Systemic Sclerosis : ADUSE – Subcutaneous injections of autologous cultured adipose-derived stroma/stem cells to heal refractory ischemic digital ulcers – STUDY UNDERGOING IMPLEMENTATION

SPONSOR : CHU de Toulouse

COORDINATING/ PRINCIPAL INVESTIGATOR :
Dr. Grégory PUGNET
Service de Médecine Interne,
Hôpital Purpan, 1 Place du Docteur Baylac,
31059 Toulouse Cedex 9
Tel : +33-5 61 77 71 26 / Fax : +33-5 61 77 71 24
e-mail : pugnet.g@chu-toulouse.fr

TITLE : Subcutaneous injections of autologous cultured adipose-derived stroma/stem cells to heal refractory ischemic digital ulcers in patients with scleroderma: A phase II study (ADUSE)

JUSTIFICATION/ CONTEXT
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, auto-amputation, impaired hand use and impaired quality of life. The management of DUs is often based on optimal wound care to promote healing 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 (ASC) in this indication is based on the finding of ASC, in vitro and in vivo, angiogenic and anti-inflammatory potential in other ischemic pathologies, with an excellent safety profile. The ACellDREAM trial (NCT01211028) demonstrated the feasibility and safety of autologous ASC transplantation in patients with non- revascularizable critical limb ischemia and showed improvement in ulcer evolution and wound healing. The EFS ASC culture procedure safety is validated and is already in use in ongoing French and European clinical trials. Two pilot studies showed the safety of autologous adipose tissu grafting for scleroderma-Induced DU. The SCLERADEC pilot study outlines the safety, in 12 SSc patients, of the digital injection of adipose- derived autologous stromal vascular fraction, which is a heterogeneous population of cells including only 36% of uncultured ASC. An improvement in hand disability, quality of life and DUs was observed, the phase II is ongoing.

The hypothesis of our study is that digital injection of autologous cultured adipose-derived stromal cell could be efficacious for scleroderma-induced refractory ischemic DUs healing by digital vascular regeneration and ulcer prevention in a clinical situation where no alternative therapy is validated.

OBJECTIVES

Primary Objective :
To compare efficacy and safety of digital injection of autologous cultured adipose-derived stromal cell versus placebo for healing refractory (chronic and/or recurrent in the 3 months following a DU occurrence) active ischemic digital ulcers in patients with systemic sclerosis in a 16 weeks placebo- controlled trial.

Secondary objectives :
1. To evaluate the efficacy of local injections of autologous cultured ASCs on:

    – The proportion of patients with complete healing of the DU after 16 weeks,
    – The proportion of patients with partial healing of the DU (> 50% reduction of the DU area) after 16 weeks,
    – The percentage of DU area reduction (if present),
    – The proportion of patients who do not develop any new DU after 28 days of treatment with the study drug up to week 16,
    – The number of DU complication occurrence in SSc patients with ongoing DU disease,
    – The change between baseline and week 16 in pain,
    – The evolution of the severity of Raynaud’s phenomenon between baseline and week 16,
    – The change between baseline and week 16 in digital microvascular flow and the neo-angiogenesis of the treated fingers,
    – The change between baseline and week 16 in quality of life and hand function.

2. To evaluate phenotype, cytokinin profile, and immune-modulating and angiogenic activity of the injected adipose-derived stromal cells.

3. Immunomonitoring of scleroderma antibodies and vascular biomarkers

4. Biobanking

EVALUATION CRITERIA

Primary judgment criteria:
Proportion of refractory active ischemic digital ulcers healed (complete or partial) without recurrence at 16 weeks.

Secondary judgment criteria:
1. Rate of ischemic digital ulcers with complete healing. Complete healing is defined as 100% re-epidermisation,
2. Rate of ischemic digital ulcers with only partial healing. Partial healing is defined as > 50% reduction of the DU area or > 50% re epidermisation of the DU,
3. Occurrence of new digital ulcers: Proportion of patients who do not develop any new DU between week 4 and 16 of the study,
4. Change in pain between baseline and week 16 (VAS),
5. Severity of Raynaud’s phenomenon on a 100mm VAS,
6. Change in digital microvascular flow between baseline and week 16 (laser Doppler flowmetry, transcutaneous oxygen pressure, nailflod capillaroscopy),
7. Change in hand function and quality of life between baseline and week 16 (Echelle de la main de Cochin and SHAQ),
8. Proportion of patients with complicated DU (infection, gangrene, amputation, DU requiring IV prostanoids),
9. Phenotype and cytokine profile of adipose-derived stromal cells in SSc patients will be studied in vitro,
10. Scleroderma autoantibodies and vascular biomarkers will be measured at D1 and W16.

