Clinical Trials Register

Summary
EudraCT Number:	2021-000469-33
Sponsor's Protocol Code Number:	NL.76663.018.21
National Competent Authority:	Netherlands - Competent Authority
Clinical Trial Type:	EEA CTA
Trial Status:	Trial now transitioned
Date on which this record was first entered in the EudraCT database:	2021-03-25
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

Netherlands - Competent Authority

A.2

EudraCT number

2021-000469-33

A.3

Full title of the trial

A Prospective Multicenter Randomized Controlled, Open-label Study to Compare the Efficacy of Subcutaneous Infliximab Monotherapy with Subcutaneous Infliximab and Concomitant Immunosuppression in the Treatment of Moderate to Severe Crohn’s Disease.

Een prospectief Multi centrum Randomisatie Gecontroleerd, Open-label Onderzoek ter vergelijking van de Effectiviteit van Subcutane Infliximab Monotherapy en Subcutane Infliximab met Concomitant Immunosuppressiva in de Behandeling van Milde tot Ernstige Ziekte van Crohn.

A.3.1

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

Scientific medical research comparing the effectiveness of Infliximab by injection in the abdominal tissiue (subcutaneous) monotherapy and infliximab subcutaneous injection with anti-inflammatory drugs in the treatment of moderate to severe chronic inflammatory bowel disease.

Wetenschappelijk medisch onderzoek in de vergelijking van de werkzaamheid van Infliximab via een injectie in de buikplooi (subcutaan) monotherapie en infliximab subcutane injectie met afweer remmende medicatie in de behandeling van matige tot ernstige chronisch darm ontstekingen.

A.3.2

Name or abbreviated title of the trial where available

DIRECT CD

A.4.1

Sponsor's protocol code number

NL.76663.018.21

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	Amsterdam UMC location AMC
B.1.3.4	Country	Netherlands
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	Celltrion Healthcare Netherlands B.V.
B.4.2	Country	Korea, Republic of
B.5 Contact point designated by the sponsor for further information on the trial
B.5.1	Name of organisation	Amsterdam UMC location AMC
B.5.2	Functional name of contact point	Krisztina Gecse
B.5.3	Address:
B.5.3.1	Street Address	Meibergdreef 9
B.5.3.2	Town/ city	Amsterdam
B.5.3.3	Post code	1105AZ
B.5.3.4	Country	Netherlands
B.5.4	Telephone number	+310205664401
B.5.6	E-mail	k.b.gecse@amsterdamumc.nl

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	Remsima
D.2.1.1.2	Name of the Marketing Authorisation holder	Celltrion Healthcare Hungary Kft.
D.2.1.2	Country which granted the Marketing Authorisation	European Union
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	Remsima
D.3.2	Product code	EMEA/H/C/002576
D.3.4	Pharmaceutical form	Solution for infusion in pre-filled syringe
D.3.4.1	Specific paediatric formulation	No
D.3.7	Routes of administration for this IMP	Subcutaneous use
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	Yes
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.2.1.1.1	Trade name	Puri Nethol
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Puri Nethol
D.3.2	Product code	RVG00859
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.3.11 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.IMP: 3
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	Imuran
D.2.1.1.2	Name of the Marketing Authorisation holder	Aspen
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Imuran
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.3.11 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.IMP: 4
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	Thiosix
D.2.1.1.2	Name of the Marketing Authorisation holder	Teva
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Thiosix
D.3.2	Product code	RVG 114681
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.3.11 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.IMP: 5
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	Ebetrex 15 mg = 0,75 ml, oplossing voor injectie in voorgevulde injectiespuit 20 mg/ml
D.2.1.1.2	Name of the Marketing Authorisation holder	Sandoz
D.2.1.2	Country which granted the Marketing Authorisation	Netherlands
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	Ebetrex
D.3.2	Product code	RVG 116648
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.3.11 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

E. General Information on the Trial

E.1 Medical condition or disease under investigation

E.1.1

Medical condition(s) being investigated

Crohns disease

Ziekte van Crohn

E.1.1.1

Medical condition in easily understood language

Moderate to severe chronic inflammatory bowel disease

Matige tot ernstige chronisch darm ontstekingen

E.1.1.2

Therapeutic area

Body processes [G] - Biological Phenomena [G16]

