4 pressure injuries (as 
defined by the National Pressure Ulcer Advisory Panel 
[NPUAP]). 
 
Protocol Number: 
CA2016-001 
 
Study Design: 
A three arm, parallel-design, randomized study comparing 2 
experimental arms to a single control arm.  The primary 
comparison will be Group 1 (MicroMatrix® with CytalTM Burn 
Matrix 2-Layer vs. Group 3 (NPWT) to determine if Group 1 
is superior to Group 3.   NPWT is the standard of care 
(SOC) for patients with Stage 3 or 4 pressure ulcers and is 
the active control arm for the study. 
 
A secondary comparison will be conducted comparing 
Group 2 (MicroMatrix® with CytalTM Burn Matrix 2-Layer plus 
NPWT) vs. Group 3 (NPWT) to determine if Group 2 is 
superior to Group 3.     
Patients who meet the inclusion and exclusion criteria for the 
study will be randomized (1:1:1) to Group 1, 2, or 3 using a 
permuted block randomization scheme.   
 
Objectives: 
 
1. To compare the incidence of complete epithelization at 
12 weeks between Group 1 and Group 3, and Group 2 to 
Group 3.  
2. To compare the time to complete epithelization between 
Group 1 and Group 3, and Group 2 to Group 3.  

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3. To compare the rate of wound epithelization between 
Group 1 and Group 3, and Group 2 to Group 3 over time 
in cm2/week. 
4. To evaluate improvements in the clinical efficacy and 
impact of MicroMatrix® and CytalTM Burn Matrix 2-Layer 
treatments as compared to NPWT. 
5. To compare direct and indirect pressure ulcer related 
costs by subject. 
6. To compare the treatment-emergent adverse event (AE) 
safety profile between CytalTM Burn Matrix 2-Layer, 
MicroMatrix®, and NPWT. 
Endpoints: 
Primary Endpoint 
Incidence of complete epithelization at 12 weeks between 
Group 1 and Group 3, and Group 2 to Group 3.  
 
Secondary Endpoints 
1. Time to complete wound epithelization between Group 1 
and Group 3, and Group 2 to Group 3. 
2. Compare rate of wound epithelization, measured by 
change in pressure ulcer area over time, in cm2/week. 
3. Impact of the treatments, measured by: 
a. Patient satisfaction using the Short Form (SF)-
20 Health Survey, Wong-Baker FACES® Visual 
Pain 
Scale 
(VPS), 
and 
Katz 
Index 
of 
Independence in Activities of Daily Living 
(ADL) 
b. Type of tissue developed (Pressure Ulcer 
Scale for Healing [PUSH] Tool) 
i. Ulcer area changes and decrease in 
wound margins 
ii. Granulation, 
epithelization, 
and 
exudates changes 
iii. Time to healing 
c. Pain evaluation and narcotic use 
d. Nursing contact time (time required for 
dressing changes)  
e. Length of hospital stay for in-patient patients 
f. Length of stay at skilled nursing facilities (SNF) 
for patients who are discharged to SNF 
 

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Tertiary Endpoints 
1. Cost Analysis 
a. Direct and indirect pressure ulcer related costs 
by subject.  This is measured by total inpatient 
and outpatient expenses, stratified by product 
and care cost 
b. Current employment status and return to work 
status  
c. Frequency (and associated expenses) of 
pressure ulcer specific AEs, UADEs and SAEs 
 
Number of Subjects: 
60 patients who present to the physician in the hospital or 
wound care clinic with at least one Stage 3 or 4 pressure 
ulcer will be considered for enrollment and randomization.  
Given that the primary endpoint is dichotomous, patients 
who withdraw prematurely (<12 weeks from randomization 
and 
treatment 
assignment) 
without 
complete 
wound 
epithelialization will be considered in the analysis as not 
having met the definition for epithelialization. 
 
Study Criteria 
Inclusion Criteria  
1. Provision of signed and dated informed consent form by 
subject or legally authorized representative.  
2. Stated willingness to comply with all study procedures 
and availability for the duration of the study.  
3. Male or female patients that are ≥ 21 years of age. 
4. Body Mass Index (BMI) <45. 
5. At least one Stage 3 or 4 pressure injury (NPUAP 
Staging Guidelines) present at the Screening and/or 
Treatment Visit located in any of the following regions: 
a. Occipital 
b. Back 
c. Flank 
d. Upper Extremity 
i. Arm 
ii. Elbow 
iii. Wrist 
iv. Hand 
e. Sacral 
f. Hip 

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g. Gluteal 
h. Ischial 
i. Lower Extremity 
i. Leg 
ii. Knee 
iii. Ankle 
iv. Heel 
v. Foot 
6. Surface dimensions of pressure injury must be between 
9 to 64 cm2 inclusive (as measured prior to treatment 
using a cm-scale ruler). The longest dimension must not 
exceed 10 cm; depth must not exceed 5 cm.   
7. Wound must be >5 cm from the anus if colostomy not 
performed. 
8. For lower extremity ulcers: Adequate arterial blood flow 
and perfusion near the site of the injury (the foot is warm 
to the touch and has palpable pulses), per Investigator 
judgement.  
9. Confirmed pressure injury versus moisture-associated 
skin damage or friction injury. 
10. Ability to maintain an intact occlusive dressing for 4-7 
days with reinforcement without contamination of urine or 
stool. 
11. Confirmed fecal (Colostomy) and/or urine incontinence 
(Foley) maintenance/management, if necessary. 
12. Consent to off-loading (turns) from pressure sites a 
minimum of every 2 hours (if possible).  
13. Consent to sharp debridement of necrotic tissue in the 
wound bed unless the wound has already undergone 
debridement within 5 days prior to the Treatment Visit. 
14. For females of reproductive potential (defined as females 
≤ 55 years of age): Negative pregnancy test required 
prior to surgical debridement per hospital procedures. 
 
Exclusion Criteria 
1. Surgical treatment of pressure injury 30 days prior to the 
Treatment Visit and/or pressure injury in previously 
irradiated areas. 
2. Inability to manage fecal and/or urine incontinence or 
patient refusal of its maintenance/management (as 

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determined medically necessary).  Patient may be 
rescreened 
and 
enrolled 
if 
urinary 
and/or 
fecal 
continence status or management change after failure to 
comply with requirement. 
3. Allergy or hypersensitivity to materials in porcine-based 
study 
products 
(per 
subject 
report) 
or 
personal 
preference. 
4. Currently treated for an active malignant disease. 
5. Prior diagnosis of active malignant disease, and is less 
than 1 year disease-free. 
6. History of malignancy within the wound. 
7. Presence of any conditions that are contraindicated with 
NPWT. 
8. Any condition associated with a wound healing 
abnormality (e.g.: connective tissue disorder or immune 
disorder). 
9. Dermatologic comorbid disease (e.g., cutis laxa or 
collagen vascular disease). 
10. Bleeding diathesis. 
11. Patients with primary treatment ulcers from burns (from 
exposure to high heat) or venous leg ulcers.  A patient 
may have concomitant non-pressure ulcers present in 
non-pressure ulcer treatment regions. 
12. Received biological-based therapy in any pressure 
wound within 3 months of the Treatment Visit. 
13. Severe or significant hypoalbuminemia (albumin <2.5 
g/dL, and/or pre-albumin <5 mg/dL), or hypoproteinemia 
(protein <6 g/dL). 
14. Moderate to severe anemia (Hgb <7 g/dL). 
15. Severely uncontrolled diabetes mellitus (defined as 
HA1C >12%). 
16. Subject report of concurrent participation in another 
clinical trial that involves an investigational drug or device 
that would interfere with this study. 
17. Subject report of previous participation in other 
interventional wound healing clinical investigation within 
60 days prior to the Screening Visit. 
18. The subject has any physical or psychiatric condition that 
in the Investigator's opinion would warrant exclusion from 
the study or prevent the subject from completing the 

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study. 
 
Number of Sites: 
1 
Site Locations: 
Saint Vincent’s Medical Center Riverside 
1 Shircliff Way 
Jacksonville, FL 32204 
 
Saint Vincent’s Medical Center Southside 
4201 Belfort Road 
Jacksonville, FL 32216 
 
Wells Surgical Services, LLC 
1395 Cassat Avenue, Suite 1 
Jacksonville, FL 32205 
 
11512 Lake Mead Avenue 
Suite 531 
Jacksonville, FL 32256 
 
3 Shircliff Way 
Dillon Building Suite 630 
Jacksonville, FL 32204 
ACell 
Study 
Product(s): 
1. MicroMatrix® 
2. CytalTM Burn Matrix 2-Layer  
Participant & Study 
Duration: 
The duration of this study for each subject will be a 
maximum of up to 27 weeks.   
 
Subject recruitment is planned to last for 6-9 months, 
starting in early 2017.  The study will end in mid-2018 after 
the database has been locked. The actual overall study 
duration or subject recruitment period may vary.  
Statistical 
Methodology: 
All statistical tests will be conducted using a type 1 error rate 
of 5%.  Simultaneous testing for the primary endpoint of 
Group 1 vs. Group 3 and Group 2 vs. Group 3 will be 
conducted.  The analyses of the secondary endpoints will be 
conducted using a hierarchical plan: if the primary analysis is 
significant in favor of Group 1 over Group 3, the secondary 
and tertiary analyses can be conducted in sequential order 
using a type 1 error rate of 5%.  If the primary analysis is 

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significant in favor of Group 2 over Group 3, the secondary 
and tertiary analyses will be conducted in sequential order 
using a type 1 error rate of 5%.  The testing will continue, 
provided the prior analysis was significant in favor of the 
study product.   
 
The analysis of the primary endpoint will be based on a 
generalized linear model specifying the distribution as 
binomial.  If a patient withdraws prior to the 12-week wound 
evaluation visit and the last recorded observation revealed 
complete wound epithelialization, the patient will be counted 
in the primary analysis as having achieved complete wound 
epithelialization.  If a patient withdraws prior to the 12-week 
wound evaluation visit and the last recorded observation 
revealed the wound had not closed, the patient will be 
counted in the primary analysis as not having achieved 
complete wound epithelialization.       
 
The analysis of the time of the initial observation of complete 
wound epithelialization will be conducted using a log rank 
test. If a patient withdraws prior to achieving complete 
wound epithelialization, the patient will be censored using 
the time of the last observation.   
 
To estimate the sample size for this clinical investigation, the 
difference in the incidence of patients who achieve complete 
wound epithelialization (primary endpoint) was used.  
Estimates were prepared considering complete closure in the 
NPWT arm of 20% to 40% and a type 1 and 2 error rate of 
5% and 20%, respectively.  Based on these estimates, if the 
incidence in Group 1 is 45% greater than the incidence in 
Group 3, the difference will be significant (p<0.05).     
 
