Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12621000337875
Ethics application status
Approved
Date submitted
28/01/2021
Date registered
25/03/2021
Date last updated
25/03/2021
Date data sharing statement initially provided
25/03/2021
Type of registration
Retrospectively registered

Titles & IDs
Public title
The treatment of foot problems in patients with diabetes or reduced blood flow to the legs
Scientific title
Australia and New Zealand Diabetic and Ischaemic Foot Outcomes Study
Secondary ID [1] 303238 0
None
Universal Trial Number (UTN)
Trial acronym
ANZ-DIFOS
Linked study record

Health condition
Health condition(s) or problem(s) studied:
type 1 diabetes mellitus 320393 0
type 2 diabetes mellitus 320394 0
peripheral arterial disease 320395 0
Lower limb ulceration 320396 0
lower limb gangrene 320397 0
Lower limb rest pain 320398 0
Condition category
Condition code
Metabolic and Endocrine 318301 318301 0 0
Diabetes
Skin 318716 318716 0 0
Other skin conditions
Cardiovascular 318717 318717 0 0
Diseases of the vasculature and circulation including the lymphatic system

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
1
Target follow-up type
Years
Description of intervention(s) / exposure
This is an observational prospective study which will collect information on healing in diabetic foot disease and critical limb ischaemia across three major centres. There is recruitment consultation, and follow up at 1 month, 3 months, 6 months and 12 months.

