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    Summary
    EudraCT Number:2014-004942-91
    Sponsor's Protocol Code Number:1423M0634
    National Competent Authority:Italy - Italian Medicines Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-04-02
    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 number2014-004942-91
    A.3Full title of the trial
    A Phase 3 Randomised, Double-blind, Placebo-controlled Study to Assess the Safety and Efficacy of S-888711 (Lusutrombopag) for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Elective Invasive Procedures (L-PLUS 2)
    Studio randomizzato di Fase 3, in Doppio cieco, controllato con Placebo per Valutare la Sicurezza e l’Efficacia di S-888711 (Lusutrombopag) nel Trattamento della Trombocitopenia in Pazienti affetti da Malattia Epatica Cronica Sottoposti a Procedure Invasive Elettive (L-PLUS 2)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and Efficacy Study of Lusutrombopag for the Treatment of Thrombocytopenia in Patients with Chronic Liver Disease Undergoing Elective Invasive Procedures
    Studio sulla Sicurezza e l’Efficacia di Lusutrombopag per il Trattamento della Trombocitopenia in Pazienti affetti da Malattia Epatica Cronica Sottoposti a Procedure Invasive Elettive
    A.3.2Name or abbreviated title of the trial where available
    L-PLUS 2
    L-PLUS 2
    A.4.1Sponsor's protocol code number1423M0634
    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 Ltd
    B.1.3.4CountryUnited Kingdom
    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 supportShionogi & Co., Ltd
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShionogi & Co., Ltd
    B.5.2Functional name of contact pointCorporate Communications Department
    B.5.3 Address:
    B.5.3.1Street Address1-8, Doshomachi 3-chome
    B.5.3.2Town/ cityChuo-ku, Osaka
    B.5.3.3Post code541-0045
    B.5.3.4CountryJapan
    B.5.4Telephone number+81 6 6209 7885
    B.5.6E-mailshionogiclinicaltrial888711@shionogi.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 nameLusutrombopag
    D.3.2Product code S-888711
    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 INNLusutrombopag
    D.3.9.1CAS number 1110766-97-6
    D.3.9.2Current sponsor codeS-888711
    D.3.9.3Other descriptive nameLUSUTROMBOPAG
    D.3.9.4EV Substance CodeSUB170962
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number3.0
    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 placeboFilm-coated tablet
    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
    Thrombocytopenia in patients with Chronic Liver Disease (CLD)
    Trombocitopenia in Pazienti affetti da Malattia Epatica Cronica (CLD)
    E.1.1.1Medical condition in easily understood language
    Thrombocytopenia in patients with Chronic Liver Disease (CLD)
    Trombocitopenia in Pazienti affetti da Malattia Epatica Cronica (CLD)
    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 17.1
    E.1.2Level PT
    E.1.2Classification code 10043554
    E.1.2Term Thrombocytopenia
    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 compare the efficacy of S-888711 with placebo for the treatment of thrombocytopenia in patients with CLD who are undergoing elective invasive procedures
    Confrontare l'efficacia di S-888711 con placebo nel trattamento della trombocitopenia in pazienti affetti da malattia epatica cronica (CLD) sottoposti a procedure invasive elettive
    E.2.2Secondary objectives of the trial
    •To assess the safety and tolerability of S-888711 treatment compared with placebo
    •To assess the platelet response following treatment with S-888711 compared with placebo
    •To assess the pharmacodynamics and pharmacokinetics of S-888711
    • Valutare la sicurezza e la tollerabilità del trattamento con S-888711 rispetto al placebo
    • Valutare la risposta piastrinica successiva al trattamento con S-888711 rispetto al placebo
    • Valutare la farmacodinamica e la farmacocinetica di S-888711
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Able to understand the study and comply with all the study procedures
    2.Willing to provide written informed consent prior to Screening
    3.Male or female
    4.18 years of age or older at the time of signing informed consent
    5.Platelet count < 50 × 10^9/L at baseline on Day 1 prior to randomisation
    6.Undergoing an elective invasive procedure
    7.In the opinion of the investigator, able to meet the requirements of the study
    8.Male patients who are sterile or who agree to use an appropriate method of contraception (including use of a condom with spermicide) from screening to completion of the Post-treatment Period
    9.Female patients who are not postmenopausal or surgically sterile need to agree to use highly effective contraception (including contraceptive implant, injectable contraceptive, combination hormonal contraceptive [including vaginal rings], intrauterine contraceptive device or vasectomised partner) from screening to completion of the Post-treatment Period. Barrier method with or without spermicide, double barrier contraception and oral contraceptive pill are in sufficient methods on their own.
