Prospective, Multi-center, Randomized, Controlled Trial Evaluating the Use of PriMatrix Dermal Repair Scaffold for the Management of Diabetic Foot Ulcers
Phase: NA
Conditions: Diabetic Foot Ulcer
Sponsor: Integra LifeSciences Corporation

Protocol Number: T-PMXDFU-01 
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PROSPECTIVE, MULTI-CENTER, RANDOMIZED CONTROLLED TRIAL EVALUATING 
THE USE OF PRIMATRIX DERMAL REPAIR SCAFFOLD FOR THE MANAGEMENT OF 
DIABETIC FOOT ULCERS 
Short Title: Efficacy of PriMatrix in the Management of Diabetic Foot 
Ulcers 
Protocol Number: T- PMXDFU-01 
Protocol Version: 5.0 
Protocol Version Date: 06 Nov 2018 
Sponsor: 
Integra LifeSciences 
311 Enterprise Drive, Plainsboro, New Jersey 08536 
www.integralife.com  
Phone: +1-609-275-0500 • Fax: +1-609-750-4277 
Sponsor Contact(s):  
Main Contact: 
Jessica Knowlton, MS CRA 
Clinical Research Manager 
Phone: +1-609-750-7825 • Cell: +1-609-325-0111 
jessica.knowlton@integralife.com  
Confidentiality Statement 
This protocol is provided for conducting a clinical research study. The information contained in this 
document is confidential and, except to the extent necessary to obtain informed consent or Independent 
Ethics Committee/Institutional Review Board approval, cannot be disclosed unless required by 
governmental regulation. Persons to whom any portion of the contents of this document is disclosed must 
be informed that the information is confidential and may not be further disclosed by them. 
NCT03010319

 
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Contents 
LIST OF FIGURES .......................................................................................................................................... 5 
LIST OF TABLES 5 
STATEMENT OF COMPLIANCE ..................................................................................................................... 6 
DEFINITIONS AND ABBREVIATIONS............................................................................................................. 7 
PROTOCOL SYNOPSIS ................................................................................................................................ 10 
1. 
Introduction .................................................................................................................... 18 
1.1. 
Background ..................................................................................................................... 18 
1.2. 
Clinical Use of PriMatrix to Treat Diabetic Foot ulcers ................................................... 18 
1.3. 
PriMatrix Description ...................................................................................................... 18 
1.4. 
PriMatrix Indication ......................................................................................................... 19 
2. 
Study Objective ............................................................................................................... 20 
3. 
Study Design .................................................................................................................... 20 
3.1. 
Treatment Groups (Further defined in Section 5) .......................................................... 20 
3.2. 
Study Phases ................................................................................................................... 20 
3.2.1. Screening Phase .............................................................................................................. 20 
3.2.2. Treatment Phase ............................................................................................................. 20 
3.2.3. Follow-up Phase .............................................................................................................. 21 
3.3. 
Study Duration ................................................................................................................ 21 
4. 
Study Population: Eligibility Criteria ................................................................................ 22 
4.1. 
Inclusion Criteria ............................................................................................................. 22 
4.2. 
Exclusion Criteria ............................................................................................................. 22 
5. 
Description of Protocol Assessments & Procedures ....................................................... 23 
5.1. 
Informed Consent and HIPAA Authorization .................................................................. 23 
5.2. 
Inclusion/Exclusion Criteria ............................................................................................. 23 
5.3. 
Medical Resource Utilization (MRU) ............................................................................... 24 
5.4. 
Baseline Demographics ................................................................................................... 24 
5.5. 
Medical History ............................................................................................................... 24 
5.6. 
Physical Examination ....................................................................................................... 25 
5.6.1. Physical Examination ....................................................................................................... 25 
5.6.1.1. Ankle-Brachial Index (ABI) ............................................................................................... 26 
5.6.1.2. Systolic Pressure of the Great Toe .................................................................................. 26 
5.6.1.3. Transcutaneous Oxygen Pressure ................................................................................... 26 

 
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5.6.2. 
Number and Location of Study Ulcer(s) .......................................................................... 26 
5.7. 
Ulcer Assessments ........................................................................................................... 26 
5.7.1. Extent and Location of Ulceration ................................................................................... 26 
5.7.2. Ulcer Exudate Assessments ............................................................................................. 27 
5.7.3. Ulcer Infection Assessment ............................................................................................. 27 
5.8. 
Study Ulcer Photography ................................................................................................ 28 
5.9. 
Sharp Debridement ......................................................................................................... 28 
5.9.1. Debridement Certification .............................................................................................. 28 
5.10. 
Ulcer Measurements ....................................................................................................... 29 
5.10.1. Computerized Planimetry ............................................................................................... 29 
5.10.2. Ulcer Area Reduction ...................................................................................................... 30 
5.11. 
Standard of Care (Control) Treatment ............................................................................ 30 
5.12. 
Compliance with Offloading & Dressing Changes ........................................................... 31 
5.13. 
Appropriate Off-loading/Protective Device .................................................................... 31 
5.14. 
Concomitant Medications and Non-Study Treatments .................................................. 32 
5.14.1. Prohibited Medications and Therapies ........................................................................... 32 
5.15. 
Adverse Events ................................................................................................................ 33 
5.15.1. 
Definitions ....................................................................................................................... 33 
5.15.2. 
AE Severity Assessments ................................................................................................. 34 
5.15.3. 
Adverse Event Relatedness Assessments ....................................................................... 35 
5.15.4. 
Adverse Event Expectedness ........................................................................................... 36 
5.15.5. 
Adverse Event Reporting Procedures ............................................................................. 38 
5.15.6. 
Adverse Event Follow-up ................................................................................................ 39 
5.16. 
Method for Assigning Eligible Subjects to Treatment (i.e., Randomization) .................. 39 
5.17. 
Active Treatment ............................................................................................................. 40 
5.17.1. PriMatrix Dermal Repair Scaffold Disposition, Storage and Accountability .................... 40 
5.17.2. PriMatrix Application Training ........................................................................................ 40 
5.17.3. PriMatrix Application ...................................................................................................... 40 
5.17.4. PriMatrix Re-Application ................................................................................................. 41 
5.18. 
Investigator Assessments of Ulcer Closure ..................................................................... 42 
5.19. 
Investigator Assessment of Ulcer Recidivism .................................................................. 42 
6. 
Study Activities by Phase and Visit .................................................................................. 43 
6.1. 
Screening Phase .............................................................................................................. 43 

 
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6.1.1. Screening Visit 1 (SV1) ..................................................................................................... 43 
6.1.2. Screening Visit 2 (SV2) ..................................................................................................... 44 
6.2. 
Treatment Phase ............................................................................................................. 45 
6.2.1. Randomization/TV 1 (Day 0) ........................................................................................... 45 
6.2.2. Subsequent Treatment Phase Visits (TVs 2 through 13) ................................................. 46 
6.2.3. Closure Confirmation Visit (7±3 days after ulcer determined to be closed)................... 47 
6.2.4. 4-Week Follow-Up Visit (28±3 days after Confirmation Visit) ........................................ 48 
6.2.5. Unscheduled Visits .......................................................................................................... 48 
7. 
Study Discontinuation and Withdrawal .......................................................................... 50 
8. 
Statistical Analysis ........................................................................................................... 50 
8.1. 
Treatment Groups ........................................................................................................... 51 
8.2. 
Description of Study Endpoints ....................................................................................... 51 
8.2.1. Primary Efficacy Endpoint ............................................................................................... 51 
8.2.2. Secondary Efficacy Endpoints ......................................................................................... 51 
8.2.3. Exploratory Endpoints ..................................................................................................... 51 
8.2.4. Safety Endpoints ............................................................................................................. 52 
8.3. 
Sample Size Determination and Rationale ...................................................................... 52 
8.4. 
Randomization ................................................................................................................ 52 
8.5. 
Blinding ............................................................................................................................ 52 
8.6. 
Interim Analysis for Sample Size Adjustment ................................................................. 53 
8.7. 
General Statistical Considerations .................................................................................. 53 
8.8. 
Subject Disposition .......................................................................................................... 53 
8.9. 
Demographic and Baseline Characteristics ..................................................................... 54 
8.10. 
Analysis Populations ........................................................................................................ 54 
8.10.1. Intent-to-Treat Population .............................................................................................. 54 
8.10.2. Per Protocol Population .................................................................................................. 54 
8.10.3. Safety Population ............................................................................................................ 54 
8.11. 
Statistical Methods .......................................................................................................... 54 
8.12. 
Efficacy Analyses ............................................................................................................. 54 
8.12.2. Exploratory Analyses ....................................................................................................... 55 
8.12.3. Treatment Failures .......................................................................................................... 56 
8.12.4. Safety Analyses ................................................................................................................ 56 
8.12.5. Adverse Events ................................................................................................................ 56 

 
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8.12.6. Supportive Analysis ......................................................................................................... 56 
9. 
Direct Access to Source Data/Documentation ................................................................ 56 
10. 
Quality Control and Quality Assurance ........................................................................... 57 
10.1. 
Monitoring Requirements ............................................................................................... 57 
10.2. 
Acceptability of Case Report Forms ................................................................................ 58 
10.3. 
Reporting Protocol Deviations ........................................................................................ 58 
10.4. 
Study Device Accountability ............................................................................................ 58 
11. 
Ethics and Regulatory Requirements .............................................................................. 58 
11.1. 
Institutional Review Board/Independent Ethics Committee .......................................... 59 
11.2. 
investigator’s Responsibilities ......................................................................................... 59 
11.3. 
Subject Informed Consent Requirements ....................................................................... 59 
12. 
Data Handling and Record Keeping ................................................................................. 60 
12.1. 
Recording and Collection of Data .................................................................................... 60 
12.2. 
Clinical Data Management .............................................................................................. 60 
12.3. 
Archiving .......................................................................................................................... 60 
13. 
Publication Plan ............................................................................................................... 61 
14. 
Protocol Versions ............................................................................................................ 62 
15. 
References ....................................................................................................................... 63 
 
LIST OF FIGURES 
Figure 1: Study Design................................................................................................................................. 21 
Figure 2: Images of Proper Debridement ................................................................................................... 29 
Figure 3: SAE Expectedness Determination Decision Tree ......................................................................... 38 
Figure 4: Images of Proper PriMatrix Application ....................................................................................... 41 
 
LIST OF TABLES 
Table 1 Adverse Event Severity – Description of Severity Grades .............................................................. 35 
Table 2: Adverse Event Causality Categories .............................................................................................. 35 
Table 3: Schedule of Events ........................................................................................................................ 49 
Table 4: Previous Versions and Overview of Changes to the Previous Version ......................................... 62 
 
 

 
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STATEMENT OF COMPLIANCE 
 
By signing this document, I, the investigator, certify that this trial will be carried out in accordance with 
International Conference on Harmonization Good Clinical Practice (ICH GCP) and the following:  
 
• 
United States (US) Code of Federal Regulations (CFR) applicable to clinical studies (45 CFR Part 46, 
21 CFR Part 11, 21 CFR Part 50, and 21 CFR Part 56) 
 
Additionally, I and any clinical trial site staff who are responsible for the conduct, management, or 
oversight of this trial will complete Human Subjects Protection/ICH GCP Training. 
 
The protocol, informed consent form(s), any recruitment materials, and/or all subject materials associated 
with this trial will be submitted to an Institutional Review Board (IRB) for review and approval.  Approval 
of both the protocol and the consent form must be obtained before any subject is screened.   
 
Finally, I understand that any amendments to the protocol or consent forms will require review and 
approval by the sponsor and IRB before the changes are implemented to the study.   
 
 
 
 
Investigator Name 
 
 
 
Investigator Signature  
Date 
 
 
 
 
 

 
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DEFINITIONS AND ABBREVIATIONS 
TERM 
DEFINITION 
(ICH) GCP 
(International Conference on Harmonisation) Good Clinical Practice 
510(k) 
The regulatory pathway companies use to obtain marketing clearance for 
Class II devices. 
ABI 
Ankle-Brachial Index 
Active Treatment 
Group 
The cohort which will be treated with the PriMatrix product in addition to 
standard of care materials and procedures.  (See Section 5.17) 
AE 
Adverse Event, See Section 5.15 for Definitions 
Anticipated 
A determination of expectedness of a SAE that is related to the study 
product or procedures.  (See Section 5.15.4) 
BMI 
Body Mass Index 
CE Marked 
A certification that indicates conformity with health, safety, and 
environmental protection standards for products sold within the European 
Economic Area. 
CFR 
Code of Federal Regulations 
CMH 
Cochran-Mantel-Haenszel test; a statistical test used in the analysis of data 
from this trial. 
Complete Wound 
Closure  
100% re-epithelialization of the ulcer surface without detectable exudate, 
confirmed on 2 consecutive study visits 1 week apart (i.e., Treatment Visit 
where 100% re-epithelialization of the ulcer surface without detectable 
exudate was initially documented and the Closure Confirmation Visit).  (See 
Section 5.18) 
Control Treatment 
Group [i.e., Standard of 
Care (SOC)] 
The cohort that the active treatment group will be compared against.  The 
terms Standard of Care (SOC) and Control Treatment are synonymous for 
this protocol. (See Section 5.11) 
DFU 
Diabetic Foot Ulcer 
DM 
Diabetes Mellitus 
eCRF 
Electronic Case Report Form 
EDC 
Electronic Data Capture 
FDA 
Food and Drug Administration 
Female of child-bearing 
potential 
A subject who is neither post-menopausal nor sterile, either naturally or 
through surgical methods. 

 
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TERM 
DEFINITION 
Full-Thickness 
Refers to the depth of an ulcer in which both the epidermis and dermis are 
lost.  
HbA1c 
Glycosylated Hemoglobin 
HIPAA 
Health Insurance Portability and Accountability Act 
HIV 
Human Immunodeficiency Virus 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
Integra 
Integra LifeSciences Corporation, this study’s sponsor 
IRB 
Institutional Review Board 
ITT 
Intent-to-Treat 
LOCF 
Last Observation Carried Forward; a method of analysis where certain values 
are missing in the data set. 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRU 
Medical Resource Utilization 
Partial-Thickness 
Refers to the depth of an ulcer involving only a portion of the dermal layer 
of the skin and the entire epidermal layer of the skin.   
Plethysmography 
In this protocol, a synonym for toe pressure. 
PP 
Per-Protocol  
PriMatrix 
PriMatrix Dermal Repair Scaffold; The investigational product being studied 
in this trial.  This term is synonymous with Active Treatment in this protocol. 
QC 
Quality Control 
SAE 
Serious Adverse Event, See Section 5.15.1 for definition 
SAP 
Statistical Analysis Plan 
SAS 
Statistical Analysis System 
Sharp Debridement 
The removal of all devitalized tissue involving the use of a knife, curette or 
blade. (See Section 5.9.1 for full debridement requirements) 
SNF 
Skilled Nursing Facility 
SOC 
Standard of Care; The terms Standard of Care and Control Treatment are 
synonymous for this protocol. (See Section 5.11) 
SOP 
Standard Operating Procedures 

 
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TERM 
DEFINITION 
SV 
Screening Visit 
TcPO2  
Transcutaneous Oxygen Pressure 
TV 
Treatment Visit 
UADE 
Unanticipated Adverse Device Effect 
Unanticipated 
A determination of expectedness of a SAE that is related to the study 
product or procedures.  (See Section 5.15.4) 
US(A) 
United States (of America) 
Wound 
Also known as “ulcer”.  In this protocol, the two terms are synonymous. 
 
