Clinical trial NCT03985306: Treatment of Diabetic Foot Ulcers With Inforatio Technique to Promote Wound Healing
Official title: Treatment of Diabetic Foot Ulcers With Inforatio Technique to Promote Wound Healing: a Feasibility Trial
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: NA
Conditions: Diabetic Foot Ulcer
Diabetic Foot
Wound Heal
Ulcer Foot
Ulcer Healing
Keywords: Diabetic foot ulcer
Wound treatment
Inforatio technique
Diabetes
Foot ulcer
Outpatient clinic
Feasibility trial
Punch biopsy
Foot ulcer treatment
Lead sponsor: Zealand University Hospital
Sponsor class: OTHER
First posted: 2019-06-13
Enrollment: 12
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: NA
Intervention model: SINGLE_GROUP
Intervention model description: The trial is a single-center single-group feasibility trial in outpatient clinical settings.

The trial will be reported with reference to the extended CONSORT guidelines.
Primary purpose: TREATMENT

Brief summary: This trial will examine the feasibility of conducting a definitive randomized clinical trial that tests whether inforatio technique will reduce time to healing of diabetic foot ulcers. Inforatio technique is a procedure where small punch biopsies are taken from the wound bed near the edge of the wound. With this technique, the investigators wish to initiate an acute inflammatory response that increases the generation of granulation tissue with subsequent healing by scar formation. Thus, the investigators hypothesize that inforatio technique will promote healing of diabetic foot ulcers.

Based on clinical experience, the investigators have previously detected a reduction in time to healing as an unexpected effect when multiple punch biopsies are taken from the wound bed of diabetic foot ulcers. To the knowledge of the investigators, methods similar to the inforatio technique has not previously been studied.

Detailed description: BACKGROUND

The prevalence of diabetic foot ulcers is expected to increase considerably due to a continuously increasing prevalence of diabetes. The healing process of diabetic foot ulcers is complicated by a complex pathophysiology of the distal lower extremities and a constant exposure to bacteria and pressure. Improving healing of diabetic foot ulcers will have several benefits including higher quality of life, reduced morbidity, reduced mortality and lower socioeconomic costs. Nonetheless, there are few randomized controlled clinical trials on surgical and non-surgical treatment chronic foot ulcers and many studies on the topic have a low level of evidence.

TRIAL AIMS

The investigators aim to assess the feasibility of conducting a definitive randomized controlled trial by exploring recruitment, patient acceptability, protocol adherence and adverse effects.

The success criteria of the trial is as follows:

* Weekly recruitment rates at two patients or more.
* Time from first outpatient visit to recruitment at 21 days or less.
* Retention rate at 90-day follow-up at 50% or more
* No appearance of unacceptable adverse effects In addition, the trial aims to assess logistic concerns regarding the trial and to improve the method of inforatio application.

Based on findings from the feasibility trial, the investigators may amend the design of the definitive trial.

RECRUITMENT

Patients are eligibility-screened and identified by the primary investigator and wound care staff when patients visit wound outpatient clinics at the recruiting facilities.

INCLUSION AND FOLLOW-UP

Eligible patients are included if they give their oral and written consent to participate. The baseline trial visit take place on the day that patients give their consent to participate.

The trial comprises a 90-day clinical follow-up. Follow-up visits will be at 10, 21, 42 and 90 days after baseline (give or take 3 days). Wounds are assessed at each trial visit. The inforatio technique is applied at baseline and again at the 21-follow-up day if the wound still has a diameter larger than four mms. Participants unable to attend at the precise dates for midtrial follow-up will be eligible for follow-up three days before or after the intended date. The participants who cannot attend during this window will skip the follow-up day in concern. If the participants miss the second intervention at the 21-day follow-up, they are excluded. For the 90-day follow-up, participants are recalled two times by the primary investigator within two weeks before being excluded.

Participants exit from the trial if following occurs during follow-up:

* they undergo surgeries described in the exclusion criteria
* they get acute signs of infection, gangrene or osteomyelitis in their foot in concern
* their tendons, joints or bone become exposed in the wound bed
* they develop an acute phase of charcot arthropathy in their foot in concern
* they get admitted for reasons related to their foot ulcer
* they die or emigrate

The trial is stopped if the intervention shows an unintended effect or potential harm.

