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HELP-Apheresis in Diabetic Ischemic Foot Treatment (H.A.D.I.F) (HADIF)

Primary Purpose

Foot Ulcers, Arteriosclerosis Obliterans, Diabetes Mellitus

Status
Completed
Phase
Not Applicable
Locations
Italy
Study Type
Interventional
Intervention
LDL-apheresis
Sponsored by
Universita di Verona
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for Foot Ulcers focused on measuring diabetic foot ulcers,, peripheral arterial disease,, heparin-induced extracorporal lipid apheresis., inflammatory markers, type 2 diabetes, LDL-cholesterol

Eligibility Criteria

18 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Diabetic patients
  • Ischemic diabetic ulcers (class I, II and III Texas Wound Classification System);
  • documented peripheral vasculopathy with at least a previous event of failed revascularization (no ulcer healing).

Exclusion Criteria:

  • Patient refusal to participate
  • BMI > 35 kg/m2
  • Ischemic diabetic ulcers class III Texas Wound Classification System
  • Patients presenting a bleeding diathesis, malignant tumor, heart failure not allowing extracorporeal technique.
  • Haemodialysis

Sites / Locations

  • universita Verona

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

No Intervention

Arm Label

LDL-apheresis and TT

Traditional Treatment

Arm Description

The patient of the experimental Arm, in addition to Traditional Therapy (TT), will undergo a cycle of 10 LDL-apheresis session. Apheretic treatment scheme: 10 apheretic session carried out as follow: first and second apheresis with a 3 days interval (i.e. 2 treatment in one week), then one 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.

All patients will receive the traditional treatment for the ulcer healing Standardized medication. All lesions taken into consideration will be treated in a standardized way, with a different approach according to the presence of a possible infection. The evolution of lesions might be documented by means of mapping the same by drawing their profiles on an Opsite film. antibiotics therapy (according to antibiogram). Anti-platelet therapy. Statin therapy.

Outcomes

Primary Outcome Measures

Proportion of subjects obtaining the ulcer healing (Class 0A according to TEXAS classification) after 12 month from the study starts.
Ulcer evaluation: staging according to Texas Wound classification System and ulcer evaluation (surface diameter, mapping of the lesions by means of drawing their profiles on Opsite film,and digital picture), at basal, at 9th week and after a 3-6-9-12 month follow-up.

Secondary Outcome Measures

Improvement of the peripheral oxygenation evaluated by means of transcutaneous oximetry measurement at foot level: TcP O2 (mmHg).
Evaluation of pain level variation (verbal numeric range; score from 1 to 10)
Lowering of circulating inflammation markers (C Reactive Protein, Fibrinogen). CRP plasmatic concentration (mg/L) and fibrinogen (g/L)
Rate of cardiovascular events in the observation period (1-year follow-up).
proportion of subjects with minor amputation (only toe or part of the foot removed)- in agreement with the approved amendment
proportion of subjects with major amputation (these are usually below the knee or above the knee)- in agreement with the approved amendment

Full Information

First Posted
January 22, 2012
Last Updated
January 2, 2017
Sponsor
Universita di Verona
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1. Study Identification

Unique Protocol Identification Number
NCT01518205
Brief Title
HELP-Apheresis in Diabetic Ischemic Foot Treatment (H.A.D.I.F)
Acronym
HADIF
Official Title
HELP-Apheresis in Diabetic Ischemic Foot Treatment (H.A.D.I.F): a RCTrial to Evaluate the Effect of LDL-apheresis on the Recovery of Diabetic Ulcers in Patients With Peripheral Vasculopathy Not Susceptible to Revascularization.
Study Type
Interventional

2. Study Status

Record Verification Date
January 2017
Overall Recruitment Status
Completed
Study Start Date
February 2012 (undefined)
Primary Completion Date
September 2015 (Actual)
Study Completion Date
December 2015 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Universita di Verona

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief 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.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Foot Ulcers, Arteriosclerosis Obliterans, Diabetes Mellitus
Keywords
diabetic foot ulcers,, peripheral arterial disease,, heparin-induced extracorporal lipid apheresis., inflammatory markers, type 2 diabetes, LDL-cholesterol

