Assessment of Wound Closure Comparing Synthetic Hybrid-Scale Fiber Matrix With Standard of Care in Treating Diabetic Foot Ulcers (DFU) and With Living Cellular Skin Substitute in Treating Venous Leg Ulcers (VLU)
Phase: NA
Conditions: Diabetic Foot Ulcer, Venous Leg Ulcer
Sponsor: Acera Surgical, Inc.

 Protocol Number 21-RES-001 Rev.  03 
  Acera Surgical, Inc. 
Acera Surgical, Inc.  Company Confidential 
Page 1 of 52 
Assessment of Wound Closure Comparing Synthetic Hybrid-
Scale Fiber Matrix with Standard of Care in Treating Diabetic 
Foot Ulcers (DFU) and with Living Cellular Skin Substitute in 
Treating Venous Leg Ulcers (VLU) 
Protocol Number: 21-RES-001 
Revision:  03 
Date:  30 September 2022 
Acera Surgical, Inc. 
 1650 Des Peres Rd., Ste. 120 
Saint Louis, MO 63131 
844-879-2237
This document contains confidential information belonging to Acera Surgical. Except 
as may be otherwise agreed to in writing, by accepting or reviewing these materials, 
you agree to hold such information in confidence and not to disclose it to others 
(except where required by applicable law), nor to use it for unauthorized purposes. In 
the event of actual or suspected breach of this obligation, Acera Surgical should be 
promptly notified. 
NCT04927702

 Protocol Number 21-RES-001 Rev. 01 
            Acera Surgical, Inc. 
 
PROTOCOL APPROVAL SIGNATURE PAGE 
Assessment of Wound Closure Comparing Synthetic Hybrid-Scale Fiber 
Matrix with Lyophilized Acellular Fish Skin in Treating Diabetic Foot 
Ulcers (DFU) and with Living Cellular Skin Substitute in Treating Venous 
Leg Ulcers (VLU) 
Protocol Number:  21-RES-001 
Revision: 01 
 
 
Matthew MacEwan, PhD                                                                                             Date                  
Chief Science Officer 
Acera Surgical, Inc. 
!
                                                                           2/8/2021 
         Pamela McKeown, M.A.                       
      Date 
         Vice President, Health Policy and Reimbursement                                                                               
Acera Surgical, Inc. 
!
 
Feb 7, 2021 
William Marston, M.D.                                                                                               Date 
Principal Investigator 
Acera Surgical, Inc. Ñ Company Confidential 
Page !  of !
2
60
2/8/2021

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Page 3 of 52 
 
 
 
 
PRINCIPAL INVESTIGATOR SIGNATURE PAGE 
 
Assessment of Wound Closure Comparing Synthetic Hybrid-Scale Fiber 
Matrix with Standard of Care Standard of Care in Treating Diabetic 
Foot Ulcers (DFU) and with Living Cellular Skin Substitute in Treating 
Venous Leg Ulcers (VLU) 
 
Protocol Number:  21-RES-001 
Revision:  03 
 
 
The trial will be conducted in accordance with the ethical principles that have their origin in the 
Declaration of Helsinki and in compliance with this protocol, Good Clinical Practice (GCP) 
guidelines, and applicable regulatory requirements and laws. 
 
 
I hereby confirm that I approve of this Clinical Study Protocol and agree to comply with its 
terms as laid out in this document.  I agree to ensure that all staff members involved in the 
conduct of this study are informed about their obligations in meeting the above commitments. 
 
 
 
 
         Printed Name                                       Signature                                         Date 
          
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
1. PROTOCOL SUMMARY .....................................................................................................6 
2. INTRODUCTION & PURPOSE ...........................................................................................8 
2.1. Background .......................................................................................................................8 
2.2. Purpose ...........................................................................................................................10 
2.3. Intended Use/Indications of Synthetic Hybrid-Scale Fiber Matrix ................................10 
  2.4. Intended Use/Indications of Comparison Products.11    
3. STUDY DESIGN.................................................................................................................11 
4. PATIENT SELECTION ......................................................................................................14 
4.1. Diabetitic Foot Ulcers .....................................................................................................14 
4.2. Venous Leg Ulcers .........................................................................................................16 
5. STUDY CONDUCT ............................................................................................................17 
5.1. Schedule of Events for DFU Patients .............................................................................18 
5.2. Schedule of Events for VLU Patients .............................................................................19 
5.3. Screening ........................................................................................................................22 
5.4. Informed Consent ...........................................................................................................22 
5.5. Run-In Period .................................................................................................................22 
5.6. Point of Enrollment ........................................................................................................24 
 5.7. Randomization... 24 
5.8. Blinding......  25 
5.9. Treatment Week 0..  27 
5.10. Study Treatment Period...  30 
5.11. 3D Wound Measurement.  31 
5.12. Virtual Visits at Weeks 5 and 9 32 
5.13. Two-Week Visit to Confirm Wound Closure.....  33 
5.14. Six-Month Telephone Call...  33 
5.15. Study Exit.....  33 
6. ADVERSE EVENTS ...........................................................................................................35 
6.1. Principal Investigator Responsibilities ...........................................................................35 
6.2. Adverse Event Definitions .............................................................................................35 
6.3. Adverse Event Assessment ...............................................................................................6 

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6.4. Adverse Event Reporting ...............................................................................................37 
7. PROTOCOL DEVIATIONS ...............................................................................................37  
8. RISKS AND BENEFITS .....................................................................................................38 
9. STATISTICAL CONSIDERATIONS.................................................................................38 
9.1. Hypotheses to be Tested .................................................................................................38 
9.2. Analysis Populations ......................................................................................................39 
9.3. Sample Size Calculation .................................................................................................39 
9.4. Interim Analysis .............................................................................................................39 
9.5. Statistical Analysis .........................................................................................................42 
9.6. Strategies to Address Missing Data ................................................................................46 
10. DATA HANDLING AND RECORD KEEPING .............................................................46 
11. ETHICS..............................................................................................................................47 
11.1. Ethical Conduct of the Study ........................................................................................47 
11.2. Insitutional Review Board ............................................................................................47 
11.3. Confidentiality ..............................................................................................................48 
12. MONITORING ..................................................................................................................48 
13. SPONSOR DISCONTINUATION CRITERIA ................................................................48 
13.1. Termination of the Study by the Sponsor .....................................................................49 
13.2. Termination of Site by the Sponsor ..............................................................................49 
13.3. Termination by the Investigator ...................................................................................49 
14. PUBLICATIONS POLICY ...............................................................................................49 
15. SUMMARY OF PROTOCOL REVISIONS .....................................................................50 
16. REFERENCES ..................................................................................................................50 
17. APPENDICES ...................................................................................................................52 
17.1. Synthetic Hybrid-Scale Fiber Matrix Instructions for Use ...........................................52 
17.2. Standard of Care Instructions for Use5317.3. Living Cellular Skin Substitute Instructions 
for Use ......................................................................................................................54 
  
1.  PROTOCOL SUMMARY 
Title 
Assessment of Wound Closure Comparing Synthetic Hybrid-Scale Fiber Matrix 
with Standard of Care in Treating Diabetic Foot Ulcers (DFU) and with Living 
Cellular Skin Substitute in Treating Venous Leg Ulcers (VLU) 

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Protocol 
Number 
21-RES-001; Revision: 03 
Protocol Date 
08 March 2021 
Study Design 
Prospective, randomized, single-blinded, comparison, non-inferiority study  
Study Sponsor 
Acera Surgical, Inc. 
1650 Des Peres Rd., Ste. 120St. Louis, MO 63131 
844-879-2237 
Steering 
Committee 
A Steering Committee consisting of physicians working with the Sponsor will 
provide guidance on study procedures, subject enrollment, adverse events and 
protocol compliance.   
Study Product 
Synthetic hybrid-scale fiber matrix (Restrata®)  
Indications for 
Use 
Restrata is intended for use in the management of wounds, including:  partial and full 
thickness wounds, pressure sores/ulcers, venous ulcers, diabetic ulcers, chronic 
vascular ulcers, tunneled/undermined wounds, surgical wounds (e.g., donor 
site/grafts, post-laser surgery, post-Mohs surgery, podiatric wounds, wound 
dehiscence), trauma wounds (e.g., abrasions, lacerations, partial thickness burns, skin 
tears), and draining wounds. 
Comparator 
Products 
Standard of Care for patients with diabetic foot ulcers 
 
Living cellular skin substitute (Apligraf®) for patients with venous leg ulcers 
Enrollment Size  Diabetic Foot Ulcers: The initial planned enrollment is 110 patients. An interim 
analysis will be performed after 56 patients complete the primary endpoint. 
Based on the interim analysis result, the enrollment size may be increased to a 
maximum of 166 patients. 
 Venous Leg Ulcers: The initial planned enrollment is 60 patients. An interim 
analysis will be performed after 30 patients complete the primary endpoint. 
Based on the interim analysis result, the enrollment size may be increased to a 
maximum of 90 patients. 
Primary 
Outcome 
Measure 
 Diabetic Foot Ulcers: 100% re-epithelialization of wound within 12 weeks after 
the initial application of the study product plus confirmation of no drainage or 
need for additional dressing 2 weeks after 100% re-epithelialization 

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 Venous Leg Ulcers: 100% re-epithelialization of wound within 16 weeks after 
the initial application of the study product plus confirmation of no drainage or 
need for additional dressing 2 weeks after 100% re-epithelialization 
Secondary 
Outcome 
Measures 
1. Decrease in wound area  
2. Time from initial application of study product to 100% re-epithelialization of 
wound  
3. Total number of product applications  
Tertiary 
Outcome 
Measures 
1. Quality of Life - SF-36 Questionnaire 
2. Pain reported by patient 
3. Incidence of adverse events 
4. Ease of Use and handling of study product 
5. Cost effectiveness / economic model (amount of product usage, length of 
treatment) 
6. Reimbursement and/or payer access 
Assessment 
Time-Points 
➢ Run-In Period to verify enrollment criteria: 2 weeks before initial application of 
study product 
➢ Product Application: 
o DFUs:  
▪ Patients randomized to synthetic hybrid-scale fiber matrix:  
Biweekly application for either 12 weeks or until 100% re-
epithelialization (whichever occurs first) 
▪ Patients randomized to Standard of Care:  
Weekly dressing application for either 12 weeks or until 100% re-
epithelialization (whichever occurs first) 
o VLUs: Biweekly application for either 16 weeks or until 100% re-
epithelialization (whichever occurs first) 
➢ Wound assessment, imaging, and AEs: 
o DFUs: Day of initial product application and weekly for either 12 weeks 
or until 100% re-epithelialization (whichever occurs first) 
o VLUs: Day of initial product application and weekly for either 16 weeks 
or until 100% re-epithelialization (whichever occurs first) 
➢ Quality of Life and Pain Assessments: 
o DFU patients: Day of initial product application and at either 100% re-
epithelialization or 12 weeks (whichever occurs first) 
o VLU patients: Day of initial product application and at either 100% re-
epithelialization or 16 weeks (whichever occurs first) 

