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    EudraCT Number:2009-016950-42
    Sponsor's Protocol Code Number:0913M0621
    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:2011-09-14
    Trial results
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    A. Protocol Information
    A.1Member State ConcernedItaly - Italian Medicines Agency
    A.2EudraCT number2009-016950-42
    A.3Full title of the trial
    A multicenter, randomized, double-blind, placebo-controlled, parallel-group study to investigate the efficacy and safety of S 888711 tablets administered once-daily for 42 days to adult subjects with relapsed persistent or chronic immune thrombocytopenia with or without prior splenectomy
    A multicenter, randomized, double-blind, placebo-controlled, parallel-group study to investigate the efficacy and safety of S 888711 tablets administered once-daily for 42 days to adult subjects with relapsed persistent or chronic immune thrombocytopenia with or without prior splenectomy
    A.4.1Sponsor's protocol code number0913M0621
    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 SponsorSHIONOGI USA, 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 support
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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.3.2Product code S-888711
    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 INN(E)-3-[2,6-Dichloro-4-[4-[3-[(S)-1-hexyloxyethyl]-2-methoxyphenyl]-thiazol-2-ylcarbamoyl]-phenyl]-2-methylacrylic acid
    D.3.9.1CAS number 1110766-97-6
    D.3.9.2Current sponsor codeS-888711
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.3Concentration number.25
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboTablet
    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
    Relapsed persistent or chronic immune thrombocytopenia with or without prior splenectomy.
    Trombocitopenia recidivante persistente o immunitaria cronica con o senza precedente splenectomia
    E.1.1.2Therapeutic area Diseases [C] - Blood and lymphatic diseases [C15]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 14.0
    E.1.2Level LLT
    E.1.2Classification code 10043569
    E.1.2Term Thrombopenia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system 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 assess the efficacy of 3 dose levels of S-888711 (0.50 mg, 0.75 mg, and 1.0 mg) and placebo on platelet count.
    Valutare l'efficacia di 3 livelli di dosaggio di S-888711 (0,50 mg, 0,75 mg e 1,0 mg) e di placebo sul conteggio piastrinico.
    E.2.2Secondary objectives of the trial
    To assess the: safety of S-888711; pharmacokinetic (PK) profile of S-888711 using sparse PK sampling; PK profile of S-888711 using serial PK sampling in a selected subset of subjects; pharmacodynamic (PD) effect of S-888711 on platelet count and markers of platelet function, such as endogenous thrombopoietin (TPO); PK/PD relationship of S-888711 with respect to platelet count; and impact of S-888711 on the incidence and severity of bleeding. Exploratory Objective: to evaluate the bone marrow histology in subjects electing to undergo serial bone marrow biopsies during the administration of S-888711.
    Valutare: la sicurezza di S-888711; il profilo farmacocinetico (PK) di S-888711 utilizzando campionamento PK ridotto;il profilo PK di S-888711 utilizzando campionamento PK seriale in un sottogruppo selezionato di soggetti; l'effetto farmacodinamico (PD) di S-888711 sul conteggio piastrinico e sui marker della funzione piastrinica, quali la trombopoietina endogena (TPO); la relazione PK/PD di S-888711 rispetto al conteggio piastrinico; e l'impatto di S-888711 sull'incidenza e gravita' del sanguinamento. Obiettivo esplorativo:la valutazione istologica del midollo osseo in pazienti che hanno accettato di sottoporsi a biopsie seriali del midollo osseo durante la somministrazione di S-888711.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    A subject will be eligible for study participation if he/she meets the following criteria: 1. A signed and dated written informed consent obtained prior to the performance of Screening procedures. 2. Males and females ≥ 18 years of age prior to Screening. 