Clinical Trials Register

Summary
EudraCT Number:	2015-001410-10
Sponsor's Protocol Code Number:	GIS-SUSANTI-TNF-2015
National Competent Authority:	Spain - AEMPS
Clinical Trial Type:	EEA CTA
Trial Status:	Completed
Date on which this record was first entered in the EudraCT database:	2016-05-17
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

Spain - AEMPS

A.2

EudraCT number

2015-001410-10

A.3

Full title of the trial

Anti-TNF discontinuation in patients with inflammatory bowel disease: Multicentre, prospective, randomized clinical trial and economic evaluation

SUSPENSIÓN DEL TRATAMIENTO ANTI-TNF EN PACIENTES CON
ENFERMEDAD INFLAMATORIA INTESTINAL:
ENSAYO CLÍNICO MULTICÉNTRICO, PROSPECTIVO Y
ALEATORIZADO

A.3.1

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

Anti-TNF discontinuation in patients with inflammatory bowel disease

Suspensión del tratamiento anti-TNF en pacientes con enfermedad inflamatoria intestinal

A.3.2

Name or abbreviated title of the trial where available

EXIT

A.4.1

Sponsor's protocol code number

GIS-SUSANTI-TNF-2015

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	Fundación de Investigación Biomédica Hospital Universitario de la Princesa
B.1.3.4	Country	Spain
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	Instituto de Salud Carlos III
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	Fundación de Investigación Biomédica Hospital Universitario de la Princesa
B.5.2	Functional name of contact point	Eva Rodríguez
B.5.3	Address:
B.5.3.1	Street Address	Diego de León 62, 1ª planta
B.5.3.2	Town/ city	Madrid
B.5.3.3	Post code	28006
B.5.3.4	Country	Spain
B.5.4	Telephone number	915202540
B.5.5	Fax number	915202425
B.5.6	E-mail	secretariacientifica1@geteccu.org

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.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	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.3.9.1	CAS number	170277-31-3
D.3.9.4	EV Substance Code	SUB02681MIG
D.3.10	Strength
D.3.10.1	Concentration unit	mg/kg milligram(s)/kilogram
D.3.10.2	Concentration type	equal
D.3.10.3	Concentration number	5
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	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.IMP: 2
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.2.1.2	Country which granted the Marketing Authorisation	Spain
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.3.4	Pharmaceutical form	Injection
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
D.3.8 to D.3.10 IMP Identification Details (Active Substances)
D.3.8	INN - Proposed INN	ADALIMUMAB
D.3.9.1	CAS number	331731-18-1
D.3.9.4	EV Substance Code	SUB20016
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	40
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	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	Infusion
D.8.4	Route of administration of the placebo	Intravenous use
D.8 Placebo: 2
D.8.1	Is a Placebo used in this Trial?	Yes
D.8.3	Pharmaceutical form of the placebo	Injection
D.8.4	Route of administration of the placebo	Subcutaneous use

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Inflammatory bowel disease

Enfermedad inflamatoria intestinal

E.1.1.1

Medical condition in easily understood language

Crohn disease and ulcerative colitis

Enfermedad de Crohn y colitis 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	19.0
E.1.2	Level	LLT
E.1.2	Classification code	10021973
E.1.2	Term	Inflammatory bowel disease NOS
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

To assess the percentage of patients with IBD who, after stopping anti-TNF treatment, have sustained clinical remission at one year compared to those in which the treatment is continued at stable doses

Evaluar el porcentaje de pacientes con EII que, tras suspender el tratamiento anti-TNF,
presentan remisión clínica sostenida al año de seguimiento, en comparación con aquéllos
en los que se continúa el tratamiento a dosis estables

E.2.2

Secondary objectives of the trial

To compare treatment discontinuation vs. treatment continuation of anti-TNF agents in patients with Crohn?s disease or ulcerative colitis in terms of:
a) remission (relapse-free) time,
b) phenotype changes with both strategies
c) mucosal healing,
d) radiologic healing
e) impact on quality of life and productivity
f) safety
g) to identify relapse predictive factors.
h) To identify relapse predictive factors after anti-TNF drug discontinuation
i) Determining the profile of serum cytokines in patients with both strategies, depending on drug exposure and if maintained clinical remission or relapse.

