Venous Insufficiency, Venous Reflux, Lower Extremity Ulcer
Conditions
Keywords
Venous Insufficiency, Reflux, Lower Extremity Ulcer
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.
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.
Interventions
DEVICEMIST Therapy
Non-contact low frequency ultrasound therapy
Sponsors
Celleration, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
18 Years to 90 Years
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| 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
| Measure | Time frame | Description |
|---|---|---|
| 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. |
| 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. |
Countries
United States
Participant flow
Pre-assignment details
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).
Participants by arm
| Arm | Count |
|---|---|
| Standard Care (SC) 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 | 40 |
| SC + 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.
MIST Therapy: Non-contact low frequency ultrasound therapy | 41 |
| Total | 81 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Physician Decision | 1 | 1 |
| Overall Study | Withdrawal by Subject | 1 | 0 |
Baseline characteristics
| Characteristic | SC + Mist Therapy | Total | Standard Care (SC) |
|---|---|---|---|
| Age, Continuous | 58.0 years | 59.0 years | 60.0 years |
| BMI | 37.4 kg per meter squared | 34.7 kg per meter squared | 33.2 kg per meter squared |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Black or African American | 13 Participants | 24 Participants | 11 Participants |
| Race (NIH/OMB) More than one race | 6 Participants | 11 Participants | 5 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) White | 22 Participants | 46 Participants | 24 Participants |
| Region of Enrollment United States | 41 participants | 81 participants | 40 participants |
| Sex: Female, Male Female | 13 Participants | 24 Participants | 11 Participants |
| Sex: Female, Male Male | 28 Participants | 57 Participants | 29 Participants |
| Wound Age at Randomization | 10.3 months | 10.3 months | 8.9 months |
| Wound Area at Randomization | 12.4 centimeters squared | 11.0 centimeters squared | 9.8 centimeters squared |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 0 / 40 | 0 / 41 |
| serious Total, serious adverse events | 0 / 40 | 0 / 41 |
Outcome results
Primary
Wound Area Mean Percent Reduction
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)
Population: eligible subjects that were randomized
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Standard Care (SC) | Wound Area Mean Percent Reduction | 45.8 percentage of mean area reduction | Standard Deviation 32.5 |
| SC + Mist Therapy | Wound Area Mean Percent Reduction | 61.6 percentage of mean area reduction | Standard Deviation 28.9 |
p-value: <0.024t-test, 2 sided
Secondary
Change in Pain VAS Scores
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
Population: Eligible Subjects Randomized
| Arm | Measure | Group | Value (MEDIAN) |
|---|---|---|---|
| Standard Care (SC) | Change in Pain VAS Scores | Randomization (baseline) VAS Score | 3.0 VAS pain level measured in centimeters |
| Standard Care (SC) | Change in Pain VAS Scores | 4 Week post-randomizaton VAS Score | 2.4 VAS pain level measured in centimeters |
| SC + Mist Therapy | Change in Pain VAS Scores | Randomization (baseline) VAS Score | 3.0 VAS pain level measured in centimeters |
| SC + Mist Therapy | Change in Pain VAS Scores | 4 Week post-randomizaton VAS Score | 0.6 VAS pain level measured in centimeters |
p-value: <0.0126ANCOVA
Secondary
Heal Rates
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
Population: Eligible subjects randomized
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Standard Care (SC) | Heal Rates | 10 participants |
| SC + Mist Therapy | Heal Rates | 16 participants |