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    Summary
    EudraCT Number:2013-004668-71
    Sponsor's Protocol Code Number:11/0499
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Ongoing
    Date on which this record was first entered in the EudraCT database:2016-08-05
    Trial 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 ConcernedSpain - AEMPS
    A.2EudraCT number2013-004668-71
    A.3Full title of the trial
    An Open Label Randomised Controlled Trial of Mycophenolate Mofetil Versus Cyclophosphamide for the Induction of Remission of Childhood Polyarteritis Nodosa
    Ensayo clínico abierto controlado y aleatorizado de micofenolato mofetil (MMF) frente a ciclofosfamida para inducir la remisión en poliarteritis nodosa juvenil (PAN).
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of treatment for polyarteritis nodosa in children
    Estudio del tratamiento de la poliarteritis nodosa juvenil
    A.3.2Name or abbreviated title of the trial where available
    MYPAN
    A.4.1Sponsor's protocol code number11/0499
    A.5.4Other Identifiers
    Name:EudraCTNumber:2013-004668-71
    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 SponsorUniversity College London
    B.1.3.4CountryUnited Kingdom
    B.3.1 and B.3.2Status of the sponsorNon-Commercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportUCL
    B.4.2CountryUnited Kingdom
    B.4.1Name of organisation providing supportARUK
    B.4.2CountryUnited Kingdom
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity College London
    B.5.2Functional name of contact pointMrs Farhat Gilani
    B.5.3 Address:
    B.5.3.1Street AddressJoint Research Office, 1st Floor Maple House (Suite A), 149 Tottenham Court Road
    B.5.3.2Town/ cityLondon
    B.5.3.3Post codeW1T 7DN
    B.5.3.4CountryUnited Kingdom
    B.5.4Telephone number02076796594
    B.5.5Fax number02031082312
    B.5.6E-mailf.gilani@ucl.ac.uk
    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 CellCept
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCellCept (Mycophenolate Mofetil)
    D.3.4Pharmaceutical form Powder for oral suspension
    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 INNMycophenolate mofetil
    D.3.9.1CAS number 24280-93-1
    D.3.9.4EV Substance CodeAS1
    D.3.10 Strength
    D.3.10.1Concentration unit g/ml gram(s)/millilitre
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number1 to 5
    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.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 CellCept
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCellCept (Mycophenolate Mofetil)
    D.3.4Pharmaceutical form Capsule, hard
    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 INNMycophenolate mofetil
    D.3.9.1CAS number 24280-93-1
    D.3.9.4EV Substance CodeAS3
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number250
    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.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 CellCept (Mycophenolate Mofetil)
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCellCept (Mycophenolate Mofetil)
    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 INNMycophenolate mofetil
    D.3.9.1CAS number 24280-93-1
    D.3.9.4EV Substance CodeAS4
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number500
    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.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 Cyclophosphamide
    D.2.1.1.2Name of the Marketing Authorisation holderBaxter Healthcare Ltd
    D.2.1.2Country which granted the Marketing AuthorisationEuropean Union
    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 nameCyclophosphamide
    D.3.4Pharmaceutical form Powder for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    Oral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNCYCLOPHOSPHAMIDE
    D.3.9.1CAS number 50-18-0
    D.3.9.4EV Substance CodeSUB06859MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number20
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Childhood systemic polyarteritis nodosa (PAN)
    Poliarteritis nodosa juvenil (PAN)
    E.1.1.1Medical condition in easily understood language
    Polyarteritis nodosa (PAN)
    Poliarteritis nodosa (PAN)
    E.1.1.2Therapeutic area Diseases [C] - Immune System Diseases [C20]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.0
    E.1.2Level LLT
    E.1.2Classification code 10036026
    E.1.2Term Polyarteritis nodosa of childhood
    E.1.2System Organ Class 100000004866
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    Is mycophenelate mofetil (MMF) as effective as cyclophosphamide (CYC) at inducing remission in children with polyarteritis nodosa (PAN)?
    Es el micofenolato mofetil (MMF) tan efectivo como la ciclofosfamida (CYC) para inducir la remisión en niños con poliarteritis nodosa (PAN)?
    E.2.2Secondary objectives of the trial
    To determine whether there is a difference between CYC and MMF in terms of time to remission, vascular damage, side effects, impact on the patient (quality of life) and cost effectiveness to the health care provider.
    Determinar si existe una diferencia entre la CYC y el MMF en cuanto al tiempo hasta alcanzar la remisión, el daño vascular, los efectos secundarios, el impacto sobre el paciente (calidad de vida) y la coste efectividad para el proveedor de los servicios sanitarios
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Age at screening ≥ 4 and ≤ 18 years
    2. Children to be included must fulfil the new EULAR/PRINTO/PReS classification criteria for childhood systemic PAN (4) as defined by:
    Histopathological evidence of necrotising vasculitis in medium- or small-sized arteries or angiographic abnormality as a mandatory criterion (4); plus one of the following five:
    i. skin involvement
    ii. myalgia or muscle tenderness
    iii. hypertension
    iv. peripheral neuropathy
    v. renal involvement
    3. Newly diagnosed* and with active disease that would normally require treatment with CYC:
    i. One or more of major PVAS items (see below)
    ii. and / or three or more minor PVAS items,
    iii. and/or either of the two additional entry criteria:
    1. Severe systemic inflammation and/or features of macrophage activation syndrome due to PAN where the investigator would routinely use cyclophosphamide
    2. Demonstration of severe angiographic changes consistent with systemic PAN with other compatible clinical features, but not necessarily including the major PVAS items listed above

