Clinical Trials Register

Summary
EudraCT Number:	2011-006064-43
Sponsor's Protocol Code Number:	Cx601-0302
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:	2012-03-05
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2011-006064-43

A.3

Full title of the trial

A phase III, randomised, double blind, parallel group, placebo controlled, multicentre study to assess efficacy and safety of expanded allogeneic adipose-derived stem cells (eASCs) for the treatment of perianal fistulising Crohn’s disease over a period of 24 weeks. ADMIRE-CD study.

Studio di fase III multicentrico, randomizzato, in doppio cieco, a gruppi paralleli, controllato con placebo per valutare l'efficacia e la sicurezza delle cellule staminali allogeniche espanse derivate dal tessuto adiposo (eASCs) per il trattamento della malattia di Crohn fistolizzante perianale della durata di 24 settimane. Studio ADMIRE-CD.

A.3.1

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

Study to assess efficacy and safety of stem cells derived from allogeneic adipose tissue for the treatment of perianal fistulas in patients with Crohn's disease

Studio per valutare l'efficacia e la sicurezza delle cellule staminali allogeniche derivate dal tessuto adiposo per il trattamento delle fistole perianali nei pazienti con malattia di Crohn

A.3.2

Name or abbreviated title of the trial where available

ADIMIRE-CD study

Studio ADMIRE-CD

A.4.1

Sponsor's protocol code number

Cx601-0302

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	CELLERIX S.A.
B.1.3.4	Country	Spain
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	CELLERIX, S.A.
B.4.2	Country	Spain
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	CELLERIX, S.A.
B.5.2	Functional name of contact point	Clinical Operations
B.5.3	Address:
B.5.3.1	Street Address	C/Marconi, 1 Parque Tecnologico de Madrid
B.5.3.2	Town/ city	Tres Cantos. Madrid
B.5.3.3	Post code	28760
B.5.3.4	Country	Spain
B.5.4	Telephone number	+34 91 804 9264
B.5.5	Fax number	+34 91 804 9263
B.5.6	E-mail	lydia.dorrego@tigenix.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/3/09/667
D.3 Description of the IMP
D.3.1	Product name	Allogenic eASCs 5 milion cells/ml suspension for injection. Cx601
D.3.2	Product code	Cx601
D.3.4	Pharmaceutical form	Suspension for injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intralesional use
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	Allogenic eASCs
D.3.9.3	Other descriptive name	Expanded human allogenic mesenchymal adult stem cells extractd from adipose tissue (eASCs)
D.3.9.4	EV Substance Code	NA
D.3.10	Strength
D.3.10.1	Concentration unit	U/ml unit(s)/millilitre
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5000000
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	Yes
D.3.11.3.2	Gene therapy medical product	No
D.3.11.3.3	Tissue Engineered Product	No
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
D.8 Placebo: 1
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Suspension for injection
D.8.4	Route of administration of the placebo	Intralesional use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Perianal fistulising Crohn's disease

Malattia di Crohn fistolizzante perianale

E.1.1.1

Medical condition in easily understood language

Treatment for perianal fistulising Crohn's disease

Trattamento per le fistole anali della malattia di Crohn

E.1.1.2

Therapeutic area

Diseases [C] - Digestive System Diseases [C06]

MedDRA Classification

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	SOC
E.1.2	Classification code	10017947
E.1.2	Term	Gastrointestinal disorders
E.1.2	System Organ Class	10017947 - Gastrointestinal disorders

E.1.2 Medical condition or disease under investigation

E.1.2	Version	14.1
E.1.2	Level	PT
E.1.2	Classification code	10002156
E.1.2	Term	Anal fistula
E.1.2	System Organ Class	10017947 - Gastrointestinal 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

Evaluate the efficacy and safety of eASCs compared to placebo for the treatment of fistulising Crohn’s disease over a 24-week period.

Valutare l’efficacia e la sicurezza delle eASCs rispetto al placebo per il trattamento della malattia di Crohn fistolizzante per un periodo di 24 settimane.

