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    EudraCT Number:2018-001678-10
    Sponsor's Protocol Code Number:NL65853.029.18
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2019-02-20
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedNetherlands - Competent Authority
    A.2EudraCT number2018-001678-10
    A.3Full title of the trial
    Tofacitinib: salvage therapy for patients with RCDII - a pilot study
    Tofacitinib: laatste redmiddel voor patiënten met RCDII - een pilot study
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Research with the drug tofacitinib for patients with refractory celiac disease type II
    Onderzoek met het geneesmiddel tofacitinib bij patiënten met refractaire coeliakie type II
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberNL65853.029.18
    A.5.4Other Identifiers
    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 SponsorVU Medical Center
    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 supportVU University Medical Center
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationVU University Medical Center
    B.5.2Functional name of contact pointMDL Research
    B.5.3 Address:
    B.5.3.1Street AddressDe Boelelaan 1117
    B.5.3.2Town/ cityAmsterdam
    B.5.3.3Post code1081 HV
    B.5.4Telephone number0031204443522
    B.5.5Fax number0031204440554
    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. name Xeljanz, INN-tofacitinib citrate
    D. of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 Tablet
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNTOFACITINIB
    D.3.9.1CAS number 477600-75-2
    D.3.9.4EV Substance CodeSUB33104
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number5 to 10
    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. cell therapy medicinal product No
    D. therapy medical product No
    D. Engineered Product No
    D. ATIMP (i.e. one involving a medical device) No
    D. 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
    Refractory celiac disease type II
    Refractaire coeliakie type II
    E.1.1.1Medical condition in easily understood language
    Refractory celiac disease type II
    Refractaire coeliakie type II
    E.1.1.2Therapeutic area Diseases [C] - Digestive System Diseases [C06]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the efficacy of tofacitinib treatment in patients with RCDII with persistent or recurrent villous atrophy (Marsh III ABC) and aberrant IEL T-cells (> 20% as assessed by flow cytometry).
    Evaluatie van effectiviteit van tofacitinib bij patiënten met RCDII met persisterende of terugkerende vlokatrofie (Marsh III ABC) en aberrant IEL T-cellen (> 20% aIELS, geanalyseerd mbv flowcytometrie).
    E.2.2Secondary objectives of the trial
    - To assess the safety of tofacitinib in patients with RCDII.
    - To evaluate the effect of of tofacitinib on quality-of-life of patients with RCDII when treated with tofacitinib.
    - To evaluate predictability of response to tofacitinib therapy with an in vitro assay.
    - Evaluatie van de veiligheid van tofacitinib bij patiënten met RCDII.
    - Evaluatie van het effect van tofacitinib op de kwaliteit van leven bij patienten met RCDII.
    - Immunologische veranderingen bekijken bij patineten met RCDII wanneer behandeld met tofacitinib.
    - Evaluatie van de voorspelbaarheid van tofacitinib respons met behulp van een in vitro assay.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Adult patients ≥ 18 years old
    2. Given informed consent
    3. Diagnosis of RCDII
    4. Total adherence to a glutenfree diet for at least 6 consecutive months prior to screening. Subjects must also agree to make no changes to their current GFD for the duration of study participation.
    5. Anti-tissue transglutaminase (IgA and IgG) at screening < 2x the diagnostic level for celiac disease (weak positive or negative)
    6. In case of female fertile patients: negative serum pregnancy test prior to study enrollment; adequate contraception, up to 4 weeks after final dose.
    7. Laboratory values:
    a) Total WBC > 0.75 x 10^9/L (i.e. > 750/mm3)
    n) Hemoglobin > 5.5 mmol/L (i.e. 8.86 g/dL)
    c) Absolute neutrophil count > 1 x 10^9 / L (i.e. > 1000 cells/mm3.)
    d) Estimated eGFR > 30mL/min/1.73m2 using the Cockcroft-Gault equation.
    e) Platelets > 50 x 109/L (i.e. 50000/mm3)
    8. PET/CT-scan without signs of abnormalities suggestive for EATL within 3 months.
    9. Willingness and ability to comply with study procedures.
    10. Willingness to return for all scheduled follow-up visits.
    1. Volwassen patienten (≥ 18 jaar oud)
    2. Getekend informed consent
    3. Diagnose van RCDII
    4. Glutenvrij dieet afgelopen 6 maanden voor screening. Patiënten moeten er ook mee akkoord gaan om geen veranderingen in hun glutenvrije dieet te maken zolang ze meedoen aan de studie.
