A Prospective, Randomized, Double-Blind Multicenter Study Comparing CDO Therapy to Standard MWT in the Treatment of DFUs

The purpose of this study was to evaluate the safety and effectiveness of Continuous Diffusion of Oxygen (CDO) therapy for the treatment of Diabetic Foot Ulcers. The primary objective of this study is to evaluate the effectiveness of CDO in combination with standard moist wound therapy (MWT) on wound healing as compared to standard MWT alone.

This study was a 12-week, randomized, fully blinded, placebo-controlled, parallel group clinical trial evaluating the use of the CDO device for DFUs. The CDO device used was the TransCu O2 System. The study was approved by the Schulman Associates Institutional Review Board (Cincinnati, OH, IRB No. 201202439). Randomisation lists were made by the statistician for each clinical site in blocks of size four with SAS. Devices were labelled by the statistician before shipping to the sites. The sites assigned devices to patients sequentially at randomisation. Both arms received identical treatment (device, dressings, etc.) and the devices were functional in both arms with the exception that the oxygen did not flow to the ulcer in the placebo arm. All devices were functional in that they produced oxygen and displayed the oxygen flow rate. This had the effect that the devices appeared identical, including battery drain and oxygen flow display. The only difference was that the placebo devices did not have any oxygen flowing out of the oxygen supply port. Since the oxygen flow rate (3ml/ hour) is low enough that it cannot be felt by the subjects or physicians, the devices all appeared identical. Similarly, the dressings and offloading boots in each arm were limited and identical. The result was that the patients, doctors, evaluators, sponsor and statistician were all fully-blinded to the treatment arms until the data had been collected and verified, thereby eliminating the placebo effect.

Before assignment of a device, all patients were subjected to a run-in period during which they received standard of care dressings, debridement and off-loading to ensure that the wounds were indeed chronic in nature. There were two inclusion criteria essential to the design of the study to ensure that only chronic wounds were being included: initial or baseline wound size and initial or run-in rate of wound closure. These were defined as: 1) baseline DFU size: the ulcer area as determined by independently-verified digital planimetric analysis during screening through the randomization visit, and 2) run-in ulcer closure rate: the percentage of ulcer closure (percentage wound area reduction, or PWAR) during the run-in period before the placement of the device. All subjects received MWT during the run-in period.

The intent was to find a balance between a short run-in period and robust screening criteria to help ensure that non-chronic wounds were not included in the study. Since the PWAR assessment relied on independently-verified planimetric analysis of wound photos, some subjects were initially placed on a device at the conclusion of the run-in period and subsequently found to be not eligible for failing study inclusion/ exclusion criteria. These subjects were removed as not eligible.

The primary efficacy outcome was complete wound closure, defined as complete re-epithelialization with no drainage as assessed by the treating clinician and confirmed by a blinded observer.

Eligibility Criteria:
Inclusion Criteria:

* Subjects 30-90 years of age at the time of Informed Consent
* Subjects with type 1 or type 2 Diabetes Mellitus with a non-healing, full-thickness, University of Texas Classification of Diabetic Foot Ulcers Class IA diabetic foot ulcers
* Subjects who have an ulcer with a duration of at least 4 weeks, but not greater than 52 weeks at time of screening
* Subjects with an index ulcer measuring between 1.5 - 10 cm2 in area after debridement (Area = length x width) at time of Screening 1 and Screening 2, as measured using digital photography \& computerized planimetric analysis by Centralized Wound Measuring Center (CWMC)
* Subjects with a diabetic foot ulcer(s) at or below the malleoli
* Subjects who demonstrates adequate arterial perfusion defined as either:

  * transcutaneous oxygen measurements of the dorsum of the foot \> 30 mm Hg with a skin perfusion pressure \> 30 mm Hg, or an ankle/brachial index (ABI) above 0.7, with documented confirmation of adequate arterial perfusion, or
  * a Doppler waveform consistent with adequate flow in the foot (biphasic or triphasic waveforms) at screening, or
  * absolute toe pressure of \> 30 mm Hg
* Subject and/or caregiver must be able and willing to learn and perform the duties of dressing changes
* Subjects are able and willing to comply with standardized off-loading regimen (such as a fixed ankle walker)

Exclusion Criteria:

* Subjects \< 30 or \> 90 years of age at the time of Informed Consent

  * Subjects with Target Ulcers with a duration \< 4 weeks or \> 52 weeks
  * Subjects with ulcers measuring less than 1.5 cm2 or greater than 10 cm2 in area (Area = length x width) after debridement at the time of Screening 1 and Screening 2 to Randomization) or \> 50% during the 2 week screening period, as measured using digital photography \& computerized planimetric analysis's determined by CWMC.
  * Subjects whose ulcer decreased in area by \> 30 % during the 1 week screening period
  * Subjects with evidence of gangrene on any part of affected limb
  * Subjects with active Charcot's foot on the study limb
  * Subjects scheduled to undergo vascular surgery, angioplasty or thrombolysis at the time of enrollment
  * Subjects with active infection at the time of screening
  * Subjects with a target ulcer which has exposed tendons, ligaments, muscle, or bone
  * Subjects with active malignancy, excluding non-melanoma skin cancer
  * Subjects with a history of malignancy on study limb
  * Subjects in whom oral, or IV antibiotic/antimicrobial agents or medications have been used within 2 days (48 hours) of baseline
  * Subjects who are currently receiving or has received radiation or chemotherapy within 3 months of randomization
  * Subjects who have received growth factor therapy (e.g., autologous platelet-rich plasma gel, becaplermin, bilayered cell therapy, dermal substitute, extracellular matrix) within two weeks of screening
  * Subjects who are pregnant at the time of screening
  * Subjects who are undergoing active renal dialysis
  * Subjects who have a known immune insufficiency, excluding Diabetes Mellitus
  * Subjects with a history of peripheral vascular repair within 14 days of screening
  * Subjects with a current deep vein thrombosis (DVT)
  * Subjects with ulcers due to Raynaud's disease
  * Subjects with and ulcer due to acute thrombophlebitis
  * Subjects with inadequate perfusion to support healing
  * Subjects with necrotic wounds covered with eschar or slough
  * Subjects with wounds with fistulae or deep sinus tracts of unknown depth
  * Subjects who are receiving palliative care
  * Subjects who have a HbA1c \> 12% (uncontrolled hyperglycemia)
  * Subjects whose target ulcer has a known etiology of: malignancy, burn, collagen vascular disease, sickle cell, vasculopathy, or pyoderma gangrenosum
  * Subjects with a documented history of alcohol or substance abuse within 6 months of screening
  * Subjects who are currently enrolled or who have participated, within 30 days of screening, in another investigational device, drug or biological trial that may interfere with study results
  * Subjects with a known allergy to dressing materials, including occlusive dressings and the adhesives on such dressings