    1. Capacità di comprendere lo studio e di adeguarsi a tutte le procedure da esso previste
    2. Volontà di fornire il consenso informato scritto prima dello Screening
    3. Maschio o femmina
    4. Età uguale o superiore a 18 anni al momento della firma del consenso informato
    5. Conta piastrinica < 50 × 10^9/L al basale il Giorno 1 prima della randomizzazione
    6. Sottoporsi a una procedura elettiva invasiva
    7. A giudizio dello sperimentatore, il paziente è in grado di soddisfare i requisiti dello studio
    8. Pazienti di sesso maschile che siano sterili o che accettino di usare un metodo contraccettivo adeguato (incluso l’uso di un preservativo con spermicida) dallo screening fino al termine del periodo di post-trattamento
    9. I pazienti di sesso femminile che non sono in postmenopausa o chirurgicamente sterili devono accettare di assumere contraccettivi altamente efficaci (inclusi impianto contraccettivo, contraccettivo iniettabile, combinazione contraccettiva ormonale [inclusi gli anelli vaginali], dispositivo di contraccezione intrauterino o compagno vasectomizzato) dallo screening fino al termine del periodo di post-trattamento. Metodo barriera con o senza spermicida, la doppia barriera contraccettiva e la contraccezione orale sono metodi insufficienti da soli.
    E.4Principal exclusion criteria
    1.Any of the following diseases:
    •haematopoietic tumour
    •aplastic anaemia
    •myelodysplastic syndrome
    •myelofibrosis
    •congenital thrombocytopenia
    •drug induced thrombocytopenia
    •generalised infection requiring treatment except for viral liver disease
    •immune thrombocytopenia.
    2.History of splenectomy.
    3.History of liver transplantation.
    4.Any of the following at Screening:
    •hepatic encephalopathy uncontrolled by drugs
    •ascites uncontrolled by drugs.
    5.Portal vein tumour embolism.
    6.Known to be positive for the human immunodeficiency virus.
    7.Past or present thrombosis or prothrombotic condition (eg, cerebral infarction, myocardial infarction, angina pectoris, coronary artery stent placement, angioplasty, coronary artery bypass grafting, congestive heart failure [New York Heart Association {NYHA} Grade III/IV], arrhythmia known to increase the risk of thromboembolic events [eg, atrial fibrillation], pulmonary thromboembolism, deep vein thrombosis, or disseminated intravascular coagulation syndrome).
    8.History or evidence of any of the following diseases:
    •congenital thrombotic disease (eg, antithrombin deficiency, protein C deficiency, protein S deficiency, or coagulation factor [Factor V Leiden] mutation)
    •acquired thrombotic disease (eg, antiphospholipid antibody syndrome, paroxysmal nocturnal haemoglobinuria, hyperhomocysteinaemia, or increased factor VIII)
    •Budd Chiari syndrome.
    9.Portal vein thrombosis based on ultrasound, computed tomography (CT), or magnetic resonance imaging (MRI) within 28 days prior to randomisation or a history of portal vein thrombosis.
    10.Absence of hepatopetal blood flow in the main trunk of the portal vein as demonstrated by Doppler ultrasonography within 28 days prior to randomisation.
    11.History or evidence of disease associated with a risk of bleeding (eg, coagulation factor deficiency or von Willebrand factor deficiency).
    12.Bleeding score at randomisation ≥ Grade 2 according to the World Health Organization (WHO) Bleeding Scale.
    13.Any of the following drugs or therapies within 90 days prior to randomisation:
    •anticancer drugs
    •interferon preparations
    •radiation therapy
    •exsanguination
    •other TPO receptor agonist
    •any investigational agent.
    14.Any invasive procedure within 14 days prior to randomisation.
    15.Blood transfusion within 14 days prior to randomisation.
    16.Patients who have received S-888711 before.
    17.Pregnant or lactating female.
    18.Patients with known or suspected ongoing, active alcohol or substance abuse. Patients with a recent history who the investigator feels are able to comply with the study procedures and medications will be allowed to participate.
    19.Considered ineligible by the investigator for any other reason.
    1. Una qualsiasi delle malattie seguenti:
    • tumore ematopoietico
    • anemia aplastica
    • sindrome mielodisplastica
    • mielofibrosi
    • trombocitopenia congenita
    • trombocitopenia farmaco-indotta
    • infezione generalizzata che richiede trattamento a eccezione della malattia epatica virale
    • trombocitopenia immune.
    2. Anamnesi di splenectomia.
    3. Anamnesi di trapianto di fegato.
    4. Una qualsiasi delle seguenti condizioni allo Screening:
    • encefalopatia epatica non controllata mediante farmaci
    • ascite non controllata mediante farmaci.
    5. Embolia neoplastica della vena porta.
    6. Positività nota al virus dell’immunodeficienza umana.
    7. Condizione trombotica o protrombotica passata o presente (ad es., ictus cerebrale, infarto del miocardio, angina pectoris, posizionamento di stent aorto-coronarico, angioplastica, innesto di bypass aorto-coronarico, insufficienza cardiaca congestizia [di grado III/IV secondo la New York Heart Association {NYHA}], aritmia nota per aumentare il rischio di eventi tromboembolici [ad es., fibrillazione atriale], tromboembolia polmonare, trombosi venosa profonda, o sindrome da coagulazione intravascolare disseminata).
