SYSTEMIC SCLEROSIS – Allogeneic mesenchymal stem cell grafts – FINAL RECRUITING

Title : TREATMENT OF REFRACTORY SEVERE SYSTEMIC SCLEROSIS BY INJECTION OF ALLOGENEIC MESENCHYMAL STEM CELLS

Promoteur : Public assistance – Hospitals of Paris

ClinicalTrials.gov: NCT02213705

Principle Investigator :
Professeur Dominique FARGE
Unité de Médecine Interne et pathologie
Hôpital Saint Louis
1, avenue Claude Vellefaux,
75010 Paris
dominique.farge-bancel@aphp.fr

Clinical research coordinator :
Pauline LANSIAUX
pauline.lansiaux@aphp.fr
01 42 38 50 93

Theoretical inclusion period : 4.5 years beginning in March 2014

Theoretical follow-up period : 2 years

Total duration of research : 6.5 years

Primary objective : To analyze the tolerance for administration of allogeneic MSCs in the treatment of severe diffuse SSc, or rapidly progressing SSc that is refractory to conventional treatments with cyclophosphamide.

Secondary objectives :
1) Feasibility of administering allogeneic MSCs in the treatment of severe diffuse SSc, or rapidly progressing SSc that is refractory to conventional treatment with cyclophosphamide.
2) Tolerance more than three months after injection (including absence of malignancies).
3) Clinical response to MSC treatment, and efficacy on SSc progression: 3, 6, 9 and 12 months after the procedure.

Study design : A non-randomized, open, phase II, multicenter, national cell therapy study.

Patient population :
• Patients with severe refractory systemic sclerosis.
• Healthy donor, allogeneic, familial

Number of inclusions anticipated :
20 patients
20 MSC familial donors

Duration of participation : 2 years

Inclusion criteria :

Recipients :
1. Age> 18 years and <70 years.

2. Established diagnosis of systemic sclerosis according to the criteria from the American College of Rheumatology / the European League Against Rheumatism (ARA and ACR/EULAR 2013).

3. SSc with poor prognosis, life-threatening with severe visceral impairment (cardiac, pulmonary, or renal) and with contraindications for the use of / or resistant to immunosuppressive therapy conventionally used in severe forms of the disease as recommended by the European recommendations of EUSTAR (www.eustar.org) and EBMT (www.ebmt.org) and which then rely on high doses of iv cyclophosphamide (either in monthly bolus for at least six months or by intensification and Hematopoietic Stem Cell transplant), or SSc with fibrosing lung damage threatening vital prognosis (excluding possible lung transplants).
These forms of severe and serious SSc, at least 6 months after cessation of immmunosuppressive therapy with high doses of iv cyclophosphamide, combine to varying degrees a rapidly progressive skin lesions with a Rodnan score > 15, and one or more of the major visceral lesions defined as follows :

a) Respiratory disease :
– DLCO <60% or FVC ≤70% of the theoretical value, or change in FVC or TPC > 10% and /or DLCO > 15% relative to baseline values documented 12 +/- 6 months before inclusion.
– Presence of interstitial lung disease (abnormalities on chest radiograph and / or lung HRCT with thin sections). It is necessary to ensure that etiologies unrelated to scleroderma were eliminated. For example, obstructive lung disease (chronic obstructive pulmonary disease or pulmonary emphysema). If the fibrosing lung disease threatens the vital prognosis, we will ensure the exclusion of a possible lung transplant.

and/or

b) Heart disease :
Reversible congestive heart failure, ventricular or atrial rhythm disturbances defined as recurrent episodes of atrial fibrillation or atrial flutter, recurrent paroxysmal atrial tachycardia or ventricular tachycardia, second or third degree atrioventricular block, large pericardial effusions needing specific medical (introduction of steroids) or surgical (drainage) intervention. It is necessary to ensure that etiologies unrelated to systemic sclerosis were eliminated.

and/or

c) Renal impairment defined by one of the following criteria :
Hypertension (after two repeated measurements of systolic > 160 mm Hg or diastolic > 110 mm Hg, at least 12 hours apart) or persistent abnormal urinary sediment (proteinuria, hematuria, or cylindruria), or hemolytic anemia by thrombotic microangiopathy , or recent renal failure (recent increase – the last 6 months – of creatinine clearance above normal). It is necessary to ensure that etiologies unrelated to systemic sclerosis were eliminated.

4. Signed informed consent.

5. presence of a consenting familial MSC donor or consenting spouse. Affiliation to social security.

6. Women of childbearing age taking effective contraception.

MSC donors :
1. Adults 18 to 65 years
2. Familial donor, in order: siblings, parents, cousins or other family member, or spouse.
3. Signed informed consent form.
4. Affiliation to social security.
5. Women of childbearing age taking effective contraception

Exclusion criteria :

Recipients :
1. Pregnancy or absence of appropriate contraception throughout the study.

2. Severe concomitant conditions :

a) Respiratory Disease :
– Pulmonary arterial hypertension confirmed by right catheterization or suspected pulmonary hypertension with systolic PAP at echography > 40 mmHg or mean PAP > 25mmHg after catheterization
– DLCO <30% of the theorical value
– Respiratory failure defined by oxygen arterial pressure at rest (PaO2) <8 kPa (<60 mmHg) and / or a blood pressure of carbon dioxide at rest (PaCO2)> 6.7 kPa (> 50 mmHg) without oxygen therapy.

b) Renal disease :
– Calculated creatinine clearance <20 ml/mn/m2
– Cystopathic sequelae post treatment by cyclophosphamide

c) Heart disease :
– Clinical sign of refractory congestive heart failure.
– Left ventricular ejection fraction <35% at myocardial scintigraphy or echocardiography.
– Uncontrolled ventricular arrhythmia.
– Pericardial effusion with hemodynamic compromise assessed by echocardiography.

d) Atteinte hépatique :
– Hepatic impairment defined as a persistent increase in transaminases or bilirubin to 3 times normal.

3. Uncontrolled psychiatric disorders compromising the ability to give informed consent, including drug taking and alcohol abuse.

4. Active neoplasm or concomitant myelodysplasia, cancer history.

5. Bone marrow failure defined by neutropenia < 0.5 x 109 / L, thrombocytopenia < 50 x 109 / L, anemia < 8g/dL, CD4 lymphopenia < 200 x 106 / L.

6. Uncontrolled systemic hypertension.

7. Uncontrolled acute or chronic infection, seropositivity to HIV1/ 2 or HTLV-1/2.

8. Chronic hepatitis B or C.

9. Significant exposure to bleomycin, toxic oils, vinyl chloride, trichloroethylene or silica; eosinophilia-myalgia syndrome, eosinophilia fasciitis.

10. Risk of poor patient compliance.

11. Lack of affiliation to social security

MSC donors :
1. History of allergy to Xylocaine

2. Usual contraindications for donation of marrow and / or blood, especially:
a. Positive serology to HTLV, Ag HBs, HCV, VIH, Syphilis
b. Positive PCR to VIH VHB VHC

3. Pregnancy or absence of effective contraception

4. Lack of affiliation to social security.

Exprimental treatment :
MSCs injected by slow intravenous infusion