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Trial registered on ANZCTR


Registration number
ACTRN12620000116921
Ethics application status
Approved
Date submitted
13/01/2020
Date registered
7/02/2020
Date last updated
3/11/2020
Date data sharing statement initially provided
7/02/2020
Type of registration
Prospectively registered

Titles & IDs
Public title
Factorial4VLU: Exercise or dilute hypochlorous acid for venous leg ulcers: a factorial randomised trial
Scientific title
Factorial4VLU: A 2 x 2 factorial randomised controlled trial of exercise or dilute hypochlorous acid for healing venous leg ulcers
Secondary ID [1] 300243 0
Health Research Council of New Zealand Reference Number 19/069
Secondary ID [2] 302688 0
HRC Project Grant Number #19/069
Universal Trial Number (UTN)
U1111-1236-2997
Trial acronym
Factorial4VLU
Linked study record

Health condition
Health condition(s) or problem(s) studied:
Venous leg ulceration 315800 0
Condition category
Condition code
Cardiovascular 314090 314090 0 0
Diseases of the vasculature and circulation including the lymphatic system
Skin 314200 314200 0 0
Other skin conditions

Intervention/exposure
Study type
Interventional
Description of intervention(s) / exposure
Arm 1: Prescribed regimen of exercise plus dilute hypochlorous acid wound solution (0.003%HOCl). The prescribed regimen of progressive resistance exercise consists of daily lower leg exercises to increase calf muscle strength at least until ulcer healing (3 sets of seated exercises starting with 10 repetitions per set and increasing up to 25 repetitions per set, before progressing to standing two-legged exercises and then standing one-legged exercises) with the participants' body weight providing the resistance element. Participants progress to the next stage of exercise when they are comfortable with achieving the current step. The exercise regimen is supported with a participant resource book that demonstrates the exercises, includes goal setting (which will be assisted by trained research nurses) and an exercise diary. The prescribed regimen also includes a target of walking for 30 minutes each day, three days per week. The regimen is to be demonstrated one-to-one by the research nurses, who assist the participant with goal setting recorded in the participant diary. Participants will perform the exercise wherever they are comfortable e.g. their own home. Exercise adherence is recorded in a participant diary.

The wound solution will be sprayed on the ulcer at each at each dressing change, the wound debrided as required, devitalised tissue and debris will be removed, and the the wound solution reapplied before the ulcer is redressed. Venous ulcers are typically redressed once per week, but maybe redressed more frequently as indicated. Dressings are usually changed by nurses, but can be changed by some self-managing patients if wearing compression hosiery or wraps.

Arm 2: Prescribed regimen of exercise plus placebo wound solution (purified water). The prescribed regimen of progressive resistance exercise consists of daily lower leg exercises to increase calf muscle strength at least until ulcer healing (3 sets of seated exercises starting with 10 repetitions per set and increasing up to 25 repetitions per set, before progressing to standing two-legged exercises and then standing one-legged exercises) with the participants' body weight providing the resistance element. Participants progress to the next stage of exercise when they are comfortable with achieving the current step. The exercise regimen is supported with a participant resource book that demonstrates the exercises, includes goal setting (which will be assisted by trained research nurses) and an exercise diary. The prescribed regimen also includes a target of walking for 30 minutes each day, three days per week. The regimen is to be demonstrated one-to-one by the research nurses, who assist the participant with goal setting recorded in the participant diary. Participants will perform the exercise wherever they are comfortable e.g. their own home. Exercise adherence is recorded in a participant diary.

The wound solution will be sprayed on the ulcer at each at each dressing change, the wound debrided as required, devitalised tissue and debris will be removed, and the the wound solution reapplied before the ulcer is redressed. Venous ulcers are typically redressed once per week, but maybe redressed more frequently as indicated. Dressings are usually changed by nurses, but can be changed by some self-managing patients if wearing compression hosiery or wraps.
Intervention code [1] 316512 0
Treatment: Other
Intervention code [2] 316515 0
Treatment: Devices
Comparator / control treatment
Arm 3: Usual care (compression and a study-specific pamphlet providing general advice about venous leg ulcer care) plus dilute hypochlorous acid wound solution (0.003% HOCl). The wound solution will be sprayed on the ulcer at each at each dressing change, the wound debrided as required, devitalised tissue and debris will be removed, and the the wound solution reapplied before the ulcer is redressed. The wound solution will be used for the duration of the trial (24 weeks) or until the ulcer is healed, whichever is earlier. The unused bottles of the wound solution will be collected at 12 or 24 weeks. Venous ulcers are typically redressed once per week, but maybe redressed more frequently as indicated. Dressings are usually changed by nurses, but can be changed by some self-managing patients if wearing compression hosiery or wraps.

