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    Summary
    EudraCT Number:2016-002814-29
    Sponsor's Protocol Code Number:CETB115E2403
    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:2021-05-24
    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 number2016-002814-29
    A.3Full title of the trial
    SOAR, Interventional phase II single-arm study to assess efficacy and safety of eltrombopag combined with cyclosporine as first line therapy in adult patients with severe acquired aplastic anemia
    SOAR, Studio interventistico, di Fase II, in braccio singolo per valutare l’efficacia e la sicurezza d’impiego di Eltrombopag in associazione a ciclosporina, come terapia di prima linea, nei pazienti adulti con anemia aplastica acquisita grave
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    SOAR, Interventional phase II single-arm study to assess efficacy and safety of eltrombopag combined with cyclosporine as first line therapy in adult patients with severe acquired aplastic anemia
    SOAR, Studio interventistico, di Fase II, in braccio singolo per valutare l’efficacia e la sicurezza d’impiego di Eltrombopag in associazione a ciclosporina, come terapia di prima linea, nei pazienti adulti con anemia aplastica acquisita grave
    A.3.2Name or abbreviated title of the trial where available
    SOAR
    SOAR
    A.4.1Sponsor's protocol code numberCETB115E2403
    A.5.4Other Identifiers
    Name:-Number:-
    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 SponsorNOVARTIS PHARMA AG
    B.1.3.4CountrySwitzerland
    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 supportNovartis Pharma AG
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNOVARTIS FARMA S.p.A
    B.5.2Functional name of contact pointDrug Regulatory Affairs
    B.5.3 Address:
    B.5.3.1Street AddressLargo Umberto Boccioni, 1
    B.5.3.2Town/ cityORIGGIO
    B.5.3.3Post code21040
    B.5.3.4CountryItaly
    B.5.4Telephone number0296541
    B.5.5Fax number029659066
    B.5.6E-mailinfo.studiclinici@novartis.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 Yes
    D.2.1.1.1Trade name SANDIMMUN NEORAL - 10 MG CAPSULE MOLLI 50 CAPSULE
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    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 nameSandimmun Neoral
    D.3.2Product code [Sandimmun Neoral ]
    D.3.4Pharmaceutical form Capsule, soft
    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 INN00070500
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameCICLOSPORINA
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 2
    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.2.1.1.1Trade name SANDIMMUN NEORAL - 25 MG CAPSULE MOLLI 50 CAPSULE
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    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 nameSandimmun Neoral
    D.3.2Product code [Sandimmun Neoral]
    D.3.4Pharmaceutical form Capsule, soft
    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 INN00070500
    D.3.9.2Current sponsor code-
    D.3.9.3Other descriptive nameCICLOSPORINA
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 3
    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.2.1.1.1Trade name SANDIMMUN NEORAL - 50 MG CAPSULE MOLLI 50 CAPSULE
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    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 nameSandimmun Neoral
    D.3.2Product code [Sandimmun Neoral]
    D.3.4Pharmaceutical form Capsule, soft
    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 INN00070500
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 4
    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.2.1.1.1Trade name SANDIMMUN NEORAL - 100 MG CAPSULE MOLLI 30 CAPSULE
    D.2.1.1.2Name of the Marketing Authorisation holderNOVARTIS EUROPHARM LTD
    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 nameSandimmun Neoral
    D.3.2Product code [Sandimmun Neoral]
    D.3.4Pharmaceutical form Capsule, soft
    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 INN00070500
    D.3.9.2Current sponsor code-
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number100
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 5
    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.2.1.1.1Trade name REVOLADE - 25 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER(PA/ALU/PVC/ALU) 28 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderGLAXOSMITHKLINE TRADING SERVICES LTD
    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 nameEltrombopag
    D.3.2Product code [ETB115]
    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 INN00319301
    D.3.9.1CAS number 496775-61-2
    D.3.9.2Current sponsor codeETB115
    D.3.9.3Other descriptive nameEltrombopag
    D.3.9.4EV Substance CodeSUB30140
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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.IMP: 6
    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.2.1.1.1Trade name REVOLADE - 50 MG - COMPRESSA RIVESTITA CON FILM - USO ORALE - BLISTER(PA/ALU/PVC/ALU) 28 COMPRESSE
    D.2.1.1.2Name of the Marketing Authorisation holderGLAXOSMITHKLINE TRADING SERVICES LTD
    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 nameEltrombopag
    D.3.2Product code [ETB115]
    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 INN00319301
    D.3.9.1CAS number 496775-61-2
    D.3.9.2Current sponsor codeETB115
    D.3.9.3Other descriptive nameEltrombopag
    D.3.9.4EV Substance CodeSUB30140
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Information not present in EudraCT
    D.3.11.3.2Gene therapy medical product Information not present in EudraCT
    D.3.11.3.3Tissue Engineered Product Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    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
    First-line severe aplastic anaemia
    Terapia di prima linea, nei pazienti con anemia aplastica acquisita grave
    E.1.1.1Medical condition in easily understood language
    First-line severe aplastic anaemia
    Terapia di prima linea, nei pazienti con anemia aplastica acquisita grave
    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 20.0
    E.1.2Level PT
    E.1.2Classification code 10002967
    E.1.2Term Aplastic anaemia
    E.1.2System Organ Class 10005329 - Blood and lymphatic system disorders
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Evaluate the effectiveness of eltrombopag + ciclosporin as first-line therapy on the overall hematologic response (partial response and complete response) within 6 months.
