Clinical Trials Register

Summary
EudraCT Number:	2017-001400-29
Sponsor's Protocol Code Number:	P150302J
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:	2018-07-31
Trial results

Index
A. PROTOCOL INFORMATION
B. SPONSOR INFORMATION
C. APPLICANT IDENTIFICATION
D. IMP IDENTIFICATION
D.8 INFORMATION ON PLACEBO
E. GENERAL INFORMATION ON THE TRIAL
F. POPULATION OF TRIAL SUBJECTS
G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
P. END OF TRIAL

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A. Protocol Information

A.1

Member State Concerned

France - ANSM

A.2

EudraCT number

2017-001400-29

A.3

Full title of the trial

Treatment of severe refractory systemic lupus erythematosus by injection of allogeneic mesenchymal stem cells derived from the umbilical cord - MSC SLE

TRAITEMENT DU LUPUS ERYTHEMATEUX SYSTEMIQUE REFRACTAIRE PAR INJECTION DE CELLULES SOUCHES MESENCHYMATEUSES ALLOGENIQUES ISSUES DU CORDON OMBILICAL - MSC LES

A.3.1

Title of the trial for lay people, in easily understood, i.e. non-technical, language

Treatment of systemic lupus erythematosus by injection iv of mesenchymal stem cells (MSC-LES)

TRAITEMENT DU LUPUS ERYTHEMATEUX SYSTEMIQUE PAR INJECTION IV DE CELLULES SOUCHES MESENCHYMATEUSES ALLOGENIQUES (MSC-LES)

A.3.2

Name or abbreviated title of the trial where available

MSC-LES

A.4.1

Sponsor's protocol code number

P150302J

A.7

Trial is part of a Paediatric Investigation Plan

A.8

EMA Decision number of Paediatric Investigation Plan

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
B.1.3.4	Country	France
B.3.1 and B.3.2	Status of the sponsor	Non-Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	Fondation du Rein (FdR) sous égide de la FRM, en partenariat avec l’AFM Téléthon et l’AIRG
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	ASSISTANCE PUBLIQUE - HOPITAUX DE PARIS (AP-HP)
B.5.2	Functional name of contact point	DRCI Hôpital St Louis
B.5.3	Address:
B.5.3.1	Street Address	1 av. Claude Vellefaux
B.5.3.2	Town/ city	PARIS
B.5.3.3	Post code	75010
B.5.3.4	Country	France
B.5.6	E-mail	karine.seymour@aphp.fr

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Test
D.2	Status of the IMP to be used in the clinical trial
D.2.1	IMP to be used in the trial has a marketing authorisation	No
D.2.5	The IMP has been designated in this indication as an orphan drug in the Community	No
D.2.5.1	Orphan drug designation number
D.3 Description of the IMP
D.3.1	Product name	ALLOGENEIC MESENCHYMAL STROMAL CELLS DERIVED FROM THE UMBILICAL CORD
D.3.2	Product code	0
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intracavernous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	0
D.3.9.1	CAS number	0
D.3.9.2	Current sponsor code	P150302
D.3.9.3	Other descriptive name	CSM allogéniques issues de cordons ombilicaux ( MTI-PP)
D.3.10	Strength
D.3.10.1	Concentration unit	1X 100 milligrams/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1.106 to 4.106
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	No
D.3.11.2	Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP)	Yes
	The IMP is a:
D.3.11.3	Advanced Therapy IMP (ATIMP)	No
D.3.11.3.1	Somatic cell therapy medicinal product	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	No
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	No
D.3.11.4	Combination product that includes a device, but does not involve an Advanced Therapy	No
D.3.11.5	Radiopharmaceutical medicinal product	No
D.3.11.6	Immunological medicinal product (such as vaccine, allergen, immune serum)	No
D.3.11.7	Plasma derived medicinal product	No
D.3.11.8	Extractive medicinal product	No
D.3.11.9	Recombinant medicinal product	No
D.3.11.10	Medicinal product containing genetically modified organisms	No
D.3.11.11	Herbal medicinal product	No
D.3.11.12	Homeopathic medicinal product	No
D.3.11.13	Another type of medicinal product	No

D.8 Information on Placebo

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Treatment of Systemic Lupus Erythematosus refractory to standard treatments.

