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Treatment of Refractory Sever Systemic Scleroderma by Injection of Allogeneic Mesenchymal Stem Cells (MSC)

Primary Purpose

SYSTEMIC SCLERODERMA, ALLOGENEIC MESENCHYMAL STEM CELLS, ADULT

Status
Completed
Phase
Phase 1
Locations
France
Study Type
Interventional
Intervention
INJECTION OF ALLOGENEIC MESENCHYMAL STEM CELLS
Sponsored by
Assistance Publique - Hôpitaux de Paris
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional treatment trial for SYSTEMIC SCLERODERMA focused on measuring SYSTEMIC SCLERODERMA, TRANSPLANTATION, ALLOGENEIC MESENCHYMAL STEM CELLS, ADULT

Eligibility Criteria

18 Years - 70 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Age> 18 years and <70 years.
  • Established diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology
  • SSc of poor prognosis, involving life-threatening with sever visceral impairment (cardiac, pulmonary or renal) AND " a) contraindicating the use of or b) resistant to " immunosuppressive therapy conventionally used in severe forms of the disease according to the European recommendations of EUSTAR (www.eustar.org) and EBMT (www.ebmt.org) which then rely on high doses of iv cyclophosphamide (either in monthly bolus at least six months or by intensification and autograft of Hematopoietic Stem Cells) or SSc with fibrosing lung damage threatening the vital prognosis which excludes a lung transplant.

These forms of severe and serious SSc WITH at least 6 months follow-up after completion of prior immunosuppressive therapy by high doses of iv cyclophosphamide when they were made, combine to varying degrees : rapidly progressive skin lesions with a score of Rodnan> 15 and one or more of the major visceral lesions defined as follows :

  1. Respiratory disease :

    DLCO <60% or FVC ≤70% of the theoretical value and the presence of interstitial lung disease (abnormalities on chest radiograph and / or lung HRCT with thin sections). It is necessary to ensure that non-related etiologies to scleroderma were eliminated; example: obstructive lung disease (chronic obstructive pulmonary disease or pulmonary emphysema). If the fibrosing lung disease threatens the vital prognosis, we will ensure of the exclusion of a possible lung transplant.

    And/or

  2. Heart disease:

congestive heart failure reversible, ventricular or atrial rhythm disturbances defined as recurrent episodes of atrial fibrillation or atrial flutter, recurrent paroxysmal atrial tachycardia or ventricular tachycardia, atrioventricular block of second or third degree, pericardial effusion with high abundance needing specific treatment of medical type (introduction of steroids) or surgical type (drainage). It is necessary to ensure that non-related etiologies to scleroderma were removed.

  • Signed informed consent.
  • Presence of a consenting intrafamilial MSC donor
  • Affiliation to social security.

Exclusion Criteria:

  • Pregnancy or absence of appropriate contraception throughout the study.
  • Respiratory Disease:
  • systolic Pulmonary arterial pressure (PASP)>55mmHg (on echocardiography or after right heart catheterization);
  • DLCO <30% of the theorical ;
  • 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.

Renal Disease:

  • Calculated creatinine clearance <20 ml/mn/m2
  • Sequelae cystopathy post treatment by cyclophosphamide
  • Heart disease:
  • Clinical sign of a congestive heart failure refractory ;
  • Left ventricular ejection fraction <35% at myocardial scintigraphy or echocardiography;
  • Pulmonary arterial hypertension confirmed by right catheterization or suspected pulmonary hypertension with systolic PAP at echography > 40 mmHg
  • Chronic atrial fibrillation requiring oral anticoagulant therapy;
  • Uncontrolled ventricular arrhythmia;
  • Pericardial effusion with hemodynamic compromise assessed by echocardiography.
  • Hepatic Disease:
  • Hepatic impairment defined as a persistent increase in transaminases or bilirubin to 3 times normal.
  • Psychiatric disorders, including drug taking and alcohol abuse.
  • Active neoplasia or concomitant myelodysplasia, antecedent of neoplasia.
  • Bone marrow failure defined by neutropenia <0.5 x 109 / L, thrombocytopenia <50 x 109 / L, anemia <8 g / dL, CD4 lymphopenia <200 x 106 / L.
  • Uncontrolled systemic hypertension.
  • Uncontrolled acute or chronic infection, HIV1, 2 or HTLV-1, 2seropositivity.
  • Chronic hepatitis B or C active.
  • Significant exposure to bleomycin, toxic oils, vinyl chloride, trichloroethylene or silica; eosinophilia-myalgia syndrome, eosinophilia fasciitis.
  • Risk of poor patient compliance.

