Clinical Trials Register

Summary
EudraCT Number:	2018-001009-98
Sponsor's Protocol Code Number:	allo-APZ2-EB-II-01
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Prematurely Ended
Date on which this record was first entered in the EudraCT database:	2020-11-10
Trial results	View 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

Italy - Italian Medicines Agency

A.2

EudraCT number

2018-001009-98

A.3

Full title of the trial

An interventional, multicenter, single arm, phase I/IIa clinical trial to investigate the efficacy and safety of allo-APZ2-EB on epidermolysis bullosa (EB).

Sperimentazione clinica multicentrica, interventistica, a braccio singolo di fase I/IIa per valutare l’efficacia e la sicurezza di allo-APZ2-EB nel trattamento della epidermolisi bollosa (EB).

A.3.1

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

Study to investigate the efficacy and safety of allo-APZ2-EB on wound healing of epidermolysis bullosa (EB)

Sperimentazione per valutare l’efficacia e la sicurezza di allo-APZ2-EB per la guarigione delle feritr da epidermolisi bollosa (EB)

A.3.2

Name or abbreviated title of the trial where available

allo-APZ2-EB-II-01

A.4.1

Sponsor's protocol code number

allo-APZ2-EB-II-01

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	RHEACELL GmbH & Co. KG
B.1.3.4	Country	Germany
B.3.1 and B.3.2	Status of the sponsor	Commercial
B.4 Source(s) of Monetary or Material Support for the clinical trial:
B.4.1	Name of organisation providing support	RHEACELL GmbH & Co.KG
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	RHEACELL GmbH & Co.KG
B.5.2	Functional name of contact point	Information Office
B.5.3	Address:
B.5.3.1	Street Address	Im Neuenheimer Feld 517
B.5.3.2	Town/ city	Heidelberg
B.5.3.3	Post code	69120
B.5.3.4	Country	Germany
B.5.4	Telephone number	00496221718330
B.5.5	Fax number	004962217183329
B.5.6	E-mail	office@rheacell.com

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	allo-APZ2-EB
D.3.2	Product code	[allo-APZ2-EB]
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
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	T202-3
D.3.9.3	Other descriptive name	Allogeneic skin-derived ABCB5-positive mesenchymal stem cells
D.3.10	Strength
D.3.10.1	Concentration unit	million CFU/ml million colony forming units/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	10
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	No
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	Yes
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 (RDEB)

Epidermolisi bollosa distrofica recessiva (recessive dystrophic epidermolysis bullosa, RDEB)

E.1.1.1

Medical condition in easily understood language

Epidermolysis bullosa patients (butterfly children) have extremely fragile skin and innermost linings of the gastric and intestinal tract, leading to blisters, erosions and open wounds

Pazienti con epidermolisi bollosa (bambini-farfalla) con notevole fragilità della pelle e delle parti interne del tratto gastrointestinale che porta alla formazione di bolle, cicatrici e ferite

E.1.1.2

Therapeutic area

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

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	10014989
E.1.2	Term	Epidermolysis bullosa
E.1.2	System Organ Class	10010331 - Congenital, familial and genetic 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

The aim of this clinical trial is to investigate the efficacy (by monitoring overall improvement of EB symptoms measured by epidermolysis bullosa disease activity and scarring index [EBDASI] score and instrument for scoring clinical outcome of research for epidermolysis bullosa [iscorEB], wound healing assessed by photo documentation, and patients quality of life in EB [QOLEB] assessment) and safety (by monitoring adverse events [AEs]) of the IMP allo APZ2 EB administered intravenously to patients with EB in three applications (Day 0, Day 17 ±3, Day 35 ±3).