 
 

 
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PROTOCOL SYNOPSIS 
PROTOCOL TITLE 
Prospective, multi-center, randomized, controlled trial evaluating the use of 
PriMatrix Dermal Repair Scaffold for the management of diabetic foot ulcers 
PROTOCOL NO. 
T-PMXDFU-01 
PROTOCOL 
VERSION 
05 
PROTOCOL DATE 
06 Nov 2018 
SHORT TITLE 
Efficacy of PriMatrix in the management of diabetic foot ulcers  
DEVICES 
PriMatrix, derived from fetal bovine dermis, is a dermal repair scaffold for the 
management of challenging ulcers. PriMatrix is rich in Type III collagen, a collagen that is 
active in developing and healing tissues.  PriMatrix is a freeze-dried product that is 
stored at ambient conditions with a shelf life of five years. 
INDICATIONS FOR 
USE 
PriMatrix® is intended for the management of wounds that include: 
• 
Partial and full thickness wounds 
• 
Pressure, diabetic, and venous ulcers 
• 
Second-degree burns 
• 
Surgical wounds—donor sites/grafts, post-Moh’s surgery, post-laser 
surgery, podiatric, wound dehiscence 
• 
Trauma wounds —abrasions, lacerations and skin tears 
• 
Tunneled/undermined wounds 
• 
Draining wounds 
PriMatrix is FDA 510(k) cleared (K061407, K083440, K100261, K131286, and 
K153690) for marketing in the United States and is also marketed in the European 
Union (CE Marked), Mexico, Canada, and many other countries.   
STUDY SPONSOR 
Integra LifeSciences Corporation 
311 Enterprise Drive  
Plainsboro, NJ 08536, USA 
SPONSOR 
CONTACT 
Jessica Knowlton 
Manager, Clinical Research, Clinical Operations 
E-mail: Jessica.Knowlton@integralife.com  
Study Email: TPMXDFU1studymailbox@integralife.com   
OBJECTIVE 
The objective of this study is to evaluate the efficacy of PriMatrix in the 
management of diabetic foot ulcers (DFUs) in subjects with diabetes mellitus (DM) 
and without significantly compromised arterial circulation, in comparison to 
Standard of Care (SOC, i.e., Control) treatment.  In addition to the efficacy data, 
safety associated with the management of DFUs will be evaluated, as well as 
medical resource utilization. 
STUDY DESIGN 
This is a multicenter, randomized, parallel-group clinical trial designed to establish 
the superior efficacy of the Active Treatment (PriMatrix) over that of SOC in 
achieving complete wound closure of DFUs in diabetic subjects with adequate 
arterial circulation. The study will have three phases: A Screening Phase, a 
Treatment Phase and a Follow-up Phase. All subjects will be seen weekly in the 
Screening and Treatment Phases. Subjects that have achieved complete wound 
closure during the treatment phase will be entered into the follow-up phase and 
will return to the site 4-weeks following the confirmation visit.  Study enrollment 

 
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will be paused once 50 subjects (25 in each treatment arm) have been enrolled in 
order to perform an early data review and an interim analysis is planned after 128 
subjects have completed study participation.   
 
Screening Phase – 2 weeks ± 3 days (Max 17 days) 
Prior to any study-related procedures, subjects will sign the IRB/IEC approved 
informed consent form (ICF). Medical history will be obtained and clinical 
assessments performed to determine subject eligibility.  Certain eligibility criteria 
will be reaffirmed on Screening Visit 2 and Randomization.  Photographs and 
planimetric area evaluation will be performed to document ulcer area before and 
after debridement.  The study ulcer will receive SOC daily for two weeks.    
 
Treatment Phase – up to 13 weeks ± 3 days (Max 94 days) 
 
Randomization/Treatment Visit 1 (TV1) 
Following the two-week screening phase, the subject will return to the clinic and 
physical assessments will be made to confirm the subject’s final eligibility.  The 
ulcer will be photographed, sharply-debrided (if necessary), and photographed 
again.  Planimetric evaluation will be performed to determine the area of ulcer 
post debridement.  Subjects who meet all eligibility criteria will be randomized 1:1 
to receive either Active Treatment or Control Treatment.  
 
Treatment Visits 2 through 13 
 After randomization, subjects will be evaluated weekly (7 ± 3 days).  Assessments 
will include photographs of the study ulcers, investigator assessment of wound 
closure, and planimetric evaluations of ulcer area.  Safety parameters will be 
documented, and Medical Resource Utilization data will be collected by reviewing 
subject source documentation and medical records and subject interviews.  
Subjects will receive Active or Control treatment for up to 13 weeks or until the 
study ulcer achieves confirmed complete wound closure. 
 
Follow-up Phase – 4-weeks ± 3 days (Max 31 days) 
Subjects with complete wound closure in the treatment phase will have a final 
study visit 4-weeks after the closure confirmation visit to evaluate if the ulcer has 
remained closed.  
ENROLLMENT 
Up to 30 centers in the US will randomize up to 256 subjects.   
STUDY DURATION 
A subject may participate in the study for up to 136 days in total, inclusive of the 
allowed time range for visits. 
 
Up to 30 centers will participate in this study and it is anticipated that each site 
will enroll approximately 0.5 subject/month.  Based on this estimation, 256 
subjects will be randomized and complete the study in 30 months. 
STUDY CONDUCT 
This study will be conducted with adherence to current standards; these include 
good clinical practice (GCP) requirements and the applicable regulatory 
requirements. 

 
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SUBJECT 
ELIGIBILITY 
CRITERIA 
Inclusion Criteria 
Subjects are required to meet all of the following criteria for enrollment into the 
study and subsequent randomization: 
1. The subject has signed and dated an informed consent form. 
2. In the opinion of the investigator, subject is able and willing to comply with 
study procedures, including study visits, study dressing regimens and 
compliance with study required off-loading device. 
3. The subject is ≥ 18 years of age. 
4. The subject, if female of child-bearing potential, must not be pregnant. To 
document pregnancy status, subject statement is acceptable.   
5. The subject has Type I or Type II diabetes mellitus with investigator-confirmed 
glycosylated hemoglobin (HbA1c) of ≤ 12% within 3 months prior to screening 
visit 1. 
6. The subject has at least one diabetic foot ulcer that meets ALL of the following 
criteria: 
• 
Ulcer which has been in existence for a minimum of two weeks, prior to 
signing the Informed Consent Form for trial participation. 
• 
Ulcer is a partial or full thickness diabetic foot ulcer without 
capsule/tendon/bone exposure.   
• 
Ulcer does not have tunneling, undermining, or sinus tracts that 
necessitates 
surgical 
OR 
debridement 
and/or 
penetrates 
to 
capsule/tendon/bone.  
• 
Ulcer is located on the foot or ankle (with no portion above the top of 
the malleolus).   
• 
Ulcer size (area) is > 1 cm2 and < 12 cm2 post-debridement. 
7. There is a minimum 1 cm margin between the qualifying study ulcer and any 
other ulcer on that same foot, post-debridement.   
• 
If the subject has more than one ulcer that meets the eligibility criteria, 
the ulcer designated as the study ulcer will be at the discretion of the 
investigator.   
8. The subject has adequate vascular perfusion of the affected limb as defined 
by at least one of the following: 
• 
Ankle-Brachial Index (ABI) ≥ 0.65 or ≤1.2, performed within 3 months of 
screening,   
• 
Toe pressure (plethysmography) > 50 mmHg at time of screening,  
• 
TcPO2 > 40 mmHg at time of screening 
9. The subject or responsible caregiver is willing and able to maintain required 
applicable dressing changes as well as study required off-loading/protective 
device for the duration of the study. 
 
 
Exclusion Criteria 
Subjects will not be enrolled in the study if any of the following criteria are met: 
1. The subject was previously randomized and treated under this clinical study 
protocol. 

 
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2. The subject has suspected or confirmed gangrene or ulcer infection of the 
study ulcer or receiving systemic antibiotics for the treatment of such. 
3. The subject has suspected or confirmed osteomyelitis of the foot with the 
study ulcer.   
4. The subject has a history of hypersensitivity to bovine collagen, as determined 
by prior medical history. 
5. The subject has participated in another clinical trial involving a device or a 
systemically administered investigational study drug/treatment within 28 
days of randomization. 
6. The subject has received, within 28 of signing Informed Consent Form, or is 
scheduled to receive during study participation, a medication or treatment 
which is known to interfere with or affect the rate and quality of ulcer healing 
(e.g., systemic steroids, immunosuppressive therapy, autoimmune disease 
therapy, dialysis, radiation therapy to the foot, vascular surgery, angioplasty, 
or thrombolysis). 
7. The subject has a history of bone cancer or metastatic disease of the affected 
limb, radiation therapy to the foot, or has had chemotherapy within the 12 
months prior to signing Informed Consent Form for trial participation. 
8. In the opinion of the investigator, the subject has a history of, or is currently 
diagnosed with, any illness or condition, other than diabetes, that could 
interfere with ulcer healing (e.g., end-stage renal disease, severe malnutrition, 
liver disease, aplastic anemia, connective tissue disorder, acquired immune 
deficiency syndrome, HIV positive, or sickle cell anemia). 
9. In the opinion of the investigator, the subject has unstable Charcot foot or 
Charcot with bony prominence that could inhibit ulcer healing.  
10. The subject has ulcers secondary to a disease other than diabetes (e.g., 
vasculitis, neoplasms, or hematological disorders). 
11. In the opinion of the investigator, the subject has excessive lymphedema that 
could interfere with off-loading and/or ulcer healing. 
12. The study ulcer has received ulcer dressings that included growth factors, 
engineered tissues, or skin substitutes within 28 days of randomization or is 
scheduled to receive treatment during the study (e.g., Regranex, Dermagraft, 
Apligraf, EpiFix, GraftJacket, OASIS, Omnigraft, or Integra BMWD). 
13. At the end of the screening phase and based on planimetric assessment, the 
area of the study ulcer after sharp debridement has decreased by more than 
30% over the two-week screening period.  
ENDPOINTS 
Primary Endpoint 
The primary endpoint of this study is the incidence of complete wound closure, as 
assessed by the investigator at or before Week 12 of the treatment phase.   
Secondary Endpoints 
1. Proportion of subjects with complete closure of the study ulcer at or before 
Week 12 as assessed by computerized planimetry.  
2. Time to complete wound closure, as assessed by the investigator. 
3. Time to complete wound closure, as assessed by computerized planimetry. 
4. Rate of wound closure, as assessed by computerized planimetry. 
 

 
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Safety Endpoints 
Incidence of all adverse events (AEs) related to the study treatment, study ulcer 
or study procedures and all serious adverse events (SAEs). 
 
Exploratory Endpoints 
Medical resource utilization associated with treatment of DFU and related 
complications, including: 
• 
Interference of activities of daily living 
• 
Interference of paid work (full-time or part-time)/school 
• 
Physician office visits 
• 
Emergency room visits 
• 
Hospitalizations  
• 
Home health nursing visits 
• 
Skilled nursing facilities (SNF) 
• 
Procedures 
• 
Medication regimens to treat complications (analgesics, antibiotics, etc.) 
• 
Diagnostic tests, imaging, etc. 
• 
Treatment of AEs 
• 
Use of durable medical equipment (off-loading/protective device, 
crutches, wheelchair, etc.) 
• 
Dressing regimen and materials 
• 
wound closure/healed status at the 4-week Follow-up visit  
DATA COLLECTION 
The following data will be collected: 
• 
Medical Resource Utilization information 
• 
Demographics 
• 
Medical history 
• 
Medications and non-study treatments 
• 
AEs 
• 
Physical examination 
• 
Vascular perfusion tests, vital signs 
• 
Ulcer assessments & treatments 
• 
Supplies Usage 
• 
Duration, size, exudate, location, infection, percent re-epithelialization 
(Documented or measured using clinical judgment, photography, and/or 
computerized planimetry) 
STATISTICAL 
METHODS 
This is a prospective, multicenter, parallel-group, randomized, controlled trial 
designed to establish the superior efficacy of the Active Treatment (PriMatrix 
Dermal Repair Scaffold) over SOC in achieving complete wound closure of DFUs in 
a population with adequate arterial circulation.  Subjects will be randomized 1:1, 
stratified by site and ulcer area, to receive either the Active Treatment or SOC. 
 
Sample Size 
102 subjects in each treatment group, for a total of 204 subjects for the study, 
yields the 80% power required to demonstrate superiority of the Active Treatment 
to SOC in the proportion of subjects whose ulcer has closed by Week 12, assuming: 

 
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1. 46% of DFUs managed with the Active Treatment achieve complete wound 
closure by 12 weeks. 
2. 26% of DFUs managed with SOC achieve complete wound closure by 12 
weeks.  
 
To accommodate the potential early discontinuations, the trial proposes to 
randomize 256 subjects (128 per treatment).   
 
Overall 2-sided Type I Error rate (alpha) of 0.05. 
 
A single interim analysis, when 50% of subjects complete the trial, will be 
performed using group-sequential methods and Pocock alpha spending function, 
the hypotheses will be tested at a two-sided alpha of 0.031.   A two-sided alpha of 
0.028 will be used to test the hypothesis at the final analysis. 
 
Data Evaluation 
Analysis Population 
The Intent-to-Treat (ITT) population, defined as all randomized subjects, will be 
the primary population for the analysis of primary and secondary efficacy 
endpoints.   
 
The Per Protocol (PP) population, defined as all subjects who were not associated 
with a major protocol violation, will be used in supportive analyses of the primary 
and secondary endpoints.  
 
In all efficacy analyses, covariate analyses will be conducted to assess the impact 
of various prognostic factors on closure and also to demonstrate the robustness 
of the primary analysis.  Prognostic factors (i.e., covariates) will be included if they 
are found to be contributing factors (i.e., the individual covariate p-value is less 
than 0.05).  Potential prognostic factors to be considered include:  
• 
Ulcer area 
• 
Age of Ulcer at Baseline 
• 
Gender  
• 
HbA1c 
• 
Ulcer location 
• 
Diabetes type 
• 
Race 
• 
Nicotine Use 
• 
Baseline BMI 
 
 
Primary Efficacy Analysis 
 
The primary analysis will test the difference between the proportion of subjects 
who achieve complete wound closure by 13 weeks in the Active Treatment and 
SOC using the Cochran–Mantel–Haenszel (CMH) test.   
 
For the primary efficacy analysis, missing values will be imputed using last 
observation carried forward (LOCF).  
 

 
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Secondary Efficacy Analyses 
 
Proportion of ulcers with complete wound closure during the treatment phase as 
assessed by computerized planimetry will be compared using Logistic Regression 
with the stratification factors in the model.   
 
Time to complete wound closure will be analyzed using log rank test or Cox 
proportional regression model.  Kaplan-Meier methods will be used to present 
median time to complete wound closure.   
 
Analysis of Covariance will be used to compare the rate of wound closure for the 
two treatment groups.   
 
Safety Analyses 
AEs related to the device, study ulcer and/or study procedures and all SAEs will be 
recorded. 
 
All safety parameters will be summarized descriptively by treatment assignment.  
No inferential statistics are planned. 
 
