The Effect of Natrox® Oxygen Wound Therapy on the Healing... | NCT03905863

Status Module

Name	Class
SerenaGroup, Inc.	NETWORK

Arms/Interventions Module

Arm Groups

Label	Type	Description	Intervention Names
Standard of care arm	No Intervention	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.
Intervention arm	Active Comparator	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.	Device: Natrox® Oxygen Wound Therapy

Interventions

Name	Type	Description	Arm Group Labels	Other Names
Natrox® Oxygen Wound Therapy	Device	A battery-operated device which delivers pure humidified oxygen to the wound bed through water electrolysis via a sterile oxygen delivery system.

Outcomes Module

Primary Outcomes

Measure	Description	Time Frame
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.	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.	Twelve (12) weeks from Time 0
Percentage Reduction in Ulcer Area (cm^2).	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.	Twelve (12) weeks from Time 0

Secondary Outcomes

Measure	Description	Time Frame
Level of Pain of the Wound	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.

Eligibility Module

Eligibility Criteria

Inclusion Criteria

Subjects are male or female, 18 years of age or older. At least 50% of the enrolled population must be ≥ 65 years of age.
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
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.
Study ulcer is a minimum of 0.5 cm2 and a maximum of 25 cm2 at first treatment visit
Subjects' wound score on ISDA tool is Grade 1 or 2.
The subject is able and willing to follow the protocol requirements
Subject has signed informed consent
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.
Females of childbearing potential must be willing to use acceptable methods of contraception (birth control pills, barriers, or abstinence).
The target ulcer has been offloaded for at least 14 days prior to randomization.

Exclusion Criteria

Subject has a known life expectancy of < 1 year
Subject or caregiver is unable to manage the Natrox® device (charge and change batteries daily)
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.
Subject has major uncontrolled medical disorders such as serious cardiovascular, renal, liver or pulmonary disease, lupus, palliative care or sickle cell anemia.
Subject currently being treated for an active malignant disease or subjects with history of malignancy within the wound.
The Subject has other concurrent conditions that in the opinion of the Investigator may compromise subject safety
Known contraindications for the Natrox system
Known allergies to any of the Natrox system components
Concurrent participation in another clinical trial that involves an investigational drug or device that would interfere with this study.
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.
Subject is pregnant or breast feeding.
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.
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.
Affected extremity requiring hyperbaric oxygen during the trial or within 2 weeks of treatment visit 1.
Known HbA1C >12%
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.
An ulcer that has healed by more than 20% in the 2 weeks prior to screening: "historical" run-in period.

Name	Affiliation	Role
Thomas Serena	SerenaGroup, Inc.	Study Director

Facility	Status	City	State	ZIP	Country	Contacts
New Hope Podiatry Clinic		Los Angeles	California	90063	United States
MedCare Research

Results Section

Participant Flow Module

Arm/Group Information

ID	Title	Description
FG000	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 standardized 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.

Baseline Characteristics Module

Outcome Measures Module

Adverse Events Module

More Info Module

Type	Includes Protocol	Includes SAP	Includes ICF	Document Label	Document Date	Document Uploaded Date	Document File Name
Prot_SAP_ICF	Yes	Yes	Yes	Study Protocol, Statistical Analysis Plan, and Informed Consent Form	Nov 25, 2019

ID	Title	Description
BG000	Standard of Care Arm	Patients in the standard of care arm will receive the standard care for their type of wound from their wound care centre.
BG001	Intervention Arm	Patients in the intervention arm will receive standard of care plus Natrox® Oxygen Wound Therapy as treatment for their wound. Natrox® Oxygen Wound Therapy: A battery-operated device which delivers 98% pure humidified oxygen to the wound bed through water electrolysis via a sterile oxygen delivery system.
BG002	Total	Total of all reporting groups

Units	Counts
Participants	BG00064 BG00181 BG002145

Baseline Measures

Title

Description

Population Description

Parameter Type

Dispersion Type

Unit of Measure

Calculate Percentage

Denominator Units Selected

Denominators

Classes

Age, Continuous

Mean

Full Range

years

Title

Denominators

Categories

Intention to treat-healed

- ParticipantsOG00064
- ParticipantsOG00181

Title	Measurements
	OG00018

Primary

Percentage Reduction in Ulcer Area (cm^2).

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.

"Intention to treat" as well an "Per protocol" analysis was carried out.

Posted

Mean

Standard Deviation

Percentage reduction

Twelve (12) weeks from Time 0

ID	Title	Description
OG000	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 standardized 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.
OG001	Intervention Arm	Those subjects allocated to the intervention arm were treated using the same protocol as SOC only but were also provided with a Natrox® Oxygen Wound Therapy System, consisting of two elements: the Natrox® Oxygen Generator and the Natrox® Oxygen Delivery System. The oxygen generator is a multi-use battery powered device which generates oxygen though water electrolysis at a rate of 15mL/hr. The oxygen delivery system is a sterile, single use device which has a web-like design 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 oxygen generator via a thin flexible fine-bore tube. While the oxygen delivery device 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.

