Trial no.:	PACTR202106843726164	Date of Registration:	25/06/2021
Trial Status:	Registered in accordance with WHO and ICMJE standards

TRIAL DESCRIPTION

Public title

Home Use Photobiomodulation as an Adjunct to Standard Care for the Treatment of Diabetic Ulcers in Patients with Skin Types V and VI

Official scientific title

Effectiveness of Home Use Photobiomodulation Therapy as an Adjunct to Standard Care for the Treatment of Lower Limb Ulcers in Diabetic Patients with Skin Types V and VI

Brief summary describing the background and objectives of the trial

Diabetic patients are at increased risk for developing non-healing, chronic diabetic foot ulcers (DFUs) which often necessitate amputation, leading to reduced quality of life. There is also increased financial and psychological stress for patients and families, as well as increased need for medical care which can place a burden on healthcare facilities. The successful treatment of DFUs, and prevention of amputation, remains complicated. There has been new research at hastening healing of DFUs, including photobiomodulation therapy (PBMT). PBM is a non-invasive treatment modality that utilizes light. During PBMT, the light (photon) energy must be absorbed by the skin and absorption of this photon energy may be affected by skin color, and treatment protocols may need to be adjusted accordingly. A recent study has shown the successful use of the B-Cure laser pro device for the at-home treatment of DFUs, however this study was done in patients with lighter skin tones. This study aims to evaluate the effectiveness of home use PBM as an adjunct to standard care for the treatment of lower limb ulcers in diabetic patients with skin types V and VI. The objectives are: • Evaluate the effectiveness of the B-Cure laser pro as an adjuvant to standard treatment compared to sham control with standard treatment for healing DFUs in diabetic patients with skin types V and VI. • Compare the rate of DFU complete wound closure between experimental groups. • Determine the effect of treatment on quality of life of patients with DFUs. • Determine subjective satisfaction with the treatment procedure. • Determine long term effectiveness of the B-cure laser pro treatment. • Evaluate the effect of the treatment on tissue composition using digital photography. • Evaluate changes in thermal imaging of diabetic wounds. • Evaluate changes in nerve conduction.

Type of trial

RCT

Acronym (If the trial has an acronym then please provide)

Disease(s) or condition(s) being studied

Nutritional, Metabolic, Endocrine

Sub-Disease(s) or condition(s) being studied

Purpose of the trial

Treatment: Devices

Anticipated trial start date

01/09/2021

Actual trial start date

Anticipated date of last follow up

30/09/2022

Actual Last follow-up date

Anticipated target sample size (number of participants)

60

Actual target sample size (number of participants)

Recruitment status

Recruiting

Publication URL

Secondary Ids	Issuing authority/Trial register

STUDY DESIGN
Intervention assignment	Allocation to intervention	If randomised, describe how the allocation sequence was generated	Describe how the allocation sequence/code was concealed from the person allocating the participants to the intervention arms	Masking	If masking / blinding was used
Factorial: participants randomly allocated to either no, one, some or all interventions simultaneously	Randomised	Permuted block randomization	Numbered containers	Masking/blinding used	Care giver/Provider,Outcome Assessors,Participants