Exploratory Analyses 
Exploratory analyses will be performed to examine patterns of medical resource 
utilization by treatment group and to estimate the diabetic foot ulcer related 
treatment costs by treatment.  Additionally, wound closure status at the 4-week 
Follow-up visit will be evaluated. 
 
Early Data Review 
An early data review will be performed when 50 patients reach the primary 
endpoint.  The purpose of this review is to ensure the study execution is as 
originally planned, and therefore, no alpha spending is involved.    
 
Interim Analysis  
A single interim analysis will be performed when 50% of subjects complete the 
study.  Employing a group-sequential design with a Pocock alpha spending 
function, the following decisions will be made at the interim analysis with respect 
to the efficacy outcome: 
 
• 
Stop the study due to demonstrating statistically significant superiority of 
the Active Treatment to SOC if the two-sided p-value testing the stated 
hypotheses is ≤ 0.031 and the difference is in favor of the Active Treatment. 
 
• 
Stop the study due to demonstrating futility of the Active Treatment to SOC 
if the two-sided p-value testing the stated hypotheses is ≤ 0.031 and the 
difference is in favor of SOC. 
 

 
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• 
Continue the study if the two-sided p-value testing the stated hypotheses is 
> 0.031. 
 
With this design and assuming the 46% of DFUs managed with the Active 
Treatment achieve complete wound closure by 13 weeks and 26% achieve 
complete wound closure when managed with SOC, the probability of stopping 
early due to showing superiority with the Active Treatment is 0.479.  If the 
decision at the interim analysis is to continue the study, the hypotheses at the end 
of the study will be tested at a two-sided alpha level of 0.028 to maintain an 
overall two-sided alpha of 0.05. 
 
Further, conditional power will be calculated at the interim analysis for predicting 
the final study success.  In case more data information is needed, appropriate 
sample size re-estimation will be considered in order to meet the final study 
objective.  
 
 

 
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1. Introduction 
1.1. Background 
Diabetic foot ulcers (DFUs) are a major health complication that affects up to 15% of 
individuals with diabetes mellitus (DM) over their lifetime.  The treatment of DFUs is an 
extremely challenging task, as these ulcers may be recalcitrant to SOC modalities and may 
become infected. It is estimated that approximately 15% of all DFUs will result in a lower 
extremity amputation and develop concomitant medical complications that are associated with 
increased mortality rates.1–4 
DFUs not only have a detrimental effect on a person’s quality of life,5,6 but also pose a 
significant burden on the health care system.  It is estimated, in the USA alone, that the annual 
cost associated with the management of DFUs is as high as $13 billion, which is in addition to the 
costs associated with DM itself.7  
1.2. Clinical Use of PriMatrix to Treat Diabetic Foot ulcers 
Advanced ulcer therapies have become an important strategy in the treatment of hard-to-
heal chronic DFUs.  Since FDA clearance in 2006, more than 45,000 units of PriMatrix Dermal 
Repair Scaffold (Integra LifeSciences Corporation, Plainsboro, NJ) have been shipped and to be 
used in the management of ulcers. Both prospective and retrospective studies conducted in 
practices and centers around the country have demonstrated the clinical benefit of using 
PriMatrix to manage DFUs.   
In a recent single-arm study led by the Mayo Clinic in Rochester MN, 64% of ulcers managed 
with PriMatrix achieved closure in a 12-weektime period.8  In a head-to-head comparison against 
Apligraf (Organogenesis, Canton, MA), an alternate cellular and tissue based product, PriMatrix 
managed ulcers achieved closure in half the time as Apligraf treated ulcers.9  Furthermore, by 
matching product size to ulcer size and requiring fewer applications, significant cost savings could 
be attributed to the use of PriMatrix over Apligraf.  Additionally, the success of PriMatrix in 
managing complicated DFUs has been reported to reduce the incidence of amputation thus 
avoiding associated costs and improving patient quality-of-life.10–12  
1.3. PriMatrix Description 
PriMatrix, derived from fetal bovine dermis, is a unique dermal repair scaffold for the 
management of challenging ulcers. PriMatrix is rich in Type III collagen, a collagen active in 
developing and healing tissues.13  
The scientific foundation for PriMatrix is well-documented and has been discussed at length 
in multiple review articles that highlight the differentiating characteristics of PriMatrix.13–15  This 
scaffold has been identified for its superior biocompatibility, ability to trap and bind the 
recipient’s own cells and growth factors within the matrix, and to rebuild dermis capable of 
supporting re-epithelialization.11,16   
PriMatrix is freeze-dried and may be stored at ambient conditions with a shelf life of five 
years. 

 
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1.4. PriMatrix Indication 
PriMatrix is FDA 510(k) cleared (K061407, K083440, K100261, K131286, and K153690) for 
marketing in the United States and is also marketed in the European Union (CE Marked), Mexico, 
Canada, and many other countries.    
PriMatrix® is intended for the management of wounds that include: 
• 
Partial and full thickness wounds 
• 
Pressure, diabetic, and venous 
ulcers 
• 
Second-degree burns 
• 
Trauma wounds — abrasions, 
lacerations and skin tears 
• 
Surgical wounds — donor 
sites/grafts, post-Moh’s surgery, 
post-laser surgery, podiatric, 
wound dehiscence 
• 
Tunneled/undermined wounds 
• 
Draining wounds 

 
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2. Study Objective 
The objective of this study is to evaluate the efficacy of PriMatrix Dermal Repair Scaffold in the 
closure of DFUs in subjects with DM and without significantly compromised arterial circulation in 
comparison to Control treatment.  In addition to the efficacy data, safety associated with the 
management of DFUs will be evaluated, as well as medical resource utilization data. 
3. Study Design 
This is a multicenter, randomized, open-label, parallel-group clinical trial designed to establish 
the superior efficacy of PriMatrix over that of Control treatment in the management of DFUs in 
subjects with DM and adequate arterial circulation.  Study enrollment will be paused once 50 subjects 
(25 in each treatment arm) have been enrolled in order to do an early data review.  There will also be 
an interim analysis after 128 subjects have completed their study requirements. 
3.1. Treatment Groups (Further defined in Section 5) 
• 
Active Treatment – PriMatrix Dermal Repair Scaffold + Standard of Care 
• 
Control Treatment – Standard of Care 
3.2. Study Phases 
3.2.1. Screening Phase 
After the informed consent process is complete, medical history will be collected and 
clinical assessments will be performed to determine subject eligibility for the study.    If 
the required eligibility criteria are met, the subject will begin the two-week screening 
phase.  During this phase, the subject will receive the control treatment as defined in 
Section 5.  During the two-week screening phase, the investigator will determine if the 
subject continues to meet all eligibility criteria, and if confirmed, the subject will be 
randomized and enter the treatment phase.  For detailed information, see Figure 1 and 
Table 3 below. 
3.2.2. Treatment Phase 
Subjects will be randomized to receive the Active or Control Treatment in a 1:1 
scenario (details can be found in Section 8.4).  Efficacy evaluations during this phase 
include weekly investigator assessments of wound closure and planimetric evaluations of 
ulcer area.  Safety evaluations will include AE assessments at each visit.  Additionally, 
collection of medical resource utilization (MRU) data will occur. The randomized study 
treatment will be administered for up to 12 weeks or until the study ulcer has closed, as 
assessed by the investigator.   
At the end of the treatment phase, subjects, all of whom will be considered 
treatment phase completers, will be assigned to one of two outcomes: 
• 
Subjects with confirmed closed ulcers will be considered treatment successes. 

 
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• 
Subjects with open ulcers at the end of the treatment phase will be considered 
treatment failures. 
Unscheduled Visits (i.e., those not specifically scheduled per protocol) are at the 
discretion of the investigator.  If the unscheduled visit is for treatment of the target ulcer, 
data for that visit will be collected and reported on the Unscheduled Visit eCRF page. For 
detailed information, see Figure 1 and Table 3 below. 
3.2.3. Follow-up Phase 
Subjects whose ulcer is confirmed closed at the Confirmation Visit (i.e., 1 week after 
closure is observed) will return to the clinic 4-weeks later for a follow-up visit (28 ± 3 days) 
to evaluate if the ulcer has remained closed.  For detailed information, see Figure 1 and 
Table 3 below. 
 
3.3. Study Duration 
A subject can participate in the study for up to 136 days in total with the allowed time range 
for visits during the treatment phase. 
 
 
 
 
4 Weeks 
after FU1 
(Study Exit) 
Follow-Up 
Visits 
Treatment Visits 
Screening 
Visits 
Randomization/TV1 
If wound open at 
TV13, subject is 
exited from study 
TV2 
TV13 
SV1 SV2 
TV3 
TV4 
TV5 TV6 
If wound closes on any visit 
from TV2 through TV13, 
proceed to Confirmation Visit 
If wound reopens, subject 
returns to the study at the visit  
after next treatment visit* 
TV8 
TV9 
Conf 
Visit 
4Wk 
Visit 
If wound is 
closed at Conf, 
proceed to 4Wk 
TV7 
One Week After 
Wound Closes 
Two Weeks 
TV10 TV11 TV12 
Figure 1: Study Design 
*Only if original closure was on or before Treatment Visit 11 

 
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4. Study Population: Eligibility Criteria 
4.1. Inclusion Criteria  
Subjects are required to meet all of the following criteria for enrollment into the study and 
subsequent randomization: 
1. The subject has signed and dated an informed consent form. 
2. In the opinion of the investigator, subject is able and willing to comply with study 
procedures, including study visits, study dressing regimens and compliance with study 
required off-loading device. 
3. The subject is ≥ 18 years of age. 
4. The subject, if female of child-bearing potential, must not be pregnant. To document 
pregnancy status, subject statement is acceptable.   
5. The subject has Type I or Type II diabetes mellitus with investigator-confirmed glycosylated 
hemoglobin (HbA1c) of ≤ 12% within 3 months prior to screening visit. 
6. The subject has at least one diabetic foot ulcer that meets ALL of the following criteria: 
• 
Ulcer which has been in existence for a minimum of two weeks, prior to signing the 
Informed Consent Form for trial participation. 
• 
Ulcer is a partial or full thickness diabetic foot ulcer without capsule/tendon/bone 
exposure.   
• 
Ulcer does not have tunneling, undermining, or sinus tracts that necessitates surgical 
OR debridement and/or penetrates to capsule/tendon/bone.  
• 
Ulcer is located on the foot or ankle (with no portion above the top of the malleolus).   
• 
Ulcer size (area) is > 1 cm2 and < 12 cm2 post-debridement. 
7. There is a minimum 1 cm margin between the qualifying study ulcer and any other ulcer 
on that same foot, post-debridement.   
• 
If the subject has more than one ulcer that meets the eligibility criteria, the ulcer 
designated as the study ulcer will be at the discretion of the investigator.   
8. The subject has adequate vascular perfusion of the affected limb as defined by at least one 
of the following: 
• 
Ankle-Brachial Index (ABI) ≥ 0.65 or ≤1.2, performed within 3 months of screening,   
• 
Toe pressure (plethysmography) > 50 mmHg at time of screening,  
• 
TcPO2 > 40 mmHg at time of screening 
9. The subject or responsible caregiver is willing and able to maintain required applicable 
dressing changes as well as study required off-loading/protective device for the duration 
of the study. 
4.2. Exclusion Criteria  
Subjects will not be enrolled in the study if any of the following criteria are met: 
1. The subject was previously randomized and treated under this clinical study protocol. 
2. The subject has suspected or confirmed gangrene or ulcer infection of the study ulcer or 
receiving systemic antibiotics for the treatment of such. 
3. The subject has suspected or confirmed osteomyelitis of the foot with the study ulcer.   
4. The subject has a history of hypersensitivity to bovine collagen, as determined by prior 
medical history. 

 
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5. The subject has participated in another clinical trial involving a device or a systemically 
administered investigational study drug/treatment within 28 days of randomization. 
6. The subject has received, within 28 of signing Informed Consent Form, or is scheduled to 
receive during study participation, a medication or treatment which is known to interfere 
with or affect the rate and quality of ulcer healing (e.g., systemic steroids, 
immunosuppressive therapy, autoimmune disease therapy, dialysis, radiation therapy to 
the foot, vascular surgery, angioplasty, or thrombolysis). 
7. The subject has a history of bone cancer or metastatic disease of the affected limb, radiation 
therapy to the foot, or has had chemotherapy within the 12 months prior to signing 
Informed Consent Form for trial participation. 
8. In the opinion of the investigator, the subject has a history of, or is currently diagnosed with, 
any illness or condition, other than diabetes, that could interfere with ulcer healing (e.g., 
end-stage renal disease, severe malnutrition, liver disease, aplastic anemia, connective 
tissue disorder, acquired immune deficiency syndrome, HIV positive, or sickle cell anemia). 
9. In the opinion of the investigator, the subject has unstable Charcot foot or Charcot with 
bony prominence that could inhibit ulcer healing.  
10. The subject has ulcers secondary to a disease other than diabetes (e.g., vasculitis, 
neoplasms, or hematological disorders). 
11. In the opinion of the investigator, the subject has excessive lymphedema that could 
interfere with off-loading and/or ulcer healing. 
12. The study ulcer has received ulcer dressings that included growth factors, engineered 
tissues, or skin substitutes within 28 days of randomization or is scheduled to receive 
treatment during the study (e.g., Regranex, Dermagraft, Apligraf, EpiFix, GraftJacket, OASIS, 
Omnigraft, or Integra BMWD). 
13. At the end of the screening phase and based on planimetric assessment, the area of the 
study ulcer after sharp debridement has decreased by more than 30% over the two-week 
screening period.   
5. Description of Protocol Assessments & Procedures 
5.1. Informed Consent and HIPAA Authorization 
Written informed consent will be obtained from each subject before any study-related 
procedures may commence.  Informed consent will be obtained by the investigator or designee 
at each study site. A notation will be made in the subject’s case history/medical chart that he/she 
is participating in a clinical study and has been provided a signed and dated ICF as well as the 
required site HIPAA authorization (if separate from the ICF). 
5.2. Inclusion/Exclusion Criteria 
Site staff and the investigator will document the date of ICF signature and review all of the 
inclusion and exclusion criteria with respect to the potential subject in question.  Review of 

 
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criteria may require sites to review the potential subject’s medical records or ask questions of 
the potential subject.  All questions relevant to the visit must be answered at that visit for the 
subject to be able to proceed with that and future visits. 
5.3. Medical Resource Utilization (MRU) 
Standardized 
assessments 
to 
document 
MRU 
(e.g., 
physician 
services, 
treatment/procedures, medications, etc.) required to manage the subject’s current DFU will be 
performed by a review of the subject’s source document/medical record and by the investigator 
or designee completing an interview with the subject.   
The MRU assessment should be performed prior to any other study procedures or assessments 
in order to minimize bias.  
The following information will be collected related to the DFU and its care: 
• Physician office visits 
• Emergency room visits 
• Hospitalizations 
• Home health nursing visits 
• Skilled nursing facilities 
• Procedures 
• Diagnostic tests, imaging, etc. 
• Treatment of AEs 
• Interference with activities of daily living 
• Interference with paid work (full-time or part-time)/school 
• 
Use of durable medical equipment (e.g., off-loading/protective device, crutches, 
wheelchair, etc.) 
• Dressing regimen and materials 
5.4. Baseline Demographics 
For the purposes of this study, demographic information will include: 
• Date of birth 
• Gender 
• Race 
• Ethnicity  
• Use of nicotine products 
• Use of alcohol 
5.5. Medical History 
The site will assess and document the DM type (Type 1 or Type 2) and date/year of diagnosis.  
Subject’s HbA1c level and date of test must be recorded (Note: The test results must be valid 
within 3 months of SV1 and must be in existence on SV1).   

