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

Phase 4RecruitingNCT06754735

AOTI Ltd.212 enrolled

Overview

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

Sex: ALLMin age: 18 Years

Medical Language ↔ Plain English

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

Outcomes

Primary Outcomes

Incidence of complete wound closure within 16 weeks with the use of Topical Wound Oxygen Therapy (TWO2)

Percentage incidence of complete wound closure defined as 100% skin re-epithelialization without the need for wound dressing that is confirmed by 2 consecutive study visits 2 weeks apart.

Time frame: From Baseline to16 weeks

Secondary Outcomes

Percentage Area Reduction (PAR)

Change in wound area will be documented bi-weekly by the use of digital photography and wound mapping

Time frame: Baseline, Week 2, 4, 6, 8, 10, 12, 14 up to 16 weeks (± 2 days)

Incidence of complete wound closure at 12 weeks

Incidence of complete wound closure defined as 100% skin re-epithelialization without the need for wound dressing that is confirmed by 2 consecutive study visits 2 weeks apart.

Time frame: From Baseline to12 weeks

Incidence of complete wound closure at 52 weeks

Incidence of complete wound closure defined as 100% skin re-epithelialization without the need for wound dressing that is confirmed by 2 consecutive study visits 2 weeks apart.

Time frame: From week 16 to 52 weeks

Time to complete wound closure

Healing difference over Time will be assessed over a 16-week period

Time frame: Baseline, Week 2, 4, 6, 8, 10, 12, 14 up to 16 weeks (± 2 days), 20, 26, 52 weeks (± 2 weeks)

Pain Visual Analog Scale (VAS) score

Pain scores documented on a weekly basis measured using a 0-10 Visual Analog Scale (VAS) score, with zero (0) indicating no pain and 10 indicating the worst possible pain.

Time frame: Baseline weekly up to 16 weeks (±2 days)

Incidence of recurrence

Wounds documented as "healed" will be followed for incidence of recurrence. Count of wound recurrences of healed wounds. For healed wounds, VLU recurrence was collected via phone calls and subjects at follow up timelines.

Time frame: From Baseline up to week 16, week 20, 26 (± 1 week), 52 (± 2 weeks)

Incidence of Adverse Events at 16 weeks

Total number of different types of adverse events in participants who reported with any untoward medical event

Time frame: From Baseline to16 weeks

Incidence of Serious Adverse Events at 16 weeks

Total number of different types of serious adverse events in participants who reported that: * results in death * is life-threatening (places the subject at immediate risk of death from the experience as it occurred) * results in a persistent or significant disability/incapacity (substantial disruption of one's ability to carry out normal life functions) * results in medical or surgical intervention * results in or prolongs an existing hospitalization (even if the hospitalization is a precautionary measure for observation)

Time frame: From Baseline to16 weeks

Incidence of Serious Adverse Events at 52 weeks

Time frame: From 16 to 52 weeks

Change in Venous Clinical Severity Score (VCSS)

Mean change in Venous Clinical Severity Score (VCSS) from baseline to week 16. VCSS assesses nine common signs/symptoms of venous disease and each item is scored individually with a minimum score of "0" and maximum score of "3". The individual items are added together to assess change from baseline. Higher scores mean worst outcome.

Time frame: From Baseline to 16 weeks

Elimination of Infection

Wound cultures will be taken at the Baseline visit then again at week 6. Wounds defined as "infected" at the baseline visit and "not infection" at weeks 6, are documented as wound infection elimination.

Time frame: From Baseline to week 6

Change in Health-related Quality of Life (Venous Leg Ulcer Quality of life Questionnaire ~ (VLU-QoL-34))

Mean difference in change in Venous Leg Ulcer Quality of life Questionnaire \~ (VLU-QoL-34) from baseline to 16 weeks. Crude subscale scores for each group are not shown (each crude subscale is scored 1 to 5 at baseline and 16 weeks); higher mean differences in change from baseline to 16 weeks within groups indicate greater change on the subscales for that group.