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    Summary
    EudraCT Number:2015-000726-11
    Sponsor's Protocol Code Number:SHP616-302
    National Competent Authority:Spain - AEMPS
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-12-21
    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 ConcernedSpain - AEMPS
    A.2EudraCT number2015-000726-11
    A.3Full title of the trial
    A randomized double-blind placebo-controlled study to evaluate the efficacy and safety of Cinryze® (C1 esterase inhibitor [human]) for the treatment of acute antibody-mediated rejection in kidney transplant patients
    Estudio aleatorizado, doble ciego y controlado con placebo para evaluar la eficacia y seguridad de Cinryze® (inhibidor de la esterasa C1 [humano]) para el tratamiento del rechazo agudo mediado por anticuerpos en pacientes receptores de un trasplante renal
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study to evaluate the effect of Cinryze® (C1 esterase inhibitor [human]) for the treatment of acute antibody-mediated rejection in kidney transplant patients
    Estudio para evaluar el efecto de Cinryze® (inhibidor de la esterasa C1 [humano]) para el tratamiento del rechazo agudo mediado por anticuerpos en pacientes receptores de un trasplante renal
    A.4.1Sponsor's protocol code numberSHP616-302
    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 SponsorShire Viropharma, Inc.
    B.1.3.4CountryUnited States
    B.3.1 and B.3.2Status of the sponsorCommercial
    B.4 Source(s) of Monetary or Material Support for the clinical trial:
    B.4.1Name of organisation providing supportShire
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationShire
    B.5.2Functional name of contact pointJeffrey Bernier
    B.5.3 Address:
    B.5.3.1Street Address300 Shire Way
    B.5.3.2Town/ cityLexington
    B.5.3.3Post codeMA 02 421
    B.5.3.4CountryUnited States
    B.5.4Telephone number+34914229372
    B.5.6E-mailInfoShireIberica@shire.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 Cinryze 500 Units powder and solvent for solution for injection
    D.2.1.1.2Name of the Marketing Authorisation holderViropharma Incorporated
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameCinryze®
    D.3.4Pharmaceutical form Powder and solvent for solution for injection
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNC1 inhibitor, human
    D.3.9.2Current sponsor codeVP20624
    D.3.9.3Other descriptive nameCOMPLEMENT C1 ESTERASE INHIBITOR
    D.3.9.4EV Substance CodeSUB22696
    D.3.10 Strength
    D.3.10.1Concentration unit U unit(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number500
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin No
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) Yes
    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 Yes
    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 placeboSolution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Acute Antibody Mediated Rejection (AMR) in kidney transplant patients
    Rechazo agudo mediado por anticuerpos en pacientes con trasplante renal
    E.1.1.1Medical condition in easily understood language
    Graft rejection in kidney transplant patients.
    Rechazo de injerto en pacientes con trasplante renal
    E.1.1.2Therapeutic area Body processes [G] - Immune system processes [G12]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 18.1
    E.1.2Level PT
    E.1.2Classification code 10023439
    E.1.2Term Kidney transplant rejection
    E.1.2System Organ Class 10021428 - Immune 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 evaluate the efficacy of 20,000 total units of Cinryze given intravenously in 7 doses over 13 days as an adjunct to plasmapheresis, plasma exchange, and/or immune adsorption treatments and intravenous immunoglobulin (IVIg) for the treatment of acute antibody-mediated rejection (of renal allograft) (AMR) in kidney transplant recipients as measured by the proportion of subjects with new or worsening transplant glomerulopathy (TG) within 6 months.
    El objetivo principal de este estudio es evaluar la eficacia de 20.000 unidades totales de Cinryze administradas por vía intravenosa en 7 dosis durante 13 días como complemento de la plasmaféresis, el recambio de plasma y/o los tratamientos de inmunoadsorción y la IgIV
    para el tratamiento del RMA agudo en receptores de trasplante renal, medida mediante el porcentaje de pacientes con GT nueva o agravada en un plazo de 6 meses.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of 20,000 total units of Cinryze given intravenously in 7 doses over 13 days as an adjunct to plasmapheresis, plasma exchange, and/or immune adsorption treatments and IVIg for the treatment of acute AMR in kidney transplant recipients as measured by the proportion of subjects with all cause graft failure.