INTERVENTIONS
Intervention type	Intervention name	Dose	Duration	Intervention description	Group size	Nature of control
Experimental Group	B Cure laser pro	The dosing and administration of PBM is based on recommendations from the book "Laser Phototherapy – Clinical Practice and Scientific Background" (Hode and Tuner, 2014). The protocol used in this study was recently published by Raizman and Gavish (2020). The B-Cure laser pro is a portal, non-invasive, low level laser therapy device, that emits light in the near infrared range (808 nm) over an area of 1X4.5 cm2 with power output of 250mW, and energy dose of 1J/cm2. The wound margins, wound bed, as well as regional lymph nodes and arteries supplying the foot (in case of poor foot blood supply) will be irradiated. The treatment dose and number of applications per treatment depends on the wound size. The dimensions of the device enable covering a rectangular area of 1X4.5 cm2 per application. For example, a wound of 2.5X3.5 cm2 will require 4 applications around the margins (2 min each), 2 applications on the wound bed (0.5 min each), and 2 applications over lymph nodes (1 min each). Thus, the total treatment time would be 11 min [(4X2 min) + (2X0.5 min) + (2X1 min) = 11 min]. The treatment should be preferably performed at the same time of day. Area: Wound margins Frequency: Every dressing replacement (maximum once a day). Dose: Begin with 2 J/cm2 per application (2 min) for the first 2 weeks and if no improvement, increase to 3 J/cm2 per application (3 min). Area: Wound bed Frequency: Every dressing replacement (maximum once a day). Dose: Begin with 0.5 J/cm2 per application (0.5 min) for the first 2 weeks and if no improvement, increase to 1 J/cm2 per application (1 min). Area: Inguinal and popliteal lymph nodes Frequency: Daily (maximum twice a day). Dose: 1 J/cm2 per application (1 min). Area: Arteries supplying the foot (in case of poor foot blood supply) - dorsalis pedis, medial/lateral plantar arteries Frequency: Every dressing replacement (maximum once a day). Dose: 1 J/cm2 per application (1 min)	This study will include up to 9 visits at the clinic: a screening visit, baseline visit (may be combined with screening visit), and 7 follow-up visits at 2, 4, 6, 8, 10, and 12 weeks, and 3 months (12 weeks) after wound closure. Participants will self-treat and self-apply (or by a personal caregiver) active-PBM treatment at home every wound dressing replacement, usually daily or every other day (at least 5 times a week). Treatments will continue for 12 weeks from initiation or up to wound closure, whichever comes first. A follow-up visit 3 months after the primary endpoint (12 weeks or complete wound closure) will be conducted. • Screening visit: Eligible patients with diabetic foot ulcers will be recruited. After signing an informed consent, the researcher will examine the patients and document their medical history and study related measures. • Baseline visit: A baseline photograph/thermal image of the wound will be taken. Patients will be randomly allocated to the treatment group by selecting a device. Randomization will be done by computer generated sequences in blocks of four. The study device will be provided in the original packages with a 3-digit code (representing the coded group allocation) on each device and individual packaging in carts of four (block randomization – two sham and two active). The participant will pick a device package out of the cart, and the code recorded. When all four devices from a single cart are dispensed, the next cart of four will be opened. The researcher will explain how to use the device, and will give each patient a study diary for the documentation of treatment sessions and any adverse event/s. • Treatments: All patients will receive standard treatment. In addition, patients will self-apply (or by personal caregiver) active-PBM treatment at home. • Follow up visits: Will be conducted at the clinic every 2 weeks until 12 weeks or wound closure. The FU visits will include photography/thermal imaging and wound measurements	1. Study Intervention Description The B-Cure laser is a portal, non-invasive, low level laser therapy device, that emits light in the near infrared (808nm) over an area of 1X4.5 cm2 with power output of 250mW, and energy dose of 1J/cm2. The device is used at home and is self-applied by the patient. 2. Standard of Care Regimen Wound dressing replacement will take place every 1-2 days (by participants) and will include cleansing the wound with saline and sterile gauze. Debridement of necrotic tissue will occur during clinic visits if necessary, and wound dressing. Offloading is done by casting, orthotics, crutches, or elevation. Management of wound infection will include prescription of standard systemic anti-microbial therapy. The wound/s will be evaluated for the presence of inflammation including erythema, edema, and rise in temperature. Wounds will also be assessed for wound drainage, tissue necrosis, tissue granulation and epithelialization, pain, and bone probing. Recording blood sugar levels and HbA1c and recommending nutritional support and proper blood sugar management methods will be encouraged. To evaluate changes in nerve conduction, the monofilament test will be conducted at the screening visit, baseline visit (visit 1), and follow-up visits 3 (at 4 weeks), 5 (at 8 weeks), 7 (at 12 weeks), and 8 (3 months after the last treatment). A small strand of nylon attached to a plastic base is placed on specific areas of the foot and pressure is applied until the monofilament buckles.	30
Control Group	B Cure laser pro	The active and sham devices are externally identical and emit the same guiding light. The only difference is that the sham device does not emit the therapeutic NIR rays. The NIR light from the device (808 nm) cannot be seen by the naked eye. Participants in this group will be blinded and will receive no laser irradiation from the sham device.	This study will include up to 9 visits at the clinic: a screening visit, baseline visit (may be combined with screening visit), and 7 follow-up visits at 2, 4, 6, 8, 10, and 12 weeks, and 3 months (12 weeks) after wound closure. Participants will self-treat and self-apply (or by a personal caregiver) active-PBM treatment at home every wound dressing replacement, usually daily or every other day (at least 5 times a week). Treatments will continue for 12 weeks from initiation or up to wound closure, whichever comes first. A follow-up visit 3 months after the primary endpoint (12 weeks or complete wound closure) will be conducted. • Screening visit: Eligible patients with diabetic foot ulcers will be recruited. After signing an informed consent, the researcher will examine the patients and document their medical history and study related measures. • Baseline visit: A baseline photograph/thermal image of the wound will be taken. Patients will be randomly allocated to the treatment group by selecting a device. Randomization will be done by computer generated sequences in blocks of four. The study device will be provided in the original packages with a 3-digit code (representing the coded group allocation) on each device and individual packaging in carts of four (block randomization – two sham and two active). The participant will pick a device package out of the cart, and the code recorded. When all four devices from a single cart are dispensed, the next cart of four will be opened. The researcher will explain how to use the device, and will give each patient a study diary for the documentation of treatment sessions and any adverse event/s. • Treatments: All patients will receive standard treatment. In addition, patients will self-apply (or by personal caregiver) active-PBM treatment at home. • Follow up visits: Will be conducted at the clinic every 2 weeks until 12 weeks or wound closure. The FU visits will include photography/thermal imaging and wound measurements	1. Study Intervention Description The sham device does not emit the therapeutic NIR rays. The device will be used at home and is self-applied by the patient. 2. Standard of Care Regimen Wound dressing replacement will take place every 1-2 days (by participants) and will include cleansing the wound with saline and sterile gauze. Debridement of necrotic tissue will occur during clinic visits if necessary, and wound dressing. Offloading is done by casting, orthotics, crutches, or elevation. Management of wound infection will include prescription of standard systemic anti-microbial therapy. The wound/s will be evaluated for the presence of inflammation including erythema, edema, and rise in temperature. Wounds will also be assessed for wound drainage, tissue necrosis, tissue granulation and epithelialization, pain, and bone probing. Recording blood sugar levels and HbA1c and recommending nutritional support and proper blood sugar management methods will be encouraged. To evaluate changes in nerve conduction, the monofilament test will be conducted at the screening visit, baseline visit (visit 1), and follow-up visits 3 (at 4 weeks), 5 (at 8 weeks), 7 (at 12 weeks), and 8 (3 months after the last treatment). A small strand of nylon attached to a plastic base is placed on specific areas of the foot and pressure is applied until the monofilament buckles.	30	Placebo

