Varicose Ulcer
Conditions
Keywords
Venous Leg Ulcer, Varicose Ulcer, Chronic ulcer, Chronic wound, Ultrasound therapy, MIST device, Wound healing, Low frequency non contact ultrasound
Brief summary
Chronic venous leg ulcers (VLUs) impact negatively on patients' quality of life. Standard treatment in the UK for patients with VLUs is compression bandaging or stockings. The MIST ultrasound system is a noncontact device which delivers low frequency ultrasound through a gentle saline mist directed at a patient's wound. This study aims to determine whether the use of the MIST device used in combination with standard treatments can improve healing of VLUs compared to UK standard practice. This will be assessed by measuring any reduction in wound size in the two groups after receiving 8 weeks of either Standard Care once a week or MIST combined with Standard Care three times a week.
Detailed description
Venous leg ulcers (VLUs) are wounds which are often chronic and difficult to heal. VLUs affect between 1 and 3.2 people per 1000; they cause pain, reduced mobility and impact negatively on patients' quality of life (QoL). Standard treatment for patients with VLUs is the application of strong, sustained compression with bandages or stockings. This pragmatically-designed study aims to determine whether the use of a device called MIST used in combination with standard treatments can improve healing of VLUs compared to UK standard practice. It will also show whether the MIST regimen improves participants' QoL and reduces the incidence of infection. The MIST ultrasound system is a non-contact device which delivers low-frequency ultrasound through a gentle saline mist directed at a patient's wound. Patients (over 18 years old) will be invited to take part in this study if they have had a VLU for 6 weeks or more, which measures between 5 and 100 cm\^2, and is not infected. Participants with diabetes must show good blood glucose control, and those with underlying chronic disorders which may affect wound healing will be excluded. All study participants will receive four weeks of standard treatment once a week at a single clinic at the Wound Healing Research Unit (WHRU), University Hospital of Wales. Patients whose wounds reduce by more than 40% during this time will be withdrawn from the study. Remaining patients will be randomly allocated to either the active group or the control group to receive a further eight weeks of treatment. Participants in the active group will receive treatment with the MIST device three times a week, as well as standard care (change of compression bandage and dressings) three times a week. The control group will receive UK standard care (which is dressing and compression bandage change at least once a week). The participants' ulcers will be measured and photographed once a week, and the wound characteristics will be assessed. Changes in participants' health related QoL will be assessed using a questionnaire at the beginning and end of the trial. Wound recurrence rates 90 days after the end of the treatment will be assessed by telephoning patients.
Interventions
DEVICEMIST ultrasound therapy
Low frequency, non-contact ultrasound system delivering therapeutic ultrasound via a fine saline mist to the wound bed.
OTHERStandard Care
Compression bandaging, non-adherent dressing, and debridement if required.
Sponsors
Celleration, Inc.
Cardiff and Vale University Health Board
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Venous leg ulcers (as diagnosed by the clinician) * Ankle Brachial Pressure Index (ABPI) \>0.8 * If multiple ulcers are present treat largest ulcer only (index ulcer) with minimum distance of 1 cm between index ulcer and any other ulcer * 18 years or older * Ulcer size of 5 cm\^2 - 100 cm\^2 (with no longest length being greater than 10 cm) at randomisation point (week 5) * Mobile enough to attend clinic * Index ulcer between 6 weeks and 5 years duration prior to screening date
Exclusion criteria
* Uncontrolled diabetes (Hba1c ≥12%) as tested within the past 3 months * Index ulcer has active infection on day of inclusion requiring use or oral or IV antibiotics * Renal failure * Index ulcer has exposed tendons, ligaments, muscle, or bone * Osteomyelitis or cellulitis or gangrene in study limb * Subjects with amputation above a trans metatarsal amputation (TMA) in the study limb * Subjects with active malignancy on the study limb * Index ulcer that is of arterial disease aetiology * Females of child bearing potential who are not willing to use a method of highly effective contraception during the entire study * Planned vascular surgery, angioplasty, or thrombolysis procedures within the study period, or 6 weeks post-operatively * Planned surgical procedure during the study period for the index wound * Prior skin replacement, negative pressure therapy, ultrasound therapy applied to the index wound 2 weeks before screening * Oral or IV antibiotics within 48 hours of baseline measurements * Growth factor therapy within previous 14 days of screening date * Currently receiving or has received radiation or chemotherapy within 3 months of randomisation * Pregnant or breast feeding women * Subject is currently enrolled or has been enrolled in the last 30 days in another investigational device or drug trial * Subject's wound would require ultrasound near an electronic implant or prosthesis * Subjects lacking capacity to provide informed consent.
