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Trial registered on ANZCTR


Registration number
ACTRN12621001613897
Ethics application status
Approved
Date submitted
26/08/2021
Date registered
26/11/2021
Date last updated
1/08/2022
Date data sharing statement initially provided
26/11/2021
Type of registration
Prospectively registered

Titles & IDs
Public title
A comparison of wound healing in diabetic foot wounds using a Biodegradable Temporising Matrix (BTM) scaffold technology versus usual standard of care.
Scientific title
Overcoming barriers to wound healing in a neuroischemic diabetic foot cohort using novel tissue augmentation technology (NovoSorb® Biodegradable Temporising Matrix): a randomised control trial.
Secondary ID [1] 305146 0
None
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic neuroischemic wound 323407 0
Diabetic foot ulcer 323408 0
Diabetes 323409 0
Tissue ischemia 323410 0
Condition category
Condition code
Surgery 320963 320963 0 0
Surgical techniques
Metabolic and Endocrine 321445 321445 0 0
Diabetes
Skin 321446 321446 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
A randomised control trial, where participants undergoing minor amputation/tissue debridement surgery (index procedure) on their foot will be randomly allocated to one of two groups (interventional trial group outlined below):

i. A trial group who will receive NovoSorb BTM applied to their wound bed post-surgical debridement/revision (per standard protocol) placed into the wound bed and secured with surgical staples or non-dissolvable suture material. A Negative Pressure Wound Therapy (NPWT) (ActiV.A.C™ Therapy System, 3M, San Antonio USA) device will be placed over the NovoSorb BTM to bolster the product into the wound bed and manage wound exudate. The device will be set at -75mmHg continuous negative pressure. NPWT will continue for a total of 14 days, after which conventional wound dressings will be applied. Conventional wound dressings have been described below in the comparator/control field as these serve as the standard of care for all participants.

Application of NovoSorb BTM will be delivered via a surgeon (NovoSorb BTM is a product currently employed as part of our wound treatment milieu and therefore all surgeons at FMC have had training and experience in application of this treatment).

Post-surgical care will be provided by nursing staff as per protocol, participants will be monitored by members of the research team after surgery.

Participants will remain as an inpatient for a minimum of 7 days post index procedure, after which ongoing monitoring will be performed as per protocol by the research team in conjunction with community nursing service and outpatient clinicians. Participants will remain under the governance of the treating surgeon.

Adherence to fidelity of the intervention will be monitored via review of the surgical report and inpatient documentation by the research team.
Intervention code [1] 321555 0
Treatment: Other
Comparator / control treatment
i. A control group, who will receive the usual standard of care for peri-operative management of a diabetic neuroischemic surgical wound. The usual standard of care at our institution consists of NPWT (ActiV.A.C™ Therapy System, 3M, San Antonio USA), with review at 48 hours post-surgery. NPWT will persist for a minimum of 14 days from date of surgery unless contraindicated. In which case conventional wound dressings will be used, For this trial the NPWT treatment pressure will be at a continuous pressure of -75mmHg.

Patients will be observed as an inpatient for a minimum of 7 days post index procedure, after which ongoing monitoring will be performed as per protocol by the research team in conjunction with community nursing services and outpatient clinicians. Participants will remain under the governance of the treating surgeon.

Adherence to fidelity of the comparator treatment (control) will be monitored via review of the surgical report and inpatient documentation by the research team.

Post initial 14 days of NPWT wound dressing methods are outlined below:

Stage 2 – Day 14 post index procedure (control) / Post NovoSorb delamination to wound achieving superficial depth

During this stage the focus will be on providing a moist wound healing environment, minimising risk of infection and promotion of tissue proliferation and wound contraction.

This stage commences once the wound has been delaminated (NovoSorb BTM) or post cessation of NPWT therapy (control).

