Clinical Trials Register

Summary
EudraCT Number:	2018-000261-36
Sponsor's Protocol Code Number:	1.0
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2020-04-28
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

France - ANSM

A.2

EudraCT number

2018-000261-36

A.3

Full title of the trial

MULTICENTRE, OPEN-LABEL, UNCONTROLLED, PIVOTAL CLINICAL TRIAL
TO CONFIRM THE EFFICACY AND SAFETY OF AUTOLOGOUS FIBRINCULTURED
EPIDERMAL GRAFTS CONTAINING EPIDERMAL STEM CELLS GENETICALLY MODIFIED FOR RESTORATION OF EPIDERMIS IN PATIENTS
WITH JUNCTIONAL EPIDERMOLYSIS BULLOSA (HOLOGENE 5)

A.3.1

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

Gene Therapy for patient with Junctional Epidermolysis Bullosa

A.3.2

Name or abbreviated title of the trial where available

Hologene 5

A.4.1

Sponsor's protocol code number

1.0

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	Holostem Terapie Avanzate s.r.l.
B.1.3.4	Country	Italy
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	Holostem Terapie Avanzate s.r.l.
B.4.2	Country	Italy
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CROSS Research SA
B.5.2	Functional name of contact point	Angelo Vaccani
B.5.3	Address:
B.5.3.1	Street Address	Via FA Giorgioli 14
B.5.3.2	Town/ city	Arzo
B.5.3.3	Post code	6864
B.5.3.4	Country	Switzerland
B.5.4	Telephone number	+41916300510
B.5.5	Fax number	+41916300511
B.5.6	E-mail	angelo.vaccani@croalliance.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	Yes
D.2.5.1	Orphan drug designation number	EU/3/15/1465
D.3 Description of the IMP
D.3.1	Product name	Hologene 5
D.3.4	Pharmaceutical form	Living tissue equivalent
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Cutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	Not Yet Assigned
D.3.9.1	CAS number	Not App
D.3.9.2	Current sponsor code	Hologene 5 DS
D.3.9.3	Other descriptive name	Ex-vivo-expanded autologous human keratinocytes containing epidermal stem cells transduced with a LAMB3-encoding retroviral vector
D.3.9.4	EV Substance Code	SUB194480
D.3.10	Strength
D.3.10.1	Concentration unit	U unit(s)
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	20000000 to 30000000
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	Yes
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

Inherited Epidermolysis Bullosa (EB) is a group of rare, devastating
genetic disorders characterized by structural and mechanical fragility of
skin and mucosal membranes, impairing the patient's quality of life.
Generalized JEB is a chronic, life-threatening condition caused by
mutations in genes– encoding different chains of laminin 332. All of
these mutations hamper hemidesmosome formation, causing blisters.
The most frequent, and perhaps most severe, JEB is due to mutations in
LAMB3.

E.1.1.1

Medical condition in easily understood language

Gene Therapy for patient with Junctional Epidermolysis Bullosa

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

To evaluate the efficacy of HOLOGENE 5 at 12 months follow-up as
percentage of success based on the following assessments:
• clinical performance as % of re-epithelization in the absence
of blisters measured by Investigator through a software named
Holosnapp;
• functional evaluation based on laboratory analyses and
mechanical assessment;
• patient outcome assessment based on patients’ improvement
perception on the transplanted areas.

E.2.2

Secondary objectives of the trial

Secondary Objectives
• To evaluate efficacy as % of re-epithelization measured by
Independent Assessor through 12 months follow-up;
• To evaluate efficacy as % of re-epithelization measured by
Investigator through Holosnapp at 1, 3, 6, 9 and 12 months follow-up;
• To evaluate efficacy as Investigator judgment based on engraftment,
erosions, infection, appearance of the skin, functionality, etc. at 1, 3, 6, 9
and 12 months;
• To evaluate the dermal/epidermal junction using OCT at 12 months;
• To evaluate change in Quality of Treated Area(s) from baseline, based
on EBDASI;
• To evaluate the safety of the treatment with HOLOGENE 5 during the
study.
Exploratory:
• To evaluate potential immune reactions ;
• To evaluate change in Quality of Life from baseline;
transplantation scored as successes;
• To evaluate efficacy as intra-patient treatment;
• To evaluate improvement of patient's quality using QOLEB.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Signed and dated informed consent prior to any study-related
procedures;
2. Male and female patients between 6-month-old and 55-year-old;
3. Diagnosis of generalized intermediate LAMB3-dependent JEB,
confirmed by NGS or Sanger sequencing and
immunofluorescence;
4. Detectable residual expression of laminin 332 (and its beta3
chain) by immunofluorescence and/or Western analysis;
5. Presence of blisters and/or ≥ 10 cm2 erosions (persistent or
recurrent for more than 3 months);
6. A cooperative attitude to follow the study procedures (caregivers
in case of children);
7. Patients’ compliance with the study schedule and procedures,
including complete immobilization of the transplanted areas for at
least two weeks and hospitalization up to 1 month after
transplantation.

