Description

BACKGROUND

15-25% of diabetic patients develop chronic foot ulcers - a serious comorbidity that widely affects quality of life and is associated with increased mortality and morbidity. 50-60% of DFUs become infected, and 20% of patients with infected DFUs undergo lower extremity amputation.

Inforatio technique is a novel treatment of DFUs where small cuts are made in wound beds with punch biopsy tools without involving epithelia. The aim is to cause controlled bleeding and initiate an acute inflammatory response that may promote healing.

The research group has conducted a preceding feasibility trial that showed promising results (see study by Moeini et al. in the reference list). Inforatio technique may become a supplemental treatment option for diabetic patients worldwide if it shows a beneficial effect on healing.

TRIAL AIMS

This trial aims to assess whether the proportion of ulcers that heal within 20 weeks is higher when DFUs are treated with inforatio technique in addition to usual wound care compared to treatment with usual wound care alone.

RECRUITMENT

Patients are eligibility-screened and identified by the investigators and wound care staff when patients visit the recruiting wound outpatient clinics.

INCLUSION AND FOLLOW-UP

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

The trial comprises a 20-week clinical follow-up. Follow-up visits will be at 3, 6, 9, 12, 16 and 20 weeks after baseline (give or take 7 days for midtrial visits and from 20 to 22 weeks after baseline for the last trial visit).

Follow-up end whenever the following appears; 20-week follow-up visit, death, amputation, or the outpatient clinic staff observes healing.

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

RANDOMIZATION

Allocation of participants is conducted by block randomization with stratification by center and will be generated with Research Electronic Data Capture (REDCap)©. Block sizes will be randomly alternating between two and four. The allocation will immediately be revealed to the participant and wound care staff. Adequate allocation concealment is ensured by the irreversibility of randomization and the inability to predict the next allocation assignment in RedCap.

STATISTICAL ANALYSIS PLAN

Baseline characteristics will be reported with appropriate descriptive statistics. The analyses of primary and secondary outcomes will be performed on the intention-to-treat population with participants being analyzed as randomized regardless of the treatment received. Supplementary analyses will be performed on the per-protocol population, which excludes participants with one or more serious protocol violations as defined below:

• Participants not receiving their allocated treatment.
• Participants with inadequate adherence, which is defined as the following:
• Participants that miss more than 3 of the 6 follow-up trial visits.
• Participants in the intervention group that miss more than 2 of the 4 trial visits where inforatio is applied.

The primary analysis of the trial will be a logistic regression for proportion of healed ulcers with adjustment for center of recruitment.

EQ-5D-5L and Wound-QoL data will be presented descriptively in line with the guidelines for the questionnaires. A multivariate linear regression adjusting for baseline score will be performed for analysis of change in EQ-5D-5L index score and Wound-QoL global score.

Safety outcome will be descriptively reported and analyzed on 'as treated' basis where participants are grouped according to whether they received inforatio technique. Mean time and range from the last inforatio applied to an event is detected will be reported for the intervention group. A statistical comparison between groups will be conducted by chi square test and estimates of relative risk with 95% confidence interval. Inforatio-related adverse events will be descriptively reported.

An interim analyses will be performed after 50 participant has completed follow-up.

Significance is set at p-value <0.05 and p-values are two-tailed. Underlying statistical assumptions for linear and logistic regressions will be assessed graphically.

HANDLING OF MISSING DATA

Data on Wound-QoL global score that is missing due to death during follow-up, will not be considered in the handling of missing data. Otherwise, missing data on primary and secondary outcomes will be handled according to recommendations by Jakobsen et al. (see reference list). If the proportion of missing data on an outcome is <5%, the primary analysis of missing data will be complete-case analyses. If more than 5% data of an outcome is missing, the primary analysis will include missing data imputed by multiple imputation technique and complete case analysis will be performed as a sensitivity analysis. In both cases, a best-worst and worst-best case analysis will be conducted for missing data on healing.

SAMPLE SIZE

A meta analysis by Margolis et al. (see reference list) has reported a healing rate of 30.9% (95% CI 26.6-35.1) in 20 weeks for non-infected DFUs that were treated with standard wound care. A healing rate of 60% in 20 weeks was suggested by the preceding feasibility trial when patients receive inforatio technique in addition to usual wound care.

When the power is 80% and the alpha-level is 5%, a power calculation gives a sample size of 84 for comparison of two proportions when the outcome proportion is 30% for the control group and the aim is to assess whether the outcome improves with 30 percentage points in the intervention group. To allow an attrition of 20%, the aim is to recruit 100 participants for the trial.

ETHICAL CONSIDERATIONS AND RISK ASSESSMENT OF SIDE EFFECTS

Inforatio technique is a minimal invasive procedure. Thus, no adverse events are expected as a result of inforatio technique except from a low risk of pain during application. In the preceding feasibility trial, no intervention-related adverse events were observed and participants did not experience pain during application. Furthermore, inforatio technique showed a promising effect on healing.

The clinical assessment of the wound care staff, patient preference and patient tolerance is taken into consideration before inforatio technique is applied.

If the inforatio technique shows a significant positive effect on healing, it would become of great importance for future patients as a supplemental treatment to standard wound care of DFUs.

COMPETING INTERESTS

The trial investigators declare that they have no competing interests.

        Only one ulcer will be included from each participant. If a patient has more than one
        eligible ulcer, the largest ulcer is included. In case of equally sized ulcers, the ulcer
        with the most recent onset is included.
        EXCLUSION CRITERIA
          -  Dementia or other reasons that cause inability to give informed consent
          -  Malignant disease
          -  Current treatment with systemic immunosuppressive drugs.
        Exclusion criteria related to the index extremity:
          -  Diagnosed with or awaiting evaluation of suspected acute phase Charcot arthropathy or
             osteomyelitis
          -  Non-palpable pulse in both arteria dorsalis pedis and arteria tibialis posterior
             accompanied by systolic toe pressure <30 mmHg in the index foot.
          -  Amputation at midfoot level or proximal to midfoot level
          -  Revascularization procedure awaits or has been undertaken within the last 8 weeks or
             the patient awaits a vascular surgeons' decision on revascularization
          -  Gangrene
        Exclusion criteria related to the index ulcer
          -  Infection of the ulcer defined according to IWGDF/IDSA (International Working Group on
             the Diabetic Foot/ Infectious Diseases Society of America system) classification as
             presence of at least 2 of the following; 1) local swelling or induration; 2) erythema
             >0.5 to ≤2 cm around the ulcer; 3) local tenderness or pain; 4) local warmth; or 5)
             purulent discharge. Current antibiotic treatment due to infection of the index ulcer
             will also be considered as an ongoing infection regardless of presence of clinical
             signs of infection.
          -  Positive probe-to-bone test
          -  Exposed joint or tendon
          -  The soft tissue layer covering bone or joint is evaluated to be too thin to allow for
             inforatio technique anywhere in the wound bed.
          -  Interdigital ulcer location