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    EudraCT Number:2018-003162-13
    Sponsor's Protocol Code Number:WI232128
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2018-11-08
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2018-003162-13
    A.3Full title of the trial
    A Study to investigate Bone turnover Markers in patients planned to receive tofacitinib
    Uno studio per indagare marcatori di turnover osseo in pazienti in procinto di avviare
    la terapia con tofacitinib
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Study to investigate Bone turnover Markers in patients planned to receive tofacitinib
    Uno studio per indagare marcatori di turnover osseo in pazienti in procinto di avviare
    la terapia con tofacitinib
    A.3.2Name or abbreviated title of the trial where available
    A.4.1Sponsor's protocol code numberWI232128
    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.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 S.r.l.
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationAOUI Verona
    B.5.2Functional name of contact pointUnità Ricerca Clinica
    B.5.3 Address:
    B.5.3.1Street AddressP.le Stefani 1
    B.5.3.2Town/ cityVerona
    B.5.3.3Post code37126
    B.5.4Telephone number00390458127043
    B.5.5Fax number00390458122814
    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 5 mg film-coated tablets
    D. of the Marketing Authorisation holderPfizer Limited
    D.2.1.2Country which granted the Marketing AuthorisationItaly
    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 nameXeljanz 5mg
    D.3.4Pharmaceutical form Film-coated 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.3.9.2Current sponsor codeTOFACITINIB
    D.3.9.4EV Substance CodeSUB33104
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number5
    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
    Rheumatoid arthritis
    Artrite reumatoide
    E.1.1.1Medical condition in easily understood language
    Rheumatoid arthritis
    Artrite reumatoide
    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 20.0
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The main objective of our study is to investigate the effect of tofacitinib on serum
    levels of bone turnover markers (CTX ng/ml, P1NP ng/ml, BAP ng/ml) and modulators
    (DKK1 pmol/L, Sclerostin pmol/L, OPG pmol/L, RANKL pmol/L, PTH pg/ml, 25 OH vitamin D
    L'obiettivo principale del nostro studio è di studiare l'effetto di Tofacitinib sui
    livelli sierici dei marker di turnover osseo (CTX ng / ml, P1NP ng / ml, BAP ng / ml)
    e modulatori del turnover osseo (DKK1 pmol / L, Sclerostin pmol / L, OPG pmol / L,
    RANKL pmol / L, PTH pg / ml, 25 OH vitamina D ng / ml)
    E.2.2Secondary objectives of the trial
    1. changes versus baseline in hip and lumbar bone mineral density (BMD) by Dual X-ray
    Absorptiometry (DXA), hand BMD by DXR, bone erosions and anti-citrullinated peptides
    antibodies (ACPA),
    2. to investigate the correlations between ACPA, bone turnover markers and modulators
    (BTM), bone mineral density (BMD) by Dual X-ray Absoptiometry (DXA), metacarpal index
    (MCI) and Bone Health Index (BHI) by and Digital X-ray Radiogrammometry (DXR), and
    bone erosions in patients with RA with short disease duration.
    3. to evaluate the influence of tofacitinib on those outcomes and determinate if they
    are related to the effect on ACPA titer
    1. variazioni rispetto al basale della densità minerale ossea (BMD) dell'anca e
    lombare mediante Dual X-ray Absorptiometry (DXA), della BMD della mano mediante DXR,
    delle erosioni ossee e degli anticorpi anti-citrullinati (ACPA)
    2. indagare le correlazioni tra ACPA, marcatori e modulatori del turnover osseo (BTM),
    densità minerale ossea (BMD) mediante Dual X-ray Absoptiometry (DXA), metacarpal index
    (MCI) e Bone Health Index (BHI) mediante Digital X-ray Radiogrammometry (DXR) e
    erosioni ossee in pazienti con AR con breve durata della malattia.
    3. valutare l'influenza di tofacitinib su questi outcomes e determinare se sono
    correlati all'effetto sul titolo anticorpale di ACPA
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Age = 18 years
    • Signed and dated informed consent
    • RA diagnosis according to ACR/EULAR 2010 criteria
    • Disease onset within 3 years
    • Tofacitinib oral therapy required due to synthetic or biologic DMARD
    failure/intolerance according to EULAR recommendations
    • Glucocorticoid daily dose stable for at least 3 months and = 5 mg/day of
    prednisolone equivalent.
    • Unregarding ACPA status (both positive and negative included).
    • Wash out from previous biologic agent = 3 half lives of the biologic agent and at
    least 3 months.
    • women of childbearing age must have a negative urine pregnancy test within 7 days
    before beginning treatment and they will be informed of the need of an efficacy
    contraceptive method during the administration and after 4 weeks from the last dose of
    • patients must be negative to screening exam for latent infections ( HIV, HCV, HBV,
    quantiferon, chest x-rays)
    • Età = 18 anni
    • Consenso informato firmato e datato
    • Diagnosi di AR secondo criteri ACR/EULAR 2010
    • Esordio di malattia entro 3 anni
    • Necessità di avviare terapia orale con tofacitinib per fallimento o intolleranza
    di DMARD sintetici e/o biologici in accordo con le raccomandazioni EULAR
    • Dose stabile di glucocorticoidi da almeno 3 mesi e = 5 mg/die di prednisone
    • status sieropositivo e sieronegativo di ACPA (anticorpi anti-peptidi citrullinati)
    • Wash out dal precedente biologico = 3 emivite o almeno 3 mesi.
