Trial to Evaluate Cyclical Topical Wound Oxygen Therapy in the Treatment of Chronic Venous Leg Ulcers

The purpose of this study is to evaluate the efficacy, safety and economic benefits of Cyclical Pressure Topical Wound Oxygen (TWO2) Therapy in the treatment of venous leg ulcers. Participants will utilize standard of care (SOC) multilayer compression dressings with an inactive wound contact layer. Following a 2-week run-in period with SOC and after meeting all eligibility criteria, subjects will be randomized in a 1:1 ratio with TWO2 therapy or sham control therapy plus SOC. Participants will enter the intervention period of up to 16-weeks, followed by a long-term follow-up period of 52 weeks post randomization.

The full effect of Venous leg ulcers (VLU) on society is poorly understood. While chronic VLU are not considered to have a significant impact on mortality, the burden on patients, caregivers, healthcare systems and related economies cannot be underestimated. VLU affects 2% of the world's population, with 60% progressing to chronic wounds. (1) The reported range of VLU incidence is 0.12 - 1.69% and with a prevalence 0.3 - 1.33%. (2; 3) VLUs are a result of chronic venous insufficiency (CVI) and found to be more prevalent in females than males, with both primary (genetic) and secondary causes that result in valvular incompetence that is further exacerbated by obesity and immobility. (4) With the projected growth of aging and increasingly obese and unhealthy societies, both in the developed and developing world, the anticipated incidence of VLU is expected to rise significantly. (1; 5; 6) It has been well established that the standard of care (SOC) for VLU is the application of conventional compression dressing (CCD), as the successful management of venous hypertension is key to healing VLU. Maintaining a mobile blood flow and delivering oxygen and nutrients to tissues is essential to healing as well as preserving the integrity of skin reducing threat of developing a recurrent VLU.

The role of oxygen in wound healing has been extensively studied. An animal study by Fries et al in 2005 demonstrated that the application of oxygen in partial pressures above those delivered by a well-functioning arterial system, to wounded tissue, resulted in faster healing and more durable tissue. (19) Oxygen is also essential in fighting infection, potentiating the use of antibiotics and upregulating growth factors. (20; 21) A study by Tawfick and Sultan in 2012 demonstrated a significant benefit in healing VLU when both oxygen and cycling compression were employed simultaneously. Utilizing Topical Wound Oxygen (TWO2) therapy™, TWO2 was demonstrated to be superior to SOC, 76% vs 46% healing at 12 weeks (n = 30/65; P \< .0001), with low recurrence rates for patients followed up to three years, 6% vs 47%. Further noteworthy results from this study were the reduction of pain, 8 to 3 in 13 days (on a numerical rating scale) and subjects whose wounds were infected with MRSA demonstrated elimination 46% vs 0% at week 5 (P \<.001). (22)

All subjects will use the TWO2/Sham device for a minimum of 120 minutes a day in their home (where the infrastructure supports remote therapy), 5 times a week for the treatment phase of up to 16 weeks. Monitoring of the wound will take place with bi-weekly clinic visits to assess safety, compliance, wound progression/deterioration, wound photographs and measurements.

The maximum duration for participation in the trial is 52 weeks (+/- 2 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.

Eligibility Criteria:
Inclusion Criteria:

* Adults ≥ 18 years and able to provide written informed consent
* Patients who have a chronic venous leg ulcer (VLU) below the knee at or above the malleolus determined to be due to underlying venous disease
* Venous reflux ≥ 500 mil sec/superficial or 1 sec/deep or venous mapping after interventions following a vascular procedure
* VLU of ≥ 1.5cm2 and ≤ 50cm2 after debridement at study enrolment i.e. Screening visit
* \*Cluster wounds where the sum of the full thickness ulcer area must be ≤ 50cm2
* Study ulcer (current episode of ulceration in case of ulcer recurrence) has been present for at least 6 weeks but no more than 5 years prior to study entry
* The index ulcer has been treated with CCD of at least 30mmHg for ≥ 6 weeks prior to screening.
* Adequate perfusion with Ankle-Brachial Pressure Index (ABPI) of 0.75-1.24 inclusive measured at study entry or within 8 weeks prior to study entry AND TcpO2 \> 30mmHg OR Biphasic arterial duplex below the knee OR Toe pressure \> 30mmHg OR TBI .6
* Wound size reduction in a 2-week run-in period of ≤ 30%
* Subject understands and is willing to participate in the clinical study and comply with weekly visits and follow up regime
* Subject has read and signed IRB/EC approved ICF before screening procedures commence

Exclusion Criteria:

* • Known allergy to any of the protocol-stipulated treatments, or non-tolerance of multilayer, multicomponent compression therapy

  * Acute thrombophlebitis or Deep Vein Thrombosis (DVT) and within three months preceding study entry
  * Subject awaiting venous ablation or is less than 30 days post ablation
  * Surgery during three months prior to study entry (such as abdominal, gynecological, hip or knee replacement)
  * Wound etiology of uncertain origin or history or prior diagnosis of Systemic Lupus Erythematosus, Burger's Disease, Pyoderma Gangrenosum or other inflammatory ulceration, vasculitis
  * Documented evidence of osteomyelitis on any part of affected limb
  * Index ulcer has exposed bone, muscle and tendon
  * Index ulcer exhibits signs of unmanaged wound infection or severe clinical infection that requires hospitalization or immediate surgical intervention
  * BMI \> 45
  * Uncontrolled diabetes: HbA1c \> 12% within 60 days of screening
  * Renal dialysis or of screening EGFR less than 30 mg/dl
  * NYHA Class IV
  * Peripheral arterial reconstruction/revascularization on the affected limb within the last 30 days
  * Any medication deemed by the Investigator to potentially interfere with the study treatment (e.g. systemic steroids \> 10mg daily dose, immunosuppressive agents).
  * Active systemic treatment for malignancy
  * History of radiation at the ulcer site
  * Subject has received growth factor therapy (e.g., autologous platelet-rich plasma gel, becaplermin, bilayer cell therapy, dermal substitute, extracellular matrix) within 14 days before screening
  * Subject participated in another investigational device, drug or biological trial within four weeks prior to study entry
  * Subject may not be pregnant or breastfeeding at the time of treatment