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➢ For patients with 100% re-epithelialization:  
o Clinic visit two weeks after 100% re-epithelialization to verify wound 
closure, drainage, and need for additional dressing 
o Telephone call six-months after initial product application to verify wound 
closure, drainage, and need for additional dressing 
 
2. INTRODUCTION & PURPOSE 
2.1 Background  
Diabetes and peripheral vascular disease are both growing healthcare problems that can 
lead to chronic wounds by compromising skin integrity and impairing the wound healing 
process1. Chronic wounds affect more than 6.5 million patients annually in the United 
States2. In particular, many diabetic foot ulcers (DFUs) and venous leg ulcers (VLUs) fail 
to heal with standard options such as debridement, dressings, and infection control1. Skin 
substitutes can regenerate tissue and replace lost skin for wounds that are otherwise 
difficult to treat2.   
The process of wound healing requires a coordinated effort of cellular recruitment and 
tissue growth. Regenerative matrix materials have been used as a skin substitute to promote 
this coordination and provide immediate wound coverage to minimize the risks associated 
with infection and fluid loss.3 An ideal material for these purposes would serve as a healing 
scaffold, limit infection risk, minimize inflammation, be readily available for use, and be 
conformable to diverse wound surfaces.  
Human autografts and allografts, animal-based xenografts, and fully synthetic materials 
have been used clinically with varying degrees of success.4 Autograft availability is limited 
by definition and creates iatrogenic morbidity at donor sites.  Allografts and xenografts 
eliminate the morbidity associated with autografts but introduce additional risks of 
inflammatory response and disease transmission. 3 Furthermore, host rejection of allografts 
and xenografts remains a concern in wound populations where the rate of immune disease 
has been reported as high as 23%.  
To support the infiltration of fibroblasts, the deposition of new collagen, and re-
epithelialization of the wound surface, the wound matrix material should persist in the 
wound for at least three weeks.5 The timing of wound matrix degradation is therefore 
critical, as the wound matrix should resist degradation until sufficient new tissue growth 
has occurred. The susceptibility of biologic wound matrix materials to enzymatic 
degradation leads to a resorption rate that is poorly controlled, risking the premature 
degradation of the wound matrix prior to sufficient wound healing.  
There remains a need for materials that minimize inflammation and promote complete 
wound healing. Electrospun fibrous scaffolds may meet this need by mimicking the 

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structure of native extracellular environment while enabling resident cells to perform their 
roles in the healing cascade.6  
In 2018, a retrospective study was completed to evaluate clinical efficacy and utility of 
Restrata, a synthetic hybrid-scale fiber matrix.2 The study examined 82 chronic wounds 
including 34 DFUs, 34 VLUs, and 14 other chronic wounds (pressure ulcers, traumatic and 
postsurgical wounds, nonvenous vascular wounds and necrotic wounds). Synthetic hybrid-
scale fiber matrix was applied weekly, or as deemed appropriate for up to 12 weeks. 
Overall, treated wounds demonstrated progressive and sustained wound area reduction 
over the course of treatment, with 85 percent achieving complete closure at 12 weeks.  
Based on these clinical findings a prospective, non-randomized, single-arm study was 
conducted at 5 centers across the United States as a pilot for an expanded randomized 
controlled trial. In the study, wounds were prepared using standard methods or 
debridement, and synthetic hybrid-scale fiber matrix was then applied to the wound so that 
it completely contacted the entire surface of the wound bed. A non-adherent primary 
wound dressing was then applied, followed by appropriate secondary dressing to manage 
the wound exudate and moisture. Post-application, wounds were examined weekly for 
signs of infection, wound progression, and tissue healing for up to 12 weeks, or until 
complete closure, which was confirmed 2 weeks thereafter. The wound area was measured, 
wound appearance was photographed, and wound closure was documented if present. 
Synthetic hybrid-scale fiber matrix was then re-applied weekly or as deemed appropriate. 
At the end of the 12-week treatment period, complete wound closure occurred in 75.0% 
(18/24) of patients who received synthetic hybrid-scale fiber matrix. The average wound 
area reduction over 12 weeks was 96%, and the average time to complete wound closure 
was 6.4 weeks. A significant increase in epithelialization was observed from the initial to 
the final assessment (p<0.0001, Wilcoxon matched pairs signed rank test), with nearly 
complete covering seen at final assessment. This was paralleled by a significant decrease 
in the amount of wound exudate (p<0.0001) to a nearly dry wound at the final assessment, 
and complete disappearance of necrotic tissue over time (p=0.0001). An average of 4.3 
scaffolds were used per patient over the treatment period. Fixation was used to hold all 
scaffolds in place, with the most popular fixation technique being the use of Steri-Strips. 
The decision of the frequency of re-application was solely at the discretion of the clinician 
who was treating the wounds, and results found that half of the patents received re-
application of the nanofiber matrix on a weekly basis, whereas the other half of the patients 
had less frequent re-application rates. Neither fixation technique nor application frequency 
were found to have a statistically significant effect on complete wound closure (p=0.41, 
Chi-square test and p=0.64, Fishers exact test, respectively).  In total, the clinical results 
suggest that synthetic hybrid-scale fiber matrix offers a new and unique alternative in the 
treatment of chronic DFUs and assists in properly powering an expanded multi-center 
randomized controlled clinical trial.  
 
 

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      2.2 Purpose     
The purpose of the following prospective study is to compare synthetic hybrid-scale fiber 
matrix with standard of care in treating diabetic foot ulcers in human subjects, and to 
compare synthetic hybrid-scale fiber matrix with living cellular skin substitute in treating 
venous leg ulcers. Given the large number of skin substitute cellular tissue products in the 
marketplace, this study is being conducted to provide information on healing success with 
a new category of synthetic skin substitutes recently created by the Centers for Medicare 
and Medicaid Services (CMS). The study will demonstrate utilization with synthetic 
hybrid-scale fiber matrix and comparators in generating wound healing outcomes including 
time to wound epithelialization, decrease in wound size, and total number of study product 
applications prior to healing. This information is needed by the payor community in 
determining coverage and reimbursement for the new synthetic hybrid-scale fiber matrix. 
2.3 Intended Use / Indications of the Study Product 
Synthetic hybrid-scale fiber matrix (Restrata) received FDA 510(k) clearance effective 
April 26, 2017 (K170300). It is a sterile, single use product intended for use in local 
management of wounds. It is a soft, white, conformable, non-friable, absorbable matrix 
that acts as a protective covering for wound defects, providing a moist environment for the 
bodys natural healing process to occur. Synthetic hybrid-scale fiber matrix is a synthetic 
electrospun matrix that possesses a hybrid-scale fiber architecture similar to native 
extracellular matrix (ECM), indicated for use in the local management of wounds.  The 
mechanism of action allows for cellular ingrowth and neovascularization before 
completely degrading via hydrolysis. Synthetic hybrid-scale fiber matrix is made from 
synthetic biocompatible materials. The product permits the ingress of cells and soft tissue 
formation in the defect space / wound bed.  The product does not contain any human or 
animal materials or tissues.  
Synthetic hybrid-scale fiber matrix is supplied terminally sterile, in a single use double peel 
package in a variety of sizes. It may be fenestrated or meshed with a scalpel prior to 
application. Synthetic hybrid-scale fiber matrix must be fenestrated prior to use in any 
wound prone to exudate in order to permit effective exudate management. Contents of the 
package are guaranteed sterile and non-pyrogenic unless the package has been opened or 
damaged. 
Synthetic hybrid-scale fiber matrix is intended for use in the management of wounds, 
including:  partial and full thickness wounds, pressure sores/ulcers, venous ulcers, diabetic 
ulcers, chronic vascular ulcers, tunneled/undermined wounds, surgical wound (e.g., donor 
site/ grafts, post-laser surgery, post-Mohs surgery, podiatric wounds, wound dehiscence), 
trauma wounds (e.g., abrasions, lacerations, partial thickness burns, skin tears), and 
draining wounds. Synthetic hybrid-scale fiber matrix will be used for patients with a 
DFU(s) or VLU(s).  

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2.4 Intended Use / Indications of the Comparator Products 
2.4.1: Standard of Care (SOC) will be used for patients with diabetic foot ulcers 
(DFUs) 
Standard of Care  will include preparation of the wound bed using sharp debridement 
to ensure it is free of exudate and devitalized tissue, an aseptic technique for 
application of a non-adherent primary dressing and an off-loading boot as applicable, 
as well as training on primary dressing changes (See Appendix B). 
2.4.2: Living cellular skin substitute will be used for patients with venous leg ulcers 
(VLUs) 
Living cellular skin substitute (Apligraf®), a commercially available product 
manufactured by Organogenesis, Inc., United States, is a skin substitute that looks, 
functions, and responds like healthy skin.8 The epidermal layer contains living human 
keratinocytes and stem cells that provide potent healing signals (growth factors / 
cytokines). The dermal layer contains living human fibroblasts that are contained in a 
bovine Type I collagen lattice. Living cellular skin substitute is FDA-approved (PMA 
P950032) to treat venous leg ulcers and diabetic foot ulcers after four weeks and three 
weeks of failed conventional therapy, respectively. Living cellular skin substitute was 
chosen as a comparator as it is a skin substitute used frequently in the treatment of 
chronic venous leg ulcers. 
3. STUDY DESIGN  
Conditions : Diabetic Foot Ulcers (DFU) and Venous Leg Ulcers (VLU) 
 
Aim: Assessment of complete wound re-epithelialization by comparing synthetic hybrid-
scale fiber matrix with SOC in treating DFUs and with living cellular skin substitute in 
treating VLUs 
 
Study Type: Interventional  
 
Study Design: Prospective, randomized, single-blinded, comparison, non-inferiority study  
 
Control Group:  SOC for DFU patients and living cellular skin substitute for VLU patients   
 
Test Group:  Synthetic hybrid-scale fiber matrix for patients with DFUs and VLUs   
 
Number of Sites:  Up to 10 

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Number of Subjects: 
 Diabetic Foot Ulcers: The initial planned enrollment is 110 patients, with no more 
than 27 DFU patients enrolled at each site. An interim analysis will be performed 
after 56 patients complete the primary endpoint. Based on the interim analysis result, 
the enrollment size may be increased to a maximum of 166 patients with a maximum 
of 41 DFU patients at each site.  
 Venous Leg Ulcers: The initial planned enrollment is 60 patients, with no more than 
15 VLU patients enrolled at each site. An interim analysis will be performed after 30 
patients complete the primary endpoint. Based on the interim analysis result, the 
enrollment size may be increased to a maximum of 90 patients with a maximum of 22 
VLU patients at each site.  
 
Primary Outcome Measure:  
 
 
Diabetic Foot Ulcers:  
100% re-epithelialization of wound as assessed by the blinded evaluator via the 
eKARE inSight platform within 12 weeks after the initial application of the study 
product plus confirmation of no drainage or need for additional dressing 2 weeks after 
100% re-epithelialization 
 
 
Venous Leg Ulcers:  
100% re-epithelialization of wound as assessed by the blinded evaluator via the 
eKARE inSight platform within 16 weeks after the initial application of the study 
product plus confirmation of no drainage or need for additional dressing 2 weeks after 
100% re-epithelialization 
 
Secondary Outcome Measures:  
 
 
Decrease in Wound Area from Initial Application 
Wound area measurements will be made via the eKare inSight platform every week 
for 12 weeks for DFU patients and 16 weeks for VLU patients, or until 100% re-
epithelialization, whichever occurs first.  
 
