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    Summary
    EudraCT Number:2012-002181-12
    Sponsor's Protocol Code Number:MK8457-010
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2012-11-06
    Trial results View 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 ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2012-002181-12
    A.3Full title of the trial
    A Phase IIa, Randomized, Double-Blind, Placebo-Controlled, Parallel- Group, Multicenter, Worldwide, Proof-of-Concept Clinical Trial to Evaluate the Safety, Tolerability, and Efficacy of MK-8457 in Subjects with Active Rheumatoid Arthritis and an Inadequate Response or Intolerance to Anti- TNF-α Therapy
    Studio clinico di Fase IIa, randomizzato, in doppio cieco, controllato verso placebo, a gruppi paralleli, multicentrico, internazionale, di proof of concept per valutare la sicurezza, la tollerabilità e l'efficacia di MK-8457 in soggetti con artrite reumatoide attiva e una risposta inadeguata o intolleranza alla terapia con anti-TNF-±
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase IIa POC study to evaluate Safety, Tolerability and Efficacy in Subjects with RA
    Studio clinico di fase IIa proof of concept per valutare la sicurezza, la tollerabilit� e l'efficacia in soggetti con artrite reumatoide.
    A.3.2Name or abbreviated title of the trial where available
    A Phase IIa POC study to evaluate Safety, Tolerability and Efficacy in Subjects with RA
    Studio di fase IIa TNF-IR POC
    A.4.1Sponsor's protocol code numberMK8457-010
    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 SponsorMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportMerck Sharp & Dohme Corp., a subsidiary of Merck & Co., Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationMSD Italia S.r.l.
    B.5.2Functional name of contact pointRicerca Clinica
    B.5.3 Address:
    B.5.3.1Street AddressVia Fratelli Cervi, snc - Centro Direzionale Milano Due - Palazzo Borromini
    B.5.3.2Town/ citySegrate (MI)
    B.5.3.3Post code20090
    B.5.3.4CountryItaly
    B.5.4Telephone number+39 02 21018402
    B.5.5Fax number+39 02 21018629
    B.5.6E-mailgcto.italy@merck.com
    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 No
    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 nameMK-8457
    D.3.2Product code MK-8457
    D.3.4Pharmaceutical form Capsule
    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 INNMK-8457
    D.3.9.2Current sponsor codeMK-8457
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number25
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboCapsule
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Active rheumatoid arthritis
    artrite reumatoide attiva
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis due to overactive immune system
    Artrite reumatoide causata da iperattività del sistema immunitario.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.1
    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.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To determine the effects of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment as measured by ACR20 response. To determine the safety and tolerability of MK-8457 100 mg BID compared to placebo over 12 weeks of treatment.
    (1) Obiettivo: Determinare gli effetti del trattamento con MK-8457 100 mg due volte al giorno, rispetto al placebo, dopo 12 settimane di trattamento, misurando la risposta ACR20. (2) Obiettivo: Determinare la sicurezza e la tollerabilità di MK-8457 100 mg due volte al giorno, rispetto al placebo, dopo 12 settimane di trattamento.
    E.2.2Secondary objectives of the trial
    Key Secondary: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by ACR20 at Week 24; DAS28CRP change from baseline at Week 12; and ACR50 at Week 12. Base Study: To determine the effects of MK-8457 100 mg BID compared to placebo as measured by change from baseline in DAS28CRP at Week 24; ACR50 at Week 24; and HAQ change from baseline at Weeks 12 and 24. Safety Extension: To assess the safety and tolerability of MK-8457 during the safety extension period through Week 100.
