Clinical Trials Register

Summary
EudraCT Number:	2017-000606-37
Sponsor's Protocol Code Number:	MesenSistem-EB
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2017-09-18
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

Spain - AEMPS

A.2

EudraCT number

2017-000606-37

A.3

Full title of the trial

Safety and preliminary efficacy study of infusing mesenchymal stem cells derived from bone marrow for treating Recessive Dystrophic Epidermolysis Bullosa.

Estudio de seguridad y eficacia preliminar de la infusión de células madre mesenquimales haploidénticas derivadas de médula ósea para el tratamiento de la Epidermolisis Bullosa Distrófica Recesiva.

A.3.1

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

Safety study of mesenchymal stem cells in the treatment of Recessive Dystrophic Epidermolysis Bullosa.

Estudio de seguridad de células madre mesenquimales en el tratamiento de la Epidermolisis Bullosa Distrófica Recesiva.

A.4.1

Sponsor's protocol code number

MesenSistem-EB

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	Fundación para la Investigación Biomédica Hospital Universitario La Paz
B.1.3.4	Country	Spain
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	Ministerio de Economía y Competitividad
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospital Universitario La Paz
B.5.2	Functional name of contact point	UCICEC
B.5.3	Address:
B.5.3.1	Street Address	Paseo de la Castellana, 261
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28046
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34912071466
B.5.5	Fax number	+34912071466
B.5.6	E-mail	hoi.tong@idipaz.es

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 Stem Cells extracted from bone marrow
D.3.4	Pharmaceutical form	Solution for infusion
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	Células madre mesenquimales haploidénticas derivadas de médula ósea
D.3.9.2	Current sponsor code	MSCs
D.3.9.3	Other descriptive name	MESENCHYMAL STEM CELLS (MSCS)
D.3.9.4	EV Substance Code	SUB176600
D.3.10	Strength
D.3.10.1	Concentration unit	Other
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	2000000 to 4000000
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

Recessive Dystrophic Epidermolysis Bullosa

Epidermolisis Bullosa Distrófica Recesiva

E.1.1.1

Medical condition in easily understood language

Recessive Dystrophic Epidermolysis Bullosa

Epidermolisis Bullosa Distrófica Recesiva

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

• Assessing the safety of haploidentical Mesenchymal Stem Cells derived from bone marrow given by intravenous injection with a dose of 2-4 x 10e6 cells/kg in 3 separate infusions for 21 days each for the treatment of patients with Recessive Dystrophic Epidermolysis Bullosa.

• Evaluar la seguridad de las MSCs haploidénticas derivadas de médula ósea administradas por inyección intravenosa con una dosis de 2-4x106 células/Kg en 3 infusiones separadas por 21 días cada una para el tratamiento de pacientes con EBDR.

E.2.2

Secondary objectives of the trial

• To describe the clinical and molecular phenotype of the muco-cutaneous involvement of patients, including the characterization of the mutations responsible for the disease.

• Evaluate the preliminary efficacy of treatment with haploidentical Mesenchymal Stem Cells derived from bone marrow given by intravenous injection in 3 infusions of 2-4 x 10e6 cells/kg each separated by 21 days for the treatment of patients with EBDR. The evaluation of the symptomatic improvement of the treated patients will be made regarding the baseline situation and the response to treatment at biochemical, histological and molecular level.

• Describir el fenotipo clínico y molecular de la afectación muco-cutánea de los pacientes, incluyendo la caracterización de las mutaciones responsables de la enfermedad.

• Evaluar la eficacia preliminar del tratamiento con MSCs haploidénticas derivadas de médula ósea administradas por inyección intravenosa en 3 infusiones de 2-4x10e6 células/Kg cada una separadas por 21 días para el tratamiento de pacientes con EBDR. Se realizará la valoración de la mejoría sintomática de los pacientes tratados respecto a la situación basal y de la respuesta al tratamiento a nivel bioquímico, histológico y molecular.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients ≥ 4 and ≤ 18 years old at the time of inclusion in the study.
2. Patients with clinical, molecular and genetic diagnosis of EBDR.
3. Patients with presence of the NC-1 domain of type VII collagen in skin and/or western blot biopsies detected with a battery of specific antibodies
4. Patients with haploidentical donor
5. Subjects with a severity score of> 20 according to "The Birmingham Epidermolysis Bullosa Severity Score".
6. Minors whose legal representative / guardian has voluntarily signed informed consent prior to the first study intervention.
7. In the case of mature minors (12-17 years of age), in addition to the consent signed by the legal guardian, the child's consent will be obtained.
8. Women with reproductive capacity should have a negative pregnancy test at the time of inclusion and must have access to highly effective contraceptive methods (diaphragms plus spermicide or male condom plus spermicide, oral contraceptive combined with a second contraceptive implant method, contraceptive Injecting, permanent intrauterine device, sexual abstinence or partner with vasectomy) during their participation in the study and in the 30 following the last visit.
9. Males should agree to use a double barrier contraceptive method (condom plus spermicide or diaphragm plus spermicide) during their participation in the study and 30 days after the last dose of the study drug, or the male patient or their Female couple should be surgically sterilized or the female partner should be postmenopausal.
10. The patient should be able to attend all study visits and follow all study procedures.