L’obiettivo di questa sperimentazione clinica è quello di studiare l’efficacia (monitorando il miglioramento globale dei sintomi da EB mediante punteggio EBDASI [Epidermolysis Bullosa Disease Activity and Scarring Index], iscorEB [instrument for scoring clinical outcome of research for Epidermolysis Bullosa], guarigione delle ferite valutata in base alla documentazione fotografica, variazione nella percezione del dolore e del prurito, valutazione della qualità di vita del paziente relativa alla EB [QOLEB]) e della sicurezza (monitorando gli eventi avversi [AE]) associati al prodotto medicinale sperimentale (IMP) allo-APZ2-EB somministrato per via endovenosa a pazienti affetti da epidermolisi bollosa distrofica recessiva (recessive dystrophic epidermolysis bullosa, RDEB) con tre somministrazioni (Giorno 0, Giorno 17 ±3 giorni, Giorno 35 ±3 giorni).

E.2.2

Secondary objectives of the trial

Not Applicable

Non Applicabile

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Male or female patients aged between =18 years and =55 years; After positive safety assessment of 3 treated patients (=18 years and =55 years): male or female patients aged between =12 months and =55 years;
2. Diagnosed with RDEB;
3. Patient is eligible to participate in this clinical trial based on general health condition at the investigator's discretion;
4. Patient/legal representative understands the nature of the procedure and are providing written informed consent prior to any clinical trial procedure;
5. Women of childbearing potential must have a negative urine pregnancy test at Visit 1;
6. Women of childbearing potential and their partner must be willing to use highly effective contraceptive methods during the course of the clinical trial.

1. Pazienti di ambo i sessi, di età compresa fra =18 e =55 anni; (arruolamento sequenziale nelle seguenti coorti: Coorte 1. almeno 3 pazienti adulti (saranno eseguite valutazioni di sicurezza 2 settimane dopo l’ultima somministrazione al terzo paziente), Coorte 2. almeno 3 pazienti di età =12 e <18 anni (saranno eseguite valutazioni di sicurezza 2 settimane dopo la prima somministrazione al terzo paziente), Coorte 3. almeno 3 pazienti di età =5 e <12 anni (saranno eseguite valutazioni di sicurezza 2 settimane dopo la prima somministrazione al terzo paziente) e Coorte 4. almeno 3 pazienti di età =12 mesi e <5 anni;
2. Diagnosi di RDEB (diagnosi in base alla valutazione del genotipo [analisi della mutazione] e alla valutazione del fenotipo correlato [valutazione delle ferite]);
3. Paziente le cui condizioni generali di salute sono, a giudizio dello sperimentatore, tali da renderlo idoneo a partecipare a questa sperimentazione clinica;
4. Paziente/rappresentante legale comprendono la natura delle procedure e rilasciano il proprio consenso informato scritto prima che venga eseguita qualsiasi procedura per la sperimentazione clinica;
5. Le donne in età fertile dovranno avere un risultato negativo al test di gravidanza su urine eseguito alla Visita 1;
6. Le donne in età fertile e i propri partner dovranno essere disponibili a usare metodi contraccettivi altamente efficaci nel corso della sperimentazione clinica.

E.4

Principal exclusion criteria

1. Tumor diseases or history of tumor disease;
2. Known positive result for human immunodeficiency virus 1 and/or 2;
3. Any known allergies to components of the IMP;
4. Evidence of any other medical conditions (such as psychiatric illness or active infection) based on physical examination, or laboratory findings that may interfere with the planned treatment, affect the patient's compliance, or place the patient at high risk of complications related to the treatment; at investigators discretion;
5. History of prior thrombosis or patients at risk for thrombosis;
6. Clinically significant or unstable concurrent disease or other clinical contraindications to IMP application (based upon investigator's judgment);
7. Patient/legal representative anticipated to be unwilling or unable to comply with the requirements of the protocol;
8. Pregnant or lactating women;
9. Current or previous (within 30 days of enrollment) treatment with another IMP, or participation and/or under follow-up in another clinical trial;
10. Previous participation in this clinical trial (except for screening failures due to an exclusion criterion);
11. Known abuse of alcohol, drugs, or medicinal products;
12. Employees of the sponsor, or employees or relatives of the investigator.