 
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In addition to diabetic status, additional medical history that, in the opinion of the investigator, 
is relevant to the safety of the subject or that could impact diabetic foot ulcer healing is to be 
recorded (i.e., obesity, neuropathy, etc.).  
Relevant medical histories will be recorded using the body system categories outlined below: 
• 
Cardiovascular 
• 
Lymphatic 
• 
Respiratory 
• 
Hematologic 
• 
Gastrointestinal 
• 
Immunologic 
• 
Renal 
• 
Dermatologic 
• 
Hepatic 
• 
Psychiatric 
• 
Neurological (Including Neuropathy) 
• 
Genitourinary 
• 
Endocrine 
• 
Other 
 
For each relevant medical history, the following will be documented:   
• 
Condition (i.e., name of disease/disorder) 
• 
Medical History Category (e.g., general medical history, surgical procedure, other) 
• 
Date/ Year of Onset 
• 
Status (i.e., resolved or ongoing) 
5.6. Physical Examination 
The physical examination will include routine examinations for the following: 
• 
Abnormalities of the extremities 
• 
Neurologic abnormalities (Including Neuropathy) 
• 
Heart/cardiovascular abnormalities 
• 
Musculoskeletal abnormalities 
• 
Dermatologic abnormalities 
• 
Other abnormality (i.e., any other body system for which an abnormality is noted and 
which, in the opinion of the investigator, is relevant to the safety of the subject or could 
impact ulcer healing should be considered clinically significant.) 
• 
Height (inches) & Weight (pounds) 
 
Each abnormality will be recorded, and the investigator will record an assessment of its clinical 
significance.   Any abnormality noted at SV1 should be listed on the medical history eCRF, if 
relevant.  If an abnormality presents later in the trial, it should be listed as an AE if it meets the 
criteria in Section 5.15. 
5.6.1. Physical Examination 
Only one of the following assessments is required to verify adequate perfusion of the 
affected limb; however, more than one test may be performed to determine eligibility.  
The assessment chosen is at the discretion of the investigator; however, the acceptability 
of parameters of each test must be followed as stated below.  

 
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5.6.1.1. 
Ankle-Brachial Index (ABI) 
ABI, if conducted, will be determined on the affected side (i.e., the side of the 
body on which the study ulcer resides) according to standard 
procedure/protocol at the study site. 
If ABI is ≥ 0.65 or ≤ 1.2, then vascular perfusion is considered adequate.  An ABI 
measurement that has been collected within 3 months of screening is 
acceptable.   
5.6.1.2. 
Systolic Pressure of the Great Toe 
The systolic pressure of the great toe of the affected foot (i.e., the foot on which 
the study ulcer resides) will be obtained while the subject is sitting.  If toe 
pressure is > 50mmHg, then vascular perfusion is considered adequate.  This 
must be done at SV1; previous measurements are not accepted. 
5.6.1.3. 
Transcutaneous Oxygen Pressure  
Transcutaneous Oxygen Pressure (TcPO2) will be determined according to 
standard procedure/protocol at the study site.  If TcPO2 is > 40mmHg, then 
vascular perfusion is considered adequate.  This must be done at SV1; previous 
measurements are not accepted. 
5.6.2.  Number and Location of Study Ulcer(s)  
The number and location of any and all DFUs will be documented during the physical 
exam. 
5.7. Ulcer Assessments 
5.7.1. Extent and Location of Ulceration  
On SV1, the date that the ulcer was first observed will be documented. 
Documentation of tunneling, undermining, or sinus tracts that necessitates surgical 
debridement in the OR and/or penetrates to capsule/tendon/bone is required.  
Additionally, a determination of whether the ulcer is partial or full thickness and if there 
is exposure of capsule, tendon, or bone will be documented. 
The location of the study ulcer will be documented according to foot (left or right), 
surface (plantar or dorsal), and area (forefoot, midfoot, hindfoot [with the hindfoot area 
to include the calcaneus], ankle [with no portion above the top of the malleolus]).   
If the subject has more than one qualifying DFU, the ulcer designated as the study ulcer 
will be at the discretion of the investigator.  

 
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5.7.2. Ulcer Exudate Assessments 
The investigator will determine the amount and type, if any, of study ulcer exudate. In 
determining the amount of study ulcer exudate, the investigator must take into account 
the amount of exudate absorbed into the study ulcer dressing.  The following categories 
will be used to quantify the amount of ulcer exudate: 
• 
Not applicable: No exudate 
• 
Minimal amount 
• 
Light (scant) or small amount 
• 
Moderate amount 
• 
Heavy/large/copious amounts 
 
The following categories will be used to describe the type of exudate: 
• 
Serous: clear or light yellow watery plasma 
• 
Serosanguineous: pink to light-red watery plasma 
• 
Sanguineous: red with fresh bleeding 
• 
Purulent: thick and opaque exudate, of creamy yellow, green, white, or tan color 
 
5.7.3. Ulcer Infection Assessment 
The presence/absence of infection at the study ulcer site will be documented at each 
visit.
IMPORTANT:  If the study ulcer is considered infected during the screening phase, or at 
Randomization visit (TV1), the subject is considered a screen fail and is excluded from 
participation in the trial at that time.  The infection must be treated, and symptoms 
resolved before the subject may be re-screened (one time only, according to Section 
6.1.2).  Additionally, and per exclusion criterion 2, the subject must not be taking 
antibiotics for a DFU infection. 
If the study ulcer becomes infected after the subject is randomized, it must be recorded 
as an AE.  The study ulcer infection may be treated, per investigator judgement, and the 
subject may remain in the study unless a prohibited medication or treatment is used (see 
Section 5.14.1).   
PriMatrix is contraindicated for infected ulcers.  In the event of a study ulcer infection in 
the PriMatrix treatment group, PriMatrix may be re-applied after the study ulcer 
infection has been treated and no longer demonstrates signs/symptoms of the infection.   
All infections will be followed until resolved or the subject is withdrawn or discontinued. 
If an infection progresses to tissue necrosis requiring deep debridement which exposes 
bone, tendon or capsule, the subject must be withdrawn.  

 
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In no case, does the presentation of infection alter the study schedule of events nor allow 
the subject additional days of treatment. 
5.8. 
Study Ulcer Photography 
Photographs of the study ulcer are required at each visit except Unscheduled Visits.  The 
investigator will take a digital photograph using the study-supplied imaging system.  At 
minimum, pre-debridement photographs of the study ulcer are to be taken at every visit.   
Additionally:  
• 
At SV1 and Randomization/TV 1 (Day 0), post-debridement images are required.   
• 
Further, and if the subject is randomized to the Active Treatment cohort, 
photographs of the PriMatrix product after application are required. 
Ulcer photographs are being obtained for ulcer measurements, documentation, and archival 
purposes and may also be used in educational and/or marketing materials. 
Note: Specific imaging instructions are explained in a separate manual.   
5.9. 
Sharp Debridement 
Only sharp debridement is permitted in this study and includes debridement of all non-living 
or contaminated tissue from the wound bed.  All callus should be removed, and any 
undermined or tunneled areas explored to ensure exposure of the full wound bed.  Broad area 
cauterization should be avoided.  Anesthetics are permitted during debridement.  
IMPORTANT: Sharp debridement of the study ulcer is required at SV1 and Randomization/TV 
1 (Day 0).   
Sharp debridement includes removal of: 
• 
the surrounding callus 
• 
All non-viable tissue, as evidenced by punctate bleeding across the wound bed 
At visits other than SV1 and Randomization and if needed, sharp debridement should be 
performed to: 
• 
Remove callus or devitalized tissue 
• 
Remove infected tissue 
Whenever debridement is performed, details of debridement will be captured on the eCRF 
(i.e., reason(s) for performing debridement, type of debridement performed, and method used 
for debridement). 
5.9.1. Debridement Certification 
Each investigator and sub-investigator who will be debriding subjects for the trial is 
required to complete debridement certification prior to debriding subjects.   

 
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Certification will consist of the investigator providing a photograph of a non-study 
patient* they have debrided.  This photograph will be evaluated by the Lead 
investigator or sponsor approved personnel.  If debridement is acceptable, the 
investigator/sub-investigator will receive documentation of approval from the 
sponsor.  If debridement is not acceptable, feedback will be provided to the 
investigator/sub-investigator and the process will be repeated.  This will continue until 
the debridement technique is satisfactory.  Satisfactory verification of training must 
occur prior to enrollment of first subject.   
∗ 
An exception may be made in the case of an ethics board that does not allow for 
transmission of images for non-study subjects.  In this case, the first study subject 
debrided by the investigator will serve as the certification subject.  If the 
debridement on this subject is not certified, the subject is screen failed.  As above, 
the process repeats until a sufficiently debrided image is produced.  
The images in figure 2 have been supplied to provide examples of acceptable and 
unacceptable debridement. 
 
5.10. Ulcer Measurements 
5.10.1. Computerized Planimetry 
Ulcer measurements are required at each visit. The study DFU area will be determined 
by computerized planimetric analysis of digital photographs using software created 
by an external vendor.  
The software allows the user to capture digital ulcer images and generate area 
measurements. Data collected by the software will be uploaded to a central server. 
All ulcer assessment data will be organized as a patient record on a central server and 
available for review and reporting.   To ensure consistency between sites, training for 
procedures will be provided by a representative from the external vendor or by a 
trained sponsor representative. A manual containing information regarding how to 
use the software will be provided to the sites. 
Unacceptable 
Acceptable Debridement 
Figure 2: Images of Acceptable Debridement 
Before
After
Before                      After 

 
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In addition, measurements will be performed by the investigator or qualified site staff 
at each visit.   
5.10.2. Ulcer Area Reduction 
Percent change in study ulcer area from the post-debridement SV1 to post 
debridement randomization will be calculated by the imaging vendor using 
computerized planimetry of images taken of the ulcers.   
At the Randomization/TV 1 (Day 0), ulcer area reduction will be used to qualify the 
subject for randomization and study enrollment.  The reduction in study ulcer area 
may not exceed 30% after sharp debridement in order for the subject to be 
randomized.  
5.11. Standard of Care (Control) Treatment 
During the Screening Phase of the study, all subjects will have SOC products applied by the 
investigative site at the weekly visits. They will be then instructed on how to change their 
dressings on a daily basis.  After randomization, only subjects who are randomized to the SOC 
cohort will continue daily dressing changes. Those subjects in the Active Treatment cohort will 
only have their dressings changed weekly at follow-up visits until the investigator determines 
that their wound has closed.  If the wound closes on or before treatment visit 13, offloading (if 
previously utilized for that subject) will continue without dressings during the follow-up period. 
Application of the dressings & boot by the Investigator: 
1. 
Gently remove any dressing previously applied to the wound and clean the area with a 
gentle cleanser. 
2. 
If appropriate, debridement and hemostasis will be performed. (Note: in this study only 
sharp debridement will be used) 
3. 
During Screening and for SOC-randomized subjects: Instruct the subject on the proper 
way to change dressing 
• 
Inspect the wound and perform study assessments as directed elsewhere 
4. 
Apply normal saline gel to the thickness of a coin. 
5. 
Cover the gel with a foam dressing. 
6. 
Secure the foam dressing with conforming roller gauze. 
7. 
Cover the roller gauze with Coban. 
8. 
For subjects who have ulcers that require offloading, apply the boot. 
Daily Changing of the Dressings by the Subject: 
1. Remove boot, if applicable 
2. Gently remove dressings 
3. Clean the wound with tap water and pat the area dry 

 
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4. Inspect the wound 
a. Subject will contact the site by phone if they believe there is anything wrong with the 
wound. 
5. Apply normal saline gel to the thickness of a coin. 
6. Cover the gel with a foam dressing. 
7. Secure the dressings with conforming roller gauze. 
8. Cover the roller gauze with Coban. 
9. For subjects who have ulcers that require offloading, re-apply the boot.  
Note: Subjects who use the offloading boot will be instructed that it is to be worn at all times 
except when bathing or sleeping. 
5.12. Compliance with Offloading & Dressing Changes 
At SV1, and as indicated in Section 5.11 above, subjects will be instructed on the proper use of 
the off-loading/protective device and in the proper procedures for dressing changes and care 
as required by the treatment assignment.  At SV2 through TV13 and unscheduled visits, the 
subject will be queried about their compliance with dressing changes and offloading, as 
prescribed.  If subject non-compliance is noted, documentation of the incident will be 
recorded.  If continued non-compliance is detected, the subject may be withdrawn from the 
study at the discretion of the investigator and/or sponsor.   
5.13. Appropriate Off-loading/Protective Device  
The off-loading/protective device to be used in this study will be provided by the sponsor 
through a specific distributor. This off-loading/protective device will be used by all subjects 
with study ulcers located on the plantar or lateral surfaces of the foot (i.e., any location 
experiencing weight-bearing or shear forces) throughout the Screening, Treatment and Follow-
up phases.   
All subjects enrolled in this study are required to use the sponsor-provided off-
loading/protective device for the duration of their participation (see Inclusion Criteria 9).   
Off-loading devices MUST be continually used throughout the entire duration that the subject 
is enrolled in the study.   
Note:  If a subject is wheelchair bound, meaning that their primary form of locomotion is in the 
wheelchair, the offloading boot will not be required.  If at any point in time, the subject ceases 
to be wheelchair bound, they will begin using the offloading boot if necessary. 
Subjects with ulcers located on non-weight bearing surfaces (i.e., the dorsum of the foot) may 
use the provided off-loading boot as a protective device or may use another form of protective 
foot wear.  The off-loading/protective device used will be noted in the eCRF. 