3. All subjects must agree to use exclusively progestin-based and/or barrier method contraception if engaging in sexual intercourse. Female subjects of child bearing potential must not be breast-feeding and must use a reliable barrier method for at least 7 days prior to the first dose of study drug and continuing throughout the study until 6 weeks after the last dosing, except if surgically sterilized or have been post-menopausal for at least 12 months. Hormone based contraceptives (e.g., pills, patch, shots, implants) that are not exclusively progestin-based are prohibited. Male subjects should either remain abstinent or use a condom during the time interval between taking the first dose and 6 weeks following the last study drug dose. 4. Diagnosis of ITP by American Society of Hematology criteria for at least 12 weeks prior to Screening. 5. Subjects > 60 years of age must have had a diagnostic bone marrow aspiration showing normal or increased numbers of megakaryocytes. 6. Relapsed persistent or chronic ITP status, with or without prior splenectomy (In Hungary only subjects undergoing splenectomy will be enrolled), after having failed at least 1 prior ITP therapy (excluding TPO agonists) and have a platelet count < 30,000/μL if not taking medications or < 50,000/μL despite concomitant steroids or other ITP therapies, such as danazol or immunosuppressive drugs. 7. Subjects receiving chronic maintenance steroid therapy must have received a stable dose (same milligram amount ? 10%) for at least 2 weeks prior to Screening. 8. Prothrombin time (PT) and activated partial thromboplastin time (APTT) within 20% of the upper limit of normal at Screening. 9. Subjects receiving stable dosages of cyclosporine A, mycophenolate mofetil, azathioprine, or danazol are allowed. The dosages of all these medications must be stable for at least 4 weeks prior to Visit 1 (Day 1).
    Un soggetto risultera` idoneo per la partecipazione allo studio se soddisfera` i seguenti criteri: 1. Un consenso informato scritto firmato e datato ottenuto prima delle prestazioni delle procedure di screening. 2. Maschi e femmine di eta` ≥ 18 anni prima dello screening. 3. Tutti i soggetti devono accettare di utilizzare un metodo di contraccezione a base di progestinico o di barriera in caso di rapporti sessuali. Le donne in eta` fertile non devono allattare al seno e devono utilizzare un metodo di contraccezione sicuro per almeno 7 giorni prima della prima dose del farmaco di studio, durante l`intero studio, e fino a 6 settimane dopo l`ultima dose, escluse le donne chirurgicamente sterili o in stato di postmenopausa) per almeno 12 mesi. I contraccettivi ormonali(es. pillole, cerotti, iniezioni, impianti) che non siano esclusivamente a base di progestinico, sono vietati. Gli uomini devono astenersi da rapporti sessuali, oppure utilizzare un profilattico nel periodo compreso tra la prima dose e 6 settimane dopo l`ultima somministrazione del farmaco di studio. 4. Diagnosi di ITP in base ai criteri dell`American Society of Hematology per almeno 12 settimane prima dello screening. 5. I soggetti di eta` &gt; 60 anni devono essere stati sottoposti a un`aspirazione diagnostica del midollo osseo indicante un numero di megacariociti normale o aumentato. 6. Stato di ITP persistente recidivante o cronica, con o senza precedente splenectomia (eccezione: in Ungheria saranno arruolati solo soggetti sottoposti a splenectomia), dopo aver fallito almeno 1 precedente terapia per ITP (fatta eccezione per i farmaci TPO agonisti) e avere avuto un conteggio piastrinico &lt; 30.000/μl senza assunzione di farmaci o &lt; 50.000/μl nonostante steroidi concomitanti oppure altre terapie ITP, quali danazolo o farmaci immunosoppressivi. 7. I soggetti che ricevevano una terapia steroidea cronica di mantenimento devono aver ricevuto una dose stabile (lo stesso numero di milligrammi ? 10%) per almeno 2 settimane prima dello screening. 8. Tempo di protrombina (PT) e tempo di tromboplastina parziale attivata (APTT) entro il 20% del limite normale superiore allo screening. 9. Sono consentiti soggetti che ricevevano dosaggi stabili di ciclosporina A, mofetil micofenolato, azatioprina o danazolo. I dosaggi di tutti questi farmaci devono essere stabili per almeno 4 settimane prima della visita 1 (giorno 1).