 
Time to 100% re-epithelialization  
The number of weeks from initial application of study product until 100% re-
epithelialization is first identified.   
 

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 Number of Product Applications  
The number of study product applications including the initial application until 12 
weeks for DFU patients and 16 weeks for VLU patients, or until 100% re-
epithelialization, whichever occurs first.   
 
Tertiary Outcome Measures: 
 
 Quality of Life (SF-36)  
 
o For DFU patients, day of initial application and at either 12 weeks or at 100% re-
epithelialization (whichever occurs first) 
 
o For VLU patients, day of initial application and at either 16 weeks or at 100% re-
epithelialization (whichever occurs first) 
 
 
Pain reported by patient 
 
o For DFU patients, day of initial application and at either 12 weeks or at 100% re-
epithelialization (whichever occurs first) 
 
o For VLU patients, day of initial application and at either 16 weeks or at 100% re-
epithelialization (whichever occurs first) 
 
 
Incidence of adverse events  
 
 
Ease of use and handling of study product 
 
 
Cost effectiveness / Economic model (amount of product usage, length of treatment) 
 
 
Reimbursement access 
    

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4. PATIENT SELECTION 
4.1 Enrollment Criteria for Patients with Diabetic Foot Ulcers (DFUs) 
Patients must meet all inclusion criteria and no exclusion criteria in order to be enrolled 
and randomized to a study product. If the patient has more than one DFU, then each DFU 
must meet the criteria in order for that DFU to be enrolled.  
4.1.1 Inclusion Criteria for DFUs 
1. Patient is at least 18 years old 
2. Patient is willing and capable of complying with all protocol requirements 
3. Patient or legally authorized representative (LAR) is willing to provide written 
informed consent prior to or at the beginning of the run-in period 
4. Patient has Type 1 or Type 2 diabetes (criteria for the diagnosis of diabetes 
mellitus per American Diabetes Association) 
5. Ulcer(s) must be located at least in part on the foot or ankle 
6. Ulcer(s) must be present for more than 28 days prior to randomization and initial 
application of study product, and has not adequately responded to conventional 
ulcer therapy  
7. Wound size must be >1.0 cm2 and < 25 cm2 on the day of randomization and 
initial application of the study product, after initial debridement 
8. Patient has adequate circulation to the affected extremity(ies), as demonstrated by 
at least ONE of the following within 60 days prior to enrollment/randomization: 
a. Dorsum transcutaneous oxygen test (TcPO2) of study leg(s) with results 
≥40mmHg, OR 
b. Ankle-Brachial Index (ABI) of study leg(s) with results of  ≥ 0.7 and ≤ 1.3, 
OR 
c. Toe-Brachial Index (TBI) of study extremity(ies) with results of  ≥ 0.5 
4.1.2 Exclusion criteria for DFUs 
1. Patient has been previously enrolled into this study, or is currently participating in 
another prospective drug or device study that has not reached its primary endpoint 
2. Patient is pregnant, breast feeding or planning to become pregnant 

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3. Patient has a known allergy to resorbable suture materials, e.g., Polyglactin 910 
(PGLA), Polydioxanone (PDS) 
4. Patient has a life expectancy less than six months as assessed by the investigator 
5. Patient has received skin substitutes during the run-in period or within 14 days 
prior to beginning of run-in period 
6. Patient has an additional wound within 3 cm of the study wound(s) or study 
wounds are less than 3 cm apart 
7. Hgb A1c > 12% within 3 months prior to randomization  
8. Patient not in reasonable metabolic control in the judgment of the investigator 
9. Patient with a known history of poor compliance with medical treatments 
10. Patient currently undergoing cancer treatment 
11. Patient has been diagnosed with at least one of the following autoimmune 
connective tissue diseases: lupus, vasculitis, sickle cell, or uncontrolled 
rheumatoid arthritis 
12. Patient is taking parenteral corticosteroids or any cytotoxic agents for 7 
consecutive days during the run-in period or up to 30 days before the run-in 
period.  Chronic oral steroid use is not excluded if dose is < 10 mg per day for 
prednisone. 
13. Active infection, undrained abscess, or critical colonization of the wound(s) with 
bacteria in the judgment of the investigator 
14. Osteomyelitis or exposed bone, probes to bone or joint capsule on investigators 
exam or radiographic evidence 
15. Patient unwilling or unable to safely utilize appropriate offloading device to 
unweight wound(s) 
16. Study ulcer(s) experiences greater than 30% reduction over the 2-week run-in 
period 
17. Patient also has a venous leg ulcer that is enrolled into this study 
 

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4.2 Enrollment Criteria for Patients with Venous Leg Ulcers (VLUs) 
Patients must meet all inclusion criteria and no exclusion criteria in order to be enrolled 
and randomized to a study product. If the patient has more than one VLU, then each VLU 
must meet the criteria in order for that VLU to be enrolled. 
4.2.1 Inclusion Criteria for VLUs 
1. Patient is at least 18 years old 
2. Patient is willing and capable of complying with all protocol requirements 
3. Patient or legally authorized representative (LAR) is willing to provide written 
informed consent prior to or at the beginning of the run-in period 
4. Patient has peripheral venous disease per investigator judgment or diagnostic 
confirmation 
5. Ulcer(s) must be venous in origin, located on a lower extremity 
6. Ulcer(s) must be present for more than 28 days prior to randomization and initial 
application of study product, and has not adequately responded to conventional 
ulcer therapy  
7. Wound(s) size must be >1.0 cm2 and < 50 cm2 on the day of randomization and 
initial application of the study product, after initial debridement 
8. Patient has adequate circulation to the affected extremity(ies), as demonstrated by 
at least ONE of the following within 60 days prior to enrollment/randomization: 
a. Dorsum transcutaneous oxygen test (TcPO2) of study leg(s) with results              
≥ 40mmHg, OR  
b. Ankle-brachial index (ABI) of study leg(s) with results of  ≥ 0.7 and ≤ 1.52, 
OR 
c. Toe-Brachial Index (TBI) of study leg(s) with results of  ≥ 0.5, OR 
d. Doppler arterial waveforms, which are triphasic or biphasic at the ankle of the 
affected leg(s) 
4.2.2 Exclusion Criteria for VLUs 
1. Patient has been previously enrolled into this study, or is currently participating in 
another prospective drug or device study that has not reached its primary endpoint 

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2. Patient is pregnant, breast feeding or planning to become pregnant 
3. Patient has a known allergy to resorbable suture materials, e.g. Polyglactin 910 
(PGLA), Polydioxanone (PDS) 
4. Patient has a known allergy to bovine materials or agarose shipping materials 
5. Patient has a life expectancy less than six months as assessed by the investigator 
6. Patient has received skin substitutes during the run-in period or within 14 days 
prior to the beginning of the run-in period 
7. Patient has an additional wound within 3 cm of the study wound or study wounds 
are less than 3 cm apart 
8. Hgb A1c > 12% within 3 months prior to randomization in patients with a known 
history of diabetes 
 
9. Patient is not in reasonable metabolic control in the judgment of the investigator 
10.  Patient has a known history of poor compliance with medical treatments 
11.   Patient currently undergoing cancer treatment 
 
12. Patient has been diagnosed with at least one of the following autoimmune 
connective tissue diseases: lupus, vasculitis, sickle cell, or uncontrolled 
rheumatoid arthritis 
13. Patient is taking parenteral corticosteroids or any cytotoxic agents for 7 
consecutive days during the run-in period or up to 30 days before the run-in 
period.  Chronic oral steroid use is not excluded if dose is < 10 mg per day for 
prednisone. 
 
14. Active infection, undrained abscess, or critical colonization of the wound(s) with 
bacteria in the judgment of the investigator 
15. Patient unwilling or unable to tolerate use of compression therapy for the duration 
of the study 
16. Study ulcer(s) experiences greater than 30% reduction over the 2-week run-in 
period 
 
17. Patient also has a diabetic foot ulcer that is enrolled into this study 
5. STUDY CONDUCT 

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5.1 Schedule of Events for Diabetic Foot Ulcer (DFU) Patients: 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
     Notes:  
 
X  Requirement completed during patient encounter 
 
(1)  Treatment period visits will cease after 100% re-epithelialization of all study wounds is confirmed.  
 
(2)  An in-person visit two weeks (± 3 days) after 100% re-epithelialization is first identified, and a telephone call six months (± 1 month) after Week 0 are required for patients with 
100% wound re-epithelialization of at least one wound. These visits are NOT required if there is not 100% re-epithelialization of any wound at or before 12 weeks.     
 
(3)  Weeks 5 and 9 may be conducted virtually at the discretion of the investigator and based on the evaluators assessment at Weeks 4 and 8. A visual wound assessment and wound 
imaging are not required if the visit is virtual. If the patient is randomized to SOC, then SOC would not be applied during a virtual visit (at the physicians discretion). 
 
(4)  HbA1c and a vascularization assessment can be completed anytime within 60 days prior to Week 0 
 
(5)  SF-36 Questionnaire and Pain Scale will be completed during the visit when 100% re-epithelialization of all wounds is first identified or at 12 weeks (whichever occurs first) 
 
Requirement 
Run-In Period 
Treatment Period (1)  
Week 0 is the initial application of study product and occurs 14 to 17 
days after the start of the run-in period. 
Visit window for Weeks 1 through 12 is (± 3 days) 
Two-Week 
In-Person 
Follow-Up     
(2) 
Six-Month 
Telephone 
Follow-Up ( 2) 
 
 
Start 
7 days 
(± 3 days) 
0 
1 
2 
3 
4 
5 
(3) 
6 
7 
8 
9 
(3) 
10 
11 
12 
2 weeks after 
each wound 
closure 
(± 3 days) 
Six-Months After 
Week 0 
(± 1 month) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c 
X(4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascularization (ABI, TBI or TcPO2) 
X(4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of re-epithelialization 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (2) 
 
SF-36 Questionnaire and Pain Scale  
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
X (5) 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual examination of wound(s) and 
imaging with eKARE inSight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (2) 
 
Product application with Restrata 
 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
 
 
 Standard of Care 
 
 
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  (2) 
X (2) 
Telephone follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (2) 

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5.2 Schedule of Events for Venous Leg Ulcer (VLU) Patients 
Requirement 
Run-In Period 
Treatment Period (1)  
Week 0 is the initial application of study product and occurs 14 to 17 days after the start 
of the run-in period. 
Visit window for Weeks 1 through 16 is (± 3 days) 
Two-Week 
In-Person 
Follow-Up 
(2) 
Six-Month 
Telephone 
Follow-Up 
(2) 
 
Start 
7 days 
(± 3 
days) 
0 
1 
2 
3 
4 
5 
(3) 
6 
7 
8 
9 
(3) 
10 
11 
12 
13 
14 
15 
16 
2 weeks 
after each 
wound 
closure 
(± 3 days) 
Six-Months 
After Week 
0 
(± 1 month) 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Screening 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics and history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
HbA1c  
X(4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Vascularization (ABI, TBI, TcPO2, or DUS) 
X(4) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Assessment of re-epithelialization 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
SF-36 Questionnaire and Pain Scale 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (5) 
 
 
Randomization 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Visual examination of wound(s) and 
imaging with eKARE inSight 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X (2) 
 
Product application (for both assignments) 
 
 
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 
X (2) 
X (2) 
Telephone follow-up 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X (2) 
Notes:  
 
-  
 
X  Requirement completed during patient encounter (1)  Treatment period visits will cease after 100% re-epithelialization of all study wounds is confirmed.  
 
