Diabetic Foot UlcerTWO2DFUNCT02326337
Efficacy, Safety and Economic Benefits of Topical Wound Oxygen Therapy in the Treatment of Chronic Diabetic Foot Ulcers
A study testing TWO2 Device in people with Diabetic Foot Ulcer, run by AOTI Ltd. at 17 sites in 5 countries.
Trial 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. Read more about this study
- Who is it for?
- Ages 18 to 89 years
- Conditions the study is for
- Diabetic Foot Ulcer
- What is being tested?
- TWO2 Device
- Type of treatment
- Medical device
- Could I receive a placebo?
- Yes, some participants may receive a placebo
- How many people
- 73 participants
- Where
- 17 sitesin 5 countries
- Study dates
- Oct 2014to 25 Oct 2018
- Phase
- Interventional
- Are there results?
- Yes, posted in the registrySummary in the doctors' view
Key requirements
Who can take part, as listed by the sponsor. Only the study team can confirm whether you are eligible, so take this list to your doctor.
- Ages 18 to 89 years
- All sexes
- No healthy volunteers
- Adult, Older adult
Who may be able to join
- 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
Show all 12Show fewer
- 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
Who cannot join
- 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
Show all 14Show fewer
- 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
Trial locations and contacts
17 sites in 5 countries.
17 sites in 5 countries
United States10 sites
Edward Hines, Jr. VA Hospital
Chicago, Illinois, 60141
The Research Center Inc.
Hialeah, Florida, 33013
Advanced Foot & Ankle Center
Las Vegas, Nevada, 89119
Advanced Research Institute of Miami
Miami, Florida, 33012
Advanced Research Institute of Miami
Miami, Florida, 33134
Carl T. Hayden VA Medical Center
Phoenix, Arizona, 85012
Hunter Holmes McGuire VA Medical Center
Richmond, Virginia, 23249
Salem VA Medical Center
Salem, Virginia, 24153
NorthBay Center for Wounds
Vacaville, California, 95687
Washington DC VA Medical Center
Washington D.C., District of Columbia, 20422
France3 sites
Avicenne Hospital
Bobigny, 93000
Hospital Simone Veil
Eaubonne, 95600
Montpellier University Hospital
Montpellier, 34000
United Kingdom2 sites
Northwick Park Hospital
Harrow, HA1 3UJ
King's College Hospital
London, SE5 9RS
About this study
Official title: A Multi-national, Multi-center, Prospective, Randomized, Double Blinded, Placebo-controlled Trial to Evaluate the Efficacy of HyperBox Cyclical Topical Wound Oxygen Therapy (TWO2) in the Treatment of Chronic Diabetic Foot Ulcers
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.
Read the 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.
- Conditions
- Diabetic Foot Ulcer
- Being tested
- TWO2 Device, Placebo Device
- Medical subject headings
- Diabetic Foot
What participants receive
What participants receive. In a randomised study each person is assigned to one group by chance.
TWO2 DeviceDevice
Also called TWO2 Therapy
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.
Placebo DeviceDevice
Also called Sham Device, Control 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.
| Study group | Role | What they receive |
|---|---|---|
| Topical Wound Oxygen Device | Active comparator | 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 Receives: Device: TWO2 Device |
| Placebo Device | Placebo comparator | 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. Receives: Device: Placebo Device |
What is being measured
The primary outcome is the main question the study is designed to answer.
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.
Measured: 12 weeks
Secondary outcomes (7)
Absolute Change in Ulcer Area
Absolute change in ulcer area over 12 weeks in cm2
Measured: 12 weeks
Ulcer Recurrence
Number of diabetic foot ulcers with recurrence at 12 months
Measured: 12 months
Number of Amputation Events
Number of amputation events during interventional period of the study.
Measured: 12 weeks
Incidence of Adverse Events
Incidence of serious adverse events and adverse events
Measured: 54 weeks
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.
Measured: 12 weeks
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.
Measured: 12 weeks
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.
Measured: 12 weeks or wound closure
Timeline
From the start of the study to its completion; the mark is today. Estimated dates are the sponsor’s plan.
