Clinical Trials Register

Summary
EudraCT Number:	2012-001653-13
Sponsor's Protocol Code Number:	FARM97BHH4
National Competent Authority:	Italy - Italian Medicines Agency
Clinical Trial Type:	EEA CTA
Trial Status:	Ongoing
Date on which this record was first entered in the EudraCT database:	2013-03-27
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

Italy - Italian Medicines Agency

A.2

EudraCT number

2012-001653-13

A.3

Full title of the trial

New Therapeutic Options for the Maintenance of Remission of the Ulcerative Colitis in Pediatric
Patients

Mantenimento della remissione nella rettocolite ulcerosa in età pediatrica: nuove strategie terapeutiche

A.3.1

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

New Therapeutic Strategy in Ulcerative Colitis

Nuove strategie terapeutiche nella rettocolite ulcerosa

A.4.1

Sponsor's protocol code number

FARM97BHH4

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	Dipartimento di Pediatria Università Federico II di Napoli
B.1.3.4	Country	Italy
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	AIFA (bandi per la ricerca indipendente)
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	Università di Napoli "Federico II
B.5.2	Functional name of contact point	Dipartimento di Scienze Mediche Tra
B.5.3	Address:
B.5.3.1	Street Address	Via S. Pansini, 5
B.5.3.2	Town/ city	NAPOLI
B.5.3.3	Post code	80131
B.5.3.4	Country	Italy
B.5.4	Telephone number	00390817462679
B.5.5	Fax number	00390815451278
B.5.6	E-mail	staiano@unina.it

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	AZAFOR 50mg
D.2.1.1.2	Name of the Marketing Authorisation holder	SOFAR SpA- Via Firenze, 40 - 20060 Trezzano Rosa (MI)
D.2.1.2	Country which granted the Marketing Authorisation	Italy
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	AZATIOPRINA
D.3.2	Product code	AZA
D.3.4	Pharmaceutical form	Tablet
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Oral use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	AZATHIOPRINE
D.3.9.1	CAS number	446-86-6
D.3.9.2	Current sponsor code	AZA
D.3.9.3	Other descriptive name	AZATHIOPRINE
D.3.9.4	EV Substance Code	SUB05647MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg milligram(s)
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	50
D.3.11 The IMP contains an:
D.3.11.1	Active substance of chemical origin	Yes
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)	No
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	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	Tablet
D.8.4	Route of administration of the placebo	Oral use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Ulcerative Colitis

Rettocolite Ulcerosa

E.1.1.1

Medical condition in easily understood language

Ulcerative Colitis

Rettocolite Ulcerosa

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	15.1
E.1.2	Level	LLT
E.1.2	Classification code	10045365
E.1.2	Term	Ulcerative colitis
E.1.2	System Organ Class	100000004856

E.1.3

Condition being studied is a rare disease

E.2 Objective of the trial

E.2.1

Main objective of the trial

The primary objective is to determine whether the addition of azathioprine to a standard therapeutic regimen (mesalazine and steroid association) improves disease remission rates in children affected by newly diagnosed moderate-to-severe Ulcerative Colitis, during the first eighteen months of treatment.

L'obbiettivo principale è di determinare se l’aggiunta di azatioprina ad un regime terapeutico standard (mesalazina e steroidi associazione) migliora il mantenimento della remissione dalla malattia nei bambini affetti da nuova diagnosi di RU moderato-grave, durante i primi 18 mesi di trattamento.

E.2.2

Secondary objectives of the trial

1)To assess the efficacy of the azathioprine, mesalazine and steroid association versus the steroid and mesalazine standard therapy on the induction of remission, on the maintenance of remission at eighteen months of follow-up.
2) To compare time to steroid independence in each of the study groups, as defined in the paragraph Intervention.
3) To evaluate and compare the quality of the life with the two therapeutic strategies.
4) To assess the safety and tolerability of the azathioprine, mesalazine and steroid association in children.

