HELP-Apheresis in Diabetic Ischemic Foot Treatment (H.A.D.I.F)
Condition: Foot Ulcers; Arteriosclerosis Obliterans; Diabetes Mellitus
MeSH terms: Arteriosclerosis; Arteriosclerosis Obliterans; Foot Ulcer; Ulcer
Study type: Interventional

Summary: 
      Diabetic foot (DF) is a common, severe and costly complication of diabetes. DF is underlied
      by neuropathy, atherosclerosis of distal arteries and infection, which result in tissue
      ulcers and necrosis. Alterations in microcirculatory function and in blood rheology may
      concur in causing tissue damage.

      In recent years there has been accumulating evidence that LDL apheresis (LA) does not only
      reduce cholesterol but also has a series of pleiotropic effects that improve the
      microcirculation, increasing peripheral tissue perfusion.

      HADIF is a randomized, multicentric, prospective clinical study aimed at assessing the effect
      of LDL apheresis treatment in association with traditional therapy for ulcers, in patients
      with an ischemic diabetic foot ulcer (class I and II Texas Wound Classification System)and
      peripheral vasculopathy not susceptible to revascularization. A total of 132 patients will be
      enrolled. Participants will be centrally randomized to receive traditional therapy alone (TT)
      or in association with LA. TT includes standard medication of ulcers, antiaggregant therapy
      and statins. LA will be performed with HELP system, for a total of 10 sessions in 9 weeks.
      The primary end-point of the study is ulcer healing; secondary endpoints include improvements
      of peripheral oxygenation, resolution of pain, reduction of circulating inflammatory markers,
      cardiovascular events during one year's follow-up.

      This clinical Study has been approved by local EC on 25 may 2011 (Study number 1953).

      TO BE NOTED: since diabetic patients in our "Diabetic-Foot UNIT" often presented foot ulcers
      more severe than class II Texas, a formal amendment has been submitted to EC for recruiting
      patients with diabetic foot ulcer of class III Texas. The amendment was already approved on 5
      may 2012.
    

Detailed description: 
      Aim of the protocol is to evaluate the effect of LDL-apheresis in combination with
      traditional therapy, on the recovery of diabetic ulcers in patients suffering from diabetic
      ischemic foot and peripheral vasculopathy that cannot be revascularized.

      Patients who qualify for the study will be randomized to the traditional treatment combined
      to apheresis (Experimental Arm) or to the standard treatment only (control Arm).

      The randomization stratified according to the lesion gravity level (class TEXAS I vs II vs
      III),allocation 1:1. The randomization list will be generated by the statistic software
      "Stata 11". The lists of randomization (one list for each class TEXAS ) will be generated and
      will be stored by the coordinator centre. When a patient satisfies the study inclusion
      criteria, will be contacted the coordinator centre (by phone/mail) for group allocation.

      132 patients will be enrolled (66 patients in experimental arm, 66 patients in control arm).

      Traditional Therapy (TT) includes standard medication of ulcers, antiaggregant therapy and
      statins.

      LDL-apheresis (intervention Arm) will be performed with HELP system, for 10 session in 9
      weeks.

      Blood samples will be collected (at basal, and after 3-6-9-12 months) in order to determine
      the following parameters: glycaemia, insulin, glycated haemoglobin,
      microalbuminuria/creatinuria,CBC, fibrinogen, total cholesterol, HDL-cholesterol,
      LDL-cholesterol, Triglycerides, Lp(a), C-reactive protein (CRP), pentraxin3 (PTX3).

      Furthermore, in patients of experimental arm, blood samples will be collected at basal and at
      the end of LDL-apheresis sessions no. 2 and 10 in order to determine CBC, fibrinogen, total
      cholesterol, HDL-cholesterol, LDL-cholesterol, Triglycerides, Lp(a), CRP, PTX3 (time
      schedule, after 1 and 9 weeks).

      The value of the lab tests obtained at the end of apheresis will be normalized due to a
      possible hemodilution, according to the following formula:

      F dil= (1 - Htc pre-apheresis) / ( 1 - Htc post-apheresis). Xcorrect = Xmeasured * Fdil.

      Ulcer evaluation: staging according to Texas Wound classification System and ulcer surface
      evaluation (diameter, mapping of the lesions by means of drawing their profiles on Opsite
      film; digital picture): at basal, at 9th week and after a 3-6-9-12 month follow-up.

      The ulcers evolution will be "in blind" monitored by an evaluator who will check ulcer-map
      and digital picture without knowing to which randomization arm they belong.

      Transcutaneous oximetry: basal, at 4th week (i.e. after the 5th apheretic session). at 9th
      week (at the end of the 10 apheresis sessions) and after the next 3-6-9-12 month follow-up.

      Questionnaire on quality of life (SF36): basal, at 9th week (at the end of the 10 apheresis
      sessions) and after the next 6-12 month follow-up.

      Pain intensity rate (verbal numeric range) basal, at 9th week (at the end of the 10 apheresis
      sessions) and after the next 3-6-9-12 month follow-up.

      Doppler flowmeter : basal, at 9th week (at the end of the 10 apheresis sessions) and in the
      subsequent follow-up at 6 and 12 months.
    

Intervention name(s): LDL-apheresis
Intervention type(s): Device
Intervention description(s): The patient of the Arm "LDL-apheresis" in addition to standard therapy, will undergo a cycle of LDL-apheresis.
LDL-apheresis will be performed with B.Braun Avitum H.E.L.P. System. Apheretic treatment scheme: 10 apheretic sessions carried out as follows: the first 2 with a 3 day distance (i.e. 2 treatments in one week), successively 1 session per week (every 7 days).
To perform the treatment, the forearm surface veins will be punctured by means of 17 Ga needles, as an alternative a two-ways CVC will be used.
Other intervention name(s): H.E.L.P. apheresis; TT: traditional therapy
Allocation: Randomized
Intervention model: Parallel Assignment
Masking: None (Open Label)
Primary purpose: Treatment
Keywords: diabetic foot ulcers,; peripheral arterial disease,; heparin-induced extracorporal lipid apheresis.; inflammatory markers; type 2 diabetes; LDL-cholesterol