- First posted29 Dec 2014 (estimated)
- Study startOct 2014
- Primary completion5 Feb 2018
- Study completion25 Oct 2018
Resources
- Official record on ClinicalTrials.govThe registry entry this page is built from, with its full change history.
- Posted resultsParticipant flow, outcome measures and adverse events reported by the sponsor.
- Publications (1)Papers the sponsor has linked to this study.
- Other trials for Diabetic Foot UlcerStudies of the same condition, open and under way.
- What the trial phases meanHow a treatment moves from first tests in people to approval.
More details
For doctors and researchers: how the study is designed, who runs it, and its registry IDs.
Study design
- Study type
- Interventional
- Phase
- Phase N/A
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Model description
- Group Sequential Design of a maximum of 220 subjects with two predetermined interim analyses at 73 and 146 subjects
- Masking
- Quadruple blind
- Who is masked
- Participant, Care provider, Investigator, Outcomes assessor
- Enrolment
- 73 participants (actual)
Sponsor and investigators
- Lead sponsor
- AOTI Ltd.
- Sponsor type
- Industry (pharma, biotech, devices)
- Responsible party
- Sponsor
- Investigators
- Robert G Frykberg, DPM, Principal investigator, Carl T. Hayden VA Medical Center
IDs, dates and publications
- ClinicalTrials.gov ID
- NCT02326337
- Sponsor's protocol ID
- AOTI- TWO2DFU-01
- Acronym
- TWO2DFU
- Status last verified
- Oct 2025
- First submitted
- 19 Nov 2014
- Last updated
- 27 Oct 2025
- Results posted
- Yes, on ClinicalTrials.gov
- Data monitoring committee
- Yes
- FDA-regulated drug
- No
- FDA-regulated device
- Yes
Publications
Frykberg RG, Franks PJ, Edmonds M, Brantley JN, Teot L, Wild T, Garoufalis MG, Lee AM, Thompson JA, Reach G, Dove CR, Lachgar K, Grotemeyer D, Renton SC; TWO2 Study Group. A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study. Diabetes Care. 2020 Mar;43(3):616-624. doi: 10.2337/dc19-0476. Epub 2019 Oct 16.
PubMed 31619393
Study at a glance
From the registry record, last updated by the sponsor on 27 Oct 2025. Recruitment status is as the sponsor reported it: confirm with the study team.
- Official title
- A Multi-national, Multi-center, Prospective, Randomized, Double Blinded, Placebo-controlled Trial to Evaluate the Efficacy of HyperBox Cyclical Topical Wound Oxygen Therapy (TWO2) in the Treatment of Chronic Diabetic Foot Ulcers
- ClinicalTrials.gov ID
- NCT02326337
- Acronym / sponsor ID
- TWO2DFU / AOTI- TWO2DFU-01
- Conditions
- Diabetic Foot Ulcer
- Study type
- Interventional
- Recruitment status
- Completed
- Enrolment
- 73 participants (actual)
- Lead sponsor
- AOTI Ltd.Industry (pharma, biotech, devices)
- Study start
- Oct 2014 (actual)
- Primary completion
- 5 Feb 2018 (actual)
- Study completion
- 25 Oct 2018 (actual)
- First posted
- 29 Dec 2014 (estimated)
- Results
- Posted 20 Apr 2025
Clinical summary
The research question as the sponsor registered it. This describes what the study plans to test, not what it found.
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.
Study design
- Primary purpose
- Treatment
- Allocation
- Randomised
- Intervention model
- Parallel groups
- Masking
- Quadruple blind (participant, care provider, investigator, outcomes assessor)
- Number of arms
- 2
- Model description
- Group Sequential Design of a maximum of 220 subjects with two predetermined interim analyses at 73 and 146 subjects
| Arm | Type | Receives |
|---|---|---|
| Topical Wound Oxygen Device | Active comparator | Device: TWO2 DeviceApplication 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 |
| Placebo Device | Placebo comparator | Device: Placebo DeviceApplication 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. |
Who may qualify
- Ages
- 18 to 89 years
- Sex
- All
- Healthy volunteers
- Not accepted
- Age groups
- Adult, Older adult
Key inclusion criteria (12 listed)
- 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)
Key exclusion criteria (14 listed)
- 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
Eligibility is decided by the study team after screening; this overview does not establish that a patient qualifies. Full inclusion and exclusion criteria.