Arm 4: Usual care (compression and a study-specific pamphlet providing general advice about venous leg ulcer care) plus placebo wound solution (purified water). The wound solution will be sprayed on the ulcer at each at each dressing change, the wound debrided as required, devitalised tissue and debris will be removed, and the the wound solution reapplied before the ulcer is redressed. The wound solution will be used for the duration of the trial (24 weeks) or until the ulcer is healed, whichever is earlier. The unused bottles of the wound solution will be collected at 12 or 24 weeks. Venous ulcers are typically redressed once per week, but maybe redressed more frequently as indicated. Dressings are usually changed by nurses, but can be changed by some self-managing patients if wearing compression hosiery or wraps.
Control group
Placebo

Outcomes
Primary outcome [1] 322482 0
Number of participants with complete healing of reference ulcer as adjudicated by blinded review of ulcer photographs. Complete healing is defined as full epithelialisation of the ulcer with no scab.
Timepoint [1] 322482 0
12 weeks after randomisation
Secondary outcome [1] 378661 0
Number of participants with complete healing of reference ulcer as adjudicated by blinded review of ulcer photographs
Timepoint [1] 378661 0
At 24 weeks after randomisation
Secondary outcome [2] 378662 0
Time to complete healing with date of healing being the date healing first recorded in the participant's clinical record.
Timepoint [2] 378662 0
Up to 24 weeks after randomisation
Secondary outcome [3] 378663 0
Change in estimated ulcer area from baseline with dimensions obtained for maximum ulcer width and length (at 90 degrees to the maximum width) and estimated ulcer area determined from area for an ellipse. Maximum length and width will be obtained using tape measures and recorded in millimetres.
Timepoint [3] 378663 0
At 24 weeks after randomisation
Secondary outcome [4] 378664 0
Change in 2-Minute Walk Test from baseline
Timepoint [4] 378664 0
At 12 and 24 weeks
Secondary outcome [5] 378665 0
Change in health-related quality of life from baseline using generic quality of life instrument (SF-12 acute version).
Timepoint [5] 378665 0
At 24 weeks after randomisation
Secondary outcome [6] 378666 0
Change in ulcer-related pain using a 0 to 10 visual analog scale in a participant in pain diary.
Timepoint [6] 378666 0
Recorded weekly in pain dairy for up to 12 weeks after randomisation or ulcer healing, whichever is sooner.
Secondary outcome [7] 378667 0
Adherence to prescribed exercise regimen using a participant-recorded exercise diary.
Timepoint [7] 378667 0
Recorded daily in exercise diary for up to 24 weeks after randomisation or ulcer healing, whichever is sooner.
Secondary outcome [8] 378668 0
Incidence of all-cause adverse events using participant self-report and linkage to medical records.
Timepoint [8] 378668 0
Up to 24 weeks after randomisation
Secondary outcome [9] 379338 0
Change in health-related quality of life from baseline using generic quality of life instrument (EQ5D-5L).
Timepoint [9] 379338 0
At 24 weeks after randomisation
Secondary outcome [10] 379339 0
Change in health-related quality of life from baseline using disease-specific quality of life instrument (Charing Cross Venous Ulcer Questionnaire).
Timepoint [10] 379339 0
At 24 weeks after randomisation

Eligibility
Key inclusion criteria
Aged 18 years or older, determined to have a VLU (clinical indications of venous ulceration, Ankle Brachial Index greater than or equal to 0.8, and other causative aetiologies ruled out), able to tolerate compression therapy, able to provide written informed consent, and able to walk safely independently (aids allowed).
Minimum age
18 Years
Maximum age
No limit
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
Have hypersensitivity to hypopchlorous acid or sodium hypochlorite, have a fixed ankle joint, have VLU with current infection (may be eligible once infection cleared), have VLU with exposed bone or tendon, have history of rheumatoid arthritis or vasculitis, have uncontrolled diabetes (HbA1c > 100), have severe liver, heart, or renal failure, have severe peripheral arterial disease, have suspected or diagnosed skin malignancy associated with the leg ulcer, or have any other threat to safe participation.

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 Research Nurse accesses randomisation via a computer tablet, completes data entry on eligibility, and then generates the allocation.
Methods used to generate the sequence in which subjects will be randomised (sequence generation)
Consented participants who fulfil entry criteria will be randomly allocated to one of the four trial groups using stratified blocked randomisation with varying block sizes of 2 and 4. The randomisation sequence will be prepared by the trial statistician and loaded into a secure database. Randomisation will be stratified by trial centre and a two level prognostic index forcer healing (normal healer/slow healer) based on ulcer area and ulcer duration.
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
Factorial
Other design features
Phase
Phase 3
Type of endpoint(s)
Efficacy
Statistical methods / analysis
An estimated 380 participants will be required to detect a 17% difference in the proportion of participants with completely healed VLU at 12 weeks with 90% power and an alpha of 0.05, assuming a baseline healing rate of 50% in the control group and 10% loss to follow up.

Data analyses will be specified a priori in a statistical analysis plan. Analysis will be at the margins comparing each intervention (exercise versus no exercise, HOCl versus placebo). There will be no analysis for interaction and analyses will use intention-to-treat principle. Binary outcomes will be analysed using logistics regression. Sensitivity analyses will be undertaken to determine the impact of missing data. Continuous outcomes (with 95% CIs) will be analysed using multiple linear regression and adjusted for baseline value and other covariates if needed. Change in ulcer-related pain and the 2-MWT will be analysed using repeated measures model with adjustment for baseline value. Time-to-event data will be analysed using Kaplan Meier plots and log rank test. Cox regression will be used with time-to-event data to take into account known covariates and the varying times since randomisation. The assumption of proportionality will be checked using standard graphical techniques. Adverse events will be analysed using incidence rate ratios. No interim analyses are planned.