Recruitment Observational Data
At the time of recruitment, we will collect the following data: service details, baseline demographic and clinical history details, wound data on both lower limbs and discharge information.
Baseline service details will include the service the participant is attending at the time of recruitment, the date and source of referral to the current service, and all the relevant services/teams that are currently involved with the participant’s management.
Baseline demographic and clinical history details will include the participants age in years, gender and the ethnicity that the participant identifies with. The New Zealand (NZ) ethnicity selection will align with NZ census and research standards. In Australia, participants will be asked to identify as Aboriginal or Torres Strait Islander, or non-Aboriginal/Torres Strait Islander. In addition, the history of diabetes mellitus will be collected including whether the participant has been diagnosed with diabetes, the year of diabetes diagnosis, the type of diabetes the participant is diagnosed with, current glycaemic control with a HbA1c dated within the last 3 months. Adjustments will later be made for differing of HbA1c reporting between Australia (%) and New Zealand (mol/mmol). Other baseline health status data collection will include recent haemoglobin level and date, presence of transfusion of red blood cells in last 3 months, current dialysis status for renal replacement therapy and dialysis modality, recent eGFR and creatinine, smoking history listed as current, ex-smoker less than 12 months, ex-smoker greater than 12 months or non-smoker; and number of smoking pack years (number of packs of cigarettes smoked per day by the number of years the participant has smoked), concomitant medications that the participant is currently taking. The presence of vascular risk factors will be noted including a family or personal history of ischaemic heart disease, cerebrovascular accident or peripheral artery disease, hypertension, hypercholesterolaemia, presence of lipid lowering medications, diabetes, and smoking history. In addition, the height (m) and weight (kg) to calculate BMI, most recent vitamin A, vitamin C, vitamin D, zinc, ferritin and vitamin B12 levels, the average grip strength out of three attempts for both hands using a dynamometer, and the Clinical Frailty Scale (1-9) produced by Geriatric Medicine Research, Dalhousie University, Canada will be recorded. Also collected will be whether the participant is currently admitted to hospital, recently discharge in the last 1 month with duration of stay or whether admission is required from this review, and any recent vascular or diabetic foot disease related interventions in the past 6 weeks, including the name the intervention, date and angioplasty or lower limb bypass occurred, the details of which vessels were involved in the treatment.
Baseline wound data will be collected on both lower limbs (including contralateral asymptomatic limbs) including presence of peripheral neuropathy based on a 10g monofilament examination, palpable dorsal pedis or posterior tibial pulses, the Pedal Acceleration Time (PAT) in milliseconds for both legs via ultrasound examination and date. The foot arteries able to be examined in PAT are the arcuate artery, dorsal metatarsal artery, medial plantar artery, lateral plantar artery and deep plantar artery. The toe pressure and toe pressure location (great toe or second toe) will be recorded. If the toe pressure is not attainable, the reason for a lack of toe pressure reading, such as multiple toe amputation, forefoot amputation, callus, significant oedema, or very poor perfusion will be recorded. The inability to obtain a toe pressure with damped or monophonic waveforms will layer be scored in severe ischaemia category (i=3) on Wound, Ischaemia, Foot Infection (WIfI) assuming “very poor perfusion” as the cause. The reports of imaging in past 6 months including foot x-ray, arterial lower limb duplex ultrasound, computerised tomography (CT), magnetic resonance imaging (MRI) or digital subtraction angiography (DSA); and whether surgical revascularisation has occurred since the imaging will be recorded. The current target artery path (TAP) status will be collected. An intact TAP is defined as there being <50% stenosis in the iliac/femoral arteries with at least 1 vessel run off to the foot; and intact if there is a >50% stenosis in the iliac/femoral arteries and/or there is no vessel run off to the foot. In addition, whether the participant has undergone a minor or major limb amputation in the past, time since amputation and site of site of the amputation will be recorded; along with whether the participant has a past history of ulceration on each foot, the current presence of rest pain, foot ulceration or gangrene. One wound will be chosen on each foot to be the “index” wound. This will be determined as the highest grade wound on the foot as determined by wound criteria in the WIfI scoring. The index wound type being surgical wound, ulcer or gangrene will be collected. A surgical wound is described as a wound created by a surgical procedure such as debridement or amputation, an ulcer being a tissue deficit not surgically created and gangrene as necrosis of tissue. A wound labelled ulcer or gangrene may change to a surgical wound if a surgical debridement or amputation takes place. However, once labelled a surgical wound, the wound shall remain labelled surgical wound until healed. The location, depth and duration in weeks of the index surgical wound, ulcer or gangrene will be collected utilising patient recall and medical records, followed by a description of all foot wounds, ulcer(s) or gangrene and size (mm2) using a wound measurement device to measure the collective size surgical wounds and ulcers. If the index is a surgical wound, the duration of ulcer or gangrene prior to the first debridement or amputation in weeks will be collected. The depth will be defined as superficial , deep or extensive ulcer based on wound criteria for depth in WIfI scoring. Also recorded will be the highest CRP within the last two weeks and date, details of current antimicrobial therapy including antibiotic prescribed and duration of therapy, recent microbiology results relevant to the limb ulcer or wound, sensitivities and date. A wound ,ischaemia, and foot infection grade based on WIfI for each limb will be recorded and used to calculate the WIfI score for amputation risk at one year and benefit of revascularisation. The current offloading measures defined as no offloading, removable ankle (or knee) high device, therapeutic footwear, and surgical offloading.
Baseline discharge information will record the service discharge destination including diabetic foot clinic, GP, acute hospital admission, waitlist for surgery, palliative care, residential aged care series or patient discharged self at risk.