 

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1 
KEY ROLES 
 
Elizabeth A. Smith  
Senior Director of Clinical Research, ACell Inc. 
(443) 283–2768  
elizabethsmith@acell.com 
 
Tejal Gambhir, MPH, CCRP 
Clinical Research Manager, ACell Inc. 
tejalgambhir@acell.com 
 
Jessica M. Warren, RN, BSN, MA, FCCS, CCRC 
Sr. Clinical Research Associate, ACell Inc. 
(443) 283–2885 
jessicawarren@acell.com 
 
Mike Anibaba 
Clinical Research Assistant, ACell Inc. 
(443) 283–2798   
mikeanibaba@acell.com 
 
Cindy Mattingly 
Senior Clinical Data Manager, ACell Inc. 
(410) 953- 8539 
cindymattingly@acell.com 
 
Bruce C. Stouch, Ph.D. 
Principal Biostatistician, BCS Statistical Solutions LLC 
Biostatistics Department 
Suite 300 
29 Harrison Drive 
Newtown Square, PA 19073  
(610) 356-8658 
BCSSTATS@aol.com  
 
Carol Bowen-Wells, MD 
Principal Investigator, Wells Surgical Services, LLC  
(904) 503-8335 
carol.bwells@wsrfi.com 
 
Belma Dzafo 

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Study Coordinator, Wells Surgical Services, LLC 
(904) 503-8335 
belma.dzafo@wellssurgicalservices.com 
 
Tahitia K. Elliot, MD 
Study Coordinator, Wells Surgical Services, LLC 
(904) 503-8335 
1tahitia@gmail.com 
 
 
 
 

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2  
INTRODUCTION: BACKGROUND INFORMATION AND SCIENTIFIC 
RATIONALE  
 
2.1 
BACKGROUND INFORMATION  
 
A pressure injury is localized damage to the skin and/or underlying soft tissue usually 
over a bony prominence or related to a medical or other device.1 The injury occurs as a 
result of intense and/or prolonged pressure or pressure in combination with shear, and 
may present as intact skin or an open ulcer.1 The staging of a pressure injury includes1: 
 
Stage 1: Non-blanchable erythema of intact skin 
Intact skin with a localized area of non-blanchable erythema, which may appear 
differently in darkly pigmented skin. Presence of blanchable erythema or changes in 
sensation, temperature, or firmness may precede visual changes. Color changes do not 
include purple or maroon discoloration; these may indicate deep tissue pressure injury. 
 
Stage 2: Partial-thickness skin loss with exposed dermis 
Partial-thickness loss of skin with exposed dermis. The wound bed is viable, pink or red, 
moist, and may also present as an intact or ruptured serum-filled blister. Adipose (fat) is 
not visible and deeper tissues are not visible. Granulation tissue, slough and eschar are 
not present. These injuries commonly result from adverse microclimate and shear in the 
skin over the pelvis and shear in the heel.  This stage should not be used to describe 
moisture associated skin damage (MASD) including incontinence associated dermatitis 
(IAD), intertriginous dermatitis (ITD), medical adhesive related skin injury (MARSI), or 
traumatic wounds (skin tears, burns, abrasions). 
 
Stage 3: Full-thickness skin loss 
Full-thickness loss of skin, in which adipose (fat) is visible in the ulcer and granulation 
tissue and epibole (rolled wound edges) are often present. Slough and/or eschar may 
be visible. The depth of tissue damage varies by anatomical location; areas of 
significant adiposity can develop deep wounds.  Undermining and tunneling may occur. 
Fascia, muscle, tendon, ligament, cartilage and/or bone are not exposed. If slough or 
eschar obscures the extent of tissue loss this is an Unstageable Pressure Injury. 
 
Stage 4: Full-thickness skin and tissue loss 
Full-thickness skin and tissue loss with exposed or directly palpable fascia, muscle, 
tendon, ligament, cartilage or bone in the ulcer. Slough and/or eschar may be visible. 
Epibole (rolled edges), undermining and/or tunneling often occur. Depth varies by 

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anatomical location. If slough or eschar obscures the extent of tissue loss this is an 
Unstageable Pressure Injury. 
 
Unstageable Pressure Injury: Obscured full-thickness skin and tissue loss 
Full-thickness skin and tissue loss in which the extent of tissue damage within the ulcer 
cannot be confirmed because it is obscured by slough or eschar.  If slough or eschar is 
removed, a Stage 3 or Stage 4 pressure injury will be revealed. Stable eschar (i.e. dry, 
adherent, intact without erythema or fluctuance) on an ischemic limb or the heel(s) 
should not be removed. 
 
Deep Tissue Pressure Injury: Persistent non-blanchable deep red, maroon or 
purple discoloration 
Intact or non-intact skin with localized area of persistent non-blanchable deep red, 
maroon, purple discoloration or epidermal separation revealing a dark wound bed or 
blood filled blister. Pain and temperature change often precede skin color changes. 
Discoloration may appear differently in darkly pigmented skin.  This injury results from 
intense and/or prolonged pressure and shear forces at the bone-muscle interface.  The 
wound may evolve rapidly to reveal the actual extent of tissue injury, or may resolve 
without tissue loss. If necrotic tissue, subcutaneous tissue, granulation tissue, fascia, 
muscle or other underlying structures are visible, this indicates a full thickness pressure 
injury (Unstageable, Stage 3 or Stage 4). Do not use Deep Tissue Pressure Injury to 
describe vascular, traumatic, neuropathic, or dermatologic conditions. 
 
Pressure injuries have previously been called pressure ulcers, pressure sores, 
bedsores, and decubitus ulcers, terms that imply that only bed-bound, non-ambulatory 
patients develop pressure injuries.1  However, patients who are ambulatory can also 
develop pressure ulcers, although reduced mobility is still a major risk factor.1 
 
Pressure injury prevalence in health care setting ranges from 0%2 to 72.5%,3 with large 
variations observed between countries and clinical settings (e.g., acute care, aged care 
and community care).1 Average prevalence in acute care settings is cited as 
approximately 10%.4  In general acute care, there appears to be a gradual decline in 
pressure injury prevalence over the past decade, 5 due to the growing international 
health policy focus on prevention of pressure injuries.1  However, there are no clear 
trends in other clinical settings.1  Prevalence and incidence rates are generally higher in 
populations who are at elevated risk, 1 such as those receiving palliative care,4 those 
with spinal cord injuries6, and individuals in critical care. 7, 8 
 
In 2001, the National Pressure Ulcer Advisory Panel (NPUAP) described the incidence 
of pressure injuries as ranging from 0.4% to 38% in hospitals, from 2.2% to 23.9% in 

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skilled nursing facilities and from 0.0% to 17% for home health agencies.5  Since then, 
hospitals have increased their efficiency in pressure ulcer prevention, and incidence 
rates have dropped from 7% in the 2000s to 4.5% in 2012.9, 10  
 
Pressure injury treatment begins with an accurate diagnosis and the classification of 
pressure injury.  Current treatments include wound bed preparation (cleansing, 
debridement and dressing), biophysical agents, surgery, and wound off-loading. 
 
Pressure ulcers represent a major burden of sickness and reduced quality of life for 
patient consumers and their care givers.1  Increased morbidity and mortality associated 
with pressure ulcer development in hospitalized patients is documented in multiple 
studies.12,13  According to NPUAP, hospital lengths of stay, readmission rates, and 
hospital charges are greater in individuals who develop a pressure ulcer than in those 
remaining ulcer free.1  The development of a single pressure ulcer in hospitals in the 
United States can increase the patients’ length of stay five-fold.14  Additionally, the 
personal burden associated with a chronic wound, including pain and discomfort; stress, 
anxiety and depression; lowered autonomy and security; and impaired social functioning 
is immeasurable.1 
 
Pressure injuries acquired during hospitalization, evaluated as either Stage 3 or 4 are 
considered among the eight preventable conditions identified by the Centers for 
Medicare and Medicaid Services (CMS).11 Since October of 2008, hospitals no longer 
receive higher Medicare payments related to the ulcer specific care of patients who 
acquire Stage 3 or 4 pressure injuries during their inpatient stay.11  
 
Pressure injuries are often documented in hospitalized patients as a secondary 
diagnosis rather than the primary reason.11  In 2007, CMS reported 257,412 cases of 
secondary, Stages 3 or 4 pressure injuries, at a cost per case of $43,180 (USD).11  
However, this may be a serious underestimation of the problem, because physician 
discharge diagnoses may not include presence of a pressure injury even when the 
patient has a Stage 3 or Stage 4 ulcer.11  Physicians often see pressure injury detection 
and prevention as a nursing issue and fail to include this data in their discharge 
summaries, which are used by coders for billing purposes.11 
 
2 
OBJECTIVES AND PURPOSE 
 
The primary objectives of the study are: 
 
1. To compare the incidence of complete epithelization at 12 weeks between Group 
1 and Group 3, and Group 2 to Group 3.  

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The secondary objectives  of the study are: 
 
1. To compare the time to complete epithelization between Group 1 and Group 3, 
and Group 2 to Group 3.  
2. To compare the rate of wound epithelization between Group 1 and Group 3, and 
Group 2 to Group 3 over time in cm2/week. 
3. To evaluate improvements in the clinical efficacy and impact of MicroMatrix® and 
CytalTM Burn Matrix 2-Layer treatments as compared to NPWT  
 
The tertiary objectives  of the study are: 
 
1. To compare direct and indirect pressure ulcer related costs by subject measured 
by total inpatient and outpatient expenses.  
2. To compare the treatment-emergent AE safety profile between CytalTM, 
MicroMatrix® and NPWT. 
 
3 
STUDY DESIGN AND ENDPOINTS 
 
3.1 
DESCRIPTION OF THE STUDY DESIGN 
 
A three arm, parallel-design, randomized study comparing 2 experimental arms to a 
single control arm.  The primary comparison will be Group 1 (MicroMatrix® with CytalTM 
Burn Matrix 2-Layer) vs. Group 3 (NPWT) to determine if Group 1 is superior to Group 
3.   NPWT is the SOC for patients with Stage 3 or 4 pressure ulcers and is the active 
control arm for the study. 
 
A secondary comparison will be conducted comparing Group 2 (MicroMatrix® with 
CytalTM Burn Matrix 2-Layer plus NPWT) vs. Group 3 (NPWT) to determine if Group 2 is 
superior to Group 3.     
Patients who sign the informed consent form and meet all inclusion and exclusion 
criteria for the study will be randomized (1:1:1) to Group 1, 2, or 3 using a permuted 
block randomization scheme.   
 
The duration of this study for each subject will be a maximum of up to 27 weeks.   
 
Subject recruitment is planned to last for 6-9 months, starting in early-2017.  The study 
will end mid-2018 after the database has been locked. The actual overall study duration 
or subject recruitment period may vary. 
 

