E.1 Medical condition or disease under investigation |
E.1.1 | Medical condition(s) being investigated |
Patients with systemic sclerosis presenting digital ulcer :
- located beyond the proximal interphalangeal joint, on finger surface (included periungueal ulcers), - of ischemic origin according to the physician, - not over subcutaneous calcifications or bone relief, - active DU - refractory after 10±2 weeks of standard of care (that is either still active or new occurrence despite standard of care)
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E.1.1.1 | Medical condition in easily understood language |
Patients with systemic sclerosis presenting refractory active digital ulcer, located beyond the proximal interphalangeal joint, on finger surface (included periungueal ulcers).
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E.1.1.2 | Therapeutic area | Diseases [C] - Immune System Diseases [C20] |
MedDRA Classification |
E.1.3 | Condition being studied is a rare disease | Yes |
E.2 Objective of the trial |
E.2.1 | Main objective of the trial |
Primary Objective is 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.
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E.2.2 | Secondary objectives of the trial |
- To evaluate after 16 weeks the efficacy of local injections of autologous cultured ASCs on the proportion of DU with complete healing, the proportion of DU with partial healing (> 50% reduction), the percentage of DU with area reduction (<50%), 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. To evaluate between baseline and week 16 the change in pain, the evolution of the severity of Raynaud’s phenomenon, the change in digital microvascular flow and the neo-angiogenesis of the treated fingers, the change in quality of life and hand function. -To evaluate the immune-modulating and angiogenic activity of the injected cells, -To evaluate phenotype and cytokin profile of adipose-derived stromal cells in SSc patients, -To perform an immunomonitoring of vascular biomarkers. -To perform a serum and plasma biobanking
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E.2.3 | Trial contains a sub-study | No |
E.3 | Principal inclusion criteria |
-Over 18 years old systemic sclerosis according to the 2013 ACR/EULAR classification criteria, -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) - 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 - Patient must have provided written informed consent prior to enrolment, -Patient must be able to understand their requirements of participating in the protocol, -Patient affiliated to a social security system.
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E.4 | Principal exclusion criteria |
Relative to the patient -Current smoker or tobacco consumption stopped for less than 3 months prior to inclusion, - Patient participating in a clinical trial or having participated in a clinical trial within the previous 3 months, - 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, - 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”, - Treatment with disease modifying agents such as methotrexate, mycophenolate mofetil, azathioprine, tacrolimus, Interferons and cyclophosphamide, - Treatment with oral corticosteroids (> 10 mg/day of prednisone or equivalent), - Systemic antibiotics (oral and TV) to treat infected DU(s) within 4 weeks prior to “inclusion visit”, - Use of topical growth factors, hyperbaric oxygen, - Local injection of botulinum toxin in an affected finger within 4 weeks prior to “inclusion visit”, - Surgical sympathectomy of the upper limbs or surgical wound debridement within 1 month prior to “inclusion visit”, - Liposuction technically impossible, - Patient who underwent autologous hematopoietic stem cell transplantation (HSCT) within less than 1 year, - Patients with an indication for intensification by autologous HSCT (according to EBMT guidelines), - 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, - Subjects who have active proliferative retinopathy, - Positive HIV-1 or 2, HTLV-1 or 2, HBV or HCV, - Patients with a history of stroke, myocardial infarction or severe arrhythmia in the last 6 months - Patient who had severe cardiac failure in the last 6 months, - Females who are pregnant or breastfeeding or plan to do so during the course of this study, - Patient under judicial protection, - Refusal of the patient to participate in the study.
Relative to each DU - Digital ulcer due to conditions other than scleroderma, - Non ischemic digital ulcer, - Ulcers with osteomyelitis, or clinically uncontrolled infection, - Infected digital ulcer requiring systemic antibiotherapy, - Digital ulcer requiring urgent surgery.