    8. Anamnesi o evidenza di una qualsiasi delle malattie seguenti:
    • malattia trombotica congenita (ad es., deficit di antitrombina, deficit di proteina C, deficit di proteina S, o mutazione del fattore di coagulazione [fattore V di Leiden])
    • malattia trombotica acquisita (ad es., sindrome da anticorpi antifosfolipidi, emoglobinuria parossistica notturna, iperomocisteinemia, o aumento del fattore VIII)
    • sindrome di Budd Chiari.
    9. Trombosi della vena porta come dimostrato da ecografia, tomografia computerizzata (TC), o risonanza magnetica (RMI) nei 28 giorni precedenti la randomizzazione o anamnesi di trombosi della vena porta.
    10. Assenza di flusso epatopeto nel tronco centrale della vena porta come dimostrato da ecodoppler nei 28 giorni prima della randomizzazione.
    11. Anamnesi o evidenza di malattia associata a rischio di emorragia (ad es., deficit del fattore di coagulazione o deficit del fattore di von Willebrand).
    12. Punteggio del sanguinamento alla randomizzazione ≥ grado 2, in base alla scala del sanguinamento dell’Organizzazione Mondiale della Sanità (OMS).
    13. Uno qualsiasi dei seguenti farmaci o terapie nei 90 giorni precedenti la randomizzazione:
    • farmaci anticancro
    • preparazioni a base di interferone
    • radioterapia
    • svuotamento ematico
    • altro agonista del recettore della TPO
    • qualsiasi agente sperimentale.
    14. Una qualsiasi procedura invasiva nei 14 giorni precedenti la randomizzazione.
    15. Trasfusione di sangue nei 14 giorni precedenti la randomizzazione.
    16. Pazienti già trattati con S-888711 in precedenza.
    17. Donne in stato di gravidanza o allattamento.
    18. Pazienti con dipendenza in corso nota o sospetta da alcol o sostanze stupefacenti. È ammessa la partecipazione di pazienti con un’anamnesi recente che, secondo l’opinione dello sperimentatore, sono in grado di adeguarsi alle procedure e ai farmaci dello studio.
    19. Pazienti considerati non idonei dallo sperimentatore per qualsiasi altro motivo.
    E.5 End points
    E.5.1Primary end point(s)
    •Proportion of patients who require no platelet transfusion prior to the primary invasive procedure and no rescue therapy for bleeding from randomisation through 7 days after the primary elective procedure.
    Percentuale di pazienti che non richiede una trasfusione di piastrine prima della procedura invasiva principale e una terapia di salvataggio per emorragia dalla randomizzazione fino a 7 giorni dopo la procedura elettiva principale.
    E.5.1.1Timepoint(s) of evaluation of this end point
    On or after Day 8, but no more than 2 days prior to the elective invasive procedure.
    Al giorno 8 o più tardi, ma non più di 2 giorni prima della procedura invasiva elettiva.
    E.5.2Secondary end point(s)
    •Proportion of patients who require no platelet transfusion during the study
    •Proportion of responders: patients who achieve a platelet count of ≥ 50 × 109/L with an increase of ≥ 20 × 109/L from baseline at any time during the study
    •Duration of the platelet count defined as the number of days during which the platelet count was maintained as ≥ 50 × 109/L
    •Proportion of patients who require rescue therapy for bleeding at any time during the study
    •Frequency of platelet transfusions
    •The change from baseline in platelet count over time (time course of platelet count)
    •Safety and tolerability
    •Assessment of plasma concentrations of S-888711
    • Percentuale di pazienti che non richiede una trasfusione di piastrine durante lo studio
    • Percentuale di rispondenti: pazienti che raggiungono una conta piastrinica ≥ 50 × 10^9/L con un aumento di ≥ 20 × 10^9/L dal basale in qualsiasi momento durante lo studio
    • Durata della conta piastrinica definita come il numero di giorni durante i quali la conta piastrinica si è mantenuta ≥ 50 × 10^9/L
    • Percentuale di pazienti che necessita di terapia di salvataggio in qualsiasi momento durante lo studio
    • Frequenza delle trasfusioni di piastrine
    • Variazione dal basale della conta piastrinica nel tempo (decorso temporale della conta piastrinica)
    • Sicurezza e tollerabilità
    • Valutazione delle concentrazioni plasmatiche di S-888711
    E.5.2.1Timepoint(s) of evaluation of this end point
    63 days
    63 giorni
    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 Yes
    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
    tolerability
    tollerabilità
    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) Yes
    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 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 concerned16
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA61
    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
    Argentina
    Australia
    Austria
    Belgium
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Israel
    Italy
    Korea, Republic of
    Poland
    Romania
    Russian Federation
    Spain
    Taiwan
    Thailand
    Turkey
    Ukraine
    United Kingdom
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months2
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months4
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 100
    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 state36
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 123
    F.4.2.2In the whole clinical trial 200
    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)
    After participation in the trial patients will be treated with the current standard therapy and no additional trial medication will be made available.
    Dopo la partecipazione allo studio i pazienti saranno trattati con l’attuale terapia standard e non verrà reso disponibile alcun ulteriore farmaco sperimentale.
    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 Decision2015-07-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-04-29
    P. End of Trial
    P.End of Trial StatusCompleted
    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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