Cold Plasma Therapy for Acceleration of Wound Healing in Diabetic Foot

Cold Plasma Therapy for Acceleration of Wound Healing in Superficial, Infected Diabetic Foot

Diabetic foot is a common complication of diabetes mellitus and requires specialized treatment. Wounds are characterized by persistent infection and chronic inflammatory processes, impeding well directed matrix remodelling and wound closure. Cold plasma applications have demonstrated beneficial effects on wound healing in several case reports. The investigator-initiated "Kaltplasma Wund (KPW)-Trial" was performed to prove beneficial effects of cold plasma in wound healing in a prospective, placebo-controlled, randomized bi-center study.

Study Overview

• Status: Active, not recruiting
• Conditions: Diabetic Foot
• Intervention / Treatment: Device: Argon Plasma Jet; Device: Placebo

Detailed Description

Diabetic foot (DF) is a major complication in patients with diabetes leading to increased risk of hospitalization, lower limb amputation, and death, as well as a significant decrease in quality of life. During lifetime the risk for developing DF is assumed to be 25%; with 30% of DF resulting in lower limb amputation. If compared to general population people with diabetes have a 20-fold higher risk for amputation. Diabetes mellitus is the leading cause of lower limb amputation. Ulceration and impaired wound healing are commonly associated with common co-morbidities; the increased risk of infection amongst patients with diabetes is driving chronification and accounts for lack of wound healing.

Non-thermal atmospheric pressure plasma has been proposed as a tool for various biological and medical applications relying on its capacity to reduce bacterial load in the wound and to initiate wound healing. Biological plasma effects are largely dependent on plasma-generated reactive species in the gas phase, which subsequently diffuse or react with proteins and lipids in cells or tissues.

Thus, the objective of this placebo-controlled patient-blinded study was to show that application of cold plasma in addition to standard care treatment compared to placebo could accelerate wound healing in terms of more rapid and clinical meaningful wound surface regression. Wound closure progression and microbiological analysis were monitored time dependently to prove the effects. Patient's well-being and subjective perceptions were evaluated during treatment.

• Study Type: Interventional
• Enrollment (Actual): 65
• Phase: Not Applicable

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 80 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

• Type 1 or Type 2 Diabetes mellitus
• HbA1c ≤ 10%
• at least one chronic wound persisting for at least three weeks without healing tendency following standard care wound therapy (Armstrong Wagner Grade Ib or IIb)

Exclusion Criteria:

• concomitant wound treatment with local vacuum therapy or maggot therapy
• dialysis
• use of topical active antibiotics,
• concomitant treatment with platelet rich fibrin,
• presence of critical limb ischemia defined as ankle brachial index below 0.5 or transcutaneous oxygen pressure below 15 mmHg.
• participation in another clinical trial
• women of child bearing potential without effective contraception or active breastfeeding

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Single

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Plasma; regular treatment with Argon Plasma Jet according to manufacturer's instructions, 8 times within 14 days	Device: Argon Plasma Jet; Cold Plasma (CP) therapy is applied in the first week of treatment on a daily schedule, in the second week CP is applied every second day. In total, 8 applications are performed with a one day schedule variance.
Sham Comparator: Placebo; Sham-treatment with Argon Plasma Jet, Plasma producing electric field switched off - no Plasma is produced, just argon gas as effluent, 8 times within 14 days	Device: Placebo; Sham Cold Plasma (sham-CP) (switched off Electric field, no plasma production, just gas) therapy is applied in the first week of treatment on a daily schedule, in the second week sham-CP is applied every second day. In total, 8 applications are performed with a one day schedule variance.

