Diabetic Foot Ulcer
Conditions
Brief summary
The purpose of this study is to evaluate the efficacy, safety and economical benefits of Cyclical Pressure Topical Wound Oxygen (TWO2) Therapy in the treatment of chronic diabetic foot ulcers. Subjects will wear a standardized off-loading device and use advanced moist wound therapy (AMWT) dressings. Following a 2 week run-in period with the standardized care and after meeting all the eligibility criteria, half the subjects will use the TWO2 device, while the other half will use a sham device.
Detailed description
Subjects meeting the initial eligibility criteria will enter a 2 week run-in period with a standardized off-loading device, advanced moist wound therapy (AMWT) dressings and will receive sharp debridement. Subjects with wounds that do not decrease more than 30% at the end of the 2 week run-in period and where all other eligibility criteria are met, will be randomized to either the TWO2 device arm, or sham (placebo) device arm. All subjects will use the TWO2/Sham device for 90 minutes a day at their home or nursing care facility 5 times a week for the treatment phase of up to 12 weeks. Monitoring of the wound will take place with weekly clinic visits for safety and compliance assessment and documentation. Weekly wound photographs and measurements will be taken. Wounds that close at, or before, 12 weeks will continue to use TWO2/sham device, off-loading and AMWT and have an additional visit two weeks later to confirm wound closure. All subjects whether healed or not will enter a follow up period of an additional 12 and 38 weeks. The maximum duration for participation in the trial is 54 weeks. During the follow-up phase, subjects will receive standard care according to the clinician's recommendation and will be asked not to participate in another wound care trial during this period.
Interventions
DEVICETWO2 Device
Application of the Topical Wound Oxygen (TWO2) device that supplies cyclical oxygen pressure directly to the wound site within a sealed and humidified environment for 90 minutes, 5 times a week with AMWT dressings.
DEVICEPlacebo Device
Application of placebo device that does not supply cyclical oxygen pressure directly to the wound site within a sealed and humidified environment for 90 minutes, 5 times a week with AMWT dressings.
Sponsors
AOTI Ltd.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Intervention model description
Group Sequential Design of a maximum of 220 subjects with two predetermined interim analyses at 73 and 146 subjects
Eligibility
Sex/Gender
ALL
Age
18 Years to 89 Years
Healthy volunteers
No
Inclusion criteria
* Subject has a documented diagnosis of Diabetes mellitus Type 1 or 2 * Foot ulcer at or below ankle with duration of more than 4 weeks but no longer than 1 year * If the index ulcer is a post amputation wound date of surgery must be \> 30 days * 2 week run in period with less than 30% wound size reduction * University of Texas Grade 1A, 1B, 1C, 1D, 2A, 2B, 2C, or 2D (Appendix I) * Ulcer is ≥ 1cm2 and ≤ 20cm2 after debridement at start of run-in period * If more than one ulcer is present on the foot, only the largest is considered in the study (Index ulcer) * Index ulcer must be ≥ 1cm away from any other ulcers present on the foot * Adequate perfusion with ABI \> 0.7 And TcpO2 \> 30mmHg OR skin perfusion \> 30mmHG OR Toe pressure \> 30mmHg OR Duplex with biphasic waveforms below the knee * No planned revascularization procedure or vascular surgery within the last/next 30 days * Subject and/or caregiver are willing and able to comply with all specified care and visit requirements * Subject has a reasonable expectation of completing the study; according to the Investigator's clinical judgment
Exclusion criteria
* Evidence of gangrene on any part of affected limb * Documented evidence of osteomyelitis on any part of affected limb * Index ulcer has exposed bone * Index ulcer exhibits signs of severe clinical infection that requires hospitalization or immediate surgical intervention * Active Charcot foot on the study limb * Subject participated in another investigational device, drug or biological trial within last 30 days * Uncontrolled diabetes: HbA1c \> 12 % * Renal dialysis or creatinine \> 2.5 * Known immune insufficiency * Chronic steroid use or immunosuppressive agents within the last three (3) months or is anticipated to require them during the course of the study * Active treatment for malignancy (not specific to study limb) * Patient has a Deep Vein Thrombosis within the last 30 days * Subject has received growth factor therapy (e.g., autologous platelet-rich plasma gel, becaplermin, bilayered cell therapy, dermal substitute, extracellular matrix) within the screening period * Subject may not be pregnant at the time of treatment
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Wound Closure Within 12 Weeks With the Use of Topical Wound Oxygen Therapy (TWO2) | 12 weeks | Number of Participants with complete wound closure defined as 100% skin re-epithelialization without dressing requirements which is confirmed by 2 consecutive study visits 2 weeks apart. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Ulcer Recurrence | 12 months | Number of diabetic foot ulcers with recurrence at 12 months |
| Number of Amputation Events | 12 weeks | Number of amputation events during interventional period of the study. |
| Incidence of Adverse Events | 54 weeks | Incidence of serious adverse events and adverse events |
