A Clinical Evaluation of an Esterified Hyaluronic Acid Matrix on Preparing Wounds in Burn Patients for Split-thickness Skin Grafting
Phase: NA
Conditions: Burn Wound
Sponsor: Medline Industries

  
  
 
A clinical evaluation of an esterified hyaluronic acid matrix on preparing wounds in burn patients for split-thickness 
skin grafting  
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Medline Industries, Inc.  
A clinical evaluation of an esterified hyaluronic acid matrix on preparing wounds 
in burn patients for split-thickness skin grafting  
  
  
Protocol Number MED-2018-DIV31-006  
  
  
  
8-July-2020  
Version 2.0  
  
  
  
  
  
  
Prepared by:  
  
Medline Industries  
Three Lakes Drive  
Northfield, IL 60093   
  
  
  
  
  
  
  
  
  
 
Prepared by (Signature)  
  
Date  
 
Reviewed by (Signature)  
  
Date  
Medline Industries, Inc.  
Three Lakes Drive  
  
  
Northfield, IL 60093  

  
  
 
A clinical evaluation of an esterified hyaluronic acid matrix on preparing wounds in burn patients for split-thickness 
skin grafting  
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Contents  
INVESTIGATOR ACKNOWLEDGMENT SIGNATURE ................................................................................ 4 
DOCUMENT HISTORY ................................................................................................................................ 5 
1.  PROTOCOL SUMMARY ......................................................................................................................... 7 
1.1.  Synopsis ............................................................................................................................................ 7 
1.2.  Schedule of Activities (SOA) ........................................................................................................... 12 
2.  INTRODUCTION .................................................................................................................................... 15 
2.1.  Background & Rationale .................................................................................................................. 15 
2.2.  Clinical Product................................................................................................................................ 15 
2.3.  Risk/Benefit Profile .......................................................................................................................... 15 
2.3.1.  Potential Study Risks ................................................................................................................ 15 
2.3.2.  Potential Study Benefits ............................................................................................................ 16 
2.3.3.  Assessment of Potential Risk/Benefit Profile ............................................................................ 16 
3.  OBJECTIVES AND ENDPOINTS .......................................................................................................... 16 
4.  STUDY DESIGN .................................................................................................................................... 17 
4.1.  Overall Design ................................................................................................................................. 17 
4.2.  End of Study Definition .................................................................................................................... 17 
5.  STUDY POPULATION ........................................................................................................................... 18 
5.1.  Inclusion Criteria .............................................................................................................................. 18 
5.2.  Exclusion Criteria ............................................................................................................................ 18 
5.3.  Strategies for Recruitment and Retention ....................................................................................... 19 
6.  STUDY PROCEDURES AND ASSESSMENTS .................................................................................... 19 
6.1.  Phase I – Pre-STSG ........................................................................................................................ 19 
6.1.1.  Day 0 – Screening Visit and Informed Consent........................................................................ 19 
6.1.2.  Day 1 – Initial Visit .................................................................................................................... 20 

  
  
 
A clinical evaluation of an esterified hyaluronic acid matrix on preparing wounds in burn patients for split-thickness 
skin grafting  
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6.1.3.  Interim Visits – Day 7, 14, 21, 28, 35, 42 .................................................................................. 21 
6.2.  Phase II – Post-STSG ..................................................................................................................... 21 
6.2.1.  Interim Visits – Post-STSG Days 7, 14, 21, 28,........................................................................ 21 
7.  ADVERSE EVENTS............................................................................................................................... 22 
7.1.  Definition of Adverse Event ............................................................................................................. 22 
7.2.  Definition of Serious Adverse Event ................................................................................................ 22 
7.3.  Severity of Adverse Event ............................................................................................................... 22 
7.4.  Relatedness of Adverse Event and Serious Adverse Event ........................................................... 23 
7.5.  Expectedness .................................................................................................................................. 23 
7.6.  Adverse Event Reporting ................................................................................................................ 23 
7.7.  Serious Adverse Event Reporting ................................................................................................... 24 
8.  STATISTICAL CONSIDERATIONS ....................................................................................................... 24 
8.1.  Sample Size Determination ............................................................................................................. 24 
8.2.  Populations for Analyses ................................................................................................................. 24 
8.3.  Statistical Analysis ........................................................................................................................... 24 
9.  SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ................................. 25 
9.1.  Clinical Monitoring ........................................................................................................................... 25 
9.2.  Regulatory and Ethical Considerations ........................................................................................... 26 
9.2.1.  Confidentiality and Privacy ....................................................................................................... 26 
9.2.2.  Safety Oversight ....................................................................................................................... 27 
9.2.3.  Data Handling and Record Keeping ......................................................................................... 27 
9.2.4.  Study Records Retention .......................................................................................................... 27 
9.2.5.  Study Discontinuation ............................................................................................................... 28 
9.2.6.  Study Closeout ......................................................................................................................... 28 
9.2.7.  Conflict of Interest Policy .......................................................................................................... 28 
9.3.  Protocol Deviations ......................................................................................................................... 28 
9.4.  Abbreviations ................................................................................................................................... 28 

  
  
 
A clinical evaluation of an esterified hyaluronic acid matrix on preparing wounds in burn patients for split-thickness 
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10. REFERENCES ..................................................................................................................................... 29 
11. APPENDIX ............................................................................................................................................ 29 
11.1.  Hyalomatrix® Wound Device Instructions for Use ......................................................................... 29 
 
