Trial Review

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Trial registered on ANZCTR


Registration number
ACTRN12616001709437
Ethics application status
Approved
Date submitted
3/11/2016
Date registered
13/12/2016
Date last updated
23/07/2019
Date data sharing statement initially provided
23/07/2019
Date results provided
23/07/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Effect of cathodal and anodal electrical stimulation on pressure ulcer healing
Scientific title
Evaluation of the effect of cathodal and anodal electrical stimulation on pressure ulcer healing in people with central nervous system injuries. A prospective, randomized, double-blind, controlled, clinical study
Secondary ID [1] 289767 0
Nill known
Universal Trial Number (UTN)
Trial acronym
Linked study record

Health condition
Health condition(s) or problem(s) studied:
pressure ulcer 299633 0
Wound healing 299634 0
Chronic wound healing 299635 0
Central nervous system injury 299636 0
Condition category
Condition code
Physical Medicine / Rehabilitation 299588 299588 0 0
Physiotherapy
Skin 299589 299589 0 0
Other skin conditions
Neurological 300750 300750 0 0
Other neurological disorders

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
The purpose of this prospective, parallel-group, randomized, double-blind, controlled, clinical trial is to evaluate the activity of cytokines, growth factors and healing rates of pressure ulcers (PU) in people with central nervous system injures after 4 weeks of intervention involving standard wound care (SWC), SWC in conjunction with high voltage monophasic pulsed current (HVMPC) delivered by the cathode, and SWC combined with HVMPC delivered by the anode as the treatment electrodes.

Demographic information on the patients will be compiled during standardized interviews and physical examinations, as well as from additional examinations of the patients and the documentation of their concomitant diseases.

The patients’ physical and mental conditions, activity, mobility and incontinence will be assessed using the Norton scale (a score < 14 indicated a high risk of PU development). To assess the possibility of friction and shear and wound moisture, as well as sensory perception of the patients, their physical activity and mobility the Braden Scale will be applied (a score < 16 pointed to a high risk of PU development). Patients’ nutritional status will be identified by means of the Nutritional Risk Score (NRS-2002).
Wound severity at enrolment will be assessed based on the National Pressure Ulcer Advisory Panel criteria: Category II ulcers = partial-thickness loss of the dermis presenting as a shallow open ulcer with a red pink wound bed, without slough; Category III ulcers = full-thickness tissue loss; subcutaneous fat may be visible but bone, tendon or muscle are not exposed; Category IV ulcers = full-thickness tissue loss with exposed tendon, muscle or bone. Slough or eschar may be present on some parts of the wound bed. Can include undermining and tunnelling.

SWC programme administered to both electrical stimulation groups.
All patients will be treated to prevent the development of new PUs. Pressure-redistribution surfaces, devices and pillows will be applied as needed. A nurse or physiotherapist will reposition the immobile patients every 2 hours at the least.
Blood tests will be carried out to screen for nutritional status markers and metabolic disorders such as anaemia (iron deficiency anaemia or anaemia of chronic disease), thyroid dysfunction, impaired glycaemic control, dehydration, protein deficit, hypoalbuminemia.

Wounds will be regularly assessed by the attending physician over the period of the study to select topical treatments appropriately addressing moisture control, bacterial burden, and debridement needs; microbiological culture and sensitivity tests will also be performed.

A team formed of a physician, a nurse, a physical therapist and a dietician will make comprehensive, interdisciplinary assessments of the patients to develop SWC programmes meeting their specific demands, for instance consisting of nutritional intervention, optimization of the wound dressing protocol, and incontinence management. The clinician caregivers will be blinded to participant’s group.

Patients in both electrical stimulation groups will receive similar standard topical care, selected to address their individual needs and to promote moist interactive healing.
All immobilized patients will receive low-molecular-weight heparin (enoxaparin) as a standard therapy. Patients with elevated leukocyte levels will be treated with antibiotics selected following microbiological culture and sensitivity testing of the PU swab.