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3.2 
STUDY ENDPOINTS 
 
3.2.1 PRIMARY ENDPOINT 
 
The primary endpoint of the study is the incidence of complete epithelization at 12 
weeks between Group 1 and Group 3, and Group 2 to Group 3.  
3.2.2 SECONDARY ENDPOINTS 
 
The secondary endpoints of the study include: 
 
1. Time to complete wound epithelization between Group 1 and Group 3, and 
Group 2 to Group 3. 
2. Compare rate of wound epithelization, measured by changes in pressure ulcer 
area over time, in cm2/week. 
3. Impact of the treatments, measured by: 
a. Patient satisfaction using the Short Form (SF)-20 Health Survey, Wong-
Baker FACES®  Visual Pain Scale (VPS), and Katz Index of Independence 
in Activities of Daily Living (ADL) 
b. Type of tissue developed (PUSH Tool) 
i. Ulcer area changes and decrease in wound margins 
ii. Granulation, epithelization, and exudates changes 
iii. Time to healing 
c. Pain evaluation and narcotic use 
d. Nursing contact time (time to change dressing)  
e. Length of hospital stay for in-patient patients 
f. Length of stay at SNF for patients who are discharged to SNF 
 
 
3.2.3 TERTIARY ENDPOINTS 
 
Tertiary endpoints of the study include: 
 
1. Cost Analysis 
1. Direct and indirect pressure ulcer related costs by subject.  This is 
measured by total inpatient and outpatient expenses, stratified by product 
and care cost 
2. Current employment status and return to work status  
3. Frequency (and associated expenses) of pressure ulcer specific AEs, 
UADEs and SAEs 
 

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4 
STUDY ENROLLMENT AND WITHDRAWAL 
 
4.1 
PARTICIPANT INCLUSION CRITERIA 
 
In order to be eligible to participate in this study, an individual must meet all of the 
following criteria:  
Inclusion Criteria  
1. Provision of signed and dated informed consent form by subject or legally authorized 
representative.  
2. Stated willingness to comply with all study procedures and availability for the 
duration of the study.  
3. Male or female patients that are ≥ 21 years of age. 
4. Body Mass Index (BMI) <45. 
5. At least one Stage 3 or 4 pressure injury (NPUAP Staging Guidelines) present at the 
Screening and/or Treatment Visit located in any of the following regions: 
a. Occipital 
b. Back 
c. Flank 
d. Upper Extremity 
i. Arm 
ii. Elbow 
iii. Wrist 
iv. Hand 
e. Sacral 
f. Hip 
g. Gluteal 
h. Ischial 
i. Lower Extremity 
i. Leg 
ii. Knee 
iii. Ankle 
iv. Heel 
v. Foot 
6. Surface dimensions of pressure injury must be between 9 to 64 cm2 inclusive (as 
measured prior to treatment using a cm-scale ruler). The longest dimension must not 
exceed 10 cm; depth must not exceed 5 cm.   
7. Wound must be > 5 cm from the anus if colostomy not performed. 

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8. For lower extremity ulcers: Adequate arterial blood flow and perfusion near the site 
of the injury (the foot is warm to the touch and has palpable pulses), per Investigator 
judgement.  
9. Confirmed pressure injury versus moisture-associated skin damage or friction injury. 
10. Ability to maintain an intact occlusive dressing for 4-7 days with reinforcement 
without contamination of urine or stool. 
11. Confirmed 
fecal 
(Colostomy) 
and/or 
urine 
incontinence 
(Foley) 
maintenance/management, if necessary. 
12. Consent to off-loading (turns) from pressure sites a minimum of every 2 hours (if 
possible).  
13. Consent to sharp debridement of necrotic tissue in the wound bed unless the wound 
has already undergone debridement within the previous 5 days of the Treatment 
Visit. 
14. For females of reproductive potential (defined as females ≤ 55 years of age): 
Negative pregnancy test required prior to surgical debridement per hospital 
procedures. 
 
4.2 
PARTICIPANT EXCLUSION CRITERIA 
 
An individual who meets any of the following criteria will be excluded from participation 
in this study: 
 
Exclusion Criteria 
1. Surgical treatment of pressure injury 30 days prior to the Screening Visit and/or 
pressure injury in previously irradiated areas. 
2. Inability to manage fecal and/or urine incontinence or patient refusal of its 
maintenance/management (as determined medically necessary).  Patient may be 
rescreened and enrolled if urinary and/or fecal continence status or management 
change after failure to comply with requirement. 
3. Allergy or hypersensitivity to materials in porcine-based study products (per subject 
report) or personal preference. 
4. Currently treated for an active malignant disease. 
5. Prior diagnosis of active malignant disease, and is less than 1 year disease-free. 
6. History of malignancy within the wound. 
7. Presence of any conditions that are contraindicated with NPWT. 
8. Any condition associated with a wound healing abnormality (e.g.: connective tissue 
disorder or immune disorder). 
9. Dermatologic comorbid disease (e.g., cutis laxa or collagen vascular disease). 
10. Bleeding diathesis. 

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11. Patients with primary treatment ulcers from burns (from exposure to high heat) or 
venous leg ulcers.  A patient may have concomitant non-pressure ulcers present in 
non-pressure ulcer treatment regions. 
12. Received biological-based therapy in any pressure wound within 3 months of the 
Treatment Visit. 
13. Severe or significant hypoalbuminemia (albumin <2.5 g/dL, and/or pre-albumin <5 
mg/dL), or hypoproteinemia (protein <6 g/dL). 
14. Moderate to severe anemia (Hgb <7 g/dL). 
15. Severely uncontrolled diabetes mellitus (defined as HA1C >12%). 
16. Subject report of concurrent participation in another clinical trial that involves an 
investigational drug or device that would interfere with this study. 
17. Subject report of previous participation in other interventional wound healing clinical 
investigation within 60 days prior to the Screening Visit. 
18. The subject has any physical or psychiatric condition that in the Investigator's 
opinion would warrant exclusion from the study or prevent the subject from 
completing the study. 
 
4.3 
STRATEGIES FOR RECRUITMENT  
 
Eligible subjects will be recruited and enrolled from the in-patient facility or from consult 
referrals to Wells Surgical Services, LLC, under the responsibility of the Principal 
Investigator.   
 
4.4 
PARTICIPANT WITHDRAWAL OR TERMINATION 
 
4.4.1 REASONS FOR WITHDRAWAL OR TERMINATION 
A subject may be discontinued from the study at any time if the subject, the Investigator, 
or the Sponsor feels that it is not in the subject’s best interest to continue.  The following 
is a list of possible reasons for study treatment discontinuation:  
 
 Screen Failure 
 Subject withdrawal of consent  
 Subject is not compliant with study procedures 
 Adverse Event that in the opinion of the Investigator would be in the best interest 
of the subject to discontinue study participation 
 Protocol violation requiring discontinuation  
 Lost to follow-up 
 Sponsor request for early termination of study 

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 Subject death 
All subjects are free to withdraw from participation at any time, for any reason, specified 
or unspecified, and without prejudice. 
Reasonable attempts will be made by the Investigator to provide a reason for subject 
withdrawals.  The reason for the subject’s withdrawal from the study will be specified in 
the subject’s source documents and the Case Report Form (CRF).   
If a subject is withdrawn from treatment due to an AE, the subject will be followed and 
treated by the Investigator until the abnormal parameter or symptom has resolved or 
stabilized. 
 
The Investigator must make every effort to contact subjects who are lost to follow-up.  
Three (3) attempted telephone contacts should be documented by key research 
personnel in order to consider the participant lost to follow-up.  Furthermore, a certified 
letter will be mailed to the participant’s address.  If the participant does not respond, the 
certified letter receipt should be filed in the individual’s research record with a copy of 
the letter sent.  Attempts to contact such subjects must be documented in the patients’ 
records (e.g., times and dates of attempted telephone contact, receipt for sending a 
registered letter, etc.). 
 
4.4.2 HANDLING OF PARTICIPANT WITHDRAWALS OR TERMINATION 
 
Although subjects may withdraw from the study at any time and for any reason, (or may 
be withdrawn at the Investigator’s discretion), subject withdrawal should be avoided as 
much as reasonably possible.  In any case, appropriate follow-up for endpoints should 
be continued.   
 
Subjects who prematurely discontinue are not to be replaced.  For subjects considered 
lost to follow-up, the CRF must be completed up to the last visit performed. 
 
4.5 
PREMATURE TERMINATION OR SUSPENSION OF STUDY 
 
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the Investigator, 
the Sponsor and the Institutional Review Board (IRB), as appropriate.  If the study is 
prematurely terminated or suspended, the Investigator will promptly inform the IRB and 
will provide the reason(s) for the termination or suspension.  

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Circumstances that may warrant termination or suspension include, but are not limited 
to:  
 Determination of unexpected, significant, or unacceptable risk to participants  
 Demonstration of efficacy that would warrant stopping  
 Insufficient compliance to protocol requirements  
 Data that are not sufficiently complete and/or evaluable  
 Determination of futility  
 
Study may resume once concerns about safety, protocol compliance, data quality are 
addressed and satisfy the Sponsor and/or the IRB. 
 
5 
STUDY DEVICE 
 
5.1 
STUDY DEVICE DESCRIPTION 
 
5.1.1 DEVICE DESCRIPTION  
 
MicroMatrix® 
MicroMatrix® is composed of a porcine-derived extracellular matrix known as urinary 
bladder matrix and is intended for the management of topical wounds including: partial 
and full-thickness wounds, pressure ulcers, venous ulcers, diabetic ulcers, chronic 
vascular ulcers, tunneled/undermined wounds, surgical wounds (donor sites/grafts, 
post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), trauma wounds 
(abrasions, lacerations, second-degree burns, skin tears) and draining wounds. The 
device is intended for one-time use. 
 
The devices are supplied in a particle form in masses up to 1000mg, and packaged in a 
glass vial and a peel-open pouch. 
 
Refer to Instructions for Use for further details. 
 
CytalTM Burn Matrix 2-Layer  
CytalTM Burn Matrix 2-Layer is composed of a porcine-derived extracellular matrix also 
known as urinary bladder matrix. The device is intended for the management of wounds 
including: partial and full-thickness wounds, pressure ulcers, venous ulcers, diabetic 
ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wounds (donor 
sites/grafts, post-Mohs surgery, post-laser surgery, podiatric, wound dehiscence), 

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trauma wounds (abrasions, lacerations, second-degree burns, skin tears) and draining 
wounds. The device is intended for one time use. 
 
The devices are supplied in a fenestrated sheet configuration in sizes up to 10 cm x 15 
cm and packaged in double peel-open pouches. 
 
Refer to Instructions for Use for further details. 
 
Negative Pressure Wound Therapy 
KCI, Inc. 
The V.A.C.Via™ Negative Pressure Wound Therapy System is an integrated wound 
management system for use in acute, extended and home care settings. It is intended 
to create an environment that promotes wound healing by secondary or tertiary 
(delayed primary) intention by preparing the wound bed for closure, reducing edema, 
promoting granulation tissue formation and perfusion, and by removing exudates and 
infectious material. It is indicated for patients with chronic, acute, traumatic, subacute 
and dehisced wounds, partial-thickness burns, ulcers (such as diabetic, pressure or 
venous insufficiency), flaps and grafts. 
 
GenaDyne, Inc. 
Genadyne A4 Wound Vacuum System is indicated for patients who would benefit from 
a suction device, particularly as the device may promote wound healing by the removal 
of excess exudates, infectious material and tissue debris. 
 
