Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12624000302550
Ethics application status
Approved
Date submitted
22/12/2023
Date registered
21/03/2024
Date last updated
21/03/2024
Date data sharing statement initially provided
21/03/2024
Type of registration
Prospectively registered

Titles & IDs
Public title
Investigating the ability of an innovative point of care test to predict foot ulcer healing in people with diabetes
Scientific title
Assessing the feasibility and accuracy of a novel point of care test to predict foot ulcer healing in people with diabetes
Secondary ID [1] 309297 0
none
Universal Trial Number (UTN)
Trial acronym
PREDICT-U
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetes related foot ulcer 330747 0
Condition category
Condition code
Metabolic and Endocrine 327590 327590 0 0
Diabetes
Skin 329436 329436 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
This study is primarily to determine if we can analyse matrix metalloproteinase MMP-9 (MMP-9) in foot ulcer wound fluid at the chair-side using a Point of care test (POCT) (InflammaDry®) during consultation at the time of treating the foot ulcer and to determine if this test can predict healing outcome.
At each visit patients will receive standard clinical care in accordance with best practice guidelines for their diabetes related foot ulcer (Lazzarini PA, Raspovic A, Prentice J, Commons RJ, Fitridge RA, Charles J, Cheney J, Purcell N, Twigg SM, on behalf of the Australian Diabetes-related Foot Disease Guidelines & Pathways Project. 2021 Australian evidence-based guidelines for diabetes-related foot disease; version 1.0. Brisbane, Australia: Diabetes Feet Australia, Australian Diabetes Society; 2021). Collection of the wound fluid for the POCT will take approximately 5 minutes (see method & equipment below). Once the podiatrist has taken the wound fluid they will continue with the clinical management of the patient and the principal investigator (Senior Podiatrist) will prepare the wound fluid and apply it to the POCT. The POCT is not being used for any clinical decision making in the current proposal but in assessment of its feasibility and accuracy as a point of care test.
Participants with a diabetes related foot ulcer will undertake a four week run-in period at the interdisciplinary High Risk Foot Service (iHRFS) managed with optimized standard care. After informed consent is obtained participants will be seen every 1 to 2 weeks based on their clinical need during this 4-week run-in period to confirm eligibility. The study visit will occur in conjunction with the iHRFS appointment (duration of 60 minutes). At week 0 and week 4 the POCT will be used to measure MMP-9 obtained from wound fluid samples and performed by a podiatrist at the iHRFS. For ulcers treated with dried human placental derived allograft (Revita), we also plan to determine MMP-9 by POCT at week 8 (4 weeks after Revita® application) to obtain some indication as to whether the MMP-9 POCT may reflect a beneficial effect of Revita in ulcer healing. At the end of the four week run-in period patients who have complied with using the prescribed offloading device, have less than 50% reduction in wound size as measured by macroscopic wound planimetry (ulcer tracings on acetate paper with marker pens - 2 Dimensional measurement), will be offered the dried human placental allograft (Revita). If the patient declines Revita therapy then they will remain in the study and receive standard care.
Revita is a dried, sterile human tissue allograft derived from intact human placental membrane. The podiatrist will undertake sharp wound debridement (removal of all non-viable tissue from the peri-wound edge and wound base) and irrigation of the wound using 10mls of sterile saline. Revita (primary wound dressing) is cut to the shape of the ulcer and placed in the wound cavity by the treating podiatrist at the iHRFS. Revita is required to stay in place for 14 days. To ensure this remains undisturbed a non-medicated ointment dressing (Atrauman) will be placed over the allograft and secured with steri-strips. The secondary dressing will be selected based on exudate levels (biatain foam or zetuvit) & blue-line tubifast to hold in place. The secondary dressing will be changed every second day or twice a week dependent on the exudate levels by the patient, carer or nurse. Re-application of Revita will be based on the podiatrists assessment of the wound bed at week 6,8,10,12,14 at the High risk foot service . If the patient declines this dressing they can continue in the study and will receive the best available standard care.
A maximum of 6 separate placental derived allografts may be administered over a 14 week period. The frequency of application is determined by clinical assessment of the treating clinician and this is in-line with manufacturer advice and available evidence. Point Of Care Test Method & Equipment:
1. Immerse the Paper Point in multiple locations along the inside of the wound to collect the wound fluid until saturation (fluid reaching to the top blue line “24” of the Paper Point).
2. Transfer the Paper Point into a microtube with 500 µL of PBS.
3. Soak for 5 minutes at room temperature.
4. Quick mix by vortex 10 seconds.
5. Transfer the tube into a centrifuge and spin at 5000rpm for 5 minutes.
6. Remove the Paper Point from the tube and discard it.
7. Use a transfer pipette to collect wound fluid from the tube (~10 µL) and add to the sampling fleece of the Sample Collector until saturated, when the fleece will glisten and may turn patchy pink.
8. Close the Sample Collector into the Test Cassette. Press firmly where indicated . A double-click means the test is properly assembled.
9. Label the test Cassette with the patients REDcap number, MRN and DOB.
10. Immerse the absorbent tip into the provided buffer vial for a minimum of 20 seconds until a purple fluid wave is observed moving across the result window.
11. Replace the protective cap and lay the test flat on a horizontal surface.
After 10 minutes, read the test results. If the test is negative after 10 minutes, allow an additional 5-10 minutes before reading test results.
Intervention code [1] 326566 0
Treatment: Devices
Comparator / control treatment
There is no reference standard point of care test for MMP-9 in wounds and therefore will be no comparison for the MMP-9 POCT. Current standard for predicting healing outcome is based on healing trajectory in the first 4 weeks.