MedDRA Classification

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 aim of this study is to investigate the efficacy of subcutaneous IFX in the treatment of moderate to severe Crohn’s disease with and without concomitant immunosuppression, as measured by the proportion of patients in corticosteroid-free clinical remisison (as defined by a CDAI<150) and endoscopic response (as defined by a SES-CD drop of at least 50%) at week 26. We hypothesize that subcutaneous IFX monotherapy is non-inferior to subcutaneous IFX with concomitant immunosuppression in inducing this combined primary endpoint of CSF clinical remission and endoscopic response by week 26.

Het doel van deze studie is om de werkzaamheid van subcutane IFX te onderzoeken bij de behandeling van matige tot ernstige ziekte van Crohn met en zonder gelijktijdige immunosuppressie, gemeten aan de hand van het aantal patiënten met corticosteroïdvrije klinische remisison (zoals gedefinieerd door een CDAI <150). en endoscopische respons (zoals gedefinieerd door een SES-CD-daling van ten minste 50%) in week 26. We veronderstellen dat subcutane IFX-monotherapie niet inferieur is aan subcutane IFX met gelijktijdige immunosuppressie bij het induceren van dit gecombineerde primaire eindpunt van klinische remissie van liquor en endoscopisch reactie in week 26.

E.2.2

Secondary objectives of the trial

E.2.3

Trial contains a sub-study

E.3

Principal inclusion criteria

Patients 18 years or older diagnosed with Crohn’s disease

Patients with moderate to severely active Crohn’s disease with a Crohn’s Disease Activity Index (CDAI) of 220 to 450 and presence of endoscopic ulceration in the terminal ileum, colon or both. Minimal SES-CD is ≥ 6 or ≥ 4 for isolated ileal disease.

Patients who had no response or loss of response to or have had intolerable side effects to one or more to the following: glucocorticoids, thiopurines (azathioprine/6-mercaptopurin/6-thioguanin), methotrexate , adalimumab, vedolizumab or ustekinumab OR patients in need of immediate top-down treatment with IFX at the discretion of the treating physician.

In the opinion of the investigator, the subject is capable of understanding and complying with protocol requirements.

The subject signs and dates a written, informed consent form and any required privacy authorization prior to the initiation of any study procedure.

Male or non-pregnant, non-lactating females. No wish to become pregnant in the coming 26 weeks.

Patiënten van 18 jaar of ouder bij wie de ziekte van Crohn is vastgesteld

Patiënten met matige tot ernstige actieve ziekte van Crohn met een Crohn's Disease Activity Index (CDAI) van 220 tot 450 en aanwezigheid van endoscopische ulceratie in het terminale ileum, colon of beide. Minimale SES-CD is ≥ 6 of ≥ 4 voor geïsoleerde ileale ziekte.

Patiënten die geen respons of verlies van respons hadden op of ondraaglijke bijwerkingen hebben gehad op een of meer van de volgende: glucocorticoïden, thiopurines (azathioprine / 6-mercaptopurine / 6-thioguanine), methotrexaat, adalimumab, vedolizumab of ustekinumab OF-patiënten die een onmiddellijke top-downbehandeling met IFX nodig hebben, naar het oordeel van de behandelende arts.

Naar het oordeel van de onderzoeker is de proefpersoon in staat de protocolvereisten te begrijpen en na te leven.

De proefpersoon ondertekent en dateert een schriftelijk, geïnformeerd toestemmingsformulier en de eventuele vereiste privacy autorisatie voordat een studieprocedure wordt gestart.

Mannen en vrouwen niet zwangere, of borstvoeding gevend. Geen wens om de komende 26 weken zwanger te worden.