Electrical stimulation with the cathode.
In the cathode ES group, patients will be administered HVMPC in addition to SWC.

The device for applying HVMPC will be the Intelect Advanced Combo (by Chattanooga, USA).

The device generates a twin-peak monophasic pulse consisting of two 77- microsecond exponential pulses in rapid succession (the twin-peak pulse duration was 154 microseconds). Pulse frequency will be 100 pps.

ES will not cause muscle contractions. Patients who retained the sensory function will only experience sensory effects. Amperage will be applied at a level of 0.36 A. If the sensory experience is too strong (patients with sensory function) the amperage will be reduced but not below 0.25 A. Accordingly, the electrodes will deliver an electrical charge of 250- 360 microcoulomb per second.

This HVMPC protocol has been adopted following the positive results of earlier clinical trials on patients with PUs and venous leg ulcers..

Each patient will have his or her own set of electrodes made of conductive carbon rubber. The treatment electrode (of a size matching the wound surface area) will be placed on an aseptic gauze pad saturated with physiological saline overlaying the wound site. The dispersive electrode (bigger than the treatment electrode) closing the electrical circuit will be positioned at least 20 cm from the PU. Before and after each ES procedure, the electrodes will be sterilized in a disinfectant solution.

Over the period of the intervention, the negative electrode (cathode) will be used to treat PUs. The authors of some other clinical studies on PUs have also used cathodal stimulations.

In the experiment, five 50-minute sessions will be held per week (one a day), following the approach adopted by other authors.

PUs will be thoroughly cleansed with a 0.9% sodium chloride solution and covered with the earlier described dressings immediately after the ES procedure.


Electrical stimulation with the anode.

Patients in the anodal ES group will receive HVMPC in the same way as patients in the cathodal ES group, but the treatment electrode will be the anode. The authors of other clinical studies on PUs used anodal stimulation.

HVMPC with the cathode (in the cathode ES group) and with the anode (in the anode ES group) will be applied for a period of 4 weeks (total of 20 HVMPC sessions), during which wounds will be observed for healing progress.
Intervention code [1] 295417 0
Rehabilitation
Intervention code [2] 295418 0
Treatment: Devices
Intervention code [3] 295419 0
Treatment: Other
Comparator / control treatment
SWC programme, the same as to the electrical stimulation groups, will be administered to In the control group (placebo ES group).

In addition to standard wound care described above, the control group will also receive sham ES. The electrodes will be arranged in the same way as in the ES groups and all current parameters will also be displayed on the monitor, but the current itself will not be applied. Five 50-minute sessions of sham ES will be held per week (one a day).

Sham HVMPC will be applied for a period of 4 weeks (total of 20 sham HVMPC sessions), during which wounds will be observed for healing progress.
Control group
Placebo

Outcomes
Primary outcome [1] 299062 0
Changes in the concentration of polypeptide growth factors in peripheral blood (FGF; IGF-1; VEGF, EGF, KGF, TGF beta1).
Timepoint [1] 299062 0
At baseline, week 2 and week 4
Primary outcome [2] 299063 0
Changes in the concentration of pro-inflammatory cytokines in peripheral blood (IL-1Beta, IL-6, TNF-alpha)
Timepoint [2] 299063 0
At baseline, week 2 and week 4
Primary outcome [3] 300339 0
Changes in the concentration of anti-inflammatory cytokines in peripheral blood (IL-10).
Timepoint [3] 300339 0
At baseline, week 2 and week 4
Secondary outcome [1] 326050 0
Changes in gene expression for growth factors and their receptors in the specimen of granulation tissue taken from wound edge (FGF; IGF-1; VEGF, EGF, KGF, TGF beta1).
Timepoint [1] 326050 0
At baseline, week 2 and week 4
Secondary outcome [2] 326051 0
Changes in gene expression for pro-inflammatory cytokines in the specimen of granulation tissue taken from wound edge.(IL-1Beta, IL-6, TNF-alpha)
Timepoint [2] 326051 0
At baseline, week 2,, and week 4
Secondary outcome [3] 329731 0
Changes in gene expression for anti-inflammatory cytokines in the specimen of granulation tissue taken from wound edge.(IL-10)
Timepoint [3] 329731 0
At baseline, week 2 and week 4
Secondary outcome [4] 329732 0
Percentage change/decrease in WSA after 4 weeks of intervention with SWC + sham ES, SWC + cathode HVMPC, and SWC + anode HVPC (to compare changes in PU surface area between the groups).

