Ischemic digital ulcers (DUs) are a frequent complication in systemic sclerosis with a major impact on hand function and quality of life. Digital injection of cultured adipose-derived stromal cell (AdMSC) constitutes a promising approach to treat scleroderma-induced refractory ischemic DUs where no alternative therapy is validated. The aim of this phase 2 study is to compare efficacy and safety of digital injection of AdMSC versus placebo for healing refractory active ischemic digital ulcers in patients with systemic sclerosis.
Systemic sclerosis (SSc) is a systemic autoimmune disease characterized by an autoimmune-mediated microangiopathy and progressive fibrosis. Ischemic digital ulcers (DUs) are frequent in the disease course. DUs are an expression of the severity of the microangiopathy. DUs lead to pain, infection, gangrene, autoamputation, impaired hand use and impaired quality of life. The management of DUs is often based on optimal wound care to promote healing and and repeated hospitalizations to perform onerous prostacyclin infusions to reduce pain and accelerate healing. With optimal standard of care, only 60% of DUs are healed after 3 months and 46.2% experiences recurrence during that time among them 11.2% experiences a chronic evolution. No drug has demonstrated a positive effect on refractory DUs healing. The rational underlying the use of cultured adipose-derived stromal cell (AdMSC) in this indication is based on the finding of AdMSC, in vitro and in vivo, angiogenic and anti-inflammatory potential in other ischemic pathologies, with an excellent safety profile. The pilot phase of the ACellDREAM trial demonstrated the feasibility and safety of AdMSC transplantation in patients with non- revascularizable critical limb ischemia and showed improvement in ulcer evolution and wound healing. The EFS-O culture procedure safety is validated and is already in use in ongoing French and European clinical trials. Two pilot studies showed the safety of adipose tissue grafting for scleroderma-Induced DU. The SCLERADEC pilot study outlines the safety, in 12 SSc patients, of the digital injection of adipose- derived stromal vascular fraction, which is a heterogeneous population of cells including only 36% of uncultured AdMSC. An improvement in hand disability, quality of life and DUs was observed, the phase II is ongoing. The hypothesis of the study is that digital injection of AdMSC could be efficacious for scleroderma-induced refractory ischemic DUs healing by digital vascular regeneration in a clinical situation where no alternative therapy is validated.
Study Type
INTERVENTIONAL
Allocation
RANDOMIZED
Purpose
TREATMENT
Masking
QUADRUPLE
Enrollment
32
Grenoble Hospital
Grenoble, France
NOT_YET_RECRUITINGLille Hopsital
Lille, France
NOT_YET_RECRUITINGMarseille Hospital
Marseille, France
NOT_YET_RECRUITINGMontpellier Hospital
Montpellier, France
NOT_YET_RECRUITINGNantes Hospital
Nantes, France
NOT_YET_RECRUITINGPoitiers Hospital
Poitiers, France
NOT_YET_RECRUITINGCHU de Toulouse - Hôpital PURPAN-TSA
Toulouse, France
RECRUITINGProportion of refractory active ischemic digital ulcers healed (complete or partial)
Partial healing is defined as \> 50% reduction of the DU area or \> 50% re epidermisation of the DU.
Time frame: 16 weeks
Composite endpoint combining healing (complete or partial) without recurrence and without local or general complications
Partial healing is defined as \> 50% reduction of the DU area or \> 50% re epidermisation of the DU. Local complications resulting from DU worsening: * Critical ischemic crisis necessitating hospitalization, * Gangrene, (auto) amputation, * Failure of conservative management: Surgical and chemical sympathectomy, vascular reconstructions, or any unplanned surgery in the management of hand SSc manifestation(s), * Use of parenteral prostanoids after treatment injection, * Requiring class II, III or IV narcotics or increase in existing dose of \> 50 % as compared to baseline, * Initiation of systemic antibiotics for the treatment of infection attributed to digital ulceration. General complications will be assessed by: * Clinical examination * Patient reported-outcomes * Laboratory assessments
Time frame: 16 weeks
Percentage of participants with Digital Ulcer complete healing
Number of complete ulcer Healing. Complete healing is defined as 100% re-epidermisation.
Time frame: 16 weeks
Percentage of participants with Digital Ulcer partial healing
Number of partial ulcer Healing. Partial healing is defined as \> 50% reduction of the DU area or \> 50% re epidermisation of the DU.
Time frame: 16 weeks
Percentage of participants with wound surface reduction <50%
the wound surface reduction is defined by analysis photography
Time frame: 16 weeks
Percentage of participants with new Digital Ulcer
Number of patients who do not develop any new DU.
Time frame: 16 weeks
Percentage of participants with Digital Ulcer complication
A complication is an infection, gangrene, amputation or a DU requiring IV prostanoids.
Time frame: 16 weeks
Change from Baseline in Pain Scores
Evaluation of pain on a Visual Analog Scale. The visual scale measures the intensity of pain on a scale ranging from 0 (no pain) to 10 (maximum pain).
Time frame: 16 weeks
Change from Baseline in severity of Raynaud's phenomenon
Change in severity of Raynaud's phenomenon on a Visual Analog Scale. The visual scale is in a form of plastic ruler and measures the severity of Raynaud's phenomenon on a scale ranging from 0 (no pain) to 100 (maximum pain).
Time frame: 16 weeks
Change from Baseline in Digital ischaemia
Change in digital ischaemia of the treated fingers on Digital arterial pressure.
Time frame: 16 weeks
Change from Baseline in cutaneous ischaemia
Change in cutaneous ischaemia of the treated fingers on transcutaneous oxygen pressure (TcPO2).
Time frame: 16 weeks
Change from Baseline in Digital microvascular organisation
Change in digital microvascular organisation of the treated fingers on nailfold capillaroscopy.
Time frame: 16 weeks
Change from Baseline in hand functional disability
Evaluation of hand functional disability by the Cochin Hand Function Scale.
Time frame: 16 weeks
Change from Baseline in quality of life in systemic sclerosis
Evaluation of quality of life in systemic sclerosis by scleroderma health assesment (SHAQ).
Time frame: 16 weeks
Change from Baseline in quality of life
Evaluation of quality of life by the SF36.
Time frame: 16 weeks
Change from Baseline in health status
Evaluation of health status by the EQ5D.
Time frame: 16 weeks
Vascular biomarkers
Endothelin-1, Endostatin, Endogline, Angiotensin I and II, Tie 1 and 2, V-EGF, sICAM-1, sVCAM, E-selectin, CXCL4 plus anti-AT1R, anti-ETAR, anti Annexin V will be measured out in blood samples by Luminex
Time frame: 16 weeks
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