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Percentage Change in Wound Area | Week 5 to 13 | Wound area is measured weekly using a digital wound imaging device. The wound boundary is digitally traced by a blinded assessor. Percentage and actual change in wound area between start of treatment (week 5) and end of treatment (week 13) is evaluated. |
| Actual Change in Wound Area | Week 5 to 13 | Wound area is measured weekly using a digital wound imaging device. The wound boundary is digitally traced by a blinded assessor. Percentage and actual change in wound area between start of treatment (week 5) and end of treatment (week 13) is evaluated. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Incidence of Wound Infection | Weeks 5 to 13 | Median number of wound infections per patient (as demonstrated by clinical symptoms) from beginning of treatment (week 5) and end of treatment (week 13). |
| Change in Overall Health Related Quality of Life (HRQoL) From Week 1 (Start) and Week 13 (Exit) | Week 1 (start) and week 13 (exit) | On the first and final visit participants were invited to complete a Cardiff Wound Impact Schedule (CWIS) a validated questionnaire designed to measure the impact of chronic wounds on patient health-related quality of life (HRQoL). The overall HRQoL question asks patients to rate their overall quality of life over the past week by circling a number between 0 and 10. Low scores indicate poor quality of life, and high score indicate good quality of life. Change in HRQoL was calculated by subtracting week 1 values from week 13 values. CWIS has been validated in the following paper: Price and Harding (2004) The Cardiff Wound Impact Schedule: the development of a condition specific questionnaire to assess health-related quality of life in patients with chronic wounds. International Wound Journal 1(1):10-17 |
| Wound Recurrence Rate | 90 days after time of healing | Patients whose wound has healed (defined as 100% epithelialisation with no scab present) before or at the end of treatment will be asked 90 days after date of healing if their wound has remained closed. |
| Number of Non-serious Adverse Events in Each Group | Week 5 to 13 | Adverse events (AEs) were defined as any undesirable clinical occurrence in a subject whether it is thought to be related to the investigational device or not. |
| Change in Ulcer Pain Between Week 5 (Randomisation) and Week 13 (Exit) | Weeks 5 to 13 | Pain was scored by each patient on a visual analogue score (VAS) from 0 to 100. A VAS score of 0 indicated no pain whilst a VAS score of 100 indicated worst possible pain. Change in pain scores were calculated by subtracting week 5 values from week 13 values. |
Countries
United Kingdom
Participant flow
Recruitment details
Study procedures took place in a single dedicated unit specialising in wound healing research, between August 2012 and November 2013.
Pre-assignment details
All enrolled patients received 4 weeks of SOC prior to random allocation (run-in phase). Patients whose wounds reduced by \>40% in the first 4 weeks were withdrawn and did not progress to random allocation.
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care Standard of Care (SOC) was compression bandaging and non-adherent dressing at least once a week (more frequent visits if clinically necessary). Debridement was performed as required. | 19 |
| NLFU and Standard of Care Non-contact low frequency ultrasound (NLFU) using MIST ultrasound therapy is applied for between 3 and 12 minutes (depending on wound size) 3 times a week in combination with standard treatment for VLUs of compression bandaging and non-adherent dressing change 3 times a week, with debridement as required. | 17 |
| Total | 36 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| 4 Week run-in Phase | Adverse Event | 1 | 0 |
| 4 Week run-in Phase | Not eligible | 9 | 0 |
| 4 Week run-in Phase | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | Standard of Care | NLFU and Standard of Care | Total |
|---|---|---|---|
| Age, Continuous | 68.2 years STANDARD_DEVIATION 12.2 | 70.5 years STANDARD_DEVIATION 12.7 | 69 years STANDARD_DEVIATION 12 |
| Change in wound size during run-in phase (%) | -13.0 percentage change in wound area STANDARD_DEVIATION 25.2 | -10.9 percentage change in wound area STANDARD_DEVIATION 23.9 | -12.0 percentage change in wound area STANDARD_DEVIATION 24.3 |
| History of leg ulceration (months) | 94.7 months STANDARD_DEVIATION 83.2 | 109.7 months STANDARD_DEVIATION 112.2 | 101.8 months STANDARD_DEVIATION 96.8 |
| Index ulcer duration (months) | 22.3 months STANDARD_DEVIATION 18.5 | 15.7 months STANDARD_DEVIATION 12 | 19 months STANDARD_DEVIATION 16 |
| Region of Enrollment United Kingdom | 19 participants | 17 participants | 36 participants |
| Sex: Female, Male Female | 12 Participants | 9 Participants | 21 Participants |
| Sex: Female, Male Male | 7 Participants | 8 Participants | 15 Participants |
| Wound size at enrolment (cm^2) | 19.4 cm^2 STANDARD_DEVIATION 14.9 | 15.9 cm^2 STANDARD_DEVIATION 9.9 | 17.8 cm^2 STANDARD_DEVIATION 12.7 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 19 / 19 | 15 / 17 |
| serious Total, serious adverse events | 0 / 19 | 0 / 17 |
Outcome results
Primary
Actual Change in Wound Area
Wound area is measured weekly using a digital wound imaging device. The wound boundary is digitally traced by a blinded assessor. Percentage and actual change in wound area between start of treatment (week 5) and end of treatment (week 13) is evaluated.
