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    Summary
    EudraCT Number:2021-004131-84
    Sponsor's Protocol Code Number:ChronIA001
    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:2021-09-08
    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 number2021-004131-84
    A.3Full title of the trial
    Chronotherapy in Inflammatory Arthritis (ChronIA trial): a randomized controlled trial comparing the effectiveness of morning and evening dosing of tofacitinib extended-release
    Chronotherapie in inflammatoire arthritis: een gerandomiseerd onderzoek waarin de inname van Tofacitinib XR in de ochtend wordt vergeleken met inname in de avond.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Comparing the effectiveness of tofacitinib extended release (XR) chronotherapy, morning versus evening dosing, in rheumatoid arthritis (RA) and psoriatic arthritis (PsA) patients from a patient’s, clinical as well as a translational point of view.
    Het vergelijken van de effectiviteit van Tofacitinib XR inname in de ochtend met de avond, oftewel chronotherapie, in patiënten met reumatoïde artritis of een artritis psoriatica vanuit een klinisch, patiënten alsmede een translationeel perspectief.
    A.3.2Name or abbreviated title of the trial where available
    ChronIA trial
    ChronIA studie
    A.4.1Sponsor's protocol code numberChronIA001
    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 SponsorErasmus Medical Center
    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 supportPfizer B.V.
    B.4.2CountryNetherlands
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationErasmus Medical Center
    B.5.2Functional name of contact pointPascal H.P. de Jong
    B.5.3 Address:
    B.5.3.1Street AddressDr. Molewaterplein 40
    B.5.3.2Town/ cityRotterdam
    B.5.3.3Post code3015 GD
    B.5.3.4CountryNetherlands
    B.5.4Telephone number00310653995477
    B.5.6E-mailp.h.p.dejong@erasmusmc.nl
    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 Xeljanz XR
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer B.V.
    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 nameTofacitinib XR
    D.3.2Product code EMEA/H/C/004214
    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.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
    Rheumatoid arthritis or psoriatic arthritis according to respectively 2010 criteria or CASPAR criteria
    Reumatoïde artritis of artritis psoriatica volgens respectivelijk de 2010 classificatie criteria danwel de CASPAR criteria
    E.1.1.1Medical condition in easily understood language
    (Symmetrical) joint inflammation with or without auto-antibodies (i.e. rheumatoid factor and/or anti-citrullinated protein antibodies) or psoriasis
    (Symmetrische) gewrichtsontstekingen aan meerdere gewrichten met of zonder auto-antistoffen (reumafactor en/of anti-CCP) of psoriasis
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 23.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 21.0
    E.1.2Level LLT
    E.1.2Classification code 10037160
    E.1.2Term Psoriatic arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue disorders
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary outcome is the difference in self-reported disease activity, measured with the Routine Assessment of Patient Index Data 3 (RAPID-3), between morning and evening dosing of tofacitinib XR after 3 months of treatment.
    De primaire uitkomstmaat is het verschil in de zelfgerapporteerde ziekteactiviteit, gemeten met de Routine Assessment of Patient Index Data 3 (RAPID-3), tussen ochtend- en avonddosering tofacitinib XR na 3 maanden behandeling.
    E.2.2Secondary objectives of the trial
    Secondary endpoints are: (self-reported) disease activity (states); morning stiffness; general health; fatigue; pain; sleep; functional ability; quality of life; worker productivity; treatment satisfaction; and compliance. In addition, we will investigate whether the expression of circadian clock genes and microbiota composition change over time and whether these changes correlate with treatment response.
    Secundaire uitkomstmaten zijn: (zelfgerapporteerde) ziekte-activiteit (stadia); ochtendstijfheid; algemene gezondheid; vermoeidheid; pijn; slaap; functionaliteit; kwaliteit van leven; productiviteit; behandeltevredenheid en compliantie. Daarnaast zullen we onderzoeken of de expressie van klokgenen en de samenstelling van de darmflora verandert over de tijd en/of deze verandering geassocieerd is met de behandelrespons.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    In order to be eligible to participate in this study, a subject must meet all of the following criteria:
    - RA or PsA, , according to respectively the ACR/EULAR 2010 criteria for RA and CASPAR criteria
    - Active disease, respectively defined as a DAS>2.4 or DAPSA>14
    - Age ≥18 years
    - Reumatoïde artritis of artritis psoriatica volgens respectivelijk de 2010 classificatie criteria danwel de CASPAR criteria
    - Actieve ziekte, gedefinieerd als DAS>2.4 of DAPSA>14
    - Leeftijd ≥18 jaar
    E.4Principal exclusion criteria
    - Current or previous treatment of arthritis with tsDMARD(s)
    - Prednisone (or equivalent) usage at a dose of >7.5mg
    - Work in shifts
    - (Relative) contraindications for study medication:
    a. Evidence of ongoing infectious or malignant process obtained within 3 months prior to screening and evaluated by a qualified health care professional.