The wound bed is to be dressing with Aquacel® Ag Extra™ (ConvaTec Group PLC, Reading UK) an antimicrobial hydrofibre which has gelling and exudate transference properties. This dressing is to be used as the primary dressing on the wound bed until wound exudate fails to stain through to the secondary dressings (gauze and combine dressings) in greater than or equal to a 48-hour period.

Once the wound has contracted and granulated to a depth of less than or equal to 2mm the wound will be considered to have transitioned to stage 3.

Frequency of dressing change for wounds in this stage to be a minimum of 3 times a week.

Stage 2 dressing summary: Aquacel® Ag Extra™ applied as primary wound dressing. Gauze and combine dressings to be used as secondary dressings, secured to the foot with either Hyperfix (BSN Medical, Australia) or combination Softban and crepe bandage. Dressings to be changed minimum 3 times a week.

Stage 3 – Superficial depth to complete epithelialisation

This stage signals the final stages of wound healing, where a wound of superficial depth progresses to final epithelialisation and complete wound healing.

The dressing regime for this stage consists of Inadine (Acelity, San Antonio TX USA) as primary dressing. Inadine is a povidone iodine, paraffin, and gauze dressing – a topical antimicrobial dressing which provides a moist wound environment for moderate to low exuding wounds.

This dressing is to be used in combination with either a polyurethane foam or gauze and combine as secondary dressings, secured with Hyperfix fixation adhesive or combination Softban and crepe bandage.

Frequency of dressing change for wounds in this stage to be a minimum of 2 times a week.

Stage 3 dressing summary: Inadine covered with polyurethane foam or gauze / combine. Secured with Hyperfix or Softban and crepe bandage. Dressings to be changed minimum 2 times a week.
Control group
Active

