Clinical Trials Register

Summary
EudraCT Number:	2021-003220-32
Sponsor's Protocol Code Number:	EpicStudy
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:	2021-10-22
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

2021-003220-32

A.3

Full title of the trial

Impact of early proactive therapeutic drug monitoring on the durability and efficacy of infliximab therapy in pediatric inflammatory bowel disease: a multicenter open-label randomized-control trial.

Impatto del monitoraggio terapeutico proattivo precoce sulla durata e l'efficacia della terapia con infliximab nelle malattie infiammatorie croniche intestinali pediatriche: uno studio multicentrico randomizzato-controllato in aperto

A.3.1

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

Modulation of infliximab therapy based on blood drug levels in pediatric inflammatory bowel disease.

Modulazione della terapia con infliximab in base ai livelli ematici di farmaco nelle malattie infiammatorie croniche intestinali pediatriche.

A.3.2

Name or abbreviated title of the trial where available

Proactive therapeutic drug monitoring of infliximab therapy

Monitoraggio terapeutico proattivo della terapia con infliximab

A.4.1

Sponsor's protocol code number

EpicStudy

A.5.4

Other Identifiers

Name:

EPIC study

Number:

5mille_CT2

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	IRCCS MATERNO INFANTILE BURLO GAROFOLO
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	IRCCS BURLO GAROFOLO
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	IRCCS Burlo Garofolo
B.5.2	Functional name of contact point	SCR Epidemiologia e Biostatistica
B.5.3	Address:
B.5.3.1	Street Address	VIA DELL`ISTRIA 65/1
B.5.3.2	Town/ city	Trieste
B.5.3.3	Post code	34137
B.5.3.4	Country	Italy
B.5.4	Telephone number	+390403785297
B.5.5	Fax number	+390403785411
B.5.6	E-mail	segreteria.irb@burlo.trieste.it

D. IMP Identification
D.IMP: 1
D.1.2 and D.1.3	IMP Role	Comparator
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.2.5	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	infliximab
D.3.2	Product code	[N.A.]
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INFLIXIMAB
D.3.9.2	Current sponsor code	infliximab
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	100
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)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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.IMP: 2
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.2.5	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	infliximab
D.3.2	Product code	[N.A.]
D.3.4	Pharmaceutical form	Powder for concentrate for solution for infusion
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Intravenous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	INFLIXIMAB
D.3.9.2	Current sponsor code	Infliximab
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	100
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)	No
D.3.11.3.1	Somatic cell therapy medicinal product	Information not present in EudraCT
D.3.11.3.2	Gene therapy medical product	Information not present in EudraCT
D.3.11.3.3	Tissue Engineered Product	Information not present in EudraCT
D.3.11.3.4	Combination ATIMP (i.e. one involving a medical device)	Information not present in EudraCT
D.3.11.3.5	Committee on Advanced therapies (CAT) has issued a classification for this product	Information not present in EudraCT
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

Pediatric Inflammatory Bowel Disease

Malattie infiammatorie croniche intestinali pediatriche

E.1.1.1

Medical condition in easily understood language

Pediatric Inflammatory Bowel Disease

Malattie infiammatorie croniche intestinali pediatriche

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	20.0
E.1.2	Level	LLT
E.1.2	Classification code	10021184
E.1.2	Term	IBD
E.1.2	System Organ Class	100000004856

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 evaluate the impact of a proactive therapeutic drug monitoring strategy introduced as early as the induction phase (E-pTDM) compared to the standard infliximab dosing schedule on infliximab durability and efficacy during the first year of treatment.

Valutare l'impatto del monitoraggio terapeutico proattivo introdotto nella fase di induzione (E-pTDM) rispetto allo schema di dosaggio standard dell'infliximab sulla durata e sull'efficacia della terapia durante il primo anno di trattamento.

E.2.2

Secondary objectives of the trial

1- To evaluate the efficacy of E-pTDM in reducing the frequency of subtherapeutic IFX concentrations,
2- To evaluate the efficacy of E-pTDM on endoscopic healing at 54 week
3- To evaluate the efficacy of E-pTDM on clinical remission at week 14,
4- To evaluate the efficacy of E-pTDM on clinical and biochemical remission at week 14
5- To evaluate the efficacy of E-pTDM in reducing the frequency of ATI,
6- To evaluate the efficacy of E-pTDM in reducing the frequency of infusion reactions,

Additional objective
- To improve the current knowledge on biomarkers predictive of anti-TNF response and failure.