    4. Written informed consent for study participation obtained from the patient or parents / legal guardian, with assent as appropriate by the patient, depending on the level of understanding.

    Sufficient disease activity for trial entry (see inclusion criteria 3 above) requires at least one major or 3 minor PVAS items as listed below, and/or at least one of the additional criteria listed in the following section.


    Major PVAS items (indicated in bold in the PVAS form):
    Trial entry criteria or major relapse require the recurrence or new appearance of major organ involvement, if they are attributable to active vasculitis:
    1. Severe cutaneous vasculitis: significant infarct, ulcer or gangrene. Other significant cutaneous vasculitis such as widespread bullous vasculitic skin disease would also be an inclusion criterion.
    2. Threatened vision from any of: retinal vasculitis, retinal vessel thrombosis, scleritis, retinal exudates, or retinal haemorrhages.
    3. Major chest involvement: major pulmonary bleeding, with shifting pulmonary infiltrates; other causes of bleeding should be excluded if possible.
    4. Cardiovascular involvement: loss of pulses, bruits over accessible arteries, blood pressure discrepancy more than 10 mmHg in any limb, claudication of extremities, ischaemic cardiac pain, cardiomyopathy, congestive cardiac failure, valvular heart disease, pericarditis.
    5. Abdominal involvement: abdominal pain, blood in stools or bloody diarrhoea, or bowel ischaemia. Pancreatitis, whilst not specifically listed as a PVAS item, would also be an indication for inclusion.
    6. Renal involvement: hypertension, significant proteinuria, significant haematuria (if microscopic haematuria > 5 red blood cells per high power field, or red cell casts), GFR < 80 mls/min/1.73m2 , rise in creatinine > 10% or creatinine clearance (GFR) fall > 25%. Biopsy is strongly recommended for recurrent haematuria or unexplained rise in creatinine EXCEPT where large renal arterial aneurysms have been demonstrated.
    7. Nervous system involvement: meningitis or encephalitis, organic confusion /cognitive dysfunction, non-hypertensive seizures, stroke, cord lesion, cranial nerve palsy, sensory peripheral neuropathy, or motor mononeuritis multiplex. (Imaging of brain/cord providing supportive evidence that these lesions are due to vasculitis are usually present for those items pertaining to the brain or cord).