Outcomes
Primary outcome [1] 328737 0
Complete wound healing (100% epithelialisation). This will be determined by visual inspection of the wound by a member of the clinical team (clinicians registered as part of the trial)
Timepoint [1] 328737 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months (primary time point).
Secondary outcome [1] 400188 0
Wound surface area reduction at 12 months, assessed using wound planimetry measurements via the Smith and Nephew Visitrak Digital device. Measurements obtained via Smith and Nephew Opsite Flexifix placed on top of the wound and traced using permanent marker.
Timepoint [1] 400188 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [2] 400189 0
Time to complete wound healing, ascertained by visual inspection by a member of the clinical team.
Timepoint [2] 400189 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [3] 400190 0
Hospital length of stay during index admission, obtained via the medical records
Timepoint [3] 400190 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [4] 400191 0
Volume of wound dressing changes (duration of therapy less than or equal to 12 months), obtained through hospital medical records and community data collection sheets,
Timepoint [4] 400191 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [5] 400192 0
Number and severity of wound complications (wound dehiscence, progression/advancement of ischemic tissue, proximal amputation, tissue infection). This is a composite secondary outcome. The nature of data related to wound complications are collected simultaneously (eg number and nature) and will be obtained through interrogation of medical records and data collection sheet.
Timepoint [5] 400192 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [6] 400193 0
Number and severity of systemic complications, This is a composite secondary outcome. The nature of data related to systemic complications are collected simultaneously (eg number and nature) and will be obtained through interrogation of medical records and data collection sheet.
Examples of systematic complications include sepsis, myocardial infarctions, deep vein thrombosis, allergic reactions.
Timepoint [6] 400193 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [7] 400194 0
Major amputations (transtibial, transfemoral), data obtained from interrogation of the medical records.
Timepoint [7] 400194 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [8] 400195 0
Participant adherence to wearing of offloading devices, data obtained from a patient questionnaire requested by investigators at each review time point.
Timepoint [8] 400195 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [9] 400196 0
All-cause/disease specific hospital readmissions. This is a composite secondary outcome. The nature of data related to hospital readmissions are collected simultaneously (eg causality and specifics of disease related to admission) and will be obtained through interrogation of medical records and data collection sheet.
Timepoint [9] 400196 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [10] 400197 0
Date of post-procedure revascularisations (participant endpoint), captured through interrogation of the medical records.
Timepoint [10] 400197 0
Day 2 post surgery, day 7 post surgery, day 14 post surgery, day 28 post surgery and every 28 day thereafter until wound is healed or 12 months.
Secondary outcome [11] 400198 0
Quality of life comparison using the Australian Vascular Quality of Life Index (AUSVIQOL).
Timepoint [11] 400198 0
At baseline, 3 months and 12 months post index procedure
Secondary outcome [12] 400199 0
Health economics - comparison of aggregate costs of hospital bed days for index admission, admissions for complications related to the index procedure and volume of wound dressing changes related to the index wound / index procedure.
Data will be obtained from interrogation of the medical records linked to hospital health economic data obtained form service business managers.
Timepoint [12] 400199 0
Evaluated at 12 months post index procedure
Secondary outcome [13] 400201 0
Specimen outcomes:
1. Stored Serum will be analysed to assess anti-inflammatory and anti-oxidative effect of NovoSorb BTM in context of wound healing and neuroischemic tissue. Specifically, the markers of oxidative stress hydrogen peroxide, haemoxygenase and NADPH Oxidases (NOX) have been linked to impaired wound healing and will be assayed using ELISA techniques. Similarly, pro-inflammatory and pro-atherogenic markers IL-1, IL-2, IL-6 TNF-alpha, and PDGF will also be assessed using ELISA techniques. Prolonged elevation of these markers is linked to an abnormal pro-inflammatory response and delayed wound healing.
Timepoint [13] 400201 0
Serum samples taken at baseline and 28 days post index procedure.
Secondary outcome [14] 401828 0
Specimen outcome
Tissue biopsies of wound bed for cell characterisation and distribution by IHC/flow cytometry
Timepoint [14] 401828 0
Day of index procedure, day 14 post procedure, day 28 post procedure.
Secondary outcome [15] 401829 0
Specimen outcome
3. Wound exudate sampling will be subjected to ELISA and proteomics providing a wide profile of marker proteins including MMP-2, MMP-9, neutrophil elastase, IL-6, PDGF, VEGF, FGF, Fibrinogen and C5.
Timepoint [15] 401829 0
Performed at day 2 post index procedure, day 7 and day 14 post index procedure.
Secondary outcome [16] 403036 0
Tissue biopsies of wound bed for gene expression by RT/PCR. Normal wound healing sees early recruitment of inflammatory cells (neutrophils, macrophages, and fibroblasts) which release corresponding cytokines.
Timepoint [16] 403036 0
Day of index procedure, day 14 post procedure, day 28 post procedure.

Eligibility
Key inclusion criteria

Subjects must fulfill all the following inclusion criteria to be eligible to participate in the study:

i) Any patient scheduled to undergo:
(1) minor amputation of the lower limb (defined as amputation of any anatomical structure distal of the proximal metatarsals).
(2) incision and drainage of infected tissue of the foot.
(3) surgical revision of existing wound on the lower limb.
(4) surgical revision of previous amputation site.
(5) any surgery of the lower limb resulting in significant tissue deficit not able to be closed by primary intention

ii) Who has an established or new diagnosis of diabetes as determined by HbA1C >6.5% (48mmol/mol) or as represented by pre-existing prescription of diabetes medication (e.g., insulin or oral hypoglycaemics)
iii) Whose wounds are scored a moderate (stage 3) or high (stage 4) risk of lower limb amputation based on their presenting wound condition, extent of infection and most recent perfusion assessment (toe pressures or transcutaneous oximetry) using the Society for Vascular Surgery Wound Ischemia and foot Infection (WIfI) classification system.
iv) Provides written informed consent prior to any clinical study procedures being performed.
v) Willing to comply with all study procedures and expects to be available for the duration of the study
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Subjects will not be included if any one or more of the following conditions exist:

i. Patients who live interstate, rural or remote or who are not able to attend the scheduled appointed review time frames.
ii. Patients under 18 years of age.
iii. Patients who are unable to give informed consent due to language difficulties or physical/mental incapacity.
iv. Patients planned for a minor amputation or surgical procedure of the lower limb where the operative wound bed will/has been closed using primary closure methods (suture, staples).
v. Patients with known hypersensitivity to any polyurethane components of NovoSorb™ BTM.
vi. Patients who are pregnant or nursing an infant.

