The Effect of Natrox® Oxygen Wound Therapy on the Healing Rate of Chronic Diabetic Foot Ulcers

• ClinicalTrials.gov Identifier: NCT03905863
• Recruitment Status: Completed
• First Posted: April 5, 2019
• Results First Posted: November 22, 2021
• Last Update Posted: November 22, 2021
• Sponsor: Inotec AMD Limited
• Collaborator: SerenaGroup, Inc.
• Information provided by (Responsible Party): Inotec AMD Limited

Tracking Information

• First Submitted Date: April 3, 2019
• First Posted Date: April 5, 2019
• Results First Submitted Date: September 22, 2021
• Results First Posted Date: November 22, 2021
• Last Update Posted Date: November 22, 2021
• Actual Study Start Date: June 4, 2019
• Actual Primary Completion Date: October 18, 2020 (Final data collection date for primary outcome measure)

Current Primary Outcome Measures (submitted: November 18, 2021)

• Number of Participants That Achieve Complete Wound Closure During the Twelve Week Study and the Percentage Change in Participant Ulcer Size at 12 Weeks From Baseline. [ Time Frame: Twelve (12) weeks from Time 0 ]
  Photographic wound evaluation and measurements were conducted utilizing an AI-driven computerized planimetry imaging system (Tissue Analytics, Inc., Baltimore, MD USA).15 This system obtained both 2D and 3D assessments of the wound at each visit through a standardized mobile device; in addition, the lead investigator reviewed all digital images.
• Percentage Reduction in Ulcer Area (cm^2). [ Time Frame: Twelve (12) weeks from Time 0 ]
  Wound size change over time using a wound imaging measurement system. Percentage change in ulcer area was calculated on the basis of area change from the start of the study to the final recorded value. Any healed ulcer was recorded as having achieved 100% reduction in area; positive values indicate a reduction in size over the 12-week period while negative values indicate that the ulcer increased in size.

Original Primary Outcome Measures (submitted: April 4, 2019)

Percentage of wounds that heal [ Time Frame: Twelve (12) weeks from Time 0 ]

Wounds will be visually assessed by clinicians as healed or not healed

Current Secondary Outcome Measures (submitted: October 21, 2021)

• Level of Pain of the Wound [ Time Frame: Up to twelve (12) weeks from Time 0 ]
  Does pain associated with the wound change over time using a Visual Analogue Scale Pain intensity of the reference DFU is to be assessed before any dressing changes or other ulcer manipulations at all screening and treatment visits. Subject will be asked to indicate a numerical value that best represents the pain intensity at ulcer site on a scale of 0 to 10 anchored by word descriptors at each end, as "no pain" on the left side and "worst possible pain" on the right side of the number line. The number 0 represent "no pain", the number 5 represents "moderate pain" and the number 10 represents the "worst possible pain". The subject indicates the level of pain intensity by selecting a number on the line that represents their perception of their current state.
• Number of Adverse Events [ Time Frame: Up to twelve (12) weeks from time 0 ]
  Number of adverse events, such as infections, that are found associated with the study wound

Original Secondary Outcome Measures (submitted: April 4, 2019)

• Arbitrary scale of ease of implementation of Natrox® [ Time Frame: Twelve (12) weeks from Time 0 ]
  Questionnaire to assess how easy or difficult clinicians found the addition of Natrox® to standard therapy regimens.
• Wound size change [ Time Frame: Twelve (12) weeks from Time 0 ]
  Wound size change over time using a wound imaging measurement system
• Level of pain of the wound [ Time Frame: Twelve (12) weeks from Time 0 ]
  Does pain associated with the wound change over time using a Visual Analogue Scale
• Number of Infections [ Time Frame: Twelve (12) weeks from Time 0 ]
  Number of new infections associated with the study wounds
• Number of Dressing changes [ Time Frame: Twelve (12) weeks from Time 0 ]
  Number of dressing changes that are done on the study wound

• Current Other Pre-specified Outcome Measures: Not Provided
• Original Other Pre-specified Outcome Measures: Not Provided

Descriptive Information

• Brief Title: The Effect of Natrox® Oxygen Wound Therapy on the Healing Rate of Chronic Diabetic Foot Ulcers
• Official Title: A Randomized Controlled Multicentre Trial, Examining the Effect of Natrox® Oxygen Wound Therapy on the Healing Rate of Chronic Diabetic Foot Ulcers
• Brief Summary: A Multicentre Randomized Controlled Trial to Investigate the Effect of Natrox Topical Oxygen Wound Therapy on the Healing rates of Diabetic Foot Ulcers.
• Detailed Description: Patients with diabetic foot ulcers will be enrolled into the trial at multiple wound care centers and hospital research centers across the United States of America. After qualifying per protocol, patients will be randomized to receive standard wound care or standard wound care plus Topical Oxygen Wound Therapy for their wounds. Patients will be monitored for 12 weeks. The primary comparator between the groups will be complete wound healing at 12 weeks, but other parameters will be assessed, such as pain, wound size reduction and infection status.
• Study Type: Interventional
• Study Phase: Not Applicable
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment

Condition

• Diabetic Foot Ulcer
• Surgical Wound

Intervention

Device: Natrox® Oxygen Wound Therapy

A battery-operated device which delivers pure humidified oxygen to the wound bed through water electrolysis via a sterile oxygen delivery system.

