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

• Study Type: Interventional
• Study Design: Allocation: Randomized; Intervention Model: Parallel Assignment; Masking: None (Open Label); Primary Purpose: Treatment
• Conditions: Diabetic Foot Ulcer; Surgical Wound
• Intervention: Device: Natrox® Oxygen Wound Therapy
• Enrollment: 145

Participant Flow

Recruitment Details

Participants were initially screened and documentation was investigated. If all inclusion criteria were met, and the patient had a documented healing rate of <20% reduction in wound size, the patients were entered into the 2-week run-in period. All patients were allocated to standard of care (SOC). At the baseline visit, if all inclusion and exclusion criteria were still applicable and the wound had not reduced in size by >20%, the patient was then randomized.

Pre-assignment Details

During run-in period patients either exceeded the percentage of acceptable healing per the protocol or had an adverse event preventing continuation in the trial.

Arm/Group Title	Standard of Care Arm	Intervention Arm
Arm/Group Description	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.	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.
Period Title: Overall Study
Started	64	81
Completed	59	69
Not Completed	5	12
Reason Not Completed
Adverse Event	2	4
Withdrawal by Subject	2	2
Physician Decision	0	3
Lost to Follow-up	1	0
Protocol Violation	0	2
Death	0	1

Baseline Characteristics

Arm/Group Title		Standard of Care Arm	Intervention Arm	Total
Arm/Group Description		Patients in the standard of care arm will receive the standard care for their type of wound from their wound care centre.	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.	Total of all reporting groups
Overall Number of Baseline Participants		64	81	145
Baseline Analysis Population Description		[Not Specified]
Age, Continuous; Mean (Full Range); Unit of measure: Years
	Number Analyzed	64 participants	81 participants	145 participants
		62.69; (34 to 91)	64.2; (33 to 93)	63; (33 to 93)
Sex: Female, Male [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	64 participants	80 participants	144 participants
	Female	11 17.2%	26 32.5%	37 25.7%
	Male	53 82.8%	54 67.5%	107 74.3%
		[1] Measure Analysis Population Description: One patient did not declare.
Race and Ethnicity Not Collected [1]; Measure Type: Count of Participants; Unit of measure: Participants
	Number Analyzed	0 participants	0 participants	0 participants
				0
		[1] Measure Analysis Population Description: Race and Ethnicity were not collected from any participant.
Region of Enrollment; Measure Type: Number; Unit of measure: Participants
Puerto Rico	Number Analyzed	64 participants	81 participants	145 participants
		8	5	13
United States	Number Analyzed	64 participants	81 participants	145 participants
		56	76	132
Current use Tobacco; Measure Type: Count of Participants; Unit of measure: Participants
Yes	Number Analyzed	64 participants	81 participants	145 participants
		11 17.2%	11 13.6%	22 15.2%
No	Number Analyzed	64 participants	81 participants	145 participants
		51 79.7%	68 84.0%	119 82.1%
Not declared	Number Analyzed	64 participants	81 participants	145 participants
		2 3.1%	2 2.5%	4 2.8%
Diabetes duration [1] [2]; Mean (Full Range); Unit of measure: Years
	Number Analyzed	60 participants	76 participants	136 participants
		18.33; (3 to 62)	18.35; (1 to 55)	18.34; (1 to 62)
		[1] Measure Description: Missing data for 4 patients in Standard of Care and 5 patients in Standard of Care plus Topical Oxygen Therapy.; [2] Measure Analysis Population Description: Analysis was only completed on the 2 individual study arms.
BMI [1] [2]; Mean (Full Range); Unit of measure: Kg/m^2
	Number Analyzed	60 participants	76 participants	136 participants
		31; (19 to 51)	30.8; (16 to 54)	30.9; (16 to 54)
		[1] Measure Description: Missing data on 4 patients in SOC and 5 patients in SOC plus TOT.; [2] Measure Analysis Population Description: BMI Analysis: Was only completed on the 2 individual arms.

Outcome Measures

1. Primary Outcome

Title	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.
Description	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.
Time Frame	Twelve (12) weeks from Time 0

Outcome Measure Data

Analysis Population Description

Intention to treat

Arm/Group Title		Standard of Care Arm	Intervention Arm
Arm/Group Description:		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.	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.
Overall Number of Participants Analyzed		64	81
Measure Type: Count of Participants; Unit of Measure: Participants
Intention to treat-healed	Number Analyzed	64 participants	81 participants
		18 28.1%	36 44.4%
Per protocol-healed	Number Analyzed	59 participants	69 participants
		18 30.5%	36 52.2%