  
INVESTIGATOR ACKNOWLEDGMENT SIGNATURE  
• 
I agree to conduct the study in accordance with the relevant, current protocol and will make 
changes in the protocol only after notifying the Sponsor, except when necessary to protect 
the safety, rights, or welfare of subjects.  
• 
I agree to personally conduct and supervise the investigation as described within.  
• 
I agree to inform all subjects that the device is being used for the purposes of an 
investigational study.   
• 
I will ensure that requirements relating to obtaining informed consent in the guidelines for 
Good Clinical Practices, and 21 CFR Part 50 and institutional review board (IRB) review 
and approval in 21 CFR Part 56 are met.  
• 
I agree to report to the Sponsor, IRB and/or Ethics Committee, according to the protocol, 
adverse experiences that occur during the course of the investigation in accordance with  
guidelines for Good Clinical Practices, and 21 CFR 812.  
• 
I have read and understand the information in the protocol, including the potential risks.  
• 
I agree to maintain adequate and accurate records in accordance with guidelines for Good 
Clinical Practices and 21 CFR 812.140 and to make those records available for inspection.  
• 
I will ensure that an IRB compliant with the requirements of guidelines for Good Clinical 
Practices and 21 CFR Part 56 will be responsible for the initial and continuing review and 
approval of the clinical investigation. I also agree to promptly report to the IRB all changes 
in the research activity and all unanticipated problems involving risks to human subjects or 
others.   
• 
I agree to comply with all other requirements regarding the obligations of clinical 
investigators and all other pertinent requirements in the guidelines for Good Clinical 
Practices, and the Code of Federal Regulations.  
I have received and reviewed this Investigational Plan. I will conduct the study as described.  
  

  
  
 
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Principal Investigator (Print):  
 
Principal Investigator (Signature):  
Date (MM-DD-YYYY):  
  
  
DOCUMENT HISTORY  
  
VERSION  
DATE  
DESCRIPTION  
Version 1.0  
12-Sep-2018  
Initial Release  

  
  
 
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skin grafting  
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Version 2.0  
8-July-2020  
Following protocol edits were made:  
  
1. The “Investigator Acknowledgement 
Signature” page was modified.  
2. The economic outcomes were 
removed from the secondary 
objectives.  
3. Secondary endpoints were modified in 
order to obtain a more comprehensive 
study design.  
4. The “Study Population” section was 
modified to also include patients with 
electrical burns.  
5. Inclusion and exclusion criteria were 
added in the synopsis.  
6. Inclusion and exclusion criteria were 
modified in order to further streamline 
the screening process.    
7. The “post-market” phase was added 
in the synopsis.  
8. The “Participant Duration” section of 
synopsis was modified to provide 
more clarity to the “End of study 
definition” section of the protocol.  
9. The “Schedule of Activities” section 
was modified to align with the study 
procedures and assessments.  
10. The “Assessment of potential 
risk/benefit profile” section was 
modified in order to show a favorable 
risk-benefit profile of this study.  
11. The “Study procedures and 
assessments” section was modified to 
align with the changes in the study 
design.  
12. The language in the “Adverse Events” 
section was updated to reflect the new 
grading system.   
13. The language in the “Serious Adverse 
Events” section was modified, in 
order to align with the current updated 
processes.  

  
  
 
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14. The title of Kara Cassady was changed 
from Associate Director of Clinical 
Operations to Director of Clinical 
Operations.  
15. The “Key roles and Study  
Governance” section was removed.  
16. The language in “Clinical  
Monitoring” section was modified to 
provide a more realistic monitoring 
activity by the Clinical Research 
Associate(s).  
17. The “Confidentiality and Privacy” section 
was modified to include paper  
files, in addition to electronic database.  
18. The statistical analysis system was 
updated in the “Data handing and record 
keeping” section.  
19. The “Study closeout” section was 
modified such that now Medline 
Industries, Inc. (sponsor) is not required to 
share with the site(s) the final analysis of 
data for study completed at the site(s).  
20. Updated instructions for use (IFU) 
document was added.  
21. Screening form, case report forms, AE 
form, and SAE form were removed from 
the protocol. They will be provided by 
Medline Industries, Inc. but will go as a 
separate document.  
  
  
1. PROTOCOL SUMMARY  
1.1. Synopsis  
  
Title:  
A clinical evaluation of an esterified hyaluronic acid matrix on preparing post-
escharectomy wounds for split-thickness skin grafting in burn patients.   
 

  
  
 
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Study Description:  
Objectives:  
Hyaluronic acid is a major component of the extracellular matrix. During the 
wound healing process, hyaluronic acid impacts several stages of healing by 
modulating  
inflammation,  cellular  proliferation,  and  
migration. 
Consequently, matrices composed of hyaluronic acid may accelerate the 
wound healing process and lead to improved patient outcomes. This 
multisite case series will evaluate the impact of a specific matrix composed 
of esterified  
hyaluronic  
acid  
(Hyalomatrix®  Wound  Device)  on 
the management of wounds in burn patients. Study participants will 
have wounds that are clinically suitable to be managed by the use of a 
regenerative matrix followed by final wound closure with split thickness 
skin graft (STSG).  
 
 
 
Primary Objective: Evaluate the capability of a hyaluronic acid wound 
matrix to prepare a post-escharectomy wound, in burn patients, to receive 
an STSG.  
Secondary Objectives:  Evaluate clinical and health outcomes relating to the 
wound and STSG.   
 
Endpoints:  
Primary Endpoint: Number of days from initial application of Hyalomatrix® 
Wound Device to approval of wound to receive an STSG.  
 
Secondary Endpoints: (1a) Change in wound volume from the time prior to 
application of the Hyalomatrix® Wound Device to the time before the 
application of STSG and after STSG, (1b) Length-of-stay in inpatient unit, (1c) 
Patient pain rating, (1d) Proportion of STSG take for the wound at 28 days, 
per clinician judgement, (1e) Proportion of patients who develop an 
infection of the target wound at any time, per confirmation with culture, 
(2a) Length-of-stay as inpatient, (2b) Discharge destination.  
 
 
Study Population:  
Twenty thermal or electrical burn patients (18-85 years old) who have a 
wound with a total body surface area (TBSA) between 0.5% and 20%, and 
the wound (per the investigator) requires treatment in an inpatient setting. 
The admission need not be the initial presentation of the burn. Patients 
must have a wound from a thermal or electrical burn that has undergone  
escharectomy and likely requires an STSG to heal. All patients must meet 
treatment indications for Hyalomatrix® Wound Device.   
  