1. Pacientes varones o mujeres ≥ 4 y ≤ 18 años de edad en el momento de la inclusión en el estudio.
2. Pacientes con diagnóstico clínico, molecular y genético de EBDR.
3. Pacientes con presencia del dominio NC-1 del colágeno de tipo VII, en las biopsias de piel y/o en el western-blot, detectado con una batería de anticuerpos específicos
4. Pacientes con donante haploidéntico
5. Sujetos con una puntuación de gravedad > 20 según “The Birmingham Epidermolysis Bullosa Severity Score”.
6. Sujetos menores cuyo representante/tutor legal hayan firmado voluntariamente el consentimiento informado antes de la primera intervención del estudio.
7. En el caso de menores maduros (12 - 17 años de edad), además del consentimiento firmado por el tutor legal, se obtendrá el asentimiento del menor.
8. Mujeres con capacidad de procrear deben tener una prueba de embarazo negativa en el momento de la inclusión y deben acceder a usar métodos anticonceptivos altamente eficaces (diafragmas más espermicida o preservativo masculino más espermicida, anticonceptivo oral combinado con un segundo método implante anticonceptivo, anticonceptivo inyectable, dispositivo intrauterino permanente, abstinencia sexual o pareja con vasectomía) durante su participación en el estudio y en los 30 siguientes a la última visita.
9. Los varones deben acceder a usar un método anticonceptivo de doble barrera (preservativo más espermicida o diafragma más espermicida) durante su participación en el estudio y en los 30 días siguientes a la última dosis del fármaco del estudio, o el paciente varón o su pareja femenina deben estar esterilizados quirúrgicamente o la pareja femenina debe ser postmenopáusica.
10. El paciente debe ser capaz de acudir a todas las visitas del estudio y acatar todos los procedimientos del estudio.

E.4

Principal exclusion criteria

1. Subjects that for medical reasons can not be transferred to La Paz University Hospital in Madrid.
2. Subjects who have received immunotherapy, including oral corticosteroids (> 15 mg / day) for more than 1 week (except for intranasal and topical preparations) or chemotherapy within 8 days prior to inclusion in the study. Inclusion of the patient is understood from the signing of informed consent.
3. Subjects with a known allergy to any component of the product under investigation (including penicillin and streptomycin), or who can not receive antihistamine and / or corticoid treatment.
4. Subjects with signs of active systemic infection at the time of inclusion in the study.
5. Subjects with a history or signs of malignancy, including cutaneous squamous cell carcinoma.
6. Subjects with circulating anti-C7 antibodies and anti-C7 antibodies deposited at the dermoepidermal junction detected in skin biopsies by indirect immunofluorescence.
7. Pregnant women at the time of inclusion or women of childbearing age who do not practice abstinence or use acceptable means of contraception, as determined by the investigator during the trial.
8. Biochemical abnormalities at the time of inclusion: albumin <2.5 g / dL, Hemoglobin <7.5 g / dL.
9. Subjects who have been given other investigational drugs within 90 days prior to the treatment phase.
10. Subjects who are not able to understand the information sheet and are unable to sign informed consent.

1. Sujetos que por razones médicas no puedan trasladarse al Hospital Universitario La Paz en Madrid.
2. Sujetos que hayan recibido inmunoterapia, incluyendo corticoides orales (> 15 mg/día) durante más de 1 semana (exceptuando preparaciones intranasales y tópicas) o quimioterapia los 8 días previos a la inclusión en el estudio. La inclusión del paciente se entiende desde la firma del consentimiento informado.
3. Sujetos con alergia conocida a cualquiera de los componentes del producto en investigación (incluido penicilina y estreptomicina), o que no puedan recibir tratamiento con antihistamínicos y/o corticoides.
4. Sujetos con signos de infección sistémica activa en el momento de la inclusión en el estudio.
5. Sujetos con antecedentes o signos de malignidad, incluyendo carcinoma cutáneo de células escamosas.
6. Sujetos con anticuerpos circulantes anti C7 y con anticuerpos anti C7 depositados en la unión dermoepidérmica detectados en biopsias de piel por inmunofluorescencia indirecta.
7. Mujeres embarazadas en el momento de la inclusión o mujeres en edad fértil que no practican la abstinencia o emplean medios aceptables de anticoncepción, según lo determinado por el investigador durante el ensayo.
8. Anormalidades bioquímicas en el momento de la inclusión: albúmina < 2.5 g/dL, Hemoglobina < 7.5 g/dL.
9. Sujetos a quienes se les haya administrado otros medicamentos en investigación en los 90 días anteriores a la fase de tratamiento.
10. Sujetos que no sean capaces de comprender la hoja de información e incapaces de firmar el consentimiento informado.

E.5 End points

E.5.1

Primary end point(s)

Safety assessment: Proportion of adverse events over a period of 12 months after treatment. The type, duration, intensity, severity and causal relationship with the treatment of adverse events shall be recorded. Safety assessments will include active interrogation of adverse events, physical, analytical and molecular examination. A long-term clinical follow-up of at least 5 years after completion of study medication will be included as part of the care activity in order to primarily monitor the occurrence of cutaneous squamous cell carcinoma.