Valutare l'impatto dell'E-pTDM rispetto al dosaggio standard di infliximab su:
1- concentrazioni ematiche del farmaco
2- la remissione mucosale a 54 settimane.
3- la remissione clinical di malattia a 14 settimane
4-la remissione clinica a biochimica a 14 settimane
5- la frequenza di sviluppo di anticorpi anti-farmaco (ATI)
6- la frequenza di reazioni infusionali al farmaco durante il primo anno di trattamento

Obiettivo aggiuntivo è migliorare le nostre conoscenze sui predittori di risposta alla terapia con infliximab.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Inclusion criteria are:
1. Anti-TNF naïve children and adolescents, 6-17 years, with a diagnosis of IBD confirmed by a prior endoscopic biopsy that is consistent with the diagnosis
2. Indication to start anti-TNF therapy in accordance with current guidelines for the treatment of pediatric IBD,
3. Active inflammation supported by CRP > 5mg/L and /or FC > 150 µg/g before the 1st IFX dose

1. Bambini e adolescenti di età compresa tra i 6 e i 17 anni, naïve agli anti-TNF con una diagnosi confermata endoscopicamente di IBD.
2. Indicazione di iniziare la terapia con infliximab secondo le attuali linee guida per il trattamento delle IBD pediatriche.
3. Infiammazione attiva supportata da PCR> 5mg/L e/o calprotectina fecale > 150 µg/g prima della prima dose di infliximab

E.4

Principal exclusion criteria

1. Consent withdrawal,
2. Stenosing or penetrating disease requiring surgery, abdominal abscess, symptomatic stricture,
3. Abdominal surgery within the previous 6 months,
4. Acute severe UC attack defined by a PUCAI score > 65,
5. Infective contraindication to IFX treatment including positive tuberculin skin test or Quantiferon-TB test, recent opportunistic infection, infection with hepatitis B (HBV), C (HCV), human immunodeficiency virus (HIV),
6. Previous exposure to anti-TNF;
7. Exposure to concomitant prohibited medications including other biologics (including but not limited to ustekinumab, vedolizumab, abatacept, anakinra..), thalidomide, investigational drugs
8. Pregnancy or lactation

1. Ritiro del consenso
2. Malattia stenosante o penetrante che richiede un intervento chirurgico, ascesso addominale, stenosi sintomatica,
3. Chirurgia addominale nei 6 mesi precedenti,
4. Attacco acuto severo di colite definito da PUCAI score > 65
5. Controindicazione infettiva al trattamento con infliximab (IFX) (test cutaneo positivo alla tubercolina o quantiferon, infezione opportunistica recente, infezione da epatite B, C, virus dell'immunodeficienza),
6. Precedente esposizione agli anti-TNF,
7. Esposizione a terapie proibite dal protocollo incluso altri biologici (es. ustekinumab, vedolizumab, abatacept, anakinra..), talidomide, terapia sperimentali.
8. Gravidanza o allattamento

E.5 End points

E.5.1

Primary end point(s)

The primary composite endpoint is the frequency of IFX discontinuation or need for treatment intensification due to non-response or loss of response during the first year of treatment.

L'outcome composito sarà la frequenza di interruzione della terapia con infliximab o la necessità di intensificazione del trattamento per non risposta o perdita di risposta durante il primo anno di trattamento.

E.5.1.1

Timepoint(s) of evaluation of this end point

54 weeks

54 settimane

E.5.2

Secondary end point(s)

1. The cumulative probability of IFX discontinuation
2. The cumulative probability of LOR
3. Subtherapeutic IFX concentrations,
4. Occurrence of ATI
5. Occurrence of infusion reactions
6. Endoscopic remission at 54 weeks
7. Treatment response at the end of induction between 12-14 weeks
8. Clinical remission at week 14
9. Clinical and biochemical remission at week 14

Exploratory endpoints
Single Nucleotide Polimorfism (SNPs) from peripheral blood, DNA methylation and transcription profiling from IECs, will be analyzed to identify genetic and epigenetic patterns that predict response or failure to IFX.

1. probabilità cumulativa di interruzione di infliximab
2. probabilità cumulativa di ricaduta di malattia,
3. la frequenza di concentrazioni subterapeutiche di infliximab,
4. la frequenza di anticorpi anti-infliximab (ATI)
5. la frequenza di reazioni infusionali al farmaco durante il primo anno di trattamento
6. la frequenza di remissione mucosale a 54 settimane.
7. frequenza di risposta alla terapia al termine dell'induzione tra le 12 e le 14 settimane.
8. Remissione clinica a 14 settimane
9. Remissione clinica e biochimica a 14 settimane

Endpoint esplorativi
In un sottogruppo di pazienti saranno determinati i polimorfismi dei singoli nucleotidi su DNA da sangue periferico, lo stato di metilazione del DNA e il profilo di espressione genica dalle cellule epiteliali intestinali prima del trattamento con infliximab e alla 54 settimana e saranno confrontati tra i pazienti che rispondono e non rispondono alla terapia con infliximab.

E.5.2.1

Timepoint(s) of evaluation of this end point

54 weeks

54a settimana

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

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

E.8.2

Comparator of controlled trial

E.8.2.1

Other medicinal product(s)

Yes

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

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)

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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2021-10-22.

Yes

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

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)

Continuation of therapy as per common clinical practice

Prosecuzione della terapia come da comune pratica clinica

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

2022-01-18

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-11-23

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

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