 
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Complete compliance information on the use of the off-loading/protective device by the 
subject will be collected by the study staff at each visit via subject interviews. Off-loading 
information collected will include type of off-loading/protective device used, number of hours 
per day that the device was not used since the last study visit and what proportion of that time 
involved weight-bearing, and any problems or issues with the off-loading/protective device. 
Subjects will be instructed to wear the off-loading/protective device at all times, except during 
sleeping, bathing, or showering.  
5.14. Concomitant Medications and Non-Study Treatments  
Only therapies/medications that may impact healing, are related to AEs (e.g., 
antibiotics/antimicrobials, surgical excision/amputation) or linked to DM (i.e., insulin and oral 
hypoglycemics) will be collected.  These medications/therapies administered or taken by the 
subject beginning 28 days prior to signing the ICF and throughout the study will be recorded in 
the source documents and, for randomized subjects, on the appropriate eCRF. For each 
medication and non-study treatment, the following will be documented: 
• 
Medication/treatment name (generic name may be used if trade name is unknown) 
• 
Dose, unit, and frequency of dosing (individual dosage, not total daily dose).  
• 
Each new dose of medication should be recorded as a separate entry, with the 
exception of medications that are given on a sliding scale. For these, it is acceptable to 
enter the range of the dosage, including the start and stop dates for which the specified 
dosage range was used. 
• 
Route of dosing 
• 
Indication for use 
• 
The start date  
• 
Whether the medication is ongoing or was discontinued 
• 
The stop date (if medication/therapy is not ongoing) 
• 
Adverse event number (if applicable) 
 
5.14.1. Prohibited Medications and Therapies 
The following treatments/medications/procedures are prohibited during the subject 
participation in this study, beginning with the first Screening Visit (SV1) and should 
they be medically required, the subject must be discontinued from the study. 
To the study ulcer: 
• 
Application of growth factors, engineered tissues or skin substitutes, other 
than the Active Treatment (PriMatrix), including but not limited to: Regranex® 
(Smith & Nephew), Dermagraft® (Organogenesis), Apligraf® (Organogenesis), 
EpiFix (MiMedx), AMNIOEXCEL (Integra), GraftJacket® (KCI, an Acelity 
Company), OASIS (Smith & Nephew), MatriStem® (ACell), Omnigraft® (Integra 

 
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LifeSciences), or Integra BMWD® (Integra LifeSciences) Enzymatic debriding 
agents 
• 
Topical Oxygen Therapy 
• 
Negative Pressure Wound therapy 
 
To the subject: 
• 
Systemic investigational treatment/medications 
• 
Dialysis 
• 
Immunosuppressive agents 
• 
Systemic steroids/oral corticosteroids (>25mg/d for >3 days) (Note: inhaled 
steroids are acceptable) 
• 
Autoimmune disease therapies 
• 
Radiation therapy to the foot 
• 
Cytostatic drugs 
• 
Vascular surgery of the affected limb 
• 
Thrombolysis and/or angioplasty 
 
Only dressing materials provided by the sponsor may be used on the target ulcer.  
Ulcer dressings that have not been provided by the study sponsor for use in the trial 
may be used on ulcers that are NOT designated as the study ulcer.   
5.15. Adverse Events  
5.15.1. Definitions 
An adverse event (AE) is defined as any untoward medical occurrence occurring in a 
clinical trial. An AE does not necessarily have a causal relationship with the device. A 
device-related AE can be any unfavorable and unintended sign, symptom, or disease 
temporally associated with the use of a study device, whether or not related to the 
device.  
For the purposes of this study, only AEs that are possibly, probably, or definitely 
related to the study ulcer, study treatment, and/or study procedures are to be 
recorded. All events starting or worsening beginning at SV2 through Treatment Visit 
Week 13 and unscheduled visits will be collected. Follow-up treatment and evaluation 
should continue until the AE has resolved or until 2 weeks after the final visit, 
whichever occurs first. 
AEs not related or unlikely related to the study treatment, study ulcer and/or study 
procedures are not to be recorded for this study.   
A Serious Adverse Event (SAE) is defined as any AE that: 
• 
Results in death 

 
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• 
Is life threatening (the subject is at immediate risk of dying from the adverse 
experience) 
• 
Requires subject hospitalization or prolongs existing hospitalization 
• 
Results in persistent or significant disability/incapacity  
• 
Is a congenital anomaly/birth defect 
• 
Important medical events that may not result in death, be life-threatening, or 
require hospitalization may be considered a serious adverse device effect 
when, based upon appropriate medical judgment, they may jeopardize the 
subject or subject and may require medical or surgical intervention to prevent 
one of the outcomes listed in this definition. 
For the purposes of this study, only SAEs that are possibly, probably, or definitely 
related to the study ulcer, study treatment, and/or study procedures are to be 
recorded. All events starting or worsening after the first randomized treatment 
through Treatment Visit Week 12 will be collected. Follow-up treatment and 
evaluation should continue until the SAE has resolved or until 2 weeks after the final 
visit, whichever occurs first. 
SAEs not related or unlikely related to the study treatment, study ulcer and/or study 
procedures are not to be recorded for this study.   
5.15.2. AE Severity Assessments 
The guidelines outlined in Table 1 will be used for severity assessments.  
Note: The term “severe” is a measure of intensity and a severe AE is not necessarily 
serious. 

 
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Table 1 Adverse Event Severity – Description of Severity Grades 
Severity 
Grade 
Description 
Mild  
Symptoms barely perceptible by the patient, do not affect his/her 
performance or activity, do not normally require the administration 
of drugs for relief of the symptoms but they may, however, be 
administered depending on the patient’s needs. 
Moderate  
Symptoms sufficiently serious to cause patient discomfort, having 
impact on the performance of daily activities; the patient may be 
able to continue in the study, but it may be necessary to treat the 
symptoms. 
Severe  
Symptoms cause serious discomfort and they may be serious to a 
degree that the patient may not be able to continue in the study; 
treatment may be administered for the symptoms and/or the 
patient hospitalized. 
 
5.15.3. Adverse Event Relatedness Assessments 
All AEs will be assessed for their relatedness to the study device or the procedures.  An 
AE is considered device-related if there is a reasonable possibility that the device 
caused or contributed to the event. Information that “reasonably suggests” a causal 
relationship includes any information such as professional, scientific or medical facts 
and observations or opinions that would reasonably suggest that a device has caused 
or may have caused or contributed to the event. If the chance that a device may have 
caused or contributed to an event is very remote or very unlikely, the event should be 
considered not related to the device.  
AE causality will be assessed using the guidelines outlined in Table 2. 
Table 2: Adverse Event Causality Categories 
Relationship 
Comment 
Definitely 
 
This category applies to those AEs which the investigator feels are 
incontrovertibly related to the study treatment, study ulcer or study 
procedures. An AE may be assigned an attribution of definite if or when 
(must have all three): 
a) It follows a reasonable temporal sequence from application of the 
device. 
b) It could not be reasonably explained by the known characteristics of 
the subject’s clinical state, environmental or toxic factors or other 
modes of therapy administered to the subject. 
c)    It follows a known response pattern to treatment with the device. 

 
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Probable 
This category applies to those AEs which, after careful medical 
consideration at the time they are evaluated, are felt with a high degree of 
certainty to be related to the device. An AE may be considered probable if 
or when (must have three): 
a) It follows a reasonable temporal sequence from application of the 
device. 
b) It could not readily have been produced by the subject’s clinical 
state, environmental or toxic factors, or other therapies administered 
to the subject. 
c) Disappears or is decreased upon removal of the device. 
d) It follows a known response pattern to treatment with the device. 
Possibly 
 
This category applies to those AEs which, after careful medical 
consideration at the time they are evaluated, are judged unlikely but 
cannot be ruled out with certainty to the device. An AE may be considered 
possible if or when (must have two): 
a) It follows a reasonable temporal sequence from application of the 
device. 
b) It could not readily have been produced by the subject’s clinical 
state, environmental or toxic factors, or other therapies administered 
to the subject. 
c) 
Disappears or is decreased upon removal of the device. 
d) It follows a known response pattern to treatment with the device. 
Unlikely 
 
In general, this category can be considered applicable to those AEs which, 
after careful medical consideration at the time they are evaluated, are 
judged likely to be unrelated to the device. An AE may be considered 
unlikely if or when (must have two): 
a) It does not follow a reasonable temporal sequence from application 
of the device.   
b) It could not readily have been produced by the subject’s clinical 
state, environmental or toxic factors, or other therapies administered 
to the subject. 
c) Disappears or is decreased upon removal of the device. 
d) It does not follow a known or expected response pattern to 
treatment with the device. 
Unrelated 
 
This category applies to those AEs that, after careful consideration, are 
clearly and incontrovertibly due to extraneous causes (disease, 
environment, etc.) and determined with certainty to have no relationship 
to the study device. 
5.15.4. Adverse Event Expectedness 
If an AE is determined to be serious and related, either possibly, probably, or definitely 
related, to the study device or procedure, a determination of expectedness will be 
made.  Expectedness is specifically related to the functioning of the product or the 
conduct of the procedure and is NOT related to whether the study team perceived that 
the AE might have happened in the subject.  That is, the question is “Have we seen this 
SAE in relation to the product/procedure?” and is not “Did we think this SAE would 
happen in this subject?”.   

 
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A SAE is expected, that is “Anticipated” if the SAE is (1) related to the product or 
procedure and (2) the nature, severity, or frequency of the SAE has been seen 
previously either in personal experience or documented in literature.  Note: The vast 
majority of related SAEs are Anticipated. 
Conversely, a SAE is not expected, that is “Unanticipated” if the SAE is (1) related to 
the product or procedure and (2) the nature, severity, or frequency of the SAE has NOT 
been seen previously either in personal experience or documented in literature.  Note: 
The vast minority of related SAEs are unanticipated. 
Therefore, an unanticipated adverse device effect (UADE) is defined as any serious 
adverse effect on health or safety or 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 investigational plan or IFU, 
or any other unanticipated serious problem associated with a device that relates to 
the rights, safety, or welfare of subjects.  
The decision tree in figure 3 should be used when determining expectedness.  
For the purposes of this study, the following AEs commonly occur in individuals with 
DM and DFUs and are thereby defined as Anticipated if they were to occur:    
• 
Ulcer enlargement, tunneling 
and/or undermining  
• 
Malodor 
• 
Erythema 
• 
Edema 
• 
Maceration 
• 
Excessive drainage 
• 
Development of a new ulcer,  
• 
Ulcer infection or abscess,  
• 
Osteomyelitis 
• 
Trauma/falls and  
• 
Amputation 

 
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Questions about any AEs or SAEs should be directed to the sponsor for clarification; 
however, the ultimate decision for grading severity and expectedness resides with the 
study investigators. 
 
5.15.5. Adverse Event Reporting Procedures  
All AEs related to study treatment, study ulcer and/or study procedures spontaneously 
reported by the subject and/or in response to an open question from study personnel 
or revealed by observation, physical examination or other diagnostic procedures will 
be evaluated.   
At each visit, after the subject has had the opportunity to spontaneously mention any 
problems, the investigator should inquire about AEs by asking standard questions such 
as: 
• 
“Have you had any (other) medical problems since your last visit / assessment?” 
• 
“Have you taken any new medicines since your last visit /assessment?” 
The following AEs will be recorded on the appropriate eCRF: 
• 
All AEs related to study treatment, study ulcer and/or study procedures occurring 
after the 1st randomization treatment. 
Is the  
nature, severity, or 
frequency of the SAE 
consistent with the risk 
information previously 
described for the 
product or procedure? 
Yes 
Is the AE Serious? 
Is the SAE  
Product Related? 
Yes 
Expectedness 
is Not 
Applicable 
Is the SAE  
Procedure Related? 
No 
No 
No 
Yes 
This SAE is 
ANTICIPATED 
Report to 
EDC 
Yes 
This SAE is UNANTICIPATED 
REPORT TO THE SPONSOR WITHIN 10 
BUSINESS DAYS via the EDC system.  
Check and Follow IRB Reporting 
Requirements. 
No 
Start 
Figure 3: SAE Expectedness Determination Decision Tree 

 
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• 
All SAEs occurring after signing of ICF through the last study visit 
When possible, signs and symptoms indicating a common underlying pathology should 
be noted as one comprehensive event. 
Special instructions for SAEs 
Study centers are instructed to report SAEs to Integra within 5 business days of 
becoming aware of the SAE.  
SAEs must be reported by the investigator to Integra by completing the eCRF SAE Form. 
Only SAEs that are considered causally related to the study device or procedures need 
to be reported.  Reporting will utilize the standard AE eCRF.  Note: Follow-up 
information on the SAE may be requested by the sponsor. 
5.15.6. Adverse Event Follow-up 
All AEs will be followed until resolution or stabilization to the best of the site’s ability.  
Any subjects reporting SAEs that have not resolved by their last treatment visit will be 
followed via phone or clinic visit through resolution or 14 days post final visit, 
whichever comes first. 
5.16. Method for Assigning Eligible Subjects to Treatment (i.e., Randomization) 
Once it has been determined that a subject meets all eligibility criteria, subjects will be 
assigned to one of the following treatment groups, based on a randomization schedule 
provided by the sponsor. 
Randomization is accomplished through the Clindex EDC system.  After entering your name 
and password, you will go into the RDE System and click on Subject List or Visit Manager.  After 
selecting the subject to be randomized, click on the Randomization eCRF in the Randomization 
Visit.  You will be asked to answer the following: 
• 
Did the subject meet all eligibility criteria?  
o Select Yes if eligible 
o Select No if not eligible 
• 
Is the percent ulcer reduction ≤ 30%* since the initial screening visit?  
o Select Yes if the ulcer decreased in size less than or equal to 30% or if the ulcer 
got bigger 
o Select No if the area of the ulcer decreased in size more than 30% during the 
screening period 
o Enter the size of the decrease or increase 
• 
Is the area of the study ulcer between 1cm2 and 12cm2*? 
o Select Yes if between 1 and 12cm2 

 
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o Select No if not between 1 and 12cm2 
o Enter the size of the ulcer area. 
*Important: Rounding up or down is not allowed to achieve eligibility.  For 
instance, if the ulcer decreased 30.1% between SV1 and Randomization, the 
subject is still ineligible for randomization.  Similarly, if the area of the wound is 
0.99cm2 at either SV1 or Randomization, the subject is ineligible. 
After all of the questions have been answered, you will click on the Save button.  Click “Yes” 
on each of the following pop-up screens.  A third screen will pop up with the randomization 
group: Active or Control.  The active treatment is the PriMatrix product (see Section 5.17 
below).  The control treatment is SOC that has been used during the past two screening visits.   
5.17. Active Treatment 
5.17.1. PriMatrix Dermal Repair Scaffold Disposition, Storage and Accountability 
PriMatrix will be supplied sterile, in single use, double peel packages.  For the 
purposes of this study, it will only be supplied in 4 x 4cm, meshed sheets with 1 sheet 
per box.  Once received, PriMatrix should be stored at ambient conditions and has a 
shelf life of five years.  Upon receipt, each piece will be logged on the Device 
Accountability Log, which will be updated each time PriMatrix is used.   
The investigator will also use the device accountability log to maintain current and 
accurate inventory records covering the dispensing and the disposal of the study 
devices.  At the conclusion of the study, the investigator must agree to return or 
destroy all study device materials as instructed by the sponsor.   
5.17.2. PriMatrix Application Training 
All investigators and Sub-investigators who will be applying PriMatrix for the trial will 
be trained on the use of the study device, PriMatrix, for the management of DFUs, 
along with other study-related procedures.   
5.17.3. PriMatrix Application 
Active treatment for this trial is PriMatrix Dermal Repair Scaffold plus secondary 
dressings to maintain a moist wound environment and an appropriate off-
loading/protective device.  After randomization, subjects assigned to the active 
treatment group will not perform any dressing changes but rather have their 
dressings changed weekly at the site.   
PriMatrix and secondary dressing kits will be provided to the site.  Dressing kits will 
be used on every subject at each dressing change.  PriMatrix is ONLY to be applied to 
a freshly debrided ulcer with punctate bleeding and will always be handled using 
aseptic technique. PriMatrix will be rehydrated using a sterile saline solution at room 
temperature and allowed to soak for at least 2 minutes. The product should be kept 
in the solution until ready for application.  

 
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Once ready to apply, the product will be cut to fit the ulcer bed and applied 
immediately following ulcer bed preparation and hemostasis.  Note: PriMatrix should 
turn red as it absorbs the blood from the debrided wound bed (Figure 4).  If the 
PriMatrix is white, debridement is likely insufficient.  As well, it is critical that the 
PriMatrix be in direct contact with the ulcer bed.  Any air bubbles should be carefully 
removed by gentle rolling with a moistened cotton tip application.  PriMatrix should 
be secured in place with adhesive strips, staples, sutures or bolster. 
 
