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Trial registered on ANZCTR


Registration number
ACTRN12618000511235
Ethics application status
Approved
Date submitted
19/03/2018
Date registered
9/04/2018
Date last updated
3/09/2018
Type of registration
Prospectively registered

Titles & IDs
Public title
Spray on skin for diabetic foot ulcers: an open label randomised controlled trial
Scientific title
Spray on skin for diabetic foot ulcer healing: an open label randomised controlled trial
Secondary ID [1] 294387 0
None
Universal Trial Number (UTN)
Trial acronym
Diabetic Foot SOS Trial
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic Foot Ulcers 307110 0
Condition category
Condition code
Metabolic and Endocrine 306229 306229 0 0
Diabetes
Infection 306230 306230 0 0
Other infectious diseases
Cardiovascular 306276 306276 0 0
Diseases of the vasculature and circulation including the lymphatic system
Skin 306277 306277 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The application of autologous skin cells in a suspension (Spray on skin) is the intervention. This is achieved using a proprietary product (ReCell® Avita Medical), a pre-prepared kit for autologous cell skin cell preparation. Through a series of well described enzymatic preparation and cell filtering steps, the procedure enables disaggregation of cells from a patient’s skin sample and the preparation of a suspension of these cells that can be sprayed or dropped directly onto the prepared wound bed. The procedure to harvest, prepare and administer skin cells will be performed once only by a vascular or plastic surgeon. The skin from which the suspension is prepared comes from a small split skin graft (SSG) that is taken from the patients’ thigh using topical local anaesthetic . An electric dermatome set at 2mm depth with a standard width will be used to harvest the skin and will enable accurate assessment of the area of the harvest site. The entire procedure will take ~30 minutes. Each patient will receive a single administration of cells harvested on a single occasion. The total number of cells administered (ie dose) is not quantifiable but will be all of the cells harvested from a 2cm2 piece of skin.
Intervention code [1] 300684 0
Treatment: Other
Intervention code [2] 300786 0
Treatment: Devices
Comparator / control treatment
The comparator group will receive standard care from the multi-disciplinary foot ulcer team for their diabetic foot ulcer. All elements of standard care will be recorded including wound care, footwear, antibiotic use, diabetes management and vascular interventions. Taken together these elements are the key components of a fully functional tertiary level foot ulcer service. The elements of standard care are not based on specific guidelines, but determined by the team's assessment of best practice within the constraints of our particular service.
Control group
Active

Outcomes
Primary outcome [1] 305246 0
The primary outcome for the trial will be a dichotomous outcome of complete healing of the index ulcer at 6 months from enrolment as defined by full epithelialisation, after debridement of callus, lasting for at least 2 weeks. Primary outcome arbitration will be performed using the database, wound dimension and clinical images by two independent senior clinicians blinded (not investigators) to the intervention. Discordant outcome assessments will be resolved by consensus.
Timepoint [1] 305246 0
The primary outcome is assessed for each individual at 6 months following the date of the enrolment. The planned interim analysis does not refer to the assessment of any individual, rather when the primary outcome is available for the first 80 participants.
Secondary outcome [1] 344618 0
The total number index ulcer free days at 12 months from enrolment. The definition of ulcer-free corresponds with full epithelialisation, after debridement of callus, lasting for at least 2 weeks and not requiring dressings. This outcome will be assessed by the clinical research team.
Timepoint [1] 344618 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [2] 344688 0
The time in days to full epithelialisation of the index ulcer from enrolment. The definition of full epithelialisation will be met if there is no ulcer and no requirement for dressings after debridement of callus.This outcome will be assessed by the clinical research team.
Timepoint [2] 344688 0
The outcome will be assessed at scheduled visits at 4, 10, 18, 26, 39 and 52 weeks and fortnightly by phone in between these visits.
Secondary outcome [3] 344689 0
Trajectory of wound healing of the index ulcer (defined as volume and measured using Silhouette™). This will be defined as the log transformed slope of the line of best fit for each individual. This outcome will be assessed by the clinical research team.
Timepoint [3] 344689 0
The outcome will be assessed at scheduled visits at 4, 10, 18, 26, 39 and 52 weeks
Secondary outcome [4] 344690 0
Any major adverse events.
Major adverse events include:
1. Death from any cause
2. Major limb amputation of the same leg as the index ulcer at any stage up to 12 months from enrolment
3. Major infection of the harvest site as defined as the requirement for admission to hospital, surgical debridement or intravenous antibiotics
This outcome will be assessed by the clinical research team.
Timepoint [4] 344690 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [5] 344691 0
Either a minor or a major amputation.
A minor amputation is an amputation below the ankle including toe, metatarsal-phalangeal and midfoot amputations. A major amputation is an amputation above the ankle including below knee and above knee amputations. This outcome will be assessed by the clinical research team.
Timepoint [5] 344691 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [6] 344692 0
All-cause mortality. This will be assessed from the hospital records by the clinical research team.
Timepoint [6] 344692 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [7] 344693 0
Re-ulceration of the index ulcer. Re-ulceration is defined as healing of index ulcer followed by subsequent ulceration with loss of epithelialisation at the same location. This outcome will be assessed by the clinical research team.
Timepoint [7] 344693 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [8] 344694 0
The development of any new ulcers. The definition of a new ulcer is one that occurs at a site on either foot away from the index ulcer. This outcome will be assessed by the clinical research team.
Timepoint [8] 344694 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [9] 344695 0
Total costs of inpatient and outpatient costs.
The cost data will be extracted for each individual participant by the study co-ordinator who will refine the details and assign contemporary unit costs for each component. It is expected that overall costs will be determined by length of hospital stay, number and nature of operating theatre visits, use of pathology and radiology services, length of “hospital in the home” treatment, direct antibiotic costs, consumables associated with wound management (dressings, debridement, human skin replacements, negative pressure wound therapy dressings; Silver Chain database, ComCare Wound Module, home nursing attendances (Silver Chain), orthotic appliances (prostheses, casting, shoes, in-soles). To enable to ascertain granular data on direct costs for outpatient home care nursing we will extract data from the Silver Chain electronic data collection tool. This tool will enable us to determine direct costs for individuals in terms of dressings, parenteral antibiotics and nursing home visits. Outpatient visit costs will be derived from Medicare rebates (for multidisciplinary team visits and single specialty attendances at podiatry, infectious diseases or vascular), whilst drug costs will be estimated from listed drug costs from Pharmaceutical Benefits Scheme (PBS) published listing, or in the case of moxifloxacin, piperacillin-tazobactam, ertapenem and other non-PBS drugs, from direct pharmacy costs. All costs will be adjusted on a year-by-year basis according to the medical services component of the Consumer Price Index to a single financial year for comparisons (2018).