Sites / Locations

  • Saint-Louis Hospital

Arms of the Study

Arm 1

Arm Type

Experimental

Arm Label

INJECTION OF ALLOGENEIC MESENCHYMAL STEM CELLS

Arm Description

Administration of allogeneic MSCs in the treatment of severe diffuse SSc or rapidly progressive and refractory to conventional treatments by prior cyclophosphamide

Outcomes

Primary Outcome Measures

Immediate Toxicity
Immediate Toxicity/tolerance defined as grade 3 or above toxicity base on the CTCAE - Cancer Therapy Evaluation Program (CTEP), observed during the first 10 days (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf)

Secondary Outcome Measures

Medium-term tolerance
Treatment-related event-free survival at 2 years. Treatment-related event (morbidity) being defined by the onset of clinical events induced by the procedure and not explained by the natural or expected course of the scleroderma disease.
Survival
Time from inclusion to death
Progression free survival
Defined as the time in days from the day of inclusion until the occurrence of changes compared to the initial assessment, documented and re-evaluated at two successive examinations 3 months
CBC
complete blood count (CBC)
Platelet
Platelet blood count
Lymphocyte
Lymphocyte subpopulation blood count measured by flow cytometry
Antibody
Antibody response
Rodnan score
modified Rodnan Score
SHAQ
Scleroderma Health Assessment Questionnaire (SHAQ)
Clinical progression
Occurence of visceral involvement, defined as any of the following: Pulmonary: diffusion capacity of CO (DLCO and DLCO/VA), forced vital capacity (FVC), total lung capacity (TLC), residual volume (RV), pulmonary artery pressure (measured by echocardiography or right heart catheterisation), arterial blood gases (pO2, pCO2, p(A-a)O2) in ambient air, Myocardial: ECG, left ventricular function measured by echocardiography (and cardiac MRI and/or Gating in the event of cardiac abnormality or suspected LV dysfunction on ultrasound) with semi-quantitative analysis of the degree of cardiac damage according to the cardiac score (based on the presence or absence of left axial deviation on the electrocardiogram and/or moderate or significant pericardial effusion according to the echocardiogram), Renal: 24-hour proteinuria, creatinine clearance, Patient's weight in kg,
Clinical response
Defined by a 25% improvement in modified Rodnan Score and/or ≥10% in DLCO or FVC compared to baseline state without the need to reintroduce other immunosuppressants.

Full Information

First Posted
July 17, 2014
Last Updated
October 31, 2022
Sponsor
Assistance Publique - Hôpitaux de Paris
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1. Study Identification

Unique Protocol Identification Number
NCT02213705
Brief Title
Treatment of Refractory Sever Systemic Scleroderma by Injection of Allogeneic Mesenchymal Stem Cells
Acronym
MSC
Official Title
Treatment of Refractory Sever Systemic Scleroderma by Injection of Allogeneic Mesenchymal Stem Cells
Study Type
Interventional

2. Study Status

Record Verification Date
October 2020
Overall Recruitment Status
Completed
Study Start Date
May 6, 2014 (Actual)
Primary Completion Date
February 9, 2020 (Actual)
Study Completion Date
June 16, 2022 (Actual)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Sponsor
Name of the Sponsor
Assistance Publique - Hôpitaux de Paris