    Minor PVAS items:
    Minor entry criteria or minor relapse require the recurrence of disease activity of less severity, such as the following, if they are attributable to active vasculitis:
    1. Myalgia, arthralgia, arthritis
    2. Less severe cutaneous vasculitis: polymorphous exanthema; livedo reticularis; panniculitis; purpura; skin nodules; other less severe cutaneous vasculitic phenomena
    3. Mouth ulcers
    4. Non-imminently site threatening eye involvement: episcleritis; blepharitis; conjunctivitis; uveitis

    *Newly diagnosed is defined for the purposes of the trial as a diagnosis of systemic PAN less than 3 months (12 weeks) prior to screening for MYPAN. If the PAN diagnosis was more than 3 months (12 weeks) prior to the date of initial screening, please discuss with the Chief Investigator.
    1.        Edad en el screening ≥ 4 y ≤ 18 years
    2.        Los niños que sean incluidos deben cumplir con los nuevos criterios EULAR/PRINTO/PReS de clasificación de la PAN sistémica juvenil (4) definidos por:
    Evidencia histopatológica de vasculitis necrotizante de arterias de mediano o pequeño tamaño y de anomalía angiográfica como criterio mandatorio (4); además uno de los cinco siguientes:
    i.        afectación cutánea
    ii.        mialgia o dolor muscular
    iii.        hipertensión
    iv.        Neuropatía periférica
    v.        Afectación renal i
    3.        Recientemente diagnosticados* y con enfermedad activa que normalmente requerirían tratamiento con CYC:
    i.        Uno o más de los ítems mayores de PVAS (mirar más abajo)
    ii.        y / o tres o más de los ítems  de PVAS,
    iii.        y/o alguno de los dos criterios de entrada adicionales:
    1.        Inflamación sistémica severa y/o características de síndrome de activación macrofágica debido a la PAN en los que el investigador usaría de forma rutinaria la ciclofosfamida
    2.        Demostración de cambios angiográficos severos consistentes con PAN sistémica con otras características clínicas compatibles, pero no necesariamente incluyendo los ítems mayores de PVAS listados más arriba.

    4.        Consentimiento informado escrito para la participación en el estudio obtenido de los pacientes o de los padres/tutores legales del paciente con el asentimiento adecuado para el paciente dependiendo de su nivel de madurez y comprensión.

