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    Summary
    EudraCT Number:2021-005613-14
    Sponsor's Protocol Code Number:REUM-2021-01
    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:2021-12-27
    Trial results
    Index
    A. PROTOCOL INFORMATION
    B. SPONSOR INFORMATION
    C. APPLICANT IDENTIFICATION
    D. IMP IDENTIFICATION
    D.8 INFORMATION ON PLACEBO
    E. GENERAL INFORMATION ON THE TRIAL
    F. POPULATION OF TRIAL SUBJECTS
    G. INVESTIGATOR NETWORKS TO BE INVOLVED IN THE TRIAL
    N. REVIEW BY THE COMPETENT AUTHORITY OR ETHICS COMMITTEE IN THE COUNTRY CONCERNED
    P. END OF TRIAL
    Expand All   Collapse All
    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2021-005613-14
    A.3Full title of the trial
    Immune-Related Rheumatological Adverse Events study.
    Data collection from patients with cancer to evaluate rheumatological adverse events in patients treated with immune-checkpoint inhibitors.
    Immuun-gerelateerde reumatische adverse events studie.
    Data verzameling van patiënten met kanker om reumatische adverse events te evalueren in patiënten behandeld met immuuncheckpoint inhibitors.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Rheumatical complaints after specific immune checkpoint inhibitor treatment data collection.
    Reumatische klachten na immuuncheckpoint inhibitor behandeling data verzameling.
    A.3.2Name or abbreviated title of the trial where available
    IRRAE-study
    IRRAE-studie
    A.4.1Sponsor's protocol code numberREUM-2021-01
    A.7Trial is part of a Paediatric Investigation Plan No
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    D. IMP Identification
    D.IMP: 1
    D.1.2 and D.1.3IMP RoleComparator
    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 Glucotrace
    D.2.1.1.2Name of the Marketing Authorisation holderUniversité de Liège
    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.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Intravenous bolus use (Noncurrent)
    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
    Any cancer patients starting immune checkpoint inhibitor therapy (ICI-therapy).
    Any patient exhibiting a rheumatological immune-related adverse event (R-irAE).
    Patients with newly developed rheumatoid arthritis.
    Elke kankerpatiënt startend met immuun checkpoint inhibitor therapie (ICI-therapie).
    Elke patiënt met een reumatologisch immuun-gerelateerd adverse event (R-irAE).
    Patiënten met nieuw ontwikkelde reumatoïde artritis.
    E.1.1.1Medical condition in easily understood language
    Any cancer patient starting specific immunotherapy.
    Any patient with rheumatic complaints during/after start ICI-therapy.
    Patients with newly developed rheumatoid arthritis.
    Elke kankerpatiënt beginnend met specifieke immuuntherapie.
    Elke patiënt met reumatische klachten tijdens/na start ICI-therapie. Patiënten met nieuw ontwikkelde reumatoïde artritis.
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    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
    To collect clinical data on diagnosis and management of R-irAE’s induced by checkpoint inhibitors through prospective data collection of cancer patients in a multicenter setting.
    Om prospectief klinische patiënten data over de diagnose en management van R-irAE's geïnduceerd door ICI-therapie te verzamelen van patiënten met maligniteit in een multicenter setting.
    E.2.2Secondary objectives of the trial
    To investigate the immunological phenotype(s) characterizing irAE arthritis in a subgroup of cancer patients treated with ICI therapy by collecting additional PET-CT imaging, histological samples though arthroscopy and more extensive serology.
    Om karakteriserende immunologische fenotypen van R-irAE artritis te onderzoeken in patiënten met maligniteit en behandeld met ICI-therapie door verzameling van aanvullende PET-CT beeldvorming, histologische samples middels artroscopie en uitgebreidere serologie.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    8 Cohorts in study: M1-3, S1-3, S2.1 and S3.1:

    Main cohort M1/Subgroup S1:
    - ≥18 yr.
    - Diagnosed with any oncological disease
    - Starting with ICI therapy (ICI therapy defined as treatment with anti-PD1, anti-PDL1, anti-CTLA-4 or anti-Lag3, either in mono- or combination therapy)

    Main cohort M2:
    - ≥18 yr.
    - Diagnosed with any oncological disease
    - Current or recently (<3 months) completed treatment with ICI therapy (see M1)
    - Development of any R-irAE diagnosed by a physician using established criteria(CTCAE)

    Main cohort M3:
    - ≥18 yr.
    - Pre-existing rheumatological disease as diagnosed by rheumatologist
    - Diagnosed with any oncological disease
    - Initiation with ICI therapy (see M1)

    Subgroup S2:
    - Participant in M1 cohort
    - Specific R-irAE of arthritis in at least one joint

    - PET-subgroup S2.1:
    - Arthroscopy possible in affected joint

    Subgroup S3:
    - ≥18 yr.
    - De novo RA according to ACR/EULAR criteria 2010.

    - PET-subgroup S3.1:
    - Arthroscopy possible in affected joint
    8 Cohorten in studie: M1-3, S1-3, S2.1 en S3.1:

    Hoofd/subgroep cohort M1/S1:
    - ≥18 jaar.
    - Gediagnosticeerd met oncologische ziekte
    - Start immuun checkpoint inhibitor therapie (ICI-therapie) (ICI-therapie gedefinieerd als behandeling met anti-PD1, anti-PDL1, anti-CTLA-4 of anti-Lag3, zowel mono- als combinatietherapie)

    Hoofd cohort M2:
    - ≥18 jaar.
    - Gediagnosticeerd met oncologische ziekte
    - Huidige of recent (<3 maanden) afgesloten ICI-therapie (zie M1)
    - Ontwikkeling van rheumatologische adverse event (R-irAE) gediagnosticeerd door arts door middel van bestaande CTCAE criteria

    Hoofd studie cohort M3:
    - ≥18 jaar.
    - Preexistente reumatologische ziekte gediagnosticeerd door reumatoloog.
    - Gediagnosticeerd met oncologische ziekte
    - Start met ICI-therapie (zie M1)

    Subgroep S2:
    - Deelname M1 cohort
    - Specifiek R-irAE artritis in tenminste 1 gewricht

    - PET-subgroep S2.1:
    - Artroscopie mogelijk in aangedaan gewricht

    Subgroep S3:
    - ≥18 jaar
    - De novo reumatoïde artritis volgens ACR/EULAR criteria 2010

    Subgroep S3.1:
    - Artroscopie mogelijk in aangedaan gewricht
    E.4Principal exclusion criteria
    8 Cohorts in study: M1-3, S1-3, S2.1 and S3.1:

    Main study cohort M1:
    - Pre-existing rheumatological disease as diagnosed by a rheumatologist
    - Previous treatment with ICI therapy

    Main/substudy cohorts M2/S2/S3:
    - Any other identified cause of the R-irAE or RA, not being ICI therapy
    - Previous treatment with ICI therapy

    Main study cohort M3:
    - No cohort-specific exclusion criteria
    - Previous treatment with ICI therapy

    Subgroup S1:
    - Pre-existing rheumatological disease
    - Development of a R-irAE(in these cases switch to M2/S2 cohort possible depending on specific irAE)

    Subgroup S2:
    - No cohort specific exclusion criteria beyond M1 criteria

    - Subgroup 2.1
    - Research related radiation exposure (cumulative ≥ 5 mSv) in the year before inclusion
    - Pregnancy and/or breastfeeding (in female participants of reproductive potential)
    - Previous local injection, arthroscopy, surgery or other medical intervention on selected arthritic joint for arthroscopy in the past 1 year
    - History of joint-replacement surgery of the joint chosen for arthroscopy.