Timepoint [9] 344695 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [10] 344696 0
Readmission to hospital. Any readmission to hospital will be captured from the hospital record.
Timepoint [10] 344696 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.
Secondary outcome [11] 344697 0
Quality of life will be assessed using a validated general well-being score (Euro QoL Five-Dimension [EQ-5D]). This descriptive system comprises five dimensions: mobility, self-care, usual activities, pain/discomfort and anxiety/depression. The EQ VAS records the patient’s self-rated health on a vertical visual analogue scale. This can be used as a quantitative measure of health outcome that reflects the patient’s own judgement. The scores on these five dimensions can be presented as a health profile or can be converted to a single summary index number.
Timepoint [11] 344697 0
The secondary outcome is assessed for each individual at 12 months following the date of the enrolment.

Eligibility
Key inclusion criteria
i) Age greater than 18years
ii) Diabetes (type 1 or 2) defined according to international consensus guidelines
iii) Admission to FSH or visit to outpatients department at FSH with a DFU requiring local debridement or minor amputation
iv) Ulcer area greater than or equal to 6cm2
v) The ulcer location, contour, shape and wound base is deemed to be suitable for administration of spray on skin
vi) No further debridement or amputation is anticipated
vii) Wound bed is adequately vascularised as determined by the presence of at least one palpable pulse in the affected foot, or at least single vessel run off visualised by arterial Doppler ultrasonography, MRI, CT or conventional angiography (including following revascularisation procedures)
viii) Competent and willing to provide informed consent
ix) Able to be followed up by Silver Chain for community nursing
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
i) Non-diabetic neuropathic ulcer
ii) Wounds deemed unsuitable on the basis of contour, location, vascularity or other factors
iii) Limb threatening ischaemia or sepsis requiring early major amputation
iv) Not competent to provide informed consent
v) Unlikely to be accessible for follow-up visit over the next 12 months
vi) Unable to be followed up by Silver Chain ambulatory care nurses

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)
Nil
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Computer generated
Masking / blinding
Open (masking not used)
Who is / are masked / blinded?



Intervention assignment
Parallel
Other design features
Phase
Not Applicable
Type of endpoint(s)
Efficacy
Statistical methods / analysis
The sample size calculations are informed from local data collected by Silver Chain that indicate that, at present, 45% of patients with DFU will achieve complete healing at 6 months. We estimate that 136 (with continuity correction) patients are required to have 80% chance of detecting, as significant at the 5% level, an increase in the primary outcome measure from 45% in the control group to 70% in the spray-on skin group. To account for drop outs, we will aim to recruit 150 participants in total.
All analyses will be conducted according to the intention-to-treat principle. Baseline characteristics will be compared by treatment group. Effects of treatment on the primary study endpoint (complete healing of the index ulcer at 6 months) will be estimated with the use of unadjusted logistic regression with last observation carried forward (LOCF) for those lost to follow-up. All P-values will be two-sided and P-values less than 0.05 will be considered to indicate statistical significance. Prognostic factors such as vascular insufficiency and site of DFU (fore-, mid- or hind foot) which are strongly correlated with the outcome (r greater than 0.3) will be adjusted for using multiple logistic regression. Binary secondary outcomes at 12 months will be analysed similarly. For continuous secondary outcomes, change score analysis that determines treatment effect based on the difference between baseline and post treatment score (basic adjustment) will be undertaken. Multiple linear regression adjusting for i) the baseline value of the outcome variable in the model (model 1), and ii) model 1 + adjustment for prognostic baseline factors (model 2) will be undertaken. Data will be analysed using IBM SPSS Statistics 22 (IBM Corporation, Armonk, New York, USA).