    5. Anti-tissue transglutaminase (IgA and IgG) bij screening < 2x diagnostic levle voor coeliakie (zwak positief of negatief)
    6. Bij vrouwelijke patiënten in vruchtbare periode: negatieve serum zwangerschapstest; adequate contraceptie, tot 4 weken na de laatste dosis tofacitinib.
    7. Labwaardes:
    a) Totaal WBC > 0.75 x 10^9/L (i.e. > 750/mm3)
    b) Hemoglobine > 5.5 mmol/L (i.e. 8.86 g/dL)
    c) Absolute neutrophil count > 1 x 10^9 / L (i.e. > 1000 cells/mm3.)
    d) Geschatte eGFR > 30mL/min/1.73m2 using the Cockcroft-Gault equation.
    e) Trombocyten > 50 x 10^9/L (i.e. 50000/mm3)
    8. PET/CT-scan zonder tekenen/abnormaliteiten suggestief voor EATL binnen de afgelopen 3 maanden.
    9. Bereidheid en mogelijkheid om te voldoen aan de onderzoeksprocedures.
    10. Bereidheid om terug te keren voor alle onderzoeksbezoeken.
    E.4Principal exclusion criteria
    1. Diagnosis of RCDI, EATL
    2. Presence of any of the following diagnosis:
    a) Active acute infections, which require systemic treatments (specific attention for treatment with ketoconazol or fluconazole (as well CYP3A4 metabolizers).
    b) Severe infection prior to screening
    c) Active tuberculosis (TBC) (as confirmed in PET/CT-scan; chest radiography)
    d) Untreated or inadequately treated latent TB (as confirmed with a positive IGRA test (QuantiFERON-TB Gold Plus test)).
    - NB. Subjects are permitted to enroll in study after ≥ 4 months treatment with rifampicine)
    e) History within 3 years of opportunistic infections typical of those seen in immunocomprised patients, such as systemic candida infection.
    f) Severe liver insufficiency (Child Pugh Score 10-15)
    3. Positive Hep B, Hep C or HIV test results at the time of screening.
    4. Vaccination with live, attenuated vaccines (such as varicella zoster vaccine, yellow fever, oral typhoid vaccine) within 2 weeks before start of tofacitinib.
    5. History of significant immune suppression:
    a) BMT therapy less than 6 months prior to baseline
    b) Potent systemic immune suppressants (e.g., azathioprine, within specified time periods per drug type) prior to baseline.
    6. Subjects receiving moderate/potent CYP3A inducers or inhibitors in the specified time periods prior to the first dose of study drug:
    - Moderate/potent CYP3A inducers, within 28 days of 5 half-lives, whichever is longer, prior to first dose of study drug;
    - Moderate/potent CYP3A inhibitors, within 7 days or 5 half-lives, whichever is longer, prior to first dose of study drug.
    i. NB.Topical (including skin or mucous membranes) application of antimicriobial and antifungal medications is permitted.
    7. Screening 12-lead ECG that demonstrates clinically relevant abnormalities which may affect subject safety or interpretation of study results.
    8. History or presence of clinically significant disease that in the opinion of the investigator would confound the subject’s participation and follow-up in the clinical trial or put the subject at unnecessary risk (e.g. uncontrolled cardiac diseases, uncontrolled/chronic pulmonary, renal, endocrine, hematological, gastrointestinal, immunologic, dermatological, neurological or psychiatric dysfunction).