E.4

Principal exclusion criteria

Patients at imminent need of surgery as judged by the treating clinician

Patients with the short bowel syndrome, an ostomy or a symptomatic non-inflammatory stricture

Patients previously exposed to IFX (intravenous or subcutaneous)

Previously unacceptable side effects or intolerance to all immunosuppressants (both thiopurines and methotrexate)

Treatment with adalimumab within 15 days and vedolizumab and ustekinumab within 30 days

Patients who have had a primary non-response to adalimumab or had intolerable class-related side effects (as evaluated at the discretion of the treating physician)

Enteric pathogens (such as Salmonella, Shigella, Yersinia, Campylobacter and C. difficile) detected by stool analysis within 2 weeks prior to enrollment or at screening

Ongoing participation in another interventional trial

Patients with Ulcerative Colitis or IBD-U

Patients with ongoing abdominal or undrained perianal abscess

Patients with a history of colon cancer or colonic dysplasia, unless sporadic adenoma, which has been removed

Active or latent tuberculosis (screening according to national guidelines)

Cardiac failure in NYHA stage III-IV

History of demyelinating disease

Recent live vaccination (≤ 4 weeks)

Patients with ongoing acute/chronic infection (including but not limited to HIV, hepatitis B and C) with the exception of chronic herpes labialis or cervical HPV

History of cancer in the last 5 years with the exception of non-melanoma skin cancer

Male patients with EBV negative serology

A history of alcohol or illicit drug use that in the opinion of the principal investigator (PI) would interfere with study procedures

Patients with psychiatric problems that in the opinion of the PI would interfere with study procedures

Patients unable to attend all study visits

Patients with a history of non-compliance with clinical study protocols

Contraindication for endoscopy

Patients who received any investigational drug in the past 30 days or 5 half-lives, whichever is longer

Pregnancy or lactation or wish to become pregnant in the coming 26 weeks

Patiënten bij wie een operatie dreigend nodig is, zoals beoordeeld door de behandelende arts

Patiënten met het short bowel syndrome, een stoma of een symptomatische niet-inflammatoire strictuur

Patiënten die eerder zijn blootgesteld aan IFX (intraveneus of subcutaan)

Eerder onaanvaardbare bijwerkingen of intolerantie voor alle immunosuppressiva (zowel thiopurines als methotrexaat)

Behandeling met adalimumab binnen 15 dagen en vedolizumab en ustekinumab binnen 30 dagen

Patiënten die een primaire non-respons op adalimumab hebben gehad of ondraaglijke klassegerelateerde bijwerkingen hadden (zoals beoordeeld naar goeddunken van de behandelende arts)

Darmpathogenen (zoals Salmonella, Shigella, Yersinia, Campylobacter en C. difficile) gedetecteerd door stoelganganalyse binnen 2 weken voorafgaand aan inschrijving of bij screening

Doorlopende deelname aan een ander interventioneel onderzoek

Patiënten met colitis ulcerosa of IBD-U

Patiënten met aanhoudend abdominaal of ongedraineerd perianaal abces

Patiënten met een voorgeschiedenis van colonkanker of colondysplasie, tenzij sporadisch adenoom, dat is verwijderd

Actieve of latente tuberculose (screening volgens landelijke richtlijnen)

Hartfalen in NYHA stadium III-IV

Geschiedenis van demyeliniserende ziekte

Recente levende vaccinatie (≤ 4 weken)

Patiënten met aanhoudende acute / chronische infectie (inclusief maar niet beperkt tot HIV, hepatitis B en C) met uitzondering van chronische herpes labialis of cervicale HPV

Geschiedenis van kanker in de afgelopen 5 jaar met uitzondering van niet-melanome huidkanker

Mannelijke patiënten met EBV-negatieve serologie

Een geschiedenis van alcohol- of illegaal drugsgebruik die naar de mening van de hoofdonderzoeker (PI) de studieprocedures zou verstoren

Patiënten met psychiatrische problemen die naar het oordeel van de PI de studieprocedures zouden verstoren

Patiënten die niet alle studiebezoeken kunnen bijwonen

Patiënten met een voorgeschiedenis van niet-naleving van klinische studieprotocollen

Contra-indicatie voor endoscopie

Patiënten die een geneesmiddel voor onderzoek hebben gekregen in de afgelopen 30 dagen of 5 halfwaardetijden, welke van beide het langst zijn

Zwangerschap of borstvoeding of zwanger willen worden in de komende 26 weken

E.5 End points

E.5.1

Primary end point(s)

Proportion of patients in corticosteroid-free clinical remission (as defined by CDAI<150) AND endoscopic response (a drop of at least 50% in SES-CD compared to baseline) at week 26

