Clinical Trials Register

Summary
EudraCT Number:	2012-002067-10
Sponsor's Protocol Code Number:	MSC-JIA
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-09-24
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

Netherlands - Competent Authority

A.2

EudraCT number

2012-002067-10

A.3

Full title of the trial

Mesenchymal stromal cells for treatment of drug resistant
pediatric Juvenile idiopathic arthritis

Mesenchymale stromale cellen voor de behandeling van therapie-resistente juveniele idiopathische artritis op de kinderleeftijd

A.3.1

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

Adult bonemarrow stem cells for treatment of juvenile arthritis in childhood

Volwassen beenmergstamcellen voor de behandeling van therapie-resistente jeugdreuma op de kinderleeftijd

A.3.2

Name or abbreviated title of the trial where available

MSC-JIA

A.4.1

Sponsor's protocol code number

MSC-JIA

A.5.4

Other Identifiers

Name:

Nederlands Trial Register

Number:

NTR4146

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	University Medical Center Utrecht
B.1.3.4	Country	Netherlands
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	University Medical Center Utrecht
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	ZonMw (The Netherlands Organisation for Health Research and Development)
B.4.2	Country	Netherlands
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Medical Center Utrecht
B.5.2	Functional name of contact point	Business Manager
B.5.3	Address:
B.5.3.1	Street Address	PO Box 85090, intern mail address KB 03.057.1
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3508 AB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31887554250
B.5.6	E-mail	A.M.W.Laeven@umcutrecht.nl

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	Mesenchymal Stromal Cells
D.3.2	Product code	TC-MSC
D.3.4	Pharmaceutical form	Suspension and solvent for suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	mesenchymal stromal cells
D.3.9.3	Other descriptive name	EX VIVO CULTURED HUMAN MESENCHYMAL STEM CELLS
D.3.9.4	EV Substance Code	SUB27304
D.3.10	Strength
D.3.10.1	Concentration unit	million CFU million colony forming units
D.3.10.2	Concentration type	not less then
D.3.10.3	Concentration number	2 million CFU/kg
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)	Yes
D.3.11.3.1	Somatic cell therapy medicinal product	Yes
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

juvenile idiopathic arthritis

juveniele idiopathische artritis

E.1.1.1

Medical condition in easily understood language

juvenile rheumatoid arthritis

jeugdreuma

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	17.0
E.1.2	Level	PT
E.1.2	Classification code	10059176
E.1.2	Term	Juvenile idiopathic arthritis
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

Onderzoeken of intraveneuze MSC een veilige behandeling is voor kinderen met therapie-resistente jeugdreuma.

To find out if intravenous MSC is a safe treatment for children with therapy-resistant JIA

E.2.2

Secondary objectives of the trial

1. Effectiveness as measured by the percentage of individual change by ACR Pediatric 30 criteria (see 6.1.2)
2. Effectiveness as measured by the a composite disease activity score for JIA, the Juvenile Arthritis Disease Activity Score (JADAS) which has the advantage of the measurement of actual disease activity and the comparison of one patient's absolute response with that of another patient's since it quantifies the absolute level of disease activity by providing one summary number on a continuous scale.
3. Does infusion of MSC induce remission of inflammation as seen on MRI?
4. Does infusion of MSC induce immunoregulatory mechanisms leading to a less pro-inflammatory milieu in the serum?

1. Effectiviteit zoals gemeten met het percentage van de individuele verandering door ACR Pediatric 30 criteria (zie 6.1.2)
2. Doeltreffendheid gemeten door een samengestelde ziekteactiviteit score JIA, de Juveniele Artritis Disease Activity Score (Jadas) hetgeen het voordeel heeft dat de werkelijke ziekteactiviteit wordt gemeten en een vergelijking van absolute respons van een patiënt met die van een andere patiënt mogelijk is omdat deze score het absolute niveau van de ziekte-activiteit kwantificeert door middel van een samengesteld getal op een continue schaal.
3. Kan infusie van MSCremissie induceren van ontsteking zoals te zien op de MRI?
4. Kan infusie van MSC immuunmodulatie geven leidend tot een minder pro-inflammatoire milieu in het serum?