    Valutare l’efficacia di eltrombopag + ciclosporina come terapia di prima linea sulla risposta ematologica complessiva (risposta parziale e risposta completa) entro 6 mesi.
    E.2.2Secondary objectives of the trial
    The following secondary objectives will be evaluated at 6 months (all patients), and 24 months (responder only), as appropriate, and will be reported on a cumulative basis.
    Necessary to evaluate:
    - effect of eltrombopag + cyclosporine on the overall hematologic response (partial response and complete response) at 3 months and 12 months;
    - duration of hematologic response;
    - percentage of patients showing recurrence;
    - clonal evolution to myelodysplasia, paroxysmal nocturnal hemoglobinuria (PNH) and leukemia;
    - Red blood cell transfusion (RBC) addiction;
    - need for platelet transfusions;
    -longer time interval without blood and platelet transfusions;
    -effect of Eltrombopag and cyclosporine on symptoms and quality of life related to the patient's health;
    - safety of use and tolerability of eltrombopag + ciclosporin;
    -Characterize the pharmacokinetics of eltrombopag when associated with cyclosporine;
    I seguenti obiettivi secondari saranno valutati a 6 mesi (tutti i pazienti), e 24 mesi (solo responder), come appropriato, e saranno riportati su base cumulativa.
    Necessari per valutare:
    - effetto di eltrombopag + ciclosporina sulla risposta ematologica complessiva (risposta parziale e risposta completa) a 3 mesi e a 12 mesi;
    - durata della risposta ematologica;
    - percentuale di pazienti che manifesta recidiva
    - evoluzione clonale a mielodisplasia, emoglobinuria parossistica notturna (PNH) e leucemia;
    - dipendenza dalle trasfusioni di sangue globuli rossi (RBC);
    - necessità di trasfusioni di piastrine;
    - intervallo di tempo più lungo senza trasfusioni di sangue e di piastrine;
    - effetto di Eltrombopag e ciclosporina sui sintomi e sulla qualità della vita correlata alla salute del paziente;
    - sicurezza d’impiego e la tollerabilità di eltrombopag + ciclosporina;
    -Caratterizzare la farmacocinetica di eltrombopag quando associato a ciclosporina;
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Patient has signed the Informed Consent (ICF) prior to any screening procedures being performed.
    2.Patient is male/female > 18 years old at the time of informed consent and able to swallow a tablet.
    3.Patient has SAA characterized by:
    a.Bone marrow cellularity <30% (excluding lymphocytes) and
    b.At least two of the following (peripheral blood):
    •Absolute neutrophil count <500/ µL
    •Platelet count <20,000/ µL
    •Absolute reticulocyte count <60,000/ µL
    4.Normal ECG defined as the following as determined via the mean of a triplicate ECG
    • Resting heart rate
    •QTcF at screening <450 msec (male patients), 460 msec (female patients)
    1. Pazienti che hanno firmato il consenso informato (ICF) scritto prima di qualsiasi procedura di screening;
    2. Pazienti di entrambi i generi, di età > 18 anni al momento del consenso informato e che riescono a deglutire una compressa.