TRIAL STANDARD TREATMENT

The participants receive a trial standard treatment at every trial visit. The treatment is conducted by the primary investigator in cooperation with wound care nurses and podiatrists. The standard treatment is defined based on Danish National guidelines, local guidelines of the recruiting facilities and guidelines of the National Institute for Health and Care Excellence.

The treatment is based on a flowchart that individualizes treatment based on clinical wound characteristics.

INFORATIO TECHNIQUE

The technique is described in the Arms and Interventions section.

TRIAL MEASURES

Wound assessment: Wounds are assessed at every trial visit. To monitor the ulcer area during follow-up, the investigators will analyze digital photos of the ulcer by using Image J which is a wound planimetry software. The depth of the ulcers are measured with sterile wound probes and reported by intervals of 5 millimeters. Undermining will be assessed with the same method as for depth and in intervals of 5 millimeters.

Microbial samples: At both stages of inforatio application, three punch biopsies are sent for cultivation to analyze bacterial species, bacterial load and resistance patterns of the bacteria.

Patient and staff interviews: described in the Outcome Measures section

STATISTICAL ANALYSIS

With descriptive statistics participants' demographics, the quantitative success criteria, the quantitative outcome measures and time to healing will be reported. Clinical healing is defined by intact epithelia.

The investigators will use statistical software SPSS version 21.0 (IBM Corp., Armonk, New York).

SAMPLE SIZE CONSIDERATION

Because effectiveness is not evaluated, a formal power calculation is not considered necessary for the objectives of a feasibility trial.

To minimize the number of patients that are exposed to a new intervention meanwhile keeping a level of precision for the variance estimate, the rule of thumb by Julious et al will be used for determination of the trial sample size. Thus, 12 participants will be included in the trial. Julious et al argues that a sample size of 12 per group gives a sufficient precision of the mean and variance estimates. Other studies report rules of thumbs with larger sample size to gain sufficient power for a pilot or feasibility trial.

ETHICAL CONSIDERATIONS AND RISK ASSESSMENT OF SIDE EFFECTS

The procedure of the intervention is small with an expectedly small risk of harm outcomes. The punch biopsies from the inforatio technique is relatively shallow therefore it is not expected that it will penetrate important anatomical structures or expose bone.

The primary investigator's clinical assessment, patient preference and patient tolerance is taken into consideration before inforatio technique is applied. Minimal discomfort is expected for the participants when they receive the inforatio technique treatment. Previous applications by the investigators showed that patients reported no or little pain during application.

The inforatio technique treatment has previously shown potential to improve healing thus participants may gain an improvement in healing of their foot ulcers.

If this trial shows that a definitive randomised clinical trial will be feasible, the investigators will examine the effect of inforatio technique through a larger randomised clinical trial. If the inforatio technique shows significant positive effect on time to healing it would become of great importance for future diabetic foot ulcer patients. The inforatio technique would become an addition to available therapeutic options. The technique is simple and only requires a punch biopsy tool. Nurses and general practitioners can be potential applicants that apply the treatment at clinics close to patient habitats making visits for wound treatment more convenient for the patients. If there is a significant positive effect on healing, it is expected that it will result in reduction of hospital admissions and less surgical interventions including amputations.

This project may contribute to more focus on treatment of patients with diabetic foot ulcers - a field of research that still needs studies to enable evidence-based treatment.

Inspectors from The National Committee of Health Research Ethics will have the authorization to quality control the trial.

COMPETING INTERESTS

The trial investigators declare that they have no competing interests.

Eligibility criteria: INCLUSION CRITERIA:

We include diabetic patients with foot ulcers that are more than six weeks old and which are located distal to the malleoli.

The diameters of the ulcers must be at least four mms. One wound from each foot of a patient can be included. If a patient's foot have more than one ulcer that meets the abovementioned criteria, the biggest wound is included. If there is no difference in size, the wound that has the most recent onset is included. If two wounds are close to each other and separated by less than 5 mm intact skin, we will consider it as one wound.

