Novel Biomaterial Containing Gelatin, Manuka Honey, and Hydroxyapatite Enhanced Secondary Intention Healing vs. Standard Secondary Intention Healing in Mohs Surgical Defects on the Head and Distal Lower Extremities - A Randomized Clinical Trial
Phase: NA
Conditions: Wound Heal
Sponsor: Vanderbilt University Medical Center

Protocol Version #2: 
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Protocol Date: 07/01/2021 
NCT04545476
Novel Biomaterial Containing Gelatin, Manuka 
Honey, and Hydroxyapatite Enhanced 
Secondary Intention Healing vs. Standard 
Secondary Intention Healing in Mohs Surgical 
Defects on the Head and Distal Lower 
Extremities – A Randomized Clinical Trial 
Karen Arnaud, MD 
Dermatology Resident Physician 
Vanderbilt Dermatology One Hundred Oaks 
719 Thompson Lane, Suite 26300 
Nashville, TN 37204 
Anna S. Clayton, MD 
William G. Stebbins, MD 
Michel A. McDonald, MD 

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Table of Contents: 
 
Study Schema 
1.0 
Background 
2.0 
Rationale and Specific Aims 
3.0 
Animal Studies and Previous Human Studies 
4.0 
Inclusion/Exclusion Criteria 
5.0 
Enrollment/Randomization 
6.0 
Study Procedures 
7.0 
Risks of Investigational Agents/Devices (side effects) 
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
9.0 
Study Withdrawal/Discontinuation 
10.0 Statistical Considerations 
11.0 Privacy/Confidentiality Issues 
12.0 Follow-up and Record Retention 
 

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1.0 
Background 
Brief Summary: 
The purpose of this study is to elucidate if a novel biomaterial containing gelatin, 
manuka honey, and hydroxyapatite enhances secondary intention healing when 
compared to conventional secondary intention healing for surgical defects after Mohs 
micrographic surgery on the head and distal lower extremities (below the knee). 
Detailed Description: 
Secondary intention healing (SIH) is often underutilized and has several advantages 
compared to primary surgical repair.1,2 Wound care is minimal, bleeding and infection 
are rare, and risks associated with primary closure (e.g. hematoma, suture granuloma, 
graft or flap failure) are non-existent.3 Importantly, SIH facilitates surveillance of tumor 
recurrence, whereas flaps and grafts may bury residual tumor.1,3 When used in 
appropriate anatomical locations, SIH leads to high patient satisfaction.1,2,4 However, 
SIH requires regular wound care that can be cumbersome to patients.3,5  
Prior studies utilizing biologic dressings have shown patients report better quality of life 
during the post-operative period related to less pain, decreased dressing changes, and 
faster healing times.5,6 Biologic dressings provide an alternative to surgical autografts 
and eliminate the risks associated with graft harvesting (e.g. pain, infection, and 
scarring).5,7 For many patients, the cosmetic outcome following healing is important. 
However, cosmetic outcome with SIH is variable and depends on many factors, namely 
location (e.g. concavities favorable), skin laxity, and underlying musculature.1,2,8 
Exuberant granulation tissue, hypopigmented and telangiectatic scars are the most 
frequent adverse cosmetic outcomes with SIH.3,9 
The novel biomaterial APIS® (SweetBio, Inc. Memphis, TN) is an advanced synthesis of 
gelatin, manuka honey, and hydroxyapatite bioengineered to protect wounds, manage 
exudate, and maintain a moist environment. It is FDA cleared (FDA number K1827250) 
for wound management across 9 indications including surgical wounds. It has been used 
successfully in a small case series of 8 patients for post-operative Mohs surgical wounds 
on the head and distal lower extremities. Time to complete re-epithelialization was 6 
weeks (42 days), suggesting a reduction in healing time compared to standard SIH 
times for the leg and head of 127 and 57 days, respectively.10,11 Use of this novel 
biomaterial to enhance SIH is hypothesized to reduce healing times when compared to 
standard SIH wound care. This provides a useful option to aid SIH in sites like the lower 
legs, where healing can be prolonged due to intrinsic factors (e.g., cardiovascular 
disease, peripheral vascular disease, diabetes) or extrinsic factors (e.g., increased risk of 
surgical site infection following dermatologic surgery at sites below the knee).10,12 