7. Study Design

Primary Purpose
Treatment
Study Phase
Not Applicable
Interventional Study Model
Parallel Assignment
Masking
None (Open Label)
Allocation
Randomized
Enrollment
13 (Actual)

8. Arms, Groups, and Interventions

Arm Title
LDL-apheresis and TT
Arm Type
Experimental
Arm Description
The patient of the experimental Arm, in addition to Traditional Therapy (TT), will undergo a cycle of 10 LDL-apheresis session. Apheretic treatment scheme: 10 apheretic session carried out as follow: first and second apheresis with a 3 days interval (i.e. 2 treatment in one week), then one 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.
Arm Title
Traditional Treatment
Arm Type
No Intervention
Arm Description
All patients will receive the traditional treatment for the ulcer healing Standardized medication. All lesions taken into consideration will be treated in a standardized way, with a different approach according to the presence of a possible infection. The evolution of lesions might be documented by means of mapping the same by drawing their profiles on an Opsite film. antibiotics therapy (according to antibiogram). Anti-platelet therapy. Statin therapy.
Intervention Type
Device
Intervention Name(s)
LDL-apheresis
Other Intervention Name(s)
H.E.L.P. apheresis, TT: traditional therapy
Intervention Description
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.
Primary Outcome Measure Information:
Title
Proportion of subjects obtaining the ulcer healing (Class 0A according to TEXAS classification) after 12 month from the study starts.
Description
Ulcer evaluation: staging according to Texas Wound classification System and ulcer evaluation (surface diameter, mapping of the lesions by means of drawing their profiles on Opsite film,and digital picture), at basal, at 9th week and after a 3-6-9-12 month follow-up.
Time Frame
12 months
Secondary Outcome Measure Information:
Title
Improvement of the peripheral oxygenation evaluated by means of transcutaneous oximetry measurement at foot level: TcP O2 (mmHg).
Time Frame
basal, at 4th and 9th week and after 3-6-9-12 month follow-up
Title
Evaluation of pain level variation (verbal numeric range; score from 1 to 10)
Time Frame
basal, at 4th and 9th week and after 3-6-9-12 month follow-up
Title
Lowering of circulating inflammation markers (C Reactive Protein, Fibrinogen). CRP plasmatic concentration (mg/L) and fibrinogen (g/L)
Time Frame
at the beginning of the study and respectively after 3 - 6 - 9 e 12 months.
Title
Rate of cardiovascular events in the observation period (1-year follow-up).
Time Frame
12 months
Title
proportion of subjects with minor amputation (only toe or part of the foot removed)- in agreement with the approved amendment
Time Frame
12 months
Title
proportion of subjects with major amputation (these are usually below the knee or above the knee)- in agreement with the approved amendment
Time Frame
12 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Diabetic patients Ischemic diabetic ulcers (class I, II and III Texas Wound Classification System); documented peripheral vasculopathy with at least a previous event of failed revascularization (no ulcer healing). Exclusion Criteria: Patient refusal to participate BMI > 35 kg/m2 Ischemic diabetic ulcers class III Texas Wound Classification System Patients presenting a bleeding diathesis, malignant tumor, heart failure not allowing extracorporeal technique. Haemodialysis
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Maria Grazia Zenti, MD
Organizational Affiliation
Division of Endocrinology and Metabolic Diseases, University Hospital of Verona
Official's Role
Principal Investigator
First Name & Middle Initial & Last Name & Degree
Enzo Bonora, MD, PhD
Organizational Affiliation
Division of Endocrinology and Metabolic Diseases, University Hospital of Verona
Official's Role
Study Director
Facility Information:
Facility Name
universita Verona
City
Verona
ZIP/Postal Code
37100
Country
Italy

12. IPD Sharing Statement

Plan to Share IPD
No

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HELP-Apheresis in Diabetic Ischemic Foot Treatment (H.A.D.I.F)

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