Secondary dressings, supplied by the sponsor will include the following and should be 
applied as follows:  
1. Non-adherent contact layer  
2. Bolster of saline moistened gauze (if necessary to maintain intimate contact 
between PriMatrix and ulcer bed)  
3. 0.9% sodium chloride gel applied over contacting non-adherent layer, if 
necessary to maintain a moist wound environment  
4. Non-adhesive foam  
5. Elastic gauze  
6. Self-adherent wrap  
 
Care should be taken to ensure that the 0.9% sodium chloride gel is applied only to 
the ulcer bed and not to the intact skin on the ulcer perimeter.   
5.17.4. 
PriMatrix Re-Application  
PriMatrix may be reapplied a second time, if appropriate, based upon the 
investigator’s judgement, given the clinical assessment of the ulcer. PriMatrix may be 
replaced if any of the following are satisfied:     
• 
At any point, the PriMatrix is non-adherent or sloughing,  
Inadequate Absorption 
Adequate Absorption 
Figure 4: PriMatrix Application 

 
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• 
At any point, PriMatrix is lost due to infection. The infection will be treated 
and resolve before PriMatrix is replaced.   
• 
If at 4-weeks after initial application, the rate of closure is 30% or less.   
IMPORTANT: If the investigator feels a third application of PriMatrix is necessary 
during the trial, the Integra Clinical Research Manager or site’s CRA must be 
consulted prior to reapplication.  Note that review of these requests may take up 
to 1 day, so the subject may need to return the next day for re-application. 
The reason for PriMatrix loss/reapplication will be recorded in the source document 
and eCRF.  All PriMatrix applications must be documented on the Device 
Accountability Form. 
When replacing PriMatrix, follow application procedures described in Section 5.17.3 
of this protocol. 
5.18. Investigator Assessments of Ulcer Closure 
Complete wound closure is defined as 100% re-epithelialization of the ulcer surface without 
detectable exudate, confirmed on 2 consecutive study visits 1 week apart (i.e., Treatment Visit 
where 100% re-epithelialization of the ulcer surface without detectable exudate was initially 
documented and the Closure Confirmation Visit).  For efficacy analyses, the first date of 
assessment of 100% re-epithelialization of the ulcer surface without detectable exudate will 
be used as the date of closure. 
If, at Treatment Week 12, the ulcer remains open, the investigator will document why, in his 
opinion, the ulcer did not close.  
5.19. Investigator Assessment of Ulcer Recidivism 
If, following confirmed ulcer closure, the ulcer is open at the 4-week Follow-up visit, the 
investigator will document why, in his/her opinion, the ulcer re-opened.  NOTE: The subject 
will not re-enter the study at this visit.  According to section 6.2.3, subjects can re-enter the 
study at the Confirmation Visit if the wound reopens.  This opportunity is not available at the 
4-week Follow-up visit. 

 
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6. Study Activities by Phase and Visit 
The schedule for the protocol-specific assessments and procedures in each phase are detailed below 
and are summarized in Table 3: Schedule of Events. Detailed descriptions of these assessments and 
procedures have been previously defined in Section 5. 
The results from all of the assessments and procedures discussed in the sections below will be 
recorded in source documents and on the appropriate eCRF.   
6.1. Screening Phase  
6.1.1. Screening Visit 1 (SV1) 
At SV1, the following data will be collected, or activities performed: 
1. Informed Consent and HIPAA Authorization 
o Note: Once the ICF and HIPAA authorization are signed, the screening 
assessments/activities identified must be completed within a 30-day window 
from the date of ICF signature. Further, all screening assessments/procedures 
must be completed on the same day, and that date will constitute the first day of 
the screening phase.  
2. Review of Inclusion and Exclusion criteria for eligibility 
3. Demographics  
4. Medical history, medications, and non-study treatments  
5. Physical exam (including vital signs, height and weight) 
6. Vascular perfusion  
7. Perform ulcer assessments  
8. Photograph the study ulcer pre-debridement 
9. Perform ulcer measurements pre-debridement 
10. Perform sharp debridement of the study ulcer  
11. Photograph of the study ulcer post-debridement 
12. Perform ulcer measurements post-debridement  
13.  Apply SOC treatment to the ulcer (see Section 5.11 for specific application processes) 

 
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14. Discuss treatment compliance with the subject 
15. If appropriate, apply the off-loading/protective device and discuss compliance 
with its use 
16. Document applicable Concomitant Medications noted by the subject or seen within 
the subject’s medical records (see Section 5.14 for information on which medications 
require documentation). 
*Remember to schedule the next visit for SV2, 7±3 days from SV1. 
6.1.2. Screening Visit 2 (SV2) 
Screening Visit 2 assessments and procedures are summarized in Table 3.  At SV2 the 
following data will be collected, and procedures performed: 
1. Review Inclusion and Exclusion criteria for continued eligibility 
2. Medical Resource Utilization assessment will be performed (see Section 5.3 for 
specific information on how to perform this assessment). 
3. Ask subject about compliance with the treatment during the previous week 
4. Perform ulcer assessments  
5. Photograph the study ulcer pre-debridement 
6. Perform ulcer measurements pre-debridement 
7. Perform sharp debridement of the study ulcer, if necessary per investigator 
discretion.  
8. Photograph of the study ulcer post-debridement, if debridement occurred. 
9. Perform ulcer measurements post-debridement, if debridement occurred. 
10. Apply SOC treatment to the ulcer (see Section 5.11 for specific application processes) 
11. Discuss treatment compliance with the subject 
12. If appropriate, apply the off-loading/protective device and discuss compliance with 
its use 
13. Document applicable Concomitant Medications noted by the subject or seen within 
the subject’s medical records (see Section 5.14 for information on which medications 
require documentation). 
14. Document any applicable AEs as noted by the subject or as documented in their 
medical record (see Section 5.15 for information on which AEs require 
documentation).  
* Remember to schedule the next visit for Randomization/TV 1 (Day 0), 14±3 days from 
SV1.  
IMPORTANT: If a subject initially fails to meet inclusion/exclusion criteria, e.g., because the ulcer 
is too large or is infected, and is later reconsidered for participation, the subject will be re-

 
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consented and assigned a new screening number at the time of re-screening.  Subjects who fail 
their first screening attempt may be re-screened a maximum of one time and may be entered 
into the study a second time if they are found to meet ALL inclusion and NO exclusion criteria. 
6.2. Treatment Phase 
The treatment phase of the study begins when the subject completes the two-week screening 
phase, meets all eligibility criteria, and is randomized.  
During this phase, subjects will return to the clinic every 7±3 days for up to 13 weeks or until 
confirmed ulcer closure. When determining the visit dates, the reference should always be to 
the Randomization/TV 1 (Day 0) date and not the subject’s previous visit.  Every attempt should 
be made to maintain subjects on their original treatment schedule.  
The schedule of assessments for the treatment phase of the study is provided in Table 3.  Detailed 
descriptions of these assessments and procedures have been previously defined in Section 5. 
6.2.1. Randomization/TV 1 (Day 0) 
1. Review Inclusion and Exclusion criteria for eligibility 
• 
Important: The final exclusion criteria will only be determined after debridement 
and measurement as detailed below in this Section. 
2. Medical Resource Utilization assessment will be performed (see Section 5.3 for 
specific information on how to perform this assessment). 
3. As subject about compliance with the treatment during the previous week 
4. Perform ulcer assessments  
5. Photograph the study ulcer pre-debridement 
6. Perform ulcer measurements pre-debridement 
7. Assess the ulcer for wound closure status 
• 
If the wound is closed, the subject is exited at this point; complete the study 
exit form. 
8. Perform sharp debridement of the study ulcer 
9. Photograph of the study ulcer post-debridement 
10. Perform ulcer measurements post-debridement 
11. Document ulcer size reduction 
12. Complete the randomization process in the EDC system. 
13. Apply either SOC or the Active treatment to the ulcer, depending on the cohort that 
is assigned during the randomization process (see Section 5.16 for specific application 
processes) 

 
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14. Discuss treatment compliance with the subject 
15. If appropriate, apply the off-loading/protective device and discuss compliance with 
its use 
16. Document applicable Concomitant Medications noted by the subject or seen within 
the subject’s medical records (see Section 5.14 for information on which medications 
require documentation). 
17. Document any applicable AEs as noted by the subject or as documented in their 
medical record (see Section 5.15 for information on which AEs require 
documentation).  
* Remember to schedule the next visit for Treatment Visit Week 2, 7±3 days from 
Randomization/TV 1. 
6.2.2. Subsequent Treatment Phase Visits (TVs 2 through 13) 
The subject will return every 7±3 days for treatment visits for 13 weeks or until the ulcer 
is confirmed closed, whichever occurs first.   The following data will be collected, and 
procedures performed:   
1. Medical Resource Utilization assessment will be performed (see Section 5.3 for 
specific information on how to perform this assessment). 
2. As subject about compliance with the treatment during the previous week 
3. Perform ulcer assessments  
4. Photograph the study ulcer pre-debridement 
5. Perform ulcer measurements pre-debridement 
6. Assess the ulcer for wound closure status 
• 
If criteria for complete wound closure are met at a visit, the subject will return 
to the clinic 7±3 days for a Confirmation Visit.  If the first assessment of 
complete wound closure occurs at the Week 12 Visit, a Confirmation visit will 
be required at 7±3 days to confirm complete wound closure. 
• 
If criteria for complete wound closure are not met and the subject has not 
yet completed 13 weeks of treatment the subject will be instructed to return 
to the clinic in 7±3 days for the next visit in the treatment phase. 
• 
If criteria for complete wound closure are not met, but the subject is at 
Treatment Visit 13, the subject will not have items 7 through 12 below  
completed; the subject has completed their study requirements and is to be 
exited.  
7. Perform sharp debridement of the study ulcer, if necessary per investigator 
discretion.  
8. Photograph of the study ulcer post-debridement, if debridement occurred. 
9. Perform ulcer measurements post-debridement, if debridement occurred. 

 
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10. Apply either SOC or the Active treatment to the ulcer, depending on the cohort that 
is assigned during the randomization process (see Section 5.11 or 5.17 for specific 
application processes of SOC or Active treatment, respectively.) 
11. Discuss treatment compliance with the subject 
12. If appropriate, apply the off-loading/protective device and discuss compliance with 
its use 
13. Document applicable Concomitant Medications noted by the subject or seen within 
the subject’s medical records (see Section 5.14 for information on which 
medications require documentation). 
14. Document any applicable AEs as noted by the subject or as documented in their 
medical record (see Section 5.15 for information on which AEs require 
documentation).  
15. investigator assessment for Complete Wound Closure (Section 5.18).  
* Remember to schedule the next Treatment Visit (TV) if the wound is still open and the current 
visit is not TV 13.  If the subject’s ulcer is not closed at TV 13, the subject is exited; complete the 
study exit form.  If the wound is closed on or before TV13, schedule the Closure Confirmation 
Visit (Section 6.2.3). 
6.2.3. Closure Confirmation Visit (7±3 days after ulcer determined to be closed) 
Closure Confirmation assessments and procedures are identified in Table 3. 
1. Medical Resource Utilization assessment will be performed (see Section 5.4 for 
specific information on how to perform this assessment). 
2. Perform ulcer assessments  
3. Photograph the study ulcer 
4. Assess the ulcer for wound closure status 
5. Document any applicable AEs as noted by the subject or as documented in their 
medical record (see Section 5.15 for information on which AEs require 
documentation).  
Special Instructions: If the subject returns for the closure confirmation visit AND the ulcer 
has reopened AND Treatment Visits 12 or 13 has not yet been reached, the subject re-
enters the study at the visit after the previously scheduled next visit (e.g., if the ulcer 
closed at TV9, but at the Confirmation Visit the ulcer is reopen, the subject re-enters at 
TV11).  The subject will then return every 7±3 days for up to 13 weeks or until the ulcer 
closure is confirmed, whichever occurs first.  This process repeats until all treatment visits 
are used up.  If the subject’s wound is closed on TV 12 or 13, but is open at the 
Confirmation Visit they do not re-enter the study and are exited. 
* Remember to schedule the next Treatment Visit or the 4-Week Follow-Up visit as 
appropriate. 

 
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6.2.4. 4-Week Follow-Up Visit (28±3 days after Confirmation Visit) 
The 4-week follow-up visit assessments and procedures are identified in Table 3. 
1. Perform ulcer assessments  
2. Photograph the study ulcer 
3. Assess the ulcer for wound closure status 
6.2.5. Unscheduled Visits 
IMPORTANT: Unscheduled visits are to ONLY be used when a subject has an unexpected 
clinic visit that falls outside the next visit window.  If the date of the unexpected visit falls 
within the window of the next regular visit, the procedures for that visit will be followed. 
In the event an unscheduled visit occurs, the following will be occur: 
1. Perform ulcer assessments  
2. Perform sharp debridement of the study ulcer, if necessary per investigator 
discretion.  
3. Apply either SOC or the Active treatment to the ulcer, depending on the cohort that 
is assigned during the randomization process (see Section 5.11 or 5.17 for specific 
application processes of SOC or Active treatment, respectively.). 
4. Discuss treatment compliance with the subject 
5. If appropriate, apply the off-loading/protective device and discuss compliance with 
its use 
6. Document applicable Concomitant Medications noted by the subject or seen within 
the subject’s medical records (see Section 5.14 for information on which medications 
require documentation).  
7. Document any applicable AEs as noted by the subject or as documented in their 
medical record (see Section 5.15 for information on which AEs require 
documentation). 
Important: If the Unscheduled Visit occurs between the closure visit and either 
the Confirmation Visit or the 4-Week follow-up visit, activities 2 through 5 will not 
be performed.  If the wound is open at the follow-up visit, and the subject has not 
reached their Confirmation Visit, the subject will be re-entered per the Special 
Instructions in 6.2.3.  SOC dressings may be applied until the next Treatment Visit.  
If the subject is open between the Confirmation Visit and the 4-Week follow up 
visit, the subject is exited.  