Study design
Purpose of the study
Treatment
Allocation to intervention
Randomised controlled trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Sealed opaque envelopes
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Sequence generation will be facilitated using www.sealedenvelope.com, using the following parameters: Two treatment groups assigned as "BTM" and "Standard" and further stratified to “WIfI High” and “WIfI Moderate”; WIfI High will be assigned block sizes of 2 (total 7), 4 (total 4) and 6 (total 4); WIfI Moderate with be assigned block sizes of 2 (total 3) and 4 (total 1) for a total list length of 64 subject allocations, stratified into 54 WIfI High (27 each arm) and 10 WIfI Moderate (total 5 each arm). Subject sequenced allocation, derived from the above method, will be placed in sealed envelopes using aluminium wrapping to conceal envelope content impermeable to intense light. The envelopes will be prepared by a staff member independent of the study project to maintain blinding of random assignment of envelope content from the research project team. Envelopes will be externally labelled WIfI High and WIfI Moderate for the purpose of stratification.
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
The primary analysis will be undertaken on an intention-to-treat (ITT) basis with those lost to follow-up before 12 months having their last observation / measure carried forward. For per-protocol analysis all subjects lost to follow-up will be excluded from the analysis. Statistical Package for Social Sciences version 27 (SPSS Inc, Chicago IL, USA) will be used to perform statistical analyses. Continuous data will be reported as mean (SD) or median (IQR) according to normality and categorical data as n (%).

Difference within groups for continuous data will be tested using paired samples t-test or Wilcoxon Signed Rank test and change from baseline to 12 months between groups using independent samples t-test or Mann-Whitney U test.

Difference between groups for categorical data will be tested using Chi square test. Relationships between variables will be assessed using Pearson’s or Spearman’s correlation coefficient depending on tests for normality of the data distribution.

A statistical significance of P <0.05 will be utilized.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
13/05/2022
Actual
5/05/2022
Date of last participant enrolment
Anticipated
3/04/2023
Actual
Date of last data collection
Anticipated
5/04/2024
Actual
Sample size
Target
64
Accrual to date
8
Final
Recruitment in Australia
Recruitment state(s)
SA
Recruitment hospital [1] 20352 0
Flinders Medical Centre - Bedford Park
Recruitment postcode(s) [1] 35115 0
5042 - Bedford Park

Funding & Sponsors
Funding source category [1] 309537 0
Government body
Name [1] 309537 0
Southern Adelaide Local Health Network
Country [1] 309537 0
Australia
Primary sponsor type
Hospital
Name
Flinders Medical Centre
Address
Flinders Drive, Bedford Park, SA 5042
Country
Australia
Secondary sponsor category [1] 310530 0
None
Name [1] 310530 0
Address [1] 310530 0
Country [1] 310530 0
Other collaborator category [1] 281959 0
Commercial sector/Industry
Name [1] 281959 0
PolyNovo Biomaterial Pty Ltd
Address [1] 281959 0
Unit 2/320 Lorimer Street, Port Melbourne, Victoria 3207,
Country [1] 281959 0
Australia
Other collaborator category [2] 281960 0
University
Name [2] 281960 0
Flinders University
Address [2] 281960 0
GPO Box 2100, Adelaide 5001, South Australia
Country [2] 281960 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 309319 0
Southern Adelaide Clinical Human Research Ethics Committee
Ethics committee address [1] 309319 0
Flinders Drive
Bedford Park, SA 5042
Ethics committee country [1] 309319 0
Australia
Date submitted for ethics approval [1] 309319 0
05/08/2021
Approval date [1] 309319 0
23/08/2021
Ethics approval number [1] 309319 0
2021/HRE00214