    Subgroup S3:
    - Pre-existing rheumatological disease
    - Previous or current use of prednisone, disease modifying anti-rheumatic drugs (DMARD’s) or biological treatment (NSAID’s/Paracetamol allowed)

    Subgroup S3.1:
    - Research related radiation exposure (cumulative ≥ 5 mSv) in the year before inclusion
    - Pregnancy and/or breastfeeding (in female participants of reproductive potential)
    - Previous local injection, arthroscopy, surgery or other medical intervention on selected arthritic joint for arthroscopy in the past 1 year
    - History of joint-replacement surgery of the joint chosen for arthroscopy.
    8 Cohorten in studie: M1-3, S1-3, S2.1 en S3.1:

    Hoofdstudie cohort M1:
    - Preexistente reumatologische ziekte gediagnosticeerd door reumatoloog
    - Eerdere behandeling met ICI-therapie

    Hoofd/substudie cohorten M2/S2/S3
    - Andere aanwijsbare oorzaak van R-irAE of artritis, niet zijnde ICI-therapie
    - Eerdere behandeling met ICI-therapie

    Hoofd studie cohort M3:
    - Geen cohort-specifieke exclusie criteria
    - Eerdere behandeling met ICI-therapie

    Subgroep S1:
    - Preexistente reumatologische ziekte gediagnosticeerd door reumatoloog
    - Ontwikkeling R-irAE (in deze gevallen mogelijk switch naar M2/S2 cohort)

    Subgroup S2:
    - Geen cohort specifieke exclusie criteria buiten M1 criteria

    Subgroep 2.1
    - Research gerelateerde stralingsbelasting (cumulatief ≥ 5 mSv) in het jaar voorafgaand aan inclusie.
    - Zwangerschap of borstvoeding (in vrouwelijke participanten van vruchtbare leeftijd)
    - Eerdere lokale injectie, artroscopie, operatie of andere interventies van geselecteerde artritische gewricht in voorgaande 1 jaar
    - Voorgeschiedenis van prothese plaatsing van voor artroscopie gekozen gewricht

    Subgroep S3:
    - Preexistente reumatologische ziekte
    - Voorgaand of huidig gebruik van prednison, DMARD's,of biological behandeling (NSAID/paracetamol toegestaan)