(2)  An in-person visit two weeks (± 3 days) after 100% re-epithelialization is first identified, and a telephone call six months (± 1 month) after Week 0 are required for patients with 
100% re-epithelialization of at least one wound. These visits are NOT required if there is not 100% re-epithelialization of any wound at or before 16 weeks.     
 
(3)  Weeks 5 and 9 may be conducted virtually at the discretion of the investigator and based on the evaluators assessment at Weeks 4 and 8. A visual wound assessment and wound 
imaging are not required if the visit is virtual.  
 
(4)  HbA1c (for patients with a known history of diabetes) and a vascularization assessment can be completed anytime within 60 days prior to Week 0 
 
(5)  SF-36 Questionnaire and Pain Scale will be completed during the visit when 100% re-epithelialization of all wounds is first identified or at 16 weeks (whichever occurs first) 

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5.3 Screening 
A patient screening log will be maintained. For patients who do not meet eligibility 
criteria, the reason(s) for exclusion from the study will be documented.  
Patients will undergo the benefit insurance verification process via the third-party 
Reimbursement Support Hotline prior to or during the run-in period.  Product 
Reimbursement will be confirmed for the comparison product (Apligraf).  
 
5.4 Informed Consent 
Prior to the start of the 2-week run-in period and the completion of any non-standard of 
care study activities, written informed consent shall be obtained from the patient or the 
patients legally authorized representative (LAR). The investigator (or designee) must 
ensure that each patient (or LAR) is fully informed about the nature of the study, study 
objectives, study products, study procedures, and possible risks and benefits associated 
with participation in this study. Information shall be provided to the patient (or LAR) in a 
language and level of complexity so that he/she understands. The patient (or LAR) will 
have adequate time to consider participation in the study and have the opportunity to ask 
questions. The patient (or LAR) will sign and date the informed consent form, and he/she 
shall be provided a signed copy of the form. The investigator (or designee) will retain 
each patients original signed informed consent form.  
 
If significant new information is obtained after a patient is enrolled, the patient will be 
informed about the new information if the patient has not exited the study. Any 
discussions with the patient about new information should be documented. Patients will 
sign a new informed consent form at the discretion of the investigator and/or the IRB/EC.  
 
The initial informed consent form and any revisions made during the course of the study 
must be approved by both the IRB/EC and Acera Surgical, Inc. before use.   
 
5.5 Run-In Period 
A 2-week run-in period will be required prior to enrollment/randomization and treatment 
in order to complete screening assessments and confirm that the wound(s) has not 
decreased in size by more than 30%. Written informed consent must be obtained prior to 
or at the beginning of the run-in period.  
More than one wound per patient may be screened, enrolled and randomized to a study 
product. All wounds screened/enrolled must be either DFUs or VLUs. A patient may not 
have both a DFU and VLU that are screened and randomized to a study product. If more 
than one wound is enrolled, then the wounds must be at least 3 cm apart. Additionally, 

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the run-in period will begin on the same day for all wounds. A patient may not have a 
separate run-in period for each wound. 
 
5.5.1 First Visit of Run-In Period (14 to 17 days before randomization) 
An in-person visit will be completed at the beginning of the 2-week run-in period, 
and the following will be completed: 
 Written informed consent will be obtained 
 Assessment of inclusion/exclusion criteria 
 Collection of demographics and medical history information 
 Assessment of HbA1c in patients with known history of diabetes if it was not 
completed within the previous 42 days 
 If vascularization in the study leg(s) was not assessed within the previous 42 
days, then at least ONE of the following shall be completed: 
o Ankle-brachial index (ABI) of study leg(s) 
o Toe-brachial index (TBI) of study extremity(ies) 
o TcPO2 of study leg(s) 
o Doppler waveform of study leg(s) (VLU patients only) 
 Assessment of ulcer(s) size via the eKare inSight platform according to the 
eKare in Sight instructions. If debridement is completed during this visit, then 
the assessment must be completed after debridement.  
 Assessment of wound(s) for signs of infection, wound progression, and tissue 
healing.  Gross observation will be utilized to determine the need for change 
in dressing type or dressing replacement/change.   
NOTE: Informed consent must be obtained prior to the above assessments if 
they are not considered standard of care at this visit. 
If the patient does not continue to meet all inclusion/exclusion criteria by the end 
of the visit, then they will be considered a screen failure and should not proceed 
with additional visits/assessments. If a patient has more than one wound that is 
screened, then wound(s) that do not continue to meet all inclusion/exclusion 
criteria will not be randomized to a study product. 
 
5.5.2 Second Visit of Run-In Period (7 days ± 3 days After First Visit)  
An in-person visit will be completed 7 days after the first run-in visit (± 3 days), and 
the following will be completed 
 Assessment of ulcer(s) size via the eKare inSight platform according to the 
eKARE in Sight instructions. If debridement is completed during this visit, 
then the assessment must be completed after debridement. 

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 Assessment of wound(s) through gross observation and analysis for signs of 
infection, wound progression, and tissue healing.  Gross observation will be 
utilized to determine the necessity of standard dressing change.   
 Continued assessment of inclusion/exclusion criteria.  
 
If the patient does not continue to meet all inclusion/exclusion criteria, then they 
will be considered a screen failure and should not proceed with additional 
visits/assessments. If a patient has more than one wound that is screened, then 
wound(s) that do not continue to meet all inclusion/exclusion criteria will not be 
randomized to a study product. 
 
5.6 Point of Enrollment 
Patients will be considered enrolled after ALL of the following requirements are met: 
 Written informed consent is provided 
 For patients with a DFU(s), the patient meets all DFU inclusion criteria and no DFU 
exclusion criteria  
 For patients with a VLU(s), the patient meets all VLU inclusion criteria and no 
VLU exclusion criteria  
 The patient has completed the 2-week run-in period with < 30% reduction in 
wound(s) size 
 The patient is randomized 
 
5.7 Randomization 
The randomization process will be pre-programmed into the electronic data capture (EDC 
system) prior to enrollment of the first study patient.  
Once the patient meets all enrollment criteria and has completed the 2-week run-in 
period, the patient will be randomized. Patients with a DFU(s) will be randomized to 
receive either synthetic hybrid-scale fiber matrix (treatment group) or SOC (control 
group). Patients with a VLU(s) will be randomized to receive either synthetic hybrid-
scale fiber matrix (treatment group) or living cellular skin substitute (control group).  
Randomization will be stratified by wound size:  
 DFUs will fall into two groups (>1.0 cm2 and < 12.5 cm2) and (≥ 12.5 cm2 and < 
25 cm2). Patients within each group will be randomized in a 1:1 ratio to receive 
either synthetic hybrid-scale fiber matrix or SOC.  
 VLUs will fall into two groups: (>1.0 cm2 and < 25 cm2) and (≥ 25 cm2 and < 50 
cm2). Patients within each group will be randomized in a 1:1 ratio to receive 
either synthetic hybrid-scale fiber matrix or living cellular skin substitute. 

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Once the patient is ready to be randomized, the randomization form will be completed by 
study personnel in the electronic data capture (EDC) system. The randomization 
assignment will be obtained from the EDC system prior to the initial application of the 
study product. If a patient has more than one wound that meets all enrollment criteria, 
then all wounds will be randomized to the same study product. The largest wound that 
meets enrollment criteria will determine the size stratification for the patient. 
Any patients that exit the study before randomization are considered screen failures. A 
study exit CRF shall be completed if the patient is not eligible for randomization.  
 
 5.8 Activities for Research Personnel 
. 
 
The following summarizes activities for research personnel from the time of 
enrollment/randomization through the remainder of the study. See the Schedule of Events 
Table for additional details.  
 
 The Evaluator(s) will complete the following activities: 
o Informed consent 
o Screening assessments 
o Before randomization: administration of the SF-36 Questionnaire and pain 
scale  
o Before randomization: obtain images of wound(s) via the eKARE inSight 
Platform  
o Before randomization: assessment of wound(s) through gross observation 
and analysis for signs of infection, wound progression, and tissue healing  
o Before randomization: wound care including debridement and dressing 
changes  
 
 Review of wound image(s) during the treatment period for 100% re-
epithelialization 
o At Weeks 4 and 8: specify whether or not the patient is likely to have 
100% re-epithelialization within the next week so that the investigator can 
determine whether Weeks 5 and 9 will be completed virtually or in-
person. See Section 5.12 for additional details.  
o Review of wound image(s) at follow-up visit two weeks after 100% re-
epithelialization to verify wound closure 
  
o Obtain randomization assignment 
o After randomization: obtain images of wound(s) via the eKARE inSight 
Platform  
o After randomization: assessment of wound(s) through gross observation 
and analysis for signs of infection, wound progression, and tissue healing  
o Initial application and re-application of study product 

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o After randomization: wound care including debridement and dressing 
changes  
o After randomization: assessment of adverse events and medications  
o After randomization: administration of the SF-36 Questionnaire and pain 
scale 
o Virtual visits at Weeks 5 and 9, if conducted 
o Telephone call six-months after initial product application to verify wound 
closure, drainage, and need for additional dressing 
 
 
5.9 Treatment Week 0  
An in-person visit will be completed 14 to 17 days after the beginning of the run-in 
period. 
The following will be completed PRIOR TO randomization: 
 Verify that the patient has active insurance. 
 Review of the patients medical history  
 Assessment of medications including steroid use 
 Assessment of Quality of Life - SF-36  
 Pain Scale 
 Assessment of wound(s) for signs of infection, wound progression, and tissue 
healing.  Gross observation will be utilized to determine the necessity of standard 
dressing change.  
 After initial debridement, assessment of ulcer size via the eKARE Insight 
platform according to the eKARE in Sight instructions. Document whether or not 
the ulcer size has decreased by < 30% since the beginning of the run-in period. If 
more than one ulcer is screened for the study, then only ulcers that have decreased 
in size < 30% may be randomized. 
After the eKARE Insight assessment is complete, review all inclusion/exclusion criteria 
to verify the patient is eligible for enrollment and randomization. Once all criteria is 
confirmed, the patient will be randomized. If the patient does not meet all 
inclusion/exclusion criteria, then the patient will be considered a screen failure, and a 
study exit CRF shall be completed. If the patient has more than one ulcer that has been 
screened, ulcers that do not meet all inclusion/exclusion criteria will not be randomized 
and should receive treatment according to standard of care. All ulcers that meet 
enrollment criteria will be treated with the same study product beginning on the same 
day. 
 