Evaluación de seguridad: Proporción de acontecimientos adversos durante un periodo de 12 meses después del tratamiento. Se registrará el tipo, duración, intensidad, gravedad y relación de causalidad con el tratamiento de los acontecimientos adversos. Las evaluaciones sobre seguridad incluirán interrogatorio activo sobre acontecimientos adversos, examen físico, analítico y molecular. Se incluirá un seguimiento clínico a largo plazo de al menos 5 años tras la finalización de la medicación de estudio como parte de la actividad asistencial con objeto de vigilar principalmente la aparición de carcinoma cutáneo de células escamosas.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

12 meses

E.5.2

Secondary end point(s)

• Cutaneous mechanical resistance measured using a negative pressure cutaneous suction device from Electronic Diversities (model NP-2). The mechanical resistance will be determined as the minimum time required to induce a 5 mm diameter ampulla at a constant pressure in the forearm of the subject.
• Percentage of skin surface affected
• Evaluation of the number of blisters.
• Improvement of hematological and serological markers of generalized inflammation.
• Severity Score according to "The Birmingham Epidermolysis Bullosa Severity Score" and "The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI)" before and after treatment.
• Expression of Collagen VII (C7) in cutaneous biopsy before and after infusion of MSCs.
• Analysis of anchor fibrils by electron microscopy in skin biopsy after treatment.
• Variation of pain with respect to baseline that will be assessed by the Visual Analogue Scale (EVA) at all visits following the first infusion.
• Assessment of the change in perceived itching from baseline that will be assessed by Leuven Itch Scale at all visits after the first infusion.
• Assessment of change in quality of life: a specific quality of life assessment survey (European Quality of Life-5 Dimensions-5 level). The survey will be conducted before treatment and at all follow-up visits.
• Analysis of circulating anti-C7 antibodies determined by ELISA before and after treatment.
• Analysis of detectable levels of anti-C7 antibodies in the dermo-epidermal junction by indirect immunofluorescence before (exclusion criterion) and after treatment.
• Assessment of the general condition of the patient. To do this, each visit to the patient and the doctor will be surveyed by recording the overall assessment using a Likert scale.
• Analysis of pro-inflammatory cytokines before and after infusion of MSCs.
• Presence of donor cells (dermal chimerism).

• Resistencia mecánica cutánea medida empleando un dispositivo de succión cutánea de presión negativa de Electronic Diversities (modelo NP-2). La resistencia mecánica se determinará como el tiempo mínimo necesario para inducir una ampolla de 5mm de diámetro a una presión constante en el antebrazo del sujeto.
• Porcentaje de superficie cutánea afectada
• Evaluación del número de ampollas.
• Mejora de los marcadores hematológicos y serológicos de inflamación generalizada.
• Índice de gravedad según el “The Birmingham Epidermolysis Bullosa Severity Score” y “The Epidermolysis Bullosa Disease Activity and Scarring Index (EBDASI)" antes y después del tratamiento.
• Expresión del Colágeno VII (C7) en biopsia cutánea antes y después de la infusión de las MSCs.
• Análisis de las fibrillas de anclaje por microscopía electrónica en biopsia de piel después del tratamiento.
• Variación del dolor respecto al basal que se valorará mediante la Escala Visual Analógica (EVA) en todas las visitas posteriores a la primera infusión.
• Valoración del cambio en el picor percibido respecto al basal que se valorará mediante Leuven Itch Scale en todas las visitas posteriores a la primera infusión.
• Valoración del cambio en la calidad de vida: encuesta de valoración específica de la calidad de vida (European Quality of Life-5 Dimensions-5 level). La encuesta se realizará antes del tratamiento y en todas las visitas de seguimiento.
• Análisis de los anticuerpos circulantes anti-C7 determinados por ELISA antes y después del tratamiento.
• Análisis de niveles detectables de anticuerpos anti-C7 en la unión dermo-epidérmica por inmunofluorescencia indirecta antes (criterio de exclusión) y después del tratamiento.
• Valoración del estado general del paciente. Para ello se encuestará en cada visita al paciente y al médico registrando la valoración global a través de una escala de tipo Likert.
• Análisis de las citoquinas pro-inflamatorias antes y después de la infusión de las MSCs.
• Presencia de células del donante (quimerismo dérmico).

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months.

12 meses.

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)

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

Exploratory clinical trial to evaluate the safety and preliminary efficacy

Ensayo clínico exploratorio de evaluación de la seguridad y eficacia preliminar

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.8.2.4

Number of treatment arms in the trial

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

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

Última visita del último sujeto

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

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)

A monitoring period arises long period provided in routine clinical practice to monitor the possible occurrence of AA until at least five years after treatment administration of the investigational product.

Se plantea un período de seguimiento a largo plazo contemplado dentro de la práctica clínica habitual para vigilar la aparición de posibles AA hasta al menos 5 años tras la administración del producto en investigación.

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

2017-11-16

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2017-11-07

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

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