    • Donne in età fertile devono avere un test di gravidanza sulle urine negative entro
    i 7 gg antecedenti l’inizio della terapia e devono essere informate sulla necessità di
    un metodo contraccettivo efficace durante la somministrazione e fino a 4 settimane dopo
    l’ultima somministrazione di tofacitinib.
    • I pazienti devono essere negativi agli esami di screening per infezioni latenti
    (HIV, HCV, HBV, quantiferon, Rx torace)
    E.4Principal exclusion criteria
    • Other rheumatic diagnosis other than RA
    • Bone diseases other than osteoporosis
    • Severe liver or kidney disease
    • Not-controlled endocrine disease
    • Contraindication to tofacitinib (concomitant recurrent or chronic infections,
    tumor in the previous 5 years)
    • Previous treatment with other biologic agents within 3 months or 3 half lives of
    the last one
    • Concomitant (or before 12 months, except for zoledronate that is before 24
    months) treatment with bisphosphonate, strontium ranelate, teriparatide, selective
    estrogen receptor modulators (SERM) or denosumab.
    • Intra-articular injections at MCPs or MTPs in the 3 months before.
    • Pregnancy or breast feeding status
    • Prisoners or subjects who are compulsory detained
    • Presenza di altre diagnosi reumatologiche oltre all’artrite reumatoide
    • Malattie metaboliche ossee diverse dall’osteoporosi
    • Significativa compromissione renale o epatica
    • Malattie endocrinoogiche non controllate
    • Controindicazioni a tofacitinib (infezioni ricorrenti o croniche, neoplasie negli
    ultimi 5 anni)
    • Precedente trattamento con farmaci biologici nei tre mesi precedenti o 3 emivite
    del farmaco.
    • Trattamento concomitante o nei precedenti 12 mesi (o 24 mesi per lo zoledronato)
    con bisfosfonati, ranelato di stronzio, teriparatide, modulatori selettivi dei recettori
    per estrogeni (SERM) o denosumab.
    • Iniziezioni intrarticolari a livello delle articolazioni metacarpo-falangea nei
    precedenti tre mesi.
    • Stato di gravidanza o allattamento.
    • Carcerati
    E.5 End points
    E.5.1Primary end point(s)
    Serum levels of bone turnover markers (CTX ng/ml, P1NP ng/ml, BAP ng/ml) and
    modulators (DKK1 pmol/L, Sclerostin pmol/L, OPG pmol/L, RANKL pmol/L, PTH pg/ml, 25 OH
    vitamin D ng/ml) serum levels at multiple timepoints (M1, M2, M3, M6, M9 e M12) versus
    pre-treatment levels (M0)
    Livelli sierici dei marker di turnover osseo (CTX ng / ml, P1NP ng / ml, BAP ng / ml)
    e dei suoi modulatori (DKK1 pmol / L, Sclerostin pmol / L, OPG pmol / L, RANKL pmol/L, PTH pg / ml, 25 OH vitamina D ng / ml) a più timepoints (M1, M2, M3, M6, M9 e M12)
    rispetto ai livelli pre-trattamento (M0)
    E.5.1.1Timepoint(s) of evaluation of this end point
    M0 vs M1, M2, M3, M6, M9, M12
    M0 vs M1, M2, M3, M6, M9, M12
    E.5.2Secondary end point(s)
    Systemic BMD (lumbar e femoral T and Z-scores) and hand MCI/BHI, evaluation of bone
    erosions (Sharp van der Heijde Score), RF U/ml, ACPAU/ml at multiple timepoints (M0,
    M1, M2, M3, M6, M9 e M12). These endpoints refers to secondary objectives 1., 2., 3
    BMD sistemica (T e Z-scores lombare e femorale) e MCI/BHI della mano, valutazione
    erosioni ossee (Sharp van der Heijde Score), fattore reumatoide U/ml, Anti- CCP U/ml a
    più timepoints (M0, M1, M2, M3, M6, M9 e M12). Tali endpoint si rifanno agli obiettivi
    secondari 1., 2., 3
    E.5.2.1Timepoint(s) of evaluation of this end point
    M0, M1, M2, M3, M6, M9, M12
    M0, M1, M2, M3, M6, M9, M12
    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 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 Yes
    E.6.13.1Other scope of the trial description
    To evaluate the effect of Tofacitinib on bone metabolism
    Valutare l'effetto di Tofacitinib sul metabolismo osseo
    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) No
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) Yes
    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.8.2.4Number of treatment arms in the trial1
    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 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
    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 months1
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    E.8.9.2In all countries concerned by the trial months1
    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: 20
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 30
    F.4.2.2In the whole clinical trial 30
    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)
    Patients will be treated according to the best clinical practice
    I pazienti saranno trattati come da migliore pratica clinica
    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 Decision2019-01-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-01-23
    P. End of Trial
    P.End of Trial StatusOngoing
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