Clinical Trials Register

Summary
EudraCT Number:	2012-000605-72
Sponsor's Protocol Code Number:	CB+MSCforEB
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2013-08-12
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

2012-000605-72

A.3

Full title of the trial

Unrelated cord blood transplantation after reduced toxicity conditioning with mesenchymal stromal cell co-infusion in patients with severe epidermolysis bullosa

Allogene stamcel transplantatie middels navelstreng bloed na verminderd toxiciteit conditionering met mesenchymale stromale cel co-infusie voor ernstige vormen van epidermolysis bullosa

A.3.1

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

Stem cell transplantation with cord blood and mesenchymal stem cells after reduced intensity conditioning for severe forms of the blistering disease epidermolysis bullosa

Stamcel transplantation middels navelstreng bloed met mesenchymale stamcellen na verminderd toxische chemotherapie als behandeling voor het ernstige blaarziekte epidermolysis bullosa

A.3.2

Name or abbreviated title of the trial where available

CB+MSCforEB

A.4.1

Sponsor's protocol code number

CB+MSCforEB

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	Universitair Medisch Centrum 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	Stichting Vlinderkind
B.4.2	Country	Netherlands
B.4.1	Name of organisation providing support	Zeldzame Ziekten Fonds
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	Universitair Medische Centrum Utrecht
B.5.2	Functional name of contact point	Dr. J.J.Boelens
B.5.3	Address:
B.5.3.1	Street Address	Lundlaan 6
B.5.3.2	Town/ city	Utrecht
B.5.3.3	Post code	3503 AB
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	31887554003
B.5.5	Fax number	31887555350
B.5.6	E-mail	j.j.boelens@umcutrecht.nl

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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	TC-MSC
D.3.4	Pharmaceutical form	Infusion
D.3.4.1	Specific paediatric formulation	Yes
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.3.9.2	Current sponsor code	TC-MSC
D.3.10	Strength
D.3.10.1	Concentration unit	thousand organisms/ml thousand organisms/millilitre
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	1000 to 2000
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.IMP: 2
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Busilvex
D.2.1.1.2	Name of the Marketing Authorisation holder	Pierre Fabre Médicament
D.2.1.2	Country which granted the Marketing Authorisation	France
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.3.4	Pharmaceutical form	Concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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.IMP: 3
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	Fludarabine
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz B.V.
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	FLudarabine
D.3.4	Pharmaceutical form	Concentrate for solution for injection/infusion
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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.IMP: 4
D.1.2 and D.1.3	IMP Role	Comparator
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	Yes
D.2.1.1.1	Trade name	THYMOGLOBULINE
D.2.1.1.2	Name of the Marketing Authorisation holder	GENZYME EUROPE B.V
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Thymoglobuline
D.3.4	Pharmaceutical form	Powder and solvent for solution for infusion
D.3.4.1	Specific paediatric formulation	Yes
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	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

The source population consists of patients referred to or within the UMC Groningen because they have diagnosed clinically and genetically severe generalized RDEB.

E.1.1.1

Medical condition in easily understood language

Epidermolysis Bullosa is a genetic skin disease characterized by blistering and chronic wounds of the skin and mucous membranes.

E.1.1.2

Therapeutic area

Diseases [C] - Skin and Connective Tissue Diseases [C17]

MedDRA Classification

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

1) To investigate the safety of unrelated cord blood transplantation with additional mesenchymal stromal cell co-infusion, preceeded by reduced toxicity conditioning in patients with severe generalized dystrophic epidermolysis bullosa.

2) To assess clinical improvement of skin with regards to wound healing and blister formation. To study the biology of engraftment of hematopoietic & non-hematopoietic stem cells in skin on a molecular basis with a variety of laboratory techniques. Focus will be on expression of C7 and anchoring fibrils at the dermal-epidermal junction for RDEB-sev-gen before and after transplantation.

E.2.2

Secondary objectives of the trial

1) Sustained full cord blood donor chimerism.
2) Toxicity: acute-GvHD, chronic-GvHD prevention with standard chemotherapy prophylaxis
3) To investigate whether infusion of a single cord blood unit with additional mesenchymal stromal cell co-infusion preceded by the standard “reduced toxicity” conditioning regimen (UMC Utrecht protocol for non malignant disease) will ameliorate the blistering phenotype clinically seen in patients with severe generalized recessive dystrophic epidermolysis bullosa (RDEB-sev-gen).