Study Arms

• No Intervention: Standard of care arm
  SOC was defined to include wound cleansing with sterile water or saline solution, and gentle irrigation of the study ulcer with warm tap water; sharp debridement using a standardised protocol based on TIME principles for wound bed preparation; offloading with a TCC twice in the first week and weekly thereafter (all exceptions had to be agreed by the lead investigator; a fixed ankle walker boot or similar device was acceptable as an alternative, but shoe inserts were not deemed to provide sufficient offloading); moisture balance was provided using a hydrofibre or alginate dressing. In addition, patients were instructed on adherence to the protocol and given instructions to call their clinic if they suspected any signs of an infection.
• Active Comparator: Intervention arm
  Same protocol as SOC only but were also provided with a Natrox® Oxygen Wound Therapy System, consisting of two elements: the Natrox® OG and the Natrox® ODS. The OG is a multi-use battery powered device which generates oxygen though water electrolysis at a rate of 15mL/hr. The ODS is a sterile, single use device that allows wound exudate to pass through to the secondary dressing while allowing the diffusion of oxygen across the wound bed. It connects directly to the OG via a thin flexible fine-bore tube. While the ODS can remain in situ for 7 days, it should be changed at each dressing change, based on exudate level or clinical judgement. This is a battery-operated system with a 30-hour battery life; the kit includes two interchangeable, rechargeable batteries. Each participant was advised to charge one battery while the other was in use, as the battery required changing daily. The oxygen generator is worn in a holster so that patients can remain ambulatory.
  Intervention: Device: Natrox® Oxygen Wound Therapy

• Publications *: Not Provided

Recruitment Information

• Recruitment Status: Completed
• Actual Enrollment (submitted: September 22, 2021): 145
• Original Estimated Enrollment (submitted: April 4, 2019): 150
• Actual Study Completion Date: October 18, 2020
• Actual Primary Completion Date: October 18, 2020 (Final data collection date for primary outcome measure)

Eligibility Criteria

Inclusion Criteria

1. Subjects are male or female, 18 years of age or older. At least 50% of the enrolled population must be ≥ 65 years of age.

2. Subjects with one of the following wounds:

   A. Diabetic foot ulcer present for greater than 4 weeks (documented in the medical record) but less than 12 months duration if being treated with active SOC.

   B. Minor amputation wound sites

3. Subject has clinical documentation of no visible wound improvement in the after 4 weeks of standard of care. Objectively, less than 40% healing in the past four weeks from the first treatment visit.
4. Study ulcer is a minimum of 0.5 cm2 and a maximum of 25 cm2 at first treatment visit
5. Subjects' wound score on ISDA tool is Grade 1 or 2.
6. The subject is able and willing to follow the protocol requirements
7. Subject has signed informed consent
8. Adequate circulation to the affected foot as demonstrated by a dorsum transcutaneous oxygen measurement (TCOM) or a skin perfusion pressure (SPP) measurement of ≥ 30 mmHg; an ABI between 0.7 and ≤ 1.3, or TBI of >6 within 3 months of the first Screening Visit.
9. Females of childbearing potential must be willing to use acceptable methods of contraception (birth control pills, barriers, or abstinence).
10. The target ulcer has been offloaded for at least 14 days prior to randomization.

Exclusion Criteria

1. Subject has a known life expectancy of < 1 year
2. Subject or caregiver is unable to manage the Natrox® device (charge and change batteries daily)
3. Subject has ulcers that are completely necrotic or if the clinician feels it is clinically necessary to cover the wound surface in gel or creams that would prevent the transmission of oxygen to the wound surface.
4. Subject has major uncontrolled medical disorders such as serious cardiovascular, renal, liver or pulmonary disease, lupus, palliative care or sickle cell anemia.
5. Subject currently being treated for an active malignant disease or subjects with history of malignancy within the wound.
6. The Subject has other concurrent conditions that in the opinion of the Investigator may compromise subject safety
7. Known contraindications for the Natrox system
8. Known allergies to any of the Natrox system components
9. Concurrent participation in another clinical trial that involves an investigational drug or device that would interfere with this study.
10. Index ulcer has reduced in area by 20% or more after 2 weeks of standard of care from the first screening visit (S1) to the TV1/randomization visit.
11. Subject is pregnant or breast feeding.
12. Subjects with a history of more than two weeks treatment with immunosuppressants (including systemic corticosteroids >10mg daily dose), cytotoxic chemotherapy, or application of topical steroids to the ulcer surface within one month prior to first Screening Visit, or who receive such medications during the screening period, or who are anticipated to require such medications during the course of the study.
13. Index ulcer has been previously treated with tissue engineered materials (e.g. Apligraf® or Dermagraft®) or other scaffold materials (e.g. Oasis, Matristem) within the last 30 days preceding the first treatment visit.
14. Affected extremity requiring hyperbaric oxygen during the trial or within 2 weeks of treatment visit 1.
15. Known HbA1C >12%
16. An ulcer that has visible signs of improvement in the four weeks prior to randomization defined objectively as a 40% reduction in surface area in the four weeks prior to enrollment.
17. An ulcer that has healed by more than 20% in the 2 weeks prior to screening: "historical" run-in period.

Sex/Gender

• Sexes Eligible for Study: All

• Ages: 18 Years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Contacts: Contact information is only displayed when the study is recruiting subjects
• Listed Location Countries: Puerto Rico, United States

Administrative Information

• NCT Number: NCT03905863
• Other Study ID Numbers: 1
• Has Data Monitoring Committee: No

U.S. FDA-regulated Product

• Studies a U.S. FDA-regulated Drug Product: No
• Studies a U.S. FDA-regulated Device Product: Yes
• Product Manufactured in and Exported from the U.S.: No

IPD Sharing Statement

• Plan to Share IPD: No

• Current Responsible Party: Inotec AMD Limited
• Original Responsible Party: Same as current
• Current Study Sponsor: Inotec AMD Limited
• Original Study Sponsor: Same as current
• Collaborators: SerenaGroup, Inc.

Investigators

• Study Director: Thomas Serena; SerenaGroup, Inc.

• PRS Account: Inotec AMD Limited
• Verification Date: November 2021