A4-XLR8 Foam Dressing is appropriate for use on the following wounds: 
 
 Pressure ulcers 
 Diabetic/Neuropathic ulcers 
 Venous insufficiency ulcers 
 Traumatic wounds 
 Post-operative and dehisced surgical wounds 
 Skin flap and grafts 
Products used by the treating Investigator which are part of his/her SOC will be used as 
per manufacturer specific approved recommendations. 
 
5.1.2 ACQUISITION AND ACCOUNTABILITY 
The Sponsor (or designee) will ship MicroMatrix® (only) to the investigational site.  The 
initial study product shipment will be shipped after site activation (i.e., when all required 
regulatory documentation has been received by the Sponsor and a contract has been 

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executed). Subsequent study product shipments will be made after the site requests for 
resupply. 
 
Upon receipt of the MicroMatrix®, an inventory check must be performed against the 
device receipt log, filled out and signed by the person accepting the shipment.  It is 
important that the designated study staff counts and verifies that the shipment contains 
all the items noted in the shipment inventory.  Any damaged or unusable study devices 
in a given shipment will be documented in the study files.  The Investigator must notify 
the study Sponsor of any damaged or unusable study devices that were supplied to the 
Investigator’s site. 
 
Regular study device reconciliation will be performed to document device assigned and 
used. This reconciliation will be logged on the Device Accountability Log and Device 
Dispensing Log, each signed and dated by the PI. 
 
5.1.3 STUDY DEVICE STORAGE  
 
MicroMatrix® and CytalTM Burn Matrix 2-Layer should be stored at room temperature in a 
clean, dry environment, in the unopened and undamaged package. The products 
should be protected from freezing temperatures, excessive heat, and high humidity. 
 
 
 
 
5.1.4 RETURN OR DESTRUCTION OF STUDY DEVICE 
 
All unused MicroMatrix® will be retrieved by the Sponsor.  A detailed Device 
Accountability Log and a Storage Attestation Form of the returned study product(s) will 
be provided to the Sponsor at the end of the study. 
 
5.2 
POTENTIAL RISKS AND BENEFITS  
 
5.2.1 POTENTIAL RISK AND PRODUCT WARNINGS 
 
MicroMatrix® and Cytal™ Burn Matrix 2-Layer 
Complications and reactions are possible with any soft tissue repair, including but not 
limited to:  
 Infection 
 Increased chronic inflammation 

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 Allergic reaction 
 Unexplained fever or chills 
 Excessive redness, pain or swelling 
 Odor associated with the use of products during the healing phase 
 Excessive drainage from the wound 
Warnings for MicroMatrix®  
 If active infection is present, treat patient to resolve infection prior to device 
implantation.  
 Do not re-use or re-sterilize; can damage the device and lead to device failure 
and/or patient injury.  
 Do not use after printed expiration date.  
 Do not use if package is compromised, which may indicate loss of device sterility.  
 Do not use device if cracked, broken or otherwise damaged.  
Warnings for Cytal™ Burn Matrix 2-Layer  
 Do not use if cracked, broken, or otherwise damaged.  
Precautions for Cytal™ Burn Matrix 2-Layer 
 Do not re-use or re-sterilize.  
 Do not use after printed expiration date.  
 Do not use device if package seal has been broken.  
 Exposure to a contaminated or infected field can lead to rapid breakdown of 
device.  
 If an active infection is present, treat.  
Negative Pressure Wound Therapy  
NPWT is contraindicated on the following situations: 
 Exposed organs, blood vessels, vascular grafts, or unexplored enteric fistulas  
 Active, untreated infection  
 Necrotic tissue  
 Malignancy tissue (within the wound)  
 Fragile skin  
 Active hemorrhage / coagulopathy / anticoagulation  
 Adhesive allergy  
 
Bleeding is the most common significant complication associated with NPWT. Minor 
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controlled using direct pressure. Severe hemorrhage may occur in patients who are 
anticoagulated or in patients with exposed blood vessels or grafts. Infection is most 
commonly due to inadequate debridement and control of the initial wound infection. 
 
5.2.2 POTENTIAL BENEFITS  
 
This study may not directly benefit participants but may provide information that will 
benefit future patients that develop pressure injuries.   
 
MicroMatrix® 
MicroMatrix® is constructed of a naturally-occurring biomaterial designed to manage 
wounds.  The devices can be applied dried or hydrated prior to placement by adding 
room temperature sterile saline.  The biomaterial is a resorbable extracellular matrix 
scaffold containing epithelial basement membrane which allows for tissue ingrowth and 
integration by the surrounding host tissue to facilitate wound healing by the body.  
 
Cytal™ Burn Matrix 2-Layer 
Cytal™ Burn Matrix 2-Layer is constructed of a naturally-occurring biomaterial designed 
to manage wounds.  The devices may be cut to size and must be hydrated prior to 
placement by immersion in room temperature sterile saline.  The biomaterial is a 
resorbable extracellular matrix scaffold containing basement membrane which facilitates 
constructive remodeling of host tissue by integration. 
 
Negative Pressure Wound Therapy  
NPWT is designed to potentially promote wound healing by applying a vacuum to a 
wound using a sealed dressing over the area being treated.  The vacuum can draw fluid 
from the wound and may increase blood flow to the area. The vacuum may be applied 
continuously or intermittently, depending on the wound being treated and the judgement 
of the clinician treating the wound.  
 
 
 
 
6 
STUDY PROCEDURES AND SCHEDULE 
 
6.1 
STUDY PROCEDURES/EVALUATIONS 
 
6.1.1 STUDY SCHEDULE  

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A Schedule of Events representing the required testing procedures to be performed for 
the duration of the study is diagrammed in Appendix I.  All Follow-Up Visits will occur 
relative to the Treatment Visit, as outlined below: 
 
Screening Visit – between Study Days -5 – 0  
Treatment Visit – Study Day 1 
Follow-Up Visit 1 – between Study Days 2 – 7 
Follow-Up Visit 2 – between Study Days 8 – 14 
Follow-Up Visit 3 – between Study Days 15 – 21 
Follow-Up Visit 4 – between Study Days 22 – 28 
Follow-Up Visit 5 – between Study Days 29 – 35 
Follow-Up Visit 6 – between Study Days 36 – 42 
Follow-Up Visit 7 – between Study Days 43 – 49 
Follow-Up Visit 8 – between Study Days 50 – 56 
Follow-Up Visit 9 – between Study Days 57 – 63 
Follow-Up Visit 10 – between Study Days 64 – 70 
Follow-Up Visit 11 – between Study Days 71 – 77 
Follow-Up Visit 12 – between Study Days 78 – 84 
Follow-Up Visit 13 – between Study Days 85 – 91 
 
6.1.2 SCREENING VISIT (STUDY DAY -5 TO 0) 
 
The Screening Visit will occur up to 5 days prior to the Treatment Visit. 
 
1. Obtain informed consent from the potential subject, or legally authorized 
representative. 
2. Assign subject identification number (SID).  SIDs will be assigned in consecutive 
order and not be re-used in the case of Screen Failures.      
3. Collect demographic data including: date of birth, gender, race, ethnicity, 
employment status and ambulatory status (bed, wheelchair, independent [with or 
without assistance]). 
4. Document weight, height, and BMI.    
5. Review alcohol and tobacco use.  
6. Review and record medical history, surgical history, and medication history to 
determine eligibility based on inclusion/exclusion criteria.  
7. Record presence of medications associated with the pressure ulcer(s) for pain 
(narcotic, 
steroidal, 
non-steroidal, 
and 
opioids), 
antibiotics, 
nutritional 
supplements and anti-hypertensives.  Indicate type, dose, frequency, duration, 
and indication for each medication). 

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8. Administer SF-20 Health Survey, Visual Pain Scale (VPS), and Katz Index of 
Independence in Activities of Daily Living (Katz ADL).  
9. Perform physical examinations needed to determine eligibility based on 
inclusion/exclusion criteria.  
10. Record the following information for all pressure ulcers present: 
 Classification 
 Anatomic location 
 Initial measurements of length, width, and depth in centimeters, and 
surface area 
11. Collect blood sample(s) for pre-albumin, albumin, protein, and hemoglobin (only 
if these results are not documented in the subject’s medical chart within 30 days 
of the Screening Visit). ).  HA1C levels will be drawn on known diabetics only (if 
this result is not documented in the subject’s medical chart within 30 days of the 
Screening Visit). HA1C levels are not required for non-diabetic. 
 
6.1.3 TREATMENT VISIT (DAY 1)  
 
After all inclusion/exclusion criteria have met, the patient becomes eligible for 
randomization.  Randomization assignment may be obtained from ACell any time after 
eligibility is verified and prior to device application. 
 
1. Verify inclusion/exclusion criteria continue to meet.  
2. Perform physical examination. 
3. Perform urinary pregnancy test for women of childbearing potential. 
4. Record changes to medications associated with the pressure ulcer(s) for pain 
(narcotic, 
steroidal, 
non-steroidal, 
and 
opioids), 
antibiotics, 
and 
anti-
hypertensives.  Indicate type, dose, frequency, duration for each medication). 
5. Record the following information for all pressure ulcers present: 
a. Confirmation of length, width, and depth in centimeters  
b. Wound appearance and characteristics: 
i. Presence of epibole, eschar, undermining, tunneling, sinus tracts, 
adverse odor, and/or suspected infection. 
ii. Appearance of Exudate: Serous; Serosanguinous; Purulent; Bloody 
iii. Appearance of Wound Bed: Beefy Red; Red; Pink; White; Yellow 
iv. Categorize the pressure ulcer(s) with respect to surface area 
(length x width), exudate amount, and type of wound tissue using 
the PUSH Tool. 
v. Document volume of the wound(s) (length x width x depth). 
6. Obtain photographs of the eligible wound(s) post debridement and prior to device 
application.  

