Clinical Trials Register

Summary
EudraCT Number:	2019-003215-63
Sponsor's Protocol Code Number:	69HCL19_0032
National Competent Authority:	France - ANSM
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2019-11-27
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

2019-003215-63

A.3

Full title of the trial

Cultured Autologous Oral Mucosa Epithelial sheet for the Treatment of Bilateral Limbal Stem Cell Deficiency - FEMJA for « Feuillet Epithélial de Muqueuse Jugale Autologue »

Culture d’un Feuillet Epithélial de Muqueuse Jugale Autologue pour le traitement de patients atteints d’une déficience bilatérale en cellules souches limbiques - Etude FEMJA pour « Feuillet Epithélial de Muqueuse Jugale Autologue »

A.3.1

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

Cultured Autologous Oral Mucosa Epithelial sheet for the Treatment of Bilateral Limbal Stem Cell Deficiency - FEMJA for « Feuillet Epithélial de Muqueuse Jugale Autologue »

A.3.2

Name or abbreviated title of the trial where available

FEMJA

A.4.1

Sponsor's protocol code number

69HCL19_0032

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	Hospices Civils de Lyon - Direction de la Recherche Clinique et de l'Innovation
B.1.3.4	Country	France
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	Direction Générale de l'Offre de Soins
B.4.2	Country	France
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Hospices Civils de Lyon - Direction de la Recherche Clinique et de l'Innovation
B.5.2	Functional name of contact point	Catherine CERESER
B.5.3	Address:
B.5.3.1	Street Address	3 quai des Célestins
B.5.3.2	Town/ city	Lyon cedex 02
B.5.3.3	Post code	69229
B.5.3.4	Country	France
B.5.4	Telephone number	+33472 40 68 93
B.5.5	Fax number	+33472 11 51 90
B.5.6	E-mail	drci_promo@chu-lyon.fr

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.2.1.2	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.3.1	Product name	Feuillet Epithélial de Muqueuse Jugale Autologue
D.3.2	Product code	FEMJA
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	Ocular use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.9.2	Current sponsor code	FEMJA
D.3.9.3	Other descriptive name	Autologous oral mucosal epithelial cells
D.3.10	Strength
D.3.10.1	Concentration unit	cm2 square centimeter
D.3.10.2	Concentration type	range
D.3.10.3	Concentration number	4 to 5
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)	Yes
	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

Bilateral Limbal Stem Cell Deficiency

Déficience bilatérale en cellules souches limbiques

E.1.1.1

Medical condition in easily understood language

Bilateral Limbal Stem Cell Deficiency

Déficience bilatérale en cellules souches limbiques

E.1.1.2

Therapeutic area

Diseases [C] - Eye Diseases [C11]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	20.1
E.1.2	Level	PT
E.1.2	Classification code	10072138
E.1.2	Term	Limbal stem cell deficiency
E.1.2	System Organ Class	10015919 - Eye disorders

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

Improvement of visual acuity at 24 months after jugal mucosa epithelial sheet (FEMJA) transplantation on the grafted eye (one eye treated per patient).

Amélioration de l’acuité visuelle 24 mois après la transplantation du feuillet épithélial de la muqueuse jugale (FEMJA) sur l’œil greffé (un œil traité par patient)

E.2.2

Secondary objectives of the trial

- Feasibility of the jugal mucosa epithelial sheet graft;
- Tolerance of the jugal mucosa epithelial sheet;
- Efficacy of the jugal mucosa epithelial sheet in terms of quality of the reconstructed epithelium (physical signs), neovascularization, and symptoms (functional signs);
- Graft rejection for patients with secondary corneal graft;
- Relation between biological FEMJA characteristics (extraction yield, percentage of proliferative epithelial cells) and change in visual acuity.

