Clinical Trials Register

Summary
EudraCT Number:	2014-002845-23
Sponsor's Protocol Code Number:	CCD-GPLSCD01-03
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:	2015-10-05
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

Spain - AEMPS

A.2

EudraCT number

2014-002845-23

A.3

Full title of the trial

Multinational, multicentre, prospective, open-label, uncontrolled clinical trial to assess the efficacy and safety of Autologous Cultivated Limbal Stem Cells Transplantation (ACLSCT) for restoration of corneal epithelium in patients with limbal stem cell deficiency due to ocular burns

Ensayo clínico no controlado, abierto, prospectivo, multicéntrico y multinacional para evaluar la eficacia y la seguridad del Transplante Autólogo de Células Madre Limbares Cultivadas (TACMLC) para la restauración del epitelio corneal en pacientes con Deficiencia de Células Madre Limbares por quemaduras oculares (HOLOCORE)

A.3.1

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

A clinical study to follow the implantation of Holoclar on the cornea in patients with occular burns

Ensayo clínico para evaluar la implantación de Holoclar en la córnea de pacientes con quemaduras oculares

A.3.2

Name or abbreviated title of the trial where available

HOLOCORE

A.4.1

Sponsor's protocol code number

CCD-GPLSCD01-03

A.7

Trial is part of a Paediatric Investigation Plan

Yes

A.8

EMA Decision number of Paediatric Investigation Plan

P/199/2012

B. Sponsor Information
B.Sponsor: 1
B.1.1	Name of Sponsor	Chiesi Farmaceutici S.p.A.
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	Chiesi Farmaceutici S.p.A.
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	CHIESI ESPAÑA S.A.
B.5.2	Functional name of contact point	Silvia Caño (Medical Advisor)
B.5.3	Address:
B.5.3.1	Street Address	Torre Realia BCN - Plaça d'Europa, 41-43, planta 10
B.5.3.2	Town/ city	L'Hospitalet de Llobregat - Barcelona (España)
B.5.3.3	Post code	08908
B.5.3.4	Country	Spain
B.5.4	Telephone number	3493 445 6993
B.5.5	Fax number	3493 494 8030
B.5.6	E-mail	s.cano@chiesi.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	Yes
D.2.1.1.1	Trade name	HOLOCLAR
D.2.1.1.2	Name of the Marketing Authorisation holder	Chiesi farmaceutici SpA
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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/3/08/579
D.3 Description of the IMP
D.3.1	Product name	Holoclar
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	Ophthalmic use (Noncurrent)
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	NA
D.3.9.1	CAS number	NA
D.3.9.2	Current sponsor code	CCD-GPLSCD01-03
D.3.9.3	Other descriptive name	EX VIVO EXPANDED AUTOLOGOUS HUMAN CORNEAL EPITHELIAL CELLS CONTAINING STEM CELLS
D.3.9.4	EV Substance Code	SUB172912
D.3.10	Strength
D.3.10.1	Concentration unit	cm2 square centimeter
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	3.8
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	Yes
D.3.11.3.5.1	CAT classification and reference number	Tissue Engineered Product (EMA/54465/2011)
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

corneal lesions with associated moderate to severe limbal stem cell deficiency due to ocular burns

lesiones corneales asociadas a deficiencias de Células Madre Limbares por quemaduras oculares de moderadas a graves.

E.1.1.1

Medical condition in easily understood language

corneal damage due to ocular burns

daños corneales debidos a quemaduras oculares

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	18.0
E.1.2	Level	LLT
E.1.2	Classification code	10011012
E.1.2	Term	Corneal epithelium opacity
E.1.2	System Organ Class	100000004853

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 demonstrate the efficacy of Holoclar at one year after the first treatment in patients suffering from moderate to severe (at least two corneal quadrants, central corneal involvement resulting in severe visual impairment) LSCD secondary to ocular burns.

Demostrar la eficacia de Holoclar un año después del primer tratamiento en pacientes que sufren Deficiencia de Células Madre Limbares (DCML) (al menos dos cuadrantes de la córnea, con afectación corneal central que resulta en deficiencia visual grave) secundaria a quemaduras oculares de moderadas a graves.

E.2.2

Secondary objectives of the trial

To evaluate the efficacy of one or two treatments with Holoclar at one year after the last treatment.

Evaluar la eficacia de uno o dos tratamientos con Holoclar un año después del último tratamiento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1.      Written informed consent prior to any study-related procedures;
2.      Adult male and female patients (?18 years old) - [Five Paediatric patients aged 2 to 17 years will be also enrolled for safety purposes only];
3.      LSCD secondary to unilateral or bilateral ocular burns, with at least 1-2 mm2 of undamaged limbus to harvest stem cells for expansion in culture. LSCD will be considered for inclusion in presence of superficial neo-vascularization invading at least two corneal quadrants with central corneal involvement (including corneal neo-vascularisation, corneal opacity or corneal dyschromia) according to the independent assessors;
4.      Stability of LSCD, defined by a duration of disease of at least 24 months at the time of the Screening Visit and presence of continuum epithelium as per fluorescein staining scored as none or trace;
5.      Presence of severe impairment in visual acuity at the Snellen chart (legal blindness) after best correction (i.e. Best Corrected Visual Acuity);
6.      Absence of other clinical contraindications to ACLSC transplantation based upon investigator?s judgment;
7.      A cooperative attitude to follow up the study procedures (Caregivers in case of minors).

