Effects of Non Contact Low Frequency Ultrasound in Healing Venous Leg Ulcers

• Sponsor: Celleration, Inc. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT01549860
• Collaborator: (none)
• Enrollment: 156
• Location: 1
• Arms: 2
• Duration (Months): 36
• Patients Per Site Per Month: 4.3

Study Details

Study Description

Brief Summary

This trial is a prospective, randomized, controlled, multi-center study of subjects presenting with chronic lower extremity venous ulcers. The study will evaluate the safety and effectiveness of MIST Therapy® plus standard of care (MIST+SOC) compared to Standard of Care (SOC) alone in the treatment of lower extremity venous ulcers.

Condition or Disease	Intervention/Treatment	Phase
Venous Insufficiency; Venous Reflux; Lower Extremity Ulcer	Device: MIST Therapy	N/A

Detailed Description

The study compared the treatment effect of non-contact low frequency ultrasound in addition to standard of care versus standard of care alone in healing chronic venous leg ulcers in subjects who had documented venous stasis and reflux. Subjects that were screened and met the major inclusion criteria received standardized treatment of 30 to 40 mmHg compression, moist wound healing dressings, and debridement for a two week run-in period. If their study ulcer did not decreased by greater than 30% they were eligible for randomization. The primary endpoint was wound area reduction after four (4) weeks of study treatment. The study was performed at 22 study centers. The study included two sub-studies: fluid and tissue analysis and a wound recidivism registry that are ongoing.

Study Design

• Study Type: Interventional
• Actual Enrollment: 156 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Single (Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: IN-BALANCE VLU Inflammation, Bacteria, & Angiogenesis Effects in Launching Venous Leg Ulcer Healing
• Study Start Date: Apr 1, 2012
• Actual Primary Completion Date: May 1, 2014
• Actual Study Completion Date: Apr 1, 2015

Arms and Interventions

Arm	Intervention/Treatment
No Intervention: Standard of Care 30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed. Minimum of one treatment per week and up to 3 times per week per investigator discretion for 4 weeks
Experimental: SOC + Mist Therapy 30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed plus non-contract low frequency ultrasound 3 x per week for 4 weeks.	Device: MIST Therapy; Non-contact low frequency ultrasound therapy

Outcome Measures

Primary Outcome Measures

1. Wound Area Mean Percent Reduction [4 weeks post baseline visit (randomization visit)]

   Compare between the treatment groups percent wound area reduction at four weeks of study treatment. H0: µMIST+SC -- µSC = 0 HA: µMIST+SC -- µSC ≠ 0 Where µ = percent reduction in wound size.

Secondary Outcome Measures

1. Heal Rates [12 weeks post randomization]

   Compare rate of wound closure between study arms for 12 weeks post randomization. Descriptive statistics as not a powered endpoint.

2. Change in Pain VAS Scores [Baseline, 2 weeks and 4 weeks post randomization]

   Compare VAS Pain Scores between arms at baseline and 4 weeks post randomization Subjects indicate their pain level by drawing a mark on a 10 cm line on a visual analog scale (VAS) at randomization and 4 week post treatment visit. The left end of the line indicates "no pain" and the right end of line indicates "worst pain imaginable". VAS score is determined by using a ruler placed at 0 (left end of scale) and measuring the distance from zero to the patient's mark . The objective is to compare the change in VAS values in MIST+SC to SC alone. H0: The average change in pain level is not different between MIST and SC HA: The average change in pain level is different between MIST and SC H0: µMIST = µSC vs HA: µMIST ≠ µSC, Statistical Analysis. A repeated measures ANCOVA will be used to test for differences in change in VAS with an indicator variable to indicate treatment, any demographic variables which were significant in the baseline comparisons.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years to 90 Years
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Lower extremity full thickness venous ulcer of > 30 days duration

• Subject's wound must be between 4 cm² and 50 cm² at screening

• Documented ABI that is between 0.8 and 1.2 on the study limb or transcutaneous partial pressure oxygen (TcpO2) > 40 mmHG; or a toe pressure > 40 mmHG; or a Doppler waveform consistent with adequate flow in the foot (biphasic or triphasic waveforms) at time of screening

• Biopsy for wounds > 6 months duration

• Documented index wound etiology of venous stasis with reflux and /or incompetent valves

Exclusion Criteria:

• Index ulcer wound that is less than 1 cm in distance from another ulcer wound

• 5 ulcers on the index leg

• Index ulcer wound has exposed tendons, ligaments, muscle, or bone

• Index ulcer wound presents with clinical signs of acute infection, suspected or known

• Subjects with evidence of osteomyelitis or cellulitis or gangrene in the study limb

• Subjects with amputation above a Trans Metatarsal Amputation (TMA) in the study limb

• Subjects with active malignancy on the study limb except non-melanoma skin cancer

• Index ulcer that is of arterial disease etiology

• Index ulcer of other primary etiology (ie. vasculitis, arterial, pyoderma)

• Subjects with planned vascular surgery, angioplasty or thrombolysis procedures within the study treatment phase

• Subjects with planned surgical procedure during the study treatment phase for the index wound including skin flap or skin graft

• Subjects within 6 weeks postoperatively of a vascular o skin graft procedure.