Traitement du Lupus Erythémateux Systémique réfractaire aux traitements standards.

E.1.1.1

Medical condition in easily understood language

Patients with refractory systemic Lupus Erythematosus severe prior conventional treatments (Cyclophosphamide (CY), MMF or corticosteroids with or without corticosteroids)

Patients atteints de Lupus Erythémateux Sytémique réfractaire sévère aux traitements classiques préalables (Cyclophosphamide (CY), MMF ou corticoïdes avec ou sans corticoïdes)

E.1.1.2

Therapeutic area

Diseases [C] - Immune System Diseases [C20]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.0
E.1.2	Level	PT
E.1.2	Classification code	10042945
E.1.2	Term	Systemic lupus erythematosus
E.1.2	System Organ Class	10028395 - Musculoskeletal and connective tissue disorders

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

To analyze the tolerance of the administration of allogeneic CSM in the treatment of systemic Lupus Erythematous System (SLE) refractory to conventional treatments (Cyclophosphamide (CY), MMF or corticosteroids with or without corticosteroids)

Analyser la tolérance de l'administration de CSM allogéniques dans le traitement du Lupus Erythémateux Sytémique (LES) réfractaire sévère aux traitements classiques préalables (Cyclophosphamide (CY), MMF ou corticoïdes avec ou sans corticoïdes)

E.2.2

Secondary objectives of the trial

1- Feasibility of the administration of allogeneic CSM in the treatment of refractory patients with refractory severe prior conventional treatments
2- Tolerance at more than three months after injection, taking into account the morbidity observed and the overall survival of patients with SLE treated up to 1 year after the procedure (with 1 year of follow-up after the end of the study ).
3- Analysis of clinical and biological response according to clinico-biological criteria for routine surveillance of lupus by functional scores (SELENA-SLEDAI, BILAG, SF36, EQ5D, SRI, SLICC-SLE)
4- Analysis of the efficacy at 3 months of injection of allogeneic MSCs by evaluating the proportion of patients presenting a Major Clinical Response (MCR).
5- Evaluate the percentage of patients with Partial Clinical Response (CPR) during the 12-month follow-up period of the study.
6- Evaluation of the immunomodulatory action

1- Faisabilité de l'administration de CSM allogéniques dans le traitement des patients atteints de LES réfractaires sévères aux traitements classiques préalables
2- Tolérance à plus de trois mois après injection, en tenant compte de la morbidité observée et de la survie globale des patients atteints de LES traités jusqu'à 1 an après la procédure (avec 1 an de suivi après la fin de l'étude).
3- Analyse de la réponse clinique et biologique selon les critères clinico-biologique de surveillance de routine du lupus par les scores fonctionnels (SELENA-SLEDAI, BILAG, SF36, EQ5D, SRI, SLICC-SLE)
4- Analyse de l'efficacité à 3 mois de l'injection des CSM allogeniques en évaluant la proportion de patients présentant une Réponse Clinique Majeure (RCM).
5- Evaluer le pourcentage de patients présentant une Réponse Clinique partielle (RCP) au cours des 12 mois de suivi de l'étude.
6- Evaluation de l'action immunomodulatrice