  
  
 
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Inclusion Criteria  
Patients will be eligible to participate in the study if they satisfy ALL of the 
inclusion criteria below:  
• 
Patients who are 18-85 years old  
• 
Patient with a wound originating from a thermal or electrical 
burn  
• 
Total burn area is less than 20% of TBSA  
• 
Target burn wound is greater than 0.5% of TBSA  
• 
Patient has undergone escharectomy procedure or will undergo 
escharectomy on the target wound before application of 
Hyalomatrix® Wound Device, and resulting wound will likely 
need an STSG, but wound site is not immediately ready for 
grafting.  
• 
For patients with diabetes, an A1C hemoglobin level below 11 
percent (taken within 90 days).  
  
Exclusion Criteria  
A participant is ineligible for the study if he or she meets ANY of the criteria 
below:  
• 
Current active diagnosis of substance abuse, per the  
Investigator  
• 
Patient currently taking non-inhaled corticosteroids   
• 
Patient needs or is likely to need Negative Pressure Wound 
Therapy (NPWT) of the target wound after application of 
Hyalomatrix® Wound Device  
• 
Patient is pregnant, planning to become pregnant during study 
period, or breastfeeding  
• 
Unstable medical condition as determined by the site 
investigator or sub-investigator   
• 
Patients with known sensitivities to hyaluronan, hyaluronan 
derivatives, silicone, or any other ingredients of the 
Hyalomatrix® Wound Device  
  
  
  
  

  
  
 
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Description of  
Sites/Facilities 
Enrolling 
Participants:  
 
Multiple burn centers within acute care facilities.   
Phase  
Description of Study  
Post-market  
 
Intervention:  
 
This is a case series, in which burn patients meeting all of the inclusion 
criteria and none of the exclusion criteria will receive Hyalomatrix® Wound 
Device as a matrix for their wound, in conjunction with the standard-of-care 
for managing these types of wounds. The study will be divided into two 
phases. Phase I will entail intervention with the Hyalomatrix® Wound Device 
and will continue until one of the following occurs, (1) sufficient granulation 
has occurred and the patient can receive an STSG and proceed to Phase II, 
(2) the patient’s physician determines an STSG is no longer necessary, or (3)  
two applications with the Hyalomatrix® Wound Deviceoccur and no STSG is 
approved. Phase II will begin following the STSG procedure. In this phase 
the wound will be monitored and proportion of STSG take will be evaluated, 
but no application of the Hyalomatrix® Wound Devicewill take place. This 
phase will continue for 28 days or if the physician deems the patient no 
longer needs regular care to monitor the wound, whichever occurs earlier.   
 
 
  
Participant Duration:  Participant duration will begin upon obtaining informed consent and will end 
when one of the following occurs:  
(1) The patient completes Phase II,   
(2) the patient’s physician determines an STSG is no longer necessary,   
(3) the patient is unwilling or clinically inappropriate, per determination by 
the Investigator, to receive a second application of Hyalomatrix® 
Wound Device or STSG. The silicone backing should be removed at 21 
days but the decision to reapply the Hyalomatrix® Wound Device or 
schedule the STSG may happen up to three days thereafter,  
(4) the patient is not ready to receive an STSG after two applications with 
the Hyalomatrix® Wound Device. The silicone backing should be 
removed 21 days after the second application of Hyalomatrix® Wound 
Device but the decision to schedule the STSG may happen up to three 
days thereafter,,  (5) the patient develops an infection of the target 
wound at any time, (6) the patient needs NPWT of the target wound 
after application of the Hyalomatrix® Wound Device.    
  

  
  
 
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Overall time will be variable depending on the patient’s wound and 
condition; however, typical time for a wound to be ready for grafting 
following the use of the Hyalomatrix® Wound Device is 14-21 days after 
initial matrix application. Time to heal after STSG application is typically two 
weeks, but the patient will remain in the Phase II portion of the study while 
the wound is still open, up to a maximum period of 28 days post STSG.  
  

 Medline Industries, Inc.  
 
 
 
 
  
  
1.2. Schedule of Activities (SOA)  
REQUIRED ASSESSMENTS & 
ACTIVITIES  
SCREENING 
VISIT Day 0  
PHASE I:  
INITIAL VISIT  
Day 1  
PHASE I:  
ASSESSMENT VISITS  
Days 7, 14, 21, 28, 35, 42b  
PHASE II:  
ASSESSMENT 
VISITS  
Days 7, 14, 21, 28 c,  
post-Phase I completion  
Informed consent  
X  
  
  
  
Wound assessment for eligibility  
X  
  
  
  
Review of medical history to determine 
eligibility  
X  
  
  
  
A1C test a  
X  
  
  
  
Demographics, comorbidities, wound 
history & medication(s)  
  
X  
  
  
Wound photograph, infection 
evaluation, & pain assessment  
  
X  
X  
  
Application of Hyalomatrix® Wound  
Device and secondary dressing  
  
X  
  
  
Record analgesic use  
  
X  
X  
X  

 Medline Industries, Inc.  
 
 
Wound assessment for STSG eligibility  
  
  
X  
  
Wound photograph and STSG take 
assessment   
  
  
  
X  
Adverse event assessment  
  
  X--------------------------------------------------------------------X  
a Only for diabetic patients who do not have an A1C reading within the past 90 days  
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b Days must be +/- two days within target day. In most cases, Phase I will end by 21 days. In the event Phase I extends beyond 21 days, a second 
application of the Hyalomatrix® Wound Device will occur c Days must be +/- two days within target day. Phase II may end earlier depending on 
participants wound progress. 