2. Primary Outcome

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

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title		Standard of Care Arm	Intervention Arm
Arm/Group Description:		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.	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.
Overall Number of Participants Analyzed		64	81
Mean (Standard Deviation); Unit of Measure: Percentage reduction
Intention to treat - percentage reduction	Number Analyzed	64 participants	81 participants
		41.05 (69.82)	46.38 (100.24)
Per protocol-percentage reduction	Number Analyzed	59 participants	69 participants
		40.44 (72.1)	70.18 (45.5)

3. Secondary Outcome

Title	Level of Pain of the Wound
Description	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.
Time Frame	Up to twelve (12) weeks from Time 0

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Standard of Care Arm	Intervention Arm
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	64	81
Mean (Standard Deviation); Unit of Measure: score on a VAS 0-10 scale
Baseline	2.02 (2.57)	1.81 (2.53)
Twelve weeks of final visit if healed during study	0.68 (1.43)	0.95 (1.9)

4. Secondary Outcome

Title	Number of Adverse Events
Description	Number of adverse events, such as infections, that are found associated with the study wound
Time Frame	Up to twelve (12) weeks from time 0

Outcome Measure Data

Analysis Population Description

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

Arm/Group Title	Standard of Care Arm	Intervention Arm
Arm/Group Description:	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.	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.
Overall Number of Participants Analyzed	64	81
Measure Type: Number; Unit of Measure: Number of adverse events
Number of adverse events	32	41
Relationship to the product/unrelated	30	37
Relationship to the product/Unlikely	1	2
Relationship to the product/ Possibly related	1	1
Relationship to the product/ probably related	0	1

Adverse Events

Time Frame	During the12 week intervention period patients were monitored for adverse events.
Adverse Event Reporting Description	Severity of adverse events: Mild, Moderate, Severe, Life Threatening.; Outcome: Recovered, Recovered with sequelae, Not recovered, Lost to follow-up, Death.; Relationship to product: Unrelated, Unlikely, Possibly related, Probably related.; Action taken: Continued, Interrupted time in study, Discontinued.
Arm/Group Title	Standard of Care Arm		Intervention Arm
Arm/Group Description	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.		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.
All-Cause Mortality
	Standard of Care Arm		Intervention Arm
	Affected / at Risk (%)		Affected / at Risk (%)
Total	0/64 (0.00%)		1/81 (1.23%)
Serious Adverse Events
	Standard of Care Arm		Intervention Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	8/64 (12.50%)		6/81 (7.41%)
Blood and lymphatic system disorders
Bacteremia † [1]	1/64 (1.56%)	1	0/81 (0.00%)	0
General disorders
Pain †	1/64 (1.56%)	1	0/81 (0.00%)	0
Infections and infestations
Gangrene †	1/64 (1.56%)	1	1/81 (1.23%)	1
Infection †	1/64 (1.56%)	1	2/81 (2.47%)	2
Metabolism and nutrition disorders
Acute hypokalemic † [2]	0/64 (0.00%)	0	1/81 (1.23%)	1
Musculoskeletal and connective tissue disorders
Osteomyelitis †	0/64 (0.00%)	0	1/81 (1.23%)	1
Respiratory, thoracic and mediastinal disorders
Shortness of Breath †	3/64 (4.69%)	3	0/81 (0.00%)	0
Skin and subcutaneous tissue disorders
Cellulitis †	1/64 (1.56%)	1	1/81 (1.23%)	1
† Indicates events were collected by systematic assessment; [1] Linked to cellulitis previously recorded as an AE; [2] Associated hypotension and nonischemic cardiomyopathy
Other (Not Including Serious) Adverse Events
Frequency Threshold for Reporting Other Adverse Events	1%
	Standard of Care Arm		Intervention Arm
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	13/64 (20.31%)		19/81 (23.46%)
Infections and infestations
Wound Infection †	2/64 (3.13%)	2	6/81 (7.41%)	6
Infections †	3/64 (4.69%)	4	1/81 (1.23%)	1
Injury, poisoning and procedural complications
Falls †	2/64 (3.13%)	2	4/81 (4.94%)	7
Skin and subcutaneous tissue disorders
New Wound †	7/64 (10.94%)	8	6/81 (7.41%)	6
Maceration †	2/64 (3.13%)	4	2/81 (2.47%)	2
Pain † [1]	1/64 (1.56%)	1	3/81 (3.70%)	3
† Indicates events were collected by systematic assessment; [1] Wound/leg pain

Limitations and Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.

Results Point of Contact

• Name/Title: Dr Thomas Serena
• Organization: Serena Group Inc
• Phone: 671-945-5225
• EMail: serena@serenagroups.com

• Responsible Party: Inotec AMD Limited
• ClinicalTrials.gov Identifier: NCT03905863
• Other Study ID Numbers: 1
• First Submitted: April 3, 2019
• First Posted: April 5, 2019
• Results First Submitted: September 22, 2021
• Results First Posted: November 22, 2021
• Last Update Posted: November 22, 2021