| Absolute Change in Ulcer Area | 12 weeks | Absolute change in ulcer area over 12 weeks in cm2 |
| Quality of Life Assessment | 12 weeks | The Cardiff Wound Impact Schedule questionnaire to measure quality of life. Measure of well-being items from each scale are summated, physical symptoms, everyday living and social life. The items are rated for the extent of the experience and each item is given a number value. This allows the patients to weight the items included in the scale. The well-being scale is scored on a 5-point Likert scale, with response options from 'strongly agree' to 'strongly disagree'. All three scales are then transformed onto a minimum = 0 up to a maximum = 100, where a low score indicates worse, and a high score indicates better feeling of well-being. |
| Time to Complete Wound Closure in Weeks | 12 weeks or wound closure | Time to 100% wound closure utilizing Cox proportional hazards model, a statistical measure of difference of time to event (healing). Subjects who withdraw from treatment will be entered into the analysis and censored at the time they withdraw from the trial or are lost to follow up. The analysis will consider covariates that might influence the outcome in the trial. |
| Economic Analysis | 12 weeks | Not performed or reported. Economic Analysis is a composite measure of the wound before the study (up to one year) and for the duration of the study. The assessment is obtained by documenting treatment history of the wound that includes types of dressings used, time taken for dressing changes, by whom dressings are changed, and type and duration of hospitalization as well as the administration of the EQ-5D questionnaire at the Baseline visit, weeks 4, 8 and 12 on treatment. |
Countries
France, Germany, Luxembourg, United Kingdom, United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Topical Wound Oxygen Device Application of the Topical Wound Oxygen (TWO2) device that supplies cyclical oxygen pressure directly to the wound site within a sealed and humidified environment for 90 minutes, 5 times a week with Advanced Moist Wound Therapy (AMWT) dressings.
Other Names:
* Topical Wound Oxygen Therapy
* TWO2
TWO2 Device: Application of the Topical Wound Oxygen (TWO2) device that supplies cyclical oxygen pressure directly to the wound site within a sealed and humidified environment for 90 minutes, 5 times a week with AMWT dressings. | 36 |
| Placebo Device Application of placebo device that does not supply cyclical oxygen pressure directly to the wound site within a sealed and humidified environment for 90 minutes, 5 times a week with AMWT dressings.
Placebo Device: Application of placebo device that does not supply cyclical oxygen pressure directly to the wound site within a sealed and humidified environment for 90 minutes, 5 times a week with AMWT dressings. | 37 |
| Total | 73 |
Baseline characteristics
| Characteristic | Topical Wound Oxygen Device | Total | Placebo Device |
|---|---|---|---|
| Age, Continuous | 64.6 years STANDARD_DEVIATION 10.3 | 63.3 years STANDARD_DEVIATION 9.9 | 61.9 years STANDARD_DEVIATION 9.5 |
| Ankle brachial index, ratio (SD) | 1.07 Ratio STANDARD_DEVIATION 0.23 | 1.03 Ratio STANDARD_DEVIATION 0.23 | 1.00 Ratio STANDARD_DEVIATION 0.23 |
| BMI | 30.8 Kg/m^2 STANDARD_DEVIATION 5.9 | 31 Kg/m^2 STANDARD_DEVIATION 6.8 | 31.2 Kg/m^2 STANDARD_DEVIATION 7.6 |
| Diabetes Type 2 | 32 Participants | 65 Participants | 33 Participants |
| HbA1c, % (SD) | 8.43 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.75 | 8.25 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.64 | 8.14 Percentage of glycosylated hemoglobin STANDARD_DEVIATION 1.49 |
| Neuropathic foot | 28 Participants | 57 Participants | 29 Participants |
| Race/Ethnicity, Customized American Indian | 0 Participants | 1 Participants | 1 Participants |
| Race/Ethnicity, Customized Asian | 2 Participants | 3 Participants | 1 Participants |
| Race/Ethnicity, Customized Black | 5 Participants | 10 Participants | 5 Participants |
| Race/Ethnicity, Customized Not reported | 3 Participants | 9 Participants | 6 Participants |
| Race/Ethnicity, Customized White/Hispanic | 26 Participants | 50 Participants | 24 Participants |
| Sex: Female, Male Female | 4 Participants | 10 Participants | 6 Participants |
| Sex: Female, Male Male | 32 Participants | 63 Participants | 31 Participants |
| Smoker | 13 Participants | 23 Participants | 10 Participants |
| The University of Texas Staging System for Diabetic Foot Ulcers Grade I | 22 Participants | 53 Participants | 31 Participants |
| The University of Texas Staging System for Diabetic Foot Ulcers Grade II | 14 Participants | 20 Participants | 6 Participants |
| Ulcer duration (days) | 160.3 Days STANDARD_DEVIATION 96 | 166.4 Days STANDARD_DEVIATION 95 | 174.6 Days STANDARD_DEVIATION 94 |
| Wound area (cm2) | 3.02 cm^2 STANDARD_DEVIATION 2.66 | 3.13 cm^2 STANDARD_DEVIATION 2.57 | 3.22 cm^2 STANDARD_DEVIATION 2.54 |
| Wound perimeter (cm) | 6.22 cm STANDARD_DEVIATION 2.85 | 6.54 cm STANDARD_DEVIATION 3.55 | 6.85 cm STANDARD_DEVIATION 4.18 |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 2 / 36 | 2 / 37 |
| other Total, other adverse events | 6 / 36 | 7 / 37 |
| serious Total, serious adverse events | 6 / 36 | 7 / 37 |
Outcome results
Primary
Wound Closure Within 12 Weeks With the Use of Topical Wound Oxygen Therapy (TWO2)
Number of Participants with complete wound closure defined as 100% skin re-epithelialization without dressing requirements which is confirmed by 2 consecutive study visits 2 weeks apart.