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

In order to be eligible to participate in this study, a subject must meet all of the following criteria: Patients (4-18 years of age) diagnosed with juvenile idiopathic arthritis according to the ILAR-criteria with active arthritis resistant to intra-articular steroids and systemic use of methotrexate and for whom no on-label indication exists for (not yet used) biologicals. The patient is followed for adverse events via the Pharmachild database.

Patiënten (4-18 jaar) gediagnosticeerd met juveniele idiopathische artritis op basis van de Ilar-criteria met actieve artritis resistent tegen intra-articulaire steroïden en systemisch gebruik van methotrexaat voor wie er geen (nog niet gebruikt) on-label biological beschikbaar is. De patient wordt gevolgd voor bijwerkingen via Pharmachild database.

E.4

Principal exclusion criteria

Concurrent use of biological response modifiers.
Concurrent infection, febrile illness or malignancy.
Pregnancy.

Gelijktijdig gebruik van biological response modifiers.
Gelijktijdige infectie, met koorts gepaard gaande ziekte of een maligniteit.
Zwangerschap.

E.5 End points

E.5.1

Primary end point(s)

Total number of adverse events in the 3 months prior to MSC infusion and the number of adverse events 3 months after MSC infusion.

Totaal aantal bijwerkingen in de 3 maanden voorafgaand aan MSC infusie en het aantal bijwerkingen 3 maanden na MSC infusie.

E.5.1.1

Timepoint(s) of evaluation of this end point

52 weeks after the (first) MSC injection

52 weken na de (eerste) MSC injectie

E.5.2

Secondary end point(s)

The ACR Pediatric 30 criteria should be met.
The ACR Pedi 30 criteria are defined as improvement of ≥ 30% in at least 3 of 6 core response variables used to assess disease activity with no more than 1 variable worsening by ≥ 30%.

Clinical outcomes:
Clinical visits (at least 7 times in the first year 0-51 wks): -13, 0, 4, 8, 12, 16, 26, 39, 52 weeks
The visits will encompass complete medical history and monitoring for side effects. Furthermore complete physical examination including total joint count. Validated health and functionality related questionnaires (see below) will be provided to the parents/patients. Global assessments by the parents/patients measured with a 10-cm VAS.
Most widely used questionnaire for JIA is the Childhood Health Assessment Questionnaire (C-HAQ 30+8).
In children with JIA, a functional measure focused to assess the function of individual joint groups, the Juvenile Arthritis Functionality Scale (JAFS), detects with greater precision the functional impact of arthritis in specific body areas than does a standard questionnaire based on the assessment of activities of daily living (the C-HAQ).
Normal evaluation of JIA includes: articular index of tender joints, evaluation of the joint range of motion (EPM-ROM scale) 44 and will contain an evaluation of all joints as described previously. In short the joints will be assessed as being normal, warm, painful/tender, tender on passive motion, limited in motion. The degrees of passive motion will be noted for all limited joints. Global assessments by the physician measured with a 10-cm visual analogue scale (VAS).
A weighted joint score improves the information provided by joint counts on the severity of arthritis and its impact on patients' well-being since a small finger joint of the non-dominant hand does not have the same impact as a knee that's is involved.
ACR Pedi 30, 50, 70 and 90-scores are most frequently used for clinical trials. A composite disease activity score for JIA, the Juvenile Arthritis Disease Activity Score (JADAS), has the advantage of the measurement of actual disease activity and the comparison of one patient's absolute response with that of another patient's since it quantifies the absolute level of disease activity by providing one summary number on a continuous scale. All the above will be evaluated since all these parameters are complementary.
Lastly the proposed preliminary definition of minimal disease activity in polyarticular JIA, the proposed preliminary definition of inactive disease in polyarticular JIA and the cut-off values for various disease states for the JADAS scores will be evaluated.

