Blu Light for Ulcers Reduction
Condition: Leg Ulcers Venous; Dehiscence, Surgical Wound
MeSH terms: Varicose Ulcer; Leg Ulcer; Ulcer; Surgical Wound Dehiscence; Surgical Wound
Study type: Interventional

Summary: 
      Multi-center study on the effectiveness of treatment with a blue light medical device
      (EmoLED) in the reduction of ulcer surface in 10 weeks.

      The aim of BLUR clinical trial is to verify if the proposed treatment represents a valid and
      significant remedy for Chronic Venous Insufficiency ulcers. The effectiveness will be
      measured through the evaluation of the reduction percentage of the lesion area during 10
      weeks of treatment comparing the lesion (or portion of it) treated with EmoLED versus the
      control lesion (or portion of it) treated only according to current Standards of Care(SOC).

      In the 10 weeks following the recruitment, the patient continues to follow the usual topical
      therapy with a frequency of once a week visit. The patient will be monitored up to the first
      event occurring: Complete healing or ten weeks. During the study, reports and evaluations
      will be made by medical staff on the device safety and usability.

      90 patients will be recruited corresponding to the following criteria:

        -  Subjects suffering from venous, arterial and mixed skin ulcers and surgical dehiscence
           lesions;

        -  Presence of similar multiple lesions or lesions larger than 5 cm ;

        -  Men and women ≥ 18 years old;

        -  The patient must be able to understand the aims of the clinical study and provide
           informed consent in writing;

        -  Chronicity of the lesion: at least 8 weeks. The present clinical trial will be a
           multi-center prospective, controlled study with the aim of verifying the clinical
           efficacy of a portable battery-powered device based on blue LEDs.

      We expect to record at least 20% of the difference between treated lesion and untreated
      lesion on the same patient during observation time.

      The treatment, additional to the standard therapy for the patient, will be performed at each
      visit for 60 seconds on each 5 cm diameter sub-area of the selected lesion or on part of it.

      In case of multiple lesions, one will be treated with EmoLED and one will be selected as a
      control lesion. In case of a very extensive lesion, it will be divided into two and one half
      will be the control of the other.

      All lesions will be cleansed with saline solution and a surgical debridement will be
      performed with a scalpel if a slough/black base is present. Only then the treatment with
      EmoLED will begin.

      If the patient has more than one lesion at the recruitment time, and all lesions are less
      than 5 cm in diameter, the worst lesions will be treated entirely with the EmoLED device and
      the others will constitute the control lesions. The evolution of all lesions in the ten weeks
      of the study duration will be evaluated.

      If the patient has only one lesion greater than 5 cm in diameter at the recruitment time, the
      lesion will be divided into two parts along the major side and one half of the lesion area
      will be treated. The other half of the lesion will be masked with multi-layered sterile gauze
      during treatment. The point of division of the lesion into two parts will be indicated with
      an indelible marker and retouched at each visit.

      If, at the time of recruitment, the patient has more than one lesion with a diameter greater
      than 5 cm, all lesions will be divided into two along the major side and will be treated as
      in the previous case.

      After treatment with EmoLED, a hydrofiber dressing will be applied to the lesion. If clinical
      signs of infection occur, a hydrofiber dressing with silver will be applied. If necessary,
      compressive bandage of the limb will be carried out.
    

Detailed description: 
      A total of 90 subjects will be recruited at the facilities involved in the clinical study.
      All patients, both hospitalised and outpatient, will be considered for inclusion in this
      study.

      The patients will be using a standard procedure that includes the evaluation of anamnesis and
      a physical examination.

      All inclusion and exclusion criteria must be satisfied before recruitment. Any concomitant
      pharmacological therapy must be maintained.

      Patients recruitment and screening The Principal Investigator or his delegate selects the
      enrolled patients on the basis of the inclusion and exclusion criteria of the study. Once the
      patient's correspondence with the study's criteria has been verified, the Principal
      Investigator or his delegate asks the patient for consent to use the EmoLED treatment device,
      and briefly explains the characteristics of the device and the expected effect. If the
      patient agrees, the Principal Investigator or his delegate proceeds to treatment. The patient
      must give his readiness to return to the structure every week for the established observation
      time.

      Patient Identification Register The Principal Investigator is responsible for the updating
      and custody of the Patient Identification Register.