1. Malattie tumorali maligne oppure storia di malattia tumorale maligna;
2. Nota positività per il virus dell’immunodeficienza umana 1 e/o 2;
3. Allergia nota a qualsiasi fra i componenti del medicinale sperimentale;
4. Evidenza di altre condizioni mediche (ad esempio disturbi psichiatrici oppure infezioni attive) rilevate all’esame obiettivo, oppure risultati di laboratorio che a giudizio dello sperimentatore sono tali da interferire con il trattamento programmato, influenzare l’aderenza del paziente ai requisiti del protocollo oppure porre il paziente a rischio elevato di complicanze causate dal trattamento;
5. Storia di pregressa trombosi oppure pazienti a rischio di trombosi;
6. Patologia concomitante clinicamente significativa oppure instabile, oppure altre controindicazioni cliniche (in base al giudizio dello sperimentatore);
7. Paziente/rappresentante legale che si prevede non saranno disposti o in grado di attenersi ai requisiti del protocollo;
8. Donne in stato di gravidanza oppure che stanno allattando al seno;
9. Trattamento concomitante oppure pregresso (nei 30 giorni precedenti l’arruolamento) con un altro medicinale sperimentale, oppure partecipazione e/o periodo di follow-up in un’altra sperimentazione clinica;
10. Partecipazione pregressa alla presente sperimentazione clinica (eccetto in caso di screening failure in base a un criterio di esclusione);
11. Noto abuso di alcolici, stupefacenti oppure farmaci;
12. Dipendenti del promotore, dipendenti del centro o parenti dello sperimentatore.

E.5 End points

E.5.1

Primary end point(s)

1. Efficacy endpoint:
Overall improvement of EB symptoms after 12 weeks (measured by percentage change of a patient's EBDASI score), or last available postbaseline measurement if the Week 12 measurement is missing (last observation carried forward [LOCF]).
2. Safety endpoint:
Adverse events.

Endpoint primario di efficacia: Miglioramento globale dei sintomi da EB dopo 12 settimane (misurato in base alla variazione percentuale del punteggio EBDASI del paziente), oppure ultima misurazione post-basale disponibile qualora sia mancante la misurazione della Settimana 12 (ultima osservazione disponibile, last observation carried forward - LOCF]).

E.5.1.1

Timepoint(s) of evaluation of this end point

1. Week 12, after first IMP application or timepoint of last observation carried forward.
2. During all patient visits except screening.

1. 12 Settimane, dalla prima somministrazione dell’IMP oppure con l’ultima misurazione post-basale
2. Durante tutte le visite del paziente ad eccezione di quella di screening

E.5.2

Secondary end point(s)

Secondary efficacy endpoints:
1. Overall improvement of EB symptoms after 12 weeks (measured by percentage change of a patient's EBDASI score, without LOCF);
2. Overall improvement of EB symptoms after 12 weeks (measured by percentage change of patient's iscorEB), or last available post-baseline
measurement if the Week 12 measurement is missing (LOCF);
3. Overall improvement of EB symptoms after 12 weeks (measured by percentage change of patient's iscorEB, without LOCF);
4. Overall improvement of EB symptoms at Day 17 (measured by percentage change of a patient's EBDASI score and patient's iscorEB);
5. Overall improvement of EB symptoms at Day 35 (measured by percentage change of a patient's EBDASI score and patient's iscorEB);
6. Inflammation (measured by panel of inflammation markers);
7. Pain assessment as per numerical rating scale (NRS);
8. Itch assessment as per NRS;
9. Assessment of QOLEB.; Secondary safety endpoint:
1. Physical examination and vital signs;
2. Overall survival at month 12.