    Actividad de la enfermedad suficiente para entrar en el ensayo clínico (mirar el  criterio de inclusión 3 más arriba) requiere por lo menos uno de los ítems de PVAS mayores y 3 de los ítems de PVAS menores enumerados más abajo y/o por lo menos uno de los criterios adicionales enumerados en la siguiente sección.
    Ítems mayores de PVAS (indicados en negrita en el formulario de PVAS):
    Los criterios de entrada en el ensayo clínico o de recaída mayor requieren la recurrencia de la nueva aparición de afectación orgánica mayor siempre y cuando ésta sea atribuible a la vasculitis activa:
    1.        Vasculitis cutánea severa: infarto significativo, úlcera o gangrena. Otras vasculitis cutáneas significativas como la vasculitis bullosa cutánea diseminada  podrían también considerarse un criterio de inclusión.
    2.        Afectación visual con amenaza severa de la agudeza visual debido a cualquiera de las siguientes manifestaciones: vasculitis retiniana, trombosis de los vasos de la retina, escleritis, exudados retinianos, o hemorragia retiniana.
    3.        Afectación torácica mayor: sangrado pulmonar mayor, con infiltrados pulmonares migratorios; otras causas de sangrado deberían ser excluidas siempre que sea posible
    4.        Afectación cardiovascular: pérdida de pulsos, soplos sobre arterias accesibles, discrepancia en la presión sanguínea de más de 10 mmHg en cualquier extremidad, claudicación de las extremidades, dolor torácico isquémico, cardiomiopatía, insuficiencia cardíaca congestiva, valvulopatía cardíaca, pericarditis.
    5.        Afectación abdominal: dolor abdominal, sangre en las heces, o isquemia intestinal. La pancreatitis, aunque no esté en la lista de ítems de PVAS, podría ser un indicador de inclusión
    6.        Afectación renal: hipertensión, proteinuria significativa, hematuria significativa, FGR< 80 mls/min/1.73m2 , aumento de la creatinina > 10% o disminución del aclaramiento de la creatinina > 25%. La biopsia renal es muy recomendada para la hematuria recurrente o para el aumento inexplicado de la creatinina EXCEPTO cuando se demuestre la presencia de grandes aneurismas de la arteria renal.
    7.        Afectación del sistema nervioso: meningitis o encefalitis, confusión orgánica /disfunción cognitiva, convulsiones no hipertensivas, ictus, lesión medular, parálisis nerviosa de nervios craneales, neuropatía sensorial periférica o mononeuritis múltiple motora.
    Ítems menores de PVAS:
    Los criterios menores de entrada o de recaída menor requieren la recurrencia poco severa de la actividad de la enfermedad, como son los siguientes ítems, siempre y cuando éstos sean atribuibles a la vasculitis activa:
    1.        Mialgia, artralgia, artritis
    2.        Vasculitis cutánea menos severa: exantema polimorfo; livedo reticularis; paniculitis; púrpura; nódulos cutáneos; otros fenómenos vasculíticos menos severos.
    3.        Úlceras orales
    4.        Afectación visual sin inmediata amenaza de la agudeza visual debido a: episcleritis; blefaritis; conjuntivitis; uveítis
    *Recientemente diagnosticados se define para los propósitos del ensayo clínico, como el diagnóstico de la PAN sistémica menos de 3 meses (12 semanas) previos al screening para el MYPAN. Si el diagnóstico de  la PAN se realizó más de de 3 meses (12 semanas)  previos a la fecha del screening inicial, por favor, póngase en contacto con el investigador principal.
    E.4Principal exclusion criteria
    Exclusions related to vasculitis type and/ or severity
    1. Diagnosis of alternative vasculitic syndrome e.g. HSP, or ANCA vasculitis
    2. Patients requiring dialysis

    Exclusions related to general health
    3. Evidence of other significant uncontrolled concomitant disease that in the investigator’s view would preclude or interfere with patient participation. This will be recorded in the screening log.
    4. Primary or secondary immunodeficiency including known history of human immunodeficiency virus (HIV) infection
    5. Known active and/or chronic infection of any kind (excluding fungal nail and/or minor fungal skin infections)
    6. History of serious recurrent or chronic infection including tuberculosis (a screening chest radiograph will be performed if not performed within 12 weeks prior to randomisation)
    7. History of cancer, including solid tumours, haematologic malignancies and carcinoma in situ
    8. Participation in a clinical trial testing a medicinal product within 3 months (12 weeks) preceding randomisation for the MYPAN trial.

    Exclusions related to medications
    9. History of a severe allergic or anaphylactic reaction to any of the study medications or their excipients
    10. More than 3g of IV methylprednisolone within one month (4 weeks) prior to randomisation
    11. More than 3 weeks of oral prednisolone/prednisone at dose of 2mg/Kg once daily within one month (4 weeks) prior to randomisation
    12. Treatment with MMF or azathioprine for more than two weeks; or more than one intravenous dose of cyclophosphamide (>500 mg/m2) within one month (4 weeks) prior to randomisation
    13. Rituximab or high dose intravenous immunoglobulin within the last twelve months (48 weeks)
    14. Intolerance or contraindications to intravenous glucocorticoids
    15. Participant of reproductive potential not prepared to use a reliable means of contraception (e.g. hormonal contraceptive patch, intrauterine device, physical barrier) throughout study participation;
    a. Sexually active female not prepared to use two reliable forms of contraception for the complete duration of the trial


    Exclusions related to laboratory findings
    16. Positive urine human chorionic gonadotropin (hCG) measured at screening / (if appropriate) or a positive urine pregnancy test prior to study entry or breastfeeding
    17. Positive tests for hepatitis B surface antigen (HBsAg), hepatitis B core antibody (HBcAb) or hepatitis C serology at randomisation
    18. Absolute neutrophil count <1.5 x 109/l
    19. Estimated GFR <15 mL/min/1.73m2 (calculated using the Schwartz GFR formula – See section 7.4.2 for formula) at randomisation
    Exclusiones debidas al tipo o a la gravedad de la vasculitis:
    1.        Diagnóstico de otros síndromes vasculíticos como por ejemplo la PSH o la vasculitis ANCA positiva
    2.        Pacientes que requieran diálisis