OUTLINE OF THE RESEARCH : Phase II, double-blind, randomized (1:1), multicenter, prospective, longitudinal, comparative, placebo-controlled clinical trial. Patients will be followed-up for 16 weeks.

INCLUSION CRITERIA
1. Over 18 years old systemic sclerosis according to the 2013 ACR/EULAR classification criteria,
2. At least one digital ulcer at baseline showing all the following characteristics:

    a) located beyond the proximal interphalangeal joint, on finger surface (included periungueal ulcers),
    b) of ischemic origin according to the physician,
    c) not over subcutaneous calcifications or bone relief,
    d) active DU,
    e) refractory after 10±2 weeks of standard of care (that is either still active or new occurrence despite standard of care)

3. Women of childbearing potential must use a reliable method of contraception. Women of childbearing potential with a negative serum pre-treatment pregnancy test are allowed in the study if they consistently and correctly use (from screening and up to 30 days after study treatment discontinuation) a reliable method of contraception
4. Patient must have provided written informed consent prior to enrolment,
5. Patient agrees to come to the follow up visits inside the protocol specified range,
6. Patient must be able to understand their requirements of participating in the protocol,
7. Patient affiliated to a social security system.

EXCLUSION CRITERIA
1. Current smoker or tobacco consumption stopped for less than 3 months prior to inclusion
2. Patient participating in a clinical trial or having participated in a clinical trial within the previous 3 months
3. Patients on statins, who have received treatment for less than 3 months prior to Screening or whose treatment has not been stable during this period
4. Patients on vasodilators, such as endothelin receptor antagonists (ERAs), PDE5 inhibitors (e.g. sildenafil, tadalafil), calcium channel blockers, ACE-inhibitors, nitroglycerin, alpha adrenergic blockers, or angiotensin II receptor antagonists, N-acetylcysteine, antiplatelet aggregation therapy and low molecular weight heparin who have received treatment if present for less than 3 months prior to “inclusion visit” or whose treatment has not been stable for at least 1 month prior to “inclusion visit”
5. Treatment with disease modifying agents such as methotrexate, mycophenolate mofetil and cyclophosphamide
6. Treatment with oral corticosteroids (> 10 mg/day of prednisone or equivalent)
7. Systemic antibiotics (oral and TV) to treat infected DU(s) within 4 weeks prior to “inclusion visit”,
8. Use of topical growth factors, hyperbaric oxygen,
9. Local injection of botulinum toxin in an affected finger within 4 weeks prior to “inclusion visit”,
10. Surgical sympathectomy of the upper limbs or surgical wound debridement within 1 month prior to “inclusion visit”,
11. Liposuction technically impossible,
12. Patient who underwent autologous hematopoietic stem cell transplantation (HSCT) within less than 1 year,
13. Patients with an indication for intensification by autologous HSCT (according to EBMT guidelines),
14. History of cancer in the last five years, except for successfully excised basal cell/squamous cell carcinoma, or successfully excised early melanoma of the skin. Subjects, who had successfully tumor resection or radiation or chemotherapy more than 5 years from inclusion and no recurrence, may be enrolled in the study,
15. Subjects who have active proliferative retinopathy,
16. Positive HIV-1 or 2, HTLV-1 or 2, HBV or HCV,
17. Patients with a history of stroke, myocardial infarction or severe arrhythmia in the last 6 months
18. Patient who had severe cardiac failure in the last 6 months,
19. Females who are pregnant or breastfeeding or plan to do so during the course of this study,
20. Patient under judicial protection,
21. Refusal of the patient to participate in the study.

RESEARCH TREATMENT/ STRATEGIES/ PROCEDURES
32 patients will be included to receive 40*106 digital injection of autologous ASC or placebo solution distributed in 2 syringes of 10 mL. 0.5 mL (containing placebo or 2*106 autologous ASC) will be injected into each lateral side of each digit, using a retro-tracing technique, from distal to proximal. Each fingers with or without ulcers will receive 2 injections. In total, 20 injections will be performed.

Patients will be followed-up for 16 weeks after injection.

STUDY SIZE : 32 patients

NUMBER OF CENTRES PLANNED : 8

DURATION OF THE RESEARCH:
Duration of the inclusion period: 30 months
Duration of participation of each participant: 4 months
Total study duration: 34 months