    3. I pazienti sono affetti da anemia aplastica grave caratterizzata da:
    Cellularità del midollo osseo < 30% (esclusi linfociti) e
    - Almeno due dei seguenti (sangue periferico):
    - Conta neutrofilica assoluta < 500/µL
    - Conta piastrinica < 20.000/µL
    - Conta reticolocitaria assoluta < 60.000/µL
    4. ECG normale definito da quanto segue, determinato da una media di una triplice registrazione ECG
    - Frequenza cardiaca a riposo
    - QTcF allo screening < 450 msec (pazienti maschi), 460 msec (pazienti femmine).
    E.4Principal exclusion criteria
    1. Diagnosis of Fanconi anemia.
    2. Evidence of clonal bone marrow hematologic disorder on cytogenetics by centralized revision
    3. Previous immunosuppressive therapy with cyclosporine, alemtuzumab, rabbit or horse ATG and thrombopoietin receptor agonists (TPO-R).
    4. Hypersensitivity to eltrombopag or ciclosporin or their components and contraindications to ciclosporin.
    5. AST or ALT > 3 x ULN.
    6. Creatinine, total bilirubin and alkaline phosphatase > 3 x ULN.
    7. Patients with cirrhosis of the liver.
    8. Infection not adequately controlled with appropriate therapy; Patients who are infected with acquired immunodeficiency virus (HIV), hepatitis C virus or are positive for hepatitis B surface antigen (HbsAg). Enlistment is allowed in HCV-RNA negative patients.
    9. Agonic state or concomitance of liver, kidney, cardiac, neurological, pulmonary, infectious or metabolic pathology of such severity as to preclude the patient's ability to give consent, adhere to study procedures, tolerate protocol therapy, or patients with a life expectancy of less than 3 months.
    10. Patients with cancer who are not considered to be cured, are undergoing active chemotherapy or taking drugs with hematologic effects.
    11. Administration of an experimental drug within 30 days or 5 half-lives, whichever is longer, before administration of the first dose of the investigational treatment.
    12. Definition of pregnancy and contraceptive requirements: Pregnant or lactating women. Potentially fertile women or female partners of male patients, unless they use a highly effective method of contraception during the administration of treatment and for 3 months after discontinuation of the study treatment.
    13. Patients who do not understand the experimental nature of the study or who are unable to provide informed consent.
    14. Clinically relevant ECG changes that include cardiac arrhythmias (e.g., ventricular tachycardia), complete left branch block, high grade atrioventricular block, or inability to determine the QTcF interval at the ECG.
    15. Presence of heart disease or family history of sudden idiopathic death or congenital long QT syndrome.
    16. Risk factors for peak torsion including incorrect hypokalemia or hypomagnesemia, or use of concomitant drug(s) with a known risk of inducing prolonged QT interval that cannot be discontinued.
    17. ECOG performance status = 2.
    18. Patients under 40 years of age should be considered for bone marrow transplantation (HSCT) if HLA (human leukocyte antigen) comparison has been performed and a suitable compatible sibling donor is available and the patient is willing to undergo the transplant.
    1. Diagnosi di anemia di Fanconi.
    2. Evidenza di disturbo ematologico clonale del midollo osseo sulla citogenetica mediante revisione centralizzata
    3. Terapia immunosoppressiva precedente con ciclosporina, alemtuzumab, ATG di coniglio o di cavallo e agonisti del recettore della trombopoietina (TPO-R).
    4. Ipersensibilità a eltrombopag o ciclosporina o ai loro componenti e controindicazioni alla ciclosporina..
    5. AST o ALT > 3 x ULN.
    6. Creatinina, bilirubina totale e fosfatasi alcalina > 3 x ULN.
    7. Pazienti con cirrosi epatica.
    8. Infezione non adeguatamente controllata con terapia appropriata; Pazienti che sono affetti da infezione del virus dell’immunodeficienza acquisita (HIV), virus dell’epatite C o sono positivi all’antigene di superficie dell’epatite B (HbsAg). L’arruolamento è consentito nei pazienti HCV-RNA negativi.
    9. Stato agonico o concomitanza di patologia epatica, renale, cardiaca, neurologica, polmonare, infettiva o metabolica di tale gravità da precludere la capacità del paziente di fornire il proprio consenso, aderire alle procedure dello studio, tollerare la terapia del protocollo o pazienti con aspettativa di vita inferiore a 3 mesi.