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A clinical evaluation of an esterified hyaluronic acid matrix on preparing wounds in burn patients for split-
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2. INTRODUCTION   
2.1. Background & Rationale  
The wound healing process following burn wounds takes a coordinated biological effort involving 
inflammation, tissue proliferation, and tissue remodeling, amongst other biological processes.1 Given 
the extensive damage typically occurring in burn wounds, cellular and/or tissue-based products, which 
are applied to the wound to aid in tissue regeneration, are often prescribed to facilitate tissue 
granulation and healing. A variety of skin substitutes exist, varying in their composition (animal or 
human origin) as well as their mechanism of action.1    
Hyaluronic acid is a major component of the extracellular matrix.2 During the wound healing process, 
hyaluronic acid impacts several stages of healing by modulating inflammation, cellular proliferation 
and migration.3 Consequently, skin substitutes composed of hyaluronic acid may accelerate the 
wound healing process by providing the patient with the substrate to generate neodermis.4 In patients 
who ultimately need a split-thickness skin graft (STSG) to heal their wound, the use of a hyaluronic 
acid based skin substitute may lead to decreased time-to-grafting, improving patient outcomes and 
quality of life. The current study will evaluate the clinical use of an esterified hyaluronic acid based 
wound matrix device on time-to-STSG and ultimate wound outcome.   
2.2. Clinical Product  
Hyalomatrix® Wound Device (henceforth described as “device”) is a non-woven pad composed of 
esterified hyaluronic acid, covered with a semipermeable silicone layer to protect the wound and 
control water vapor loss. The device should be used with an appropriate secondary dressing.  
The device is currently marketed in the United States and is approved for use in numerous conditions: 
chronic vascular ulcers, diabetic ulcers, draining wounds, partial- and full-thickness wounds, pressure 
ulcers, second-degree burns, surgical wounds, trauma wounds, tunneled/undetermined wounds, and 
venous ulcers. The device achieves its effect by depositing hyaluronic acid, which is a major 
component of the extracellular matrix, into the wound bed to support the healing process. The device 
acts as a scaffold for cellular colonization and capillary growth. Further information on the product 
can be found in Appendix 11.1.   
2.3. Risk/Benefit Profile  
2.3.1. Potential Study Risks  
If the participants have an unknown sensitivity to hyaluronan, hyaluronan derivatives or silicone, 
they may experience a reaction to the device. This risk will be mitigated by screening potential 
participants regarding any sensitivity to the dressing material. Additionally, patients will be under 
the care of a physician, who will be able to appropriately address any potential reaction from the 
dressing.   

 
  
  
 
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2.3.2. Potential Study Benefits  
Through use of the wound device, patients may experience decreased time to receiving an STSG 
and achieve faster overall resolution of their wound.  
2.3.3. Assessment of Potential Risk/Benefit Profile  
Since this is a post-market study and the device is used within its intended use by or under 
supervision of the Investigator who is a burn specialist, participation in this study presents minimal 
risk to the patient, while offering the potential for benefits to the patients enrolled in the study. 
Therefore, the risk-benefit profile for the study is favorable.   
3. OBJECTIVES AND ENDPOINTS  
  
OBJECTIVES  
ENDPOINTS  
JUSTIFICATION 
FOR ENDPOINTS  
Primary  
  
  
Evaluate the capability of the device 
to 
prepare 
post-escharectomy 
wounds in burn patients to receive 
an STSG.  
  
Number 
of 
days 
from 
initial 
application of the device to approval 
of wound to receive an STSG.   
  
Marker  
of  
wound  
healing progress   
Secondary  
  
  

 
  
  
 
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1. Evaluate clinical outcomes 
of burn patients  
2. Health  outcomes  
  
(1a)  Change in wound volume from 
the time prior to application of the 
device to the time before the  
application of STSG and after STSG 
(1b) Length-of-stay at inpatient unit  
(1c) Patient pain rating  
(1d) Proportion of STSG take for the 
wound at 28 days, per clinician 
judgement  
(1e) Proportion of patients who 
develop an infection of the target 
wound at any time, per confirmation 
with culture  
 (2a) Length-of-stay as inpatient  
(2b) Type of care setting where patient 
is discharged  
  
Common  
clinical 
endpoints to measure 
outcomes  
in 
 
wound 
management.   
  
Common 
analysis 
to 
determine cost- 
effectiveness of device 
usage.  
4. STUDY DESIGN  
4.1. Overall Design  
This study is a multi-site, open-label case series collecting data on the clinical use of an esterified 
hyaluronic acid wound matrix in preparing post-escharectomy wounds in burn patients for STSGs. The 
study will be split into two phases. Phase I will include use of the device on the wound, with the intent 
of measuring how quickly the wound becomes prepared for an STSG. Phase II will occur after the STSG 
is placed; in this phase, the device will not be applied. Rather, the key assessment will be how well the 
wound is receiving the STSG. The Schedule of Activities in Section 1.2 describes the timing and 
sequencing of the events and phases.   
In addition to the use of the wound device, physicians will provide the standard of care per their 
facility. However, in order to avoid confounding any conclusions attributable to the wound matrix, 
negative pressure wound therapy (NPWT) of the target wound will not occur during the study. Patients 
having NPWT on the target wound when they are screened may be included in the study (provided 
they meet all the inclusion criteria and none of the exclusion criteria), except when NPWT is not or 
cannot be discontinued after application of the device. The potential use of NPWT on the target 
wound, after application of the device, on a patient is listed below as an exclusion criterion. During 
the course of the study, if a physician determines that a patient could benefit from NPWT on the target 
wound, the physician can implement this therapy, and the patient will be discontinued from the study.   
4.2. End of Study Definition   
A patient’s participation in the study may end at several critical points:   
• 
The patient completes Phase II.  

 
  
  
 
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• 
The patient’s physician determines a STSG is no longer necessary.   
• 
The patient is unwilling or clinically inappropriate, per determination by the Investigator, to 
receive a second application of the device or STSG. The silicone backing should be removed 
at 21 days but the decision to reapply the device or schedule the STSG may happen up to 
three days thereafter.  
• 
The patient is not ready to receive a STSG after two applications of the device. The silicone 
backing should be removed 21 days after the second application of the device but the decision 
to schedule the STSG may happen up to three days thereafter.  
• 
The patient develops an infection of the target wound at any time.  
• 
The patient needs NPWT of the target wound after application of the device.  
The end of the study will coincide with the issuance of a clinical study report that has been approved by 
Medline’s Clinical Affairs Director.   
5. STUDY POPULATION   
5.1. Inclusion Criteria  
A patient will be eligible to participate in the study if he or she satisfies ALL of the inclusion criteria 
below:  
• 
Patients who are 18-85 years old  
• 
Patient with a wound originating from a thermal or electrical burn  
• 
Total burn area is less than 20% of TBSA  
• 
Target burn wound is greater than 0.5% of TBSA  
• 
Patient has undergone escharectomy procedure or will undergo escharectomy on the target 
wound before application of the device, and resulting wound will likely need an STSG, but 
wound site is not immediately ready for grafting.  
• 
For patients with diabetes, an A1C hemoglobin level below 11 percent (taken within 90 days).  
  