Review Observational Data
Participants will be reviewed at 1, 3, 6 and 12 months during the one year follow up occurring at subsequent clinic appointments or hospital admissions. Unless italicised, data collected in the review consultation has the same definition as the recruitment information.
Review service details will include the service attended, and all the relevant services/teams currently involved in management.
Review demographic and clinical history details will include diabetes diagnosis, HbA1c dated within the last 3 months, recent haemoglobin level and date, blood transfusion in last 3 months, grip strength and the Clinical Frailty Scale (1-9). Also, whether the participant is currently admitted to hospital, recent discharge since last review with duration of stay or admission required from this review; and any recent vascular or diabetic foot disease related interventions since last review.
Review wound data will be presence of palpable pedal pulses, recent PAT and date, toe pressure, toe pressure location and reason for a lack of toe pressure reading. Recent imaging reports since last review, whether surgical revascularisation has occurred since the imaging and the TAP status. The current presence of rest pain, foot ulceration or gangrene will be collected. The index wound type, location, depth and duration will be recorded, followed by a description of all foot wounds, ulcer(s) or gangrene and size (mm2). If the index is now a surgical wound, the duration of ulcer or gangrene prior to the first debridement or amputation in weeks will be collected. The highest CRP within the last two weeks and date, details of current antimicrobial therapy, recent microbiology results relevant to the limb ulcer or wound, sensitivities and date. The WIfI grades and WIfI score for amputation risk at one year and benefit of revascularisation will be recorded. The current offloading measures will be recorded.
Review discharge information will record the service discharge destination and the outcomes of whether the right or left foot index wound has healed defined as complete re-epithelisation of the previous tissue defect and date of healing; whether a right or left major limb amputation has occurred defined as the removal of a limb above the ankle and date; whether the participant has died and date of death.
Intervention code [1] 319541 0
Not applicable
Comparator / control treatment
No control group will be used. Comparisons between study groups/cohorts will made. These comparison groups will include age, gender, ethnicity, type of diabetes, renal impairment, glycaemic control, vascular perfusion status, location of foot wound, initial WIfI score, and duration of ulceration.
Control group
Active

Outcomes
Primary outcome [1] 326276 0
Time to wound healing as assessed by clinical examination and photographs
Timepoint [1] 326276 0
One year post recruitment
Primary outcome [2] 326656 0
Major limb amputation as assessed by patient medical records
Timepoint [2] 326656 0
One year post recruitment
Primary outcome [3] 326657 0
Overall mortality as assessed from patient medical records and New Zealand Ministry of Health Records
Timepoint [3] 326657 0
One year post recruitment
Secondary outcome [1] 390867 0
Amputation-free survival (presence of major limb amputation assessed from patient medical files).
*Primary outcome
Timepoint [1] 390867 0
One year post recruitment
Secondary outcome [2] 392294 0
The influence of WIfI grading (as measured by clinical examination and toe pressure recording) on major limb amputation (assessed form patient medical files)
Timepoint [2] 392294 0
One year post recruitment
Secondary outcome [3] 392295 0
The severity of ischaemia in diabetic feet as per PAT measured by ultrasound examination
Timepoint [3] 392295 0
One year post recruitment

Eligibility
Key inclusion criteria
The inclusion criteria are those over 18 years old experiencing diabetic foot disease as defined as a diagnosis of diabetes mellitus and with lower limb infection, ulceration, non-healing surgical wounds, gangrene, peripheral neuropathy, lower limb rest pain, or foot deformity; or CLTI alone, as defined as peripheral artery disease with lower limb rest pain, gangrene or ulceration of greater than two-week duration in a person without a diagnosis of diabetes mellitus.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The exclusion criteria are the presence of previous bilateral major limb amputation, or persons unable to consent, cognitive impairment, or experiencing a palliative medical condition, or persons that cannot attend minimum follow up of 12 months.

The withdrawal criteria is patient preference.

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Convenience sample
Timing
Prospective
Statistical methods / analysis
We estimate that based on our volume numbers of diabetic patients either admitted to the vascular unit or reviewed in clinic, that we will be able to include 150-200 patients at each centre.

Continuous variables will be presented as mean for parametric data and median for nonparametric data. Differences between groups will be analysed using logistic regression, which will be used to determine predictors of time dependent events such amputation and mortality at 30 day and 1 year. Survival (time to event) analysis, time to healing and amputation-free survival will be calculated using Kaplan-Meier analysis. Cox-proportional hazard models will be used to estimate a hazard ratio with a 95% confidence interval. P values less than 0.05 will be considered significant.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
3/08/2020
Date of last participant enrolment
Anticipated
31/12/2021
Actual
Date of last data collection
Anticipated
31/12/2022
Actual
Sample size
Target
500
Accrual to date
100
Final
Recruitment in Australia
Recruitment state(s)
SA,WA
Recruitment hospital [1] 18480 0
The Royal Adelaide Hospital - Adelaide
Recruitment hospital [2] 18481 0
Sir Charles Gairdner Hospital - Nedlands
Recruitment postcode(s) [1] 32798 0
5000 - Adelaide
Recruitment postcode(s) [2] 32799 0
6009 - Nedlands
Recruitment outside Australia
Country [1] 23399 0
New Zealand
State/province [1] 23399 0
Waikato