    9. History of drug or alcohol abuse that would interfere with the ability to comply with the study protocol.
    10. History of clinically significant hypersensitivity to the study drug or to any of the excipients
    11. Females who are pregnant, becoming pregnant or are currently breastfeeding.
    12. Participation in any other investigational drug study in the past 30 days/5 half-lives.
    13. Any additional reason which would endanger safety of the subject for participation in this study, in the opinion of the investigator.
    1. Diagnosis van RCDI, EATL
    2. Aanwezigheid van een de volgende diagnoses:
    a) Actieve acute infecties waarvoor systemische behandeling wordt gegeven (met name attentie voor behandeling met ketoconazol en fluconazol (en andere CYP3A4 metabolizers)
    b) Ernstige infectie voorafgaand aan screening
    c) Actieve tuberculose (TBC)
    d) Onbehandelde of onvoldoende behandelde latente TB (zoals bevestigd met een positieve IGRA test (QuantiFERON-TB Gold Plus test)).
    e) Voorgeschiedenis in afgelopen 3 jaar van opportunistische infecties die typisch worden gezien bij immuungecompromitteerde patienten, zoals systemische candida infecties.
    f) Ernstige leverinsufficiëntie (Child Pugh Score 10-15)
    3. Positieve Hep B, Hep C of HIV test resultaten t.t.v. screening.
    4. Vaccinatie met levende, verzwakte vaccines (zoals varicella zoster vaccin, gele koorts of oraal buiktyfus vaccin), 2 weken voorafgaand aan de eerste inname van tofacitinib.
    5. Voorgeschiedenis van significante immuunsuppressie:
    a) Beenmergtransplantatie minder 6 maanden voorafgaand aan baseline.
    b) Potente systemische immuunsuppressiva (e.g. azathioprine, in tijdsperiodes specifiek per medicijn) voor baseline.
    6. Proefpersonen die matig-sterke CYP3A4 remmers of sterke CYP3A4 remmers gebruiken in de gespecificeerde tijdsperiodes voor de eerste dosis van tofacitinib:
    - Matige/sterke CYP3A inducers, binnen 28 dagen of 5 half-lives, welke langer is, voor de eerste dosis van tofacitinib;
    - Matige/sterke CYP3A remmers, binnen 7 dagen of 5 half-lives, welke langer is, voor de eerste dosis van tofacitinib.
    7. Screening 12-kanaals ECG welke klinische relevante afwijkingen laten zien die eventueel de patiënt in gevaar kunnen brengen; interpretatie van de studieresultaten kunnen beïnvloeden.
    8. Voorgeschiedenis of aanwezigheid van klinisch significante ziekte die naar mening van de onderzoeker, de deelname en follow-up van de participant in de klinische trial zou kunnen verstoren of de participant onnodig in gevaar zou kunnen brengen. (e.g. ongecontroleerde cardiale ziektes, ongecontroleerde/chronische long-, nier-, endocriene, hematologische, gastrointestinale, immunologische, dermatologische, neurologische of psychiatrische dysfunctie.
    9. Voorgeschiedenis van medicijn- of alcoholmisbruik dat ervoor zou kunnen zorgen dat de participant niet het vermogen heeft om te voldoen aan het onderzoeksprotocol.
    10. Voorgeschiedenis van klinisch significante overgevoeligheid voor het onderzoeksmedicijn of een van de hulpstoffen in het medicijn.
    11. Vrouwen die zwanger zijn, zwanger worden of borstvoeding geven.
    12. Participatie in een ander geneesmiddelenonderzoek in de laatste 30 dagen/ 5 halfwaardetijden van dat medicijn.
    13. Elke andere additionele reden die de veiligheid van de potentiele kandidaat in gevaar zou kunnen brengen, naar mening van de onderzoeker.
    E.5 End points
    E.5.1Primary end point(s)
    Primary efficacy endpoint:

    - Immunological response, as defined by:
    reduction from baseline of aberrant IELs (%) with respect to total IELs in duodenal biopsies at week 12, as assessed by flow cytometry.