5.2. Exclusion Criteria  
A participant is ineligible for the study if he or she meets ANY of the criteria below:  
• 
Current active diagnosis of substance abuse, per the Investigator  
• 
Patient currently taking non-inhaled corticosteroids   
• 
Patient needs or is likely to need NPWT of the target wound after application of the device  
• 
Patient is pregnant, planning to become pregnant during study period, or breastfeeding  
• 
Unstable medical condition as determined by the site investigator or sub-investigator  
• 
Patients with known sensitivities to hyaluronan, hyaluronan derivatives, silicone, or any 
other ingredients of the device  

 
  
  
 
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5.3. Strategies for Recruitment and Retention   
Each site investigator regularly treats burn patients at the burn centers they serve. The site 
investigators and their staff will recruit potentially eligible patients from their practice. As the use of 
the wound device in this study will be a core piece of the patient’s treatment plan, it is expected that 
retention will not be an issue during Phase I (pre-STSG).   
6. STUDY PROCEDURES AND ASSESSMENTS  
6.1. Phase I – Pre-STSG  
6.1.1. Day 0 – Screening Visit and Informed Consent  
 
6.1.1.1.  
Informed Consent  
Prior to conducting study activities, written consent will be obtained from all participating 
subjects and documented on an informed consent form (ICF) that has received approval by 
an IRB/Ethics Committee. The ICF must be written in adherence to Good Clinical Practice 
(GCP) and comply with all elements required by FDA CFR 50.25 and International Conference 
on Harmonization (ICH) 4.8, state and local regulations, and additional elements relevant to 
specific study situations, (including a statement that Medline Industries, Inc. and authorities 
have access to subject records). A copy of the signed consent form will be given to each 
participating subject.  
 
6.1.1.2.  
Eligibility Screening  
Potential participants will be screened for eligibility via a combination of the screening form, 
provided separately by Medline Industries, Inc., and by a review of the potential participant’s 
burn wound and medical chart by one of the site investigators or their staff. In the event a 
participant has multiple burn wounds, the site investigator will select the target wound that 
meets the inclusion criteria; in the event more than one wound meets all inclusion criteria, 
the site investigator will choose the wound (target wound) he or she believes to be most 
clinically appropriate for treatment with the device. If a potential participant with diabetes 
does not have an A1C level recorded in his or her chart within the past 90 days, a qualified 
member of the study staff or a site investigator’s institution will perform a blood draw to be 
used for A1C calculation. If a potential participant has NPWT on the target wound during 
screening, that participant may still be included in the study provided that participant meets 
all the inclusion criteria, none of the exclusion criteria, and if NPWT will be discontinued right 
before application of the device.   
   

 
  
  
 
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6.1.2. Day 1 – Initial Visit  
 
6.1.2.1.  
Demographics, Comorbidities, Wound history and Medication  
To allow for a deeper understanding of the effect of the device on patients’ wounds, 
demographic information, patient co-morbidities, historical treatment modalities of the 
target wound, and current medication list will be collected at the time of initial visit. Intake of 
analgesics will be captured throughout the study. Information pertaining to the escharectomy 
procedure will also be recorded. This will allow for post-hoc analyses that may inform the 
design of the larger clinical study. Information will be recorded on the Case Report Forms 
(CRFs) provided separately by Medline Industries, Inc.   
 
6.1.2.2.  
Wound Photograph and Area Measurement  
During the initial visit, a member of the study staff will take a photograph of the wound using 
a specialized wound camera with image analysis software (inSight® by eKare Inc.), 
postescharectomy and immediately prior to application of the device. The image analysis 
software will calculate wound volume and area automatically, and will collect wound depth. 
In the event the camera or software malfunction, wound area and volume will be assessed 
manually with a ruler or other measuring device used for measuring wound area and volume.   
 
6.1.2.3.  
Pain Assessment  
Patients will be asked to rate their current level of pain, both overall and at the wound, using 
a verbal Likert-type scale. Patients will respond with a whole number between 0-10, with 0 
corresponding to “no pain” and 10 corresponding to “the worst pain imaginable.”  
 
6.1.2.4.  
Analgesic Usage  
Since usage of analgesic(s) will likely affect a patient’s self-assessment of pain, analgesic usage 
will be recorded throughout the study in order to provide a full picture of pain management.  
This information will be recorded on CRFs provided separately by Medline Industries, Inc.  
 
6.1.2.5.  
Infection Evaluation  
At this visit, as well as all visits and during the continuum of the patient’s participation in the 
study, the wound site will be evaluated for the development of an infection. In the event of a 
suspected infection, clinical staff will collect a wound culture. Should a patient develop an 
infection, this will be noted as an expected adverse event (AE) and the participant’s 
participation in the study will be terminated.   
 
6.1.2.6.  
Placement of the device  
After taking wound photograph (post-escharectomy), conducting wound area and volume 
measurement and assessment, the site investigator or qualified study staff will place the 

 
  
  
 
