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Trial registered on ANZCTR


Registration number
ACTRN12616000442404
Ethics application status
Approved
Date submitted
21/03/2016
Date registered
6/04/2016
Date last updated
6/04/2016
Type of registration
Prospectively registered

Titles & IDs
Public title
An observational study of the correlation between stem/progenitor cell levels and wound healing in diabetic foot ulcers.
Scientific title
To evaluate whether number and intracellular protein content of stem/progenitor cells (SPCs) in diabetic patients with lower extremity neuropathic wounds (diabetic foot ulcer or DFU) are correlated with wound healing and with diabetes-related factors.
Secondary ID [1] 288771 0
Nil known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Diabetic Foot Ulcers 298033 0
Condition category
Condition code
Skin 298190 298190 0 0
Other skin conditions
Metabolic and Endocrine 298342 298342 0 0
Diabetes

Intervention/exposure
Study type
Observational
Patient registry
True
Target follow-up duration
16
Target follow-up type
Weeks
Description of intervention(s) / exposure
The goal of this study is to evaluate whether stem/progenitor cells (SPCs) in diabetic patients with lower extremity neuropathic wounds (diabetic foot ulcer or DFU) are correlated with wound healing and with diabetes-related factors. This study will take place over 8 -10 weeks.

This study will monitor the patient’s own CD34 endothelial progenitor cells (stem cells) being mobilized in response to trauma (debridement) and hyperbaric oxygen treatments.

Blood will be collected on a weekly basis for 8 weeks, in conjunction with debridement. It is arbitrary whether the blood is taken before or after the debridement. If indicated hyperbaric oxygen treatments will be provided on a daily basis. Debridement and hyperbaric oxygen treatments will be provided as per standard care where indicated. Only blood collection and optional punch biopsy for the thigh at entry and week 4 are considered interventions for the purpose of this research.
Intervention code [1] 294226 0
Diagnosis / Prognosis
Comparator / control treatment
No Control Group
Control group
Uncontrolled

Outcomes
Primary outcome [1] 297700 0
The primary outcome variable will be wound healing/closure. This will be assessed visually as either healed or not healed at 16 weeks, or earlier if healed before this point.
Timepoint [1] 297700 0
Wound review will occur from initial assessment on a weekly basis and measurements recorded of wound area. Final assessment of healed or not will occur at 16 weeks.
Secondary outcome [1] 321913 0
Wound healing rate
Timepoint [1] 321913 0
Weekly wound assessment including surface area calculation for 8 weeks, then final assessment at 16 weeks unless healed prior. Rate of healing will be calculated from this data
Surface area will be calculated by measurement of length in mm, multiplied by width in mm.
Secondary outcome [2] 322306 0
Amputation assessed by visualisation for missing toe/foot/limb.
Timepoint [2] 322306 0
Assessment at 16 weeks of amputation/no amputation involving foot that diabetic ulcer is present on.
Secondary outcome [3] 322307 0
Changes in wound characteristics composite outcomes i.e. maceration, exudate, granulation tissue coverage, eschar and fibrin/slough coverage of ulcer base.
Timepoint [3] 322307 0
Week 1,2,3,4,5,6,7,8 and 16
Secondary outcome [4] 322308 0
Laboratory assay of blood and tissue composite outcomes SPCs surface markers: CD34, CD45, CD133, CXCR4 and CD31; intracellular mitochondrial content and mitochondrial membrane potential. Cells will also be permeabilized with saponin so we can measure intracellular levels of the three hypoxia inducible factors (HIF-1, HIF-2 and HIF-3), thioredoxin, PGC-a and protein kinase B.
Timepoint [4] 322308 0
Week 1,2,3,4,5,6,7 and 8.
Secondary outcome [5] 322309 0
Histological changes in wound healing composite outcomes Abdominal/thigh biopsy wound margin and DFU tissue sections will be analyzed for cell surface proteins CD34, CD45, CD133, CXCR4, CD31, glycophorin A; as well as all three HIFs, thioredoxin, VEGF and SDF-1, and mitochondria.
Timepoint [5] 322309 0
Week 1,2,3,4,5,6,7 and 8.

Eligibility
Key inclusion criteria
Individuals who are 21 to 90, type 1 or type 2 diabetic patients with a neuropathic DFU Wagner grade 1 to 4 will be the study population. If a patient has more than one lower extremity ulcer, the one that would take the longest to heal in the opinion of the patient’s primary physician will be the target ulcer for study. To differentiate the neuropathic ulcer population from those patients with inadequate arterial blood flow (neuroischemic ulcers) all patients considered for the investigation will have skin perfusion pressure > 25 mmHg OR an ankle/brachial index of > 0.65 (if calcified vessels are suspected use the toe/brachial index). There is no predetermined wound care requirement prior to enrolment, and wound care as per best care will be provided in return for participation in the trial
Minimum age
21 Years
Maximum age
90 Years
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
You are under the age of 21 years old or over 90 years
You do not have diabetes
You do not have a neuropathic foot ulcer related to diabetes
You have a history of a seizure disorder
You are pregnant
You have:
Severe asthma
COPD (Chronic Obstructive Pulmonary Disease)
Spontaneous pneumothorax (ruptured lung)