    10. Pazienti con tumore che non sono considerati curati, sono in trattamento chemioterapico attivo o che assumono farmaci con effetti ematologici.
    11. Somministrazione di un farmaco sperimentale entro 30 giorni o 5 emivite, qualunque sia più lungo, prima della somministrazione della prima dose del trattamento in studio.
    12. Definizione di gravidanza e requisiti contraccettivi: Donne in gravidanza o allattamento. Le donne potenzialmente fertili o partner femminili dei pazienti maschi, a meno che non utilizzino un metodo contraccettivo di efficacia elevata durante la somministrazione del trattamento e per 3 mesi dopo la sospensione del trattamento in studio.
    13. Pazienti che non comprendono la natura sperimentale dello studio o non in grado di fornire il consenso informato.
    14. Alterazioni ECG clinicamente rilevanti che comprendono aritmie cardiache (per esempio, tachicardia ventricolare), blocco di branca sinistra completo, blocco atrioventricolare di grado elevato o impossibilità di determinare l’intervallo QTcF all’ECG.
    15. Presenza di cardiopatia o storia famigliare di morte improvvisa idiopatica o sindrome del QT lungo congenita.
    16. Fattori di rischio per torsione di punta comprese ipokaliemia o ipomagnesiemia non corrette, o impiego di farmaco/i concomitante/i con un rischio noto per indurre prolungamento dell’intervallo QT che non possono essere sospesi.
    17. ECOG performance status = 2.
    18. I pazienti di età inferiore a 40 anni devono essere considerati per il trapianto di midollo osseo (HSCT) se è stato eseguito il confronto HLA (antigene leucocitario umano) ed è disponibile un donatore fratello adatto compatibile e il paziente è disposto a sottoporsi al trapianto.
    E.5 End points
    E.5.1Primary end point(s)
    The primary analysis will be based on the calculation of the overall hematologic response rate observed within month 6 and its distribution a posteriori, using a beta-binomial model. The therapy with the association of eltrombopag + cyclosporine will be declared effective if the following criteria are met:
    a. Observed overall hematologic response rate ORR ="clinically significant" threshold (30%)
    b. The probability that the real ORR "is not clinically significant" (response =20% is less than 10%).
    L’analisi primaria sarà basata sul calcolo del tasso di risposta ematologica complessiva osservato entro il mese 6 e la sua distribuzione a posteriori, utilizzando un modello beta-binomiale. La terapia con l’associazione di eltrombopag + ciclosporina sarà dichiarata efficace se saranno soddisfatti i seguenti criteri:
    a. Tasso di risposta ematologica complessiva osservata ORR = soglia “clinicamente significativa” (30%)
    b. La probabilità che la ORR reale “non sia clinicamente significativa” (risposta =20% è inferiore al 10%
    E.5.1.1Timepoint(s) of evaluation of this end point
    Overall hematologic response rate by 6 months
    Tasso di risposta ematologico globale di 6 mesi
    E.5.2Secondary end point(s)
    The final analysis will be performed after all patients have completed 24 months of ciclosporin treatment or have discontinued ciclosporin treatment before 24 months.
    L'analisi finale sarà effettuata dopo che tutti i pazienti avranno completato i 24 mesi di trattamento con ciclosporina o avranno sospeso il trattamento con ciclosporina prima di 24 mesi.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Hematological response rate of 3 months, at 12 months and at 24 months
    Tasso di risposta ematologico di 3 mesi, a 12 mesi ed a 24 mesi
    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 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
    Biomarkers
    Biomarkers
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open No
    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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA10
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Brazil
    Hong Kong
    India
    Korea, Democratic People's Republic of
    Mexico
    Thailand
    Turkey
    Hungary
    Italy
    Netherlands
    Spain
    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
    LVLS
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years4
    E.8.9.1In the Member State concerned months9
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years4
    E.8.9.2In all countries concerned by the trial months9
    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: 35
    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 state6
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 17
    F.4.2.2In the whole clinical trial 50
    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)
    Second treatment line for SAA
    Trattamento in seconda linea per SAA
    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 Decision2019-06-14
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-06-04
    P. End of Trial
    P.End of Trial StatusCompleted
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