    Obiettivi principali: Determinare gli effetti di MK-8457 100 mg due volte al giorno, rispetto al placebo, misurando la risposta ACR20 alla Settimana 24; la variazione nel punteggio DAS28CRP dal valore basale a quello della Settimana 12; la risposta ACR50 alla Settimana 12. Studio base: Determinare gli effetti di MK-8457 100 mg due volte al giorno, rispetto al placebo, misurando la variazione nel punteggio DAS28CRP dal valore basale a quello della Settimana 24; la risposta ACR50 alla Settimana 24; e la variazione nei punteggi HAQ dal valore basale a quello delle Settimane 12 e 24. Estensione di sicurezza: Valutare la sicurezza e la tollerabilità di MK-8457 durante il periodo di estensione di sicurezza fino alla Settimana 100.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    • Subject has a diagnosis of RA for at least 6 months prior to screening. • Subject has active RA as defined by the presence of 6 swollen joints (of 66 joint count) AND 6 tender joints (of 68 joint count) at screening (Visit 1) and baseline (Visit 2). • Subject has a C-reactive protein (CRP) blood level > 0.9 mg/dL from the central reference laboratory at screening. • Subject is anti-cyclic citrullinated antibody positive and/or rheumatoid factor positive at screening. • Subject is ACR functional Class I, II, or III. • Subject must have received MTX for a minimum of 3 months prior to screening with a regionally appropriate stable weekly dose for at least 4 weeks prior to screening (15-25 mg/wk for regions outside of Asia, and 6-25 mg/week for Asia). The subject's dose of weekly MTX must remain stable through week 24 of the study. • Subject must have either failed treatment with 1 or 2 anti-TNF therapies or was intolerant to anti-TNFtherapy prior to screening. For subjects who have failed therapy, the treatment with anti-TNF therapies must have been for at least 3 months. Note: The inadequate response or intolerance to anti-TNF therapy will be defined by the Investigator's assessment and will be recorded. Typically, an inadequate response is based on clinical reasons (e.g., no improvement or worsening of RA). Lack of access to the medication or financial reasons are not considered an inadequate response
    - Il soggetto ha una diagnosi di AR da almeno 6 mesi prima dello screening - Il soggetto ha un’AR attiva, definita dalla presenza di ≥6 articolazioni tumefatte (in base al conteggio su 66 articolazioni) E ≥6 articolazioni dolenti (in base al conteggio su 68 articolazioni) allo screening (Visita 1) e al basale (Visita 2). - Il soggetto ha un livello di proteina C-reattiva nel sangue &gt;0,9 mg/dl, misurato allo screening dal laboratorio centrale di riferimento - Il soggetto è positivo all’anticorpo anti-peptide citrullinato (anti-citrullinated protein antibody, ACPA) e/o positivo al fattore reumatoide allo screening - Il soggetto rientra in una classe funzionale I, II, III dell’ACR - Il soggetto deve aver assunto il metotressato (MTX) per almeno 3 mesi prima dello screening, con una dose settimanale stabile per almeno 4 settimane prima dello screening, definita in base alla regione (15-25 mg/settimana per regioni non appartenenti all’Asia e 6-25 mg/settimana per l’Asia). La dose settimanale di metotressato (MTX) per il soggetto deve restare stabile fino alla settimana 24 dello studio. - Il soggetto deve aver fallito il trattamento con 1 o 2 terapie anti-TNF-α o essere intollerante a terapia anti-TNF-α prima dello screening. I soggetti che hanno fallito il trattamento devono essere stati trattati per almeno 3 mesi con terapie anti-TNF-α. Nota: la risposta inadeguata o l’intolleranza alla terapia anti-TNF sarà definita in base alla valutazione dello sperimentatore e sarà registrata. Di solito, una risposta inadeguata si basa su motivi clinici (ad es., nessun miglioramento o peggioramento dell’AR). La mancanza di accesso al farmaco o i motivi economici non sono considerati una risposta inadeguata.
    E.4Principal exclusion criteria
    • Subject has inflammatory disease other than RA, including but not limited to psoriatic arthritis, ankylosing spondylitis, systemic lupus erythematosus, or Lyme disease. • Previous exposure to fostamatinib or other splenic tyrosine kinase (SYK) inhibitors. • Previous exposure to any biological agents other than anti-TNF therapeutic agents, including but not limited to abatacept, tocilizumab, rituximab or other biological agents used for the treatment of RA. • Subject has received any treatment (listed in the table below) more recently than the indicated washout period prior to randomization. Washout Period for Medications Prior to Randomization Medications, Supplements, and Other Substances Washout Period Prior to Randomization Anti-TNF-α Therapies: Adalimumab Certolizumab Etanercept Golimumab Infliximab 8 weeks 8 weeks 4 weeks 8 weeks 8 weeks Cyclosporine, corticosteroids¹ (parenteral, intra-articular), azathioprine, sulfasalazine, hydroxychloroquine 4 weeks Leflunomide² 8 weeks unless subject undergoes standard cholestyramine or activated charcoal washout in which case 4 weeks washout is required. Cytotoxic agents including chlorambucil, cyclophosphamide, nitrogen mustard, or other alkylating agents 3 months Live vaccinations 1 month Investigational medications 30 days or 5 half lives of the investigational agent whichever is longer Bacille Calmette-Guerin (BCG) vaccination 1 month 1 Subjects will be allowed to take stable doses of oral corticosteroids as specified in inclusion criterion #10; i.e., subjects must be on a stable dose of ≤10 mg prednisone per day (or equivalent) for at least 2 weeks prior to first administration of study medications. 2 Subjects may be allowed to use leflunomide instead of methotrexate on or after Week 24 of study treatment.