      The Patient Identification Register contains the personal data of the patients participating
      in the study, the date of recruitment and the patient code (the structure number followed by
      a progressive two-digit numerical code).

      Only the Principal Investigator and, at the discretion of the Principal Investigator, the
      members of his team know the identity of the patients enrolled in the study.

      If a patient withdraws from the study, the Principal Investigator or his delegate records the
      event in the Patient Identification Register and on the Data Collection Form and stores all
      documentation.

      Patient Enrolment Format For each new patient, the Principal Investigator or his delegate
      fills the Patient Enrolment Format that contains data such as patient identification (Name
      and Surname are to be understood as those of the data collection form, ie identification code
      of the center and number), age, gender, aetiology of the ulcer, any concomitant diseases,
      drug therapy, date of ulcers beginning and date of recruitment.

      The second part of the format contains a table in which the date of the visit, the data on
      the patient's health, and the data collected are recorded at each visit.

      Registration of clinical data The data related to the evaluation of the study endpoints are
      acquired at precise times, corresponding to the timepoints reported in the protocol and in
      the Data Collection Form.

      The parameters of the Data Collection Form are acquired and maintained on paper format for
      the duration of the trial. Once the study on the patient has been completed, they are kept in
      both paper and digital format, after scanning the paper form. The photos of the wound are
      acquired and stored in digital format, both for the duration of the study and subsequently.

      Data Collection Form The Data Collection Form is unique for each patient. It consists of some
      columns to fill in according to the observation times. At each visit, the doctor indicates
      with an "X" the value chosen for each parameter.

      The Data Collection Form is scanned and archived after the patient's discharge or withdrawal
      of the trial.

      Centralised database The Principal Investigator sends to the Project Manager the Patient
      Enrolment Formats of the new recruited patients and the photographic records of the all
      patients returned to the control every week. For patients leaving the study, the Data
      Collection Form will also be transmitted.

      The Project Manager creates a unique database of all the patients, updated every week with
      the latest available data and consulted by the Principal Investigators. The creation of this
      database allows investigators to be aware of the number of patients still to be recruited and
      of the study progress.

      Data recording Following the recruitment and the signing of the informed consent, the data
      relevant to each patient will be collected in the Data Collection Form at different times: S0
      (Week 0: recruitment and first treatment), S1, S2, S3 ... up to S10 (visits in the 10 weeks
      following recruitment).

      Patients may miss a maximum of two not consecutive visits, starting from the fifth visit. The
      patient who misses one of the first four visits or two consecutive visits, will be excluded
      from the study.

      The parameters used to define the study result will be found through:

        -  photographic images of lesions treated with EmoLED and control lesions

        -  Data Collection Form filled by the personnel during the visit.

      SERIOUS ADVERSE EVENTS (SAE) Although the available literature and the in vivo tests
      performed provide reasonable certainty of the safety of the device in case of the occurrence
      of SAE it will be managed according to the following procedures: Good Clinical Practice Med
      Dev 2.7/3 and International Standard Organisation 14155. There will be a constant monitoring
      of the health condition of the patient during the trial phase and for a reasonable period of
      time after the trial end. Any SAE reported by the patient and/or the investigator or any
      member of his team will be reported through the module "Adverse Event Module" and timely
      communicated to the Competent Authority.

      CALCULATION OF SAMPLE NUMEROSITY The choice of the statistical model used is based on the
      literature research on wound healing trends and the past clinical experience and recorded
      data of the hospital center involved in the study. The most relevant information emerged is
      that at 10 weeks is expected a 30% variability in the reduction percentage of the wound
      dimension. This value is confirmed by [15 see citation] where has been used for the sample
      sizing. Moreover in [16 see citation] a 53% deviation standard of the lesion reduction
      percentage in the worst case of venous ulcers.