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E.5 End points |
E.5.1 | Primary end point(s) |
Proportion of refractory active ischemic digital ulcers healed (complete or partial) without recurrence at 16 weeks. The main evaluation criterion is a composite endpoint combining healing (complete or partial) without recurrence at 16 weeks and without local or general complications. |
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E.5.1.1 | Timepoint(s) of evaluation of this end point |
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E.5.2 | Secondary end point(s) |
1. a) Rate of ischemic digital ulcers with complete healing after 16 weeks. Complete healing is defined as 100% re-epidermisation, b) Rate of ischemic digital ulcers with only partial healing after 16 weeks. Partial healing is defined as > 50% reduction of the DU area or > 50% re epidermisation of the DU, c) Rate of DU with area reduction ( <50%) after 16 weeks. d) Occurrence of a new digital ulcers on the same finger: Proportion of patients who do not develop any new DU up to 16 weeks follow-up , e) Proportion of DU with a complication (infection, gangrene, amputation, DU requiring IV prostanoids), f) Change in pain between baseline and week 16 (VAS), g) Change in severity of Raynaud’s phenomenon on a 100mm VAS during the week before evaluation between baseline and week 16, h) Change in digital microvascular flow of the treated fingers between baseline and week 16 (Digital arterial pressure, transcutaneous oxygen pressure, nailflod capillaroscopy), i) Change in hand function and quality of life between baseline and week 16 (Echelle de la main de Cochin, SHAQ, SF36 and EQ5D), 2. Immune-modulating and angiogenic activity of adipose-derived stromal cells in SSc patients will be studied in vitro, 3. Phenotype and cytokine profile of adipose-derived stromal cells in SSc patients will be studied in vitro, 4. 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 at inclusion and W16, 5. Not an evaluation criterion but the creation of a biobank.
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E.5.2.1 | Timepoint(s) of evaluation of this end point |
1. a) after 16 weeks. b) after 16 weeks. c) after 16 weeks. d) Up to 16 weeks follow-up f) Between baseline and week 16 (VAS), g) Between baseline and week 16, h) Between baseline and week 16 i) Between baseline and week 16
2. Will be studied in vitro after the sampling
3. Will be studied in vitro after the sampling,
4. Will be measured out in blood samples at inclusion and W16,
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E.6 and E.7 Scope of the trial |
E.6 | Scope of the trial |
E.6.1 | Diagnosis | No |
E.6.2 | Prophylaxis | No |
E.6.3 | Therapy | Yes |
E.6.4 | Safety | No |
E.6.5 | Efficacy | No |
E.6.6 | Pharmacokinetic | No |
E.6.7 | Pharmacodynamic | No |
E.6.8 | Bioequivalence | No |
E.6.9 | Dose response | No |
E.6.10 | Pharmacogenetic | No |
E.6.11 | Pharmacogenomic | No |
E.6.12 | Pharmacoeconomic | No |
E.6.13 | Others | No |
E.7 | Trial type and phase |
E.7.1 | Human pharmacology (Phase I) | No |
E.7.1.1 | First administration to humans | No |
E.7.1.2 | Bioequivalence study | No |
E.7.1.3 | Other | No |
E.7.1.3.1 | Other trial type description | |
E.7.2 | Therapeutic exploratory (Phase II) | Yes |
E.7.3 | Therapeutic confirmatory (Phase III) | No |
E.7.4 | Therapeutic use (Phase IV) | No |
E.8 Design of the trial |
E.8.1 | Controlled | Yes |
E.8.1.1 | Randomised | Yes |
E.8.1.2 | Open | No |
E.8.1.3 | Single blind | No |
E.8.1.4 | Double blind | Yes |
E.8.1.5 | Parallel group | No |
E.8.1.6 | Cross over | No |
E.8.1.7 | Other | No |
E.8.2 | Comparator of controlled trial |
E.8.2.1 | Other medicinal product(s) | No |
E.8.2.2 | Placebo | Yes |
E.8.2.3 | Other | No |
E.8.2.4 | Number of treatment arms in the trial | 2 |
E.8.3 |
The trial involves single site in the Member State concerned
| No |
E.8.4 | The trial involves multiple sites in the Member State concerned | Yes |
E.8.4.1 | Number of sites anticipated in Member State concerned | 8 |
E.8.5 | The trial involves multiple Member States | No |
E.8.6 Trial involving sites outside the EEA |
E.8.6.1 | Trial being conducted both within and outside the EEA | No |
E.8.6.2 | Trial being conducted completely outside of the EEA | No |
E.8.7 | Trial has a data monitoring committee | Yes |
E.8.8 |
Definition of the end of the trial and justification where it is not the last
visit of the last subject undergoing the trial
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E.8.9 Initial estimate of the duration of the trial |
E.8.9.1 | In the Member State concerned years | |
E.8.9.1 | In the Member State concerned months | 34 |
E.8.9.1 | In the Member State concerned days | |
E.8.9.2 | In all countries concerned by the trial months | 34 |