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MIST Ultrasound Therapy Compared to United Kingdom Standard Care for the Treatment of Non-healing Venous Leg Ulcers

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ClinicalTrials.gov Identifier: NCT01671748
Recruitment Status : Completed
First Posted : August 24, 2012
Results First Posted : August 26, 2015
Last Update Posted : August 26, 2015
Sponsor:
Collaborator:
Celleration, Inc.
Information provided by (Responsible Party):
Professor Keith G Harding, Cardiff University

Study Type Interventional
Study Design Allocation: Randomized;   Intervention Model: Parallel Assignment;   Masking: Single (Outcomes Assessor);   Primary Purpose: Treatment
Condition Varicose Ulcer
Interventions Device: MIST ultrasound therapy
Other: Standard Care
Enrollment 47
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40% in the first 4 weeks were withdrawn and did not progress to random allocation.
Arm/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description 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. 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.
Period Title: 4 Week run-in Phase
Started 47 0
Completed 36 0
Not Completed 11 0
Reason Not Completed
Withdrawal by Subject             1             0
Adverse Event             1             0
Not eligible             9             0
Period Title: 12 Week Treatment Phase
Started 19 17
Completed 19 17
Not Completed 0 0
Arm/Group Title Standard of Care NLFU and Standard of Care Total
Hide Arm/Group Description 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. 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. Total of all reporting groups
Overall Number of Baseline Participants 19 17 36
Hide Baseline Analysis Population Description
[Not Specified]
Age, Continuous  
Mean (Standard Deviation)
Unit of measure:  Years
Number Analyzed 19 participants 17 participants 36 participants
68.2  (12.2) 70.5  (12.7) 69  (12.0)
Sex: Female, Male  
Measure Type: Count of Participants
Unit of measure:  Participants
Number Analyzed 19 participants 17 participants 36 participants
Female
12
  63.2%
9
  52.9%
21
  58.3%
Male
7
  36.8%
8
  47.1%
15
  41.7%
Region of Enrollment  
Measure Type: Number
Unit of measure:  Participants
United Kingdom Number Analyzed 19 participants 17 participants 36 participants
19 17 36
History of leg ulceration (months)  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 19 participants 17 participants 36 participants
94.7  (83.2) 109.7  (112.2) 101.8  (96.8)
Index ulcer duration (months)  
Mean (Standard Deviation)
Unit of measure:  Months
Number Analyzed 19 participants 17 participants 36 participants
22.3  (18.5) 15.7  (12.0) 19  (16)
Wound size at enrolment (cm^2)  
Mean (Standard Deviation)
Unit of measure:  Cm^2
Number Analyzed 19 participants 17 participants 36 participants
19.4  (14.9) 15.9  (9.9) 17.8  (12.7)
Change in wound size during run-in phase (%)  
Mean (Standard Deviation)
Unit of measure:  Percentage change in wound area
Number Analyzed 19 participants 17 participants 36 participants
-13.0  (25.2) -10.9  (23.9) -12.0  (24.3)
1.Primary Outcome
Title Percentage Change in Wound Area
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 19 17
Mean (Standard Deviation)
Unit of Measure: percentage change in wound area
-39.2  (38.0) -46.6  (38.1)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard of Care, NLFU and Standard of Care
Comments 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.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.565
Comments ANCOVA was used to analyse differences between the NLFU+SOC and SOC arms of the primary endpoint, percentage change in wound area from baseline (week 5) to final visit (week 13). Patients’ baseline (week 5) wound area was used as the covariate.
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -7.4
Confidence Interval (2-Sided) 95%
-33.4 to 18.6
Estimation Comments [Not Specified]
2.Primary Outcome
Title Actual Change in Wound Area
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
As previous
Arm/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 19 17
Mean (Standard Deviation)
Unit of Measure: cm2
-5.3  (5.5) -6.2  (5.5)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard of Care, NLFU and Standard of Care
Comments [Not Specified]
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.618
Comments [Not Specified]
Method ANCOVA
Comments Patients’ baseline (week 5) wound area was used as the covariate.
Method of Estimation Estimation Parameter Mean Difference (Final Values)
Estimated Value -0.9
Confidence Interval (2-Sided) 95%
-4.7 to 2.9
Estimation Comments [Not Specified]
3.Secondary Outcome
Title Change in Overall Health Related Quality of Life (HRQoL) From Week 1 (Start) and Week 13 (Exit)
Hide Description