Percentage WSA reduction from baseline at week 4 (PAR4) will be calculated with the following formula: PAR4 = initial WSA (cm2) – WSA (cm2) at week 4 x 100% / Initial WSA (cm2)
Timepoint [4] 329732 0
At baseline, and week 4
Secondary outcome [5] 329733 0
Absolute average change in wound surface area (WSA) (cm2) after treatment in relation to its baseline in all groups (showing how effective treatment will be in particular groups).
Timepoint [5] 329733 0
At baseline, and week 4

Eligibility
Key inclusion criteria
Patient eligibility for the experiment will be established by their physician according to the following criteria: patients with either paraplegia or quadriplegia caused by congenital, medical, or traumatic central nervous system injury, over the age of 18 years, hospitalized in rehabilitation centre, with a Category II, III or IV PU of at least 0.5 cm2 in size and of minimal duration 4 weeks.
Minimum age
18 Years
Maximum age
No limit
Sex
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
The patients who do not qualify for ES (cancer, electronic implants, malignant, tunnelling and necrotic wounds, osteomyelitis, PU requiring surgical intervention) will be excluded from participating, as well as those with diagnoses that might interfere with wound healing, such as diabetes (HbA1C > 7%), venous insufficiency, critical infection.

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)
The selected patients (or their legal guardians) who will give their consent to participate in the study will be randomly assigned to the control group (SWC plus sham ES), the cathode HVMPC group (SWC plus cathode HVMPC) or the anode HVPC group (SWC plus anode HVMPC) using a concealed process.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Patient allocation to groups will be independent of when and who will deliver the treatment.

The group allocation sequence will be concealed. Simple randomisation with numbered envelopes will be used.

An independent person will receive three batches of 15 pieces of paper, each marked with a letter indicating to which group the patient should go, i.e. A for the SWC+cathodal HVMPC group, B for the SWC+anodal HVMPC group and C for the SWC+sham ES group.. The person, unaware of what the symbols mean, will insert the pieces of paper into 45 envelopes randomly drawn by the computer. The sealed envelopes will be transferred to the main investigator in charge of patients’ allocation to groups. Before the treatment, the envelopes will be opened one-by-one in the presence of a physiotherapist and the patient concerned will be directed to the appropriate study group.
Masking / blinding
Blinded (masking used)
Who is / are masked / blinded?
The people receiving the treatment/s
The people administering the treatment/s
The people assessing the outcomes
The people analysing the results/data
Intervention assignment
Parallel
Other design features
To evaluate the changes, of concentration of growth factor, pro-inflammatory and anti-inflammatory cytokines peripheral blood samples of 5 ml will be taken from the patients before ES therapy and then after 2 and 4 weeks into the treatment period.

To evaluate the changes in gene expression for growth factors, pro-inflammatory, anti-iflammatory cytokines and their receptors, a granulation tissue specimen of 5 mm in diameter will be taken before ES therapy and then after 2 and 4 weeks into the treatment period.

WSA will be determined using the same method that was already employed in several previous clinical trials. First wound contours will be copied onto transparent film sheets. The contours will be then measured with the planimeter to establish the surface area of each wound. The obtained data will be processed by a digitizer (Mutoh Kurta XGT, Altek, USA) connected to a personal computer (C-GEO v. 4.0 Nadowski, PL) which will be also used to store the results.