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device on the wound, along with an appropriate secondary dressing. Wound photograph will 
also be taken immediately after application of the device.  
6.1.3. Interim Visits – Day 7, 14, 21, 28, 35, 42  
At the interim visits during Phase I, patients will have their wound assessed, and will then be 
photographed using the same method as described in section 6.1.2.2. Remaining Interim visit 
activities will then be performed as stated in 6.1.2.3 through 6.1.2.5. The site investigator will 
assess if the wound is ready to receive an STSG at these visits. If the wound is ready for an STSG, 
the date of STSG approval and planned date of STSG procedure will be noted on the CRF provided 
by Medline Industries, Inc.. Should the site investigator deem that healing has progressed such 
that an STSG is no longer necessary, the patient’s participation in the study will be discontinued. 
If after 21 days of device usage the patient is not ready to receive an STSG, a second application 
of the device may be applied and Phase I will be extended for an additional 21 days (for a 
maximum of 42 total days of device usage). If the patient is unwilling or clinically inappropriate, 
per determination by the PI, to receive a second application of wound matrix or STSG after 21 
days, the patient’s participation in the study will end. Alternatively, if the site investigator believes 
the wound will be ready to receive an STSG within three additional days of healing, but does not 
require another device application, the silicone backing of the device will be removed at Day 21 
and the STSG will be scheduled by the Investigator or treating physician. Similarly, after 21 days 
of second application of the device, if the site investigator believes the wound will be ready to 
receive an STSG within three additional days of healing, the silicone backing of the device will be 
removed 21 days after the second application of the device and the STSG will be scheduled by the 
investigator or treating physician.STSG will be scheduled by the investigator or treating physician.  
Information pertaining to length-of-stay and discharge will also be collected. The timing of the 
visit days is approximate, as scheduling challenges may cause the exact visit days to not occur 
exactly every seven days. However, visits should occur within +/- two days of the original sevenday 
interval.   
6.2. Phase II – Post-STSG  
6.2.1. Interim Visits – Post-STSG Days 7, 14, 21, 28,   
Following the completion of the STSG procedure, the patient will attend up to four interim visits 
to monitor wound healing progress and percent take of the STSG. Also, at Day 7 visit, information 
relating to the graft procedure will be recorded on the Surgical Procedures CRF provided 
separately by Medline Industries, Inc. At each visit, a photograph of the wound will be taken and 
the site investigator will also determine the percentage of STSG take at each visit, which will be 
based on the clinical judgement. The patient will also rate current pain level (overall and at the 
target wound) in an identical fashion to Section 6.1.2.3. A patient’s participation in Phase II of the 
study will continue for 28 days post-STSG or until the site investigator determines weekly care is 
no longer needed. To document wound healing completion, a photograph of the healed wound 
will be taken. In order to track the participant’s overall outcomes, any returns to the operation 

 
  
  
 
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room to treat the target wound, any additional inpatient stays, and the type of facility the patient 
goes to at discharge will be captured on the CRFs. The timing of the visit days is approximate, as 
scheduling challenges may cause the exact visit days to not occur exactly every seven days. 
However, visits should occur within +/- two days of the original seven-day interval.   
7. ADVERSE EVENTS   
7.1. Definition of Adverse Event  
Since this is a post-market study and the device is used within its intended use, participation in the 
study presents minimal risk to the patient. Additionally, this patient population may have numerous 
comorbidities and health issues unrelated to the wound. Therefore, a narrower definition of a 
nonserious adverse event (AE) will be used. In this study, an AE is any untoward medical occurrence 
related to the wound or treatment of the wound, including infection, significant increases in pain, and 
unexpected reactions at the site of wound device placement.   
7.2. Definition of Serious Adverse Event  
The FDA definition of a serious adverse event (SAE) will be used in this study: An AE or suspected 
adverse reaction is considered "serious" if, in the view of either the site investigator or sponsor, it 
results in any of the following outcomes:   
• 
Death  
• 
A life-threatening adverse event  
• 
Inpatient hospitalization or prolongation of existing hospitalization   
• 
A persistent or significant incapacity or substantial disruption of the ability to conduct normal 
life functions or,  
• 
A congenital anomaly/birth defect.   
Important medical events that may not result in death, be life-threatening, or require hospitalization 
may be considered serious when, based upon appropriate medical judgment, they may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in 
this definition. All SAEs will be reported to the sponsor, regardless of potential relationship to the 
wound or treatment of the wound.   
7.3. Severity of Adverse Event  
The severity of all adverse events will be graded on a scale of one through five according to the 
Common Terminology Criteria for Adverse Events guideline, where each grade represents a unique 
clinical description based on this general guideline:  
  
• 
Grade 1: Mild; asymptomatic or mild symptoms; clinical or diagnostic observation only; 
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• 
Grade 2: Moderate; minimal, local or noninvasive intervention indicated; limited 
ageappropriate instrumental activities of daily living.  
• 
Grade 3: Severe or medically significant but not immediately life-threatening; hospitalization 
or prolongation of hospitalization indicated; disabling; limiting activities of daily living 
involving self-care.   
• 
Grade 4: Life threatening consequences; urgent intervention indicated  
• 
Grade 5: Death related to AE  
7.4. Relatedness of Adverse Event and Serious Adverse Event  
  
• 
Unrelated: This category applies to those adverse events which, after careful consideration, 
are clearly and incontrovertibly due to extraneous causes (disease, environment, etc.)  
• 
Possible: This category applies to those adverse events for which, after careful medical 
consideration at the time they are evaluated, a connection with the Investigational Product 
administration appears unlikely but cannot be ruled out with certainty.  
• 
Probable: This category applies to those adverse events which, after careful medical 
consideration at the time they are evaluated, are felt with a high degree of certainty to be 
related to the Investigational Product.  
• 
Definite: This category applies to those adverse events which, after careful consideration, 
are clearly and incontrovertibly due to the Investigational Product.  
7.5. Expectedness  
The site investigator will be responsible for determining whether an AE or SAE is expected or 
unexpected. An AE will be considered unexpected if the nature, severity, or frequency of the event is 
not consistent with the risk information previously described for the device.   
Expected AEs include a reaction at the wound site following application of the wound device or 
infection.   
7.6. Adverse Event Reporting  
AEs will be recorded on the AE form provided separately by Medline Industries, Inc. Changes in the 
severity of an AE will be documented to allow an assessment of the duration of the event at each level 
of severity. Changes in severity will necessitate a new AE form to document the new level of severity. 
AEs characterized as intermittent require documentation of onset and duration of each episode.  
Non-serious AEs should be reported to the study sponsor routinely at a cadence negotiated by the site 
and CRA.  Any AE that meets the requirements for IRB reporting should be done so according to the 
timeline for this per the IRB.    