Evaluar el tiempo libre de recidiva con ambas estrategias (suspensión o mantenimiento del tratamiento anti-TNF).
- Evaluar los cambios de fenotipo con ambas estrategias.
- Evaluar la curación mucosa (endoscópica) con ambas estrategias.
- Evaluar la curación radiológica con ambas estrategias.
- Identificar factores predictores de recidiva tras la suspensión del tratamiento anti-TNF.
- Comparar el impacto sobre la calidad de vida y la productividad laboral de los pacientes con ambas estrategias.
- Comparar la seguridad de ambas estrategias.
- Determinar el perfil de citocinas séricas en los pacientes con ambas estrategias, en función de la exposición al fármaco y de si mantienen la remisión clínica o si recidivan.

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

?Patients diagnosed with IBD (Crohn's disease or ulcerative colitis)
? Patients diagnosed with IBD by the usual criteria; both Crohn's and ulcerative colitis disease.
? Patients older than 18 years.
? Have received treatment with an anti-TNF drug to induce clinical remission of IBD by clinical practice.
? Being the first anti-TNF drug received and the first course of the drug.
? In the case of patients with Crohn's disease the indication treatment with anti-TNF it must have been for luminal involvement (no perianal).
? Are currently in clinical remission.
? The pretreatment period with anti-TNF must have been at least 1 year (and with stable doses during the last year).
? The clinical remission period it must have been at least 6 months.
? At the time of inclusion, the patient should be receiving concomitant immunosuppressants (thiopurine or methotrexate) to anti-TNF treatment, and must have received these immunosuppressive drugs at stable doses for at least the last 3 months.
? In patients with Crohn's disease or ulcerative colitis disease, at baseline colonoscopy (made up to 30 days before inclusion) should not be "significant" injuries.
? In the case of patients with Crohn's ileal or ileocolic disease, in magnetic resonance whole should not be "significant" injuries.

?Pacientes diagnosticados de EII por los criterios habituales; tanto con enfermedad de Crohn como colitis ulcerosa.
?Pacientes mayores de 18 años.
?Haber recibido tratamiento con un fármaco anti-TNF para inducir la remisión clínica de la EII por práctica clínica.
?Ser el primer fármaco anti-TNF que recibe y el primer curso de dicho fármaco.
?En el caso de pacientes con enfermedad de Crohn, la indicación del tratamiento con anti-TNF debe haber sido por afectación luminal (no perianal).
?Estar actualmente en remisión clínica.
?El período de tratamiento previo con el anti-TNF debe haber sido de al menos 1 año (y con dosis estable durante el último año).
?El período de remisión clínica debe haber sido de al menos 6 meses.
?En el momento de la inclusión, el paciente deberá estar recibiendo tratamiento concomitante con inmunosupresores (tiopurínicos o metotrexato) al tratamiento anti-TNF, y deberá haber recibido estos fármacos inmunosupresores a dosis estables durante al menos los últimos 3 meses.
?En los pacientes con enfermedad de Crohn o colitis ulcerosa, en la colonoscopia basal (realizada un máximo de 30 días antes de la inclusión) no deberán existir lesiones "significativas".
?En el caso de pacientes con enfermedad de Crohn ileal o ileocólica, en la entero-resonancia magnética no deberán existir lesiones "significativas".

E.4

Principal exclusion criteria

? Age less than 18 years.
? Patients who have been treated with anti-TNF for other indication than the IBD.
? Patients who, at some point, have received an anti-TNF drug dose higher than the standard, intensified; that is, more than 5 mg / kg / 8 weeks, in the case of infliximab, or 40 mg / 2 weeks, in the case of adalimumab.
? Patients with Crohn's disease in which the indication for treatment with anti-TNF has been the perianal involvement (or luminal and perianal both); or showing active perianal disease at the time of inclusion.
? Patients who have previously discontinued treatment with anti-TNF and subsequently been restarted.
? Patients who have previously received it another anti-TNF drug.
? Patients with IBD who began treatment with anti-TNF being in clinical remission.
? Patients who are not receiving concomitant treatment with immunosuppressants (thiopurine or methotrexate) at the moment (and in the previous 3 months).
? Patients undergoing bowel resection surgery; therefore, patients who began anti-TNF therapy to prevent or treat postoperative recurrence in Crohn's disease will be excluded.
? Presence of "significant" endoscopic or radiological lesions
? Advanced chronic illness or any other condition that prevents the patient from coming to the clinic for monitoring or follow-up.
? Patients who are pregnant, breastfeeding or intending to become pregnant during the course of the study.
? Refusal to give consent for participation in the study.