ELIGIBILITY CRITERIA
List inclusion criteria	List exclusion criteria	Age Category	Minimum age	Maximum age	Gender
• Male or female. • Fitzpatrick skin type V-VI. • Type I or Type II DM. • Age: 18-90 years old. • Presence of a DFU located on the ankle area or below that has persisted a minimum of 4 weeks prior to the initial screening visit. • Ulcer grade classified as < IIIA according to the University of Texas Classification of Diabetic foot ulcers (Lavery et al., 1996). • Area of ulcer (after debridement) is at least 2 cm2. • Patients who demonstrate adequate arterial perfusion defined as either: Ankle-brachial index (ABI) above 0.7 or that have documented confirmation of adequate arterial perfusion. • State willingness to comply with all the procedures and availability for the duration of the study. • Patients and/or caregivers must be able and willing to learn and perform the duties of dressing changes. • Provision of signed and dated informed consent form. • For females of reproductive potential: use of highly effective contraception for at least 1 month prior to screening and agreement to use such a method during study participation (safe use of photobiomodulation or low level laser therapy during pregnancy has not been established).	• Pre-existing conditions- evidence of gangrene on any part of affected limb, infection at screening, deep vein thrombosis (DVT), active malignancy, anaemia (Hb<9 gr/dL). • Known allergies to dressing materials, including occlusive dressings and the adhesive on such dressings. • Scheduled to undergo vascular surgery, angioplasty, or thrombolysis at the time of screening or history of peripheral vascular repair within 4 weeks of screening. • History of malignancy in study limb or currently receiving or has received radiation or chemotherapy within 3 months of randomization. • Taking immunosuppressive medication. • Received growth factor therapy within 2 weeks of screening. • Has an HbA1c level of > 12% (indication of uncontrolled DM). • Has serum albumin level of <3 g/dL (indication of malnutrition). • Documented history of alcohol or substance abuse within 6 months of screening. • Currently enrolled or who have participated, within 30 days of screening, in another investigational device, drug or biological trial that may interfere with study results. • Pregnant at time of screening. • Has any PBM device at home.	Adult: 18 Year(s)-44 Year(s)	18 Year(s)	90 Year(s)	Both