Secondary

Level of Pain of the Wound

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.

VAS scores were taken weekly. On a scale of 0-10, 0 is least pain and 10 is the most pain

Posted

Mean

Standard Deviation

score on a VAS 0-10 scale

Up to twelve (12) weeks from Time 0

ID	Title	Description
OG000	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 standardized 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.

Secondary

Number of Adverse Events

Number of adverse events, such as infections, that are found associated with the study wound

Adverse reactions were recorded and reported throughout the study as they occurred.

Posted

Number

Number of adverse events

Up to twelve (12) weeks from time 0

ID	Title	Description
OG000	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 standardized 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.
OG001	Intervention Arm	Those subjects allocated to the intervention arm were treated using the same protocol as SOC only but were also provided with a Natrox® Oxygen Wound Therapy System, consisting of two elements: the Natrox® Oxygen Generator and the Natrox® Oxygen Delivery System. The oxygen generator is a multi-use battery powered device which generates oxygen though water electrolysis at a rate of 15mL/hr. The oxygen delivery system is a sterile, single use device which has a web-like design 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 oxygen generator via a thin flexible fine-bore tube. While the oxygen delivery device 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.

Serious Adverse Events

Term	Organ System	Assessment Type	Notes	Statistical Information
Shortness of Breath	Respiratory, thoracic and mediastinal disorders	Systematic Assessment		EG0003 events3 affected64 at risk EG0010 events0 affected81 at risk
Cellulitis	Skin and subcutaneous tissue disorders	Systematic Assessment		EG0001 events1 affected64 at risk EG0011 events1 affected81 at risk
Gangrene	Infections and infestations	Systematic Assessment		EG0001 events1 affected64 at risk EG0011 events1 affected81 at risk
Infection	Infections and infestations	Systematic Assessment		EG0001 events1 affected64 at risk EG0012 events2 affected81 at risk
Bacteremia	Blood and lymphatic system disorders	Systematic Assessment	Linked to cellulitis previously recorded as an AE	EG0001 events1 affected64 at risk EG0010 events0 affected81 at risk
Osteomyelitis	Musculoskeletal and connective tissue disorders	Systematic Assessment		EG0000 events0 affected64 at risk EG0011 events1 affected81 at risk
Pain	General disorders	Systematic Assessment		EG0001 events1 affected64 at risk EG0010 events0 affected81 at risk
Acute hypokalemic	Metabolism and nutrition disorders	Systematic Assessment	Associated hypotension and nonischemic cardiomyopathy	EG0000 events0 affected64 at risk EG0011 events1 affected81 at risk

Other Adverse Events

Term	Organ System	Assessment Type	Notes	Statistical Information
New Wound	Skin and subcutaneous tissue disorders	Systematic Assessment		EG0008 events7 affected64 at risk EG0016 events6 affected81 at risk
Falls	Injury, poisoning and procedural complications	Systematic Assessment		EG0002 events2 affected64 at risk EG0017 events4 affected81 at risk
Maceration	Skin and subcutaneous tissue disorders	Systematic Assessment		EG0004 events2 affected64 at risk EG0012 events2 affected81 at risk
Wound Infection	Infections and infestations	Systematic Assessment		EG0002 events2 affected64 at risk EG0016 events6 affected81 at risk
Infections	Infections and infestations	Systematic Assessment		EG0004 events3 affected64 at risk EG0011 events1 affected81 at risk
Pain	Skin and subcutaneous tissue disorders	Systematic Assessment	Wound/leg pain	EG0001 events1 affected64 at risk EG0013 events3 affected81 at risk

ID	Term
D017719	Diabetic Foot
D000072836	Surgical Wound
D010146	Pain
D007239	Infections

ID	Term
D003925	Diabetic Angiopathies
D014652	Vascular Diseases
D002318	Cardiovascular Diseases
D016523	Foot Ulcer
D007871	Leg Ulcer
D012883	Skin Ulcer
D012871	Skin Diseases
D017437	Skin and Connective Tissue Diseases
D048909	Diabetes Complications
D003920	Diabetes Mellitus
D004700	Endocrine System Diseases
D003929	Diabetic Neuropathies
D014947	Wounds and Injuries
D009461	Neurologic Manifestations
D012816	Signs and Symptoms
D013568	Pathological Conditions, Signs and Symptoms

ID	Title	Description	Deaths (Affected)	Deaths (At Risk)	Serious Events (Affected)	Serious Events (At Risk)	Other Events (Affected)	Other Events (At Risk)
EG000	Standard of Care Arm	Patients in the standard of care arm will receive the standard care for their type of wound from their wound care centre which typically includes a primary and secondary dressing to the wound.	0	64	8	64	13	64
EG001	Intervention Arm	Patients in the intervention arm will receive standard of care plus Natrox® Oxygen Wound Therapy as treatment for their wound. 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.	1	81	6	81	19	81