- Faisabilité de la greffe de feuillet épithélial de la muqueuse jugale
- Tolérance du feuillet épithélial de la muqueuse jugale
- Efficacité du feuillet épithélial de la muqueuse jugale en termes de qualité de l’épithélium généré (signes physiques), de néovascularisation, et de symptômes (signes fonctionnels)
- Rejet de greffe pour les patients ayant bénéficié d’une greffe de la cornée secondaire
- Relation entre les caractéristiques biologiques de FEMJA (rendement d’extraction, pourcentage de prolifération des cellules épithéliales) et le changement de l’acuité visuelle

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

- Male or female aged ≥ 18 years
- Signed and dated informed consent for participation in the study
- Total bilateral limbal stem-cell deficiency
- Caused by thermal or chemical burn, cornea transplantation, and other bilateral disorders of the ocular surface
- Severe loss of vision (<2/10 on decimal scale or/and EDTRS)
- The subject must be covered by a social security system

- Homme ou femme d'âge ≥ 18 ans
- Consentement daté et signé pour participer à cette étude
- Déficit en cellules souches limbiques totale et bilatérale
- Causé par une brûlure thermique ou chimique, une transplantation de la cornée ou autres troubles bilatéraux de la surface oculaire
- Perte de vision sévère (<2/10 échelle décimale et/ou ETDRS)
- Patient affilié à un régime de sécurité sociale ou assimilé

E.4

Principal exclusion criteria

- Eye inflammation
- Strictly unilateral ocular affliction
- Acute systemic infection, objectified during consultation by the investigator and on the following paraclinical parameters: Erythrocyte Sedimentation Rate (ERS), C Reactive Protein rate
- History of acute phase of ocular inflammation in the previous year
- History of neoplasic disease
- Glaucoma defined as intra ocular pressure (air tonometer and applanation tonometer) ≥ 22mmHg
- Total symblepharon (comprising eyelid aperture): impossibility to open the 2 eyes
- History of hyper sensibility or allergy to antibiotics or serum
- Women who are or may be pregnant or breastfeading
- Patients with any infectious disease (HBV, HCV, HIV, HTLV-1 and syphilis)
- Patients who are otherwise ineligible for participation in the study in the opinion of the investigator.
- Delay of less than one year after chemical or thermal burns
- Person under judicial protection
- Contraindication related to anesthesia
- Oral mucosa tumor or infection

- Inflammation oculaire
- Atteinte oculaire strictement unilatérale
- Infection systémique aigue : diagnostiquée durant la consultation par l’investigateur et selon les paramètres suivants : vitesse de sédimentation (VS) et protéine C réactive (CRP).
- Antécédent d’une phase d’inflammation aiguë oculaire dans l’année précédente
- Antécédent de maladie néoplasique oculaire
- Glaucome défini par une pression intraoculaire (tonométrie à air et tonométrie à aplanation) ≥ 22mmHg
- Symblepharon total (comprimant l’ouverture de la paupière) : impossibilité d’ouvrir les deux yeux
- Antécédent d’hypersensibilité ou d’allergies aux antibiotiques ou sérum
- Femme enceinte ou susceptible de l’être ou allaitante
- Patient avec une infection VHB, VHC, VIH, HTLV-1 ou syphilis
- Patients non éligible pour participer à l’étude selon l’avis de l’investigateur
- Délai de moins de 1 an après une brûlure oculaire chimique ou physique
- Patient sous protection judiciaire, tutelle ou curatelle
- Contre-indication à l’anesthésie
- Tumeur ou infection de la muqueuse buccale

E.5 End points

E.5.1

Primary end point(s)

Number of patients with any improvement in visual acuity, measured at baseline (i.e. the day of jugal mucosa biopsy; preoperative status) and 24 months after jugal mucosa epithelial cell sheet (FEMJA) transplantation, according to the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. ETDRS LogMAR tests allow measurement of very low visual acuity.