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1) Diagnosed recessive dystrophic EB, severe generalized type (complete loss of functional type VII collagen by immunofluorescence microscopy and confirmed by molecular analysis).
2) having a single matching (≥ 5/6) umbilical CB unit available with sufficient cell count total NC count > 3 * E7/kg
3) Lansky / Karnofsky > 40
4) Age <18 *( *= Karnofs364 days)
5) Signed Informed Consent
6) Approval by International Expert Advisory Panel (Annex 7) & UMCU kernteam-HCT

E.4

Principal exclusion criteria

1) Creatinine clearance < 40 ml/min
2) Cardiac dysfunction (SF < 30%) (Ejection fraction < 45%), unstable angina, or unstable cardiac arrhythmias
3) Pulmonary function test (for those who can do: age dependent) VC, FEV1 and/ or DOC< 50%
4) Subjects with medical history of evidence of malignancy, including cutaneous squamous cell carcinoma
5) Patients with positive auto-antibodies to type VII collagen Determined with blood sample and salt split skin test (Immunodermatology lab UMCG)
6) Allergy to any of the known constituents found in the investigational products (reduced toxicity chemotherapy drugs, CB and MSC)
7) HIV seropositive infection

E.5 End points

E.5.1

Primary end point(s)

Safety:
The primary efficacy in this Phase II trial will be based on the safety of the administration of the IMPs in this disease population measured according to Transplantation related mortality (Death associated with the procedure: <40%) at day+100
Biology:
• Clinical improvement of wound healing and shorter time to blister formation
• Punch biopsies: Assessment of protein expression at the dermal-epidermal junction using immunofluorescence (Antigen mapping): Collagen VII deposition at various time points (prior to transplantation, D60, 180, 240, 365, and 730) 6 times during course of the trial, 2 biopsies each time
• Quantitative analysis of the donor cells dermal chimerism (Days: see above, same biopsy is used). Fluorescence in-situ hybridization (FISH)

E.5.1.1

Timepoint(s) of evaluation of this end point

The primary efficacy in this Phase II trial will be based on the safety of the administration of the 3 IMPs (reduced intensity conditioning, cord blood transplantation and mesenchymal stromal cells) in this disease population measured according to Non-Relapse mortality (Death associated with the procedure). This will be measured at the classical TRM endpoint for allogeneic stem cell transplantation at day+100.
Biology:
Clinical improvement of wound healing and shorter time to blister formation
Assessment of protein expression at the dermal-epidermal junction: Collagen VII deposition at the DEJ at various time points (D60, 180, 240, 365 and 730)
Quantitative analysis of the donor cells dermal chimerism (Days: see above)

E.5.2

Secondary end point(s)

• Disease specific outcomes: Clinical blister assessment: Suction Blister Time (Electronic Diversities. U.S.A) & Skin Rub Test (Kiritsi et al, 2013 personal communication)
• Acute GVHD (Grade II-IV: Gluckberg Criteria)
• Engraftment: Neutrophils > 500K/uL for 3 consecutive days and Platelet (day 180 > 50 K) engraftment.
• Loss of CB chimerism (<25%) at 6 mths post HSCT
• Event Free Survival (>6 mths follow up). Event defined as: death, graft-failure (<25% total donor chimerism) or relapse.
• Overall Survival
• Chronic GVHD: limited and extensive (Shulman Criteria)
• VOD (Seattle Criteria)
• Mucositis ≥ CTC grade 3
• ISCOREB: Disease specific severity score and quality of life assessment
• Antibody formation (Col7) Blood sample during routine control is used

E.5.2.1

Timepoint(s) of evaluation of this end point

Protein expression/skin chimerism assessment: (prior to transplantation, D60, D180, D240, D365, and D730)
Quality of Life/Disease Specific Severity Score: (prior to transplantation, D60, D180, D240, D365 and D730)
Clinical Blister testing (Suction & Rub Test): Prior to transplantation, D180, D365 and D730)
Phenotype improvement: (prior to transplantation, D0, D30, D60, D120, D180, D240, D365, and D730)
Hematologic assessment will be done during admission and by regular control visits

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

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)

E.7.1.1

First administration to humans

E.7.1.2

Bioequivalence study

E.7.1.3

Other

E.7.1.3.1

Other trial type description

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

E.8.4

The trial involves multiple sites in the Member State concerned

Yes

E.8.4.1

Number of sites anticipated in 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)

Yes

F.1.1.3.1

Number of subjects for this age range:

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

Information not present in EudraCT

F.3.3.2

Women of child-bearing potential using contraception

Information not present in EudraCT

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)

Subjects participating in the trial will continue under the care of the Centre for Blistering Diseases in UMC Groningen, the Netherlands. Should they have complications pertaining to the allogeneic stem cell transplantation itself they will be seen at UMC Utrecht.

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

2013-03-28

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2014-02-06

P. End of Trial
P.	End of Trial Status	Prematurely Ended

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