 
  
  
 
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7.7. Serious Adverse Event Reporting  
The site investigator shall complete an SAE Form provided separately by Medline Industries, Inc. and 
submit to the study sponsor as soon as possible, but in no event later than 48 hours after the PI first 
learns of the event. The PI will be responsible for reporting the event to the IRB if applicable per the 
IRB’s reporting requirements. The study sponsor is responsible for conducting an evaluation of the 
SAE and shall report the results of such evaluation to the FDA, if applicable, and to all reviewing IRBs, 
if applicable, within 10 working days after the sponsor first receives notice of the event. Thereafter, 
the sponsor shall submit such additional reports concerning the event as FDA requests.  
  
For questions regarding this process or the event, you may contact your Medline clinical designee or 
the Medline Director of Clinical Operations:  
Name: Kara Cassady  
Phone:  847-643-3809  
E-mail:  kcassady@medline.com  
8. STATISTICAL CONSIDERATIONS  
8.1. Sample Size Determination   
This study is a case series meant to evaluate the clinical usage of the device and is not intended to 
inform any hypothesis testing. Therefore, a sample size of 20 patients was chosen, which is consistent 
with a case-series.   
8.2. Populations for Analyses  
An evaluable population will be used for all analyses, with the definition of evaluable depending on 
the Phase of the study. For Phase I, all patients with an initial visit and a final interim visit resulting in 
resolution of Phase I will be included. In Phase II, patients with data from any interim visits who also 
complete Phase II to resolution will be included in analyses for Phase II.   
8.3. Statistical Analysis  
Descriptive statistics, including measures of central tendency (mean or median), measures of variation 
(standard deviations, coefficients of variation) and 95% confidence intervals and interquartile ranges, 
as appropriate, for the data distribution will be calculated for all endpoints. Demographic and baseline 
characteristics will be assessed as above and additional statistical analyses may be conducted in an 
exploratory fashion, as appropriate, for the data distribution.  
• 
Time (in days) from initial application of wound matrix to approval of wound to receive an STSG.  
• 
Change in wound volume from the time prior to application of the wound matrix to the time 
before the application of STSG and after STSG  
• 
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• 
Patient pain ratings  
• 
Proportion of STSG take, per clinician judgement, for the wound at 28 days   
• 
Proportion of patients who develop an infection of the target wound at any time, per confirmation 
with culture   
• 
Type of care setting where patient is discharged  
Healthcare economics outcomes will be explored by combining length-of-stay data (both phases) and 
the type of care setting where the participant is discharged, with standard costs, reimbursement codes 
and other relevant health economics economic factors.   
9. SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS  
9.1. Clinical Monitoring  
The Clinical Research Associate (CRA) will confirm that the rights and well-being of subjects are 
protected, and that the reported trial data are accurate, complete, and verifiable from source 
documents. Moreover, the CRA will confirm the conduct of the trial by the site investigators and 
sites are in compliance with the protocol, GCP, and regulatory requirements as well as any 
applicable institution or IRB and federal or local processes. Monitoring will occur at minimum every 
two months, or more or less depending on enrollment, during the study duration or more 
frequently if:  
• 
The volume or quantity of data is large or there is a backlog of review due to unexpected 
issues  
• 
This would also include any large volume of CRFs to be reviewed   
• 
The site compliance with the protocol or compliance with expected ICH/GCP and 
regulatory requirements is lacking or there are continuing unresolved compliance issues  
• 
There are unexpected AE/SAE or subject safety concerns noted   
• 
There are any unexpected inconsistencies with study product management  
• 
There is a request for more frequent monitoring by the site  
• 
Any mutually agreeable situation as determined by the sites and Medline   
The frequency of routine monitoring may be increased to a longer interval after three monitoring 
cycles if on-site situations support this change. CRA will discuss this with Medline Director or Clinical 
Managers and will inform the site investigator prior to implementation.   
Monitoring activities will include subject eligibility, source data review, CRF completion verification, 
product accountability, site continued suitability, investigator study oversight, compliance, and all 
general monitoring activities as outlined in FDAs Code of Federal Regulations and ICH/GCP 
guidelines that guide that activity.    
Medline Industries Inc. may, on occasion, contract with external Clinical Research Organizations to 
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It is expected that the site will be compliant with any institutional Standard Operating Procedures 
during the execution of the protocol and evidence of that compliance should be readily 
documented and verifiable by the CRA.   
The CRA will generate an internal Medline Industries Inc. visit report that will be filed with the 
Medline Industries, Inc. trial master file and will provide the site investigators a detailed follow-up 
letter after each monitoring visit that will outline the completed monitoring activities as well as any 
identified areas of concern and the expected/applicable corrections needed. Medline Industries 
Inc., reserves the right to perform audit of the study activities – either routine or for-cause – as 
needed, and may also perform clinical monitoring audit as well.  
9.2. Regulatory and Ethical Considerations  
9.2.1. Confidentiality and Privacy  
Participant confidentiality and privacy is strictly held in trust by the site investigators, their staffs, 
and the Sponsor. Therefore, documentation, data, and all other information generated will be 
held in strict confidence. No information concerning the study or the data will be released to any 
unauthorized third party without prior written approval of the Sponsor. All study data and study 
records will be managed and stored in accordance with the site’s HIPAA compliant policies on 
data storage and security. All electronic transmission of data will adhere to HIPAA Security Rules.  
  
The study monitor, other authorized representatives of the Sponsor, representatives of the IRB 
and regulatory agencies may inspect all documents and records required to be maintained by the 
site investigators, including but not limited to, medical records (office, clinic, or hospital) and 
pharmacy records for the participants in this study. The clinical study sites will permit access to 
such records.  
  
