Clinical Trials Register

Summary
EudraCT Number:	2014-003561-15
Sponsor's Protocol Code Number:	MYSTEP1
National Competent Authority:	Germany - PEI
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2015-12-18
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

Germany - PEI

A.2

EudraCT number

2014-003561-15

A.3

Full title of the trial

Safety and Tolerance of Immunomodulating Therapy with Donor-specific Mesenchymal Stem Cells in Pediatric Living-Donor Liver Transplantation

Sicherheit und Verträglichkeit der Anwendung von Mesenchymalen Stammzellen zur immunmodulatorischen Therapie bei pädiatrischer Lebertransplantation durch Lebendspende

A.3.1

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

Mesenchymal Stem Cells after liver transplantation in children

Mesenchymale Stammzellen nach Lebertransplantation im Kindesalter

A.3.2

Name or abbreviated title of the trial where available

MYSTEP1

A.4.1

Sponsor's protocol code number

MYSTEP1

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 Hospital of Tuebingen
B.1.3.4	Country	Germany
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 Hospital of Tuebingen
B.4.2	Country	Germany
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	University Children’s Hospital Tuebingen
B.5.2	Functional name of contact point	Dr. Steffen Hartleif (MD)
B.5.3	Address:
B.5.3.1	Street Address	Hoppe-Seyler-Straße 1
B.5.3.2	Town/ city	Tuebingen
B.5.3.3	Post code	72076
B.5.3.4	Country	Germany
B.5.4	Telephone number	+49707129-83781
B.5.6	E-mail	Steffen.Hartleif@med.uni-tuebingen.de

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	Donor-specific Mesenchymal Stem Cells
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intravenous use Intraportal use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Donor-specific Mesenchymal Stem Cells
D.3.9.3	Other descriptive name	University Hospital Tuebingen
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1000000 to 1500000
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)	No
	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

Side effects of life-long immunosuppressive medication account for major morbidity after pediatric liver transplantation and impair quality of life. In-vivo and in-vitro studies have shown that MSCs may act beneficial in the setting of solid organ transplantation, suppressing immune-active cells directed against the graft while promoting tolerance-inducing Tregs and graft regeneration. Finally, immunosuppressive medication can be used in lower dose with beneficial toxicity profile.

E.1.1.1

Medical condition in easily understood language

Children after liver transplantation

Kinder nach Lebertransplantation

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	18.1
E.1.2	Level	LLT
E.1.2	Classification code	10024716
E.1.2	Term	Liver transplantation
E.1.2	System Organ Class	100000004865

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

Safety and Tolerance of Donor-specific Mesenchymal Stem Cell therapy in context of pediatric liver transplantation

Sicherheit und Verträglichkeit von Spender-spezifischen MSCs in der Anwendung bei Kindern nach Lebertransplantation durch Lebendspende

E.2.2

Secondary objectives of the trial

Efficacy
Hematologic and immunologic function

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent (patients, both parents and / or legal guardian)
2. age ≥ 8 weeks and ≤ 18 years
3. undergoing living donor liver transplantation for chronic terminal liver failure
4. Body weight > 5kg

E.4

Principal exclusion criteria

1. No suitability of the living-donor
2. Pregnant or breastfeeding
3. If appropriate: no use of adequate contraception
4. Acute liver failure; highly urgent transplantations
5. Receiving any form of solid organ retransplantation
6. Multi-Organ-Transplantations
7. Active autoimmune disease, e.g. autoimmune hepatitis
8. Pre-existing renal failure with eGFR < 50 ml/min/1.73 m2 or requiring hemodialysis
9. Reduced pulmonary function (children older than 6 years: FEV1 and FVC < 70% of age-appropriate norm)
10. History of pulmonary embolism
11. Pulmonary hypertension and / or right ventricular load in echocardiography
12. Cardiac function: left ventricular shortening fraction (FS) < 25%
13. Clinically significant systemic infections
14. Critical care treatment like mechanical ventilation, dialysis or vasopressor agents.
15. HIV seropositive, HTLV seropositive, Hepatitis B/C seropositive
16. Hepato-biliary malignancies or history of any extra-hepatic malignancy
17. Thrombophilia
18. Budd-Chiari syndrome
19. Pre-existent thrombosis of portal vein
20. Doppler-sonographic evidence for relevant porto-systemic shunts, e.g. persistent Ductus Venosus
21. Cold ischemia time > 90 min
22. Known allergy to DMSO

E.5 End points

E.5.1

Primary end point(s)

Incidence, timing and severity of any clinical complication related to MSC infusion, using toxicity scoring system

Incidence of severe adverse events (SAE)

Graft function after liver transplantation, measured in ALT, AST, GGT, bilirubin, albumin and INR

E.5.1.1

Timepoint(s) of evaluation of this end point

Toxicity Score: day 2, 4, 7 and 10 after pediatric liver transplantation
Monitoring of SAEs: continuosly
Graft function: 360 and 720 days after liver transplantation

E.5.2

Secondary end point(s)

Feasibility and safety of tapering immunosuppressive medication according to standard guidelines (Banff criteria, AASLD guidelines)

Time to first biopsy-proven acute rejection

Patient and graft survival

E.5.2.1

Timepoint(s) of evaluation of this end point

Tapering Immunosuppression: 180, 270, 360, 450, 630 and 720 days after liver transplantation

Time to first biopsy-proven acute rejection: continously

Patient and graft survival: 360 and 720 days after liver transplantation

E.6 and E.7 Scope of the trial

E.6

Scope of the trial

E.6.1

Diagnosis

E.6.2

Prophylaxis

Yes

E.6.3

Therapy

Yes

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

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

Donor-specific immune response of recipients

Recipient immunologic function in allograft tolerance

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

Clinical Pilot Trial

E.7.2

Therapeutic exploratory (Phase II)

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

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

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)

Yes

F.1.1.4.1

Number of subjects for this age range:

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

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

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)

An individual follow-up will be be done up to five years after termination of the study. Patients are seen at least every 12 months in our transplant out-patient care. Patient’s history, physical examination, blood tests and a doppler ultra-sound will be performed. Furthermore, cardiac function and bone development (bone mineral density) is monitored every 2 years. Protocol biopsies are part of our standard monitoring and performed every 5 years after liver transplantation.

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1
G.4.1	Name of Organisation	MiSOT Study Group

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

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-07-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-08-30

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

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