4. Oversight

5. Study Description

Brief Summary
The main ailm of this phase I-II study is to evaluate toxicity and efficacy of allogenic mesenchymal stem cell therapy to treat severe systemic sclerosis. In practice this treatment will be given to patients with a rapidly evolutive disease or refractory to cyclophosphamide.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
SYSTEMIC SCLERODERMA, ALLOGENEIC MESENCHYMAL STEM CELLS, ADULT
Keywords
SYSTEMIC SCLERODERMA, TRANSPLANTATION, ALLOGENEIC MESENCHYMAL STEM CELLS, ADULT

7. Study Design

Primary Purpose
Treatment
Study Phase
Phase 1, Phase 2
Interventional Study Model
Single Group Assignment
Masking
None (Open Label)
Allocation
N/A
Enrollment
20 (Actual)

8. Arms, Groups, and Interventions

Arm Title
INJECTION OF ALLOGENEIC MESENCHYMAL STEM CELLS
Arm Type
Experimental
Arm Description
Administration of allogeneic MSCs in the treatment of severe diffuse SSc or rapidly progressive and refractory to conventional treatments by prior cyclophosphamide
Intervention Type
Biological
Intervention Name(s)
INJECTION OF ALLOGENEIC MESENCHYMAL STEM CELLS
Primary Outcome Measure Information:
Title
Immediate Toxicity
Description
Immediate Toxicity/tolerance defined as grade 3 or above toxicity base on the CTCAE - Cancer Therapy Evaluation Program (CTEP), observed during the first 10 days (http://ctep.cancer.gov/protocolDevelopment/electronic_applications/docs/ctcaev3.pdf)
Time Frame
10 days
Secondary Outcome Measure Information:
Title
Medium-term tolerance
Description
Treatment-related event-free survival at 2 years. Treatment-related event (morbidity) being defined by the onset of clinical events induced by the procedure and not explained by the natural or expected course of the scleroderma disease.
Time Frame
2 years
Title
Survival
Description
Time from inclusion to death
Time Frame
2 years
Title
Progression free survival
Description
Defined as the time in days from the day of inclusion until the occurrence of changes compared to the initial assessment, documented and re-evaluated at two successive examinations 3 months
Time Frame
2 years
Title
CBC
Description
complete blood count (CBC)
Time Frame
1, 2, 3, 4, 8, 12, 16, 20, 24 weeks
Title
Platelet
Description
Platelet blood count
Time Frame
1, 2, 3, 4, 8, 12, 16, 20, 24 weeks
Title
Lymphocyte
Description
Lymphocyte subpopulation blood count measured by flow cytometry
Time Frame
3, 6, 9, 12, 15, 18, 24 months
Title
Antibody
Description
Antibody response
Time Frame
3, 6, 9, 12, 15, 18, 24 months
Title
Rodnan score
Description
modified Rodnan Score
Time Frame
3, 6, 9, 12, 15, 18, 24 months
Title
SHAQ
Description
Scleroderma Health Assessment Questionnaire (SHAQ)
Time Frame
3, 6, 9, 12, 15, 18, 24 months
Title
Clinical progression
Description
Occurence of visceral involvement, defined as any of the following: Pulmonary: diffusion capacity of CO (DLCO and DLCO/VA), forced vital capacity (FVC), total lung capacity (TLC), residual volume (RV), pulmonary artery pressure (measured by echocardiography or right heart catheterisation), arterial blood gases (pO2, pCO2, p(A-a)O2) in ambient air, Myocardial: ECG, left ventricular function measured by echocardiography (and cardiac MRI and/or Gating in the event of cardiac abnormality or suspected LV dysfunction on ultrasound) with semi-quantitative analysis of the degree of cardiac damage according to the cardiac score (based on the presence or absence of left axial deviation on the electrocardiogram and/or moderate or significant pericardial effusion according to the echocardiogram), Renal: 24-hour proteinuria, creatinine clearance, Patient's weight in kg,
Time Frame
3, 6, 9, 12, 15, 18, 24 months
Title
Clinical response
Description
Defined by a 25% improvement in modified Rodnan Score and/or ≥10% in DLCO or FVC compared to baseline state without the need to reintroduce other immunosuppressants.
Time Frame
3, 6, 9, 12, 15, 18, 24 months