ETHICS APPROVAL

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

22/07/2021

University of Johannesburg Faculty of Health Sciences

Ethics Committee Address
Street address	City	Postal code	Country
37 Nind St, Doornfontein	Johannesburg	2028	South Africa

Has the study received appropriate ethics committee approval

Date the study will be submitted for approval

Date of approval

Name of the ethics committee

Yes

24/03/2022

University of Johannesburg Faculty of Health Sciences. Research Ethics Committee

Ethics Committee Address
Street address	City	Postal code	Country
37 Nind Street, Doornfontein,	Johannesburg	2028	South Africa

OUTCOMES
Type of outcome	Outcome	Timepoint(s) at which outcome measured
Primary Outcome	To evaluate the effectiveness of the B-cure laser pro as an adjuvant to standard treatment (experimental group) compared to sham-control with standard treatment (control group) for healing diabetic foot ulcers in patients with skin types V and VI. The primary endpoint is the incidence of complete (100%) wound closure defined as complete re-epithelialization without drainage.	12 weeks from initiation of treatments
Secondary Outcome	To compare the rate of diabetic foot ulcer complete wound closure between groups. The secondary endpoint is the time to 100% wound closure.	12 weeks from initiation of treatments.
Secondary Outcome	To compare the rate of diabetic foot ulcer wound closure between groups. The endpoint is the time to 50%, 75% and 90% wound closure.	Up to 12 weeks from initiation of treatments.
Secondary Outcome	To determine the effect of treatment on quality of life of patients with diabetic foot ulcers. The endpoint is the Quality of Life improvement from day 0 to week 12 or closure using the Diabetic Foot Ulcer Scale - Short Form.	baseline, week 6 and 12 or wound closure, and 3 months after wound closure.
Secondary Outcome	To determine subjective satisfaction with the treatment procedure. Subjective satisfaction based on a 5-point Likert scale [very dissatisfied to very satisfied].	At 6 and 12 weeks or wound closure
Secondary Outcome	To evaluate the long-term effectiveness of the B-cure treatment. The endpoint is the change in wound size from wound closure or 12 weeks	3 months after 12 weeks or wound closure
Secondary Outcome	To evaluate the effect of the treatment on tissue composition using digital photography. Changes in tissue composition from baseline as analyzed by the digital photography.	baseline, weeks 2, 4, 6, 8, 10, and 12 or wound closure, and 3 months after wound closure
Secondary Outcome	To evaluate changes in thermal imaging of diabetic wounds. The endpoint is the change in wound thermal imaging from baseline.	Baseline, 2, 4, 6, 8, 10, and 12 weeks or wound closure and 3 months after wound closure
Secondary Outcome	To evaluate changes in nerve conduction. The endpoint is the change in pressure applied from baseline using the monofilament test.	Baseline, and weeks 4, 8 and 12 or wound closure and 3 months after wound closure