 
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Table 3: Schedule of Events 
Procedure 
Screening 
Phase 
Treatment Phase 
Follow-Up Phase 
Unscheduled 
Visit1,2 
SV 1 
-14±3d 
SV 2 
-7±3d 
Randomiza-
tion/ TV3 1 
(Day 0) 
TV 2 
7±3d 
TV 3 
14±3d 
TV 4 
21±3d 
TV 5 
28±3d 
TV 6 
35±3d 
TV 7 
42±3d 
TV 8 
49±3d 
TV 9 
56±3d 
TV 10 
63±3d 
TV 11 
70±3d 
TV 12 
77±3d 
TV 13  
84±3d 
Conf Visit 
7±3d 
After 
Closure 
4-Week 
28±3d 
After 
Confirm. 
Inf. Consent/HIPAA 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/Exclusion 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MRU Assessment 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical Exam 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascular Perfusion 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Ulcer Assessments4 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ulcer Photography 
X5 
X6 
X4,7 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X6 
X8 
X8 
 
Ulcer Debridement 
X 
X9 
X 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
X9 
 
 
 
 X9 
Ulcer Measurement 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Control Treatment 
X 
X 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
X10 
 
 
 
X10 
Treatment Compliance 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Offloading11 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
X 
Adverse Events 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Ulcer Size Reduction 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Active Treatment 
 
 
X12 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
X13 
 
 
 
X13 
Closure Assessment 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X14 
X 
X 
 
 
                                                          
1 Only to be used for a visit that falls out of range of one of the other visit windows.  If the proposed Unscheduled Visit falls within the next visit window, use that visit instead of documenting an unscheduled visit. 
2 See important information in section 6.2.5 for guidance on Unscheduled Visits after wound closure. 
3 “TV” = Treatment Visit 
4 Study Ulcer Assessments include: 1) location 2) duration 3) size 4) exudate 5) infection 6) measurement of ulcer area 
5 Collect pre- and post-debridement images 
6 Collect pre-debridement image; if performing debridement, collect post-debridement image  
7 Post-application image required if randomized to PriMatrix 
8 Image of the closed wound area to be taken 
9 Debride, if necessary 
10 If randomized to the Standard of Care cohort 
11 Not required for dorsal wounds; required for plantar ulcers or lateral ulcers that would benefit from offloading 
12 If randomized to the Active Treatment and if necessary; see Section 5.17 for guidelines on applying PriMatrix. 
13 Optional application of PriMatrix.  See Section 5.17 for guidelines on applying or re-applying PriMatrix 
14 If wound is not healed at Treatment Week 13, Investigator will document why, in his opinion, the wound did not heal. 
 

 
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7. Study Discontinuation and Withdrawal 
All subjects have the right to withdraw at any point during treatment without prejudice. If for any 
subject, study treatment or observations were discontinued, the reason(s) will be recorded and the 
sponsor will be notified promptly. Reasons that a subject may discontinue participation in a clinical 
study include: 
• 
Subject withdrew consent 
• 
Subject chooses to withdraw due to an adverse experience 
• 
Lost to follow-up (LTFU) 
 
Before a subject is identified as LTFU, the site will make all reasonable efforts to contact the subject. 
These attempts will be documented and will include, at a minimum two phone calls and/or email 
communications and one follow-up letter sent via certified mail.  
The investigator may discontinue a subject at any time if it is considered medically necessary.  
Rationale for discontinuation of a subject for medical reasons include, but are not limited to, the 
following:  
• 
Repeat infections with no response to allowable treatments 
• 
Subject repeated non-compliance with randomized treatment 
• 
It is in the best interest of the subject to not participate in the study. 
• 
Medical reason or situation in which the subject is no longer under the care of the investigator 
and unable to return for required study visits (e.g., hospitalization). 
 
Every attempt should be made to collect follow-up information. The reason for treatment 
discontinuation or withdrawal from the study will be recorded in the source documents and on the 
appropriate eCRF.  
The subject may be discontinued by the sponsor if the study is discontinued or for lack of 
compliance/protocol deviations.   
All subjects choosing to withdraw from the study will be asked to undergo the appropriate study visit 
procedures for the visit at which they are withdrawing. All subjects being discontinued by either the 
investigator or the sponsor will undergo the appropriate study visit procedures for the visit at which 
the decision is made to withdraw them from the study. 
Subjects who are discontinued or withdrawn and who have not achieved 100% ulcer closure during 
the treatment phase of the study will not be replaced and will be categorized as treatment failures. 
8. Statistical Analysis  
This Section presents general information about statistical methodologies and concepts for this study.  
Further technical details (e.g., data poolability across sites) will be provided in the Statistical Analysis 
Plan (SAP).  

 
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8.1. 
Treatment Groups  
The following treatment groups will be assessed: 
Group 
Description 
Control (SOC) 
Moist ulcer dressings consisting of 0.9% sodium 
chloride gel plus secondary dressings and an 
appropriate off-loading/protective device. (See Section 
5.11 for full information) 
Active Treatment 
PriMatrix Dermal Repair Scaffold plus secondary 
dressings to maintain a moist wound healing 
environment and an appropriate off-loading/protective 
device.  (See Section 5.17 for full information) 
8.2. Description of Study Endpoints  
8.2.1. Primary Efficacy Endpoint 
The primary efficacy endpoint for the study is the incidence of confirmed complete 
wound closure of the study ulcer, as assessed by the investigator, during the 12-week 
treatment phase. 
8.2.2. Secondary Efficacy Endpoints 
The secondary endpoints are: 
1. Proportion of subjects with complete wound closure of the study ulcer during the 
12-week treatment phase as assessed by computerized planimetry, during the 
treatment phase 
2. Time to complete wound closure, as assessed by the investigator. 
3. Time to complete wound closure, as assessed by computerized planimetry. 
4. Rate of ulcer closure as assessed by computerized planimetry. 
8.2.3. Exploratory Endpoints 
9. Medical resource utilization associated with treatment of DFU and related 
complications, including: 
• Interference of activities of daily living 
• Interference of paid work (full-time or part-time)/school 
• Physician office visits 
• Emergency room visits 
• Hospitalizations 
• Home health nursing visits 
• Skilled Nursing Facilities 
• Procedures 
• Medication regimens to treat complications (analgesics, antibiotics, etc.) 

 
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• Diagnostic tests, imaging, etc. 
• Treatment of AEs 
• Use of durable medical equipment (off-loading/protective device, crutches, 
wheelchair, etc.) 
• Dressing regimen and materials 
10. Wound closure status at the 4-week follow-up visit 
8.2.4. Safety Endpoints 
Safety will be assessed through reports of AEs and SAEs.  
8.3. 
Sample Size Determination and Rationale 
This is a randomized study with two treatment groups. Assuming: 
• 46% of DFUs receiving PriMatrix close by 12 weeks (84 days). 
• 26% of DFUs receiving with SOC close by 12 weeks (84 days). 
Overall 2-sided Type I Error rate (alpha) of 0.05.  Under the above assumptions, 102 subjects 
per treatment group will be required to meet the Type I error rate of 0.05 and 80% power; 
for a total of 204 subjects for the study. As the treatment duration is short, the 
discontinuation rate is predicted to be around 15%.  To accommodate the potential 
discontinuations, 256 subjects will be randomized (128 per treatment group) to this trial. The 
subjects will be randomized to the treatment groups in a 1:1 ratio.   
A single interim analysis when 50% of subjects complete the trial, using group-sequential 
methods and Pocock alpha spending function, where the hypotheses will be tested at a two-
sided alpha of 0.031 at the interim analysis and at a two-sided alpha of 0.028 at the final 
analysis. 
8.4. 
Randomization 
The randomization will be stratified by center and will use mixed blocks of 2 and 4 with a 1:1 
ratio of Active Treatment to Control Treatment to ensure even distribution of Active and 
Control subjects at each site. Trial ulcer size (area) at the time of randomization (2 strata: 1 
cm2 to ≤3 cm2 vs. >3 cm2 to 12 cm2) will also be used as a stratification factor to ensure balance 
between each treatment group in this stratum.  
8.5. 
Blinding 
Due to the nature of this trial and the product, the subjects, investigators and personnel 
involved in this trial cannot be blinded.  The assessment of ulcer closure, determination of 
ulcer area and ulcer closure parameters will be determined by both the investigator and by 
computerized planimetric analysis of digital photographs of the DFU using an imaging system 
and associated software.  

 
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8.6. 
Interim Analysis for Sample Size Adjustment  
A single interim analysis will be completed when 50% of subjects complete the study.  
Employing a group-sequential design with a Pocock alpha spending function the following 
decisions will be made at the interim analysis with respect to the efficacy outcome: 
1. Stop the study due to demonstrating statistically significant superiority of the Active 
Treatment to SOC if the two-sided p-value testing the stated hypotheses is ≤ 0.031 
and the difference is in favor of the Active Treatment. 
2. Stop the study due to demonstrating futility of the Active Treatment to SOC if the 
two-sided p-value testing the stated hypotheses is ≤ 0.031 and the difference is in 
favor of SOC. 
3. Continue the study if the two-sided p-value testing the stated hypotheses is > 0.031. 
With this design and assuming 46% of DFUs managed with the Active Treatment achieve 
complete wound closure by Week 12 (or by TV13) and 26% achieve complete wound closure 
when managed with the Control Treatment, the probability of stopping early due to showing 
superiority with the Active Treatment is 0.479.  If the decision at the interim analysis is to 
continue the study, the hypotheses at the end of the study will be tested at a two-sided alpha 
level of 0.028 to maintain an overall two-sided alpha of 0.05. 
Further, conditional power will be calculated at the interim analysis for predicting the final 
study success.  In case more data is needed, sample size re-estimation will be considered in 
order to meet the final study objective. 
In addition, an early data review will be performed when 50 patients reach the primary 
endpoint.  The purpose of this review is to ensure the study execution is as originally planned, 
and therefore, no alpha spending is involved.    
8.7. 
General Statistical Considerations  
All collected study data will be presented in subject data listings. Statistical analyses will be 
performed using SAS® for Windows, version 9.2 or later. Descriptive statistics (n, mean, 
standard deviation, median, minimum and maximum) will be calculated by treatment group 
for continuous variables. Frequencies and percentages will be presented by treatment group 
for categorical variables.  
8.8. 
Subject Disposition  
The disposition of all subjects who sign an ICF will be provided. The numbers of subjects 
screened, randomized, completed, and discontinued during the study, as well as the reasons 
for all post-randomization discontinuations will be summarized by treatment group, for all 
centers combined and each center separately. Disposition and reason for study 
discontinuation will also be provided as a by-subject listing.   

 
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8.9. 
Demographic and Baseline Characteristics  
Demographics and baseline characteristics will be summarized by treatment group using 
appropriate descriptive statistics. 
8.10. 
Analysis Populations  
8.10.1. 
Intent-to-Treat Population 
The Intent-to-Treat (ITT) population is defined as all randomized subjects. The 
Intent-to-Treat population will be the primary population for the analysis of the 
primary and secondary endpoints.  
8.10.2. 
Per Protocol Population 
The Per Protocol (PP) population is defined as all randomized subjects who were 
not associated with a major protocol violation. This population will be identified 
before the database lock. The PP analysis of primary and secondary endpoints will 
be considered supportive. 
For the per protocol analysis, no data points will be imputed, all missing values will 
remain as missing.   
8.10.3. 
Safety Population 
The Safety population is defined as any subject receiving the allocated treatment 
after randomization. This population will be used for the analysis of safety 
parameters.  
8.11. 
Statistical Methods  
A Statistical Analysis Plan (SAP) will be developed and approved before the database is locked. 
The SAP will present the detailed statistical methodology to be used in analyzing the efficacy 
and safety data from this trial. 
8.12. 
Efficacy Analyses 
8.12.1. 
Primary Analysis  
Primary Endpoint: The primary analysis will be conducted on the ITT population. 
The proportion of subjects with confirmed closed study ulcers during the treatment 
phase of the study, as assessed by the investigator, will be compared using the 
Cochran–Mantel–Haenszel (CMH). For the primary efficacy analysis, missing values 
will be imputed using last observation carried forward.   
For the primary analysis, the first date of assessment of 100% re-epithelialization of 
the ulcer surface without detectable exudate will be used. 
The Breslow-Day test will be used to assess the homogeneity of the primary 
endpoint across study sites.  If the Breslow- Day test concludes lack of homogeneity 

 
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(at a two-sided alpha level of 0.10), additional exploratory analyses will be 
performed to characterize the differences in results among sites.   
Secondary Endpoints: To maintain the trial-wise Type I error rate at 0.05, a closed 
test procedure will be used for the secondary endpoints. For efficacy analyses, the 
first date of assessment of 100% re-epithelialization of the ulcer surface without 
detectable exudate or visible non-epidermal tissue will be used. 
The order of the endpoints will be as follows: 
1. Proportion of subjects with confirmed complete wound closure of the study 
ulcer during the 12-week treatment phase as assessed by computerized 
planimetry, during the treatment phase 
2. Time to complete wound closure, as assessed by the investigator. 
3. Time to complete wound closure, as assessed by computerized planimetry. 
4. Rate of ulcer closure as assessed by computerized planimetry. 
Prognostic Factors Assessments: For the Intent-to-Treat population, a covariate 
analyses will be conducted to assess the impact of various prognostic factors on 
ulcer closure and also to demonstrate the robustness of the primary analysis. 
Prognostic factors (i.e., covariates) will be included if they are found to be 
contributing factors (i.e., the individual covariate p-value is less than 0.05). 
Potential prognostic factors to be considered include:  
• 
Baseline ulcer size 
• 
DM type 
• 
Age of ulcer at baseline 
• 
Race 
• 
Gender 
• 
Nicotine Use 
• 
Recorded HbA1c 
• 
Baseline BMI 
• 
Ulcer location 
Additional planned analyses include the use of Analysis of Covariance (ANCOVA) 
models which incorporate consideration of stratification factors (i.e., site and 
baseline ulcer area) in order to compare reduction in study ulcer size between the 
two treatment groups and Kaplan-Meier analysis to assess and describe the 
differences in the time to ulcer closure in the two treatment groups.   
8.12.2. 
Exploratory Analyses 
An exploratory analysis will be performed to assess costs associated with the 
management of DFUs for the active and control groups using medical resource 
utilization data and standardized direct and in-direct unit costs.  Additionally, ulcer 
closure status at the 4-week follow up visit will be evaluated. 

 
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8.12.3. 
Treatment Failures 
Subjects who are withdrawn or discontinue during the treatment phase and/or who 
do not achieve complete wound closure during the treatment phase will not be 
replaced and will be considered treatment failures.  
For missing data that are used in continuous data analyses, the last available 
observation (LOCF) will be used. In the analyses using the planimetry data, the last 
available planimetric value will be used for discontinued subjects.  
8.12.4. 
Safety Analyses  
The Safety population will be used for the analysis of safety endpoints.   
Safety will be assessed through reports of AEs and SAEs.  AEs related to the device, 
study ulcer and/or study procedures and all SAEs will be recorded.   
All safety parameters will be summarized descriptively by treatment.  No inferential 
statistics are planned. 
8.12.5. 
Adverse Events  
AEs will be coded using the MedDRA Medical Dictionary. Treatment Emergent AEs 
(TEAEs) are defined as events with an onset on or after the first randomized treatment. 
TEAEs will be summarized by treatment group, System Organ Class, and preferred 
term. The following TEAE summaries will be provided: 
• 
TEAEs by severity grade 
• 
TEAEs by relationship to study treatment. 
In addition, separate summaries of SAEs, and AEs resulting in discontinuation of study 
treatment will be presented. 
8.12.6. 
Supportive Analysis  
To assess the robustness of the primary analysis results, supportive analysis will be 
conducted using the PP population. Statistical methodology for the supportive 
analyses will be the same as that of the primary analysis, with the exception of the 
analysis population used. The PP population will be used for the supportive analysis 
while ITT population will be used for the primary analysis. Subjects in these 
populations with no post randomization data for the primary endpoint will be 
considered NOT CLOSED, i.e., treatment failures, in this analysis.   
9. Direct Access to Source Data/Documentation 
The monitors, auditors, personnel authorized by the sponsor, and regulatory and health authority 
inspectors or their agents will be given direct access to source data and documentation (e.g., medical 
charts/records, printouts, videotapes, etc.) for source data verification, provided that subject 
confidentiality is maintained in accordance with local requirements. Access to electronic medical 

 
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records may be governed by institution policy and each site will be required to ensure access to 
medical records as allowed by institutional requirements. 
10. Quality Control and Quality Assurance 
10.1. Monitoring Requirements 
In an effort to fulfill the obligations outlined in ICH guidelines which requires the sponsor 
to maintain current personal knowledge of the progress of a study, the sponsor has 
developed a Monitoring Plan in order to establish and document practical methods for the 
clinical team in monitoring and maintaining adequate study oversight.  The sponsor's 
designated monitor will visit the center(s) during the study as well as maintain frequent 
telephone and written communication. The investigator will permit the sponsor to monitor 
the study as frequently as is deemed necessary and provide access to medical records to 
ensure that data are being recorded adequately, that data are verifiable, and that protocol 
adherence is satisfactory.  
The investigator will permit representatives of the sponsor and/or designated CRO to 
inspect all eCRFs and corresponding study subject original medical records (source 
documents) at regular intervals throughout the study. Subject original medical records and 
other relevant data must be available to support all data recorded in the eCRF. In addition 
to the original medical records, these data may include but is not limited to, study, 
laboratory and diagnostic reports, ulcer images and tracings, diary pages, quality of life 
questionnaire, etc.  
Site inspections serve to verify strict adherence to the protocol and the accuracy of the 
data being entered on the case report forms, in accordance with federal regulations. A 
Monitoring Log will be maintained at each study site which the monitor will sign, date and 
state the type of visit.  
The investigator should be aware that the study site and subject records may be inspected 
by the sponsor or other representatives or other regional regulatory authorities. 
For any data transfer through e-mail, the data file(s) will be password protected; the 
password will be exchanged in the separate e-mail or by phone.   
For the Interim Analysis, a cut-off date for data collection and monitoring will be 
determined and sites will be requested to provide current information up to the cut-off 
date. 
The final statistical analysis of data will be performed after all clinical monitoring has been 
completed, all data queries have been resolved, and all data have been verified (QC) prior 
to formal database lock. The sponsor will authorize the final database lock for all sites. 