Pre-specified sub-group analyses will be performed using the dichotomous primary study endpoint described above. Sub-groups include ulcer site (categorical variable; fore-, mid- or hind foot), WiFI Clinical Stage at baseline presentation (categorical/ordinal variable; clinical stage 1-4), co-existent moderate to severe renal disease (dichotomous variable; creatinine clearance less than 30mL/min, age (dichotomous variable; age greater than 60 years) long term diabetic control at presentation (dichotomous variable; HbA1C greater than 9%), primary surgical procedure performed (dichotomous variable; minor amputation vs. local sharp or surgical debridement).

Due to the long-time delay until the primary outcome can be ascertained for each patient, we plan a single interim analysis after the first 80 patients. We estimate that 78 (with continuity correction) patients are required to have 80% chance of detecting, as significant at the 1% level, an increase in the primary outcome measure from 45% in the control group to 85% in the spray-on skin group. If this threshold is met, the trial will be ceased early. If this threshold is not met, the trial will be completed as described above.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
WA
Recruitment hospital [1] 10419 0
Fiona Stanley Hospital - Murdoch
Recruitment postcode(s) [1] 22106 0
6150 - Murdoch

Funding & Sponsors
Funding source category [1] 299024 0
Government body
Name [1] 299024 0
Department of Health Western Australia
Address [1] 299024 0
PO Box 8172
Perth Business Centre
Perth WA 6849
Australia
Country [1] 299024 0
Australia
Primary sponsor type
Government body
Name
Department of Health Western Australia
Address
PO Box 8172
Perth Business Centre
Perth WA 6849
Australia
Country
Australia
Secondary sponsor category [1] 298249 0
None
Name [1] 298249 0
Address [1] 298249 0
Country [1] 298249 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 299959 0
South Metropolitan Health Service Human Research Ethics Committee
Ethics committee address [1] 299959 0
South Metropolitan Health Service Human Research Ethics Committee
Level 2, Education Building, Fiona Stanley Hospital
14 Barry Marshall Parade
MURDOCH Western Australia 6150
Ethics committee country [1] 299959 0
Australia
Date submitted for ethics approval [1] 299959 0
20/02/2018
Approval date [1] 299959 0
28/02/2018
Ethics approval number [1] 299959 0
RGS0000000722

Summary
Brief summary
One Australian loses a limb every 3 hours as a result of diabetic foot ulcers (DFU) with infection. This common condition accounts for substantial morbidity and mortality for affected individuals and heavy economic costs for WA Health and the community. There is an urgent need to test interventions that improve wound healing time, prevent amputations and recurrent ulceration in patients presenting with DFU whilst improving quality of life and reducing health care costs.

A novel intervention towards achieving these goals is the use of spray-on skin for patients with DFU. The application of ‘spray-on’ autologous skin grafting aids epithelial regeneration and wound healing and has been used successfully for the treatment of burns to improve healing. In this research project we will compare spray-on skin with standard care in an open label randomised controlled trial in patients presenting to hospital with DFU. We hypothesise that spray-on skin will shorten the time for the ulcer to heal completely. In doing so, this approach can be expected to prevent amputations and recurrent ulceration whilst improving quality of life.
Outpatient costs for dressings, home nursing visits and outpatient appointments are key cost drivers for DFU. If spray-on skin is effective, large cost savings to WA Health will be realised immediately through a shortened time to healing, and through a higher proportion of patients achieving complete healing. Any economic benefits are likely to be amplified across Australia and other similar demographic settings where aging populations with increased diabetes rates are considered major future challenges.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 82086 0
Dr Laurens Manning
Address 82086 0
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive
Murdoch
WA 6150
Country 82086 0
Australia
Phone 82086 0
+61861511156
Fax 82086 0
Email 82086 0
laurens.manning@uwa.edu.au
Contact person for public queries
Name 82087 0
Dr Laurens Manning
Address 82087 0
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive
Murdoch
WA 6150
Country 82087 0
Australia
Phone 82087 0
+61861511156
Fax 82087 0
Email 82087 0
laurens.manning@uwa.edu.au
Contact person for scientific queries
Name 82088 0
Dr Laurens Manning
Address 82088 0
Harry Perkins Institute of Medical Research
Fiona Stanley Hospital
102-118 Murdoch Drive
Murdoch
WA 6150
Country 82088 0
Australia
Phone 82088 0
+61861511156
Fax 82088 0
Email 82088 0
laurens.manning@uwa.edu.au

No data has been provided for results reporting
Summary results
Not applicable