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    Summary
    EudraCT Number:2013-005535-24
    Sponsor's Protocol Code Number:ABROGATE-5527
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-02-11
    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 ConcernedIreland - HPRA
    A.2EudraCT number2013-005535-24
    A.3Full title of the trial
    Abatacept (CTLA4-Ig) for the Treatment of Relapsing, Non Severe, Granulomatosis with Polyangiitis (Wegener’s) (ABROGATE)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Abatacept (CTLA4-Ig) for the Treatment of Relapsing, Non Severe, Granulomatosis with Polyangiitis (Wegener’s) (ABROGATE)
    A.3.2Name or abbreviated title of the trial where available
    ABROGATE
    A.4.1Sponsor's protocol code numberABROGATE-5527
    A.5.2US NCT (ClinicalTrials.gov registry) numberNCT02108860
    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 of South Florida
    B.1.3.4CountryUnited States
    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 supportBristol-Myers Squibb
    B.4.2CountryUnited States
    B.4.1Name of organisation providing supportNational Institutes of Health
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversity of South Florida
    B.5.2Functional name of contact pointCristina Burroughs
    B.5.3 Address:
    B.5.3.1Street Address3650 Spectrum Blvd, Ste 100
    B.5.3.2Town/ cityTampa
    B.5.3.3Post code33612
    B.5.3.4CountryUnited States
    B.5.4Telephone number+001813396-9237
    B.5.5Fax number+001877775-7987
    B.5.6E-mailabrogate@epi.usf.edu
    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 Orencia
    D.2.1.1.2Name of the Marketing Authorisation holderBristol Myers Squibb
    D.2.1.2Country which granted the Marketing AuthorisationUnited Kingdom
    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 nameAbatacept (CTLA4-Ig)
    D.3.4Pharmaceutical form Suspension for injection in pre-filled syringe
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNABATACEPT
    D.3.9.1CAS number 332348-12-6
    D.3.9.4EV Substance CodeSUB20635
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125
    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 No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 injection in pre-filled syringe
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Relapsing, Non Severe, Granulomatosis with Polyangiitis (Wegener’s)
    E.1.1.1Medical condition in easily understood language
    GPA (Wegener's Granulomatosis), a type of systemic vasculitis characterised by inflammation of the small blood vessels, including capillaries.
    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 20.0
    E.1.2Level LLT
    E.1.2Classification code 10047889
    E.1.2Term Wegeners granulomatosis
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.0
    E.1.2Level LLT
    E.1.2Classification code 10047888
    E.1.2Term Wegener's granulomatosis
    E.1.2System Organ Class 100000004866
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 20.1
    E.1.2Level PT
    E.1.2Classification code 10050894
    E.1.2Term Anti-neutrophil cytoplasmic antibody positive vasculitis
    E.1.2System Organ Class 10021428 - Immune 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
    This multicenter, randomized, placebo-controlled phase III trial will seek to determine the efficacy of abatacept to reduce the treatment failure rate
    E.2.2Secondary objectives of the trial
    The secondary study objectives include determining:
    • Duration of glucocorticoid-free periods
    • Severity of relapses in those treated with abatacept versus placebo
    • Health-related quality of life in those treated with abatacept versus placebo
    • Prevention of disease- or treatment-related damage with abatacept versus placebo
    • Safety of abatacept in GPA
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients must be considered as being best characterized as GPA and not microscopic polyangiitis (MPA) or
    eosinophilic granulomatosis with polyangiitis (EGPA) and must have met at least 2 of the 5 modified ACR
    classification criteria for GPA. These do not need to be present at the time of study entry. The modified ACR criteria are:
    a. Nasal or oral inflammation, defined as the development of painful or painless oral ulcers or purulent or bloody
    nasal discharge
    b. Abnormal chest radiograph, defined as the presence of nodules, fixed infiltrates, or cavities
    c. Active urinary sediment, defined as microscopic hematuria (>5 red
    blood cells per high power field) or red blood cell casts
    d. Granulomatous inflammation on biopsy, defined as histologic changes showing granulomatous inflammation
    within the wall of an artery or in the perivascular or extravascular area (artery or arteriole)
    e. Positive anti-neutrophil cytoplasmic antibody (ANCA) test specific for proteinase-3 or myeloperoxidase measured by
    enzyme-linked immunoassay
    2. Relapse of GPA within the 28 days prior to screening where the active disease features meet the following definition
    of non-severe disease:
    a. No disease manifestations that would be scored as a major element in the BVAS/WG
    b. Absence of any disease feature that poses an immediate threat to either a critical individual organ or the patient's
    life
    3. Age of 15 years or older
    4. Willing and able to comply with treatment and follow-up procedures
    5. Both women and men must be willing to use an effective means of birth control while receiving treatment through
    this study. Women should continue the use of an effective means of birth control for a minimum of 14 weeks after the
    last dose of study drug.