    E.4Principal exclusion criteria
    A subject will not be eligible for study participation if he/she meets any of the exclusion criteria, or will be discontinued at the discretion of the investigator if he/she develops 1 or more of the following exclusion criterion during the study: 1. History of inherited or acquired, clinically important hemorrhagic clotting disorder. 2. Females who are pregnant or lactating, or are receiving other hormone/chemical contraceptives that are not exclusively progestin-based. 3. History of alcohol/drug abuse or dependence within 1 year of Screening. 4. Use of the following drugs or treatment prior to Visit 1 (Day 1): Within 1 week Rho(D) immune globulin or intravenous immunoglobulin (IVIG); Within 2 weeks – platelet transfusions or plasmapheresis treatment. Within 4 weeks use of anti-platelet or anti-coagulant drugs. Within 8 weeks -rituximab;Within 12 weeks -alemtuzumab, multi-drug systemic chemotherapy, stem cell therapy; 5. History of clinically significant (in the opinion of the investigator) cardiovascular or thromboembolic disease within 26 weeks prior to Screening Visit. 6. Splenectomy within 4 weeks prior to Screening. 7. Laboratory abnormalities: Hemoglobin < 10.0 g/dL for men or women, not clearly related to ITP; Absolute neutrophil count < 1000/mm3;Abnormal peripheral blood smear; Total bilirubin > 1.5 x upper limit of normal;Alanine aminotransferase (ALT) > 1.5 x upper limit of normal; Aspartate aminotransferase (AST) > 1.5 x upper limit of normal;Creatinine > 1.5 x upper limit of normal; Human immunodeficiency virus (HIV) positive; Hepatitis A IgM antibody (IgM HAV) positive, hepatitis B surface antigen (HBsAg) or hepatitis C antibody (HCV) positive;Thyroid stimulating hormone (TSH) > 1.5 x upper limit of normal; Free thyroxine (T4) > 1.5 x upper limit of normal. 8. Exposure to previous approved TPO mimetics/agonists eltrombopag within 2 weeks or romiplostim within 4 weeks prior to dosing. 9. Subjects unresponsive, defined as the inability to attain adequate platelet count despite optimal dosing of previous TPO mimetics/agonists (e.g., eltrombopag, romiplostim, E5501 [AKR-501] or LGD-4665), based on investigator discretion.10.Exposure to an investigative medication within the past 4 weeks prior to Screening.
    Un soggetto non sara` idoneo per la partecipazione allo studio se soddisfa uno dei criteri di esclusione, oppure verra` sospeso a discrezione dello sperimentatore se sviluppa 1 o piu` dei seguenti criteri di esclusione durante lo studio: 1.Anamnesi di disordini emorragici della coagulazione clinicamente gravi, ereditari o acquisiti. 2.Donne in gravidanza o allattamento, o che assumono altri contraccettivi ormonali/chimici che non siano esclusivamente a base di progestinico. 3.Anamnesi di abuso o dipendenza di alcol/farmaci da almeno 1 anno dallo screening. 4.Uso dei seguenti farmaci o trattamenti prima della visita 1 (giorno 1): Entro 1 settimana -immunoglobuline Rho(D) o immunoglobuline per via endovenosa (IVIG); Entro 2 settimane - Trasfusioni piastriniche o plasmaferesi; Entro 4 settimane - uso di farmaci antipiastrinici o anticoagulanti; Entro 8 settimane -rituximab; Entro 12 settimane -alemtuzumab, chemioterapia sistemica con piu` farmaci, terapia a base di cellule staminali; 5.Anamnesi di patologie cardiovascolari o tromboemboliche clinicamente significative (in base all`opinione dello sperimentatore) entro 26 settimane prima della visita di screening. 6.Splenectomia entro 4 settimane prima dello screening. 7.Anomalie di laboratorio: lEmoglobina &lt; 10,0 g/dl per uomini o donne, non collegata chiaramente all`ITP; Conta assoluta dei neutrofili &lt; 1000/mm3; Morfologia cellulare anormale su striscio di sangue periferico Bilirubina totale &gt; 1,5 x limite normale superiore; Alanina aminotransferasi (ALT) &gt; 1,5 x limite normale superiore; Aspartato aminotransferasi (AST) &gt; 1,5 x limite normale superiore; Creatinina &gt; 1,5 x limite normale superiore; Positivita` al virus della immunodeficienza umana (HIV); Positivita` agli anticorpi IgM dell`Epatite A (IgM HAV), all`antigene di superficie dell`epatite B (HBsAg) o agli anticorpi dell`epatite C (HCV); Ormone tireostimolante (TSH) &gt; 1,5 x limite normale superiore; Tiroxina libera (T4) &gt; 1,5 x limite normale superiore;. 