• Subject has had prior skin replacement, negative pressure therapy, or traditional ultrasound therapy applied to the index wound in the 14 days prior to screening

• Subject has had ultrasound treatment (including MIST Therapy) of the index wound.

• Subject has received growth factor therapy (e.g., autologous platelet-rich plasma gel, becaplermin, bilayered cell therapy, dermal substitute, extracellular matrix) within 14 days of screening date.

• Subject is currently receiving or has received radiation or chemotherapy within 3 months of randomization.

• Female subjects that are pregnant or refuse to utilize adequate contraceptive methods and are of childbearing age during the trial.

• Subject has one or more medical condition(s), uncontrolled diabetes (i.e. HbA1c > 12), renal, hepatic, hematologic, neurologic, or immune disease that in the opinion of the investigator would make the subject an inappropriate study candidate

• Subject's wound would require ultrasound near an electronic implant or prosthesis

• Subject is known to be suffering from a disorder or other situation that the subject or investigator feels would interfere with compliance or other study requirements

• Subject is currently enrolled or has been enrolled in the last 30 days in another investigational device or drug trial

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	South Shore Hospital	Weymouth	Massachusetts	United States	02189

Sponsors and Collaborators

• Celleration, Inc.

Investigators

• Principal Investigator: Gary Gibbons, MD, South Shore Hospital
• Principal Investigator: Vicki Driver, DPM, Providence RI

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: Celleration, Inc.
• ClinicalTrials.gov Identifier: NCT01549860
• Other Study ID Numbers: IN-BALANCE VLU
• First Posted: Mar 9, 2012
• Last Update Posted: Jul 30, 2015
• Last Verified: Jul 1, 2015

• Keywords provided by Celleration, Inc.: Venous Insufficiency; Reflux; Lower Extremity Ulcer
• Additional relevant MeSH terms: Varicose Ulcer; Venous Insufficiency; Leg Ulcer; Ulcer

Study Results

Participant Flow

Pre-assignment Detail	156 subjects were consented for the study, 112 subjects met the major inclusion/exclusion criteria (study cohort), 81 subject were randomized (reduced <30% during run-in period).

Arm/Group Title	Standard Care (SC)	SC + Mist Therapy
Arm/Group Description	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed. Minimum of one treatment per week and up to 3 times per week per investigator discretion for 4 weeks	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed plus non-contract low frequency ultrasound 3 x per week for 4 weeks. MIST Therapy: Non-contact low frequency ultrasound therapy
Period Title: Overall Study
STARTED	40	41
COMPLETED	38	40
NOT COMPLETED	2	1

Baseline Characteristics

Arm/Group Title	Standard Care (SC)	SC + Mist Therapy	Total
Arm/Group Description	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed. Minimum of one treatment per week and up to 3 times per week per investigator discretion for 4 weeks	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed plus non-contract low frequency ultrasound 3 x per week for 4 weeks. MIST Therapy: Non-contact low frequency ultrasound therapy	Total of all reporting groups
Overall Participants	40	41	81
Age (years) [Median (Full Range) ]
Median (Full Range) [years]	60.0	58.0	59.0
Sex: Female, Male (Count of Participants)
Female	11 27.5%	13 31.7%	24 29.6%
Male	29 72.5%	28 68.3%	57 70.4%
Race (NIH/OMB) (Count of Participants)
American Indian or Alaska Native	0 0%	0 0%	0 0%
Asian	0 0%	0 0%	0 0%
Native Hawaiian or Other Pacific Islander	0 0%	0 0%	0 0%
Black or African American	11 27.5%	13 31.7%	24 29.6%
White	24 60%	22 53.7%	46 56.8%
More than one race	5 12.5%	6 14.6%	11 13.6%
Unknown or Not Reported	0 0%	0 0%	0 0%
Region of Enrollment (participants) [Number]
United States	40 100%	41 100%	81 100%
BMI (kg per meter squared) [Median (Full Range) ]
Median (Full Range) [kg per meter squared]	33.2	37.4	34.7
Wound Age at Randomization (months) [Median (Full Range) ]
Median (Full Range) [months]	8.9	10.3	10.3
Wound Area at Randomization (centimeters squared) [Median (Full Range) ]
Median (Full Range) [centimeters squared]	9.8	12.4	11.0