 
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10.2. Acceptability of Case Report Forms  
Electronic Case Report Forms will be used for the collection of data via electronic data 
capture (EDC). An eCRF must be completed for each subject who has signed an ICF. For 
subjects who are screen failures, this would be limited to the screen failure eCRF page. All 
source documents and eCRFs will be completed as soon as possible after the subject's visit. 
Corrections to data on the eCRFs will be documented in the electronic audit trail which is 
21 CFR Part 11 compliant. The investigator will review eCRFs to indicate that, to his/her 
knowledge, they are complete and accurate.  eCRFs will be reviewed by the 
sponsor/designee who will make a decision as to their acceptability.   
10.3. Reporting Protocol Deviations 
The investigator is obligated to follow the protocol without departure from the 
requirements written in the protocol. If the investigator deviates from the protocol 
requirements, the sponsor will make the determination as to whether the subject will 
continue in the study. The sponsor also has the right to discontinue the subject for protocol 
violations. The IRB may also have to be contacted if safety to the subject or if the scientific 
soundness of the study is involved. All protocol deviations must be documented in the 
eCRF. 
10.4. Study Device Accountability 
The investigator or designee will verify the contents of each shipment against the shipping 
documents. Verification of study device receipt will be documented on the device 
accountability log which will be provided to the site. 
The investigator will also use the device accountability log to maintain current and 
accurate inventory records covering the dispensing and the disposal of the study devices. 
At the conclusion of the study the investigator must agree to return or destroy all study 
device materials as instructed by the sponsor.   
11. Ethics and Regulatory Requirements 
This study is to be conducted in accordance with the specifications of this protocol and in 
accordance with principles consistent with Good Clinical Practice (GCP), ICH E6 and HIPAA 
regulations in 45 CFR Part 164. No protocol changes will be implemented without the prior review 
and approval of the sponsor and IRB, except where it may be necessary to eliminate an immediate 
hazard to a research subject. In such a case, the change will be reported to the IRB as soon as 
possible, according to IRB regulations. Additionally, all study products used in this study are 
manufactured, handled and stored in accordance with applicable Good Manufacturing Practices 
(GMP) and the products provided for this study will be used only in accordance with this protocol. 

 
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11.1. Institutional Review Board/Independent Ethics Committee 
The Principal investigator will provide the Institutional Review Board/Independent Ethics 
Committee (IRB/IEC) with all appropriate materials as required by their IRB/IEC, including but 
not limited to the clinical study protocol, ICF, and any advertising materials. The study will not 
be initiated until the IRB/IEC provides written approval of the aforementioned documents and 
until approval documents have been obtained by the Principal investigator and sponsor or 
sponsor designee. The investigator will not participate in the decision. If the investigator is an 
IRB or IEC member, documentation must be provided indicating recusal from the approval 
process. Appropriate reports on the progress of this study by the Principal investigator will be 
made to the IRB/IEC as required by local and applicable government regulations and in 
agreement with policy established by the sponsor. The investigator is required to maintain an 
accurate and complete record of all written correspondence to and received from the IRB/IEC 
and must agree to share all such documents and reports with the sponsor. 
11.2. investigator’s Responsibilities 
The investigator is responsible for performing the study in full accordance with the protocol 
and the current revision of the Declaration of Helsinki, the Good Clinical Practice: Consolidated 
Guideline, approved by the ICH, and any applicable national and local laws and regulations. 
Information regarding any study centers participating in this study that cannot comply with 
these standards will be documented. 
11.3. Subject Informed Consent Requirements 
Written and oral information about the study in a language understandable by the subject will 
be given to all subjects by the investigator and/or designee. Written informed consent will be 
obtained from each subject before any procedures or assessments that would not otherwise 
be required for the care of the subject are done and after the objectives, methods, anticipated 
benefits, potential hazards, and insurance arrangements in force are explained and the subject 
has been given sufficient time to ask questions and consider participation in the study. It will 
also be explained to the subjects that they are free to refuse entry into the study and free to 
withdraw from the study at any time without prejudice to future treatment. It is permissible 
for a third person (e.g., a family member) to be present during the explanation of the study. 
The written ICF is to be in compliance with Code of Federal Regulations (CFR) 21 Part 50.27 
and Good Clinical Practice (GCP) guidelines. The sponsor will approve the ICF and all 
amendments to the ICF prior to submission to the IRB/IEC. A copy of the ICF to be used will be 
submitted by the investigator to the IRB/IEC for review and approval prior to the start of the 
study. Each study site must provide the sponsor with an unsigned copy of IRB/IEC-approved 
ICF along with applicable documentation to support this approval. The original signed ICF is 
retained in the subject's study records, and a copy is provided to the subject. A second copy 
may be filed in the subject’s medical record, if allowed by institutional policy.  

 
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12. Data Handling and Record Keeping 
12.1. Recording and Collection of Data 
The Site is responsible for keeping source documents for all data collected via EDC. All 
source documents and eCRFs must be completed as soon as possible after the subject's 
visit. Corrections to data on the eCRFs will be documented in the electronic audit trail 
which is 21 CFR Part 11 compliant. The investigator will review eCRFs to indicate that, to 
his/her knowledge, they are complete and accurate. If further changes are made after this, 
the investigator will need to again sign the investigator signature page electronically. 
Designated source documents will be signed and dated by the appropriate study 
personnel. The investigator must agree to complete and maintain source documents and 
eCRFs for each subject participating in the study. 
12.2. Clinical Data Management 
The sponsor will be responsible for the processing and quality control of the data. Data 
management will be carried out as described in the sponsor’s standard operating 
procedures (SOPs) for clinical studies. 
The handling of data, including data quality control, will comply with regulatory guidelines 
(e.g., ICH E6 GCP, and local regulations where applicable) and the sponsor’s SOPs as well 
as provisions of the study-specific Data Management Plan. 
12.3. Archiving 
All study documentation at the investigator site and sponsor site will be archived in 
accordance with ICH GCP E6 and the sponsor’s quality standards and SOPs. 
Study records must be retained by the investigator for 2 years following the conclusion/ 
termination of the study and the publication (if applicable). Study records should not be 
destroyed without prior written agreement between the sponsor and the study 
investigator. At the completion of the study, details of the archival process must be 
provided to the sponsor. Study records are subject to inspection by applicable health and 
regulatory agencies at any time.   
Records to be retained by the investigator include, but are not restricted to: 
• 
Source data and the primary records upon which they are based (e.g., subject’s 
progress notes, AE data, test results, and any other diagnostic procedures required 
to evaluate the progress of the study). 
• 
Signed protocols and protocol amendments 
• 
Product (e.g., Device, SOC supplies and Off-loading/protective device) 
accountability records 
• 
Study personnel signature log 

 
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• 
Monitoring logs 
• 
Correspondence to and from the sponsor, designee and IRB 
• 
Investigator and sub-investigator CVs 
• 
Signed informed consent and HIPAA consent forms 
• 
Subject screening and randomization log 
• 
SAE reports 
• 
Institutional Review Board approval and re-approval letters 
• 
Ulcer images  
• 
Other documents pertaining to the conduct of the study 
These documents must be maintained and kept on file by the investigator so that the 
conduct of the study can be fully documented and monitored. 
13. Publication Plan 
Manuscripts and abstracts will be prepared by both the investigator(s) and the sponsor. The 
results of the study may be published in scientific literature and may also be used in submissions 
to regulatory authorities. It is the intent of the sponsor, and the Lead investigator to publish or 
present the study results together with the other sites, unless specific permission is obtained in 
advance from the sponsor to publish separate results. Co-authorship with any of the sponsor’s 
personnel will be discussed and mutually accepted upon submission of a manuscript or 
publication. 
All information concerning the sponsor’s operations (such as patent applications, formulae, 
manufacturing processes, basic scientific data, or formulation information supplied to the 
investigator and not previously published) is considered confidential by the sponsor and shall 
remain the sole property of the sponsor. The investigator agrees not to use it for other purposes 
without written consent. 
It is understood by the investigator that the sponsor will use the information developed in this 
clinical trial in connection with the development of PriMatrix Dermal Repair Scaffold. Therefore, 
this information may be disclosed as required to other investigators or appropriate regulatory 
authorities. By agreeing to participate in this clinical trial, the investigator understands that 
he/she has an obligation to provide the sponsor with complete test results and all data developed 
during this trial. 
Publication and Disclosure: Because this is a multi-center trial, site and investigator shall not 
independently publish, publicly disclose, present or discuss any results of or information 
pertaining to site’s and investigator’s activities conducted under this study protocol until such a 
multi-center publication is released under sponsor’s direction, unless otherwise agreed upon in 
the study agreement.    
 
 

 
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14. Protocol Versions 
Table 4: Previous Versions and Overview of Changes to the Previous Version 
Version 
Changes 
Version 1.0 
Original 
Version 2.0 
• 
Include preliminary analysis after enrollment of 50 subjects 
Version 3.0 
 
• 
Update sponsor contact information 
• 
Addition of protocol version table 
• 
Addition of 4-week follow-up phase 
• 
Include specific time frame for vascularization measurements 
• 
Removal of specific brands or examples from offloading/protective 
device and dressings 
• 
Specified that the investigator or designee is to act as an interviewer 
for the MRU worksheet 
• 
Clarification on osteomyelitis on the foot with the study ulcer 
• 
Clarification on undermining and tunneling 
• 
Update 30 day use of products or therapies to 28 days 
• 
Change necrotic tissue to devitalized tissue 
Version 4.0 
• 
Refer to Summary of Changes document 
Version 5.0 
• 
Refer to Summary of Changes document 
 
 

 
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15. References 
1. Singh N, Armstrong DG, Lipsky BA. Preventing Foot ulcers in Patients with Diabetes. JAMA 
2005;293(2):217-228. 
2. Snyder RJ, Cardinal M, Dauphinée DM, Stavosky J. A Post-hoc Analysis of Reduction in Diabetic 
Foot ulcer Size at 4 Weeks as a Predictor of Healing by 12 Weeks. Ostomy ulcer Management 
2010;56(3):44-50. 
3. Ramsey SD, Newton K, Blough D, et al. Incidence, outcomes and cost of foot ulcers in patients 
with diabetes. Diabetes Care 1999;22:382-387. 
4. Morbach SS, Furchert H, Gröblinghoff U, et al. Long-Term Prognosis of Diabetic Foot Patients and 
Their Limbs: Amputation and death over the course of a decade. Diabetes Care. 2012;35(1):2021-
2027. 
5. Goodridge D, Trepman E, Sloan J, et al. Quality of life of adults with unhealed and healed diabetic 
foot ulcers. Foot Ankle Int 2006; 27(4):274-280. 
6. Frykberg RG. Diabetic foot ulcers: current concepts. J Foot Ankle Surg 1998; 37:440-446. 
7. Rice J, Desai U, Cummings A, Birnbaum H, Skornick M, Parsons N. Burden of Diabetic Foot ulcers 
for Medicare and Private Insurers. Diabetes Care 2014;37(3):651-658. 
8. Kavros SJ, Dutra T, Gonzalez-Cruz R, et al. The Use of PriMatrix, a Fetal Bovine Acellular Dermal 
Matrix, in Healing Chronic Diabetic Foot ulcers: A Prospective Multicenter Study. Adv Skin ulcer 
Care 2014;27(8):356-362.  
9. Karr JC. Retrospective comparison of diabetic foot ulcer and venous stasis ulcer healing outcome 
between a dermal repair scaffold (PriMatrix) and a bilayered living cell therapy (Apligraf). Adv 
Skin ulcer Care 2011;24(3):119-125.  
10. Kavros SJ. The use of an Acellular Collagen Matrix to Treat Chronic ulcerations of the Midfoot 
associated with Charcot Neuroarthropathy. Foot Ank Spec 2002; 5(4):230-4. 
11. Lullove EJ. Acellular Fetal Bovine Dermal Matrix in the Treatment of Nonhealing ulcers in Patients 
with Complex Comorbidities. J Am Podiatr Med Assoc 2012;102(3):233-239. 
12. Strauss NH, Brietstein RJ. PriMatrixTM Dermal Repair Scaffold in the Treatment of Difficult-to-
Heal Complex ulcers. ulcers 2012;24(11):327. 
13. Larson BJ, Longaker MT, Lorenz HP. Scarless fetal ulcer healing: A basic science review. Plast 
Reconstr Surg 2010;126(4):1172-1180.  
14. Cornwell KG, Landsman A, James KS. Extracellular matrix biomaterials for soft tissue repair. Clin 
Podiatr Med Surg 2009;26(4):507-523.  
15. Landsman A, Taft D, Riemer K. The role of Collagen Bioscaffolds, Foamed Collagen, and Living 
Skin Equivalents in ulcer Healing. Clin Podiatr Med Surg 2009;26:525-533. 
16. Neill J, James K, Lineaweaver W. Utilizing biologic assimilation of bovine fetal collagen in staged 
skin grafting. Ann Plast Surg 2012;68:451-456. 

 
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17. CDCP 2008. National diabetes fact sheet: general information and national estimates on diabetes 
in the United States, 2007. Atlanta, GA: U.S. Department of Health and Human Services, Centers 
for Disease Control and Prevention, 2008. 
18. FDA 2006 Guidance for Industry Chronic Cutaneous ulcer and Burn ulcers- Developing Products 
for Treatment.  
19. Allen L, Powell-Cope G, Mbah A,Bulat T, Njoh E.  A retrospective review of adverse events related 
to diabetic foot ulcers.  Ostomy ulcer Management 2017; 63(6): 30-3.