E.2.2

Secondary objectives of the trial

There are not secondary objectives

Non ci sono obiettivi secondari

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1-Signed informed consent. 2-Patients with Crohn’s Disease (CD) diagnosed at least 6 months earlier in accordance with accepted clinical, endoscopic, histological and/or radiologic criteria. 3-Presence of complex perianal fistulas with a maximum of 2 fistulas (internal openings) and a maximum of 3 external openings, assessed by clinical assessment and MRI. Fistula must have been draining for at least 6 weeks prior to the inclusion. A complex perianal fistula is defined as a fistula that met one or more of the following criteria during its evolution: •High inter-sphincteric, trans-sphincteric, extra-sphincteric or supra-sphincteric. •Presence of ≥ 2 external openings (tracts). •Associated collections 4-Non-active or mildly active luminal CD defined by a CDAI ≤ 220. 5-Patients of either sex aged 18 years or older 6-Good general state of health according to clinical history and a physical examination. 7-For women of a childbearing age, they must have negative serum or urine pregnancy test (sensitive to 25 IU human chorionic gonadotropin [hCG]). Both men and women should use appropriate birth control methods defined by the investigator.

1-Consenso informato firmato
2-Pazienti con malattia di Crohn (CD) diagnosticata almeno 6 mesi prima in conformità ai criteri clinici, endoscopici, istologici e/o radiologici accettati.
3-Presenza di fistole perianali complesse con un massimo di 2 fistole (orifizi interni) e un massimo di 3 orifizi esterni, accertate con valutazione clinica e MRI. La fistola deve avere drenato per almeno 6 settimane prima dell’inclusione nello studio. Una fistola perianale complessa è definita come una fistola che ha soddisfatto uno o più dei seguenti criteri durante la sua evoluzione:
•Alta intrasfinterica, transfinterica, extrasfinterica o soprasfinterica.
•Presenza di 2 o più orifizi esterni (tratti).
•Collezioni associate.
4-CD luminale non attiva o lievemente attiva definita da un CDAI ≤ 220.
5-Pazienti di entrambi i sessi di età pari o superiore a 18 anni.
6-Stato generale di salute buono in base ad anamnesi clinica e visita medica.
7-Le donne in età fertile devono avere un test di gravidanza su siero o urine negativo (sensibilità 25 UI di gonadotropina corionica umana [hCG]). Sia gli uomini che le donne devono utilizzare opportuni metodi di controllo delle nascite stabiliti dallo sperimentatore.

E.4

Principal exclusion criteria

1-Presence of dominant luminal active Crohn’s disease requiring immediate therapy.
2-CDAI >220.
3-Concomitant rectovaginal fistulas
4-Patient naïve to specific treatment for perianal fistulising Crohn’s disease including antibiotics
5-Presence of an abscess or collections > 2 cm, unless resolved in the preparation procedure (week -3 to day 0).
6-Presence of > 2 fistular lesions.
7-Presence of > 3 external openings. 8-Rectal and/or anal stenosis and / or active proctitis, if this means a limitation for any surgical procedure.
9-Patient who underwent surgery for the fistula other than drainage or seton placement.
10-Patient with diverting stomas
11-Patient with ongoing steroid treatment or treated with steroids in the last 4 weeks.
12-Renal impairment defined by creatinine clearance below 60 ml/min calculated using Cockcroft-Gault formula or by serum creatinine ≥ 1.5 x upper limit of normality (ULN).
13-Hepatic impairment defined by both of the following laboratory ranges:
•Total bilirubin ≥ 1.5 x ULN
•AST and ALT ≥ 2.5 x ULN.
14-Known history of abuse of alcohol or other addictive substances in the 6 months prior to inclusion.
15-Malignant tumour or patients with a prior history of any malignant tumour, including any type of fistula carcinoma.
16-Current or recent history of abnormal, severe, progressive, uncontrolled hepatic, haematological, gastrointestinal (except CD), endocrine, pulmonary, cardiac, neurological, psychiatric, or cerebral disease.
17-Congenital or acquired immunodeficiencies.
18-Known allergies or hypersensivity to antibiotics including but not limited to penicillin, streptomycin, gentamicin, aminoglycosides; HSA (Human Serum Albumin); DMEM (Dulbecco Modified Eagle’s Medium); materials of bovin origin; local anaesthetics or gadolinium (MRI contrast).
19-Contraindication to MRI scan, (e.g., due to the presence of pacemakers, hip replacements or severe claustrophobia).
20-Major surgery or severe trauma within the previous 6 months.
21-Pregnant or breastfeeding women. 22-Patients who do not wish to or cannot comply with study procedures.
23-Patients currently receiving, or having received within 3 months prior to enrolment into this clinical study, any investigational drug.
24-Subjects who need surgery in the perianal region for reasons other than fistulas at the time of inclusion in the study, or for whom such surgery is foreseen in this region in the 24 weeks after treatment administration. 25-Contraindication to the anaesthetic procedure.