Radiological outcomes:
Magnetic Resonance Imaging (MRI 3x): MRI will be performed before MSC-infusion (wk0), 8 weeks (wk8) and 1 year after MSC infusion (wk52)
The most active (highest burden in pain/swelling/limitation) large peripheral joint will be imaged; if only small joints of hands or feet are involved a whole hand or foot will be imaged. No data on treatment will be provided to the radiologist.
Synovial enhancement, bone edema, cartilage loss, and bone erosion will all be scored as absent, mild, moderate and severe in both joints. Overall, there is fair (grade B) strength of evidence that MRI is an accurate diagnostic method for evaluating synovium and cartilage and for assessing clinical responsiveness to treatment in peripheral joints in JIA. In the case of knees the JAMRIS score can be used.

Laboratory outcomes:
Venapuncture (at least 7x in the first year): at every clinical visit -13, 0, 4, 8, 12, 16, 26, 39, 52 weeks.
The blood for erythrocyte sedimentation rate (ESR), C-reactive protein level (CRP), complete blood count, leucocyte differentiation, ASAT, ALAT, LDH, BUN, Creatinine, total IgG, Rheumatoid factor, anti-CCP. Furthermore lymphocyte subpopulations will be analyzed using our FACS Canto machine and by their cytokine production measured by Luminex as previously described by our own group: (effector and regulatory subpopulations: including CD19+, CD4+, CD8+lymphocytes and Th1-, Th2-, Th17-, FoxP3-Treg, IL10+-Treg phenotype).
Detailed B cell activation markers: within the CD19 positive B-cell we will look for CD38+, CD86+, CD10+ , CD27+, sIgM, sIgD, sIgG en sIgA. With these markers we can assess the proportion of naïve, mature and memory cells.
Serumcytokines will also be examined by Luminex (including IL1, IL6, IL12, IL17, IL23, TNFα, IFNγ, IL4, IL10).
Myeloid related proteins will be measured.
At last we will investigate the in vitro suppression by MSC and by T-regs of the proliferation of the stimulated PBMC. Supernatant of stimulated PBMC’s will be examined by Luminex.

ACR Ped 30 criteria moeten gehaald worden.

Klinische resultaten:
De meest gebruikte vragenlijst voor JIA is de Childhood Health Assessment Questionnaire (C-HAQ). Bij kinderen met JIA, is de Juvenile Arthritis Functionality Scale (JAFS) ontwikkeld, die detecteert met een grotere nauwkeurigheid de functionele gevolgen van artritis in specifieke delen van het lichaam dan een standaard vragenlijst zoals de C-HAQ. Normale evaluatie van JIA omvat: gewrichtsindex van gevoelige gewrichten, evaluatie van de bewegingsbeperkingen (EPM-ROM schaal). Een gewogen gewrichtsscore verbetert de informatie doordat verschillende gewrichten een andere impact hebben op patiënten-welzijn aangezien een ontstoken kleine vinger gewricht van de niet-dominante hand heeft niet dezelfde problemen geeft als een ontstoken enkel.
ACR Pedi 30, 50, 70 en 90 scores worden het meest gebruikt voor klinische trials. Een samengestelde ziekte-activiteitsscore voor JIA de Juvenile Arthritis Disease Activity Score (JADAS), heeft het voordeel dat de meting van de actuele ziekteactiviteit en de vergelijking van de absolute respons van een patient kan worden vergeleken met de respons van een andere patiënt aangezien het het absolute niveau van ziekte-activiteit kwantificeert met een samengesteld getal op een continue schaal.
Al het bovenstaande zal worden geëvalueerd, omdat al deze parameters complementair zijn. Ten slotte zal de voorgestelde voorlopige definitie van minimale ziekte-activiteit in polyarticulaire JIA en de voorgestelde voorlopige definitie van inactieve ziekte in polyarticulaire JIA worden geëvalueerd.