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)
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients were analysed by ITT
Arm/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 19 17
Median (Inter-Quartile Range)
Unit of Measure: units on a scale
0
(-1 to 1)
-1
(-2 to 2)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard of Care, NLFU and Standard of Care
Comments ANCOVA was used for change in HRQoL from week 1 to week 13 (with week 1 HRQoL score as the covariate).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.490
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
4.Secondary Outcome
Title Change in Ulcer Pain Between Week 5 (Randomisation) and Week 13 (Exit)
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 19 17
Mean (Standard Deviation)
Unit of Measure: scores on a scale
-5.27  (14.84) -14.35  (14.85)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard of Care, NLFU and Standard of Care
Comments ANCOVA was used for change in pain score (VAS) from week 5 to week 13 (covariate was baseline pain score).
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.078
Comments [Not Specified]
Method ANCOVA
Comments [Not Specified]
Method of Estimation Estimation Parameter Mean Difference (Net)
Estimated Value -9.08
Confidence Interval (2-Sided) 95%
-19.23 to 1.06
Estimation Comments [Not Specified]
5.Secondary Outcome
Title Incidence of Wound Infection
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
All patients included; ITT.
Arm/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 19 17
Median (Inter-Quartile Range)
Unit of Measure: Number of infections per patient
2
(1 to 3)
2
(0 to 3)
Show Statistical Analysis 1 Hide Statistical Analysis 1
Statistical Analysis Overview Comparison Group Selection Standard of Care, NLFU and Standard of Care
Comments Change in number of infections were not normally distributed and differences between the arms were tested using the non-parametric Mann-Whitney U test.
Type of Statistical Test Superiority or Other
Comments [Not Specified]
Statistical Test of Hypothesis P-Value 0.346
Comments [Not Specified]
Method Wilcoxon (Mann-Whitney)
Comments [Not Specified]
6.Secondary Outcome
Title Number of Non-serious Adverse Events in Each Group
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
[Not Specified]
Arm/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 19 17
Measure Type: Number
Unit of Measure: Number of non-serious AEs
70 59
7.Secondary Outcome
Title Wound Recurrence Rate
Hide Description 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
Show Outcome Measure DataHide Outcome Measure Data
Hide Analysis Population Description
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/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description:
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.
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.
Overall Number of Participants Analyzed 1 2
Measure Type: Number
Unit of Measure: Number of wounds remained healed
1 2
Time Frame Study period of 13 weeks
Adverse Event Reporting Description Any undesirable clinical occurrence in a subject whether it is thought to be related to the NLFU or not. All subjects experiencing AEs were monitored until symptoms subside or until there is a satisfactory explanation for the changes observed. The nature of venous leg ulcers meant that AEs were common in both the SOC and NLFU groups
 
Arm/Group Title Standard of Care NLFU and Standard of Care
Hide Arm/Group Description 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. 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.
All-Cause Mortality
Standard of Care NLFU and Standard of Care
Affected / at Risk (%) Affected / at Risk (%)
Total   --/--   --/-- 
Show Serious Adverse Events Hide Serious Adverse Events
Standard of Care NLFU and Standard of Care
Affected / at Risk (%) Affected / at Risk (%)
Total   0/19 (0.00%)   0/17 (0.00%) 
Show Other (Not Including Serious) Adverse Events Hide Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events 0%
Standard of Care NLFU and Standard of Care
Affected / at Risk (%) Affected / at Risk (%)
Total   19/19 (100.00%)   15/17 (88.24%) 
General disorders     
All adverse events  [1]  19/19 (100.00%)  15/17 (88.24%) 
Indicates events were collected by systematic assessment
[1]
Any undesirable clinical occurrence in a subject whether it is thought to be related to device or not. The recording of adverse events means that specific AE terms cannot be included. See outcome relating to infection.

Difference in treatment frequency between the groups which could potentially bias results.

Standard deviation proved to be larger than estimated from the available literature which resulted in the study having reduced statistical power.

Certain Agreements
All Principal Investigators ARE employed by the organization sponsoring the study.
Results Point of Contact
Name/Title: Dr Judith White
Organization: Cardiff and Vale University Health Board
Phone: 02920744771
Responsible Party: Professor Keith G Harding, Cardiff University
ClinicalTrials.gov Identifier: NCT01671748     History of Changes
Other Study ID Numbers: 12-SUR-5323
First Submitted: August 21, 2012
First Posted: August 24, 2012
Results First Submitted: June 4, 2015
Results First Posted: August 26, 2015
Last Update Posted: August 26, 2015