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    EudraCT Number:2019-003906-28
    Sponsor's Protocol Code Number:RC31/17/0447
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2019-11-18
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedFrance - ANSM
    A.2EudraCT number2019-003906-28
    A.3Full title of the trial
    Subcutaneous injections of autologous cultured adipose-derived stroma/stem cells to heal refractory ischemic digital ulcers in patients with scleroderma : a phase II study

    Injection de cellules souches mésenchymateuses autologues issues de tissu adipeux dans la prise en charge des ulcères digitaux de la sclérodermie systémique. Essai multicentrique, randomisé, contrôlé versus placebo de phase 2
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Adipose tissu derived-stem cells injections from patients with sclerodermia to treat thier refractory digital ulcers.
    Injection de cellules souches mésenchymateuses autologues issues de tissu adipeux chez les patients atteints de sclérodermie systémique pour traiter des ulcères digitaux.
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberRC31/17/0447
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorCHU de Toulouse
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportDGOS
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHU de Toulouse
    B.5.2Functional name of contact pointCLINICAL RESEARCH ASSISTANT
    B.5.3 Address:
    B.5.3.1Street AddressHôtel-Dieu 2 rue Viguerie TSA 80035
    B.5.3.2Town/ cityTOULOUSE
    B.5.3.3Post code31059
    B.5.4Telephone number0561778490
    B.5.5Fax number0561778411
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation No
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameautologous ASC
    D.3.4Pharmaceutical form Suspension for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Yes
    D. cell therapy medicinal product Yes
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.8 Information on Placebo
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboSuspension for injection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical 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)
    E.1.1.1Medical 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).

    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main 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.
    E.2.2Secondary 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
    E.2.3Trial contains a sub-study No
    E.3Principal 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.

    E.4Principal 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.

    E.5 End points
    E.5.1Primary 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.
    E.5.1.1Timepoint(s) of evaluation of this end point
    At 16 weeks
    E.5.2Secondary end point(s)
    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.
    E.5.2.1Timepoint(s) of evaluation of this end point
    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,
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial2
    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.8.4.1Number of sites anticipated in Member State concerned8
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial 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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months34
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months34
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 32
    F.1.3Elderly (>=65 years) No
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state32
    F.5 Plans for treatment or care after the subject has ended the participation in the trial (if it is different from the expected normal treatment of that condition)
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2020-02-24
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-01-14
    P. End of Trial
    P.End of Trial StatusOngoing
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