Percentage patiënten met corticosteroïdvrije klinische remissie (zoals gedefinieerd door CDAI <150) EN endoscopische respons (een daling van ten minste 50% in SES-CD vergeleken met baseline) in week 26

E.5.1.1

Timepoint(s) of evaluation of this end point

week14, and week 26

week 14, en week 26

E.5.2

Secondary end point(s)

The proportion of patients in endoscopic remission at week 26 (defined as the absence of ulcerations larger then 5mm)

Proportion of patients with endoscopic remission at week 26 (as measured by SES-CD≤2)

Proportion of patients with endoscopic response at week 26 (as measured by at least 50% reduction in the SES-CD as compared to baseline)

Proportion of patients in corticosteroid-free clinical remission at week 26 (defined as a CDAI<150)

The proportion of patients in CSF deep remission at week 26, as defined by corticosteroid-free clinical (CDAI<150) AND endoscopic remission (defined as the absence of ulcerations larger then 5mm)

Proportion of patients in clinical remission at week 2, 4, 8, 14 and 26 (defined as a CDAI<150)

Proportion of patients achieving clinical response at week 2, 4, 8, 14 and 26 (defined as a CDAI-70)

Proportion of patients achieving clinical response at week 26 (defined as a CDAI-100)

Proportion of patients in symptomatic remission at week 2, 4, 8, 14 and 26 (defined as a PRO-2 (stool frequency and abdominal pain) <8)

Proportion of patients achieving symptomatic response at week 2, 4, 8, 14 and 26 (defined as a PRO-2 -8)

Time to symptomatic remission (defined as a PRO-2 (stool frequency and abdominal pain)<8)

Proportion of patients in biochemical remission at week 8, 14 and 26 (CRP ≤ 5.0 mg/L and fecal calprotectin < 250 mg/g)

Time to biochemical remission (CRP ≤ 5.0 mg/L and fecal calprotectin < 250 mg/g)

Proportion of patients achieving minimally clinically important difference in quality of life at week 2, 4, 8, 14 and week 26 compared to baseline as assessed by the IBDQ and EQ-5D-5L questionnaire

Proportion of patients developing anti-drug antibodies (ADA) against IFX at week 2, 4, 8, 14 and 26 as measured by a drug-tolerant assay

IFX trough levels at week 2, 4, 8, 14 and 26

HLA haplotyping and genotyping for correlation with efficacy and ADA development

DNA methylation analysis in association in objective response to IFX

Thiopurine metabolites at baseline, week 14 and week 26 (for patients randomized for the combination therapy group, only at baseline for those in the monotherapy group and with previous IS use)

Proportion of patients having IFX trough levels of > 5ug/ml at week 26

Proportion of patients achieving histological healing at week 26

Proportion of patients (of those with active perianal disease at baseline) in clinical remission and response of their perianal disease, as defined by the fistula drainage assessment (FDA) at week 26

Proportion of patients with extraintestinal manifestations at week 26 as compared to baseline

Adverse events

Het percentage patiënten in endoscopische remissie in week 26 (gedefinieerd als de afwezigheid van ulceraties groter dan 5 mm)

Percentage patiënten met endoscopische remissie in week 26 (gemeten aan de hand van SES-CD≤2)

Percentage patiënten met endoscopische respons in week 26 (gemeten aan de hand van ten minste 50% afname van de SES-CD in vergelijking met de uitgangswaarde)

Percentage patiënten met corticosteroïdvrije klinische remissie in week 26 (gedefinieerd als een CDAI<150)

Het percentage patiënten in diepe CSF-remissie in week 26, zoals gedefinieerd door corticosteroïdvrije klinische (CDAI <150) EN endoscopische remissie (gedefinieerd als de afwezigheid van ulceraties groter dan 5 mm)

Percentage patiënten in klinische remissie in week 2, 4, 8, 14 en 26 (gedefinieerd als een CDAI<150)

Percentage patiënten dat klinische respons bereikte in week 2, 4, 8, 14 en 26 (gedefinieerd als een CDAI-70)

Percentage patiënten dat klinische respons bereikte in week 26 (gedefinieerd als een CDAI-100)

