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    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:Ongoing
    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
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-000469-33
    A.3Full 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.3.1Title 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.3.2Name or abbreviated title of the trial where available
    DIRECT CD
    DIRECT CD
    A.4.1Sponsor's protocol code numberNL.76663.018.21
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorAmsterdam UMC location AMC
    B.1.3.4CountryNetherlands
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportCelltrion Healthcare Netherlands B.V.
    B.4.2CountryKorea, Republic of
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAmsterdam UMC location AMC
    B.5.2Functional name of contact pointKrisztina Gecse
    B.5.3 Address:
    B.5.3.1Street AddressMeibergdreef 9
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1105AZ
    B.5.3.4CountryNetherlands
    B.5.4Telephone number+310205664401
    B.5.6E-mailk.b.gecse@amsterdamumc.nl
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Remsima
    D.2.1.1.2Name of the Marketing Authorisation holderCelltrion Healthcare Hungary Kft.
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameRemsima
    D.3.2Product code EMEA/H/C/002576
    D.3.4Pharmaceutical form Solution for infusion in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 2
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Puri Nethol
    D.2.1.1.2Name of the Marketing Authorisation holderAspen
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product namePuri Nethol
    D.3.2Product code RVG00859
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 3
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Imuran
    D.2.1.1.2Name of the Marketing Authorisation holderAspen
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameImuran
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 4
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Thiosix
    D.2.1.1.2Name of the Marketing Authorisation holderTeva
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameThiosix
    D.3.2Product code RVG 114681
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another type of medicinal product No
    D.IMP: 5
    D.1.2 and D.1.3IMP RoleTest
    D.2 Status of the IMP to be used in the clinical trial
    D.2.1IMP to be used in the trial has a marketing authorisation Yes
    D.2.1.1.1Trade name Ebetrex 15 mg = 0,75 ml, oplossing voor injectie in voorgevulde injectiespuit 20 mg/ml
    D.2.1.1.2Name of the Marketing Authorisation holderSandoz
    D.2.1.2Country which granted the Marketing AuthorisationNetherlands
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community No
    D.2.5.1Orphan drug designation number
    D.3 Description of the IMP
    D.3.1Product nameEbetrex
    D.3.2Product code RVG 116648
    D.3.4Pharmaceutical form Injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) No
    D.3.11.3.1Somatic cell therapy medicinal product No
    D.3.11.3.2Gene therapy medical product No
    D.3.11.3.3Tissue Engineered Product No
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) No
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product No
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy No
    D.3.11.5Radiopharmaceutical medicinal product No
    D.3.11.6Immunological medicinal product (such as vaccine, allergen, immune serum) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product No
    D.3.11.10Medicinal product containing genetically modified organisms No
    D.3.11.11Herbal medicinal product No
    D.3.11.12Homeopathic medicinal product No
    D.3.11.13Another 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.1.1Medical condition(s) being investigated
    Crohns disease
    Ziekte van Crohn
    E.1.1.1Medical condition in easily understood language
    Moderate to severe chronic inflammatory bowel disease
    Matige tot ernstige chronisch darm ontstekingen
    E.1.1.2Therapeutic area Body processes [G] - Biological Phenomena [G16]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main 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.2.2Secondary objectives of the trial
    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)
    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)
    E.2.3Trial contains a sub-study No
    E.3Principal 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.4Principal 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.5.1Primary 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.5.1.1Timepoint(s) of evaluation of this end point
    week14, and week 26

    week 14, en week 26

    E.5.2Secondary 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.5.2.1Timepoint(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.6Scope of the trial
    E.6.1Diagnosis No
    E.6.2Prophylaxis No
    E.6.3Therapy Yes
    E.6.4Safety Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic No
    E.6.13Others No
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans No
    E.7.1.2Bioequivalence study No
    E.7.1.3Other No
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) No
    E.7.3Therapeutic confirmatory (Phase III) Yes
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Monotherapie met remsima, en Combinatie therapie met remsima en immunosupressiva
    Monotherapy with remsima, and Combination Therapy with remsima and immunosupressive
    E.8.2.4Number of treatment arms in the trial2
    E.8.3 The trial involves single site in the Member State concerned No
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned20
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.7Trial has a data monitoring committee No
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero No
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.3Newborns (0-27 days) No
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.5Children (2-11years) No
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 138
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally No
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state158
    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
    None
    G. Investigator Networks to be involved in the Trial
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2021-03-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2021-10-12
    P. End of Trial
    P.End of Trial StatusOngoing
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