    Exclusiones relacionadas con la salud en general
    3.        Evidencia de otras enfermedades concomitantes significativas y no controladas que según el investigador puedan influir con la participación del paciente. Esto se recogerá en el registro del screening.
    4.       Inmunodeficiencia primaria o secundaria incluyendo la historia conocida de infección crónica por el virus de la inmunodeficiencia humana (VIH).
    5.        El conocimiento de infección activa/o crónica de cualquier tipo (excluyendo la infección fúngica ungueal y/o infecciones fúngicas menores de la piel)
    6.        Historia de infecciones severas recurrentes o infección incluyendo la tuberculosis (se realizará un screening mediante radiografía de tórax sin no se ha realizado una radiografía de tórax 12 semanas antes de la aleatorización)
    7.        Historia de cáncer, incluyendo tumores sólidos, hematológicos y carcinoma in situ
    8.        Participación en un ensayo clínico que probase algún producto medicinal 3 meses (12 semanas) antes de la aleatorización para el ensayo MYPAN.

          Exclusiones relacionadas con las medicaciones
    9.        Historia de alergia severa o  de reacción anafiláctica a cualquiera de las medicaciones en estudio o a sus excipientes
    10.        Recibir más de 3g de metilprednisolona EV un mes (4 semanas) antes de la aleatorización
    11.        Recibir más de 3 semanas de prednisolona/prednisona oral a dosis de 2mg/Kg una vez al día dentro del once  mes (4 semanas) anterior a la aleatorización
    12.        Tratamiento con MMF or azatioprina por más de 2 semanas; o más de una dosis endovenosa de ciclofosfamida (>500 mg/m2) en el mes (4 semanas) previo a la aleatorización
    13.        Rituximab o altas dosis de inmunoglobulina endovenosa dentro de los 12 últimos meses (48 semanas)
    14.        Intolerancia o contraindicación a los glucocorticoides endovenosos
    15.        Participantes con potencial para reproducirse y no preparados para usar métodos anticonceptivos fiables (i.e. parche hormonal anticonceptivo, dispositivo intrauterino, barreras físicas) durante la participación en el estudio  
    a.        Mujer sexualmente activa no preparada para usar dos métodos anticonceptivos fiables como método anticonceptivo durante la durada del estudio