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Subjects:
1- Pregnancy, breastfeeding or lack of appropriate contraception during study duration
2- Presence of:
a) Renal failure: calculated creatinine clearance of <30 ml / min
b) Cardiac failure: clinical signs of congestive heart failure; left ventricular ejection fraction <40% on echocardiography; uncontrolled ventricular arrhythmia;
c) Hepatitis defined by abnormal levels of transaminases (AST, ALT> 2 x normal) not related to disease activity.
d) Respiratory disease: mean PAP> 50 mmHg (echocardiography), respiratory failure defined by a resting blood pressure of oxygen at PaO 2 < 70 mmHg and / or PaCO2 > 50 mmHg without oxygen
3- Severe psychiatric disorders, including severe psychosis related to SLE, which would prevent to give informed consent or to undergo the procedure.
4- Active neoplasia or concomitant myelodysplasia, except for basal cell carcinoma or squamous cell carcinoma or in situ cervix carcinoma.
5- Bone marrow failure defined by neutropenia <0.5.109/L, thrombocytopenia <30. 109 / L, anemia < 8 g / dL, lymphopenia CD4 + <200 x 106 / L caused by another disease than SLE.
6- Acute or chronic uncontrolled infection: HIV 1/2, HTLV-1/2, Hepatitis B (HBsAg surface antigen), Hepatitis C with positive PCR
7- Patient having received belimumab within 2 months of belimumab within 2 months of Baseline, or having received rituximab or other B cell depleting biologic therapy within 6 months of Baseline
8- Current substance abuse or recent (within 60 days) history of substance abuse
9- Patient in periods of exclusion from the national roster of researchers
10- Patient with Linguistic or psychological incapacity to sign informed consent
11- Patient already included in another study at the same time.
12- Poor patient compliance.
13- Patient under legal protection.

Patients :
1- Grossesse, allaitement ou absence de contraception adaptée pendant la durée de l'étude.
2- Affection(s) concomitante(s) sévère(s):
a) Atteinte rénale: clearance calculée de la creatinine < 30 ml/min
b) Atteinte cardiaque: signe clinique d'insuffisance cardiaque congestive; fraction d'éjection ventriculaire gauche < 40 % à l'échographie cardiaque; arythmie ventriculaire non contrôlée;
c) Atteinte hépatique : Insuffisance hépatique définie par un taux anormal des transaminases (ASAT, ALAT > 2 fois la normal) non liée à l'activité de la maladie.
d) Atteinte respiratoire: PAP moyenne > 50 mmHg (échographie cardiaque), insuffisance respiratoire définie par une pression artérielle en oxygène au repos PaO2 < 70 mmHg et / ou une PaCO2>50 mmHg, sans oxygénothérapie
3- Troubles psychiatrique sévères, incluant la psychose sévère liée au LES, empêchant de donner par écrit un consentement éclairé ou à subir la procédure.
4- Néoplasie active ou myélodysplasie concomitante, sauf pour le carcinome basocellulaire ou le cancer épidermoïde ou le carcinome du col de l'utérus in situ.
5- Insuffisance médullaire définie par : neutropénie < 0,5.109/L, thrombopénie < 30.109/L, anémie < 8 g/dL, lymphopénie T CD4+ < 200 x 106/L causé par une autre affection que le lupus.
6- Infection aiguë ou chronique non contrôlée, séropositivité VIH 1/2, HTLV1/2, Hépatite B (antigène de surface Ag HBs), Hépatite C, PCR positive
7- Patient ayant reçu le belimumab dans les 2 mois suivant le belimumab dans les 2 mois suivant la ligne de base, ou ayant reçu un rituximab ou un autre traitement biologique appauvrissant les cellules B dans les 6 mois suivant la ligne de base
8- L'abus de substances actuelles ou les antécédents récents (dans les 60 jours) de toxicomanie
9- Personnes en période d'exclusion sur le fichier national des personnes se prêtant à une recherche
10- Patient ayant une incapacité linguistique ou psychique de signer le consentement éclairé
11- Personne déjà incluse dans une autre étude en même temps.
12- Risque de mauvaise compliance du patient.
13- Patient sous protection juridique.