Funding & Sponsors
Funding source category [1] 307648 0
Charities/Societies/Foundations
Name [1] 307648 0
2020 Vascular Foundation Project Grant
Country [1] 307648 0
Australia
Primary sponsor type
Individual
Name
Dr Odette Hart
Address
Waikato District Health Board, Pembroke Street, Hamilton, New Zealand 3204
Country
New Zealand
Secondary sponsor category [1] 308341 0
Individual
Name [1] 308341 0
Mr Manar Khashram
Address [1] 308341 0
Waikato District Health Board, Pembroke Street, Hamilton, New Zealand, 3204
Country [1] 308341 0
New Zealand
Secondary sponsor category [2] 308392 0
Individual
Name [2] 308392 0
Prof Robert Fitridge
Address [2] 308392 0
Royal Adelaide Hospital, Port Rd, Adelaide, South Australia, Australia, 5000
Country [2] 308392 0
Australia
Secondary sponsor category [3] 308393 0
Individual
Name [3] 308393 0
Prof Shirley Jansen
Address [3] 308393 0
Sir Charles Gairdner Hospital, Hospital Ave, Nedlands, Perth, Western Australia, Australia 6009
Country [3] 308393 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 307687 0
New Zealand Central Health and Disability Ethics Committee
Ethics committee address [1] 307687 0
Ministry of Health, Health and Disability Ethics Committees, PO Box 5013, Wellington 6140
Ethics committee country [1] 307687 0
New Zealand
Date submitted for ethics approval [1] 307687 0
13/05/2020
Approval date [1] 307687 0
01/01/2021
Ethics approval number [1] 307687 0
20/CEN/122

Summary
Brief summary
The purpose of this study is to observe patients for one year who present with diabetes or reduced blood flow to their legs, and are also are experiencing ulceration, pain or other issues with in their legs. There are no medications or interventions given as part of this study, we will instead record observations such as whether ulcers heal or surgery is required. We hypothesise that patients presenting with more severe disease will take longer to heal their wounds, and experience a greater number of amputations, compared to patients with less severe disease.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 108142 0
Dr Odette Hart
Address 108142 0
Waikato Hospital, Pembroke Street, Hamilton, New Zealand 3204
Country 108142 0
New Zealand
Phone 108142 0
+64 07 839 8899
Fax 108142 0
Email 108142 0
[email protected]
Contact person for public queries
Name 108143 0
Dr Odette Hart
Address 108143 0
Waikato Hospital, Pembroke Street, Hamilton, New Zealand 3204
Country 108143 0
New Zealand
Phone 108143 0
+64 07 839 8899
Fax 108143 0
Email 108143 0
[email protected]
Contact person for scientific queries
Name 108144 0
Dr Odette Hart
Address 108144 0
Waikato Hospital, Pembroke Street, Hamilton, New Zealand 3204
Country 108144 0
New Zealand
Phone 108144 0
+64 07 839 8899
Fax 108144 0
Email 108144 0
[email protected]

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
This is an observational study, the outcomes will be published in medical journal and presented at conference, however raw line-by-line participant data will not be publicly available to protect the privacy of participants.


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

Documents added manually
No documents have been uploaded by study researchers.

Documents added automatically
SourceTitleYear of PublicationDOI
EmbaseProtocol for a prospective observational study: The Australia and New Zealand Diabetic and Ischaemic Foot Outcomes Study (ANZ-DIFOS).2021https://dx.doi.org/10.1136/bmjopen-2021-050833
N.B. These documents automatically identified may not have been verified by the study sponsor.