Autologous Adipose Tissue in the Treatment of Systemic Sclerosis Digital Ulcers

Study Overview
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Brief Summary
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A randomized controlled trial will be performed to confirm preliminary uncontrolled data indicating that regional adipose tissue grafting is effective in inducing digital ulcer healing in patients with systemic sclerosis. Systemic Sclerosis patients with digital ulcers will be randomized to be blindly treated with adipose tissue implantation or a sham procedure. Adipose tissue grafting will consist of injection at the base of the finger with digital ulcer of 0.5-1 ml of adipose tissue after centrifugation of fat aspirate. Sharm procedure will consist of false liposuction and local injection of saline solution. The primary end-point will be to compare the cumulative prevalence of healed digital ulcers in the two groups within the following 8 weeks.

Detailed Description
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Systemic sclerosis (SSc) is an autoimmune disease characterized by a multifactorial pathological process where a central role is played by the progressive loss of the microvascular bed, with the consequent fibrotic changes in the involved organs and tissues. The most advanced stages of capillary loss may induce the formation of digital ulcers (DUs) on the fingertips.The healing of DUs is often a lengthy process requiring accurate and intensive topical and systemic treatment. Nevertheless, in a significant number of cases this therapeutic approach is ineffective and distal necrosis with subsequent tissue loss or phalangeal amputation may eventually occur. In a recent open pilot study performed by Del Papa et al., it has been demonstrated that autologous adipose tissue grafting (AT-G), which is known to contain both adipose-derived stem cells and a stromal/vascular fraction, was effective in inducing prompt healing of long lasting DUs localized in the fingertips of a small number of patients with SSc. The DU healing was accompanied by the rapid disappearance of local ischemic pain and evidence of a partial restoration of the capillary bed in the digits when assessed by nailfold videocapillaroscopy (NVC). With the purpose of confirming these preliminary results, the investigators have designed a monocentric randomized controlled study. In accordance with the study protocol, patients with a typical SSc-related DU on the fingertip will be randomized to undergo a regional AT-G with autologous fat as active therapy or a 'sham' procedure (SP) - that simulates the active treatment - as placebo treatment. All of the patients with SSc enrolled in both arms will be blind regarding the treatment received. Furthermore, during the study period all of the enrolled patients will receive the same systemic vasoactive and topical therapy.

Official Title
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Regional Grafting of Autologous Adipose Tissue in the Treatment of Systemic Sclerosis Digital Ulcers: a Prospective Randomized Controlled Study

Conditions
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Digital Ulcer, Systemic Sclerosis

Intervention / Treatment
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* Procedure: Autologous fat grafting
* Procedure: Sham procedure


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients candidate for enrollment in the study have to meet the 2013 classification criteria of the American College of Rheumatology/European League Against Rheumatism for SSc; Patients may have either the limited cutaneous or the diffuse cutaneous variants of SSc; All of the candidate patients must have only one active DU (cardinal ulcer), lasting for at least 6 weeks prior to enrolment time and showing no tendency to heal despite intravenous iloprost (0.5-2 ng/Kg/min), the oral administration of calcium-channel blockers (nifedipine) and local medication with surgical removal of necrotic tissue. Exclusion Criteria: Presence of severe extra-cutaneous manifestations, such as cardiac, lung and renal involvement; Concomitant treatment with immune-suppressive therapies (including prednisone equivalent >10 mg); Current therapy with dual and selective endothelin inhibitors; Concomitant diabetes and/or other vascular diseases; Current pregnancy or breastfeeding.

Ages Eligible for Study
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Minimum Age: 18 Years
Maximum Age: 70 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: Candidate SSc patients will have only one active DU of at least 6 mm in diameter, lasting for at least 6 weeks, despite conventional vascular therapy. Patients with severe visceral manifestations, diabetes and treated with immune-suppressors and endothelin inhibitors will be excluded. Active therapy: implantation of 0.5-1 ml of autologous AT at the base of the finger with DU. Autologous AT will be obtained by liposuction from abdominal fat. SP will be blindly performed in the control group to simulate the AT-G. A false liposuction will be performed followed by the injection of 0.5-1 ml of 0.9% saline solution at the base of the affected finger. Basal therapy: weekly iloprost infusion (0.5-2 ng/Kg/min), and calcium-channel blockers (oral nifedipine 20 mg daily) will be continued during the entire observation time in all of the patients recruited in both arms of the study. The administration of analgesics to alleviate the DU-related pain will be also allowed for each patient.
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Autologous fat grafting<br>Implantation of 0.5-1 ml of autologous AT at the base of the finger with DU. | Procedure: Autologous fat grafting<br>* Implantation of small amount of autologous adipose tissue at the base of the finger to induce a rapid healing of the distally located DU<br>* Other names: Iloprost infusion, oral nifedipine;|
| Placebo Comparator: Sham procedure<br>False liposuction followed by the injection of 0.5-1 ml of 0.9% saline solution at the base of the affected finger. | Procedure: Sham procedure<br>* Local injection of 0.5ml saline solution after a simulated liposuction procedure.<br>* Other names: Iloprost infusion, oral nifedipine;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Digital Ulcer healing | Prevalence of DU healing in the arm treated with autologous fat grafting in comparison with the prevalence of healing in the placebo group. | 8 weeks after either autologus fat grafting or sham procedure. | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Pain evaluation by Visual Analogue Scale (VAS) | The pain VAS is a continuous scale comprised of a horizontal line of 10 centimeters (100 mm) in length, ranging from 0 (minimum= no pain) to 100 (worst imaginable pain). The respondents will be asked to place a line perpendicular to the VAS line at the point that represents their pain intensity. Using a ruler, the score is determined by measuring the distance (mm) on the 10-cm line between the no pain anchor and the patient's mark, providing a range of scores from 0-100. In this study VAS score will be used to measure the decrease (or resolution) of pain with respect to baseline value in patients who will undergo treatment with autologous fat grafting (active arm) in comparison with patients of the placebo group. | This evaluation will be done at baseline and at the 2nd, 4th, 6th, 8th week after interventions (either autologus fat grafting or sham procedure). | 
| Neovascularization evaluation | Increase of the number of capillaries assessed by NVC in the affected digit of patients treated with autologous fat grafting in comparison with patients of the placebo group. | Baseline and 8 weeks after either autologus fat grafting or sham procedure. | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Systemic Sclerosis, Digital Ulcer, Autologous fat grafting, Adipose tissue stem cells