    - Il soggetto presenta una malattia infiammatoria diversa dall’AR, tra cui, ma non solo, l’artrite psoriasica, la spondilite anchilosante, il lupus eritematoso sistemico o la malattia di Lyme.. - Precedente esposizione a fostamatinib o ad altri inibitori della tirosin-chinasi della milza (spleen tyrosine kinase, SYK). - Precedente esposizione a qualsiasi agente biologico diverso dagli agenti terapeutici anti TNF, tra cui, ma non solo, abatacept, tocilizumab, rituximab o altri agenti terapeutici usati per il trattamento dell’AR. - Il soggetto ha ricevuto un qualsiasi trattamento elencato di seguito che sia più recente rispetto al periodo di wash-out pre-randomizzazione. Periodo di wash-out per i farmaci prima della randomizzazione Terapie anti-TNF-α: Adalimumab - 8 settimane Certolizumab - 8 settimane Etanercept - 4 settimane Golimumab - 8 settimane Infliximab - 8 settimane Ciclosporina, corticosteroidi¹ (parenterali, intra-articolari), azatioprina, sulfasalazina, idrossiclorochina – 4 Settimane Leflunomide² - 8 settimane per la colestiramina o il carbone attivo, a meno che il soggetto si sottoponga al wash-out standard, nel qual caso sono necessarie 4 settimane di wash-out. Agenti citotossici comprendenti clorambucile, ciclofosfamide, azotiprite o altri agenti alchilanti – 3 mesi Vaccinazione con vaccini vivi - 1 mese Farmaci sperimentali - 30 giorni o 5 emivite dell’agente sperimentale, in base a quale dura di più Vaccinazione contro il bacillo di Calmette-Guerin (BCG) – 1 mese 1) I soggetti potranno assumere dosi stabili di corticosteroidi orali per come specificato nel criterio di inclusione n. 10; ossia, i soggetti devono essere in trattamento a dose stabile con ≤10 mg prednisone al giorno (o equivalente) almeno 2 settimane prima della prima somministrazione dei farmaci in studio. 2) Ai soggetti sarà consentito usare leflunomide invece di metotressato (MTX) alla Settimana 24 del trattamento dello studio o dopo.
    E.5 End points
    E.5.1Primary end point(s)
    • The primary efficacy endpoint is the proportion of subjects achieving ACR20 response at Week 12. The primary safety endpoints are: • Percentage of subjects with adverse experiences; • Change from baseline in laboratory parameters; • Change from baseline in vital signs parameters; • Change in blood pressure from predose to 1 hour, 2 hours and 3 hours after the morning study drug dose at Week 2 and Week 12; and • Average change in blood pressure from predose in the 3 hours time period after am study drug dose at Week 2 and Week 12
    - L'endpoint di efficacia primario è la percentuale di pazienti che hanno ottenuto una risposta ACR20 alla settimana 12. Gli endpoint primari di sicurezza sono: - La percentuale di pazienti con eventi avversi - La variazione dei parametri di laboratorio dal baseline - La variazione dei parametri dei segni vitali dal baseline - La variazione della pressione sanguigna dalla predose alla prima, seconda e terza ora dopo la somministrazione del mattino alla settimana 2 e settimana 12 - La variazione media della pressione sanguigna dalla predose nelle 3 ore seguenti la dose mattutina di farmaco di studio alla settimana 2 e la settimana 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    Settimana 12
    E.5.2Secondary end point(s)
    The key secondary efficacy endpoints are: • Proportion of subjects achieving ACR20 response at Week 24; • Change from baseline in DAS28CRP at Week 12; and • Proportion of subjects achieving ACR50 response at Week 12. Other secondary efficacy endpoints that will be evaluated include: • Change from baseline in DAS28CRP at Week 24; • Proportion of subjects achieving ACR50 response at Week 24; and • Change from baseline in HAQ at Weeks 12 and 24. Safety endpoints will also be evaluated through Week 100 of the safety extension.
    Gli endpoint secondari di efficacia sono: - La percentuale di pazienti che ottengono una risposta ACR20 alla settimana 24. - La variazione del DAS28CRP dal baseline alla settimana 12 - La percentuale di paziente che ottengono una risposta ACR50 alla settimana 12. Altri endpoint secondari di efficacia che saranno valutati includono: - La variazione del DAS28CRP dal baseline alla settimana 24 - La percentuale di pazienti che ottengono una risposta ACR50 alla settimana 24. - La variazione dell'HAQ dal baseline alla settimana 12 e 24. Gli endpoint di sicurezza saranno valutati anche alla settimana 100 del periodo di estensione sicurezza.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 12 and 24
    Settimana 12 e 24
    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 Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    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) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    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 Yes
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    MTX come terapia di background
    All pts will take background methotrexate (MTX)
    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 Yes
    E.8.5.1Number of sites anticipated in the EEA23
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Australia
    Brazil
    Colombia
    New Zealand
    Peru
    South Africa
    United States
    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
    LVLS (Post-Study Visit is the scheduled last visit for patients)
    LVLS (Post-Study Visit è l'ultima visita programmata per i pazienti)
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months38
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months38
    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.1.1Number of subjects for this age range: 0
    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: 158
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 92
    F.4.2.2In the whole clinical trial 178
    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)
    No additional follow up monitoring or treatment is planned after the patient completes the Post-Study Visit, performed 14 days after the last dose of study medication.
    Nessun ulteriore follow-up di controllo o trattamento è previsto dopo che il paziente completa il Post-Study Visit, eseguita 14 giorni dopo l'ultima dose del farmaco in studio.
    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 Decision2013-01-10
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-10-29
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2013-09-12
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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