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7. Treat eligible wound(s) based on randomization assignment to Group 1, Group 2, 
or Group 3.  
 
a. Group 1 Procedures (ACell products) 
i. Debride the eligible pressure ulcer(s).  Wash the wound(s) and 
confirm hemostasis achieved. 
ii. Apply a thin contiguous layer of MicroMatrix® between the wound 
margins, covering the entire wound bed, to include any tunneling, 
sinus tracts, and/or undermining areas.    
iii. Place up to three (3) appropriately sized CytalTM Burn Matrix 2-
Layer sheets (previously hydrated in sterile saline, per the 
manufacturer’s Instructions for Use) over the MicroMatrix®. The 
hydrated sheet should be cut to fit the interior of the wound 
(including any tunneling, sinus tracts, and/or undermining areas).   
iv. Cover the CytalTM Burn Matrix 2-Layer sheet(s) with Mepitel® and 
secure the Mepitel® to the wound edges with staples.   
v. Apply Surgilube® to the Mepitel®, then cover with ABD and tape, or 
ABD Kerlix and Coban if on extremity.   
 
b. Group 2 Procedures (ACell products and NPWT) 
i. Debride the eligible pressure ulcer(s).  Wash the wound(s) and 
confirm hemostasis achieved. 
i. Apply a thin contiguous layer of MicroMatrix® between the wound 
margins, covering the entire wound bed, to include any tunneling, 
sinus tracts, and/or undermining areas. The distribution of the initial 
powder application should be approximately 3.5-5 mg/cm2 on the 
area to be covered.   
i. Place up to three (3) appropriately sized CytalTM Burn Matrix 2-
Layer sheet (previously hydrated in sterile saline per the 
manufacturer’s Instructions for Use) over the MicroMatrix®. The 
hydrated sheet(s) should be cut to fit the interior of the wound 
(including any tunneling, sinus tracts, and/or undermining areas), 
with no overlap onto healthy skin.  The trimmed pieces may be 
placed in the interior of the wound bed. 
ii. Cover the CytalTM Burn Matrix 2-Layer sheet with Mepitel® wound 
contact layer and surgically staple the edges of the Mepitel®. 
iii. Apply Surgilube®, cover with GranuFoam™, and apply NPWT 
therapy to the treated wound(s) according to manufacturer’s 
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MicroMatrix® and CytalTM Burn Matrix 2-Layer, vacuum should be 
applied at 100mg Hg, low intensity, and continuous therapy. 
 
c. Group 3 Procedures (NPWT) 
i. Debride the eligible pressure ulcer(s).  Wash the wound(s) and 
confirm hemostasis achieved. 
ii. Apply AQUACEL® AG, then a layer of Mepitel® wound contact 
sheet to the wound bed. 
iii. Cover the wound(s) with GranuFoam™,  gauze dressing, and tape. 
iv. Apply NPWT to treated wound(s) according to manufacturer’s 
Instructions for Use. When NPWT is used as the primary wound 
treatment, vacuum should be applied at 125mg Hg, low intensity, 
and continuous therapy. 
 
8. Record wound-related, post-treatment adverse events as reported by subject or 
observed by Investigator.  
9. Record the approximate amount of hands-on time spent on wound care (skin to 
skin time).     
10. Provide instructions to nursing staff and/or subject regarding maintenance of 
protein levels at 80-100 grams/day using supplements per Investigator’s choice 
(Ensure, Glucerna, Protein Powder, etc.).  
11. Provide instructions to nursing staff and/or family member(s) regarding off-
loading.  
12. Confirm date of next visit with subject.   
 
6.1.4 FOLLOW-UP VISITS 1 – 13  
 
1. Record weight, if possible.  
2. Record any changes to employment and ambulatory status. 
3. Provide instructions to nursing staff and/or family member(s) regarding off-
loading.  
4. Record changes to pain medication associated with pressure ulcer(s) pain and 
update Medications Log.  Also include protein supplement, antibiotics and anti-
hypertensive medications documentation.  
5. Administer SF-20 Health Survey, VPS, and Katz ADL prior to device application.  
6. Perform a physical examination. (Follow-Up Visits 1, 5, and 13 only). 
7. Record wound-related, post-treatment AEs as reported by participant or 
observed by Investigator.  
8. Collect blood sample(s) on the following days: 
a. Albumin: Visit 3 and Visit 5  

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b. Pre-albumin: Visit 3, Visit 5, Visit 7, Visit 9, Visit 11, and Visit 13 
c. Hemoglobin: PRN (only if a delay in healing [suspected infection] is noted 
by the Investigator)   
9. Record the following information for each eligible wound: 
a. Length, width, and depth. 
b. Wound appearance and characteristics: 
i. Presence of epibole, eschar, undermining, tunneling, sinus tracts, 
and/or adverse odor 
ii. Appearance of Exudate: Serous; Serosanguinous; Purulent; Bloody 
iii. Appearance of Wound Bed: Beefy Red; Red; Pink; White; Yellow 
iv. Epithelialization: As calculated by change in surface area and 
volume of wound size. 
v. Categorize the pressure ulcer(s) with respect to surface area 
(length x width), exudate amount, and type of wound tissue using 
the PUSH Tool. 
vi. Document volume of the wound(s) (length x width x depth). 
 
10. Record change in wound area and volume from the Screening Visit.  
11. 
For lower extremity ulcers: record ABI value only if a delay in healing is 
noted by the Investigator. 
12. Obtain photographs of the eligible wound(s), if possible.  
13. Proceed with treatment procedures as outlined below, as needed, depending on 
randomization of the wound(s). 
 
a. Group 1 Procedures (ACell products) 
i. Do not disturb the CytalTM Burn Matrix 2-Layer/MicroMatrix® or the 
Mepitel® wound covering, which is stapled to the perimeter of the 
wound.  
ii. Apply a new layer of Surgilube® on top of the Mepitel® sheet. 
iii. Replace gauze dressing and tape.   
iv. Record the approximate amount of hands-on time spent on wound 
care.  
 
b. Group 2 Procedures (ACell products and NPWT) 
i. Disconnect the NPWT system. 
ii. Remove the following material and/or any other dressing layers that 
are covering the wound: tape, gauze dressing, GranuFoam™, and 
Surgilube® layers.  
iii. Do not disturb the CytalTM/MicroMatrix® or the Mepitel® wound 
covering which is stapled to the perimeter of the wound.  

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iv. Clean wound bed and debride with curette, as needed.   
v. Apply Tegaderm™ over GranuFoam™ and replace gauze 
dressing, tape, and NPWT system per manufacturer’s Instructions 
for Use. 
vi. When NPWT is used in conjunction with MicroMatrix® and CytalTM 
Burn Matrix 2-Layer, vacuum should be applied at 100mg Hg, low 
intensity, and continuous therapy. 
vii. Record the approximate amount of hands-on time spent on wound 
care. 
 
c. Group 3 Procedures (NPWT) 
i. Disconnect the NPWT system.  
ii. Remove the following material and/or any other dressing layers that 
are covering the wound: tape, gauze dressing, GranuFoam™, 
Mepitel®, and AQUACEL® AG layers.  
iii. Clean wound bed and debride with curette as needed.   
iv. Replace the AQUACEL® AG layer, and cover with Mepitel®, 
GranuFoam™, and then Tegaderm™ to the periwound skin and 
bridge. 
v. Replace NPWT system per Manufacturer’s Instructions for Use. 
When NPWT is used as the primary wound treatment, vacuum 
should be applied at 125mg Hg, low intensity and continuous 
therapy. 
vi. Record the approximate amount of hands-on time spent on wound 
care. 
 
d. For Groups 2 and 3 only: If periwound maceration is observed, and the 
Investigator determines NPWT should not be continued, then the following 
procedures will be followed: 
 
i. Group 2 Procedures (ACell products and NPWT) 
1. Do not disturb the CytalTM Burn Matrix 2-Layer/MicroMatrix® 
or the Mepitel® wound covering which is stapled to the 
perimeter of the wound.  
2. Apply Surgilube® and cover with gauze dressing and tape, or 
gauze 
dressing 
and 
medical 
bandage 
material 
as 
appropriate (the latter only if the wound is on the extremity).   
3. Record the approximate amount of hands-on time spent on 
wound care 

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4. Record the length of time the NPWT is disrupted.  This time 
should be < 1 week.  
 
ii. Group 3 Procedures (NPWT) 
1. Remove the NPWT system.  
2. Remove the following material and/or any other dressing 
layers 
covering 
the 
wound: 
tape, 
gauze 
dressing, 
GranuFoam™, Mepitel®, and AQUACEL® AG layers.  
3. Clean wound bed and debride with curette as needed.   
4. Reapply AQUACEL® AG. 
5. Cover the wound(s) with gauze dressing and tape, or gauze 
dressing and medical bandage material, as appropriate (the 
latter only if the wound is on the extremity).   
6. Record the approximate amount of hands-on time spent on 
wound care.    
7. Record the length of time the NPWT is discontinued.  This 
time should be < 1 week.  
 
13. Confirm date of next visit with patient.   
14. For Visit 13 only: 
a. If complete wound healing is not observed by Visit 13: The 
Investigator will determine and record the appropriate treatment method of 
the pressure ulcer(s) for the months preceding the Final Study Visit.  
Subjects will be evaluated at the Final Study Visit for wound progression.   
b. If complete wound healing is observed by, or prior to, Visit 13: 
Subjects will be evaluated for pressure injury recurrence at approximately 
6 months from their initial Treatment Visit. 
6.1.6 FINAL STUDY VISIT [± 2 WEEKS])  
 
The Final Study Visit will occur approximately 24 weeks after the Treatment Visit . 
 
The following procedures will be completed for all subjects: 
1. Record weight (if possible) and BMI.  
2. Record any changes to employment and ambulatory status. 
3. Record changes to pain medication associated with pressure ulcer(s) pain and 
update 
Medications 
Log. 
Also 
include 
changes 
protein 
supplement 
documentation, antibiotics, and anti-hypertensive medications.  
4. Administer SF-20 Health Survey, VPS, and Katz ADL.  
5. Perform a physical examination. 

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6. Record wound-related AEs as reported by participant or observed by 
Investigator.  
7. Collect blood sample(s) for pre-albumin, albumin, protein, and hemoglobin levels. 
8. All efforts will be made to collect the total direct and indirect pressure ulcer 
related costs by subject, as measured by total inpatient and outpatient expenses, 
stratified by product and care cost.   
For those subjects who did not achieve complete wound healing by Visit 13, the 
following procedures will be done for evaluation of wound progression:   
 
1. Provide instructions to nursing staff and/or family member(s) regarding off-loading.  
2. For lower extremity ulcers: record ABI value only if a delay in healing is noted by the 
Investigator. 
3. Evaluate the pressure ulcer(s) which had not healed by Visit 13 using the PUSH 
tool. 
4. Record the following information for the wound(s) which had not healed by Visit 13: 
a. Wound appearance and characteristics: 
i. Presence of epibole, eschar, undermining, tunneling, sinus tracts, 
and/or adverse odor 
ii. Appearance of Exudate: Serous; Serosanguinous; Purulent; Bloody 
iii. Appearance of Wound Bed: Beefy Red; Red; Pink; White; Yellow 
iv. Epithelialization: As calculated by change in surface area and volume 
of wound size. 
b. Length, width, and depth  
c. Change in wound area and volume from the Screening Visit  
5. Obtain photographs of the eligible wound(s), if possible.  
For subjects in whom there was complete wound healing by or prior to Visit 13, 
the following procedures will be completed: 
1. Record if there has been a recurrence at the original anatomical location of the 
pressure ulcer(s).  If recurrence is noted: 
a. Obtain photographs of the wound(s) if recurrence is noted  
b. For lower extremity wound(s): record ABI value 
 
 
6.1.7 UNSCHEDULED VISIT  
Unscheduled visits may occur at any time between the Treatment Visit and Follow-up 
Visit 13.  Reasons for an Unscheduled Visit include, but are not limited to: pressure 
injury events, assessment and/or maintenance of adverse events, etc.  