    El objetivo secundario fundamental es evaluar la eficacia de 20.000 unidades totales de Cinryze administradas por vía intravenosa en 7 dosis durante 13 días como complemento de la plasmaféresis, el recambio de plasma y/o los tratamientos de inmunoadsorción y la IgIV
    para combatir el RMA agudo en receptores de trasplante renal, medida mediante el porcentaje de pacientes con fracaso del injerto por todas las causas.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    To be eligible for this protocol, a subject must:
    - Be >=18 years of age.
    - Weigh >= 40 kg.
    - Have had human leukocyte antigen (HLA) DSA identified at the time of diagnosis of AMR.
    - Have a first episode of AMR ("qualifying episode") in the subject´s current renal allograft within 12 months after transplant defined by a renal allograft biopsy demonstrating neutrophil and/or monocyte infiltration in the peritubular capillaries and/or glomeruli with or without evidence of C4d by immunohistopathology.
    - Have received a kidney transplant for which the qualifying episode of AMR was diagnosed and achieved an eGFR >=40 mL/minute within 3 months post-transplant as estimated by the MDRD formula.
    - Be able to receive first dose of study drug within 72 hours after the (qualifying) renal allograft biopsy that was diagnostic for AMR.
    - Be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
    - Subject, who is female, must have a negative urine pregnancy test confirmed by a negative serum beta human chorionic gonadotropin pregnancy test at the Screening Visit and must have a negative urine pregnancy test at the Day 1 visit, and agree to comply with any applicable contraceptive requirements of the protocol.
    - Tener >= 18 años de edad.
    - Pesar >= 40 kg.
    - Presentar AED contra HLA en el momento del diagnóstico del RMA.
    - Haber sufrido un primer episodio de RMA (?episodio calificador?) en el aloinjerto renal actual del paciente en los 12 meses siguientes al trasplante, definido mediante una biopsia del aloinjerto renal que demuestre la infiltración de neutrófilos o monocitos en los CPT o los glomérulos con o sin indicios de C4d mediante inmunohistopatología.
    - Haber recibido un trasplante renal en el que se diagnostique el episodio calificador de RMA y se obtenga una FGe >= 40 ml/minuto en los 3 meses siguientes al trasplante, según la fórmula de la MDRD.
    - Ser capaces de recibir la primera dosis del fármaco del estudio en un plazo de 72 horas después de la biopsia del aloinjerto renal (calificadora) diagnóstica del RMA.
    - Ser informados de la naturaleza del estudio y otorgar el consentimiento informado por escrito antes de someterse a ningún procedimiento específico del estudio.
    - Las mujeres deben tener un resultado negativo en una prueba de embarazo en orina confirmado por un resultado negativo en una prueba de embarazo en suero con gonadotropina coriónica humana beta (beta-HCG) en la visita de selección y deben tener una prueba de embarazo negativa en orina en la visita del día 1 y acceder a
    cumplir los requisitos anticonceptivos aplicables del protocolo.
    E.4Principal exclusion criteria
    Subjects are excluded from the study if any of the following exclusion criteria are met:
    - Have received pediatric en bloc kidney transplant.
    - Have focal sclerosing glomerulosclerosis, rapidly progressive glomerulonephritis, membrano proliferative glomerulonephritis type 1, or "dense deposit disease" as the cause of native kidney failure.
    - Have, as determined by the investigator and/or medical monitor, any surgical or medical condition that could interfere with the administration of study drug or interpretation of study results, including (as determined by the transplanting surgeon and documented in the operative report) any major technical complications of the renal artery, renal vein, or ureteral anastomosis.
    - Have any ongoing infection that causes hemodynamic compromise.
    - Have a history of abnormal bleeding, clotting, or any coagulopathy (excluding a history of clotted hemodialysis access or superficial thrombophlebitis in the absence of medically confirmed coagulopathy).
    - Have a history of allergic reaction to Cinryze or other blood products.
    - Have participated in the active dosing phase of any other investigational drug study within 30 days prior to dosing with study drug.
    - Have any of the following laboratory values within 48 hours prior to dosing with study drug:
    -- White blood cell count <0.5×109/L or >20×109/L
    -- Platelet count <25×109/L or >600×109/L
    - Be pregnant or breastfeeding.
    -Have received any of the following agents within 1 month prior to the first dose of study drug:
    -- Any C1 INH (plasma-derived [eg, Cinryze®, Berinert®, Cetor®] or recombinant [eg, Rhucin®])
    -- Eculizumab (Soliris®)
    -- Ecallantide (Kalbitor®)
    -- Bortezomib (Velcade®)
    Se excluirá del estudio a los pacientes que cumplan alguno de los criterios de exclusión siguientes:
    - Haber recibido un trasplante de riñón en bloque de donantes pediátricos.
