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    Summary
    EudraCT Number:2015-000726-11
    Sponsor's Protocol Code Number:SHP616-302
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2015-11-13
    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 ConcernedGermany - PEI
    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
    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
    A.4.1Sponsor's protocol code numberSHP616-302
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02547220
    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.5.6E-mailjbernier@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
    E.1.1.1Medical condition in easily understood language
    Graft rejection in kidney transplant patients.
    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 20.0
    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 Cinryze administered with plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free intravenous immunoglobulin (IVIg) for the treatment of acute antibody-mediated rejection (AMR) of renal allograft in kidney transplant recipients as measured by the proportion of subjects with new or worsening transplant glomerulopathy (TG) at 6 months after treatment initiation.
    E.2.2Secondary objectives of the trial
    To evaluate the efficacy of Cinryze administered with plasmapheresis, plasma exchange, or immune adsorption treatments and sucrose-free IVIg for the treatment of acute AMR of renal allograft in kidney transplant recipients as measured by the proportion of subjects with all cause graft failure at 4 years following treatment of the initial qualifying AMR episode.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1.Be ≥ 18 and ≤70 years of age.
    2.Weigh ≥45 kg with a body mass index (BMI) <35 kg/m2 at screening.
    3.Have HLA DSA identified at the time of diagnosis of AMR. If it is anticipated that the local DSA results will not be available within the screening period, previously obtained local DSA results can be used to assess eligibility, if obtained after kidney transplant and within 30 days prior to the qualifying AMR episode. In any instance, a local DSA test should still be performed at the time of AMR diagnosis.
    4.Have a first qualifying episode of AMR in the subject’s current renal allograft between 72 hours and 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 according to 2013 Banff criteria for AMR.
    5.Have achieved adequate renal function defined as: Pre-AMR baseline eGFRMDRD ≥20 mL/min/1.73m2 for a qualifying AMR episode occurring ≤21 days after transplant or pre-AMR baseline eGFRMDRD ≥30 mL/min/1.73m2 for a qualifying AMR episode occurring >21 days after transplant. The pre-AMR baseline is the highest eGFRMDRD value obtained following the kidney transplant and within 30 days prior to the qualifying AMR episode. If more than one eGFRMDRD value is available, a mean of the 2 highest values (at least 1 day apart and both prior to the AMR episode) will be used as the pre-AMR baseline value. If no eGFRMDRD was obtained within 30 days prior to biopsy, it can be evaluated within a 60 day period.
    6.Receive first dose of investigational product at least 7 days after kidney transplant and within 7 days after the qualifying renal allograft biopsy procedure that was positive for AMR.
    7.Be informed of the nature of the study and provide written informed consent before any study-specific procedures are performed.
    8.If female and of child-bearing potential, 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.
    9.Agree to comply with any applicable contraceptive requirements of the protocol.
    E.4Principal exclusion criteria
    1.Have received pediatric en bloc kidney transplant.
    2.Have primary Focal Segmental Glomerulosclerosis, rapidly progressive glomerulonephritis,membrano-proliferative glomerulonephritis type 1 (including C3 Glomerulopathy), “dense deposit disease”, or Thrombotic microangiopathy as the cause of native kidney failure.
    3.Have prior or concurrent non-renal solid organ transplant or hematopoietic stem cell transplant (HSCT) or have more than 2 completed kidney transplant procedures (note: 1 double kidney transplant procedure is considered to be 1 procedure).
    4.Have a known neoplastic lesion in the transplanted allograft.
    5.Have, any ongoing infection that causes hemodynamic compromise or as determined by the investigator and/or medical monitor, any surgical or medical condition that could interfere with the administration of investigational product, interpretation of study results, or could compromise patient safety, 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.
    6.Have ongoing treatment for hepatitits C virus (HCV) infection.
    7.Have had a myocardial infarction (MI) within the past 6 months and/or at the time of screening are treated with anticoagulants and/or antiplatelet agents (excluding aspirin) for a previous myocardial infarction.
    8.Have a history of abnormal bleeding, clotting events or disorders (excluding a history of clotted hemodialysis access or superficial thrombophlebitis in the absence of medically-confirmed coagulopathy), any coagulopathy (documented or clinically suspected). For example, patients should be excluded if they have a history of renal allograft arterial or venous thrombosis, deep vein thrombosis, pulmonary embolism, ischemic cerebrovascular accident (stroke) or transient ischemic attack (TIA), any large vessel thrombosis.
    9.Have a history of allergic reaction to CINRYZE or other blood products.
    10.Have had any change in androgen therapy (eg, danazol, oxandrolone, stanozolol, testosterone), tranexamic acid, epsilon-aminocaproic acid, or other fibrinolytics within 3 months before the first dose of investigational product.
    11.Have participated in the active dosing phase of any other investigational drug study within 30 days prior to dosing with investigational product.
    12.Have any of the following local laboratory values reported prior to dosing with investigational product:
    Within 24 hours prior to subject dosing, white blood cell count <0.5×10^9/L or >20×10^9/L (the value of >20 x 10^9/L should be excluded if obtained during steroid treatment)
    Within 72 hours prior to dosing , platelet count <25×10^9/L or >600×10^9/L
    13. Be pregnant or breastfeeding.
    14. Have received any of the following agents within 1 month prior to the first dose of investigational product:
    Sucrose-containing IVIg
    Any C1 INH (plasma-derived [eg, CINRYZE®, Berinert®, Cetor®] or recombinant [eg, Rhucin®])
    Eculizumab (Soliris®)
    Ecallantide (Kalbitor®)
    E.5 End points
    E.5.1Primary end point(s)
    Proportion of subjects with new or worsening TG at 6 months after treatment initiation as determined by Banff criteria.
    E.5.1.1Timepoint(s) of evaluation of this end point
    6 months
    E.5.2Secondary end point(s)
    Proportion of subjects with all-cause graft failure (ie, return to permanent dialysis and/or removal of the transplanted kidney and/or clinical determination of cessation of graft function) at 4 years following treatment of the initial qualifying AMR episode.
    E.5.2.1Timepoint(s) of evaluation of this end point
    4 years
    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 EEA19
    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 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)
    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) Yes
    F.2 Gender
    F.2.1Female Yes
    F.2.2Male Yes
    F.3 Group of trial subjects
    F.3.1Healthy volunteers No
    F.3.2Patients Yes
    F.3.3Specific vulnerable populations Yes
    F.3.3.1Women of childbearing potential not using contraception No
    F.3.3.2Women of child-bearing potential using contraception Yes
    F.3.3.3Pregnant women No
    F.3.3.4Nursing women No
    F.3.3.5Emergency situation No
    F.3.3.6Subjects incapable of giving consent personally 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 state12
    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 Decision2015-12-07
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-25
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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