Before the patient is randomized, blinded evaluators should leave the area within view of 
the patient. Study product will then be applied by study personnel.   
 

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5.9.1    Application of synthetic hybrid-scale fiber matrix 
 
Follow the instructions below for patients receiving synthetic hybrid-scale fiber 
matrix.  
 
1. Wound Bed Preparation: 
 Prepare the wound bed using standard methods to ensure it is free of exudate 
and devitalized tissue. An initial excision or debridement of the wound is 
necessary to ensure the wound edges contain viable tissue. 
 Wait for any bleeding to stop and ensure there is no active bleeding before 
applying synthetic hybrid-scale fiber matrix. 
 Cleanse the wound thoroughly with sterile saline prior to application of 
synthetic hybrid-scale fiber matrix. 
 
2. Preparation of synthetic hybrid-scale fiber matrix: 
 Select the appropriate size sheet of synthetic hybrid-scale fiber matrix based 
on the eKARE inSight measurements. 
 Heavily fenestrate with a scalpel or mesh prior to application.  Synthetic 
hybrid-scale fiber matrix must be fenestrated prior to use in any wound prone 
to exudate in order to permit effective exudate management. 
 Synthetic hybrid-scale fiber matrix is packaged in a nested pouch 
configuration. Peel open the outer foil pouch starting from the chevron sealed 
edge.  The inner TyVek® pouch is sterile and may be placed on the sterile 
field. 
 Rinse surgical gloves, if necessary, to remove any glove powder prior to 
touching the product.   
 Synthetic hybrid-scale fiber matrix can be cut to the desired shape in a wet or 
dry state. In order to increase pliability of the product, hydrate in warm, 
sterile, hypertonic solution (i.e., saline, water, etc.) for a minimum of 1 
minute.  
 
3. Application of synthetic hybrid-scale fiber matrix: 
 Apply matrix with either side towards the wound bed, and position to 
completely contact the entire surface of the wound bed and extend slightly 
beyond wound margins. The matrix can be repositioned as necessary.  
 Securely anchor the matrix as needed with suture or Steristrips.  
 Apply a non-adherent primary wound dressing over the matrix.   

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 To prevent dislodgment of product, apply appropriate secondary dressing or 
compression to maintain dressing adherence (e.g., multi-layer compression 
bandage system, or other appropriate dressing), manage the wound exudate, 
keep the matrix moist, and keep all layers securely in place. The optimum 
secondary dressing is determined by wound location, size, depth and provider 
preference.  
 Discard any unused pieces of study product.  
 
    
A non-adherent primary dressing will be applied to the wound bed.  Management 
of wound exudate will determine the required dressing.  The dressing will be 
securely in place and dressing determined by provider preference. 
 
5.9.2   Application of Living Cellular Skin Substitute (VLU Patients Only) 
Follow the living cellular skin substitute instructions for use (IFU) in Appendix C 
for VLU patients randomized to this group. Post-application, cover living cellular 
skin substitute using a non-adhesive primary dressing. Apply a secondary non-
occlusive dressing to create a bolster.   
 
5.9.3 Post-Application Procedures 
 
 Assessment of adverse events 
 
 For DFUs: To ensure off-loading, each patient will be fitted with an off-loading 
device based on the investigators decision, e.g., a boot for forefoot and a heel 
protector for hindfoot.  Patients should be instructed on how to care for the 
surgical site, utilize an off-loading device, and keep the surgical site moist and 
clean.  If the wound is dry, a hydrogel category dressing type should be used. If 
the wound has exudate, an aliginate or foam dressing is recommended.  
 
 For VLUs: Patients will be provided with a compression device. Patients 
should be instructed on how to care for the surgical site, utilize compression 
socks and/or compression wrap, e.g., ProFore or a similar product, and keep the 
surgical site moist, and clean. 
 

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5.10 Study Treatment Period - For synthetic hybrid-scale fiber matrix and comparison 
products 
Patients will have weekly visits for up to 12 weeks for patients with DFUs and up 
to 16 weeks for patients with VLUs (the window for all of these visits is ± 3 days). 
Assessment and imaging of the wound(s) will occur at each weekly visit unless the 
visit is conducted virtually (optional for Weeks 5 and 9). Assessment of adverse 
events and medications will be occur during each weekly visit. 
Study product will be re-applied:  
 DFU patients: 
o Randomized to Restrata: Biweekly (weeks 2, 4, 6, 8, 10, and 12) 
o Randomized to Standard of Care: Weekly 
 
 All VLU patients: Biweekly (weeks 2, 4, 6, 8, 10, 12, 14 and 16) 
 
If 100% re-epithelialization of all study wounds is confirmed before 12 weeks for 
DFU patients or before 16 weeks for VLU patients, then weekly visits shall cease.  
5.10.1 The evaluator will complete these assessments at each in-person weekly visit 
during the Treatment Period: 
 Review of images and documentation of 100% re-epithelialization, if present  
 
5.10.2 Personnel will administer the Quality of Life - SF-36 Questionnaire and the pain 
scale at the following time-point (whichever occurs first): 
 When complete wound re-epithelialization of all wounds is first identified, OR 
 At Week 12 for DFU patients, OR  
 At Week 16 for VLU patients 
 
5.10.3 Personnel will complete the following assessments at each weekly in-person visit: 
 Assessment of wound(s) through gross observation and analysis, wound 
progression, and tissue healing.  Gross observation will be utilized to determine 
the necessity of standard dressing change. Carefully assess the wound(s) for signs 
of infection, description of exudate present, and wound bed characteristics. 
 
 Assessment of adverse events and medications 
 
 Debridement and dressing changes may occur at each weekly visit or as needed. 
o Debride the wound(s) as needed while not disrupting healing tissue. 

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o The clinician will inspect the wound bed for signs of infection and 
healing; the secondary dressing is changed as appropriate with a nontoxic 
solution. Frequency of secondary dressing changes will be dependent upon 
the volume of exudate produced, type of dressing used and the clinicians 
decision upon inspection of the wound(s). 
 Measurement and imaging of wound area via the eKare inSight platform according 
to the eKare inSight instructions. If debridement is completed during this visit, 
then the assessment must be completed after debridement. 
 
5.10.4 Reapplication of the study product by personnel will occur: 
 DFU patients: 
o Randomized to Restrata: Biweekly up to 12 weeks 
o Randomized to Standard of Care: Weekly up to 12 weeks 
 
 All VLU patients: Biweekly up to 16 weeks 
 
If 100% re-epithelialization is confirmed before 12 weeks for DFU patients or before 
16 weeks for VLU patients, then re-application shall cease. For patients with more 
than one wound randomized to the study, re-application of product to each wound 
shall cease when 100% re-epithelialization of that wound is confirmed. The following 
will be completed by qualified personnel: 
 Evaluate the amount of study product remaining in the wound. 
 If the study product is completely intact (no resorption has occurred) and the 
wound is clean and clear of infection, then leave the product in place. 
 The study product should be reapplied over previously absorbed material. 
 If any of the study product material has resorbed, then evaluate for additional 
debridement prior to replacement with new study material. 
 In the event the material does need to be removed from the wound bed prior to 
reapplication, use warm (37C) sterile saline to continuously rinse the wound 
site to help detach the material, so as not to cause further damage to the 
wound bed. Forced removal may result in wound re-injury. 
NOTE: If excess exudate collects under Synthetic hybrid-scale fiber matrix, the 
material should be thoroughly fenestrated to allow the exudate to drain. 
  
5.11 3D Wound Measurement with the eKare inSight Platform 
Wounds will be measured using the eKare inSight platform weekly from the beginning of 
the run-in period until 12 weeks for DFU patients or 16 weeks for VLU patients (except 
Weeks 5 and 9 if conducted virtually).  If 100% re-epithelialization of all wounds is 
confirmed before 12 weeks for DFU patients or before 16 weeks for VLU patients, then 

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measurements shall cease. Qualified personnel who are trained on the system will be 
required to complete the assessment. If debridement is completed at the visit, then the 
measurement must occur after debridement. 
 
The inSight platform uses structured light to produce three-dimensional renderings of 
wounds and translates the data into area, length, width, depth and volume within seconds.  
 
Each investigational site will be provided with one system, which will need to be 
returned to the Sponsor at study conclusion.  
 
5.12 Virtual Visits at Weeks 5 and 9 
Based on the evaluators assessment of the wound image and at discretion of the 
investigator, Week 5 and Week 9 may be conducted virtually (via telephone call or web 
meeting) by un-blinded study personnel. A visual wound assessment and wound imaging 
via the eKARE inSight platform are not required if the visit is virtual. If a DFU patient 
was randomized to Standard of Care, then product reapplication is not required if the visit 
is virtual. The following will be completed during virtual visits: 
 Collect information about adverse events and medications 
 Collect information about wound drainage and dressing changes since the 
previous visit 
 Discuss wound care recommendations including any needed dressing changes 
 
At Week 4, the evaluator will complete an assessment of the wound image and 
determine whether or not 100% re-epithelialization is likely to occur before Week 5.  
 If 100% re-epithelialization of any wound is likely to occur before Week 5 based 
on the blinded evaluators assessment, then an in-person visit will be completed at 
Week 5.  
 If 100% wound re-epithelialization is unlikely to occur before Week 5 based on 
the blinded evaluators assessment, then the investigator will determine whether 
Week 5 will be completed virtually or in-person based on the patients best 
interest. For DFU patients randomized to Standard of Care, a visit may be 
conducted virtually only if the investigator determines it is in the patients best 
interest to forego product reapplication at Week 5.  
 
At Week 8, the evaluator will complete an assessment of the wound image and 
determine whether or not 100% re-epithelialization is likely to occur before Week 9.  
 If 100% re-epithelialization of any wound is likely to occur before Week 9 based 
on the evaluators assessment, then an in-person visit will be completed at Week 
9.  
 If 100% re-epithelialization is unlikely to occur before Week 9 based on the 
evaluators assessment, then the investigator will determine whether Week 9 will 
be completed virtually or in-person based on the patients best interest. For DFU 
patients randomized to Standard of Care, a visit may be conducted virtually only 
if the investigator determines it is in the patients best interest to forego product 
reapplication at Week 9. 

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5.13 Two Week Visit to Confirm Wound Closure   
An in-person visit with the patient to confirm 100% re-epithelialization will be 
completed two weeks (± 3 days) following the visit when 100% re-epithelialization was 
first identified and documented. A clinic visit is NOT required if there is not complete 
wound re-epithelialization of any wound at 12 weeks or earlier for DFU patients (or 16 
weeks or earlier for VLU patients). For patients with more than one wound, an in-
person follow-up visit will be completed two weeks following 100% re-epithelialization 
of each wound.  
      Research personnel will complete the following: 
 Measurement and imaging of wound area via the eKare inSight platform according to 
the eKare inSight instructions. 
 Wound drainage since the previous visit 
 Additional dressing changes since the previous visit 
 Adverse events 
 Review wound imaging to confirm the wound remains closed 
 
 
5.14 Six-Month Telephone Call 
For patients with 100% re-epithelialization of at least one wound, a telephone call with 
the patient will be completed six-months (± 30 days) after Week 0. The following 
information will be collected: 
 Confirmation of whether wound(s) remains closed 
 Wound drainage since the previous visit 
 Additional dressing changes since the previous visit 
 Adverse events 
               
A telephone call is not required if complete wound re-epithelialization of at least one 
study wound does not occur at or before 12 weeks for DFU patients, or at or before 16 
weeks for VLU patients.  
 