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
change in wound surface area	change in wound surface area within 14 days treatment	treatment period of max 15 days
change in signs of clinical infection	change in clinical signs of infections as judged by the investigator	treatment period of max 15 days
change in microbial load	change in microbial count, being evaluated by microbial culture	treatment period of max 15 days

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
time to significant wound surface area change	time to 10% reduction of wound surface compared to treatment start	treatment period of max 15 days
total wound surface change during treatment	total wound surface change compared to treatment start	treatment period of max 15 days
time to change in wound infection	change in wound infection over treatment	treatment period of max 15 days
changes in Quality of life (EQ5D questionnaire)	Evaluation of life quality during (EQ5D questionnaire) treatment period via questionaire	treatment period of max 15 days
changes in Quality of life (SF12 questionnaire)	Evaluation of life quality during (SF12 questionnaire) treatment period via questionaire	treatment period of max 15 days
treatment related side effects - formation of keloids	question to evaluate potential side effects of the therapy: formation of keloids will be answered in a "yes" or "no" fashion and reported	treatment period of max 15 days
treatment related side effects - presence of skin irritation	question to evaluate potential side effects of the therapy: presence of skin irritation will be answered in a "yes" or "no" fashion and reported	treatment period of max 15 days
treatment related side effects - local bleeding	question to evaluate potential side effects of the therapy: local bleeding will be answered in a "yes" or "no" fashion and reported	treatment period of max 15 days
treatment related side effects - proliferative skin reaction	question to evaluate potential side effects of the therapy: proliferative skin reaction will be answered in a "yes" or "no" fashion and reported	treatment period of max 15 days

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
treatment related side effects - formation of keloids	descriptive evaluation of side effects within 5 years after Treatment (at 1, 2 and 5 years after start of treatment) question to evaluate potential side effects of the treatment: formation of keloids will be answered in a "yes" or "no" fashion and reported	within 5 years after start of treatment (at 1, 2 and 5 years after start of treatment)
treatment related side effects - presence of skin irritation	question to evaluate potential side effects of the therapy: presence of skin irritation will be answered in a "yes" or "no" fashion and reported	within 5 years after start of treatment (at 1, 2 and 5 years after start of treatment)
treatment related side effects - local bleeding	question to evaluate potential side effects of the therapy: local bleeding will be answered in a "yes" or "no" fashion and reported	within 5 years after start of treatment (at 1, 2 and 5 years after start of treatment)
treatment related side effects - proliferative skin reaction	question to evaluate potential side effects of the therapy: proliferative skin reaction will be answered in a "yes" or "no" fashion and reported	within 5 years after start of treatment (at 1, 2 and 5 years after start of treatment)

Collaborators and Investigators

• Sponsor: Ruhr University of Bochum
• Investigators: Principal Investigator: Diethelm Tschoepe, Prof, Herz- und Diabeteszentrum NRW, Ruhr-Universität Bochum

Publications and helpful links

General Publications

• Hiller J, Stratmann B, Timm J, Costea TC, Tschoepe D. Enhanced growth factor expression in chronic diabetic wounds treated by cold atmospheric plasma. Diabet Med. 2022 Jun;39(6):e14787. doi: 10.1111/dme.14787. Epub 2022 Jan 21.
• Stratmann B, Costea TC, Nolte C, Hiller J, Schmidt J, Reindel J, Masur K, Motz W, Timm J, Kerner W, Tschoepe D. Effect of Cold Atmospheric Plasma Therapy vs Standard Therapy Placebo on Wound Healing in Patients With Diabetic Foot Ulcers: A Randomized Clinical Trial. JAMA Netw Open. 2020 Jul 1;3(7):e2010411. doi: 10.1001/jamanetworkopen.2020.10411. Erratum In: JAMA Netw Open. 2020 Oct 1;3(10):e2024427.

Study record dates

Study Major Dates

• Study Start (Actual): August 17, 2016
• Primary Completion (Actual): April 20, 2019
• Study Completion (Anticipated): April 30, 2024

Study Registration Dates

• First Submitted: December 12, 2019
• First Submitted That Met QC Criteria: December 17, 2019
• First Posted (Actual): December 20, 2019

Study Record Updates

• Last Update Posted (Actual): March 29, 2023
• Last Update Submitted That Met QC Criteria: March 28, 2023
• Last Verified: March 1, 2023

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Skin Diseases; Endocrine System Diseases; Diabetic Angiopathies; Leg Ulcer; Skin Ulcer; Diabetes Complications; Diabetes Mellitus; Diabetic Neuropathies; Foot Ulcer; Diabetic Foot
• Other Study ID Numbers: KPW2016-1.1

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO
• IPD Plan Description: no sharing of patient data planned, data are analysed locally

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No