A master list linking subject numbers to patient name and medical record number will be 
maintained in a secure database or secure paper file(s) by the site investigators. The study 
participant’s contact information will be securely stored at each clinical site for internal use during 
the study. At the end of the study, all records will continue to be kept in a secure location for at 
least a period of two years, or longer if dictated by the reviewing IRB, Institutional policies, 
Sponsor requirements, or ICH/GCP and FDA requirements.  The site investigator will agree to 
notify Sponsor of any intent to move or destroy these documents.   
Study participant research data, which is for purposes of statistical analysis and scientific 
reporting, will be maintained at the research sites on the CRFs. Copies of the CRFs, which will not 
contain any identifiable information, will be provided to the Sponsor for the purposes of data 
analysis.  The study data entry and study management systems used by clinical sites and by 
Medline Industries, Inc. research staff will be secured and stored in an access controlled locked 
drawer (any paper forms) and password protected (electronic records). At the end of the study, 

 
  
  
 
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all study databases that are not already de-identified will be de-identified and archived at Medline 
Industries, Inc.  
9.2.2. Safety Oversight  
Given that this is a post-market study on a device used in accordance with its labeling, there is 
minimal safety risk to participants. The site investigators specialize in treating burn wounds and 
are qualified to provide adequate safety oversight for the study. In the event there any AEs or 
SAEs, the site investigator will review them any make any necessary safety determinations as 
needed.   
9.2.3. Data Handling and Record Keeping  
  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the 
site investigator. The site investigator is responsible for ensuring the accuracy, completeness, 
legibility, and timeliness of the data reported.  
  
All source documents of any kind (electronic, paper, etc.) should be completed in accordance with 
Good Documentation Practices (GDP) to ensure accurate interpretation of data.  CRFs will be 
created for each subject. The CRA will verify the data entered into the CRF with the site source 
regardless of the type of source. The site will be responsible for developing a written process that 
ensures the CRA is able view the source data.     
  
Data from the CRFs will be entered into an electronic spreadsheet via dual-entry to assure no 
errors. Analyses will be conducted in the Statistical Analysis System, SAS® 9.4 of the SAS System 
for Windows. Copyright © 2013 SAS Institute Inc.  This system allows for internal quality checks, 
such as automatic range checks, to identify data that appear inconsistent, incomplete, or 
inaccurate. Medline Industries, Inc. will be responsible for overseeing final data analysis and 
confirmation of results.   
9.2.4. Study Records Retention  
  
Study documents should be retained until at least two years have elapsed since the formal 
discontinuation of the study intervention or as required by any applicable FDA guidelines or for a 
longer period if required by local regulations. No records will be destroyed without the written 
consent of the Sponsor, if applicable. It is the responsibility of the Sponsor to inform the site 
investigator when these documents no longer need to be retained. The site investigator is 
required to notify Medline if the location of the stored documents is changed after it is defined at 
the time of the Close Out Visit at study end.   

 
  
  
 
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9.2.5. Study Discontinuation   
This study may be temporarily suspended or prematurely terminated if there is sufficient 
reasonable cause.  Written notification, documenting the reason for study suspension or 
termination, will be provided by the suspending or terminating party to the site investigator, 
Sponsor, and IRB.  If the study is prematurely terminated or suspended, the site investigator will 
promptly inform the IRB and Sponsor and will provide the reason(s) for the termination or 
suspension.    
Circumstances that may warrant termination or suspension include, but are not limited to:  
• 
Determination of unexpected, significant, or unacceptable risk to participants as 
determined by AE review  
• 
Insufficient compliance to protocol requirements  
• 
Data that are not sufficiently complete and/or evaluable  
The study may resume once concerns about safety, protocol compliance, and data quality are 
addressed, and satisfy the Sponsor and/or IRB.  
9.2.6. Study Closeout  
Upon completion of the study, Medline and/or its designees will notify the sites of closeout 
related procedures and will coordinate with the site the return of equipment and/or any unused 
product.  Medline CRA will communicate closely with the site investigators at that time point and 
will review all close out steps and materials. All study data, related study documents, and unused 
study product, will be returned to the Sponsor.  The site will also notify the IRB that the study has 
completed.  
9.2.7. Conflict of Interest Policy  
The independence of this study from any actual or perceived influence is critical. Therefore, any 
actual conflict of interest of persons who have a role in the design, conduct, analysis, publication 
or any aspect of this trial will be disclosed and managed.  
9.3. Protocol Deviations  
It is the responsibility of the site investigators and study staff to use continuous vigilance to 
identify and report deviations on a routine basis. All deviations must be addressed in study source 
documents, and reported to Medline Industries, Inc. Protocol deviations must be sent to the 
reviewing IRB per their policies. The site investigator is responsible for knowing and adhering to 
the reviewing IRB requirements.  
9.4. Abbreviations  
AE  
Adverse Event  
CFR  
Code of Federal Regulations  

 
  
  
 
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CRA  
Clinical Research Associate  
CRF  
Case Report Form  
FDA  
Food and Drug Administration   
GCP  
Good Clinical Practice  
GDP  
Good Documentation Practice  
HIPAA  
Health Insurance and Portability Accountability Act  
ICF  
Informed Consent Form  
ICH  
International Conference on Harmonization  
IFU  
Instructions for Use  
IRB  
Institutional Review Board  
NPWT  
Negative Pressure Wound Therapy  
SAE  
Serious Adverse Event   
STSG  
Split-thickness skin graft  
TBSA  
Total body surface area  
  
10. REFERENCES  
1. Rowan MP, Cancio LC, Elster EA, Burmeister DM, Rose LF, Natesan S, Chan RK,Christy RJ, Chung 
KK. Burn wound healing and treatment: review and advancements. Crit Care. 2015 Jun 
12;19:243. doi: 10.1186/s13054-015-0961-2.   
2. Fraser JR, Laurent TC, Laurent UB. Hyaluronan: its nature, distribution,functions and turnover. J 
Intern Med. 1997 Jul;242(1):27-33.  
3. Voigt J, Driver VR. Hyaluronic Acid Derivatives and Their Healing Effect on Burns, Epithelial 
Surgical Wounds, and Chronic Wounds: a Systematic Review and Meta-Analysis of Randomized 
Controlled Trials. Wound Repair Regen. 2012 May-Jun;20(3):317-31.  
4. Gravante G, Sorge R, Merone A, et al. Hyalomatrix PA in Burn Care Practice: Results From a 
National Retrospective Survey, 2005–2006. Ann Plast Surg. 2010;64(1):69–79.  
11. APPENDIX  
 
11.1.  
Hyalomatrix® Wound Device Instructions for Use  

 Medline Industries, Inc.  
 
 
 
 
 
 

 Medline Industries, Inc.  
 
 
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