    b. Pregnant or nursing (lactating) women.
    c. Female participants of child bearing potential and male participants whose partner is of child bearing potential who are not willing to ensure that they or their partner use effective contraception during the trial and for 3 months thereafter as in standard practice.
    d. History of clinically significant liver disease or liver injury as indicated by abnormal liver function tests (LFT) such as aspartate aminotransferase/serum glutamic oxaloacetic transaminase (AST/SGOT), alanine aminotransferase/ serum glutamic pyruvic transaminase (ALT/SGPT), alkaline phosphatase, or serum bilirubin. The Investigator should be guided by the following criteria: Any single parameter may not exceed 2 x upper limit of normal (ULN). A single parameter elevated up to and including 2 x ULN should be re-checked once more as soon as possible, and in all cases, at least prior to enrolment/randomization, to rule out laboratory error.
    e. History of renal trauma, glomerulonephritis, or subjects with one kidney only, or a glomerular filtration rate (GFR) < 30 ml/min.
    f. Other underlying metabolic, hematologic, renal, hepatic, pulmonary, neurologic, endocrine, cardiac, infectious or gastrointestinal conditions which in the opinion of the Investigator immunocompromises the patient and/or places the patient at unacceptable risk for participation in an immunomodulatory therapy.
    g. Use of powerful CYP3A4 inhibitors (e.g. ketoconazole, fluconazole, tacrolimus and ciclosporin)
    - Unable to understand, speak and write in Dutch.
    - Huidige of eerder behandeling met tsDMARDs
    - Prednison (of equivalenten) in een dosering >7.5mg
    - Werkt in ploegendiensten
    - (Relatieve) contra-indicatie(s) voor de studiemedicatie:
    a. Aangetoonde infectieuze of maligne aandoening(en) verworven binnen 3 maanden voorafgaand aan screening en vastgesteld
    door een gecertificeerd clinicus.
    b. Zwangere vrouwen of vrouwen die borstvoeding geven.
    c. Vrouwen bij wie conceptie mogelijk is of mannen wiens partner fysiologisch in staat is zwanger te worden, die niet de garantie
    kunnen geven dat zij of hun partner een effectief anticonceptiemiddel gebruikt gedurende het onderzoek en de 3 maanden na het
    beëindigen van het onderzoek, zoals ook gebeurd in de dagelijkse praktijk.
    d. Een medische voorgeschiedenis van klinisch significante leverziekte of leverschade aangeduid door abnormale leverfunctie
    bepalingen, zoals ASAT, ALAT, AF of serum bilirubine. De onderzoeker hoort hierbij de volgende criteria in acht te nemen: Elke
    individuele parameter mag niet 2x de upper limit of normal (ULN) overstijgen. Een individuele parameter die tot en met 2xULN
    bedraagt moet z.s.m. opnieuw worden bepaald en in elk geval alvorens de patiënt wordt geïncludeerd/gerandomiseerd, ter
    voorkoming van fouten in het lab.
    e. Een medische voorgeschiedenis van renaal trauma, glomerulonefritis of proefpersonen met 1 nier of hen die een glomerulaire
    filtratie snelheid (GFR) hebben van < 30 ml/min.
    f. Overige onderliggende metabolische, hematologische, renale, hepatische, pulmonale, neurologische, endocriene,
    cardiale, infectieuze of gastro-intestinale aandoeningen die volgens de onderzoeker het immuunsysteem compromitteren en/of voor
    de patiënt een onacceptabel risico vormen voor immunomodulerende therapie.
    g. Gebruik van krachtige CYP3A4 remmers (bv. ketoconazol, fluconazol, tacrolimus en ciclosporine)
    - Slechte beheersing van de Nederlandse taal.
    E.5 End points
    E.5.1Primary end point(s)
    The primary outcome is the difference in self-reported disease activity, measured with the Routine Assessment of Patient Index Data 3 (RAPID-3), between morning and evening dosing of tofacitinib XR after 3 months of treatment.