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1. Document reason for the unscheduled visit.  
2. Record weight, if possible. 
3. Record any changes to employment and ambulatory status. 
4. Record changes to pain medication associated with pressure ulcer(s) pain and 
update Medications Log. 
5. Perform a physical examination. 
6. Record wound-related AEs as reported by participant or observed by Investigator.  
7. As applicable : 
a. Record if there has been a recurrence at the original anatomic location of the 
pressure ulcer(s).    
b. Evaluate the pressure ulcer(s) using the PUSH tool. 
c. Record the following information for the wound(s): 
i. Wound appearance and characteristics: 
1. Presence of epibole, eschar, undermining, tunneling, sinus 
tracts, and/or adverse odor 
2. Appearance of Exudate: Serous; Serosanguinous; Purulent; 
Bloody 
3. Appearance of Wound Bed: Beefy Red; Red; Pink; White; 
Yellow 
4. Epithelialization: < 25%; 25%-50%; >50%-75%; 75%-99%; 
Complete Epithelialization 
ii. Length, width, and depth  
iii. Change in wound area and volume from the Screening Visit  
8. For lower extremity ulcers: record ABI value only if a delay in healing is noted by the 
Investigator. 
9. Obtain photographs of the eligible wound(s), if possible.  
10. Record treatment method of the wound(s). 
 
7 
ASSESSMENT OF SAFETY 
 
7.1 
SPECIFICATION OF SAFETY PARAMETERS 
 
7.1.1 DEFINITION OF ADVERSE EVENTS (AE) 
 
Adverse Event means any untoward medical occurrence associated with the use of an 
intervention in humans, whether or not considered intervention-related (21 CFR 312.32 
(a)).  Adverse events of interest under this protocol are those to be considered related 
to the occurrence or presence of Stage 3 or 4 pressure ulcers. They include but are not 
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 Infection 
 Increased chronic inflammation 
 Allergic reaction 
 Unexplained fever or chills 
 Excessive redness 
 Pain – excessive or exacerbated 
 Swelling - excessive or exacerbated 
 Odor associated with the use of products during the healing phase 
 Odor from the wound bed 
 Puss drainage from the treated wound 
 Bleeding 
 Hematoma 
 Seroma 
 Skin ulcers – newly developed or worsening 
 Necrotic tissue 
 Wound dehiscence 
 Osteomyelitis 
 Cellulitis 
 Periwound maceration 
 Death 
 Malnutrition (as defined by hypoalbuminemia on follow-up serum lab work [serum 
albumin < 2.5g/dL and/or serum pre-albumin < 5mg/dL]) 
 Uncontrolled hyperglycemia (PI determination) 
 Wound recurrence (after closure) 
 Hypergranulation of  treated wound(s) 
7.1.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE) 
 
An AE or suspected adverse reaction is considered "serious" if, in the view of either the 
Investigator or Sponsor, it results in any of the following outcomes:  
 Death 
 A life-threatening adverse event 
 Inpatient hospitalization or prolongation of existing hospitalization 
 A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions 
 A congenital anomaly/birth defect 
Important medical events that may not result in death, be life-threatening, or require 
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judgment, they may jeopardize the patient or subject and may require medical or 
surgical intervention to prevent one of the outcomes listed in this definition.  
 
7.1.3 DEFINITION 
OF 
UNANTICIPATED 
ADVERSE 
DEVICE 
EFFECT 
(UADE)  
 
Unanticipated adverse device effect is any serious adverse effect on health or safety, 
any life-threatening problem or death caused by, or associated with a device, if that 
effect, problem, or death was not previously identified in nature, severity, or degree of 
incidence in the application; or any other unanticipated serious problem associated with 
a device that relates to the rights, safety, or welfare of subjects. 
 
7.2 
CLASSIFICATION OF AN ADVERSE EVENT 
 
7.2.1 SEVERITY OF EVENT 
 
The Investigator will be asked to assess the severity of the AE using the following 
categories: 
 
Mild: 
Events require minimal or no treatment and do not interfere with the 
participant’s daily activities. 
 
Moderate: 
Events result in a low level of inconvenience or concern with the 
therapeutic measures. Moderate events may cause some interference 
with functioning. 
 
Severe: 
Events interrupt a participant’s usual daily activity and may require 
systemic drug therapy or other treatment. Severe events are usually 
potentially life-threatening or incapacitating. 
 
7.2.2 RELATIONSHIP TO STUDY AGENT 
 
For all collected AEs, the clinician who examines and evaluates the participant will 
determine the AE’s causality based on temporal relationship and his/her clinical 
judgment. The degree of certainty about causality will be graded using the categories 
below.  
Definitely: 
The relationship of the AE and the study device or the study procedure 

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can definitely be established. 
 
Probably: 
While a clear relationship to the study device or to the study procedure 
cannot be established, the AE is associated with an expected AE or 
there is no other medical condition or intervention, which could explain 
the occurrence of such an event. 
 
Possibly: 
There is no clear relationship between the AE and the study device or 
study procedure; however, one cannot definitely conclude that there is 
no relationship. 
 
Unrelated: 
There is no relationship between the AE and the study device or study 
procedure.  This may include but is not limited to the incident being an 
expected outcome of a previously existing or concurrent disease, 
concomitant medication or procedure the subject experienced. 
 
7.2.3 EXPECTEDNESS  
 
The Investigator will be responsible for determining whether an AE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency 
of the event is not consistent with the risk information previously described for the study 
products. 
 
7.3 
TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND 
FOLLOW-UP 
 
The occurrence of an AE or SAE may come to the attention of study personnel during 
study visits or upon review by a study monitor.  All AEs (per Investigator discretion) 
that are possibly impactful to the development or healing of a pressure injury and 
those including local and systemic reactions not meeting the criteria for SAEs, will be 
captured on the appropriate CRF. Information to be collected includes event 
description, time of onset, clinician’s assessment of severity, relationship to study 
products (assessed only by those with the training and authority to make a 
diagnosis), and time of resolution/stabilization of the event.  All AEs will be followed 
to adequate resolution.  
 
Any medical condition that is present at the time that the participant is screened will 
be considered as baseline and not reported as an AE.  However, if the study 
participant’s condition deteriorates at any time during the study, it will be recorded as 
an AE. UADEs will be recorded in the data collection system throughout the study.  

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Changes in the severity of an AE will be documented to allow an assessment of the 
duration of the event at each level of severity to be performed.  AEs characterized as 
intermittent require documentation of onset and duration of each episode.  
The PI will record all reportable events with start dates occurring any time after informed 
consent is obtained until 7 (for non-serious AEs) or 30 days (for SAEs) after the last day 
of study participation.  At each study visit, the Investigator will inquire about the 
occurrence of AE/SAEs since the last visit.  Events will be followed for outcome 
information until resolution or stabilization. 
 
 
 
7.4 
REPORTING PROCEDURES 
 
7.4.1 ADVERSE EVENT REPORTING  
 
Adverse Events will be documented on the appropriate Case Report Form (CRF) as the 
Investigator learns of the event.  All AEs, not serious in nature, will be reviewed by the 
Sponsor during scheduled Interim Monitoring Visits (IMVs).  The Investigator will follow 
all AEs until adequate resolution is achieved.  The IRB should be notified of all AEs 
according to their notification policies. 
 
7.4.2 SAE REPORTING  
 
In the case of a SAE, the Investigator must immediately notify (within 1 working day) the 
study Sponsor (contact information is provided in Section 1, Key Roles).  The IRB 
must also be notified according to their notification policies.   
 
7.4.3 UADE REPORTING  
 
The study Investigator must immediately notify the study Sponsor and the reviewing IRB 
as soon as possible, but in no event later than 10 working days after the Investigator 
first learns of the effect. The study Sponsor contact information is provided in Section 1, 
Key Roles. The study Sponsor is responsible for conducting an evaluation of an UADE 
and shall report the results of such evaluation to the reviewing IRB and the Investigator 
within 10 working days after the Sponsor first receives notice of the effect.  
 
7.4.4 REPORTING OF PREGNANCY  
 

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If a female patient becomes pregnant during the trial, she must be followed until the 
outcome of the pregnancy is known. 
 
8 
CLINICAL MONITORING 
 
Clinical site monitoring is conducted to ensure that the rights and well-being of human 
subjects are protected, that the reported trial data are accurate, complete, and 
verifiable, and that the conduct of the trial is in compliance with the currently approved 
protocol/amendment(s), with Good Clinical Practice (GCP), and with applicable 
regulatory requirement(s). 
 
A Clinical Monitoring Plan will describe in detail who will conduct the monitoring, at what 
frequency monitoring will be done, at what level of detail monitoring will be performed, 
and the distribution of monitoring reports.  
 
 
 
9 
STATISTICAL CONSIDERATIONS  
 
9.1 
STATISTICAL AND ANALYTICAL PLANS 
 
All statistical tests will be conducted using a type 1 error rate of 5%.  The analyses will 
be conducted using a hierarchical testing strategy; provided the primary analysis is 
significant in favor of the study product, the analysis of the secondary endpoints can be 
conducted in sequential order using a type 1 error rate of 5%.  The testing will continue, 
provided the prior analysis was significant in favor of the study product.   
 
9.2 
STATISTICAL HYPOTHESES 
 
The hypothesis for the primary endpoint (Group 1 vs. Group 3) is as follows: 
1. Ho: π (incidence of complete wound closure in Group 1) > π (incidence of 
complete wound closure in Group 3) 
2. Ha: π (incidence of complete wound closure in Group 1) < π (incidence of 
complete wound closure in Group 3) 
 
The hypothesis for the primary endpoint (Group 2 vs. Group 3) is as follows: 
1. Ho: π (incidence of complete wound closure in Group 2) > π (incidence of 
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2. Ha: π (incidence of complete wound closure in Group 2) < π (incidence of 
complete wound closure in Group 3) 
 
The hypotheses for the secondary endpoints to be run separately for comparisons of 
Group 1 to Group 3 and Group2 to Group 3 are as follows: 
1. Ho: µ (time to complete closure for wounds treated with the test product) < µ 
(time to complete closure for wounds treated with the control treatment) 
2.  Ha: µ (time to complete closure for wounds treated with the test product) > µ 
(time to complete closure for wounds treated with the control treatment) 
3. Ho: µ (change from baseline in the area of the wound treated with the test 
product) > µ (change from baseline in the area of the wound for wounds treated 
with the control treatment) 
4. Ha: µ (change from baseline in the area of the wound treated with the test 
product) < µ (change from baseline in the area of the wound for wounds treated 
with the control treatment) 
The average measure of patient satisfaction and cost of treatment per patient are the 
second and third secondary endpoints; the mean values will be tabulated for each 
endpoint and compared between the treatment groups.   
 
 
9.3 
ANALYSIS DATASETS 
 
The analysis datasets will be prepared in Statistical Analysis System (SAS) and will 
contain the patient level data.  Specific flags will be derived for the intention to treat 
population and other populations of interest that will be defined in the Statistical 
Analysis Plan (SAP).   
 