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2.0 
Rationale and Specific Aims 
Randomized, comparative studies evaluating augmented SIH compared to conventional 
SIH in dermatologic surgery are limited. This study aims to evaluate whether use of a 
novel biomaterial enhances SIH, particularly in shortening time to complete re-
epithelialization. Patients undergoing Mohs micrographic surgery amenable to SIH on 
the head and distal lower extremities will be randomized into one of four groups 
(standard SIH or biomaterial APIS® enhanced SIH on the head or distal lower 
extremities). Patients will have regularly scheduled follow-up with questionnaires at each 
visit. We aim to evaluate whether use of this novel biomaterial decreases complete re-
epithelialization times, reduces infection rates, and improves cosmetic outcomes. 
Outcome Measures 
Primary:  
1. Time to complete re-epithelialization
Patients will be seen in office 14 days post-operative, then every 14 days thereafter until 
complete re-epithelialization is achieved. Patients will also submit photos via Vanderbilt 
HIPAA compliant Box at regular follow-up intervals (post-operative day 7 then every 14 
days thereafter until complete re-epithelialization is achieved). Time elapsed from 
surgery date to complete re-epithelialization will be noted in days.  
Secondary: 
1. Patient and Observer Scar Assessment Scale (POSAS) Patient Scale Score Version
2.0
Patients will complete the POSAS Patient Scale after complete re-epithelialization is 
achieved. The POSAS Patient Scale is a validated and widely accepted scar assessment 
tool. The patient scale has six questions assessing scar pain, itch, color, stiffness, 
thickness, and irregularity rated from 1 (no, not at all/normal skin) to 10 (yes, very 
much/worst imaginable). Scale from 6-60 with a final seventh question rating patient’s 
overall opinion of scar quality (1-10). 
2. Visual Analog Scale (VAS) – Provider Scar Ranking
Digital standardized photographs of scars after complete re-epithelialization is achieved 
will be assessed by two blinded dermatologists using the VAS. This scale ranges from 0 
or normal skin to 10 or worst possible scar taking into account the scar’s pigmentation, 
vascularity, contour, observer comfort, and overall severity. VAS scores of novel 
biomaterial will be compared to standard SIH. 
3. Size of wound
Post-operative wounds will be measured at regularly scheduled follow-ups. The area and 
volume for each patient’s wound will be calculated. 
4. Pain score

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Patients will self-report their surgical site/wound pain during in office follow-up visits via 
a questionnaire. Pain scale will range from 1 (no pain) to 10 (worst pain imaginable).  
5. Infection
Post-operative wounds will be assessed for infection at regularly scheduled follow-ups. 
Any suspected infection (e.g. erythema, purulence, malodor) will be cultured and 
reported. Antibiotic usage for either prophylaxis peri-operatively or treatment will be 
recorded. 
6. Bleeding
Patients will report any bleeding (yes/no) via questionnaires at regularly scheduled 
follow-ups. Additionally, if there was post-operative bleeding, was an intervention 
performed to achieve hemostasis (yes/no) and if yes, what intervention. 
7. Ease of Wound Care
Patients will self-report the ease of wound care on a scale of 1 (very easy) to 10 
(impossible) via questionnaires at regularly scheduled follow-ups. 
3.0 
Animal Studies and Previous Human Studies 
APIS® was FDA cleared in 2019 (FDA number K1827250) for management of full and 
partial thickness wounds, pressure ulcers, venous stasis ulcers, diabetic ulcers, surface 
wounds, traumatic wounds, surgical wounds, abrasions, and donor site wounds. 
A small case series of 8 patients used APIS® in SIH of Mohs surgical wounds on the head 
and distal lower extremities. Time to complete re-epithelialization was 6 weeks (42 
days), suggesting a reduction in healing time compared to standard SIH times for the 
leg and head of 127 and 57 days, respectively.10,11 
4.0 
Inclusion/Exclusion Criteria 
Inclusion Criteria: 
•
18 years of age or older
•
Post-operative wounds following Mohs surgery on the head or distal lower
extremities
•
Single Mohs post-operative defect
•
Post-operative wounds greater than 1cm in width
•
Depth of defect at least to subcutaneous tissue
•
Patients have the ability to provide their own wound care
•
Agreeable to regularly scheduled follow-up visits and transmission of photos via
HIPAA compliant Vanderbilt University Medical Center Box
•
Patients are able to provide informed consent

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Exclusion Criteria: 
•
Under 18 years of age
•
Unable to provide informed consent
•
Unable to understand oral and written English
•
Post-operative wounds not appropriate for secondary intention healing
•
Sensitivity or allergy to APIS® biomaterial including collagen and its derivatives,
porcine-derived materials or honey
•
Immunosuppressed and organ transplant patients
•
Post-operative wounds superficial to subcutaneous tissue
5.0 
Enrollment/Randomization 
Patient enrollment will occur at Vanderbilt University Medical Center One Hundred Oaks 
Department of Dermatology Mohs Surgical Unit. All patients eligible for study may be 
considered. Patients with Mohs surgical defects on the head and distal lower extremities 
amenable and conducive for SIH will be randomized to intervention or control by block 
randomization. Subjects will be randomized in a 1:1 ratio.  
Address of enrollment: 
Vanderbilt Dermatology One Hundred Oaks 
719 Thompson Lane, Suite 26300 
Nashville, TN 37204 
(615) 322-6485
6.0 
Study Procedures 
Arms and Interventions 
Two experimental groups 
1) APIS® biomaterial on the head 
2) APIS® biomaterial on the distal lower extremities
Two control groups 
1) No intervention, standard SIH wound care on the head
2) No intervention, standard SIH wound care on the distal lower extremities
Experimental (40 patients): APIS® biomaterial. APIS® biomaterial placed on post-
operative wound. 
1) Head (20 patients)
2) Distal lower extremities (20 patients)
a.
Device: APIS® biomaterial. This biomaterial was FDA cleared in 2019 for
management of full and partial thickness wounds, pressure ulcers,
venous stasis ulcers, diabetic ulcers, surface wounds, traumatic wounds,
surgical wounds, abrasions, and donor site wounds.
b. One layer of APIS® will be applied to the post-operative wound covered
by petrolatum impregnated gauze, a non-stick Telfa pad, gauze, and
Opsite tape.