Nombre de patient chez lesquels il y a une amélioration de l’acuité visuelle, mesurée le jour de la biopsie (statut préopératoire) et 24 mois après la transplantation du feuillet épithélial de la muqueuse jugale (FEMJA), selon l’échelle de l’Early Treatment Diabetic Retinopathy Study (ETDRS). Les tests ETDRS LogMAR permettent de mesurer une très faible acuité visuelle.

E.5.1.1

Timepoint(s) of evaluation of this end point

24 months after jugal mucosa epithelial cell sheet (FEMJA) transplantation

24 mois après la transplantation du feuillet épithélial de la muqueuse jugale (FEMJA)

E.5.2

Secondary end point(s)

1 / Related to feasibility: Success rates of the culture, of the detachment, and of the FEMJA graft itself: obtaining at least one sheet per patient, and transplantation of FEMJA without perforating it.

2/ Related to tolerance/safety: Adverse events related to the procedure; especially expected adverse events: inflammation, infection, and perforation.

3/ Related to efficacy:
- Number of patients with at least one point of improvement of the following items at 6 months, 12 months, 18 months and 24 months:
* Quality of reconstructed epithelium, i.e. physical signs measured by the ophthalmologist using a slit lamp, in terms of: persistant epithelial defect; superficial punctate epithelial keratitis; and conjunctival epithelium on cornea;
* Neovascularization, in terms of number of vascular pediculus near the limbus and their activity;
* Symptoms, i.e. functional signs measured with Likert scales by self-reporting from the patient, in terms of: photophobia, eye dryness, and pain.
- Number of patients with secondary corneal graft and presenting graft rejection, defined by intraocular pression (≥ 22mmHg) and corneal topography (significant increase in the thickness of the stroma of the cornea compared to the measured value just after the graft).

4/ Biological endpoints: FEMJA characteristics (extraction yield, percentage of proliferative epithelial cells) will be compared according to the clinical response for changes in visual acuity at M24.

1/ Faisabilité : Taux de succès de culture, du détachement et de la greffe de FEMJA : obtention d’au moins un feuillet par patient et transplantation de FEMJA sans le perforer.

2/ Tolérance/sécurité : Évènements indésirables liés à la procédure ; plus particulièrement les évènements indésirables attendus : inflammation, infection, et perforation.

3/ Efficacité :
- Nombre de patients avec au moins un point d’amélioration sur chaque élément suivant à 6 mois, 12 mois, 18 mois et 24 mois :
* Qualité de l’épithélium généré, c’est-à-dire les signes physiques mesurés grâce à une lampe à fente, en termes de : persistance de défaut de l’épithélium, kératite épithélial ponctuée superficielle ; et épithélium conjonctival sur la cornée ;
* Néovascularisation, en termes de nombre de pédicules vasculaires à proximité du limbe et leur activité ;
* Symptômes, c’est-à-dire les signes fonctionnels mesurés sur une échelle de Likert par le patient en termes de : photophobie, sécheresse de l’œil, et douleur.
- Nombre de patients avec une greffe de la cornée secondaire et présentant un rejet de greffe, définie par une pression oculaire ≥22mmHg et une augmentation significative de l’épaisseur du stroma de la cornée par rapport à la valeur mesurée juste post greffe en topographie cornéenne.

4/ Biologiques : les caractéristiques de FEMJA (rendement d’extraction, pourcentage de prolifération des cellules épithéliales) seront croisées aux réponses cliniques (changement d’acuité visuelle à M24).

E.5.2.1

Timepoint(s) of evaluation of this end point

6 months, 12 months, 18 months and 24 months months after jugal mucosa epithelial cell sheet (FEMJA) transplantation

6 mois, 12 mois, 18 mois et 24 mois après la transplantation du feuillet épithélial de la muqueuse jugale (FEMJA)

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

Yes

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

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

Dernière visite du dernier patient

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

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)

F.1.1.6

Adolescents (12-17 years)

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)

Yes

F.1.3.1

Number of subjects for this age range:

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)

None

Aucun

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

2020-03-10

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2020-01-07

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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