9.4 
DESCRIPTION OF STATISTICAL METHODS 
 
9.4.1 GENERAL APPROACH 
 
This parallel design will randomize patients to 3 groups.  The primary comparison will be 
Group 1 (MicroMatrix® with CytalTM Burn Matrix 2-Layer) vs. Group 3 (NPWT) to 
determine if Group 1 is superior to Group 3.   NPWT as the standard of care for patients 
with Stage 3 or 4 pressure injuries and is the active control arm for the study. 
 

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A secondary comparison will be conducted comparing Group 2 (MicroMatrix® with 
CytalTM Burn Matrix 2-Layer plus NPWT) vs. Group 3 (NPWT) to determine if Group 2 is 
superior to Group 3. 
9.4.2 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
 
The analysis of the primary endpoint will be based on a generalized linear model 
specifying the distribution as binomial.  If a patient withdraws prior to the 12-week 
wound evaluation visit and the last recorded observation revealed complete wound 
closure, the patient will be counted in the primary analysis as having achieved complete 
wound closure.  If a patient withdraws prior to the 12-week wound evaluation visit and 
the last recorded observation revealed the wound had not closed, the patient will be 
counted in the primary analysis as not having achieved complete wound closure.       
 
9.4.3 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
 
The first secondary endpoint is the time of the initial observation of complete wound 
closure; the analysis will be predicated on a time-to-event model where the time of the 
initial observation of complete wound closure will be compared between the randomized 
treatment groups.  If a patient withdraws prior to the target wounds being closed within 
12 weeks, the patient will be censored using the time of the last observation.  
Stratification factors will be added to the model to adjust for the location of the wound, 
the duration of the wound under observation, and the relative size of the wound as a 
categorical variable.  A Cox proportional hazards regression model will be used to 
derive the estimates. 
 
The second secondary endpoint is the change from baseline in the area of the wound, 
reported in square centimeters.  A 1-factor (time) repeated measures (time) analysis will 
be conducted using a generalized linear model.   Stratification factors will be added to 
the model to adjust for the location of the wound, the duration of the wound under 
observation, and the relative size of the wound.  
 
Patient satisfaction and data from the PUSH Tool will be assessed separately for each 
endpoint and wound.  The results will be tabulated and compared in a 1-factor 
(treatment) repeated measures (treatment) analysis using a generalized linear model.   
Stratification factors will be added to the model to adjust for the location of the wound, 
the duration of the wound under observation, and the relative size of the wound.  
 

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Reduction in pain/narcotic cannot be analyzed by treatment given these medications act 
systemically.  The change will be reported using the morphine equivalent units and 
descriptive statistics will be reported over time.  
  
The cost of treatment per patient for all wounds, and the nursing time will be assessed.  
A 1-factor (time) repeated measures (time) analysis will be conducted using a 
generalized linear model.   Stratification factors will be added to the model to adjust for 
the location of the wound, the duration of the wound under observation, and the relative 
size of the wound. 
 
9.4.4 SAFETY ANALYSES 
 
Safety will be assessed by physical examinations, clinical laboratory tests and collection 
of AEs as outlined in the Schedule of Events.  All summaries of AEs will be based on 
treatment-emergent AEs and presented using the incidence and a tabulation of the 
number of events.  The number and percentage of subjects experiencing AEs will be 
summarized by system organ class and description.  Summaries by maximum severity 
and relationship to the study treatment will also be provided.  SAEs and AEs leading to 
discontinuation from the study will be presented by system organ class and preferred 
term.   
 
9.4.5 ADHERENCE AND RETENTION ANALYSES 
 
The total duration for a subject on-study will be calculated as the difference between the 
date of initial exposure to the study treatment and the last day of observation plus 1 day.  
All calculations for defining the duration on-study will follow the algorithm DURATION = 
[STUDY COMPLETION OR WITHDRAW DATE – INITIAL STUDY TREATMENT DATE 
+ 1].   
 
9.4.6 BASELINE DESCRIPTIVE STATISTICS 
 
Baseline demographic factors and patient characteristics will be summarized by 
randomized treatment group.   This summary will include the gender, age in years at the 
time of entry into the study, race, ethnicity, height (inches), weight (pounds) and BMI.  
Age, height, weight, and BMI will be summarized using descriptive statistics.  The 
number and percent of each gender, race, and ethnicity category will be presented 
using counts and percentages. 
 

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The medical and surgical history will be coded for each patient and summarized based 
on the body system description.  The patients will be summarized using counts and 
percentages for those patients who had a pre-study medical history.  
 
9.4.7 PLANNED INTERIM ANALYSES  
 
Given the size of this clinical investigation, there will not be an interim analysis. 
 
9.4.8 ADDITIONAL SUB-GROUP ANALYSES  
 
Sub-groups of clinical interest will be defined in the SAP and are a function of the type 
of patients and their co-morbidities. 
 
9.4.9 MULTIPLE COMPARISON/MULTIPLICITY 
 
There will not be a correction to the type 1 error rate for the analyses because a 
hierarchical testing strategy will be used.  If the results from the primary analysis are 
significant (p<0.05) in favor of the Group 1 over Group 3, and separately Group 2 over 
Group 3, a step-down procedure will be followed for the secondary endpoints.  Each 
secondary endpoint will be tested in hierarchical order provided the previous endpoint 
tested is significant (p<0.05) in favor of the test product over control. 
 
There is no crossover of treatment designed in this trial.  Subjects who have a wound 
that has not healed by Visit 13 will be treated as medically appropriate, but considered 
to be a failure in the treatment arm they were randomized to.  
 
9.4.10 TABULATION OF INDIVIDUAL RESPONSE DATA 
 
Patient profiles will be generated to facilitate an examination of the individual response 
data. 
 
9.4.11 EXPLORATORY ANALYSES 
 
Exploratory analyses will be described in SAP and will not be part of the hierarchical 
testing strategy. 
 
9.5 
SAMPLE SIZE 
 

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To estimate the sample size for this clinical investigation, the difference in the incidence 
of patients who achieve complete wound closure (primary endpoint) was used.  
Estimates were prepared considering complete closure in the NPWT arm of 20% to 40% 
and a type 1 and 2 error rate of 5% and 20%, respectively.  Based on these estimates, if 
the incidence in Group 1 is 45% greater than the incidence in Group 3, the difference will 
be significant (p<0.05).   
Number of 
Patients in 
Group 1 
Number of 
Patients in 
Group 3 
Minimum Incidence of 
Complete Closure in 
Group 1 
Maximum Incidence of 
Complete Closure in Group 
3 
20 
20 
0.6729 
0.2000 
20 
20 
0.7324 
0.2500 
20 
20 
0.7787 
0.3000 
20 
20 
0.8167 
0.3500 
20 
20 
0.8512 
0.4000 
 
9.6 
MEASURES TO MINIMIZE BIAS 
 
The determination of complete closure and the wound measurements are quantitative 
and there will be photographs taken for substantiation. 
 
9.6.1 ENROLLMENT/ RANDOMIZATION 
A central randomization scheme will be prepared using a permuted block scheme to 
ensure balance after each block has been assigned.  ACell will be responsible for 
maintaining the randomization schedule and issuing the randomization assignment to the 
requesting clinical site.  A separate randomization plan will be prepared that will provide 
the details around the following 3 steps to randomizing a patient. 
Step 1: The clinical site will consent the patient and complete the screening and 
enrollment evaluation, and information required for randomization.  By completing the 
Request for Randomization form, the clinical site is making a declaration that the patient 
meets all of the inclusion criteria for the study and none of the exclusion criteria. 
Step 2: The clinical site can either fax or scan and e-mail the completed Request for 
Randomization form to the designated individual at ACell (between normal business 
hours [M-F 8:30am – 5:30pm]) who will maintain the randomization log. 
Step 3:  ACell will review the Request for Randomization form and ensure all of the 
information is complete.  If the form has been completed appropriately, ACell will deliver 

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the next sequential group assignment, then sign, date, and return the completed 
Request for Randomization form to the clinical site. 
10 
SOURCE DOCUMENTS AND CASE REPORT FORMS 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site Principal Investigator.  The Investigator is responsible for 
ensuring the accuracy, completeness, legibility, and timeliness of the data reported.  
All source documents should be completed in a neat, legible manner to ensure accurate 
interpretation of data.  When making changes or corrections, cross out the original entry 
with a single line, and initial and date the change. DO NOT ERASE, OVERWRITE, OR 
USE CORRECTION FLUID OR TAPE ON ANY ORIGINAL DOCUMENTS. 
Study personnel at each site will enter data from source documents corresponding to a 
subject’s visit into the protocol-specific electronic Case Report Form (eCRF) when the 
information corresponding to that visit is available.  Subjects will not be identified by 
name in the study database or on any study documents to be collected by the Sponsor 
(or designee), but will be identified by a SID and initials. 
 
Copies of the eCRF may be provided for use as source documents and maintained for 
recording data for each participant enrolled in the study.  Data reported in the eCRF 
derived from source documents should be consistent with the source documents or the 
discrepancies should be explained and captured in a progress note and maintained in 
the participant’s official electronic study record.  
If a correction is required for an eCRF, the time and date stamp track the person 
entering or updating eCRF data and creates an electronic audit trail.   
 
11 
QUALITY CONTROL AND ASSURANCE 
 
Quality Control (QC) procedures will be implemented beginning with the data entry 
system and data QC checks that will be run on the database.  Any missing data or 
data anomalies will be communicated to the site for clarification/resolution.  
Following written Standard Operating Procedures, the monitors will verify that the 
clinical trial is conducted and data are generated, documented (recorded), and reported 
in compliance with the protocol and GCP.    

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The site will provide direct access to all trial related materials, including source 
data/documents, electronic medical records (if applicable), CRFs, and reports for the 
purpose of monitoring and auditing by the Sponsor and/or the IRB. 
 
12 
ETHICS/PROTECTION OF HUMAN SUBJECTS  
 
12.1 ETHICAL STANDARD  
  
The Investigator will ensure that this study is conducted in full conformity with 
Regulations for the Protection of Human Subjects of Research codified in 45 CFR Part 
46, 21 CFR Part 50, 21 CFR Part 56, and/or the ICH E6.  
 
 
12.2 LAWS AND REGULATIONS  
  
This clinical study will be conducted in compliance with all national laws and regulations 
of the countries in which the clinical trial is performed, as well as any applicable 
guidelines. The trial will be registered on www.clintrials.gov and on other sites, as 
appropriate. 
 
12.3 INSTITUTIONAL REVIEW BOARD  
 
The protocol, informed consent form(s), and all participant materials will be submitted to 
the IRB for review and approval.  Approval of both the protocol and the consent form 
must be obtained before any participant is enrolled.  Any amendment to the protocol will 
require review and approval by the IRB before the changes are implemented to the 
study.  All changes to the consent form will be IRB approved; a determination will be 
made regarding whether previously consented participants need to be re-consented. 
 