5.15 Study Exit 
5.15.1 Study Participation Exit Points 
A patients participation in the study will end after any of the following: 
 DFU patients without 100% re-epithelialization of at least one study wound: at 12 
weeks  
 VLU patients without 100% re-epithelialization of at least one study wound: at 16 
weeks  

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 Completion of six-month telephone call (for patients with 100% re-
epithelialization of at least one study wound) 
 Patient withdrawal 
 The Investigator may withdraw the patient if he/she determines it is in the patients 
best interest 
 Patient lost to follow-up 
 Amputation of all or part of the study limb 
 Closure of study 
 Patient death 
 
5.15.2  Patient Withdrawal 
 
A patient (or patients LAR) may choose to withdraw from the study at any time 
without penalty or loss of benefits. The patient should notify the investigator (or 
designee) of his/her desire to withdraw, and the investigator (or designee) should ask 
for and document the reason for withdrawal. The investigator may also choose to 
withdraw a patient from the study at any time if he/she considers it to be in the patients 
best interest. The reason for withdrawal should be recorded. Any data collected on the 
patient up to the point of withdrawal may be used in the study. 
If complete wound closure has not been confirmed at the time of withdrawal from the 
study, then the investigator should attempt to determine the status of the wound at the 
time of the patients withdrawal to the best of the patients ability (i.e., healed, not 
healed, seeking additional treatment, not seeking additional treatment) and to complete 
as many of the patient-reported outcomes questionnaires as the patient is able and 
willing to complete.  
 
5.15.3   Patient Lost to Follow-Up 
The investigator should encourage patients to return for all required follow-up visits. 
A patient will be considered lost to follow-up after three documented phone call 
attempts or emails plus a certified letter that is sent to the patients last known address 
in which no response is received. A patient should not be automatically exited from 
the study after a missed visit(s). Rather, the patient will remain in the study until 
he/she completes the final study visit required by the protocol, withdraws from the 
study, or is considered to be lost to follow-up.  
5.15.4  Patient Death 
If known, the cause of death should be documented.  

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5.15.5 Sponsor Discontinues Study 
Premature termination of this clinical study may occur because of a regulatory authority 
decision, change in opinion of the IRB/EC, product safety concerns or at the discretion 
of Acera Surgical, Inc.  
Acera Surgical, Inc. reserves the right to discontinue the study prior to inclusion of the 
intended number of patients but intends only to exercise this right for valid scientific 
or administrative reasons.  After such a decision, the investigator must contact all 
participating patients within 30 days.   
 
6. ADVERSE EVENTS (AE) 
6.1   Principal Investigator Responsibilities 
The investigator (or designee) should record and maintain all adverse events that occur 
over the course of the patients participation in the study (randomization through study 
exit) during or outside of study visits. Adverse events that are reported to the sponsor will 
be assessed by an investigator. Adverse event assessments should include severity, 
seriousness, and relatedness to the product, study procedures and pre-existing conditions.  
See Section 6.4 for adverse events that are required to be reported to the Sponsor.  
 
6.2 Adverse Event Definitions  
Adverse Event:  
Any untoward medical occurrence (sign, symptom, illness, abnormal clinically significant 
laboratory value, or other medical event) that occurs while the patient is enrolled in the 
study whether or not it is related to the study product or study procedures. A medical 
condition (pre-existing condition) that exists at study enrollment/randomization is not 
considered an AE unless the condition worsens after enrollment. 
 
Serious Adverse Event:  
A serious adverse event is any undesirable adverse event or untoward medical occurrence 
experienced by a patient during the study that: 
 Results in death;  
 Is life-threatening; 
 Requires inpatient hospitalization or prolongation of an existing hospitalization; 
 Results in persistent or significant disability/incapacity; or 
 Requires intervention to prevent a permanent impairment of a bodily function or 
damage to a body structure.   
 

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Medical and scientific judgment should be exercised in determining whether an event is a 
serious adverse event. An important medical event may not be immediately life-threatening 
and/or result in death or hospitalization.  However, if it is determined that the event may 
jeopardize the patient and may require intervention to prevent one of the other outcomes 
listed in the definition above, the adverse event should be reported as serious. Examples of 
such events are intensive treatment in an emergency room for a bronchospasm or 
convulsions that do not result in hospitalization.  
This definition of an SAE is not intended to include hospitalization specifically to treat a 
condition that existed prior to the patients enrollment in the study (e.g., pre-existing 
cardiovascular disease that is treated during the study) or prearranged elective surgery 
performed during this study period.  
 
Adverse Device Effect: 
Any adverse event that is caused by or associated with a study product.  
 
Unanticipated Adverse Device Effect: 
Any serious adverse effect on health or safety or any life-threatening problem or  death  
caused  by  or  associated  with  a  study product,  if  that  effect,  problem  or  death  was  
not  previously  identified  in  nature,  severity  or  degree  of  incidence  in  the  Protocol  
or Instructions for Use. 
 
6.3 Adverse Event Assessment  
Adverse events that are required to be reported to the sponsor must be assessed by an 
investigator for severity, seriousness and relatedness to the product, study procedures and 
pre-existing conditions. 
 
         The following scale should be used for severity assessment: 
ADVERSE EVENT SEVERITY 
Mild 
AE is noticeable to the patient but does not interfere with routine 
activity and does not require medical treatment 
Moderate 
AE interferes with routine activity and/or requires medical treatment 
Severe 
AE results in loss of life, loss of limb, is life threatening, or results in 
permanent impairment of body structure or function 
 
The following scale should be used for an assessment of relatedness to the study product, 
study procedure(s), and pre-existing conditions: 

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 Not Related 
 Possibly Related 
 Probably Related 
 Definitely Related 
 
6.4 Adverse Event Reporting  
The following adverse events are required to be promptly reported to the sponsor on the 
adverse event eCRF:  
 Any serious adverse event whether or not it is related to a study 
product/procedure 
 Any adverse event that in the opinion of the investigator is definitely related, 
probably related, or possibly related to a study product and/or study procedure 
 The following adverse events whether or not they are related to a study 
product/procedure: 
o Infection of wound and/or area surrounding wound 
o Complete or partial amputation of lower extremity 
o Allergic reaction to a study product 
o Excessive redness, pain, swelling or blistering of wound 
 
Serious adverse product effects should be reported to the sponsor as soon as possible. 
Pre-existing conditions or adverse events that occur prior to randomization are not 
required to be reported.  
 
The investigator (or designee) is also required to report AEs to the IRB/EC if the AEs are 
required to be reported per the IRB/EC reporting requirements.  
 
 
7. PROTOCOL DEVIATIONS 
Investigators are not allowed to deviate from the protocol without prior authorization by the 
sponsor except under emergency situations when necessary to preserve the rights, safety, and 
well-being of human subjects.   
 
All deviations from the protocol should be reported on a protocol deviation eCRF, and a 
reason for the deviation should be noted. Additionally, the investigator (or designee) is also 
required to report protocol deviations to the IRB if the protocol deviations are required to be 
reported per the IRB reporting requirements. Deviations that impact the rights, welfare, or 
safety of patients shall be reported to the sponsor and IRB as soon as possible.    

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If Acera Surgical, Inc. becomes aware that an investigator is not complying with any part of 
the protocol, including signed agreements, or any conditions of approval imposed by the 
reviewing IRB/EC, Acera will promptly secure compliance and may suspend the investigators 
participation (including enrollment at the site).   
 
 
8. RISKS AND BENEFITS 
For a complete list of risks and benefits that may occur with the use of approved synthetic 
hybrid-scale fiber matrix, Standard of Care, and living cellular skin substitute, refer to the 
Instructions for Use.  
 
 
9. STATISTICAL CONSIDERATIONS 
9.1 Hypotheses to be Tested 
9.1.1 Primary Endpoints: 
9.1.1.1 DFU Arm 
The null hypothesis (H0) for the primary endpoint in the DFU arm is that the 
difference in proportion of patients achieving 100% re-epithelialization by week 
12 between the synthetic hybrid-scale fiber matrix group (π1) and the control 
group (π2) is less than or equal to the noninferiority margin of -0.10 based on a 
one-sided Farrington & Manning test. The alternative hypothesis (H1) is that the 
difference is greater than the noninferiority margin of -0.10. These can be seen in 
the equations below: 
H0: π1 - π2 ≤ -0.10 
H1: π1 - π2 > -0.10 
 
9.1.1.2 VLU Arm 
The null hypothesis (H0) for the primary endpoint in the VLU arm is that the 
difference in proportion of patients achieving 100% re-epithelialization by week 
16 between the synthetic hybrid-scale fiber matrix group (π1) and the control 
group (π2) is less than or equal to the noninferiority margin of -0.10 based on a 
one-sided Farrington & Manning test. The alternative hypothesis (H1) is that the 
difference is greater than the noninferiority margin of -0.10. These can be seen in 
the equations below: 
H0: π1 - π2 ≤ -0.10 
H1: π1 - π2 > -0.10 
9.2 Analysis Populations 
Intention to Treat Population (ITT) 

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The ITT population will consist of all enrolled patients. Patients are considered enrolled 
after meeting the criteria specified in Section 5.6. Patients in the ITT population will be 
evaluated based on the randomized treatment group. 
 
Modified Intention to Treat Population (mITT) 
The mITT population will consist of ITT patients who have at least one product 
application. This will serve as the primary analysis population for study efficacy. Patients 
in the mITT population will be evaluated based on the randomized treatment group. 
 
Per Protocol (PP) 
The PP will include all ITT patients who additionally meet all study eligibility criteria, 
have available study data for the primary study endpoint and do not have a major 
protocol violation that affects primary effectiveness. Patients in the PP population will be 
evaluated based upon the treatment that they receive. 
 
9.3 Sample Size Calculation 
9.3.1 DFU Arm 
Sample size calculations were performed using a Farrington & Manning test for non-
inferiority of the synthetic hybrid-scale fiber matrix group compared to the control 
group. Under assumptions of a closure rate of 75% for the synthetic hybrid-scale fiber 
matrix group, 60% for the control group, and a noninferiority margin of 10%, this 
results in a sample size of 44 per group (88 total) that provides a power of 0.8 and 
one-sided alpha of 0.05. After allowing for an assumed 20% lost to follow up, this 
results in a total sample size of 110 patients.  
 
9.3.2 VLU Arm   
Sample size calculations were performed using a Farrington & Manning test for non-
inferiority of the synthetic hybrid-scale fiber matrix group compared to the control 
group. Under assumptions of a closure rate of 75% for the synthetic hybrid-scale fiber 
matrix group, 50% for the control group, and a noninferiority margin of 10%, this 
results in a sample size of 24 per group (48 total) that provides a power of 0.8 and 
one-sided alpha of 0.05. After allowing for an assumed 20% lost to follow up, this 
results in a total sample size of 60 patients. 
 