Patients who decline to receive Revita will form a comparator group. The main outcome measure will be based on change in healing trajectory (percent wound reduction). Participants receiving Revita will serve as their own control. There will also be a comparison between participants who accept and any those who decline Revita and continue to receive standard care. There are no current standard of care dressings for diabetes related foot ulcers. Dressings will be selected principally on the basis of exudate control, comfort and cost (Chen P, Carville K, Swanson T, Lazzarini PA, Charles J, Cheney J, Prentice J. Australian guideline on wound healing interventions to enhance healing of foot ulcers: Part of the 2021 Australian evidence-based guidelines for diabetes- related foot disease; version 1.0. Brisbane, Australia: Diabetes Feet Australia, Australian Diabetes Society; 2021.).
Control group
Active

Outcomes
Primary outcome [1] 335426 0
Feasibility of conducting the Point of care test (POCT InflammaDry) assessed by number of completed POCT by clinicians.
Data numbers of completed POCT will be assessed using participants records located in the REDcap research database.
Wound fluid samples from diabetes related foot ulcers will be assessed using the POCT
Timepoint [1] 335426 0
The Point of care test (InflammaDry® Test) to measure pro-inflammatory protein matrix metalloproteinase-9 (MMP-9) will occur at Week 0, week 4 & week 8 post-enrolment. Week 8 will only occur if the intervention (dried placental allograft - Revita) has been applied to the diabetes related foot ulcer
Primary outcome [2] 337265 0
Feasibility of conducting the Point of care test (POCT InflammaDry) assessed by the time it takes for the clinician to complete the test. This will be assessed using a stopwatch.
Timepoint [2] 337265 0
The Point of care test (InflammaDry® Test) to measure pro-inflammatory protein matrix metalloproteinase-9 (MMP-9) will occur at Week 0, week 4 & week 8 post-enrolment. Week 8 will only occur if the intervention (dried placental allograft - Revita) has been applied to the diabetes related foot ulcer
Primary outcome [3] 337731 0
Accuracy of the Point of care test (InflammaDry®) assessed by comparison with laboratory matrix metalloproteinase-9 (MMP-9) measures (MMP-9 ELISA, and total- and active MMP-9 by Lab zymography measures).
Wound fluid samples from diabetes related foot ulcers will be assessed using the POCT and Laboratory MMP-9 measures.
Timepoint [3] 337731 0
Week 0, week 4 & week 8 post-enrolment.
Secondary outcome [1] 424488 0
Any change in wound size (2 dimensional) in diabetes-related foot ulcers dressed with dried human placental-derived allograft (Revita) assessed using macroscopic wound planimetry (wound acetate outlines). It is standard clinical practice to perform macroscopic wound planimetry using ulcer tracings on acetate paper with marker pens.
Timepoint [1] 424488 0
Percent wound reduction (2 Dimensional size) will be measured at baseline (week 0), week 4, week 8, week 12 and week 16 post-enrolment.
Secondary outcome [2] 424489 0
Any change in the percentage of diabetes related foot ulcers completely healed as verified by clinical examination.

