Clinical trial NCT06754735: Trial to Evaluate Cyclical Topical Wound Oxygen Therapy in the Treatment of Chronic Venous Leg Ulcers
Official title: A Multi-national, Prospective, Randomized, Double Blinded, Placebo-controlled Trial to Evaluate Cyclical Topical Wound Oxygen Therapy (TWO2) in the Treatment of Chronic Venous Leg Ulcers
Study type: INTERVENTIONAL
Overall status: RECRUITING
Phase: PHASE4
Conditions: Venous Leg Ulcer (VLU)
Keywords: Ulcer, Wound, Randomized, Oxygen, Placebo, Sham, Venous, Compression
Varicose Veins, Venous stasis ulcer
Topical Oxygen
Lead sponsor: AOTI Ltd.
Sponsor class: INDUSTRY
First posted: 2025-01-01
Enrollment: 212
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention model description: Randomized, Double Blinded, Placebo-controlled Trial
Primary purpose: TREATMENT

Brief summary: 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.

Detailed description: 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

Primary outcomes:
measure: Incidence of complete wound closure within 16 weeks with the use of Topical Wound Oxygen Therapy (TWO2)
timeFrame: From Baseline to16 weeks
Secondary outcomes:
measure: Percentage Area Reduction (PAR)
timeFrame: Baseline, Week 2, 4, 6, 8, 10, 12, 14 up to 16 weeks (± 2 days)
measure: Incidence of complete wound closure at 12 weeks
timeFrame: From Baseline to12 weeks
measure: Incidence of complete wound closure at 52 weeks
timeFrame: From week 16 to 52 weeks
measure: Time to complete wound closure
timeFrame: Baseline, Week 2, 4, 6, 8, 10, 12, 14 up to 16 weeks (± 2 days), 20, 26, 52 weeks (± 2 weeks)
measure: Pain Visual Analog Scale (VAS) score
timeFrame: Baseline weekly up to 16 weeks (±2 days)
measure: Incidence of recurrence
timeFrame: From Baseline up to week 16, week 20, 26 (± 1 week), 52 (± 2 weeks)
measure: Incidence of Adverse Events at 16 weeks
timeFrame: From Baseline to16 weeks
measure: Incidence of Serious Adverse Events at 16 weeks
timeFrame: From Baseline to16 weeks
measure: Incidence of Serious Adverse Events at 52 weeks
timeFrame: From 16 to 52 weeks
measure: Change in Venous Clinical Severity Score (VCSS)
timeFrame: From Baseline to 16 weeks
measure: Elimination of Infection
timeFrame: From Baseline to week 6
measure: Change in Health-related Quality of Life (Venous Leg Ulcer Quality of life Questionnaire ~ (VLU-QoL-34))
timeFrame: From Baseline to week 8, up to week 16 (± 2 days)
measure: Emotional distress
timeFrame: From Baseline to week 8, up to week 16 (± 2 days)
measure: Anxiety symptoms
timeFrame: From Baseline to week 8, up to week 16 (± 2 days)
measure: Depression
timeFrame: From Baseline to week 8, up to week 16 (± 2 days)
measure: Change in Health-related Quality of Life (EuroQol-5D 3L)
timeFrame: From Baseline to week 8, up to week 16 (± 2 days)
Other outcomes:
Locations:
city: New York
country: United States
facility: Vascular Institute of New York
state: New York
Study officials:
affiliation: AOTI Ltd.
name: Mike Griffiths, DProf, DMS, CRT, FCMI
role: STUDY_CHAIR
name: Anil Hingorani, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: University of Galway
name: Wael Tawfick, MB.BCH, MRCSI.
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: Tawfick WA, Sultan S. Technical and clinical outcome of topical wound oxygen in comparison to conventional compression dressings in the management of refractory nonhealing venous ulcers. Vasc Endovascular Surg. 2013 Jan;47(1):30-7. doi: 10.1177/1538574412467684. Epub 2012 Dec 5.
citation: Fowkes FG, Evans CJ, Lee AJ. Prevalence and risk factors of chronic venous insufficiency. Angiology. 2001 Aug;52 Suppl 1:S5-15. doi: 10.1177/0003319701052001S02.