9.4 Interim and Final Analyses 
An unblinded interim assessment for sample size re-estimation (SSR) will be performed 
on the primary endpoint in each arm of the study by an independent statistician. 
 
9.4.1 DFU Arm 
In the DFU arm, the analysis will be conducted when 50% of the mITT population 
(56 patients) have been enrolled and completed the primary endpoint evaluation. The 
analysis described below will be performed on the mITT population. 

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The purposes of the interim analysis are (1) to calculate the power for non-inferiority, 
conditioned on the interim-observed difference between treatments with respect to 
100% re-epithelialization rates and on the non-inferiority margin of 10%, and (2) 
determine if the sample size needs to be increased in order to maintain the desired 
conditional power of 80%. 
 
The conditional power will be calculated under the assumption that the interim 
observed estimate of the treatment difference is the true treatment difference.  It will 
be calculated using the following formula as discussed in Lan and Wittes (1988): 
 
where: 
 
Z1-α is the (1-α)*100% percentile of the standard normal distribution (i.e., the 
critical value used to assess non-inferiority at the final analysis at overall one-
sided significance level α). 
τ is the information fraction (= proportion of patients in the first interim analysis = 
r/M where r is the number of patients per group in the interim analysis and M is 
the planned number of patients per group for the final analysis); if the interim 
sample sizes per group are not equal due to randomness, the harmonic mean of 
the sample size will be used.   
 
Bτ = 
 where Zτ = the Farrington-Manning non-inferiority test statistic 
calculated on the interim observed data 
Φ is the cumulative distribution function of the standard normal distribution. 
 
Following the promising zone algorithm in Mehta and Pocock (2011), if the 
conditional power based on the planned final sample size of 110 patients is <42% or 
>80% at the interim stage, the study will continue as is (there will be no stoppage of 
the study for futility nor will there be a sample size increase).  If the conditional 
power is between 42-80% (the promising zone), the sample size may then be re-
estimated using the method described by Wang et al (2002) in order to maintain 80% 
conditional power without increasing the Type I error (probability of a false positive 
result) of the study. Specifically, the total revised sample size per group, M` required 
to achieve a conditional power of 80% to assess non-inferiority at the final analysis 
using a non-inferiority margin of 10% is found by solving the following equation for 
M`: 
𝑍଴.ଶ଴ට1 െ𝑟
𝑀` ൅𝑍ఛඨ𝑀`
𝑟െ𝑍ଵିఈൌ0 
 
where Z0.20 is the 20th percentile of the standard normal distribution (corresponding 
to the desired 80% conditional power) and where all other variables in this equation 
are defined above. M` will not exceed 166 patients for the DFU arm. This formula 

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assumes the interim observed effect size between treatments is the true effect size 
between treatments. 
 
Results of the interim assessment will be presented by the independent statistician to 
a select Sponsor group. The report to the Sponsor will state if additional sample is 
required to achieve a conditional power of 80%, and if so, how many additional 
patients. If additional sample size is required, the Sponsor will make a decision to 
either enroll the additional patients or not enroll and accept that the primary endpoint 
may be under-powered.  The independent statisticians report containing the results 
that led to the independent statisticians recommendation will be kept confidential 
within the select Sponsor group. 
 
The following decision rules outline the possible outcomes of the interim analysis: 
1. If the test for CPni <0.42 or ≥0.8, then there is no increase in the sample size 
and the trial will be completed on a minimum of 110 enrolled patients, as 
scheduled. 
2. If the test for conditional power is 0.42 ≤ CPni < 0.8, then the sample size will 
be increased by just the right amount such that CPni is increased to 0.8, under 
a cap of 166 patients. The range 0.42 ≤ CPni < 0.8 is called the promising 
zone for non-inferiority. Specifically, if CPni is in its promising zone, this 
decision rule increases the sample size by the smallest of 166 patients or the 
number needed to boost CPni to 0.8. 
 
 
 
9.4.2 VLU Arm 
The interim analysis for the VLU arm will be performed independently of the interim 
analysis for the DFU arm, but it will be very similar in nature.  

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In the VLU arm, the analysis will be conducted when ~50% of the mITT population 
(30 patients) have been enrolled and completed the primary endpoint evaluation. The 
methods will be the same as described above. M` will not exceed 90 patients for the 
VLU arm. 
The following decision rules outline the possible outcomes of the interim analysis: 
1. If the test for CPni <0.43 or ≥0.8, then there is no increase in the sample size 
and the trial will be completed on a minimum of 60 enrolled patients, as 
scheduled. 
2. If the test for conditional power is 0.43 ≤ CPni < 0.8, then the sample size will 
be increased by just the right amount such that CPni is increased to 0.8, under 
a cap of 90 patients. The range 0.43 ≤ CPni < 0.8 is called the promising zone 
for non-inferiority. Specifically, if CPni is in its promising zone, this decision 
rule increases the sample size by the smallest of 90 patients or the number 
needed to boost CPni to 0.8. 
 
9.5 Statistical Analysis 
Data collected in this study will be reported using summary tables and patient data 
listings. Continuous variables will be summarized using descriptive statistics (number of 
patients, mean, standard deviation [SD], median, minimum, and maximum). Categorical 
variables will be summarized using frequencies and percentages of patients in each 
category. All results will be presented by treatment group and study arm in appropriate 
patient populations. SAS software version 9.4 or higher will be used for the statistical 
analysis. 
 

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9.5.1  Demographic and Baseline Characteristics 
Patient demographics for all analysis populations will be summarized in a table. 
Gender, ethnicity, and race will be summarized with frequency and percent. Age, 
height, weight, and BMI will be summarized with N, mean, standard deviation, 
median and minimum and maximum. 
 
9.5.2  Medical History 
Patient medical history, including tobacco use, comorbidities, diabetes history, and 
wound history (where applicable) for all analysis populations will be summarized in a 
table. Categorical variables will be summarized with frequency and percent. 
Continuous variables will be summarized with N, mean, standard deviation, median 
and minimum and maximum. 
9.5.3 Procedural Information 
Descriptive statistics will be used to summarize the initial wound assessment by 
treatment group and procedural information. 
9.5.4  Primary Endpoints 
For the purpose of the primary endpoint analysis, the largest study wound will be 
analyzed. 
9.5.4.1 DFU Arm 
100% re-epithelialization will be assessed every week (except during virtual 
visits) for 12 weeks for DFU patients or until 100% re-epithelialization, 
whichever occurs first. Persistence of wound closure will be verified via 
confirmatory visit within 2 weeks after complete closure has been first 
determined.  
For the primary endpoint of 100% re-epithelialization at week 12 a two-stage 
analysis will test first if the rate of 100% re-epithelialization is non-inferior 
between groups using a Farrington & Manning test. Noninferiority for synthetic 
hybrid-scale fiber matrix will be demonstrated if the lower bound of the 90% CI 
of the difference in proportions lies above the non-inferiority margin of -10%. 
 
If non-inferiority is shown, superiority of synthetic hybrid-scale fiber matrix over 
Standard of Care will be tested using a chi-square test.  
 
9.5.4.2  VLU Arm 
100% re-epithelialization will be assessed every week (except during virtual 
visits) for 16 weeks for VLU patients or until 100% re-epithelialization, 
whichever occurs first. Persistence of wound closure will be verified via 
confirmatory visit within 2 weeks after complete closure has been first 
determined. 

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For the primary endpoint of 100% re-epithelialization at week 16 a Farrington & 
Manning test will be used. Noninferiority for synthetic hybrid-scale fiber matrix 
will be demonstrated if the lower bound of the 90% CI of the difference in 
proportions lies above the non-inferiority margin of -10%. 
 
9.5.5 Secondary Endpoints 
The following secondary endpoints will be summarized for exploratory purposes. 
There are no plans for statistical testing of secondary endpoints. 
Decrease in Wound Area from Baseline 
The difference in wound area from baseline to each time point will be summarized for 
each treatment group in each arm. The difference in mean percent change in size 
between the treatment group and control group will be calculated for each timepoint. 
Wound area measurements will be made via the eKARE inSight system every week 
(except during virtual visits) for 12 weeks for DFU patients and 16 weeks for VLU 
patients (except during virtual visits), or until 100% re-epithelialization, whichever 
occurs first. 
Time to Wound Closure  
The time to wound closure will be summarized by proportion of patients with wound 
closure at each timepoint for each treatment group in each arm. The difference in 
proportion of patients with wound closure between the treatment group and control 
group will be calculated for each timepoint. Persistence of wound closure will be 
verified via confirmatory visit within 2 weeks after complete closure has been first 
determined. 
Number of Product Applications 
The number of product applications will be summarized for each treatment group in 
each arm. The difference in mean number of applications between the treatment 
group and control group will be calculated for each timepoint. Product applications 
will be defined as the number of product applications prior to complete wound 
closure within the treatment period for each study arm.  
 
9.5.6 Tertiary Endpoints 
The following tertiary endpoints will be summarized for exploratory purposes. 
Continuous variables will be summarized using descriptive statistics (number of 
patients, mean, median, quartiles, standard deviation [SD], minimum, and maximum). 
Categorical variables will be summarized using frequencies and percentages of 
patients in each category. There are no planned statistical tests. Where possible, 
results will be summarized at each collected time point and the change from baseline 
will be presented. 
Quality of Life  SF-36  

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Results will be summarized at each time point using the proportion of patients at each 
level. Change from baseline will be assessed as the number of levels either improved 
or worsened. 
Patient Reported Pain 
Pain will be assessed using a numeric rating scale of 10-point scale. Results will be 
summarized at each time point using the average pain score and the average change 
from baseline. 
Cost effectiveness / Economic model (Amount of product usage, length of treatment) 
Results will be summarized descriptively by timepoint where applicable. 
Intraoperative notes / Ease of Use, Handling 
Results will be summarized descriptively by timepoint. 
Billing / Coding / Reimbursement information 
Results will be summarized descriptively by timepoint. 
 
9.5.7 Adverse Events 
9.5.7.1 All Adverse Events 
Summaries of incidence rates of individual AEs overall will be prepared. Only 
treatment emergent AEs will be analyzed (a treatment emergent adverse event is 
one that started or worsened in severity at or after start of randomized treatment). 
Because a patient may experience more than one AE, summaries will provide 
both the number of patients experiencing at least one event and the number of 
events within a reporting period. Percentages provided will be the percent of 
patients experiencing one or more adverse events. In addition, incidence of AEs 
will be presented by severity (mild, moderate, severe) and by relationship to 
investigational product or procedure. Patients experiencing an event more than 
once will be counted under the maximum severity/relationship experienced. 
 
A listing of all adverse events will include the patient number, AE number, days 
since index procedure, the AE name, the severity of AE, whether or not the AE is 
classified as serious (SAE), the relationship of the AE to the study product or 
procedure, the action taken, and the outcome.  
 