      The analysis for the sample sizing is based upon:

      The clinical goal expressed in the percentage of reduction of the lesion area at ten weeks;
      The non-parametric statistical test for pair of data, consisting in the Wilcoxon rank-sum
      test; An a priori hypothesis of 50% on the expected variability (conservative value); An
      average 20% difference between treated and non-treated; A statistical power equal to 80%
      (Beta=0.2) and Afa =0.05; The unilateral alternative hypothesis: the EmoLED treatment does
      not worsen the outcome; A correlation coefficient between treated area versus non treated
      area equal to 0.1, 0.3, 0,5 and 0.7; The numerosity of the sample is calculated according to
      the method of the relative asymptotic efficiency in respect to the t test (min AREA), the
      case of R =0.1 (minimum coefficient) indicate N=83 patients , this has been used to establish
      in 90 patients the sample numerosity (considering the drop out risk).

      Statistical analysis of the primary endpoint The device effectiveness will be measured
      performing a Wilcoxon signed rank test with a one-sided level of significance Alfa=0.05. This
      test is useful for analysing paired data and takes in to consideration the sign and the
      magnitude of the observed differences. There will be an analysis of the entire protocol as
      well as of different possible populations.

      STATISTICAL ANALYSIS OF THE SECONDARY ENDPOINT

        1. Safety: all SAE recorded will be managed with the appropriate statistical instrument
           according to the size and type of events reported.

        2. Comparison of the outcome in terms of percentage reduction of the wound treated with
           EmoLED + SOC versus the one treated only with SOC in the 10 weeks of observation: At
           every observation date both treated and non-treated wound will be measured. The pair
           data will be statistically analysed with repeated measures. There will be both a
           punctual analysis as well as an overall trend analysis of the whole period considered.
           In the first case the paired data will be observed using a parametric test (t-test) or a
           non-parametric test (Wilcoxon of the signed rank) according to the data distribution
           observed. A correction of the statistical significance such as the Benjamini-Hochberg
           correction will be applied. In the second case, a view of the differences in healing
           trends between treated and non- treated will be obtained through the evaluation of the
           are under the curve for each subject an in each area. The paired data will be observed
           using a parametric or a non-parametric test. In both cases, missing data will be
           replaced using the mean value of the other patients. A sensitivity analysis will be
           performed using the max and min value observed in patients.

        3. Evaluation of the gap in healing time between the two areas: A survival analysis based
           on the Akritas test applied to the Kaplan-Meier curves will be used. Such analysis is
           useful to evaluate the time to reach the event of interest that in this case is reaching
           healing level > or = to 70% in 10 weeks. Such technique can handle paired data and the
           event of possible drop outs. For each group (treated and non-treated) will be built a
           curve , the Akritas test is based on a transformation in ranks of the "survival" times
           intended as the "time to event" considered as a healing level > or = to 70% in 10 weeks.
           The ranks will be transformed according to a model that allows stop and censures.

        4. Pain reduction measured with a Visual Analogical Scale (VAS) 0-10. A non-parametric
           Friedman test will be used, the equivalent of a non-parametric test ANOVA for repeated
           measures.

      All data regarding the patients will be maintained as strictly confidential and their
      informed consensus obtained at the enrolment time will be identified with a coding system all
      investigator will keep the data up to two years after the study's end.

      MONITORING The study coordination is assigned to an independent third party qualified for the
      purpose (independent CRO), it will be responsible for the adherence to the International
      Conference on Harmonization (ICH)/Good Clinical Practice (GCP) guidelines. The coordinator
      will perform regular monitoring visits at the investigator site to make sure that all data
      are properly recorded and maintained it will have access to all data to ensure the adherence
      to the Protocol and the accuracy, coherence and precision of the data collected.

      ETHICAL CONSIDERATIONS The study will be submitted to the Ethical Committee of each
      investigator hospital for approval and in any case will be performed according to the
      Helsinki Declaration and the Italian laws and requirements in the matter of human clinical
      trials.
    

Intervention name(s): Illumination with blue light (400-430nm) for 60 seconds with a power density of 120mW/sqcm (EmoLED device)
Intervention type(s): Device
Intervention description(s): Debridement and Dressing or compressive dressing if needed
Other intervention name(s): Standard of Care (SOC)
Intervention model: Single Group Assignment
Intervention model description: Patient used as control of himself: If a patient carries a wound with a diameter larger than 5 cm the wound is divided in two parts on treated with the Device the other covered and used as control, if the patient has two or more separate wounds each smaller than 5 cm in diameter the worst of them is treated the others used as control.
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: Blue Light; Photo-bio-modulation; ulcers; leg ulcers Venous; dehiscence surgical wound; non healing wound