    De primaire uitkomstmaat is het verschil in de zelfgerapporteerde ziekteactiviteit, gemeten met de Routine Assessment of Patient Index Data 3 (RAPID-3), tussen ochtend- en avonddosering tofacitinib XR na 3 maanden behandeling.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Patients will be assessed at baseline and after 1, 3 and 6 months of treatment. At each visit patients will fill out online questionnaires and are seen by the research nurse, who calculates the DAS or DAPSA depending on the diagnosis.
    Patiënten worden bij randomisatie en na 1,3 en 6 maanden beoordeeld door een onderzoeksverpleegkundige, die afhankelijk van de diagose de DAS of DAPSA berekent. Naast de bezoekmomenten vullen patiënten ook online vragenlijsten in.
    E.5.2Secondary end point(s)
    Secondary endpoints are: (self-reported) disease activity (states); morning stiffness; general health; fatigue; pain; sleep; functional ability; quality of life; worker productivity; treatment satisfaction; and compliance. In addition, we will investigate whether the expression of circadian clock genes and microbiota composition change over time and whether these changes correlate with treatment response.
    Secundaire uitkomstmaten zijn: (zelfgerapporteerde) ziekte-activiteit (stadia); ochtendstijfheid; algemene gezondheid; vermoeidheid; pijn; slaap; functionaliteit; kwaliteit van leven; productiviteit; behandeltevredenheid en compliantie. Daarnaast zullen we onderzoeken of de expressie van klokgenen en de samenstelling van de darmflora verandert over de tijd en/of deze verandering geassocieerd is met de behandelrespons.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Patients will be assessed at baseline and after 1, 3 and 6 months of treatment. At each visit patients will fill out online questionnaires and are seen by the research nurse, who calculates the DAS or DAPSA depending on the diagnosis. Additional blood and faecal samples will be taken at baseline (T0), 1 month (T1, only blood), 3 months (T3) and 6 months (T6). Finally, patients will wear an actigraph unit, a wristwatch-like package, on the wrist 2-times for 2 weeks at home. The actigraph will be picked up by the patient in the hospital 2 weeks prior to the visit.
    We hebben geprobeerd om het onderzoek zoveel mogelijk een afspiegeling te laten zijn van de dagelijkse praktijk. Patiënten worden bij randomisatie en na 1,3 en 6 maanden beoordeeld door een onderzoeksverpleegkundige, waarna ze hun eigen reumatoloog zien. Naast de bezoekmomenten vullen patiënten online vragenlijsten in. Tevens wordt op alle meetmomenten extra bloed en ontlasting (alleen niet na 1 maand) voor het onderzoek afgenomen. De bloedafnames zullen zoveel mogelijk aan de reguliere polikliniekbezoeken worden gekoppeld, maar het kan hiervan afwijken. Als laatste zullen de patiënten tweemaal gedurende 2 weken een actigraph, een speciale horloge, dragen die zij wel in het ziekenhuizen moeten ophalen.
    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.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 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) Yes
    E.8.2.2Placebo No
    E.8.2.3Other No
    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 concerned2
    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
    The date of the last visit of the last subject to complete the entire follow-up of the trial, or the date of the last data point from the last subject that is required for primary, secondary and/or exploratory analysis, as prespecified in the protocol, whichever is the later date.
    De datum van het laatste bezoek van de laatste proefpersoon die de volledige follow-up van de studie heeft voltooid, of de datum van de laatste dataverzameling van de laatste proefpersoon die nodig is voor de primaire, secundaire en/of overige analysis, zoals geprespecificeerd in het protocol, afhankelijk van welke van de 2 de laatste datum is.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years3
    E.8.9.1In the Member State concerned months6
    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: 64
    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 state84
    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)
    The total follow-up duration within this trial is 6 months, continuation of medication at the end of the trial is left to the discretion of the treating rheumatologist and patient. Together they will weigh up the advantages (therapeutic effect) and disadvantages (side effects) of the drug and then come to a decision.
    De beslissing om de medicatie na het onderzoek te continueren ligt bij de behandelend reumatoloog en de patiënt. Zij zullen samen de voor- (therapeutisch effect) en nadelen (bijwerkingen) van het te continueren middel afwegen en dan tot een besluit komen.
    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 Decision2021-09-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2022-02-14
    P. End of Trial
    P.End of Trial StatusOngoing
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