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
Statistical approach: The appropriate database management system will be created with assistance from the Clinical Research and Computing Unit (CRCU) of the University of Pennsylvania Centre for Clinical Epidemiology and Biostatistics. Specific aims and anticipated data analysis are as follows:
(1) Determine whether SPCs mobilization/wound recruitment and HIF-related processes are associated with wound repair.
(2) Assess whether wound care practices (e.g. debridements, drugs, HB02) are associated with SPCs mobilization and wound SPCs homing.
(3) Determine if variations in SPCs are associated with healing.
(4) Assess whether SPCs differences observed between a healing acute biopsy wounds versus DFUs are related to clinical issues such as metabolic status.
A proportional hazards model was used to estimate the power to identify an association between wound SPCs recruitment and healing. For these estimates we assumed that
patients will be recruited for 4 years of a 5 year grant, allowing for logistical complications and time for final data analysis. Given NHC patient volume, we plan to enroll 800 patients. According to National Healing Corp. information, across all their clinics no more than 13% of patients who enter their system fail to complete the course of treatment (and in most, the drop-out rate is below 6%). In our published study, 8% of eligible patients declined entry and all who entered remained in the trial. Per protocol, patients may refuse one or more invasive intervention and remain in the study. Calculations were based on sample sizes of 500 or 700 patients.
Hazard ratio (HR) was calculated using the difference between SPCs recruitment to the healing acute biopsy wound and the DFU found in our preliminary study. The mean fluorescence intensity in biopsy wounds associated with SPCs was 78 whereas fluorescence intensity in the DFU margin at the outset of treatment was 31 with standard deviations of ~ 3.3.
Therefore, we used a value of 2 for the expected HR, but also performed calculations using a more conservative value of 1.5. Power was calculated using different estimates of the number of individuals exhibiting elevated levels of SPCs. The table uses [%] to indicate
different fractions of patients showing either of the two SPCs HR responses. Assuming a type 1 error of 0.05 the power to detect an association between wound SPCs and healing is as shown. Thus, under virtually all conditions our proposed study will have at least 80% power and most scenarios exceed 90%.

Recruitment
Recruitment status
Not yet recruiting
Date of first participant enrolment
Anticipated
22/04/2016
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
800
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
QLD
Recruitment hospital [1] 5458 0
The Wesley Clinic for Hyperbaric Medicine - Auchenflower

Funding & Sponsors
Funding source category [1] 293140 0
Hospital
Name [1] 293140 0
Wesley Centre for Hyperbaric Medicine
Country [1] 293140 0
Australia
Funding source category [2] 293141 0
University
Name [2] 293141 0
University of Maryland, Baltimore
Country [2] 293141 0
United States of America
Primary sponsor type
Government body
Name
National Institutes of Health (NIH),
Address
9000 Rockville Pike, Bethesda,
Maryland 20892
USA
Country
United States of America
Secondary sponsor category [1] 291936 0
Hospital
Name [1] 291936 0
Wesley Centre for Hyperbaric Medicine
Address [1] 291936 0
Suite 53, Ground Floor
Sandford Jackson Building
30 Chasely Street
Auchenuflower QLD 4066
Country [1] 291936 0
Australia

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 294637 0
UnitingCare Health Human Research Ethics Committee
Ethics committee address [1] 294637 0
Ground Floor Moorlands House
The Wesley Hospital
451 Coronation Drive, Auchenflower QLD 4066
PO Box 499 Toowong QLD 4066
Ethics committee country [1] 294637 0
Australia
Date submitted for ethics approval [1] 294637 0
17/11/2015
Approval date [1] 294637 0
08/03/2016
Ethics approval number [1] 294637 0
UnitingCare Health: 1601
Ethics committee name [2] 294638 0
University of Maryland, Baltimore IRB
Ethics committee address [2] 294638 0
University of Maryland, Baltimore
Institutional Review Board (IRB)
Office of the Provost
1420 N. Charles St, AC 21201
Ethics committee country [2] 294638 0
United States of America
Date submitted for ethics approval [2] 294638 0
Approval date [2] 294638 0
27/06/2015
Ethics approval number [2] 294638 0
HCR-HP-00055840-2

Summary
Brief summary
The goal of this study is to evaluate whether number and intracellular protein content of stem/progenitor cells (SPCs) in diabetic patients with lower extremity neuropathic wounds (diabetic foot ulcer or DFU) are correlated with wound healing and with diabetes-related factors. The hypothesis is that SPCs-specific variables can be used to predict diabetic wound healing. This study was designed based on results from a recent preliminary clinical trial
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 64426 0
Dr Graeme Kay
Address 64426 0
Wesley Centre for Hyperbaric Medicine
Suite 53, Ground Floor,
Sandford Jackson Building
30 Chasely Street
Auchenuflower QLD 4066
(Postal PO Box 1374, Toowong BC 4066)
Country 64426 0
Australia
Phone 64426 0
+61 7 3371 6033
Fax 64426 0
Email 64426 0
[email protected]
Contact person for public queries
Name 64427 0
Tony Turner
Address 64427 0
Wesley Centre for Hyperbaric Centre
Suite 53, Ground Floor
Sandford Jackson Building
30 Chasely Street
Auchenuflower QLD 4066
(Postal PO Box 1374, Toowong BC 4066)
Country 64427 0
Australia
Phone 64427 0
+61 7 3371 6033
Fax 64427 0
Email 64427 0
[email protected]
Contact person for scientific queries
Name 64428 0
Graeme Kay
Address 64428 0
Wesley Centre for Hyperbaric Centre
Suite 53, Ground Floor
Sandford Jackson Building
30 Chasely Street
Auchenuflower QLD 4066
(Postal PO Box 1374, Toowong BC 4066)
Country 64428 0
Australia
Phone 64428 0
+61 7 3371 6033
Fax 64428 0
Email 64428 0
[email protected]

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