    Effective contraception methods include abstinence, oral contraceptives (birth control pills), IUD, diaphragm, Norplant,
    approved hormone injections, condoms, or medical sterilization. If applicable, participating sites will defer to their local
    authorities if they require stricter guidelines on the types of allowable contraception methods.
    6. Willing and able to provide written informed consent (and written assent of minor participants if applicable.)
    E.4Principal exclusion criteria
    1. Presence of involvement that does not meet the criteria for nonsevere disease
    2. Treatment with CYC within 3 months prior to screening
    3. Treatment with methylprednisolone 1000 mg within 28 days prior to enrollment
    4. Treatment with prednisone or prednisolone > 30 mg/day for > 28 days immediately prior to study entry
    5. Initiation or dose increase of the maintenance immunosuppressive agent (MTX, AZA, MA, LEF) within 3 months prior to screening
    6. Evidence of active infection (includes chronic infection)
    7. Patients who are pregnant or who are nursing infants
    8. Known infection with human immunodeficiency virus (HIV), hepatitis C, or a positive hepatitis B surface antigen
    9. Inability to comply with study guidelines
    10. Cytopenia: platelet count < 100,000/mm3, white blood cell count (WBC) < 3,000/mm3
    (3 x 109/L), absolute neutrophil count < 1500/mm3, hemoglobin (Hgb) < 8.5 g/dL
    11. Chronic renal insufficiency defined by a creatinine clearance of less
    than or equal to 20 ml/min
    12. AST or ALT > 3 times above the upper limit of the normal laboratory range
    13. Known current use of illegal drugs
    14. Other uncontrolled disease (co-morbidity) that could prevent a patient from fulfilling the study requirements or that would substantially increase the risk of study procedures
    15. History of malignancy within the past five years or any evidence of persistent malignancy, except fully excised basal cell or squamous cell carcinomas of the skin, or cervical carcinoma in situ which has been treated or excised in a curative procedure
    16. Receipt of an investigational agent or device within 30 days prior to enrollment or 5 half lives of the investigational drug (whichever is longer)
    17. A live vaccination fewer than 3 months before enrollment
    18. Current clinical, radiographic, or laboratory evidence of active tuberculosis
    19. A history of active tuberculosis within the past 3 years even if treated
    20. A history of active tuberculosis greater than 3 years ago unless there is documentation of prior anti-tuberculosis treatment of appropriate duration and type
    21. Latent tuberculosis unless there is documentation of prior antituberculosis treatment of appropriate duration and type
    22. Latent tuberculosis currently being treated with isoniazid (INH) or other therapy for latent tuberculosis given according to local health authority guidelines
    (e.g., Center for Disease Control) who have received such therapy for 4 weeks or less prior to
    randomization (Day 1). Subjects with a positive tuberculosis screening test indicative of latent tuberculosis will be eligible for the study if they have no evidence of current tuberculosis on chest x-ray at screening and they are actively being treated for tuberculosis with INH or other therapy for latent tuberculosis given according to local health authority guidelines (e.g., Center for Disease Control) that has been given for at least 4 weeks prior to randomization (Day 1).
    These subjects must complete treatment according to local health authority guidelines.
    23. History of herpes zoster that resolved less than 2 months prior to enrollment
    24. Treatment with rituximab or any other biologic B cell depleting agent
    within the past 6 months
    25. Treatment with alemtuzumab or anti-thymocyte globulin within the last 12 months
    26. Treatment with intravenous immunoglobulin given at an immunomodulatory dosage or plasma exchange within the past 3 months. Patients can be enrolled if they are otherwise eligible and receiving immunoglobulin replacement for hypogammaglobulinemia.