    Subgroep S3.1:
    - Research gerelateerde stralingsbelasting (cumulatief ≥ 5 mSv) in het jaar voorafgaand aan inclusie.
    - Zwangerschap of borstvoeding (in vrouwelijke participanten van vruchtbare leeftijd)
    - Eerdere lokale injectie, artroscopie, operatie of andere interventies van geselecteerde artritische gewricht in voorgaande 1 jaar
    - Voorgeschiedenis van prothese plaatsing van voor artroscopie gekozen gewricht
    E.5 End points
    E.5.1Primary end point(s)
    The primary study end point is the collection of descriptive demographic and clinical data on patients, diagnostics and management of R-irAE’s in oncological patients treated with ICI therapy in patients both with or without preexisting rheumatological disease (with data of ICI treated oncological patients without development of irAE as reference). Endpoint of this study will therefore be defined by compiling the aforementioned dataset on R-irAE time to onset, incidence, diagnostic measures, management of said R-irAE’s including treatment type, duration, intensity and outcomes of both the adverse event itself and functional repercussions. Additional data regarding disease-specific serological markers and general inflammatory serology will be included, as well as quality of life (QOL) evaluations using standardized questionnaires.
    Het primaire studie eindpunt is het verzamelen van descriptieve demografische en klinische data van patiënten diagnose en management van R-irAE's in oncologische patiënten behandeld met ICI-therapie in patiënten met en zonder preexistente reumatische ziekte. Eindpunt is hierbij gedefinieerd als volledige compilatie van dataset van tijd tot ontstaan, incidentie, diagnostische handeling, management behandeling per behandeling type, intensiteit en duur, met uitkomsten van het adverse event en functionele resultaten. Aanvullende dat met ziekte specifieke markers en algemene inflammatie serologie zal worden geïncludeerd, net als kwaliteit van leven gebruikmakend van gestandaardiseerde vragenlijsten.
    E.5.1.1Timepoint(s) of evaluation of this end point
    The endpoint for evaluation of the primary endpoint per patient is after completing follow-up of up to 1 year in total. Evaluation of the endpoint for the entire study is defined as completion of the complete dataset and follow-up after 4 years. This is due to inclusion expected to last 3 years, followed by follow-up visits.
    Het tijdspunt voor evaluatie van het primaire eindpunt per patiënt na afronding van follow-up van maximaal 1 jaar in totaal. Evaluatie van het eindpunt voor de gehele studie is gedefinieerd als afronding van de volledige dataset en follow-up na 4 jaar. Dit in verband met inclusie gedurende 3 jaar, gevolgd door 1 jaar follow-up.
    E.5.2Secondary end point(s)
    Gathering of imaging data and histological samples to evaluate the immunohistochemical phenotype, including macrophage and T cell populations and general immunological phenotype of patients who develop irAE arthritis as compared to those who develop classical RA and to those who do not develop irAE while treated with immunotherapy using histological material gained via arthroscopy and imaging data collected through F18-FDG PET-CT imaging.
    Het verzamelen van beeldvorming data en histologische samples om immunohistochemisch fenotype te evalueren, inclusief macrofaag en T cel populaties en algemeen immunologisch fenotype van patiënten die R-irAE artritis ontwikkelen vergeleken met patiënten die de novo reumatoïde artritis ontwikkelen en zij die geen irAE's ontwikkelen tijdens ICI_therapie. Evaluatie zal plaatsvinden middels artroscopie en F18-FDG PET-CT beeldvorming.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Endpoint for this secondary objective will be defined as completion of acquisition of the abovementioned data. This data will be collected close to the first study visit after inclusion. Due to inclusion expected to last 3 years, final evaluation of this objective will therefore be after 3 years (interim analyses will be conducted at inclusion of 50% of patients).
    Eindpunt van dit secundaire doel zal worden gedefinieerd als completeren van verkrijgen van bovengenoemde data. Deze data zal kort na het eerste studiecontact worden verzameld. Wegens een verwachte inclusieduur van 3 jaar, de definitieve evaluatie van dit doel zal daarbij na 3 jaar plaatsvinden (interim analyses zullen worden uitgevoerd bij inclusie van 50% van patiënten).
    E.6 and E.7 Scope of the trial
    E.6Scope of the trial
    E.6.1Diagnosis Yes
    E.6.2Prophylaxis No
    E.6.3Therapy No
    E.6.4Safety No
    E.6.5Efficacy No
    E.6.6Pharmacokinetic No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised No
    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
    Vergelijking van ICI-therapie geïnduceerde artritis met klassieke de novo reumatoïde artritis
    Comparison of ICI-therapy induced arthritis with classical de novo rheumatoid arthritis
    E.8.2.4Number of treatment arms in the trial0
    E.8.3 The trial involves single site in the Member State concerned Yes
    E.8.4 The trial involves multiple sites in the Member State concerned Yes
    E.8.4.1Number of sites anticipated in Member State concerned5
    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
    Trial is expected to end after final study visit of follow-up of last included patient. Study is expected to require 3 years of inclusion, followed by 1 year of follow-up. In total the last visit of the last patient will thus be after 4 years after study start.
    De studie zal eindigen na het laatste studiebezoek van de laatst geïncludeerde patiënt. De studie zal naar verwachting 3 jaar inclusie vereisen, gevolgd door 1 jaar follow-up. In totaal zal het laatste bezoek van de laatste patiënt dus ongeveer 4 jaar na start van de studie zijn.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years5
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years5
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days0
    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: 494
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 1
    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 state495
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 495
    F.4.2.2In the whole clinical trial 495
    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
    Geen
    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 Decision2021-12-27
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2023-03-13
    P. End of Trial
    P.End of Trial StatusOngoing
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