1-Presenza di malattia di Crohn luminale attiva dominante che richiede terapia immediata.
2-CDAI >220.
3-Fistole rettovaginali concomitanti. 4-Paziente naïve a trattamento specifico per la malattia di Crohn fistolizzante perianale, compresi gli antibiotici.
5-Presenza di ascesso o collezioni > di 2 cm, salvo risoluzione nella procedura di preparazione (dalla settimana -3 al giorno 0).
6-Presenza di più di 2 lesioni fistolari.
7-Presenza di più di 3 orifizi esterni.
8-Stenosi rettale e/o anale e/o proctite attiva, se questo rappresenta un limite per eventuale intervento chirurgico.
9-Pazienti che sono stati sottoposti a intervento chirurgico per la fistola diverso da drenaggio o posizionamento di setone.
10-Pazienti con stomi diverticolari. 11-Pazienti con trattamento a base di steroidi in corso o trattati con steroidi nelle ultime 4 settimane.
12-Insufficienza renale definita da clearance della creatinina inferiore a 60 ml/min calcolata utilizzando la formula Cockcroft-Gault o mediante creatinina sierica > 1,5 volte il limite superiore dell’intervallo di normalità (ULN).
13-Insufficienza epatica definita da entrambi i seguenti intervalli di laboratorio:
•Bilirubina totale ≥ 1,5 volte l’ULN.
•AST e ALT ≥ 2,5 volte l’ULN.
14-Storia nota di abuso di alcol o altre sostanze che danno dipendenza nei 6 mesi precedenti l’inclusione. 15-Tumore maligno o pazienti con una precedente anamnesi di tumore maligno, incluso qualsiasi tipo di carcinoma da fistola.
16-Anamnesi attuale o recente di disturbo anomalo, grave, progressivo, non controllato di tipo epatico, ematologico, gastrointestinale (tranne CD), endocrino, polmonare, cardiaco, neurologico, psichiatrico o cerebrale.
17-Immunodeficienze congenite o acquisite.
18-Allergie note o ipersensibilità agli antibiotici, comprese, tra l'altro, penicillina, streptomicina, gentamicina, aminoglicosidi; HSA (albumina di siero umana); DMEM (Mezzo di coltura di Dulbecco modificato); materiali di origine bovina; anestetici locali o gadolinio (contrasto per MRI).
19-Controindicazioni per la scansione della MRI (per esempio, per la presenza di pacemaker, protesi all’anca o grave claustrofobia).
20-Intervento chirurgico importante o grave trauma nei 6 mesi precedenti. 21-Donne in gravidanza o che allattano al seno.
22-Pazienti che non desiderano o non possono soddisfare le procedure dello studio.
23-Pazienti che attualmente ricevono o hanno ricevuto nei 3 mesi precedenti l’arruolamento nel presente studio clinico qualsiasi farmaco sperimentale.
24-Soggetti che necessitano di intervento chirurgico nella regione perianale per motivi diversi dalle fistole al momento dell’inclusione nello studio o per i quali tale intervento chirurgico è previsto in questa regione nelle 24 settimane successive alla somministrazione del trattamento.
25-Controindicazione all’anestesia.