Summary
Brief summary
This research project aims to assess the impact of a wound healing technology (NovoSorb® BTM) on the rate of wound healing in participants who need to undergo minor amputation of their foot. A minor amputation is a procedure which is required to be performed when there is infection or damage to the tissue of the foot which is no longer able to be salvaged or healed without surgery. A minor amputation may involve one or more of your toes or a portion of your foot which has become damaged and is not able to be saved or healed without removal (amputation) of the affected tissue.

Ischemia is a condition where parts of the body are starved of blood, which provide oxygen and nutrients for survival, in turn resulting in damage to tissue which can result in wounds. Neuro-ischemia is a condition most often suffered by people with diabetes. This condition affects both the large and small blood vessels in your body, which results in ischemia to tissues. In people with diabetes this condition often affects the blood vessels in their feet which can lead to non-healing wounds. This study seeks to test the ability of the NovoSorb® BTM to heal wounds in people with wounds related to neuro-ischemia.

NovoSorb® BTM was originally designed for use in healing wounds in burns patients. The technology has proven useful in helping to heal burns wounds for more than 5 years. This technology is a piece of foam which serves as a scaffold for your healing tissue to grow through. The product is applied by a surgeon in a theatre environment and is left in place until your tissue has grown through the foam scaffold. The foam is specially formulated to slowly dissolve as your healing progresses and your tissue gets stronger. The foam is absorbed by your body and is considered safe and non-toxic.

We are seeking to assess whether NovoSorb® BTM helps to heal minor amputation wounds faster and with less risk of infection when compared with current practice (standard wound dressings – negative pressure and antimicrobial dressings).

Medications, drugs, and devices must be approved for use by the Australian Federal Government. NovoSorb® BTM is approved in Australia to treat wounds.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 113746 0
Mr Frank Guerriero
Address 113746 0
c/- L2 Car Park Building
Dept Vascular and Endovascular Surgery
Flinders Medical Centre
Flinders Drive
Bedford Park, SA 5042
Country 113746 0
Australia
Phone 113746 0
+61412767374
Fax 113746 0
+610882047106
Email 113746 0
frank.guerriero@sa.gov.au
Contact person for public queries
Name 113747 0
Mr Frank Guerriero
Address 113747 0
c/- L2 Car Park Building
Dept Vascular and Endovascular Surgery
Flinders Medical Centre
Flinders Drive
Bedford Park, SA 5042
Country 113747 0
Australia
Phone 113747 0
+61412767374
Fax 113747 0
+610882047106
Email 113747 0
frank.guerriero@sa.gov.au
Contact person for scientific queries
Name 113748 0
Mr Frank Guerriero
Address 113748 0
c/- L2 Car Park Building
Dept Vascular and Endovascular Surgery
Flinders Medical Centre
Flinders Drive
Bedford Park, SA 5042
Country 113748 0
Australia
Phone 113748 0
+61412767374
Fax 113748 0
+610882047106
Email 113748 0
frank.guerriero@sa.gov.au

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
individual participant data, post deidentification - underlying published results only
When will data be available (start and end dates)?
Immediately following publication. Data available for 15 years post date of final data point collection.
Available to whom?
Researchers who provide a methodologically sound proposal, industry collaborator (PolyNovo Biomaterials)
Available for what types of analyses?
Any purpose
How or where can data be obtained?
Access subject to approvals by Principal Investigator. Principal investigator best contacted via email - frank.guerriero@.sa.gov.au


What supporting documents are/will be available?

TypeCitationLinkEmailOther DetailsAttachment
Informed consent form  frank.guerriero@sa.gov.au 382672-(Uploaded-26-08-2021-16-47-11)-Study-related document.doc


Results publications and other study-related documents

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