    Exclusiones relacionadas con los hallazgos del laboratorio
    16.        Hormona gonadotropina coriónica humana (hCG) positiva en orina al medirse en el screening / (cuando sea apropiado) o un test urinario de embarazo positivo previo a la entrada en el estudio o estar en período de lactancia
    17.       Positividad para el antígeno de superficie de la hepatitis B (HBsAg), el anticuerpo anticore de la hepatitis B (HBcAb) o serología positiva para la hepatitis C en la aleatorización
    18.        Cifra absoluta de neutrófilos <1.5 x 109/l
    19.        Estimación del FGR <15 mL/min/1.73m2 (calculado usando  la fórmula Schwartz– mirar la sección 7.4.2 para la fórmula) en la aleatorización
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients achieving remission within 6 months, as defined as a PVAS score of zero on two consecutive readings (both within six months of randomisation) more than one month apart, with adherence to the protocolised corticosteroid taper.
    Remisión dentro de seis meses (24 semanas) después de la aleatorización, definida por un marcador PVAS igual a cero en dos evaluaciones consecutivas a una distancia ≥ 1 mes (4 semanas), con adhesión a una reducción de corticoide de acuerdo con el protocolo.
    E.5.1.1Timepoint(s) of evaluation of this end point
    18 months (72 weeks)* per participant comprising: 3-6 months (12-24 weeks)* induction therapy (MMF or CYC; plus prednisolone for both).
    Followed by 12-15 months (48-60 weeks) azathioprine plus prednisolone for all. Trial ends after 18 months (72 weeks) treatment; an additional follow up visit for 39 of the 40 patients will occur at the date of the last patient last visit to capture as much longer term follow up data as possible
    18 meses (72 semanas)* por participante, que incluyen:
    3-6 meses (12-24 semanas)* con terapia de inducción (micofenolato mofetil o ciclofosfamida, más prednisolona para los dos).
    Después, 12-15 meses (48-60 semanas) de azatioprina y prednisolona para todos los participantes. El ensayo termina después de 18 meses (72 semanas) de tratamiento; para 39 de los 40 participantes se programará una visita adicional para que coincida con la última visita del último participante incluido en en ensayo, con el objetivo de obtener el mayor número posible de datos a largo plazo.
    E.5.2Secondary end point(s)
    1. Remission within six months (24 weeks) of randomisation defined as paediatric vasculitis activity score (PVAS) of zero on two consecutive readings ≥ one month (4 weeks) apart, irrespective of adherence to a protocolised corticosteroid taper
    2. Time to remission, defined as PVAS of zero on two consecutive readings ≥ one month (4 weeks) apart, with adherence to a protocolised corticosteroid taper, measured from randomisation
    3. Paediatric vasculitis damage index (PVDI; modified from the adult VDI) at 6, 12 and 18 months (24, 48 and 72 weeks) after randomisation
    4. A functional outcome score (CHAQ) and quality of life measure (CHQ) both of which are validated and available in the different translations (including English) required by the PRINTO centres involved in MYPAN; at 6, 12 and 18 months (24, 48 and 72 weeks) after randomisation
    5. Health economics measure: Health Utility Index II at 6, 12 and 18 months (24, 48 and 72 weeks)
    6. Cumulative corticosteroid dose (at 6 months (24 weeks) and 18 months (72 weeks)): especially important in paediatrics since corticosteroid-related growth retardation (in addition to all the other well documented side effects of corticosteroids that affect adults) is an important concern
    7. Growth parameters (height and weight, expressed as age/sex Z scores), and including body mass index at 18 months (72 weeks)
    8. Relapses (time to first relapse, and number of relapses) within 18 months (72 weeks) from randomisation
    9. Adverse events, including drug toxicity
    10. Withdrawal from trial due to drug intolerance
    11. MPA 12 hour trough plasma levels
    12. Time from randomisation to death
    1. Remisión dentro de seis meses (24 semanas) después de la aleatorización, definida por un marcador PVAS igual a cero en dos evaluaciones consecutivas a una distancia ≥ 1 mes (4 semanas), independientemente de la adhesión a una reducción de corticoide, de acuerdo con el protocolo;
    2. Tiempo de remisión definida la remisión por un marcador PVAS igual a cero en dos evaluaciones consecutivas a una distancia ≥ 1 mes (4 semanas), independientemente de la adhesión a una reducción de corticoide, de acuerdo con el protocolo;
    3. Evaluación del nivel de daño de la vasculitis pediátrica (PVDI: paediatric vasculitis damage index) a 6, 12 y 18 meses (24, 48 y 72 semanas);
    4. Cuestionario de evaluación funcional (CHAQ, cuestionario de evaluación de salud infantil) y evaluación de calidad de vida (CHQ, cuestionario de la salud infantil) a 6, 12 y 18 meses (24, 48 y 72 semanas);
    5. Análisis farmacoeconómico en términos de costos marginales por AVAC (años de vida ajustados por calidad) ganado, según el Child Health Utility 9D a 6, 12 y 18 meses (24, 48 y 72 semanas);
    6. Dosis acumulativa de corticoides a los 6 meses (24 semanas) y a los 18 meses (72 semanas): especialmente importante en pediatría debido a la preocupación por el retraso en el crecimiento que causan los corticoides ;
    7. Parámetros de crecimiento (talla y peso expresadas por Z-score por edad/sexo) y el índice de masa corporal;
    8. Recaídas (tiempo para la primera recaída y número de recaídas) dentro de 18 meses (72 semanas) desde el inicio de la terapia; 9. Eventos adversos incluyendo la toxicidad farmacológica;
    10. Retirada del estudio por intolerancia al fármaco;
    11. Concentración en plasma de ácido micofenólico (MPA) a las 12 horas;
    12. Muerte dentro de los 18 meses del estudio.
    E.5.2.1Timepoint(s) of evaluation of this end point
    18 months (72 weeks)* per participant comprising: 3-6 months (12-24 weeks)* induction therapy (MMF or CYC; plus prednisolone for both).
    Followed by 12-15 months (48-60 weeks) azathioprine plus prednisolone for all. Trial ends after 18 months (72 weeks) treatment; an additional follow up visit for 39 of the 40 patients will occur at the date of the last patient last visit to capture as much longer term follow up data as possible
    18 meses (72 semanas)* por participante, que incluyen:
    3-6 meses (12-24 semanas)* con terapia de inducción (micofenolato mofetil o ciclofosfamida, más prednisolona para los dos).
    Después, 12-15 meses (48-60 semanas) de azatioprina y prednisolona para todos los participantes. El ensayo termina después de 18 meses (72 semanas) de tratamiento; para 39 de los 40 participantes se programará una visita adicional para que coincida con la última visita del último participante incluido en en ensayo, con el objetivo de obtener el mayor número posible de datos a largo plazo.
    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 No
    E.6.7Pharmacodynamic No
    E.6.8Bioequivalence No
    E.6.9Dose response No
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic No
    E.6.12Pharmacoeconomic Yes
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    E.8.1.6Cross over No
    E.8.1.7Other No
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    E.8.2.2Placebo No
    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 concerned2
    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 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
    Belgium
    Croatia
    Czech Republic
    Germany
    Greece
    Italy
    Netherlands
    Poland
    Portugal
    Slovenia
    Spain
    Sweden
    Turkey
    United Kingdom
    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
    The end of the trial is the date of database lock as defined in the MYPAN Data Management Plan. At the time of database lock, data entry privileges are withdrawn from the trial database. However, the trial may be closed prematurely by the Trial Steering Committee, or on the recommendation of the Independent Data Safety and Monitoring Committee (IDSMC).