8.Esposizione ai mimetici/agonisti di TPO approvati precedenti eltrombopag nelle 2 settimane precedenti o romiplostim nelle 4 settimane precedenti il dosaggio. 9.Soggetti non responsivi, definiti come incapacita` ad ottenere una conta piastrinica adeguata nonostante il dosaggio ottimale di precedenti farmaci TPO mimetici/agonisti (es., eltrombopag, romiplostim, E5501 [AKR-501] o LGD-4665), a discrezione del medico. 10.Esposizione a un farmaco sperimentale entro le ultime 4 settimane prima dello screening.
    E.5 End points
    E.5.1Primary end point(s)
    The primary assessments of efficacy are platelet counts (collected as part of the complete blood count and bleeding evaluation). For this study, subjects will be classified as responders if they: achieve a platelet count of ≥ 50,000/?l after 6 weeks of dosing; or are prematurely withdrawn due to a platelet count > 400,000/?l prior to Day 42. Subjects who do not meet the above condition, have received rescue medications during the Double-Blind Treatment Period, or are withdrawn for any reasons other than a platelet count > 400,000/?l will be counted as non-responders. The primary efficacy endpoint is the proportion of responder subjects in each treatment group.
    Le valutazioni primarie di efficacia sono rappresentate dai conteggi piastrinici (raccolti come parte della valutazione dell`esame emocromocitometrico completo e del sanguinamento). Per questo studio i soggetti verranno classificati come responsivi se:ottengono un conteggio piastrinico di ≥ 50.000/?l dopo 6 settimane di dosaggio; o si ritirano prematuramente a causa di un conteggio piastrinico > 400.000/?l prima del giorno 42.I soggetti che non esaudiscono tale condizione, che hanno ricevuto medicinali di soccorso durante il periodo in doppio-cieco, o che si ritirano per un qualsiasi altro motivo, diverso da un conteggio piastrinico > 400.000 /?l, verranno conteggiati come non-responsivi. L`endpoint primario d`efficacia e` la proporzione di soggetti responsivi in ciascun gruppo di trattamento.
    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 Yes
    E.6.5Efficacy Yes
    E.6.6Pharmacokinetic Yes
    E.6.7Pharmacodynamic Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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 Yes
    E.8.1.1Randomised Yes
    E.8.1.2Open Information not present in EudraCT
    E.8.1.3Single blind Information not present in EudraCT
    E.8.1.4Double blind Yes
    E.8.1.5Parallel group Yes
    E.8.1.6Cross over No
    E.8.1.7Other Information not present in EudraCT
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) No
    E.8.2.2Placebo Yes
    E.8.2.3Other No
    E.8.2.4Number of treatment arms in the trial4
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA26
    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
    I soggetti che non possono entrare nello studio di estensione dovranno fare ogni settimana per 6 settimane dopo la Visita Finale, delle visite di Follow-up per monitorare la sicurezza del trattamento
    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 months6
    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 months6
    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 Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 Yes
    F. of subjects incapable of giving consent
    Un rappresentate legale autorizzato puo' firmare il consenso informato al posto del soggetto
    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 27
    F.4.2.2In the whole clinical trial 60
    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 Decision2010-06-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2010-04-12
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2011-01-25
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