12.4 INFORMED CONSENT PROCESS  
 
Informed consent is a process that is initiated prior to the individual’s agreeing to 
participate in the study and continues throughout the individual’s study participation.  
Extensive discussion of risks and possible benefits of participation will be provided to 
the participants and their families.  Consent forms will be IRB approved and the 
participant will be asked to read and review the document.  The Investigator will explain 

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the research study to the participant and answer any questions that may arise.  All 
participants will receive a verbal explanation in terms suited to their comprehension of 
the purposes, procedures, and potential risks of the study and of their rights as research 
participants.  Participants will have the opportunity to carefully review the written 
consent form and ask questions prior to signing.  The participants should have the 
opportunity to discuss the study with their surrogates or think about it prior to agreeing 
to participate.  The participant will sign the informed consent document prior to any 
procedures being done specifically for the study.  The participants may withdraw 
consent at any time throughout the course of the trial.  A copy of the informed consent 
document will be given to the participants for their records.  The rights and welfare of 
the participants will be protected by emphasizing to them that the quality of their medical 
care will not be adversely affected if they decline to participate in this study. 
If a consent document is revised due to changes in study procedures, subjects who 
were enrolled prior to the change, but are affected by the change, will be informed of the 
changes and will sign the amended consent document.  If a consent document is 
revised due to changes in the risks or safety of the study, all active participants must 
sign the revised consent. 
12.5 PARTICIPANT AND DATA CONFIDENTIALITY  
 
Participant confidentiality is strictly held in trust by the participating Investigator(s), their 
staff, the Sponsor and their agents.  The study protocol, documentation, data, and all 
other information generated will be held in strict confidence.  No information concerning 
the study or the data will be released to any unauthorized third party without prior 
written approval of the Sponsor. 
 
The study monitor, other authorized representatives of the Sponsor, and/or 
representatives of the IRB may inspect all documents and records required to be 
maintained by the Investigator for the participants in this study.  The clinical study site 
will permit access to such records.  
The study participant’s contact information will be securely stored at the clinical site 
for internal use during the study.  At the end of the study, all records will continue to 
be kept in a secure location for as long a period as dictated by the local IRB and 
Institutional regulations.  
13 
DATA HANDLING AND RECORD KEEPING  
 
13.1 STUDY RECORDS RETENTION  

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All study documents (patient files, signed informed consent forms, Study Regulatory 
Binder, etc.) must be kept secured for a period of two years following completion of the 
study.  There may be other circumstances for which the Sponsor is required to maintain 
study records and, therefore, the Sponsor should be contacted prior to removing study 
records for any reason.  It is the responsibility of the Sponsor to inform the Investigator 
when these documents no longer need to be retained. 
13.2 PROTOCOL DEVIATIONS  
 
A protocol deviation is any noncompliance with the clinical trial protocol or GCP 
requirements. The noncompliance may be either on the part of the participant, the 
Investigator, or the study site staff. As a result of deviations, corrective actions are to be 
developed by the site and implemented promptly.   
All protocol deviations/violations should be documented using the Protocol 
Deviations/Violations CRF and submitted to the IRB according to their reporting 
guidelines.   
13.3 PUBLICATION AND DATA SHARING POLICY 
The preparation and submittal for publication of manuscripts containing the study results 
shall be in accordance with a process determined by mutual written agreement among 
the study Sponsor and participating institutions.  The publication or presentation of any 
study results shall comply with all applicable privacy laws, including, but not limited to, 
the Health Insurance Portability and Accountability Act of 1996.  
 
 
 
14 
CONFLICT OF INTEREST POLICY 
 
The independence of this study from any actual or perceived influence, such as by the 
device industry, is critical. Therefore any actual conflict of interest of persons who have 
a role in the design, conduct, analysis, publication, or any aspect of this trial will be 
disclosed and managed.  Furthermore, persons who have a perceived conflict of 
interest will be required to have such conflicts managed in a way that is appropriate to 
their participation in the trial.  The study leadership has established policies and 
procedures for all study group members to disclose all conflicts of interest and will 
establish a mechanism for the management of all reported dualities of interest. 
 

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15  
LITERATURE REFERENCES  
 
1. National Pressure Ulcer Advisory Panel, European Pressure Ulcer Advisory Panel 
and Pan Pacific Pressure Injury Alliance.  Prevention and Treatment of Pressure 
Ulcers: Clinical Practice Guideline. Emily Haesler (Ed.). Cambridge Media: Osborne 
Park, Western Australia; 2014. 
2. Hiser B, Rochette J, Philbin S, Lowerhouse N, Terburgh C, Pietsch C. Implementing 
a pressure ulcer prevention program and enhancing the role of the CWOCN: impact 
on outcomes.  Ostomy Wound Management. 2006;52(2):48-59. 
3. Samaniego IA. A sore spot in pediatrics: risk factors for pressure ulcers. Pediatric 
Nursing. 2003;29(4):278-82. 
4. Tippett AW. Wounds at the end of life. Wounds: A Compendium of Clinical Research 
& Practice. 2005:17(4):91-8. 
5. Goldberg M. General Acute Care. In: Peiper B, National Pressure Ulcer Advisory 
Panel, editors. Pressure Ulcers: Prevalence, Incidence, and Implications for the 
Future Washington, DC: NPUAP; 2012. 
6. Houghton PE, Campbell KE, CPG Panel. Canadian Best Practice Guidelines for the 
Prevention and Management of Pressure Ulcers in People with Spinal Cord Injury. A 
resource handbook for clinicians.  http://www.onf.org: Ontario Neurotrauma 
Foundation, 2013. 
7. Vangilder C, Amlung S, Harrison P, Meyer S. Results of the 2008-2009 International 
Pressure Ulcer Prevalence Survey and a 3-year, acute care, unit-specific analysis. 
Ostomy Wound Management. 2009;55:39-45. 
8. Cuddigan J. Critical Care. In: Pieper B, National Pressure Ulcer Advisory Panel, 
editors. Pressure Ulcers: Prevalence, Incidence, and Implications for the Future 
Washington, DC: NPUAP; 2012. 
9. Whittington K, Briones R. National prevalence and incidence study: 6-year 
sequential acute care data. Advances in Skin and Wound Care. 2004;17(9):490–
494. 
10. Lyder CH, Wang Y, Metersky M, et al. Hospital-acquired pressure ulcers: results 
from the national Medicare Patient Safety Monitoring System study. Journal of the 
American Geriatrics Society. 2012;60(9):1603–1608.  
11. Zaratkiewicz S, Whitney JD, Lowe JR, Taylor S, O’Donnell F, Minton-Foltz P. 
Development and Implementation of a Hospital-Acquired Pressure Ulcer Incidence 
Tracking System and Algorithm. Journal for healthcare quality: official publication of 
the National Association for Healthcare Quality. 2010;32(6):44-51.  
12. Degenholtz H, Rosen J, Castle N, Mittal V, Liu D. The association between changes 
in health status and nursing home resident quality of life. Gerontologist. 
2008;48(5):584-. 

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13. Essex HN, Clark M, Sims J, Warriner A, Cullum N. Health-related quality of life in 
hospital inpatients with pressure ulceration: assessment using generic health-related 
quality of life measures. Wound Repair and Regeneration. 2009;17(6):797-805. 
14. Allman R, Goode PS, Burst N, Bartolucci A, Thomas DR. Pressure ulcers, hospital 
complications, and disease severity: implications on hospital costs and length of 
stay. Advances in Wound Care. 1999;12(1):22-30. 

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APPENDIX I: SCHEDULE OF EVENTS 
 
PROCEDURES FOR ALL SUBJECTS  
 
SCREENING 
(-5 TO 0) 
TREATMENT 
(DAY 1) 
F/U VISIT 1 
(DAY 2 – 7) 
F/U VISITS  
2-13 
(WEEKLY) 
FINAL VISIT 
(24 WEEKS) 
UNSCHEDULED 
VISIT  
Informed Consent  
X 
 
 
 
 
 
Assign SID 
X 
 
 
 
 
 
Patient Demographics / Social Hx  
X 
 
 
 
 
 
Height, Weight, and BMI1 
X 
 
X 
X 
X 
X  
(weight only) 
Medical / Surgical / Medication Hx 
X 
 
 
 
 
 
Inclusion / Exclusion Criteria 
X 
X 
 
 
 
 
Physical Examination 
X 
X 
X 
X 
X 
X 
Laboratory Testing of Blood 
Sample2 
X 
 
X 
X 
X  
 
Employment and Ambulatory 
Status 
X 
 
X 
X 
X 
X 
Urine Pregnancy Test3  
 
X 
 
 
 
 
Randomization 
 
X 
 
 
 
 
SF-20 Health Survey, Visual Pain 
Scale, and Katz Activities of Daily 
Living4  
X 
 
X 
X 
X 
 
Photographs of Wound(s)  
 
X 
X  
(if possible) 
X  
(if possible) 
X  
(as 
applicable) 
X  
(as applicable) 
PUSH Tool 
 
X 
X 
X 
X  
(as 
applicable) 
X  
(as applicable) 
Medication Use5 
 
X 
X 
X 
X 
X 

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AE Evaluation  
 
X 
X 
X 
X 
X 
Nursing Contact Time 
 
X 
X 
X 
 
X  
(as applicable) 
Confirm Visit Schedule 
 
X 
X 
X 
 
 
Cost of Tx Method / Length of stay 
in hospital and SNF, as applicable 
 
 
 
 
X 
 
 
Wound Evaluation 
Classification  
X 
X 
 
 
 
 
Location  
X 
X 
 
 
 
 
Length, Width, and Depth 
X 
X 
X 
X 
X  
(as 
applicable) 
X  
(as applicable) 
Surface Area / Volume 
 
X 
X 
X 
X 
X 
ABI Value (as applicable) 
 
 
X 
X 
X 
X  
Wound Appearance / 
Characteristics 
 
X 
X 
X 
X  
(as 
applicable) 
X  
(as applicable) 
Change in Wound Area / Volume  
 
 
X 
X 
X  
(as 
applicable) 
X  
(as applicable) 
 
1 Height recorded at Screening Visit only.  BMI recorded at Screening and Final Study Visits only. 
2All labs collected at Screening and Final Study Visit. Albumin collected at Visit 3 and Visit 5.  Pre-albumin collected at 
Visit 3, Visit 5, Visit 7, Visit 9, Visit 11, and Visit 13.  Hemoglobin collected as required at F/U Visits.   
3 Childbearing females only4Questionnaires to be completed at Screening, Follow-Up Visits 1, 5, 13, and Final Study Visit 
only 
5 Medications to be captured are: Pain medications, antibiotics, anti-hypertensives, and nutritional protein supplement

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APPENDIX II: STATEMENT OF COMPLIANCE 
 
The trial will be conducted in accordance with the ICH E6, the United States (US) Code 
of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 21 CFR 
Part 50, 21 CFR Part 56, and 21 CFR Part 812. 
 
The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the Sponsor and documented approval 
from the Institutional Review Board, except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study 
have completed Human Subjects Protection Training. 
 
 
I agree to ensure that all staff members involved in the conduct of this study are 
informed about their obligations in meeting the above commitments. 
 
Signature of Principal Investigator 
Date (mm/dd/yy) 
 
 
Printed Name 
 
Name of Institution