Timepoint [2] 424489 0
This outcome 'healed or unhealed' will be verified by an independent research nurse who is blinded to treatment allocation at 12 and 16 weeks post-enrolment. The independent will examine the wound when treatment is complete. The assessment of the independent will be used as the outcomes measure of healed or not healed.
Secondary outcome [3] 424738 0
Any change in wound size (3 dimensional) in diabetes-related foot ulcers dressed with dried human placental-derived allograft (Revita) assessed using the Silhouette® 3D camera
Timepoint [3] 424738 0
Percent wound reduction (3 Dimensional) will be measured at baseline (week 0), week 4, week 8, week 12 and week 16 post-enrolment.
Secondary outcome [4] 431952 0
POC pH assessed using wound fluid samples from diabetes related foot ulcers.
Wound fluid sampled will be assessed using pH paper strips.
Timepoint [4] 431952 0
Baseline, week 4, week 8 and week 12 post-enrolment
Secondary outcome [5] 431954 0
Connective Tissue Growth Factor (CTGF) assessed using wound fluid samples from diabetes related foot ulcers.
Timepoint [5] 431954 0
Baseline, week 4, week 8 and week 12 post-enrolment.
Secondary outcome [6] 431955 0
Pro-inflammatory protein matrix-metalloproteinase-9 (MMP-9) assessed using wound fluid samples from diabetes related foot ulcers.
Timepoint [6] 431955 0
Baseline, week 4, week 8 and week 12 post-enrolment.
Secondary outcome [7] 431956 0
Blood monocytes assessed using a blood sample in patients with a diabetes related foot ulcer.
Timepoint [7] 431956 0
Baseline, week 4, week 8 and week 12 post-enrolment.
Secondary outcome [8] 432308 0
Offloading compliance (wearing the prescribed pressure offloading devices) assessed using self-reports of the average time in a device of most days since the last review appointment.
up to 20% of the day (most days on average) equivalent to 2.5 hours per day
50% of the day (most days on average) equivalent to 2.5 hours to 6 hours per day
80 to 90% most of the day (most days on average) equivalent to 6 hours to 9.5 hours per day
100% Never removed wake to sleep
Timepoint [8] 432308 0
Baseline, 4, 8, 12, and 16 post-enrolment

Eligibility
Key inclusion criteria
- Type 1 or type 2 diabetes and a diabetes-related foot ulcer of greater than 2 weeks duration
- Male and female
- Age 18 years and above (nil limit)
- Willingness to provide informed consent and willingness to participate and comply with the study requirements including standard care; pressure offloading, sharp debridement, weekly or second weekly clinic visits attending the Interdisciplinary High Risk Foot Service of the Diabetes Centre, Department of Endocrinology, at Royal Prince Alfred Hospital or Concord Hospital
- Participants can be recruited when perfusion restored and/or infection controlled where present
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
- Ulcer depth to bone
- Major limb ischaemia with ABPI < 0.6 or Toe pressure <40mm Hg in at least one foot artery in the affected foot
- Moderate (cellulitis) or severe (requiring hospitalisation) bacterial infection
- Duration of greater than 3 months (at the treating centre)
- Wounds are less than 0.5cm2
- Participants will be excluded from REVITA treatment if they have failed to attend 2 or more visits in the proceeding 4 weeks or if they have attended 2 or more clinic visits without wearing their pressure offloading or have self-reported less than 80% adherence to wearing pressure offloading. Thus they will be excluded from receiving Revita® if they have not received optimal interdisciplinary High Risk Foot Service care.

Study design
Purpose of the study
Treatment
Allocation to intervention
Non-randomised trial
Procedure for enrolling a subject and allocating the treatment (allocation concealment procedures)
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?


The people assessing the outcomes
Intervention assignment
Single group
Other design features
Phase
Not Applicable
Type of endpoint/s
Safety/efficacy
Statistical methods / analysis
This is a feasibility study to show if a MMP-9 POCT at our interdisciplinary High Risk Foot Service sites is achievable and if it compares well with laboratory measures, in predicting ulcer healing. The MMP-9 POCT is not being used for any clinical decision making in the current proposal but in assessment of its feasibility.