Interventions
| Intervention | Type | Arms |
|---|---|---|
| TWO2 DeviceAlso: TWO2 TherapyApplication 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. | Device | Topical Wound Oxygen Device |
| Placebo DeviceAlso: Sham Device, Control DeviceApplication 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. | Device | Placebo Device |
Primary outcome
Wound Closure Within 12 Weeks With the Use of Topical Wound Oxygen Therapy (TWO2)
Time frame: 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.
7 secondary outcomes
Absolute Change in Ulcer Area
Time frame: 12 weeks
Ulcer Recurrence
Time frame: 12 months
Number of Amputation Events
Time frame: 12 weeks
Incidence of Adverse Events
Time frame: 54 weeks
Quality of Life Assessment
Time frame: 12 weeks
Economic Analysis
Time frame: 12 weeks
Time to Complete Wound Closure in Weeks
Time frame: 12 weeks or wound closure
Results and safety
Loading the posted results from ClinicalTrials.gov…
Research links
- Official record on ClinicalTrials.govLast updated by the sponsor 27 Oct 2025.
- Posted resultsParticipant flow, baseline, all outcome measures and adverse events.
- Results publication: PubMed 31619393Frykberg RG, Franks PJ, Edmonds M, Brantley JN, Teot L, Wild T, Garoufalis MG, Lee AM, Thompson JA, Reach G, Dove CR, Lachgar K, Grotemeyer D, Renton SC; TWO2 Study Group. A Multinational, Multicenter, Randomized, Double-Blinded, Placebo-Controlled Trial to Evaluate the Efficacy of Cyclical Topical Wound Oxygen (TWO2) Therapy in the Treatment of Chronic Diabetic Foot Ulcers: The TWO2 Study. Diabetes Care. 2020 Mar;43(3):616-624. doi: 10.2337/dc19-0476. Epub 2019 Oct 16.
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Referral and contact
AzTrials does not enrol participants or take referrals. Contact the study team or a site listed below; they decide who can take part. This study is not recruiting at the moment.
Robert G Frykberg, DPM principal investigator
Carl T. Hayden VA Medical Center
17 sites in 5 countries: see every site and its status.
Questions about this trial
What is this clinical trial studying?
A study testing TWO2 Device in people with Diabetic Foot Ulcer, run by AOTI Ltd. at 17 sites in 5 countries.
The full registered description is in the About this study section and the official record.
Who may be eligible to take part?
The sponsor lists 12 inclusion and 14 exclusion criteria. Eligibility is decided by the study team after screening, so read the full criteria and contact a listed site.
Is this clinical trial currently recruiting?
The record says: finished, as of the sponsor's last update on 27 Oct 2025. Status can change between updates, so confirm with the study contact before making plans.
Where is the study taking place?
The record lists 17 sites in United States, France, United Kingdom, Germany, Luxembourg. Whether a site is taking part right now should be confirmed with that site. See every site.
What are the possible benefits and risks?
They depend on the study and the treatment, and no study can promise a benefit. Some participants in this study may receive a placebo. The study team explains the known risks during informed consent, before anyone joins; the record itself does not list them.
Are results available for this study?
Yes. Results are posted in the registry (first posted 20 Apr 2025). A summary is in the For doctors view, and the full results are on ClinicalTrials.gov.
How can a doctor refer a patient or contact the research team?
The record lists no contact. The official record names the sponsor, who can be asked directly. AzTrials does not enrol participants or take referrals.
What does the primary outcome measure?
Wound Closure Within 12 Weeks With the Use of Topical Wound Oxygen Therapy (TWO2) (time frame: 12 weeks). It is what the study was designed to measure, not a finding.
Where can I read the original study information?
On the ClinicalTrials.gov record for NCT02326337, which also lists 1 linked publication.
Does a listing mean the treatment is approved or proven to work?
No. A listing means the study is registered. It does not show that the treatment is safe, works, or is approved by a regulator.
How often is this information updated?
AzTrials copies changed records from ClinicalTrials.gov every night and reloads the whole registry every week. The sponsor last updated this record on 27 Oct 2025.