9.5.7.2 Serious Adverse Events 
Summaries of incidence rates and relationship to the study product/procedure of 
individual SAEs will be prepared. Summaries will provide both the number of 
patients and the number of events within a reporting period. Percentages provided 
will be the percent of patients experiencing one or more serious adverse events. A 
data listing of SAEs will also be provided, displaying details of the event(s) 
captured on the CRF.  
 

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9.5.7.3 Adverse Events of Interest 
Summaries of incidence rates of the following AEs by treatment group will be 
prepared: 
 Infection of wound and/or area surrounding wound 
 Amputation of lower extremity 
 Allergic reaction  
 Excessive redness, pain, swelling or blistering of wound 
 
9.6  Strategies to Address Missing Data 
Patients who are missing complete wound closure will be considered as missing data 
patients. Missing complete wound closure status will be imputed using a logistic 
regression multiple imputation approach for dichotomous outcome data. In this approach, 
missing healing status will be imputed from logistic regression models with independent 
variables of age, gender, and other variables to be specified in the formal statistical 
analysis plan.  This will be performed 50 times in each arm in order to generate 50 
complete datasets.  For the DFU arm, the one-sided Farrington & Manning test for 
assessing treatment difference will be carried out on each of the 50 complete datasets, 
with the results being combined across the 50 complete datasets using standard multiple 
imputation theory to obtain one overall p-value comparing the two treatments on the 
primary endpoint after accounting for missing data. Similarly for the VLU arm, the one 
sided Fishers Exact test for assessing treatment difference will be carried out on each of 
the 50 complete datasets, with the results being combined across the 50 complete datasets 
using standard multiple imputation theory to obtain one overall p-value comparing the 
two treatments on the primary endpoint after accounting for missing data. 
 
10. DATA HANDLING AND RECORD KEEPING 
Electronic Case Report Forms (eCRFs)  
Completed original eCRFs are the sole property of Acera Surgical, Inc. and should not be made 
available in any form to third parties, except for authorized representatives of appropriate 
regulatory authorities, without written permission from Acera. 
It is the Principal Investigator's responsibility to ensure completion of eCRFs by the clinical 
research team and to review and approve the data captured on all eCRFs as accurate.  All 
eCRFs must be signed by the investigator.  This signature serves to attest that the information 
contained on the eCRFs is true.  At all times, the investigator has final personal responsibility 
for the accuracy and authenticity of all data entered on eCRFs.  Patient source documents are 
the investigator's patient records maintained at the study site and will be used to verify data 
documented on eCRFs.   
In some cases, a portion of the source documents for a given study/site may be the eCRFs.  For 
this study, the patient questionnaires eCRFs may be considered source documents. 
 

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Source Documents 
 
Investigators are required to maintain information in the study patients medical records to 
corroborate data collected on the eCRFs. Source data includes all information, original 
records of clinical findings, observations, or other activities in a clinical trial necessary for 
the reconstruction and evaluation of the trial. Source data are contained in source documents. 
Examples of source documents are:  hospital medical records, clinic and office medical 
charts, laboratory notes, imaging, patient questionnaires and study worksheets. 
 
Maintenance of Records 
The Principal Investigator shall maintain the required records for a period of 2 years after the 
date the study is completed or terminated or the records are no longer required to support a 
submission to a regulatory agency, whichever date is later. The Principal Investigator may 
withdraw from the responsibility to maintain records for the time required by transferring  
custody  to  another  person  who  will  accept  responsibility  for  them. The sponsor must be 
notified in writing about the records transfer.  
 
11. ETHICS 
 
11.1 Ethical Conduct of the Clinical Study 
This clinical study will be conducted in accordance with the ethical principles that have 
their origin in the Declaration of Helsinki and in compliance with the protocol, Good 
Clinical Practice (GCP) guidelines, and applicable local regulatory requirements and laws. 
 
11.2 Institutional Review Board (IRB) 
It is the responsibility of the investigator to obtain prospective approval of the conduct of 
the clinical study, the final protocol, protocol amendments, informed consent forms, and 
other relevant documents (e.g. advertisements), if applicable, from the IRB.  Copies of the 
final IRB approvals must be forwarded to Acera Surgical, Inc. prior to enrolling patients 
or starting any clinical study activities. 
Protocol amendments require Acera Surgical, Inc. and IRB approval before any patient in 
this clinical study is subjected to that change.  When a change is necessary to eliminate 
apparent immediate hazards to the clinical study patients, emergency procedures can be 
used with caution to prevent exposing the patient to the hazard.   
 
11.3 Confidentiality 
Information about study patients will be kept confidential and managed according to the 
requirements of the local regulatory authority, as well as applicable US laws and 
regulations. 

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Personal Health Information (PHI) will be acquired during informed consent of the patient 
and from the medical records. This information will be utilized to identify the subject and 
contact the subject for emergencies and follow up appointments. The PHI is part of the 
patient clinic chart, and will be secured in a locked office when not in use. To ensure that 
confidentiality is maintained, patient names will not be used in this evaluation in any other 
way. A unique identifying number will be used. This identification method will be 
consistent for each subject throughout the evaluation.  
In the event that a patient revokes authorization to collect or use PHI, the Investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of the 
authorization.   
 
12. MONITORING 
Site monitoring will be conducted to ensure that the rights and well-being of human subjects 
are protected, that the reported trial data are accurate, complete, and verifiable, and that the 
conduct of the trial is in compliance with applicable regulations, agreements with the 
sponsor, the currently approved protocol, and with any requirements imposed by the IRB.  
 
Monitoring will be performed by the sponsor and/or its representatives, and monitors will be 
qualified by training and experience. On site and/or remote visits will be made before the 
study begins, at regular intervals during the study, and at the study closeout. The purpose of 
visits will be to: 
 Provide study training 
 Verify adherence to the protocol, agreements, IRB requirements, and applicable 
regulations 
 Review essential study documentation including site personnel documents, study logs 
and IRB correspondence 
 Verify informed consent was properly obtained 
 Verify the completeness and accuracy of source documentation and eCRFs 
 
 
13. SPONSOR DISCONTINUATION CRITERIA 
The Sponsor may suspend or terminate the study or part of the study at any time for any 
reason. If the investigator suspends or terminates the study at their respective site, the 
investigator will promptly inform the Sponsor and the IRB/EC and provide them with a 
detailed written explanation.  
 
 
13.1 Termination of the study by the Sponsor 
Premature termination of this clinical study may occur because of a regulatory authority 
decision, change in opinion of the IRB/EC, product safety concerns or at the discretion of 
Acera Surgical, Inc.  

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Acera Surgical, Inc., reserves the right to discontinue the study prior to inclusion of the 
intended number of patients, but intends only to exercise this right for valid scientific or 
administrative reasons. After such a decision, the investigator must contact all participating 
patients within 30 days.   
 
13.2 Termination of Site by the Sponsor 
Acera Surgical, Inc., reserves the option to terminate the participation of a study site at 
any time. Reasons for terminating the participation of a study site include, but are not 
limited to, the following:  
 Patient enrollment is unsatisfactory  
 Data recording is consistently inaccurate or incomplete  
 Investigator does not adhere to the protocol or applicable regulatory guidelines in 
conducting the study  
 IRB decides to terminate or suspend approval for the Investigator  
 Study site or Investigator violates GCP or the study agreements, disrupting the 
appropriate conduct of the trial  
 Investigator asks to withdraw from study participation  
 
13.3 Termination by the Investigator 
If the Investigator terminates the study prematurely, the Investigator must provide the 
Sponsor and IRB/EC with a written statement describing why the study was terminated 
prematurely. 
 
14.  PUBLICATIONS POLICY 
Acera Surgical, Inc. will be responsible for determining when the study results should be 
published.  The Sponsor may work jointly with the investigators to publish information.  The 
investigators shall not submit a publication to journals or professional societies without 
notification and review by the Sponsor. 
 
15.  SUMMARY OF PROTOCOL REVISIONS 
Revision 
Number 
Date 
Sections Revised Summary of Changes 

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01 
27 January 
2021 
N/A 
N/A  Initial Version 
02 
08 March 
2021 
Section 1 
 
Section 5.15.1 
Removed National PI and Added Steering 
Committee 
 
Added the following study participation 
exit point: the Investigator may withdraw 
the patient if he/she determines it is in the 
patients best interest 
03 
30 
September 
2022 
Section 1, 2.2, 
2.4.1, 3, 4.1.2, 
5.1, 5.3, 5.7, 5.9, 
5.9.2, 5.10, 
5.10.4, 5.12, 8, 
9.5.4.1, and 15 
Removed Lyophilized Fish Skin (Kerecis) 
as a comparator for DFU 
Removed references to blinding 
Added Standard of Care (SOC) as a 
comparator for DFU 
 
16.  REFERENCES 
1. Raghav A, Khan ZA, Labala RK, Ahmad J, Noor S, Mishra BK. Financial burden of 
diabetic foot ulcers to world: a progressive topic to discuss always. Ther Adv Endocrinol 
Metab. 2018;9(1):29-31. doi:10.1177/2042018817744513 
 
2. Regulski MJ and MacEwan MR. Implantable Nanomedical Scaffold Facilitates Healing 
of Chronic Lower Extremity Wounds. Wounds. 2018;30(8): E77-E80. 
 
3. Snyder DL, Sullivan N, Margolis DJ, Schoelles K. Skin substitutes for treating chronic 
wounds. Technology Assessment Program Project ID No. WNDT0818. (Prepared by the 
ECRI Institute-Penn Medicine Evidence-based Practice Center under Contract No. 
HHSA 290-2015-00005-I) Rockville, MD: Agency for Healthcare Research and Quality. 
February 2020.  
 
4. Killeen AL, Brock KM, Loya R, Honculada CS, Houston P, and Walters JL.  Fully 
Synthetic Bioengineered Nanomedical Scaffold in Chronic Neuropathic Foot Ulcers.  
Wounds 2018;30(10):E98E101. 
 
5. Macewan M R, Macewan S, Kovacs T R, et al. (October 02, 2017) What Makes the 
Optimal Wound Healing Material? A Review of Current Science and Introduction of a 
Synthetic Nanofabricated Wound Care Scaffold. Cureus 9(10): e1736. DOI 
10.7759/cureus.1736 
 

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6. MacEwan MR and MacEwan S et al.  Efficacy of a Nanofabricated Electrospun Wound 
Matrix in Treating Full-thickness Cutaneous Wounds in a Porcine Model. Wounds. 
2018;30(2):E21E24. 
 
7. Apligraf. (2020). https://apligraf.com  

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17. APPENDICES 
Appendix A: Synthetic Hybrid-Scale Fiber Matrix (Restrata) Instructions For 
Use 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix B: Standard of Care ( Instructions) 
 
To ensure off-loading, each patient will be fitted with an off-loading device based on the 
investigators decision, e.g. a boot for forefoot and a heel protector for hindfoot.  Patients is 
instructed on how to care for the surgical site, utilize an off-loading device, and keep the surgical 
site moist and clean.  If the wound is dry, a hydrogel category dressing type should be used. If 
the wound has exudate, an alginate or foam dressing is recommended. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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Appendix C: Living Cellular Skin Substitute (Apligraf) Instructions for Use

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