Measurement errors caused by different shapes of the wounds may range from 2.7% (for PUs of 60 to 70 cm2 in size) to 37.9% (for PUs < 1 cm2). The method with which measurement errors will be calculated can be found in our earlier study.
Phase
Not Applicable
Type of endpoint/s
Efficacy
Statistical methods / analysis
If, as in other studies, an average increase in expression of the analysed factors between baseline and final examination is 30% at a standard deviation of 40%, the minimum size of the group will be 9 persons. For a larger standard deviation or a smaller average increase, the size of the group will be increased.

After the experiment, patients’ characteristics will be tested for normality of distribution using the Shapiro-Wilk W test. In the case of normal distributions, the parametric ANOVA test will be used, and in the case of non-normal distributions, the non-parametric tests (Kruskal-Wallis analysis of variance for inter-group comparisons and Friedman’s ANOVA for intragroup comparisons) will be used to establish statistical significance.

Patients’ characteristics will also be tested for skewness, kurtosis and modality of distributions. In the cases when skewness and kurtosis are smaller than 4 and the distributions are unimodal, arithmetic averages and standard deviations will be used as the measures of central value and dispersion.

The level of statistical significance in all tests will be p < 0.05.

The statistical analysis will be performed using the Statistica software by StatSoft (licenced to the Medical University of Silesia).

All patients in the experiment will be assessed for the homogeneity of distribution of their characteristics. The mean percentage change in wound area (at week 4), the expression of cytokines and growth factors will be calculated (at week 2 and 4) in all groups and then an inter-group comparison will be performed.

Recruitment
Recruitment status
Completed
Date of first participant enrolment
Anticipated
Actual
4/01/2016
Date of last participant enrolment
Anticipated
30/01/2017
Actual
30/01/2017
Date of last data collection
Anticipated
27/02/2017
Actual
27/02/2017
Sample size
Target
30
Accrual to date
Final
61
Recruitment outside Australia
Country [1] 8050 0
Poland
State/province [1] 8050 0

Funding & Sponsors
Funding source category [1] 294805 0
University
Name [1] 294805 0
Academy of Physical Education
Country [1] 294805 0
Poland
Primary sponsor type
University
Name
Academy of Physical Education
Address
Mikolowska str. 72A
40-065 Katowice
Poland
Country
Poland
Secondary sponsor category [1] 293650 0
None
Name [1] 293650 0
None
Address [1] 293650 0
None
Country [1] 293650 0
Other collaborator category [1] 279280 0
University
Name [1] 279280 0
Academy of Physical Education
Address [1] 279280 0
Mikolowska 72A 40-065 Katowice
Country [1] 279280 0
Poland

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 296201 0
The Research Ethics Commitee from the Academy of Physical Education in Katowice, Poland
Ethics committee address [1] 296201 0
Ethics committee country [1] 296201 0
Poland
Date submitted for ethics approval [1] 296201 0
02/04/2014
Approval date [1] 296201 0
15/05/2014
Ethics approval number [1] 296201 0
4/2014

Summary
Brief summary
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 67746 0
Dr Anna Polak
Address 67746 0
Department of Physical Therapy, Academy of Physical Education, 40-065 Katowice, Mikolowska 72A
Country 67746 0
Poland
Phone 67746 0
+48322075318
Fax 67746 0
Email 67746 0
[email protected]
Contact person for public queries
Name 67747 0
Anna Polak
Address 67747 0
Department of Physical Therapy, Academy of Physical Education, 40-065 Katowice, Mikolowska 72A
Country 67747 0
Poland
Phone 67747 0
+48322075318
Fax 67747 0
Email 67747 0
[email protected]
Contact person for scientific queries
Name 67748 0
Anna Polak
Address 67748 0
Department of Physical Therapy, Academy of Physical Education, 40-065 Katowice, Mikolowska 72A
Country 67748 0
Poland
Phone 67748 0
+48322075318
Fax 67748 0
Email 67748 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
The results of individual patient tests were used to create a database, which is available in the form of an electronic database at the study manager. The study protocol did not provide for the publication of individual patient trial results.


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
No additional documents have been identified.