Percentage patiënten met symptomatische remissie in week 2, 4, 8, 14 en 26 (gedefinieerd als een PRO-2 (ontlastingsfrequentie en buikpijn) <8)

Percentage patiënten dat een symptomatische respons bereikte in week 2, 4, 8, 14 en 26 (gedefinieerd als een PRO-2-8)

Tijd tot symptomatische remissie (gedefinieerd als een PRO-2 (ontlastingsfrequentie en buikpijn) <8)

Percentage patiënten met biochemische remissie in week 8, 14 en 26 (CRP ≤ 5,0 mg / l en fecaal calprotectine <250 mg / g)

Tijd tot biochemische remissie (CRP ≤ 5,0 mg / l en fecale calprotectine <250 mg / g)

Percentage patiënten dat een minimaal klinisch belangrijk verschil in kwaliteit van leven bereikte in week 2, 4, 8, 14 en week 26 vergeleken met de uitgangswaarde, zoals beoordeeld door de IBDQ- en EQ-5D-5L-vragenlijst

Percentage patiënten dat anti-drug antilichamen (ADA) tegen IFX ontwikkelt in week 2, 4, 8, 14 en 26, gemeten met een medicijn tolerantie test

IFX-concentraties in week 2, 4, 8, 14 en 26

HLA-haplotypering en genotypering voor correlatie met werkzaamheid en ADA-ontwikkeling

DNA methylatie analyse in associatie met objective response IFX

Thiopurinemetabolieten bij baseline, week 14 en week 26 (voor patiënten gerandomiseerd voor de combinatietherapiegroep, alleen bij baseline voor degenen in de monotherapiegroep en met eerder IS-gebruik)

Percentage patiënten met IFX-spiegels van > 5 ug / ml in week 26

Percentage patiënten dat histologische genezing bereikt in week 26

Percentage patiënten (van degenen met actieve perianale ziekte bij baseline) in klinische remissie en respons van hun perianale ziekte, zoals gedefinieerd door de fistula drainage assessment (FDA) in week 26

Percentage patiënten met extraintestinale manifestaties in week 26 in vergelijking met baseline

Bijwerkingen

E.5.2.1

Timepoint(s) of evaluation of this end point

Proportion of patients in clinical remission at week 2, 4, 8, 14 and 26 (defined as a CDAI<150)

Proportion of patients achieving clinical response at week 2, 4, 8, 14 and 26 (defined as a CDAI-70)

Proportion of patients developing anti-drug antibodies (ADA) against IFX at week 2, 4, 8, 14 and 26 as measured by a drug-tolerant assay

IFX trough levels at week 2, 4, 8, 14 and 26

If the patient has primary non-response at week 14 (as defined by the discretion of the treating physician), the patient will be considered a study failure and will be withdrawn from the study after EOS endoscopy

Percentage patiënten in klinische remissie in week 2, 4, 8, 14 en 26 (gedefinieerd als een CDAI<150)

Percentage patiënten dat klinische respons bereikte in week 2, 4, 8, 14 en 26 (gedefinieerd als een CDAI-70)

Percentage patiënten dat anti-drug antilichamen (ADA) tegen IFX ontwikkelt in week 2, 4, 8, 14 en 26, gemeten door middel van een geneesmiddel-tolerante test

IFX-dalwaarden in week 2, 4, 8, 14 en 26

Patiënt heeft primaire non-respons in week 14 (gedefinieerde discretie behandelende arts), patiënt wordt beschouwd als onderzoeksfalen en wordt na EOS-endoscopie uit het onderzoek teruggetrokken

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

Yes

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)

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)

E.8.2.2

Placebo

E.8.2.3

Other

Yes

E.8.2.3.1

Comparator description

Monotherapie met remsima, en Combinatie therapie met remsima en immunosupressiva

Monotherapy with remsima, and Combination Therapy with remsima and immunosupressive

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

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:

138

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

158

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)

None

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

2021-03-25

Ethics Committee Opinion of the trial application

Favourable

Ethics Committee Opinion: Reason(s) for unfavourable opinion

Date of Ethics Committee Opinion

2021-10-12

P. End of Trial
P.	End of Trial Status	Trial now transitioned

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