    - Padecer glomeruloesclerosis esclerosante focal, glomerulonefritis rápidamente progresiva, glomerulonefritis membranoproliferativa de tipo 1 o ?enfermedad de depósitos densos? como causa de insuficiencia del riñón natural.
    - Tener, según lo determinado por el investigador y/o el monitor médico, cualquier proceso quirúrgico o médico que pueda interferir en la administración del fármaco del estudio o en la interpretación de los resultados del ensayo, como (según lo determinado por el cirujano encargado del trasplante y documentado en el informe quirúrgico) cualquier complicación técnica importante de la arteria renal o la vena renal, o anastomosis ureteral.
    - Padecer cualquier infección activa que tenga consecuencias hemodinámicas.
    - Tener antecedentes de hemorragia o coagulación anormal, o de cualquier coagulopatía (excluidos los antecedentes de acceso coagulado para la hemodiálisis o tromboflebitis superficial sin coagulopatía médicamente confirmada).
    - Tener antecedentes de reacción alérgica a Cinryze u otros hemoderivados.
    - Haber participado en la fase de administración activa de cualquier otro estudio con medicamentos en investigación en los 30 días previos a la administración del fármaco del ensayo.
    - Presentar cualquiera de los valores analíticos siguientes en las 48 horas previas a la administración del fármaco del estudio:
    ? Recuento de leucocitos < 0,5 × 109/l o > 20 × 109/l
    ? Recuento de plaquetas < 25 × 109/l o > 600 × 109/l
    - Estar embarazada o dando el pecho.
    - Haber recibido cualquiera de los medicamentos siguientes en el mes previo a la primera
    dosis del fármaco del estudio:
    ? Cualquier INH C1 (derivado del plasma [p. ej., Cinryze®, Berinert®, Cetor®] o
    recombinante [p ej., Rhucin®])
    ? Eculizumab (Soliris®)
    ? Ecallantida (Kalbitor®)
    ? Bortezomib (Velcade®)
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects with new or worsening TG within 6 months post treatment as determined by Banff criteria.
    Porcentaje de pacientes con GT nueva o agravada en los 6 meses siguientes al tratamiento según los criterios de Banff
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    6 meses
    E.5.2Secondary end point(s)
    - Time to all-cause graft failure
    - Proportion of subjects with graft failure due to AMR and time to graft failure due to AMR
    - Change from baseline in renal allograft function (eGFR as calculated by the MDRD formula)
    - Change from baseline in histopathology at Month 6 post treatment per Banff criteria
    - Time to first recurrence of biopsy-proven acute AMR after dosing
    - Change from baseline in serum Creatinine
    - Proportion of subjects with salvage splenectomy
    - Overall subject survival (proportion and time-to-event)
    - Frequency of DSA reduction therapy beyond protocol-mandated treatment
    - Tiempo transcurrido hasta el fracaso del injerto por todas las causas
    - Porcentaje de pacientes con fracaso del injerto por RMA y tiempo hasta el fracaso del injerto por RMA
    - Variación de la función del aloinjerto renal con respecto al momento basal (FGe calculada mediante la fórmula de MDRD)
    - Variación de la histopatología entre el momento basal y el sexto mes después del tratamiento según los criterios de Banff
    - Tiempo transcurrido hasta la primera recidiva del RMA agudo demostrado por biopsia tras la administración
    - Variación de la Cr sérica con respecto al valor basal
    - Porcentaje de pacientes con esplenectomía de rescate
    - Supervivencia global de los pacientes (proporción y tiempo hasta el acontecimiento)
    - Frecuencia del tratamiento reductor de los AED además del tratamiento exigido en el protocolo
    E.5.2.1Timepoint(s) of evaluation of this end point
    up to 4 years
    Hasta 4 años
    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 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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 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 concerned3
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA16
    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
    Canada
    France
    Germany
    Netherlands
    Spain
    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
    Last patient last visit (LPLV)
    Último paciente última visita
    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 months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years4
    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: 112
    F.1.3Elderly (>=65 years) No
    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 Yes
    F.3.3.7.1Details of other specific vulnerable populations
    Kidney transplant recipients
    F.4 Planned number of subjects to be included
    F.4.1In the member state10
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 40
    F.4.2.2In the whole clinical trial 112
    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)
    There are no plans for treatment with CINRYZE after the subject has ended his/her participation to the trial.
    Subjects will continue standard of care treatment.
    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 Decision2015-12-17
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-12-03
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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