Clinical trial NCT03406988: Autologous Adipose Tissue in the Treatment of Systemic Sclerosis Digital Ulcers
Official title: Regional Grafting of Autologous Adipose Tissue in the Treatment of Systemic Sclerosis Digital Ulcers: a Prospective Randomized Controlled Study
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: NA
Conditions: Systemic Sclerosis
Digital Ulcer
Keywords: Systemic Sclerosis
Digital Ulcer
Autologous fat grafting
Adipose tissue stem cells
Lead sponsor: ASST Gaetano Pini-CTO
Sponsor class: OTHER
Collaborators: name: Società Italiana di Reumatologia
First posted: 2018-01-23
Enrollment: 46
Sex: ALL
Minimum age (years): 18
Maximum age (years): 70
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Intervention 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.
Primary purpose: TREATMENT

Brief summary: 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: 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.

Eligibility criteria: 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.

Primary outcomes:
measure: Digital Ulcer healing
timeFrame: 8 weeks after either autologus fat grafting or sham procedure.
Secondary outcomes:
measure: Pain evaluation by Visual Analogue Scale (VAS)
timeFrame: This evaluation will be done at baseline and at the 2nd, 4th, 6th, 8th week after interventions (either autologus fat grafting or sham procedure).
measure: Neovascularization evaluation
timeFrame: Baseline and 8 weeks after either autologus fat grafting or sham procedure.
Other outcomes:
Locations:
city: Milan
country: Italy
facility: UOC Day Hospital Reumatologia, ASST G. Pini-CTO
Study officials:
affiliation: ASST Gaetano Pini-CTO
name: Nicoletta Del Papa, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Gabrielli A, Avvedimento EV, Krieg T. Scleroderma. N Engl J Med. 2009 May 7;360(19):1989-2003. doi: 10.1056/NEJMra0806188. No abstract available.
citation: Steen V, Denton CP, Pope JE, Matucci-Cerinic M. Digital ulcers: overt vascular disease in systemic sclerosis. Rheumatology (Oxford). 2009 Jun;48 Suppl 3:iii19-24. doi: 10.1093/rheumatology/kep105.
citation: Del Papa N, Di Luca G, Sambataro D, Zaccara E, Maglione W, Gabrielli A, Fraticelli P, Moroncini G, Beretta L, Santaniello A, Sambataro G, Ferraresi R, Vitali C. Regional implantation of autologous adipose tissue-derived cells induces a prompt healing of long-lasting indolent digital ulcers in patients with systemic sclerosis. Cell Transplant. 2015;24(11):2297-305. doi: 10.3727/096368914X685636. Epub 2014 Dec 12.
citation: Del Papa N, Di Luca G, Andracco R, Zaccara E, Maglione W, Pignataro F, Minniti A, Vitali C. Regional grafting of autologous adipose tissue is effective in inducing prompt healing of indolent digital ulcers in patients with systemic sclerosis: results of a monocentric randomized controlled study. Arthritis Res Ther. 2019 Jan 7;21(1):7. doi: 10.1186/s13075-018-1792-8.