?Edad inferior a 18 años.
?Pacientes que hayan recibido tratamiento con anti-TNF por otra indicación distinta a la EII.
?Pacientes que, en algún momento, hayan recibido una dosis de fármaco anti-TNF superior a la estándar, es decir, intensificada; esto es, más de 5 mg/kg/8 semanas, en el caso de infliximab, ó más 40 mg/2 semanas, en el caso de adalimumab.
?Pacientes con enfermedad de Crohn en los que la indicación del tratamiento con anti-TNF haya sido la afectación perianal (o luminal y perianal, ambas); o que presenten enfermedad perianal activa en el momento de la inclusión.
?Pacientes que hayan suspendido previamente el anti-TNF y posteriormente lo hayan reiniciado.
?Pacientes que hayan recibido otro fármaco anti-TNF previamente.
?Pacientes con EII que hayan iniciado el tratamiento con anti-TNF estando en remisión clínica.
?Pacientes que no estén recibiendo tratamiento concomitante con inmunosupresores (tiopurínicos o metotrexato) en el momento actual (y en los 3 meses previos).
?Pacientes sometidos a una cirugía de resección intestinal; por tanto, se excluirán los pacientes que hayan iniciado tratamiento anti-TNF para prevenir o tratar la recurrencia postquirúrgica en la enfermedad de Crohn.
?Presencia de lesiones endoscópicas o radiológicas "significativas".
?Enfermedad crónica avanzada o cualquier otra patología que impida acudir a controles y seguimiento.
?Pacientes embarazadas, lactantes o que pretendan quedarse embarazadas durante el desarrollo del estudio.
?Negativa a dar el consentimiento para la participación en el estudio.

E.5 End points

E.5.1

Primary end point(s)

Sustained clinical remission after one year of follow-up (after
discontinuing or continuing treatment with anti-TNF).

Remisión clínica sostenida un año tras la suspensión o el
mantenimiento del tratamiento con anti-TNF

E.5.1.1

Timepoint(s) of evaluation of this end point

12 Months

Mes 12

E.5.2

Secondary end point(s)

* Clinical activity assessment
* Endoscopic activity assessment
* Radiologic activity assessment
* Quality of life assessment
* Work productivity and activity assessment

* Valoración de la actividad clínica
* Valoración de la actividad endoscópica
* Valoración de la actividad radiológica
* Valoración de la calidad de vida
* Valoración de la productividad y actividad laboral

E.5.2.1

Timepoint(s) of evaluation of this end point

* Clinical activity assessment - Month 0, month 1, month 2, month 4, month 6, month 8, month 10, month 12
* Endoscopic activity assessment - Month 0, month 12 or relapse
* Radiologic activity assessment - Month 0, month 12 or relapse
* Quality of life assessment - Month 0, month 1, month 2, month 4, month 6, month 8, month 10, month 12
* Work productivity and activity assessment - Month 0, month 1, month 2, month 4, month 6, month 8, month 10, month 12

* Valoración de la actividad clínica - Mes 0, mes 1, mes 2, mes 4, mes 6, mes 8, mes 10, mes 12
* Valoración de la actividad endoscópica - Mes 0, Mes 12 o recidiva
* Valoración de la actividad radiológica - Mes 0, mes 12 o recidiva
* Valoración de la calidad de vida - Mes 0, mes 1, mes 2, mes 4, mes 6, mes 8, mes 10, mes 12
* Valoración de la productividad y actividad laboral - Mes 0, mes 1, mes 2, mes 4, mes 6, mes 8, mes 10, mes 12

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)

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)

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

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

ultima visita del ultimo 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

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.1.1.1

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:

250

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

300

F.4.2

For a multinational trial

F.4.2.2

In the whole clinical trial

300

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)

If clinical relapse after randomization have been made, or at the end of the monitoring period, the attending physician will take a medical or therapeutic action that it deems to be most appropriate

En caso de recidiva clínica tras haberse realizado la aleatorización, o al finalizar el período de seguimiento, el médico
responsable tomará la acción clínica o terapéutica que a su juicio considere más adecuada

G. Investigator Networks to be involved in the Trial
G.4 Investigator Network to be involved in the Trial: 1

N. Review by the Competent Authority or Ethics Committee in the country concerned

Competent Authority Decision

Authorised

Date of Competent Authority Decision

2016-06-22

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2016-06-15

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

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