Primary Objective
The n=50 should enable the MMP-9 POCT to be informative for lab MMP-9 comparisons and in ulcer healing prediction, as we have previously found that MMP-9 when measured in the laboratory by a long assay (ELISA, and zymography) can predict ulcer healing in n=28 foot ulcers, as can the MMP-9 POCT when it is used on archived wound fluid stored in the laboratory Exploring MMP-9 as a prognostic marker in post debridement wound fluid of diabetes related foot ulcers, and the possibility of a point-of-care test (M.S.G. Longfield, V. Nube, J.M. White, S.V. McLennan, P. Boughton, D. Min, S.M. Twigg. EASD oral mini-poster September, 2022). We now need to determine if the MMP-9 POCT can be used reliably and accurately at the point of care to reflect lab measured MMP-9 and to predict ulcer healing.

The greater sample size for the current study has been chosen as the test operator at the chairside of the patient will vary (more than one operator across samples), which will introduce some inter-operator variability and real life variability by at POC sample processing. In addition wound volume, not area, is being used in the current end-point calculation. The n=50 will also enable the POCT and lab MMP-9 to be compared, for the end-point of ulcer healing outcome at week 12.
The MMP-9 Point of care test (POCT), when used at point of care, is to be compared with the lab measures of MMP-9 ELISA, and total- and active MMP-9 by Lab zymography measures. The common comparator end points is ulcer healing prediction presence at week 12 (healed yes as ‘H’ or not=healed as NH at week 12). This is a dichotomous end-point as H on NH. This measure is clinical utility, not statistically a form of reliability. Thus the ability of the following tests measured at week 0 and week 4 to accurately predict H or NH will be undertaken: POCT 80 ng/mL threshold InflammaDry® MMP-9 POCT; Total MMP-9 by ELISA; MMP-9 by gelatin Zymography (total-, active-, and pro-). The POCT will be compared with these other measures at week 0 and week 4 for its accuracy in determination of sensitivity, specificity, and positive and negative predictive value (see list below).

Week 0 POCT measures and prediction of week 12 healing outcome (H or NH)
Correct (True) % Incorrect (False)%
- % Accuracy for healing outcomes
- % Accuracy compared to zymography total MMP-9 results
- % Accuracy compared to zymography active-MMP-9 results
- % Accuracy compared to zymography pro-MMP-9 results
- % Accuracy compared to ELISA total MMP-9 results
- % positive results
- % negative results

Week 4 POCT measures and prediction of week 12 healing outcome (H or NH)
Correct (True) % Incorrect (False) %
- % Accuracy for healing outcomes
- % Accuracy compared to zymography total MMP-9 results
- % Accuracy compared to zymography active-MMP-9 results
- % Accuracy compared to zymography pro-MMP-9 results
- % Accuracy compared to ELISA total MMP-9 results
- % positive results
- % negative results

For each measure an AUROC will be generated in prediction of week 12 healing outcome (H on NH), with the relevant P value in each case. The AUROC will be generated for wound volume closure rate (WVCR) alone and then WVCR with each MMP-9 measure.
Significant univariate relationships with the POCT and healing will be taken forward to multivariable analysis with healing outcome at 12 weeks as the dependent variable to build a model and determine if blood and wound fluid measures being undertaken complement each other in predicting ulcer healing by 12 weeks, when measured at 0, or 4, or 8 weeks.

The total n=50 will be required for this study including a realistic drop-out rate of 20% (n=10).

Secondary objective: To examine whether Revita application aids wound healing:
Based on our historic data for the foot ulcers planned in the current study, we expect that ~1/3 of the ulcers being treated in our high-risk foot care service enrolled in this study will not show 50% reduction in wound volume at 4 weeks despite optimised standard care. Thus, the number of patients offered Revita® is expected to be 1/3 of the total starting cohort, thus n= ~13 of 50.

Wounds unlikely to heal will be treated with Revita a dehydrated human placental membrane allograft (n=13 in total) to explore the ulcer healing trajectory, and the MMP-9 POCT will be measured in those treated wounds at week 8 to indicate if Revita® may have changed MMP-9 levels.

Significant change of 50% reduction in wound area (2 Dimensional size) and volume (3 Dimensional) by week 12, 8 weeks post application of Revita.




Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
1/04/2024
Actual
Date of last participant enrolment
Anticipated
31/12/2024
Actual
Date of last data collection
Anticipated
30/04/2025
Actual
Sample size
Target
50
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
NSW
Recruitment hospital [1] 25256 0
Royal Prince Alfred Hospital - Camperdown
Recruitment hospital [2] 25257 0
Concord Repatriation Hospital - Concord
Recruitment postcode(s) [1] 40929 0
2050 - Camperdown
Recruitment postcode(s) [2] 40930 0
2139 - Concord

Funding & Sponsors
Funding source category [1] 313492 0
Hospital
Name [1] 313492 0
Royal Prince Alfred Hospital
Country [1] 313492 0
Australia
Primary sponsor type
Hospital
Name
Royal Prince Alfred Hospital
Address
50 Missenden Rd, Camperdown NSW 2050
Country
Australia
Secondary sponsor category [1] 316579 0
None
Name [1] 316579 0
Address [1] 316579 0
Country [1] 316579 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 312679 0
SLHD RPA Research Ethics and Governance Office
Ethics committee address [1] 312679 0
Level 2, Suite 2a 100 Carillion Ave Newtown 2042 NSW
Ethics committee country [1] 312679 0
Australia
Date submitted for ethics approval [1] 312679 0
16/05/2023
Approval date [1] 312679 0
25/05/2023
Ethics approval number [1] 312679 0
X23-0106 & 2022/ETH01612

Summary
Brief summary
The aim of this study is to assess the feasibility and accuracy of a novel point of care test to predict foot ulcer healing in people with diabetes.

Specifically to define whether a point of care test (InflammaDry) measuring Matrix Metalloproteinase-9 (MMP-9) in wound fluid obtained from diabetes related foot ulcers is feasible when used in a interdisciplinary High Risk Foot Service (iHRFS) and can reflect laboratory MMP-9 measures accurately, so to then predict ulcer healing outcome.

Secondary aims are to determine if topical application of a dried human tissue allograft derived from placental membrane (Revita) may improve the healing trajectory of foot ulcers in people with diabetes whose ulcers despite receiving optimized care in a iHRFS are not demonstrating signs of healing.

If we can show that we can analyse MMP-9 at the chair-side during consultation at the time of treating the foot ulcer and determine if this test can predict healing outcomes, then in the future we could make a timely decision at the same patient consultation in the interdisciplinary High Risk Foot Service to apply intensified therapy such as Revita® treatment.

Together these studies will determine whether these MMP-9 POCT is feasible, if other biomarkers can in a complementary manner, predict the healing outcomes, and whether the Revita® treatment is well tolerated and could improve wound healing in people with delayed wound healing in diabetes.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 125538 0
Prof Stephen Twigg
Address 125538 0
Royal Prince Alfred Diabetes Centre Level 650 Missenden Road Camperdown 2050 NSW
Country 125538 0
Australia
Phone 125538 0
+61 418 637 715
Fax 125538 0
Email 125538 0
stephen.twigg@sydney.edu.au
Contact person for public queries
Name 125539 0
Mrs Jessica White
Address 125539 0
Royal Prince Alfred Diabetes Centre Level 650 Missenden Road Camperdown 2050 NSW
Country 125539 0
Australia
Phone 125539 0
+61 02 9515 5888
Fax 125539 0
Email 125539 0
jessica.white1@health.nsw.gov.au
Contact person for scientific queries
Name 125540 0
Mrs Jessica White
Address 125540 0
Royal Prince Alfred Diabetes Centre Level 650 Missenden Road Camperdown 2050 NSW
Country 125540 0
Australia
Phone 125540 0
+61 422 766 555
Fax 125540 0
Email 125540 0
jessica.white1@health.nsw.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?
Primary outcomes will available with appropriate ethics application
When will data be available (start and end dates)?
2 years after completion and up to 5 years.
Available to whom?
To researchers on written request to the CPI and with ethics approval for their project
Available for what types of analyses?
Pending request
How or where can data be obtained?
Available from the SLHD Redcap server and data custodian approval Professor Stephen Twigg. Email address: stephen.twigg@sydney.edu.au


What supporting documents are/will be available?

No Supporting Document Provided



Results publications and other study-related documents

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No documents have been uploaded by study researchers.

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