    Primaire effectiviteits eindpunten:

    - Immunologische respons, gedefinieerd door:
    vermindering van baseline in aberrante IELs (%) in verhouding tot totaal IELs, in duodenumbiopten, in week 12, geanalyseerd m.b.v. flow cytometrie.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks
    12 weken
    E.5.2Secondary end point(s)
    Secondary efficacy endpoints:
    - Histological response, as defined by: improvement from baseline in histology scores for celiac disease, as defined by Marsh classification.
    - Clinical response: changes from baseline in clinical symptoms, as assesed by:
    Bristol Stool Forming Scale (BSFS), gastrointestinal symptom rating scale (GSRS), which includes the celiac disease GSRS (CeD)-GSRS, Celiac Disease Patient Reported Outcome (CeD-PRO), Celiac Disease Symptom Diary (CDSD).

    Safety endpoints

    Exploratory endpoints:
    - Safety of tofacitinib for patients with RCDII
    - Changes in quality-of-life when using tofacitinib, as evaluated by questionnaire EQ-5D-5L.
    - Immunological changes: by tracking of immune subsets in duodenal biopsies and blood after tofacitinib treatment (single-cell CyTOF) and tracking histological changes in the small intestine after tofacitinib treatment (IHC; Vectra, imaging CyTOF).
    - In vitro tofacitinib assay: to evaluate predictability of tofacitinib responsiveness with an in vitro assay (FACS) vs. in vivo immunological response (primary efficacy endpoint)
    Secundaire effectiviteits eindpunten:
    - Histologische respons, gedefinieerd door:
    verbetering vanaf baseline in histologische scores voor coeliakie, zoals gedefinieerd door Marsh classificatie.
    - Klinische respons: veranderingen vanaf baseline in klinische symptomen, geëvalueerd door:
    Bristol Stoelgangschaal, gastrointestinal symptom rating scale (GSRS) inclusief coeliakie GSRS (CeD-GSRS), door de patiënt gerapporteerde uitkomsten van de ziekte coeliakie (CeD-PRO; CDSD).

    Veiligheid van tofacitinib bij patienten met RCDII

    Exploratieve eindpunten:
    - Verandering in kwaliteit van leven bij gebruik van het middel tofacitinib, geevalueerd door vragenlijst (EQ-5D-5L).
    - Immunologische veranderingen, geevalueerd door veranderingen in immunsubsets te bekijken in duodenumbiopten en blood na tofacitinib behandeling (single-cell CyTOF) en histologische veranderingen in de dunne darm te bekijken na tofacitinib behandeling (IHC; Vectra; imaging CyTOF).
    - In vitro tofacitinib assay: om de voorspelbaarheid van tofacitinib respons te evalueren met behulp van een in vitro assay (FACS) vs. in vivo immunologische response (7.1.1. Primair effectiviteits eindpunt)
    E.5.2.1Timepoint(s) of evaluation of this end point
    - Histology: 12 weeks
    - Clinical: continuously
    - Safety: continuously
    - Quality of life: 12 weeks
    - Immunological changes: 12 weeks
    - Histologie: 12 weken
    - Klinisch: continu
    - Veiligheid: continu
    - Kwaliteit van leven: 12 weken
    - Immunologische veranderingen: 12 weken
    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 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. trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    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 No
    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 No
    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 Yes
    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
    Last visit of the last subject in study
    Laatste visite van de laatste participant in de studie
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned 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: 2
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state5
    F.4.2 For a multinational trial
    F.4.2.2In the whole clinical trial 5
    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 it turns out tofacitinib is effective for treatment of RCDII patients, Pfizer will provide tofacitinib for treatment of RCDII patients. In the meantime, the sponsor (VUmc) will request off-label approval at the local drug regulatory authorority (College ter Beoordeling Geneesmiddelen) in the Netherlands.
    Als tofacitinib effectief blijkt te zijn voor behandeling van RCDII patienten, dan zal Pfizer tofacitinib blijven geven voor de behandeling van RCDII patienten. Ondertussen zal de sponsor (VUmc) off-label approval aanvragen bij het College ter Beoordeling Geneesmiddelen.
    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 Decision2019-02-20
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-06
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-03-17
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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