RECRUITMENT CENTRES
Name of recruitment centre	Street address	City	Postal code	Country
University of Johannesburg Podiatry Clinic	84 Sherwell St	Johannesburg	2028	South Africa
Helen Joseph Hospital	1 Perth Road	Johannesburg	2092	South Africa
Charlotte Maxeke Academic Hospital	17 Jubilee Road	Johannesburg	2193	South Africa
Chris Hani Baragwaneth Academic Hospital	26 Chris Hani Rd	Johannesburg	1864	South Africa

FUNDING SOURCES
Name of source	Street address	City	Postal code	Country
University of Johannesburg	37 Nind Street	Doornfontein	2028	South Africa

SPONSORS
Sponsor level	Name	Street address	City	Postal code	Country	Nature of sponsor
Primary Sponsor	Prof Nicolette Houreld	37 Nind Street	Johannesburg	2028	South Africa	University

COLLABORATORS
Name	Street address	City	Postal code	Country

CONTACT PEOPLE
Role	Name	Email	Phone	Street address
Principal Investigator	Nicolette Houreld	nhoured@uj.ac.za	0027115596833	37 Nind St, Doornfontein
City	Postal code	Country	Position/Affiliation
Johannesburg	2028	South Africa	Professor Laser Research Centre University of Johannesburg
Role	Name	Email	Phone	Street address
Public Enquiries	Nicolette Houreld	nhoureld@uj.ac.za	0027115596833	37 Nind Street, Doornfontein
City	Postal code	Country	Position/Affiliation
Johannesburg	2028	South Africa	Professor Laser Research Centre University of Johannesburg
Role	Name	Email	Phone	Street address
Scientific Enquiries	Nicolette Houreld	nhoureld@uj.ac.za	0027115596833	37 Nind Street, Doornfontein
City	Postal code	Country	Position/Affiliation
Johannesburg	2028	South Africa	Professor Laser Research Centre University of Johannesburg

REPORTING
Share IPD	Description	Additional Document Types	Sharing Time Frame	Key Access Criteria
Yes	Data collection is the responsibility of the researcher and together with the investigator (supervisor) is responsible for ensuring the accuracy, completeness, legibility, and timeliness of the data reported. Hardcopies of the study visit worksheets will be provided for use as source document worksheets for recording data for each participant enrolled in the study. Electronic data (clinical data entered into electronic files and participant wound photographs) will be kept in password protected files, accessible only by the researcher and supervisors, on two separate password protected devices (computer/laptop by researcher and investigator/supervisor). Electronic data will also be regularly backed-up onto a dedicated external hard drive and stored in a locked cupboard in the investigator/supervisor’s office, as well as backed-up in cloud storage. Copies of hardcopy documents will be made and stored (including originals) in different locations in a locked cupboard by the researcher and investigator/supervisors (minimum of two copies). Electronic copies of all hardcopy research documents and data will also be created and stored as indicated above, for the purposes of redundancy. Electronic data and hardcopy documents will be synchronized when changes are made to them so that there is coherence amongst all of them. Research data and documents (hardcopies and electronic copies) entering the inactive stage will be retained and archived (one copy of each; hardcopy and electronic) as described above (in locked cupboard and in password protected files on a password protected device by the supervisor/department) for 15 years.	Informed Consent Form,Study Protocol	2 years from study approval	Access to data is controlled and all requests should be emailed to the principle investigator, Prof Nicolette Houreld, who will decide based the quality of requests.
URL	Results Available	Results Summary	Result Posting Date	First Journal Publication Date
	No
Result Upload 1:	Result Upload 2:	Result Upload 3:	Result Upload 4:	Result Upload 5:

Result URL Hyperlinks	Link To Protocol
Result URL Hyperlinks

Changes to trial information

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