E.4

Principal exclusion criteria

Subjects:
1- Pregnancy, breastfeeding or lack of appropriate contraception during study duration
2- Presence of:
a) Renal failure: calculated creatinine clearance of <30 ml / min
b) Cardiac failure: clinical signs of congestive heart failure; left ventricular ejection fraction <40% on echocardiography; uncontrolled ventricular arrhythmia;
c) Hepatitis defined by abnormal levels of transaminases (AST, ALT> 2 x normal) not related to disease activity.
d) Respiratory disease: mean PAP> 50 mmHg (echocardiography), respiratory failure defined by a resting blood pressure of oxygen at PaO 2 < 70 mmHg and / or PaCO2 > 50 mmHg without oxygen
3- Severe psychiatric disorders, including severe psychosis related to SLE, which would prevent to give informed consent or to undergo the procedure.
4- Active neoplasia or concomitant myelodysplasia, except for basal cell carcinoma or squamous cell carcinoma or in situ cervix carcinoma.
5- Bone marrow failure defined by neutropenia <0.5.109/L, thrombocytopenia <30. 109 / L, anemia < 8 g / dL, lymphopenia CD4 + <200 x 106 / L caused by another disease than SLE.
6- Acute or chronic uncontrolled infection: HIV 1/2, HTLV-1/2, Hepatitis B (HBsAg surface antigen), Hepatitis C with positive PCR
7- Patient having received belimumab within 2 months of belimumab within 2 months of Baseline, or having received rituximab or other B cell depleting biologic therapy within 6 months of Baseline
8- Comorbidities requiring corticosteroid therapy
9- Current substance abuse or recent (within 60 days) history of substance abuse
10- Patient in periods of exclusion from the national roster of researchers
11- Patient with Linguistic or psychological incapacity to sign informed consent
12- Patient who has already been included in this or another study at the same time.
13- Poor patient compliance.
14- Patient under legal protection.

Patient :
1- Grossesse, allaitement ou absence de contraception appropriée pendant la durée de l'étude.
2- Présence de :
a) Atteinte rénale: clearance calculée de la creatinine < 30 ml/min
b) Atteinte cardiaque: signe clinique d'insuffisance cardiaque congestive; fraction d'éjection ventriculaire gauche < 40 % à l'échographie cardiaque; arythmie ventriculaire non contrôlée;
c) Atteinte hépatique : Insuffisance hépatique définie par un taux anormal des transaminases (ASAT, ALAT > 2 fois la normal) non liée à l'activité de la maladie.
d) Atteinte respiratoire: PAP moyenne > 50 mmHg (échographie cardiaque), insuffisance respiratoire définie par une pression artérielle en oxygène au repos PaO2 < 70 mmHg et / ou une PaCO2>50 mmHg, sans oxygénothérapie
e) Troubles psychiatrique sévères, incluant la psychose sévère liée au LES, empêchant de donner par écrit un consentement éclairé ou à subir la procédure.
3- Néoplasie active ou myélodysplasie concomitante, sauf pour le carcinome basocellulaire ou le cancer épidermoïde ou le carcinome du col de l'utérus in situ.
4- Insuffisance médullaire définie par : neutropénie < 0,5.109/L, thrombopénie < 30.109/L, anémie < 8 g/dL, lymphopénie T CD4+ < 200 x 106/L causé par une autre affection que le lupus.
5- Infection aiguë ou chronique non contrôlée, séropositivité VIH 1/2, HTLV1/2, Hépatite B (antigène de surface Ag HBs), Hépatite C, PCR positive
6- Patient ayant reçu le belimumab dans les 2 mois suivant le belimumab dans les 2 mois suivant la ligne de base, ou ayant reçu un rituximab ou un autre traitement biologique appauvrissant les cellules B dans les 6 mois suivant la ligne de base
7- Comorbidités nécessitant une corticothérapie
8- L'abus de substances actuelles ou les antécédents récents (dans les 60 jours) de toxicomanie
9- Personnes en période d'exclusion sur le fichier national des personnes se prêtant à une recherche
10- Incapacité linguistique ou psychique de signer le consentement éclairé
11- Personne ayant déjà été inclus dans cette étude ou dans une autre en même temps.
12- Risque de mauvaise compliance du patient.
13- Patient sous protection juridique.

E.5 End points

E.5.1

Primary end point(s)

Immediate tolerance assessed during the injection and the first 10 days after the injection of the allogeneic MSCs, according to the side effects defined by the CTCAE standards.

Tolérance immédiate évaluée durant l'injection et les 10 premiers jours qui suivront l'injection des CSM allogéniques, selon les effets secondaires définis par les normes CTCAE.