E.5 End points

E.5.1

Primary end point(s)

Remission of perianal fistulising Crohn’s disease at week 24 confirmed by MRI, defined as the clinical assessment of closure of all the external openings that were draining at baseline despite gentle finger compression at week 24, confirmed by MRI as absence of collections > 2 cm of the treated perianal fistulas at 24 weeks (central blind assessment).

Remissione della malattia di Crohn fistolizzante perianale alla settimana 24 confermata da MRI, definita come la valutazione clinica della chiusura di tutti gli orifizi esterni che stavano drenando alla baseline malgrado lieve compressione con le dita alla settimana 24, confermata da MRI come assenza di collezioni > di 2 cm delle fistole perianali trattate alla settimana 24 (valutazione in cieco centrale).

E.5.1.1

Timepoint(s) of evaluation of this end point

24 weeks

24 settimane

E.5.2

Secondary end point(s)

Efficacy • Response, defined as closure of at least 50% of all external openings that were draining at baseline. • Time to remission, (first visit with closure of all external openings that were draining at baseline, as clinically assessed). • Time to response (first visit with closure of at least 50% of all external openings that were draining at baseline, as clinically assessed). • Severity of the perianal Crohn’s disease, assessed with the Perianal Disease Activity Index (PDAI). • Quality of Life (QoL) assessed by the Inflammatory Bowel Disease Questionnaire (IBDQ). Safety: • Adverse events • Physical examination • Vital signs • Laboratory tests (biochemistry, haematology, urinalysis) • CDAI score

Efficacia: • Risposta definita come chiusura di almeno il 50% di tutti gli orifizi esterni che stavano drenando alla baseline. • Tempo alla remissione (prima visita con chiusura di tutti gli orifizi esterni che stavano drenando alla baseline, secondo quanto valutato clinicamente). • Tempo alla risposta (prima visita con chiusura di almeno il 50% di tutti gli orifizi esterni che stavano drenando alla baseline, secondo quanto valutato clinicamente). • Gravità della malattia di Crohn perianale, valutata con l’indice di attività della malattia perianale (PDAI). • Qualità della vita (QoL) valutata dal questionario sulla qualità della vita di pazienti con malattie infiammatorie dell’intestino (IBDQ). Sicurezza: • Eventi avversi • Visita medica • Segni vitali • Esami di laboratorio (biochimica, ematologia, analisi delle urine) • Punteggio CDAI

E.5.2.1

Timepoint(s) of evaluation of this end point

At 6, 12, 18 and 24 weeks after the treatment.

A 6, 12, 18 e 24 settimane dal trattamento

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)

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)

Yes

E.7.4

Therapeutic use (Phase IV)

E.8 Design of the trial

E.8.1

Controlled

Yes

E.8.1.1

Randomised

Yes

E.8.1.2

Open

E.8.1.3

Single blind

E.8.1.4

Double blind

Yes

E.8.1.5

Parallel group

Yes

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

Yes

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

Yes

E.8.6.2

Trial being conducted completely outside of the EEA

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

Israel

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

Final study: Last visit of last subject undergoing the trial. If the study is prematurely terminated , the reasons may include: -severity of AE. -Enrollment is unsatisfactory. -Investigator does not adhere to Protocol or applicable regulatory guidelines in conducting the study - Ethical or medical reasons.

Fine dello studio: ultima visita dell'ultimo soggetto in sperimentazione. In caso di chiusura anticipata le motivazioni possono essere: -gravità degli AE -arruolamento insoddisfacente -mananza di adesione al Protocollo -motivi etici o medici

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

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)

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:

139

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.4.2

For a multinational trial

F.4.2.1

In the EEA

183

F.4.2.2

In the whole clinical trial

208

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)

Compasive use

Uso compassionevole

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

2012-09-13

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2012-02-21

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

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