Radiologische resultaten:
MRi van aangedaan gewricht waarbij de radioloog niet word ingelicht over stadium van behandeling.
Synoviale aankleuring, bot oedeem, verlies van kraakbeen en bot erosie zullen allemaal worden gescoord als afwezig, mild, matig en ernstig in beide gewrichten. Over het geheel genomen is er redelijke (graad B) mate van bewijs dat een MRI een nauwkeurige diagnostische methode is voor het evalueren van synovium en kraakbeen en voor de beoordeling van de klinische respons op de behandeling van de perifere gewrichten bij JIA.

Laboratorium uitkomsten:
BSE en CRP.
Lymfocyten subpopulaties (effector en regulerende subpopulaties), cytokines in het serum en van supernatant van gestimuleerde PBMC's (onderzocht met Luminex). Ook de in vitro onderdrukking door MSC van de proliferatie van gestimuleerde PBMCs. Verder zijn we geïnteresseerd in de responsiviteit van effector-T-cellen op regulatoire T-cel gemedieerde onderdrukking, omdat we hebben gemerkt dat bij JIA de effector-T-cellen niet meer reageren op Treg-gemedieerde onderdrukking. De MSC behandeling zou een "reset" kunnen induceren van de effectorcellen zodat zij nu wel effectief worden onderdrukt door gebruikelijke T-regs. MRP-eiwitten in het serum worden bepaald.

E.5.2.1

Timepoint(s) of evaluation of this end point

52 weeks after the (first) MSC injection

52 weken na de (eerste) MSC injectie

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

Yes

E.6.4

Safety

Yes

E.6.5

Efficacy

Yes

E.6.6

Pharmacokinetic

E.6.7

Pharmacodynamic

Yes

E.6.8

Bioequivalence

E.6.9

Dose response

E.6.10

Pharmacogenetic

E.6.11

Pharmacogenomic

E.6.12

Pharmacoeconomic

E.6.13

Others

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

In the specific patientpopulation : safety (primary), frequency and hint of effectiveness (secondary

Bij beoogde patientenpopulatie: veiligheid (primair), frequentie en hint v effectiviteit (secundair

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

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

This is a pilot study powered for 6 study subjects.
Stopping rules: progression of arthritis after MSC infusion in >50% of patients. Any treatment related mortality within 7 days of MSC injection in the first series of 6 patients. Occurrence of malignancies.

Dit betreft een pilot studie van 6 participanten.
De pilotstudie wordt gestaakt als er progressie van de artritis optreedt in >50% van de patienten na de MSC injectie.Er wordt ook gestaakt indien er enige behandelingsgerelateerde mortaliteit is binnen 7 dagen na de MSC-injectie bij de eerste 6 patienten. Tevens wordt er gestopt indien er een maligniteit optreedt bij 1 van de patienten.

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

Yes

F.1.1

Number of subjects for this age range:

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)

Yes

F.1.1.5.1

Number of subjects for this age range:

F.1.1.6

Adolescents (12-17 years)

Yes

F.1.1.6.1

Number of subjects for this age range:

F.1.2

Adults (18-64 years)

F.1.3

Elderly (>=65 years)

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

F.3.3.2

Women of child-bearing potential using contraception

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Minors could be included in this study.

Minderjarigen mogen meedoen aan deze studie

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)

At least 36 weeks after the last MSC injection patients will be followed by outpatient clinical visits, blood monitoring and an extra MRI of most active joint. If the patient is not yet transitioned to adult rheumatology care the follow-up will be longer with routine visits at our department.

Minstens 36 weken na de laatste MSC injectie zal de patient poliklinisch vervolgd worden inclusief bloedonderzoek en een extra MRI van het meest aangedane gewricht. Als de patient niet in transitie overgaat naar de volwassen reumatologie dan zal de patient routinematig worden teruggezien op onze polikliniek.

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

2013-09-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-01-30

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

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