1) Valutare l'efficacia dell’associazione azatioprina, mesalazina, steroidi rispetto alla terapia standard a base di steroidi e mesalazina sull'induzione di remissione.
2) Confrontare il tempo di indipendenza dalla terapia steroidea in ciascuno dei gruppi in studio.
3) Valutare e confrontare la qualità di vita con le due diverse strategie terapeutiche.
4) Valutare la sicurezza e la tollerabilità dell’associazione azatioprina, mesalazina e steroidi in pazienti di età pediatrica

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

1. Children 2-17 years of age.
2. New diagnosis of UC, established by the presence of accepted clinical, radiologic, endoscopic and histological criteria.
3. Moderate to severe disease activity at the time of enrolment as judged by a Pediatric UC Activity Index (PUCAI) score ≥ 35 points.
4. In general good health (other than the diagnosis of UC), based on medical history, physical examination, and screening laboratory results.
5. Ability and acceptance to participate in the study and follow study procedures, as evidenced by a
parent/legal guardian signing a written informed consent and the child providing assent.

1. Bambini di età compresa tra 2 e 17 anni
2. Nuova diagnosi di RU, stabilita dalla presenza dei criteri clinici, radiologici, endoscopici e istologici attualmente accettati.
3. Attività della malattia da moderata a grave definita dalla presenza di un PUCAI ≥35 punti.
4. In buona salute generale (diversamente dalla diagnosi di RU), sulla base della storia clinica, dell’esame fisico, e dagli screening dei risultati di laboratorio effettuati.
5. Capacità e accettazione a partecipare allo studio e di seguire le procedure dello studio, come evidenziato dalla firma di un consenso informato scritto da parte di un genitore / custode legale e dall’assenso del bambino stesso.

E.4

Principal exclusion criteria

1. Inability or unwillingness to give informed consent.
2. Weight <12 kg at enrolment.
3. Patients with Crohn’s colitis or with Indeterminate Colitis.
4. Infectious colitis identified by stool cultures, ova and parasite examination and Clostridium difficile assay.
5. Patients in relapse or who have received other therapies inducing remission.
6. Conditions that contraindicate the use of steroids and / or immunosuppressive.
7. Patients carrying alleles associated with no detectable thiopurine methyltransferase (TPMT) activity.
8. Pregnancy. All female patients of childbearing potential will undergo urine pregnancy testing at screening, must not be lactating, and willing to use acceptable contraception if sexually active.
9. Existence of current renal disease, or a screening blood urea nitrogen (BUN) or creatinine value that is > 1.5 times the upper limit of the age appropriate normal.
10. Existence of current hepatic disease, or ALT, AST, Bilirubin > 2 times the upper limit of normal, or the existence of Primary Sclerosing Cholangitis (PSC).
11. History of recurrent pancreatitis.

1. Incapacità o non volontà a dare un consenso informato.
2. Peso <12 kg al momento dell'arruolamento.
3. I pazienti affetti da colite da Malattia di Crohn o con Colite Indeterminata
4. Colite infettiva identificata da colture fecali, esame parassitologico e test per la presenza delle tossine A e B del Clostridium difficile.
5. Pazienti in ricaduta o che abbiano già ricevuto altre terapie per indurre la remissione.
6. Condizioni che controindicano l'uso di steroidi e / o immunosoppressori.
7. Pazienti portatori di alleli associati ad attività non rilevabile dell’enzima tiopurina metiltransferasi (TPMT).
8. Gravidanza. Tutte le pazienti di sesso femminile in età fertile saranno sottoposte a test delle urine di screening per la gravidanza. In caso di positività saranno escluse dallo studio.
9. Presenza di malattia renale concomitante, o azoto ureico (BUN) o valori della creatinina > 1,5 volte il limite superiore del normale correlato per età.
10. Esistenza di malattia epatica concomitate, o ALT, AST, Bilirubina> 2 volte il limite superiore della norma, o coesistenza di colangite sclerosante primitiva (PSC).
11. Storia di pancreatite ricorrente.