    27. Treatment with infliximab, etanercept, adalimumab, tocilizumab, or any other biologic agent within the past 3 months or 5 half lives of the agent (whichever is
    longer)
    E.5 End points
    E.5.1Primary end point(s)
    The primary study end point will be the ability of abatacept to reduce the treatment failure rate. (hazard rate).
    Treatment failure is defined to be relapse, disease worsening, or failure to achieve BVAS/WG = 0 or 1 by month 6 (as per Section 5h Outcome definitions). The primary statistical test will be the Wald test directly from the Cox model.
    A one-sided logrank test with an overall sample size of 59 subjects (29 in the control group and 30 in the experimental group) achieves 80.3% power at a 0.05 significance level to detect a hazard ratio of 0.4871 when the proportion relapse free in the control group is 40% at one year. This hazard ratio corresponds to 70% relapse-free survival at one year in the experimental group. The total study duration is projected to be 7 years of which subject accrual (entry) occurs in the first 6 years.
    The accrual pattern across the accrual period is uniform (all periods equal). Making allowances for a 10% drop out rate for whom outcome data are not available, the estimated total sample size is increased to 66.
    Should the drop-out rate exceed 10%, the sample size will be recalculated to maintain the study power based on the planning parameters. The primary analyses will be based upon intent to treat. The cumulative incidence of flares over time since randomization within each treatment group will be estimated using the Kaplan-Meier method (proportion surviving flare-free as a function of time).
    The difference between groups in the cumulative incidence functions, and the associated hazard functions, will be tested at the 0.05 level, onesided, using the Cox Proportional Hazards (PH) model. The hazard ratio of flare onset between treatment arms will be estimated from the PH model.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 months following randomization
    E.5.2Secondary end point(s)
    The secondary endpoints for this trial include:
    • Duration of glucocorticoid-free periods
    • Severity of relapses in those treated with abatacept versus placebo
    • Health-related quality of life in those treated with abatacept versus placebo
    • Prevention of disease-or treatment-related damage with abatacept versus placebo
    • Safety of abatacept in GPA
    E.5.2.1Timepoint(s) of evaluation of this end point
    Assessment of the secondary objectives will be every 3 months:
    • Cumulative glucocorticoid exposure based on time and dosage
    • Duration of time BVAS/WG = 0 or 1
    • BVAS/WG at the time of relapse
    • Patient-reported outcomes (SF-36, PROMIS, patient global assessment)
    • Change in damage score using Combined Damage Assessment (CDA)
    • Infection rate in those treated with abatacept versus placebo
    • Severe adverse events rate in those treated with abatacept versus placebo
    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 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 Yes
    E.8.1.7.1Other trial design description
    open label option after
    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 Yes
    E.8.4 The trial involves multiple sites in the Member State concerned No
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA12
    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
    Australia
    Canada
    Mexico
    United States
    Belgium
    France
    Ireland
    Italy
    Spain
    Sweden
    Switzerland
    United Kingdom
    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
    Closing date will be 12 months following randomization of final patient.
    New patient accrual will be suspended in the event of the occurrence of any of the following:
    • Any deaths related to GPA
    • Any drug-related deaths or grade 4 toxicity
    Upon enrollment suspension, a full report regarding the events leading to suspension and the overall study course will be submitted to the DSMB for determination as to whether the study should be permanently halted.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months48
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months48
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Information not present in EudraCT
    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) Information not present in EudraCT
    F.1.3Elderly (>=65 years) Information not present in EudraCT
    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 40
    F.4.2.2In the whole clinical trial 66
    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)
    Patients who meet criteria for discontinuation of study drug will be taken off abatacept/placebo or open-label abatacept and be treated with best medical judgment standard therapy that may consist of reinstitution or increase of prednisone and use of other immunosuppressive agents as dictated by the manifestations and disease severity. Patients who undergo early termination will be asked to return for a post-treatment safety visit 3 months after stopping 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 Decision2016-04-08
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-05-04
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2023-07-25
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