Endpoint secondari di efficacia:
1. Miglioramento globale dei sintomi da EB dopo 12 settimane (misurato in base alla variazione percentuale del punteggio EBDASI del paziente, senza imputazione LOCF).
2. Miglioramento globale dei sintomi da EB dopo 12 settimane (misurato in base alla variazione percentuale del punteggio iscorEB del paziente), oppure ultima misurazione post-basale disponibile qualora sia mancante la misurazione della Settimana 12 (LOCF);
3. Miglioramento globale dei sintomi da EB dopo 12 settimane (misurato in base alla variazione percentuale del punteggio iscorEB del paziente, senza imputazione LOCF)
4. Miglioramento globale dei sintomi da EB al Giorno 17 (misurato in base alla variazione percentuale del punteggio EBDASI e dell’indice iscorEB del paziente)
5. Miglioramento globale dei sintomi da EB al Giorno 35 (misurato in base alla variazione percentuale del punteggio EBDASI e dell’indice iscorEB del paziente)
6. Infiammazione (misurata in base al profilo degli indici di infiammazione);
7. Valutazione del dolore mediante scala di valutazione numerica (numerical rating scale, (NRS);
8. Valutazione del prurito mediante scala NRS;
9. Valutazione del QOLEB.; Endpoint secondari di sicurezza:
1. Esame obiettivo e segni vitali;
2. Sopravvivenza globale a 24 mesi.

E.5.2.1

Timepoint(s) of evaluation of this end point

1. Day 17, 35 and week 12 after first IMP application;
2. Month 12, after first IMP application;

1. Week 12, after first IMP application;
2. Week 12, after first IMP application or timepoint of last observation carried forward;
3. Week 12, after first IMP application;
4. Day 17, after first IMP application;
5. Day 35, after first IMP application;
6. Day 0, 17 and 35 and week 12 after first IMP application;
7. Day 17 and 35 and week 12, after first IMP application;
8. Day 17 and 35 and week 12, after first IMP application;
9. Day 17 and 35 and week 12, after first IMP application;; 1. 12 Settimane, dalla prima somministrazione dell’IMP;
2. 12 Settimane, dalla prima somministrazione dell’IMP oppure con l’ultima misurazione post-basale;
3. 12 Settimane, dalla prima somministrazione dell’IMP;
4. Giorno 17, dalla prima somministrazione dell’IMP;
5. Giorno 35, dalla prima somministrazione d

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

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

Yes

E.7.1.2

Bioequivalence study

E.7.1.3

Other

Yes

E.7.1.3.1

Other trial type description

Safety and efficacy in patients and therapeutic exploratory (Phase I/IIA)

sicurezza ed efficacia nei pazienti e Valutazione terapeutica (Fase I/IIA)

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

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.8.4.1

Number of sites anticipated in Member State concerned

E.8.5

The trial involves multiple Member States

Yes

E.8.5.1

Number of sites anticipated in the EEA

E.8.6 Trial involving sites outside the EEA

E.8.6.1

Trial being conducted both within and outside the EEA

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

Information not present in EudraCT

E.8.6.3

If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned

Austria

France

Germany

Italy

United Kingdom

United States

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

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

E.8.9.2

In all countries concerned by the trial years

E.8.9.2

In all countries concerned by the trial months

E.8.9.2

In all countries concerned by the trial days

F. Population of Trial Subjects

F.1 Age Range

F.1.1

Trial has subjects under 18

Yes

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)

Yes

F.1.2.1

Number of subjects for this age range:

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.4.2

For a multinational trial

F.4.2.1

In the EEA

F.4.2.2

In the whole clinical trial

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)

After withdrawal patients will receive standard medical care according to individual needs

Al termine della loro partecipazione allo studio i pazienti riceveranno le cure come previsto dalla normale pratica clinica in accordo con le esigenze specifiche individuali.

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

2019-10-11

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2019-05-29

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

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IMP with orphan designation in the indication
Orphan Designation Number:
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