Time frame: 12 weeks
Population: Patients with diabetic foot ulcers
| Arm | Measure | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|
| Topical Wound Oxygen Device | Wound Closure Within 12 Weeks With the Use of Topical Wound Oxygen Therapy (TWO2) | 15 Participants |
| Placebo Device | Wound Closure Within 12 Weeks With the Use of Topical Wound Oxygen Therapy (TWO2) | 5 Participants |
Secondary
Absolute Change in Ulcer Area
Absolute change in ulcer area over 12 weeks in cm2
Time frame: 12 weeks
Population: Patients with open ulcers
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topical Wound Oxygen Device | Absolute Change in Ulcer Area | 1.97 cm2 | Standard Deviation 2.12 |
| Placebo Device | Absolute Change in Ulcer Area | .4 cm2 | Standard Deviation 0.041 |
Secondary
Economic Analysis
Not performed or reported. Economic Analysis is a composite measure of the wound before the study (up to one year) and for the duration of the study. The assessment is obtained by documenting treatment history of the wound that includes types of dressings used, time taken for dressing changes, by whom dressings are changed, and type and duration of hospitalization as well as the administration of the EQ-5D questionnaire at the Baseline visit, weeks 4, 8 and 12 on treatment.
Time frame: 12 weeks
Population: Patients with diabetic foot ulcers
Secondary
Incidence of Adverse Events
Incidence of serious adverse events and adverse events
Time frame: 54 weeks
Population: Patients with diabetic foot ulcers
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Topical Wound Oxygen Device | Incidence of Adverse Events | Serious Adverse Events | 10 Count of events |
| Topical Wound Oxygen Device | Incidence of Adverse Events | Adverse Events | 8 Count of events |
| Topical Wound Oxygen Device | Incidence of Adverse Events | Device related death | 0 Count of events |
| Placebo Device | Incidence of Adverse Events | Serious Adverse Events | 10 Count of events |
| Placebo Device | Incidence of Adverse Events | Adverse Events | 8 Count of events |
| Placebo Device | Incidence of Adverse Events | Device related death | 0 Count of events |
Secondary
Number of Amputation Events
Number of amputation events during interventional period of the study.
Time frame: 12 weeks
Population: Patients with Index limb amputations
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Topical Wound Oxygen Device | Number of Amputation Events | 2 Count of events |
| Placebo Device | Number of Amputation Events | 3 Count of events |
Secondary
Quality of Life Assessment
The Cardiff Wound Impact Schedule questionnaire to measure quality of life. Measure of well-being items from each scale are summated, physical symptoms, everyday living and social life. The items are rated for the extent of the experience and each item is given a number value. This allows the patients to weight the items included in the scale. The well-being scale is scored on a 5-point Likert scale, with response options from 'strongly agree' to 'strongly disagree'. All three scales are then transformed onto a minimum = 0 up to a maximum = 100, where a low score indicates worse, and a high score indicates better feeling of well-being.
Time frame: 12 weeks
Population: Study participants with open and healed ulcers.
| Arm | Measure | Value (MEDIAN) | Dispersion |
|---|---|---|---|
| Topical Wound Oxygen Device | Quality of Life Assessment | 9.1 units on a scale | Standard Deviation 13.9 |
| Placebo Device | Quality of Life Assessment | 0.1 units on a scale | Standard Deviation 16.9 |
Secondary
Time to Complete Wound Closure in Weeks
Time to 100% wound closure utilizing Cox proportional hazards model, a statistical measure of difference of time to event (healing). Subjects who withdraw from treatment will be entered into the analysis and censored at the time they withdraw from the trial or are lost to follow up. The analysis will consider covariates that might influence the outcome in the trial.
Time frame: 12 weeks or wound closure
Population: Time to complete wound closure, weeks.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Topical Wound Oxygen Device | Time to Complete Wound Closure in Weeks | 8.2 Weeks | Standard Deviation 1.9 |
| Placebo Device | Time to Complete Wound Closure in Weeks | 6.3 Weeks | Standard Deviation 4.2 |
Secondary
Ulcer Recurrence
Number of diabetic foot ulcers with recurrence at 12 months
Time frame: 12 months
Population: Patient with closed diabetic foot ulcers
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Topical Wound Oxygen Device | Ulcer Recurrence | 1 Count of wounds with recurrence |
| Placebo Device | Ulcer Recurrence | 2 Count of wounds with recurrence |