1. Consentimiento informado por escrito antes de cualquier procedimiento relacionado con el estudio. El consentimiento informado también incluirá la posibilidad de un segundo trasplante y de pasar al estudio de extensión a largo plazo HOLOCORE-FU. En el caso de que el paciente sea juzgado por el investigador como elegible para un segundo trasplante, se deberá obtener un apéndice adicional por escrito que se adjuntará al primer formulario de consentimiento informado para proceder con el segundo TACMLC;
2. Varones y mujeres adultos (? 18 años);
También se incluirá a cinco pacientes pediátricos de entre 2 y 17 años, exclusivamente con fines de seguridad.
3. DCML secundaria a quemaduras oculares físicas o químicas unilaterales o bilaterales, con al menos 1,2 mm2 de limbo en buen estado con el fin de recoger células madre para la expansión en cultivo. La DCML será considerada para su inclusión en presencia de neovascularización superficial invasora en al menos dos cuadrantes de la córnea con afectación corneal central (incluyendo neovascularización corneal, opacidad corneal o discromía corneal) de acuerdo con el criterio de los evaluadores independientes;
4. Estabilidad de la DCML, definida por una duración de la enfermedad de al menos 24 meses en el momento de la Visita de selección y por la presencia de epitelio continuo que se considere, según se desprenda mediante tinción con fluoresceína, como nulo o traza.
5. Presencia de una alteración grave de la agudeza visual definida por una puntuación de 1/10 o por debajo de 20/200 en el gráfico de Snellen (ceguera legal) después de mejor corrección (es decir, agudeza visual mejor corregida);
6. Ausencia de otras contraindicaciones clínicas del trasplante ACMLC en función del criterio del investigador;
7. Una actitud de cooperación para el seguimiento de los procedimientos del estudio (en caso de menores, los cuidadores).

E.4

Principal exclusion criteria

1. LSCD of mild degree (i.e. below 2 quadrants of neo-vessel invasion without central corneal), due to a recent burn (less than 24 months before screening), or secondary to medical conditions other than burns (i.e.radiotherapy);
2. Severe ocular inflammation according to the Efron Grading Scale for Contact Lens Complications. Patient can be re-screened after appropriate treatment;
3. Presence of eyelids malposition;
4. Conjunctival scarring with fornix shortening;
5. Tear secretion deficiency, determined by Schirmer?s test (<5 mm/ 5 min);
6. Corneal anaesthesia and conjunctival anaesthesia or severe hypoesthesia;

1. DCLM de grado leve (es decir, por debajo de 2 cuadrantes de invasión neovascular sin afectación corneal central) por una quemadura reciente (menos de 24 meses antes de la detección) o secundaria a condiciones médicas distintas de las quemaduras (por ejemplo, radioterapia);
2. Inflamación ocular grave de acuerdo con la Escala de graduación de Efron para complicaciones de lentes de contacto. Se puede volver a seleccionar al paciente después de un tratamiento adecuado;
3. Presencia de una mala posición de los párpados;
4. Cicatrización conjuntival con acortamiento del fórnix;
5. Deficiencia de secreción lagrimal grave, determinada por el tipo de prueba de Schirmer I (<5 mm/5 min);
6. Anestesia corneal y anestesia conjuntival;

E.5 End points

E.5.1

Primary end point(s)

- Percentage of patients with a success of transplantation (success is defined on the basis of the degree of ?superficial corneal neo-vascularization? and ?epithelial defects?)

Porcentaje de pacientes con éxito clínico después del trasplante (éxito definido en base a la gravedad de la neovascularización y reepitelización corneal).

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months from the first Holoclar treatment

12 meses desde el primer tratamiento con Holoclar.

E.5.2

Secondary end point(s)

- Percentage of patients with clinical success after one or two ACLSCTs (same definition of success as primary endpoint)

Porcentaje de pacientes con éxito clínico después de uno o dos TACMLC (misma definición de éxito que en la variable primaria de eficacia).

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months after the last treatment with Holoclar.

12 meses desde el primer tratamiento con Holoclar.

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)

E.7.3

Therapeutic confirmatory (Phase III)

E.7.4

Therapeutic use (Phase IV)

Yes

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

ensayo prospectivo

prospective 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

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

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

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

Last Patient Last Visit

Última visita del último paciente

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

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)

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

Yes

F.3.3.6.1

Details of subjects incapable of giving consent

Five paediatric patients between 2 and 17 included should be enrolled. These participants are under age and are not allowed to decide participation themselves. Parents must consent if the child verbally and bodily agree.

Se incluirán 5 pacientes pediátricos de entre 2 y 17 años. Dichos participantes no están autorizados a decidir su participación por sí mismos. Los padres consentirán si el menor acepta participar.

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 their participation in the trial, the subjects will be treated according to the standard treatment care expected for their condition. The patients will be proposed to enter the safety and efficacy long-term follow-up study.

Al final del estudio, los pacientes serán tratados con el tratamiento habitual para su condición. Se les propondrá participar en el estudio de seguimiento de seguridad y eficacia a largo plazo.

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

2016-05-29

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-05-12

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

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