E.5.1.1

Timepoint(s) of evaluation of this end point

Non

E.5.2

Secondary end point(s)

1-Feasibility of administering allogeneic MSCs in the treatment of refractory patients with refractory severe prior conventional treatments
2-Tolerance at more than three months after injection, taking into account the morbidity observed and the overall survival of SLE patients treated up to 1 year after the procedure (with 1 year of follow-up after the end of the study ).
3-Analysis of clinical and biological response according to clinico-biological criteria for routine lupus surveillance by functional scores (SELENA-SLEDAI, BILAG, SF36, EQ5D, SRI, SLICC-SLE)
4-Analysis of the efficacy at 3 months of injection of allogeneic MSCs by evaluating the proportion of patients presenting a Major Clinical Response (MCR).
5-Evaluate the percentage of patients presenting a Partial Clinical Response (CPR) during the 12 months of study follow-up.
6-Evaluation of immunomodulatory action

1-Faisabilité de l'administration de CSM allogéniques dans le traitement des patients atteints de LES réfractaires sévères aux traitements classiques préalables
2-Tolérance à plus de trois mois après injection, en tenant compte de la morbidité observée et de la survie globale des patients atteints de LES traités jusqu'à 1 an après la procédure (avec 1 an de suivi après la fin de l'étude).
3-Analyse de la réponse clinique et biologique selon les critères clinico-biologique de surveillance de routine du lupus par les scores fonctionnels (SELENA-SLEDAI, BILAG, SF36, EQ5D, SRI, SLICC-SLE)
4-Analyse de l'efficacité à 3 mois de l'injection des CSM allogeniques en évaluant la proportion de patients présentant une Réponse Clinique Majeure (RCM).
5-Evaluer le pourcentage de patients présentant une Réponse Clinique partielle (RCP) au cours des 12 mois de suivi de l'étude.
6-Evaluation de l'action immunomodulatrice

E.5.2.1

Timepoint(s) of evaluation of this end point

Non

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

E.6.3

Therapy

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

E.6.8

Bioequivalence

E.6.9

Dose response

Yes

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

Yes

E.6.13.1

Other scope of the trial description

Tolérance

E.7

Trial type and phase

E.7.1

Human pharmacology (Phase I)

Yes

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Analyze tolerance of administration of allogeneic MSCs

Analyser la tolérance de l'administration des CSM allogéniques

E.7.2

Therapeutic exploratory (Phase II)

Yes

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

E.8.1.1

Randomised

E.8.1.2

Open

Yes

E.8.1.3

Single blind

E.8.1.4

Double blind

E.8.1.5

Parallel group

E.8.1.6

Cross over

E.8.1.7

Other

Yes

E.8.1.7.1

Other trial design description

monocentrique, phase II

monocentric, phase II

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

E.8.2.2

Placebo

E.8.2.3

Other

E.8.3

The trial involves single site in the Member State concerned

Yes

E.8.4

The trial involves multiple sites in the Member State concerned

E.8.5

The trial involves multiple Member States

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

E.8.6.2

Trial being conducted completely outside of the EEA

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

LVLS

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

E.8.9.1

In the Member State concerned days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

F.1.1.1

In Utero

F.1.1.2

Preterm newborn infants (up to gestational age < 37 weeks)

F.1.1.3

Newborns (0-27 days)

F.1.1.4

Infants and toddlers (28 days-23 months)

F.1.1.5

Children (2-11years)

F.1.1.6

Adolescents (12-17 years)

F.1.2

Adults (18-64 years)

Yes

F.1.2.1

Number of subjects for this age range:

F.1.3

Elderly (>=65 years)

Yes

F.1.3.1

Number of subjects for this age range:

F.2 Gender

F.2.1

Female

Yes

F.2.2

Male

Yes

F.3 Group of trial subjects

F.3.1

Healthy volunteers

F.3.2

Patients

Yes

F.3.3

Specific vulnerable populations

Yes

F.3.3.1

Women of childbearing potential not using contraception For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2018-07-31.

Yes

F.3.3.2

Women of child-bearing potential using contraception

Yes

F.3.3.3

Pregnant women

F.3.3.4

Nursing women

F.3.3.5

Emergency situation

F.3.3.6

Subjects incapable of giving consent personally

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

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)

expected normal treatment of that condition

traitement normal attendu de cette maladie

G. Investigator Networks to be involved in the Trial

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2018-01-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2018-03-16

P. End of Trial
P.	End of Trial Status	Ongoing

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