    The end of trial is not defied as last visit of the last patient because there will still be data queries following this point.
    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 months10
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months10
    E.8.9.2In all countries concerned by the trial days1
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    F.1.1Number of subjects for this age range: 40
    F.1.1.1In Utero No
    F.1.1.1.1Number of subjects for this age range: 0
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) No
    F.1.1.2.1Number of subjects for this age range: 0
    F.1.1.3Newborns (0-27 days) No
    F.1.1.3.1Number of subjects for this age range: 0
    F.1.1.4Infants and toddlers (28 days-23 months) No
    F.1.1.4.1Number of subjects for this age range: 0
    F.1.1.5Children (2-11years) Yes
    F.1.1.5.1Number of subjects for this age range: 20
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 20
    F.1.2Adults (18-64 years) No
    F.1.2.1Number of subjects for this age range: 0
    F.1.3Elderly (>=65 years) No
    F.1.3.1Number of subjects for this age range: 0
    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 No
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception No
    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 state5
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 40
    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)
    ParticipantswillreceivetrialtreatmentsCYC or MMF)foraminimumof3monthsandamaximumof6months.Fortheremainingtimeinthestudy theywillbeinfollowup.Duringthisfollowupperiod,andaftertheresearchhasfinished,iftheparticipanthasarelapsethenthedoctorresponsiblefortheircarewillmakethedecisionaboutwhatmedicationissuitabletotreatthem.Thismaybeoneofthedrugs usedforthestudyifthepatientrespondedparticularlywelltoitduringthestudy,butthisdecisionremainswiththetreatingclinician.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2016-10-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-08-03
    P. End of Trial
    P.End of Trial StatusOngoing
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