Outcome Measures

1. Primary Outcome

Title	Wound Area Mean Percent Reduction
Description	Compare between the treatment groups percent wound area reduction at four weeks of study treatment. H0: µMIST+SC -- µSC = 0 HA: µMIST+SC -- µSC ≠ 0 Where µ = percent reduction in wound size.
Time Frame	4 weeks post baseline visit (randomization visit)

Outcome Measure Data

Analysis Population Description

eligible subjects that were randomized

Arm/Group Title	Standard Care (SC)	SC + Mist Therapy
Arm/Group Description	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed. Minimum of one treatment per week and up to 3 times per week per investigator discretion for 4 weeks	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed plus non-contract low frequency ultrasound 3 x per week for 4 weeks. MIST Therapy: Non-contact low frequency ultrasound therapy
Measure Participants	40	41
Mean (Standard Deviation) [percentage of mean area reduction]	45.8 (32.5)	61.6 (28.9)

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard Care (SC), SC + Mist Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.024
	Comments
	Method	t-test, 2 sided
	Comments

2. Secondary Outcome

Title	Heal Rates
Description	Compare rate of wound closure between study arms for 12 weeks post randomization. Descriptive statistics as not a powered endpoint.
Time Frame	12 weeks post randomization

Outcome Measure Data

Analysis Population Description

Eligible subjects randomized

Arm/Group Title	Standard Care (SC)	SC + Mist Therapy
Arm/Group Description	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed. Minimum of one treatment per week and up to 3 times per week per investigator discretion for 4 weeks	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed plus non-contract low frequency ultrasound 3 x per week for 4 weeks. MIST Therapy: Non-contact low frequency ultrasound therapy
Measure Participants	40	41
Number [participants]	10 25%	16 39%

3. Secondary Outcome

Title	Change in Pain VAS Scores
Description	Compare VAS Pain Scores between arms at baseline and 4 weeks post randomization Subjects indicate their pain level by drawing a mark on a 10 cm line on a visual analog scale (VAS) at randomization and 4 week post treatment visit. The left end of the line indicates "no pain" and the right end of line indicates "worst pain imaginable". VAS score is determined by using a ruler placed at 0 (left end of scale) and measuring the distance from zero to the patient's mark . The objective is to compare the change in VAS values in MIST+SC to SC alone. H0: The average change in pain level is not different between MIST and SC HA: The average change in pain level is different between MIST and SC H0: µMIST = µSC vs HA: µMIST ≠ µSC, Statistical Analysis. A repeated measures ANCOVA will be used to test for differences in change in VAS with an indicator variable to indicate treatment, any demographic variables which were significant in the baseline comparisons.
Time Frame	Baseline, 2 weeks and 4 weeks post randomization

Outcome Measure Data

Analysis Population Description

Eligible Subjects Randomized

Arm/Group Title	Standard Care (SC)	SC + Mist Therapy
Arm/Group Description	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed. Minimum of one treatment per week and up to 3 times per week per investigator discretion for 4 weeks	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed plus non-contract low frequency ultrasound 3 x per week for 4 weeks. MIST Therapy: Non-contact low frequency ultrasound therapy
Measure Participants	40	41
Randomization (baseline) VAS Score	3.0	3.0
4 Week post-randomizaton VAS Score	2.4	0.6

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Standard Care (SC), SC + Mist Therapy
	Comments
	Type of Statistical Test	Superiority or Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0126
	Comments	The MIST+SOC subjects decreased in their reported mean pain scores and reduced from a median of 3.0 to 0.6 cm after four weeks of study treatment.
	Method	ANCOVA
	Comments

Adverse Events

Time Frame	Throughout 12 week study
Adverse Event Reporting Description	Only device or study procedure related adverse events were collected in this post market study
Arm/Group Title	Standard Care (SC)		SC + Mist Therapy
Arm/Group Description	30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed. Minimum of one treatment per week and up to 3 times per week per investigator discretion for 4 weeks		30 to 40 mmHg compression, dressing for moist wound healing environment, debridement as needed plus non-contract low frequency ultrasound 3 x per week for 4 weeks. MIST Therapy: Non-contact low frequency ultrasound therapy
All Cause Mortality
	Standard Care (SC)		SC + Mist Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Standard Care (SC)		SC + Mist Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/41 (0%)
Other (Not Including Serious) Adverse Events
	Standard Care (SC)		SC + Mist Therapy
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/40 (0%)		0/41 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.