Wound onset estimates will be patient-reported.

EXCLUSION CRITERIA:

We exclude following patients:

* Patients with dementia and other patients who are not able to give their informed consent.
* Patients with gangrene, necrosis deeper than 1mm, osteomyelitis and clinical signs of infection in their foot. Infection is identified by clinical assessment based on the classical signs comprising oedema, pain, warmth, redness and purulent exudates and is assessed by an experienced orthopedic surgeon.
* Patients with ulcers that have positive probe-to-bone test and visible joint and tendons
* Patients with systolic toe pressure of \< 20 mmHg
* Patients that, since the onset of their present foot ulcer, underwent vascular surgery in the lower extremity with the same laterality as the foot ulcer.
* Patients that, since the onset of their present foot ulcer, underwent surgical off-loading and amputations
* Patients that, since the onset of their present foot ulcer, underwent surgical wound revisions in an operating room.
* Patients that have an acute phase of Charcot arthropathy in the foot that presents with a foot ulcer.
* Patients that take systemic immunosuppressive drugs.
* Patients with cancer
* Patients with scleroderma

Primary outcomes:
measure: Eligibility rates
timeFrame: The first 2 months of the trial (untill the last patient has been recruited)
measure: Refusal rates
timeFrame: The first 2 months of the trial (untill the last patient has been recruited)
measure: Time from identification to inclusion
timeFrame: The first 2 months of the trial (untill the last patient has been recruited)
measure: Qualitative assessment of unexpected factors that must cause exclusion
timeFrame: 10 months
measure: Rate of unexpected exclusion
timeFrame: 10 months
measure: Retention rates
timeFrame: 10 months
measure: Number of missed trial follow-up visits
timeFrame: 10 months
measure: Drop-out rates
timeFrame: 10 months
measure: Rate of eligible patients that accept participation
timeFrame: At baseline, each follow-up visit and when patients drop out.
measure: Qualitative assessment of patient acceptability
timeFrame: 10 months
measure: Observed harms and unexpected effects
timeFrame: 10 months
measure: Patient-reported potential side effects
timeFrame: 10 months
measure: Qualitative assessment of logistics issues regarding outpatient clinic visits
timeFrame: 10 months
measure: Time to healing of punch biopsy scars
timeFrame: 10 months
measure: Qualitative assessment of the method of wound assessment.
timeFrame: 10 months
measure: Qualitative assessment of the extent of qualitative patient measures
timeFrame: 10 months
measure: Qualitative assessment of the feasibility of culturing 3 biopsies from each round of inforatio technique applications for a future definitive trial.
timeFrame: 10 months
measure: Rates of wound treatments at trial visits that deviate from the trial standard treatment definition
timeFrame: 10 months
measure: Qualitative assessment of wound care treatments received between trial visits and the deviations from the trial definition of standard treatment.
timeFrame: 10 months
measure: Time to healing of the foot ulcers
timeFrame: 10 months
measure: Patient-reported experience of trial participation and the inforatio technique
timeFrame: 10 months
measure: Staff acceptability
timeFrame: 10 months
measure: Qualitative assessment of the inforatio technique
timeFrame: 5 months. At baseline application and at the 21-day applications.
Secondary outcomes:
Other outcomes:
Locations:
city: Herlev
country: Denmark
facility: Herlev University Hospital, Department of Orthopaedic Surgery
city: Køge
country: Denmark
facility: Zealand University Hospital, Department of Orthopaedic Surgery
Study officials:
affiliation: Zealand University Hospital Koege, Denmark
name: Sahar Moeini, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Herlev University Hospital, Denmark
name: Hans Gottlieb, Chief consultant, MD PhD
role: STUDY_CHAIR
affiliation: Hvidovre University Hospital, Denmark
name: Tue S Jørgensen, MD PhD
role: STUDY_CHAIR
affiliation: Zealand University Hospital Koege, Denmark
name: Malene RB Larsen, MD
role: STUDY_CHAIR
affiliation: Zealand University Hospital Koege, Denmark
name: Stig Brorson, Professor, MD PhD DMsc
role: PRINCIPAL_INVESTIGATOR
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