E.4

Principal exclusion criteria

1. Known or suspected intolerance to anaesthesia;
2. Bad general condition (ECOG index >1);
Presence of Squamous Cell Carcinomas (SCCs) in the area(s)
qualified for treatment;
4. Clinical and/or laboratory signs of acute systemic infections at the
time of screening. Patient can be re-screened after appropriate
treatment;
5. Female subjects: pregnant or lactating women and all women
with childbearing potential unless they are willing to use one or
more reliable methods of contraception with a Pearl index ≤1.
Reliable contraception should be maintained throughout the
study.
A pregnancy test will be performed at screening in all women of
childbearing potential and repeated before biopsy treatment and at
all visits. A pregnancy test will not be required for postmenopausal
women (physiologic menopause defined as “12
consecutive months of amenorrhea”) or women permanently
sterilized (e.g. tubal occlusion, hysterectomy or bilateral
salpingectomy).
Parental control will be applied for the pediatric population when
needed;
6. Allergy, sensitivity or intolerance to study medication excipients
or other material required by study protocol (as per Investigator’s
brochure):
- Transport medium (Dulbecco’s Modified Eagles Medium
supplemented with L-glutamine)
- Fibrin support
- Povidone iodine or Prontosan® (or equivalent selected for
the treatment in consultation with the Sponsor Medical
Expert)
7. Contraindications to the local or systemic antibiotics and/or
corticosteroids foreseen by the protocol;
8. Contraindications to undergo extensive surgical procedures;
9. Presence of i) systemic diseases, ii) clinically significant or
unstable concurrent disease, iii) other concomitant medical
conditions, iv) other clinical contraindications to stem cell
transplantation, which based on Investigator’s judgment, in
consultation with the Sponsor Medical Expert may affect the
participation in the study or the grafting procedure;
10. Patients (or parents in case of paediatric subject) unlikely to
comply with the study protocol or unable to understand the nature
and scope of the study or the possible benefits or unwanted
effects of the study procedures and treatments.
11. Previous treatments or participation in clinical trials envisaging
the use of cells (including bone marrow transplantation, BMT)
and/or both in vivo or ex vivo gene therapy products.

E.5 End points

E.5.1

Primary end point(s)

Percentage of transplantation scored as success at 12 months
follow-up based on the definition of success using the 2-steps
rule.

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months

E.5.2

Secondary end point(s)

Percentage of transplantation success at 12 months follow-up
as % of re-epithelization measured through Holosnapp by the
Independent Assessor;
• Percentage of transplantation success at 1, 3, 6, 9 and 12
months follow-up as % of re-epithelization measured through
Holosnapp by the Investigator;
• Percentage of transplantation success at 1, 3, 6, 9 and 12
months follow-up through Investigator judgment based on
engraftment, erosions, infection, aspects, functionality, etc.;
• Percentage of normal and abnormal NCS (abnormal, Not
Clinically Significant) Optical Coherence Tomography (OCT)
at 12 months follow-up
Change in Quality of Treated Areas from baseline at 12
months follow-up, based on EBDASI;
• Treatment-emergent adverse events (TEAEs), serious adverse
events (SAEs) and ADRs;
• Vital signs and laboratory results.

Exploratory Endpoints
• Percentage of patients experiencing potential immune
reactions against the transgene during the study;
• Change in Quality of Life from baseline based on the
questionnaires answered by the patients through the
application named ‘HoloApp’. Daily/ weekly answers to the
questionnaires administered to the patients through HoloApp
starting from the transplantation up to 12 months follow-up
are considered;
• Intra-patient treatment comparison based on efficacy
endpoints between skin areas treated with Hologene 5 and
areas not treated (controls) within the same patient, evaluated
at screening (Visit 1) and at the end of study (Visit 11/Month
12). At least one area used as comparison should be observed
for at least 12 months (from screening);
• Percentage of patients with one or more transplantation scored
as successes (based on 2-steps rule) at 12 months follow-up.

E.5.2.1

Timepoint(s) of evaluation of this end point

1-3-6-9-12 months

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)

Yes

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

Yes

E.8.1.7.1

Other trial design description

multicentric, prospective, uncontrolled, interventional, pivotal clinical trial.

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

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

Information not present in EudraCT

E.8.6.2

Trial being conducted completely outside of the EEA

E.8.7

Trial has a data monitoring committee

Information not present in EudraCT

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

Last Patient Last visit

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

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)

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)

None

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

2021-01-27

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-07-07

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

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