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 outside Australia
Country [1] 22217 0
New Zealand
State/province [1] 22217 0

Funding & Sponsors
Funding source category [1] 304669 0
Government body
Name [1] 304669 0
Health Research Council of New Zealand
Address [1] 304669 0
PO Box 5541
Wellesley Street
Auckland 1141
New Zealand
Country [1] 304669 0
New Zealand
Primary sponsor type
University
Name
University of Auckland
Address
School of Nursing
Faculty of Medicine and Health Sciences
Private Bag 92019
Auckland 1142
New Zealand
Country
New Zealand
Secondary sponsor category [1] 304974 0
None
Name [1] 304974 0
Address [1] 304974 0
Country [1] 304974 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 305089 0
Northern B Health and Disability Ethics Committee
Ethics committee address [1] 305089 0
Ministry of Health
PO Box 5013
Wellington 6011
New Zealand
Ethics committee country [1] 305089 0
New Zealand
Date submitted for ethics approval [1] 305089 0
04/09/2019
Approval date [1] 305089 0
06/01/2020
Ethics approval number [1] 305089 0
19/NTB/151

Summary
Brief summary
Factorial4VLU is a 2 x 2 factorial randomised controlled trial with participants allocated to prescribed progressive resistance exercises plus walking at least 3 times per week or usual care advice and/or a hypochlorous acid wound solution or placebo. The factorial design allows us to test two inventions at once.

The purpose of the study is to determine if a hypochlorous acid wound solution or an exercise regimen helps venous leg ulcer (VLU) healing. The primary outcome is the proportion of participants with a completely healed reference ulcer at 12 weeks.

Approximately 380 participants will take part from five District Nursing Services; Auckland DHB, Counties Manukau DHB (South Auckland), Capital & Coast DHB (Wellington), the Nurse Maude Association (Christchurch), and the Southern DHB (Dunedin).

Participants will all be treated with compression therapy (tight bandaging or hosiery for the lower leg) and will be allocated to one of four arms for adjuvant treatments: [1] Prescribed daily regimen of progressive resistance exercises along with walking for 30 minutes per day three days per week plus ulcer cleansing using dilute hypochlorous acid wound solution when ulcer dressings are changed; or [2] Prescribed daily regimen of progressive resistance exercises along with walking for 30 minutes per day three days per week plus ulcer cleansing using purified water when ulcer dressings are changed; or [3] Usual care advice plus ulcer cleansing using dilute hypochlorous acid wound solution when ulcer dressings are changed; or [4] Usual care advice therapy plus ulcer cleansing using purified water when ulcer dressing changed.

Participants will have four visits over 6 months (screening, baseline, week 12 and week 24) from a research nurse who is a qualified community nurse with experience in leg ulcer care. The visits will be where the participant would normally receive a district nurse visit (i.e. home or a clinic). Each visit will take about 30-60 minutes. In between the research nurse visits, the district nurse will look after the participant’s leg ulcer care.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 99234 0
Prof Andrew Jull
Address 99234 0
School of Nursing
Faculty of Medicine and Health Sciences
Private Bag 92019
Auckland 1142
Country 99234 0
New Zealand
Phone 99234 0
+64 9 923 4259
Fax 99234 0
Email 99234 0
a.jull@auckland.ac.nz
Contact person for public queries
Name 99235 0
Prof Andrew Jull
Address 99235 0
School of Nursing
Faculty of Medicine and Health Sciences
Private Bag 92019
Auckland 1142
Country 99235 0
New Zealand
Phone 99235 0
+64 9 923 4259
Fax 99235 0
Email 99235 0
a.jull@auckland.ac.nz
Contact person for scientific queries
Name 99236 0
Prof Andrew Jull
Address 99236 0
School of Nursing
Faculty of Medicine and Health Sciences
Private Bag 92019
Auckland 1142
Country 99236 0
New Zealand
Phone 99236 0
+64 9 923 4259
Fax 99236 0
Email 99236 0
a.jull@auckland.ac.nz

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
Yes
What data in particular will be shared?
All of the individual participant data collected during the trial, after de-identification.
When will data be available (start and end dates)?
Following publication, no end date.
Available to whom?
All requests for de-identified individual participant data or study documents will be considered where the proposed use aligns with public good purposes, does not conflict with other requests, or planned use by the trial steering committee, and the requestor is willing to sign a data access agreement. Contact is through the corresponding author (a.jull@auckland.ac.nz).
Available for what types of analyses?
Any purpose.
How or where can data be obtained?
Contact is through the principal investigator (Professor Andrew Jull, email a.jull@auckland.ac.nz)
What supporting documents are/will be available?
No other documents available
Summary results
No Results