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients who is in clinical remission at eighteen months. Clinical remission will be defined on the basis of a PUCAI score ≤10, without any clinical relapse or treatment failures during the first eighteen months. Clinical relapse will be defined as the occurrence or worsening of symptoms, accompanied by an increase of PUCAI >10 points, sufficient to require rescue treatment with IV corticosteroids, other immunosuppressive agents, as IV cyclosporine, anti-TNF ; or surgery. The following events will also be considered as treatment failures:
• Subject experiences a serious adverse event
• Patient fails to comply with this study protocol
• WBC < 3000 cells/mm3
• ALT > 10-fold greater than normal value
• Pregnancy

Percentuale di pazienti che è in remissione clinica a diciotto mesi. La remissione clinica sarà definita sulla base di un PUCAI ≤10, senza alcuna ricaduta clinica o fallimenti terapeutici durante i primi diciotto mesi. La recidiva clinica viene definita come il verificarsi o peggioramento dei sintomi, accompagnata da un aumento di PUCAI> 10 punti, sufficiente per richiedere il trattamento di salvataggio con corticosteroidi EV, altri immunosoppressori, come ciclosporina EV, anti-TNF, o intervento chirurgico. I seguenti eventi saranno considerati come fallimenti terapeutici:
• si verifica un evento avverso grave
• il paziente non riesce a conformarsi al presente protocollo di studio
• WBC <3000 cellule/mm3
• ALT> 10 volte superiore al valore normale
• Gravidanza

E.5.1.1

Timepoint(s) of evaluation of this end point

During the first eighteen months

Durante i primi 18 mesi

E.5.2

Secondary end point(s)

1) Reduction in total oral CS usage
2) Mean change in PUCAI score during follow up
3)Time to achieve first remission (PUCAI<10) comparing the two groups
4) Incidence of adverse events
5) Compliance between groups judged by returning of packages and self reporting
6) Percentage of relapses and treatment failures comparing the two groups
7) Mean change in IMPACT III score at 3, 6, 9, 12 months

1) Riduzione del consumo totale orale di corticosteroidi
2) Variazione media del punteggio PUCAI durante il follow up
3) Tempo di raggiungimento della prima remissione prima (PUCAI <10)
4) Incidenza di eventi avversi
5) Compliance tra i gruppi giudicata tramite il ritorno di pacchetti dei medicinali e tramite “self-reporting” dei pazienti
6) Percentuale di ricadute e fallimenti di trattamento tra i due gruppi
7) Variazione media del punteggio IMPACT III a 3, 6, 9, 12 mesi

E.5.2.1

Timepoint(s) of evaluation of this end point

1) Reduction in total oral CS usage: from 0 to 4 weeks and from 4 to 12 weeks
2) Mean change in PUCAI score during follow up: During the first eighteen months
3)Time to achieve first remission (PUCAI<10) comparing the two groups: During the first eighteen months
4) Incidence of adverse events: During the first eighteen months
5) Compliance between groups judged by returning of packages and self reporting: During the first eighteen months
6) Percentage of relapses and treatment failures comparing the two groups: During the first eighteen months
7) Mean change in IMPACT III score at 3, 6, 9, 12 months

1) Riduzione del consumo totale orale di corticosteroidi: dalla 0 alla 4 settimana e dalla 4 alla 12 settimana
2) Variazione media del punteggio PUCAI durante il follow up: durante tutti i18 mesi
3) Tempo di raggiungimento della prima remissione prima (PUCAI <10): durante tutti i 18 mesi
4) Incidenza di eventi avversi: durante tutti i18 mesi
5) Compliance tra i gruppi giudicata tramite il ritorno di pacchetti dei medicinali e tramite “self-reporting” dei pazienti: durante tutti i 18 mesi
6) Percentuale di ricadute e fallimenti di trattamento tra i due gruppi: durante tutti i 18 mesi
7) Variazione media del punteggio IMPACT III a 3, 6, 9, 12 mesi

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

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

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

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

Number of subjects for this age range:

130

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)

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

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

Children (2-11years) and Adolescents (12-17 years)

Soggetti tra i 2 e i 17 anni

F.3.3.7

Others

F.4 Planned number of subjects to be included

F.4.1

In the member state

130

F.4.2

For a multinational trial

F.4.2.1

In the EEA

130

F.4.2.2

In the whole clinical trial

130

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)

Plans for treatment of care after the subject has ended participation
are not different from the expected normal treatment for this condition

Come da trattamento previsto dalla pratica clinica per la patologia oggetto della speriementazione.

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

2013-05-17

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2013-07-10

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

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