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c.
The biomaterial will be reapplied if it is completely absorbed at follow up
and the wound depth below the epithelial level.
No intervention (40 patients): No APIS® biomaterial on post-operative wound. 
3) Head (20 patients)
4) Distal lower extremities (20 patients)
a.
Post-operative wound will heal via conventional secondary intention.
Application of petrolatum impregnated gauze, a non-stick Telfa pad, 
gauze, and Opsite tape. 
This study may be deemed complete prior to reaching above enrollment numbers if 
statistical significance is achieved or at the discretion of the research team. 
Mohs Surgery – Day 0 
Patients eligible for study will be offered opportunity to enroll. After informed consent 
has been obtained, the patient’s clinical history, medical history, social history, 
medication history, and vital signs will be reviewed and documented. Pre and post-
operative photos will be obtained and stored in the Electronic Medical Record and 
Vanderbilt HIPAA compliant Box.  
Patients on day of surgery will be provided with a post-operative wound care instruction 
sheet (for both control and experimental groups). They will also receive a detailed 
instruction sheet for uploading post-operative photos to Vanderbilt’s HIPAA compliant 
Box.  
Subsequent Post-operative Visits – Post operative Day 14 then every 14 days thereafter 
until complete re-epithelialization is achieved. Patients enrolled in study will be provided 
a brief questionnaire to complete at in-person office follow-up visits. Post-operative 
wounds will be assessed for any complications. Size of wounds in addition to 
photographs will be obtained until complete re-epithelialization is achieved. Patients will 
also upload post-operative photos to Vanderbilt’s HIPAA compliant Box post-operative 
day 7 then every 14 days thereafter until complete re-epithelialization is complete. 
7.0 
Risks 
Known and expected risks associated with the use of the intervention are the following: 
•
Allergic reaction to APIS® biomaterial
•
Surgical site pain, infection, minimal bleeding, oozing, swelling, and/or itching
•
Scar
•
Loss of confidentiality
•
Feeling uncomfortable answering questionnaire
8.0 
Reporting of Adverse Events or Unanticipated Problems involving Risk 
to Participants or Others 
Participants will be instructed at the time of consent to contact a member of the study 
team should they experience any adverse event or unanticipated problem. An on-call 

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pager number will be provided to study participants. All adverse events and 
unanticipated problems will be reported to the VUMC IRB in accordance with the VUMC 
IRB policy. Additionally, all serious adverse events will be reported to the manufacturer 
of APIS®, SweetBio, Inc (Memphis, TN).  
9.0 
Study Withdrawal/Discontinuation 
Participants have the ability to withdraw or discontinue from the study at any time. 
Subjects will be instructed to notify a member of the study team if they wish to 
withdraw, and any data collected for research will be discarded. 
Participants enrolled in the study may be terminated from the study at the investigator’s 
discretion including but not limited to the following: 
•
Lost to follow-up
•
Nonadherence with wound care
•
A participant’s health status changes significantly which makes them not eligible
for the study
•
Trauma to the post-operative wound
10.0 Statistical Considerations 
The primary endpoint is time to achieve complete re-epithelialization. The mean number 
of days required to achieve complete re-epithelialization between control and 
experimental groups will be analyzed with a Student’s T-test. The null hypothesis is that 
there is no statistically significant difference between control and experimental complete 
re-epithelialization times. Secondary outcomes of patient and observer cosmetic 
outcome will be compared similarly.  
11.0 Privacy/Confidentiality Issues 
All data will be secured, and confidentiality will be upheld by all members of the 
research team. Participants will be assigned a study identification code in order to 
deidentify the study data. A crosslink will exist to link study identification codes to 
participant identifiers. This crosslink will only be accessible to a limited number of IRB 
trained and approved study personnel. Study data will be contained in a password 
protected Excel spreadsheet and stored on the Vanderbilt HIPAA compliant Box. Patients 
enrolled in this study may request to have all data removed/destroyed from the 
database if they elect to withdraw from the study.  
12.0 Follow-up and Record Retention 
Study duration expected to be 12 months. Study data will be maintained by the research 
team for a minimum of 7 years and potentially indefinitely. This data will continue to be 
stored in a password protected database file on the Vanderbilt HIPAA compliant Box, in 
compliance with Vanderbilt University Medical Center’s record retention policies. A 
limited number of IRB trained, and approved study personnel will have access. 

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13.0 References 
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3. Donaldson MR, Coldiron BM. Scars after second intention healing. Facial Plast 
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Evaluation of patient satisfaction with second intention healing versus primary 
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6. Eaglstein WH, Iriondo M, Laszlo K. A composite skin substitute (graftskin) for
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