Clinical Trials Register

Summary
EudraCT Number:	2014-002845-23
Sponsor's Protocol Code Number:	CCD-GPLSCD01-03
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2020-10-01
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

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 (HOLOCORE).

Studio multinazionale, multicentrico, prospettico, in aperto e non controllato volto a valutare l'efficacia e la sicurezza del trapianto di colture autologhe di cellule staminali limbari (ACLSCT) per la ricostruzione dell'epitelio corneale in pazienti con deficit di cellule staminali limbari dovuto a ustioni oculari (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

Uno studio clinico per seguire l'impianto di Holoclar sulla cornea di pazienti con ustioni oculari

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 SpA
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 Farmaceutici SPA
B.5.2	Functional name of contact point	Clinical Project Manager
B.5.3	Address:
B.5.3.1	Street Address	Via Palermo 26A
B.5.3.2	Town/ city	Parma
B.5.3.3	Post code	43122
B.5.3.4	Country	Italy
B.5.4	Telephone number	05211689281
B.5.5	Fax number	0521774468
B.5.6	E-mail	clinicaltrials_info@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	France
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.3.2	Product code	[Holoclar]
D.3.4	Pharmaceutical form	Implant
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.3.9.2	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	4
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	Yes
D.3.11.13.1	Other medicinal product type	ATIMP

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

Treatment of corneal lesions with associated moderate (at least two corneal quadrants, central corneal involvement resulting in severe visual impairment) to severe limbal stem cell deficiency due to ocular burns

Trattamento di lesioni corneali con relativo deficit di cellule staminali limbari da moderato (almeno due quadranti della cornea, coinvolgimento centrale della cornea con conseguente grave compromissione dell’acutezza visiva) a grave dovuto a ustioni oculari

E.1.1.1

Medical condition in easily understood language

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

Lesioni corneali associate a riduzione da moderata a severa di cellule staminali limbari dovuta a bruciature uculari

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	20.0
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 (vascularization in two-three corneal quadrants with central corneal involvement) to severe (vascularization in four corneal quadrants with central corneal involvement) LSCD with severe visual impairment and secondary to ocular burns, in terms of percentage of patients with a success of transplantation at approximately 12 months from the first Holoclar® treatment.

Dimostrare l’efficacia di Holoclar dopo un anno dal primo trattamento in pazienti con deficit di cellule staminali limbari (LSCD) da moderato (vascolarizzazione in 2-3 quadranti con coinvolgimento della cornea centrale) a grave (vascolarizzazione in quattro quadranti corneali con coinvolgimento della cornea centrale) a causa di ustioni oculari.

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.

Valutare l’efficacia di uno o due trattamenti con Holoclar dopo un anno dall’ultimo trattamento.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Written informed consent prior to any study-related procedures. Informed consent will also include the possibility of a second transplantation and of the rolling over to the long-term extension study HOLOCORE-FU. In case the patient will be judged by the investigator as eligible to a second transplantation, an additional written addendum to the first informed consent form will have to be obtained to proceed with the second ACLSCT;
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 physical or chemical 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-vascularization or corneal opacity) according to the independent assessors;
4. Stability of LSCD, defined by a duration of disease of at least 24 months (12 months for minors) 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 defined by a score after best correction (i.e. Best Corrected Visual Acuity) equal or below 1/10th (or 20/200) at the Snellen chart (legal blindness) ;
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. Consenso informato scritto prima di qualsiasi procedura correlata allo studio. Il consenso informato prevede inoltre la possibilità di un secondo trapianto e dell‘arruolamento per lo studio di estensione a lungo termine HOLOCORE-FU. Nel caso in cui il ricercatore giudicherà il paziente idoneo ad un secondo trapianto, sarà necessario allegare un ulteriore documento scritto al primo consenso informato che permetta di procedere al secondo ACLSCT;
2. Pazienti adulti maschi e femmine (=18 anni);
Verranno arruolati anche cinque pazienti pediatrici di età compresa tra i 2 e i 17 anni a solo scopo precauzionale.
3. LSCD secondario a ustioni oculari unilaterali o bilaterali di natura chimica o fisica, con almeno 1 - 2 mm2 di limbo non danneggiato che consenta di raccogliere cellule per l’espansione in coltura. L’LSCD verrà preso in considerazione per l’inclusione in presenza di neovascolarizzazione superficiale in almeno due quadranti della cornea con coinvolgimento centrale della cornea (tra cui neovascolarizzazione corneale o opacità corneale) secondo il giudizio di valutatori indipendenti;
4. Stabilità dell’LSCD, intesa come durata della malattia di almeno 24 mesi (12 mesi per i minori) al momento della visita di screening e presenza di epitelio continuo alla colorazione con fluoresceina classificato come inesistente o in tracce.
5. Presenza di grave compromissione dell’acuità visiva definita da uno score dopo la miglior correzione (ovvero la miglior acuità visiva corretta) uguale o inferiore a 1/10° (o 20/200) secondo la tavola di Snellen (cecità legale);
6. Assenza di altra controindicazione clinica al trapianto ACLSC secondo il giudizio del ricercatore;
7. Un atteggiamento collaborativo a seguire le procedure dello studio (tutori in caso di minorenni).

E.4

Principal exclusion criteria

1. LSCD of mild degree (i.e. below 2 quadrants of neo-vessel invasion ), due to a recent burn (less than 24 months before screening for adults and 12 months for minors), 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. LSCD di lieve entità (ovvero invasione neovascolare in meno di 2 quadranti) dovuto ad un’ustione recente (meno di 24 mesi prima dello screening per gli adulti e 12 per i minori) o secondario a condizioni mediche che non siano ustioni (ovvero la radioterapia);
2. Grave infiammazione oculare secondo la scala graduata di Efron per le complicanze da lenti a contatto. Il paziente può essere sottoposto nuovamente allo screening dopo un trattamento adeguato;
3. Presenza di malposizione delle palpebre;
4. Cicatrici congiuntivali con accorciamento del fornice;
5. Grave deficit di secrezione lacrimale diagnosticato mediante il test di Schirmer di tipo I (<5 mm/ 5 min.);
6. Anestesia corneale e congiuntivale o ipoestesia severa;

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 neovascularization" and "epithelial defects")

Percentuale di pazienti con un successo di trapianto (il successo del trapianto si definisce in base al grado di “neovascolarizzazione corneale superficiale" e di “difetti epiteliali”. )

E.5.1.1

Timepoint(s) of evaluation of this end point

12 months from the first Holoclar treatment

12 mesi dopo il primo trattamento 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)

Percentuale di pazienti con successo clinico dopo uno o due ACLSCT (stessa definizione dell'endpoint primario)

E.5.2.1

Timepoint(s) of evaluation of this end point

12 months after the last treatment with Holoclar

12 mesi dopo l'ultimo trattemento 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

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

studio prospettico

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

Information not present in EudraCT

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)

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.

5 pazienti pediatrici di età compresa tra 2 e 17 anni inclusi saranno arruolati. Questi pazienti, essendo minori, non possono decidere per la partecipazione allo studio e per questo il consenso verrà richiesto ai loro genitori ed i pazienti forniran

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

Dopo la loro partecipazione alla sperimentazione, i soggetti saranno trattati secondo il trattamento standard previsto per la loro condizione.
Ai pazienti verrà proposta di entrare in un altro studio per valutare la sicurezza e l'efficacia a lungo termine dello studio.

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

2015-10-20

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2015-07-23

P. End of Trial
P.	End of Trial Status	Completed

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