Time frame: Week 5 to 13
Population: As previous
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Actual Change in Wound Area | -5.3 cm2 | Standard Deviation 5.5 |
| NLFU and Standard of Care | Actual Change in Wound Area | -6.2 cm2 | Standard Deviation 5.5 |
p-value: 0.61895% CI: [-4.7, 2.9]ANCOVA
Primary
Percentage Change in Wound Area
Wound area is measured weekly using a digital wound imaging device. The wound boundary is digitally traced by a blinded assessor. Percentage and actual change in wound area between start of treatment (week 5) and end of treatment (week 13) is evaluated.
Time frame: Week 5 to 13
Population: All patients included in the analysis; Intention to treat (ITT); Values have been adjusted for the influence of the covariate (wound area at the start of treatment)
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Percentage Change in Wound Area | -39.2 percentage change in wound area | Standard Deviation 38 |
| NLFU and Standard of Care | Percentage Change in Wound Area | -46.6 percentage change in wound area | Standard Deviation 38.1 |
Comparison: The study was powered to detect a difference in the change in wound area of 20% between the two arms with a two sided significance level and power of 90%. A standard deviation of 17.5% came from published literature. A minimum of 17 patients in each arm was required.p-value: 0.56595% CI: [-33.4, 18.6]ANCOVA
Secondary
Change in Overall Health Related Quality of Life (HRQoL) From Week 1 (Start) and Week 13 (Exit)
On the first and final visit participants were invited to complete a Cardiff Wound Impact Schedule (CWIS) a validated questionnaire designed to measure the impact of chronic wounds on patient health-related quality of life (HRQoL). The overall HRQoL question asks patients to rate their overall quality of life over the past week by circling a number between 0 and 10. Low scores indicate poor quality of life, and high score indicate good quality of life. Change in HRQoL was calculated by subtracting week 1 values from week 13 values. CWIS has been validated in the following paper: Price and Harding (2004) The Cardiff Wound Impact Schedule: the development of a condition specific questionnaire to assess health-related quality of life in patients with chronic wounds. International Wound Journal 1(1):10-17
Time frame: Week 1 (start) and week 13 (exit)
Population: All patients were analysed by ITT
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care | Change in Overall Health Related Quality of Life (HRQoL) From Week 1 (Start) and Week 13 (Exit) | 0 units on a scale |
| NLFU and Standard of Care | Change in Overall Health Related Quality of Life (HRQoL) From Week 1 (Start) and Week 13 (Exit) | -1 units on a scale |
Comparison: ANCOVA was used for change in HRQoL from week 1 to week 13 (with week 1 HRQoL score as the covariate).p-value: 0.49ANCOVA
Secondary
Change in Ulcer Pain Between Week 5 (Randomisation) and Week 13 (Exit)
Pain was scored by each patient on a visual analogue score (VAS) from 0 to 100. A VAS score of 0 indicated no pain whilst a VAS score of 100 indicated worst possible pain. Change in pain scores were calculated by subtracting week 5 values from week 13 values.
Time frame: Weeks 5 to 13
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard of Care | Change in Ulcer Pain Between Week 5 (Randomisation) and Week 13 (Exit) | -5.27 scores on a scale | Standard Deviation 14.84 |
| NLFU and Standard of Care | Change in Ulcer Pain Between Week 5 (Randomisation) and Week 13 (Exit) | -14.35 scores on a scale | Standard Deviation 14.85 |
Comparison: ANCOVA was used for change in pain score (VAS) from week 5 to week 13 (covariate was baseline pain score).p-value: 0.07895% CI: [-19.23, 1.06]ANCOVA
Secondary
Incidence of Wound Infection
Median number of wound infections per patient (as demonstrated by clinical symptoms) from beginning of treatment (week 5) and end of treatment (week 13).
Time frame: Weeks 5 to 13
Population: All patients included; ITT.
| Arm | Measure | Value (MEDIAN) |
|---|---|---|
| Standard of Care | Incidence of Wound Infection | 2 Number of infections per patient |
| NLFU and Standard of Care | Incidence of Wound Infection | 2 Number of infections per patient |
Comparison: Change in number of infections were not normally distributed and differences between the arms were tested using the non-parametric Mann-Whitney U test.p-value: 0.346Wilcoxon (Mann-Whitney)
Secondary
Number of Non-serious Adverse Events in Each Group
Adverse events (AEs) were defined as any undesirable clinical occurrence in a subject whether it is thought to be related to the investigational device or not.
Time frame: Week 5 to 13
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | Number of Non-serious Adverse Events in Each Group | 70 Number of non-serious AEs |
| NLFU and Standard of Care | Number of Non-serious Adverse Events in Each Group | 59 Number of non-serious AEs |
Secondary
Wound Recurrence Rate
Patients whose wound has healed (defined as 100% epithelialisation with no scab present) before or at the end of treatment will be asked 90 days after date of healing if their wound has remained closed.
Time frame: 90 days after time of healing
Population: Three patients healed during the study period (one NLFU+SOC patient healed after 7 weeks and one after 8 weeks of NLFU+SOC treatment, and one patient who received standard care alone healed after 4 weeks). All three of these patients remained healed 90 days after the end of their study treatment.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard of Care | Wound Recurrence Rate | 1 Number of wounds remained healed |
| NLFU and Standard of Care | Wound Recurrence Rate | 2 Number of wounds remained healed |