10. Eligibility

Sex
All
Minimum Age & Unit of Time
18 Years
Maximum Age & Unit of Time
70 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Age> 18 years and <70 years. Established diagnosis of systemic sclerosis according to the criteria of the American College of Rheumatology SSc of poor prognosis, involving life-threatening with sever visceral impairment (cardiac, pulmonary or renal) AND " a) contraindicating the use of or b) resistant to " immunosuppressive therapy conventionally used in severe forms of the disease according to the European recommendations of EUSTAR (www.eustar.org) and EBMT (www.ebmt.org) which then rely on high doses of iv cyclophosphamide (either in monthly bolus at least six months or by intensification and autograft of Hematopoietic Stem Cells) or SSc with fibrosing lung damage threatening the vital prognosis which excludes a lung transplant. These forms of severe and serious SSc WITH at least 6 months follow-up after completion of prior immunosuppressive therapy by high doses of iv cyclophosphamide when they were made, combine to varying degrees : rapidly progressive skin lesions with a score of Rodnan> 15 and one or more of the major visceral lesions defined as follows : Respiratory disease : DLCO <60% or FVC ≤70% of the theoretical value and the presence of interstitial lung disease (abnormalities on chest radiograph and / or lung HRCT with thin sections). It is necessary to ensure that non-related etiologies to scleroderma were eliminated; example: obstructive lung disease (chronic obstructive pulmonary disease or pulmonary emphysema). If the fibrosing lung disease threatens the vital prognosis, we will ensure of the exclusion of a possible lung transplant. And/or Heart disease: congestive heart failure reversible, ventricular or atrial rhythm disturbances defined as recurrent episodes of atrial fibrillation or atrial flutter, recurrent paroxysmal atrial tachycardia or ventricular tachycardia, atrioventricular block of second or third degree, pericardial effusion with high abundance needing specific treatment of medical type (introduction of steroids) or surgical type (drainage). It is necessary to ensure that non-related etiologies to scleroderma were removed. Signed informed consent. Presence of a consenting intrafamilial MSC donor Affiliation to social security. Exclusion Criteria: Pregnancy or absence of appropriate contraception throughout the study. Respiratory Disease: systolic Pulmonary arterial pressure (PASP)>55mmHg (on echocardiography or after right heart catheterization); DLCO <30% of the theorical ; 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. Renal Disease: Calculated creatinine clearance <20 ml/mn/m2 Sequelae cystopathy post treatment by cyclophosphamide Heart disease: Clinical sign of a congestive heart failure refractory ; Left ventricular ejection fraction <35% at myocardial scintigraphy or echocardiography; Pulmonary arterial hypertension confirmed by right catheterization or suspected pulmonary hypertension with systolic PAP at echography > 40 mmHg Chronic atrial fibrillation requiring oral anticoagulant therapy; Uncontrolled ventricular arrhythmia; Pericardial effusion with hemodynamic compromise assessed by echocardiography. Hepatic Disease: Hepatic impairment defined as a persistent increase in transaminases or bilirubin to 3 times normal. Psychiatric disorders, including drug taking and alcohol abuse. Active neoplasia or concomitant myelodysplasia, antecedent of neoplasia. Bone marrow failure defined by neutropenia <0.5 x 109 / L, thrombocytopenia <50 x 109 / L, anemia <8 g / dL, CD4 lymphopenia <200 x 106 / L. Uncontrolled systemic hypertension. Uncontrolled acute or chronic infection, HIV1, 2 or HTLV-1, 2seropositivity. Chronic hepatitis B or C active. Significant exposure to bleomycin, toxic oils, vinyl chloride, trichloroethylene or silica; eosinophilia-myalgia syndrome, eosinophilia fasciitis. Risk of poor patient compliance.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
dominique farges, MDPHD
Organizational Affiliation
APHP
Official's Role
Principal Investigator
Facility Information:
Facility Name
Saint-Louis Hospital
City
Paris
ZIP/Postal Code
75010
Country
France

12. IPD Sharing Statement

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Treatment of Refractory Sever Systemic Scleroderma by Injection of Allogeneic Mesenchymal Stem Cells

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