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    Summary
    EudraCT Number:2017-002214-31
    Sponsor's Protocol Code Number:XmAb5871-06
    National Competent Authority:Netherlands - Competent Authority
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2018-08-09
    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 ConcernedNetherlands - Competent Authority
    A.2EudraCT number2017-002214-31
    A.3Full title of the trial
    A Phase 3, Multicenter, Randomized, Double-Blind, Placebo-Controlled Study to Evaluate the Efficacy and Safety of XmAb®5871 in Patients with IgG4-Related Disease (INDIGO)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Study to Evaluate The Safety And Effectiveness of XmAb®5871 In Patients With IgG4-Related Disease (INDIGO)
    A.4.1Sponsor's protocol code numberXmAb5871-06
    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 SponsorXencor, 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 supportXencor, Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationXencor Inc.
    B.5.2Functional name of contact pointDebra Zack, MD, PhD
    B.5.3 Address:
    B.5.3.1Street Address12481 High Bluff Dr., Suite 200
    B.5.3.2Town/ citySan Diego
    B.5.3.3Post codeCA 92130
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1626824 9095
    B.5.6E-maildzack@xencor.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 No
    D.2.5The IMP has been designated in this indication as an orphan drug in the Community Yes
    D.2.5.1Orphan drug designation numberEU/3/17/1962
    D.3 Description of the IMP
    D.3.2Product code XmAb5871
    D.3.4Pharmaceutical form Solution for injection/infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPSubdermal use (Noncurrent)
    Subcutaneous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNXmAb5871
    D.3.9.2Current sponsor codeXmAb5871
    D.3.9.3Other descriptive nameXMAB5871
    D.3.9.4EV Substance CodeSUB79476
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number125.0
    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 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 injection
    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
    IgG4-Related Disease
    E.1.1.1Medical condition in easily understood language
    IgG4-Related Disease
    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 10071581
    E.1.2Term IgG4 related sclerosing disease
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the effect of every other week subcutaneous (SC) administration of XmAb5871 on the time to IgG4-related disease (IgG4-RD) flare following an initial course of corticosteroid therapy in subjects with active IgG4-RD
    E.2.2Secondary objectives of the trial
    • To evaluate the effect of every other week SC administration of XmAb5871 on the proportion of subjects that remain free of IgG4-RD disease flares from randomization to Study Day 701 (Week 101)
    • To evaluate the effect of every other week SC administration of XmAb5871 on the type and cumulative amount of IgG4-RD rescue therapy administered from randomization to Study Day 701 (Week 101)
    • To evaluate the effect of every other week SC administration of XmAb5871 on the number and frequency of IgG4-RD disease flares from randomization to Study Day 701 (Week 101)
    • To evaluate differences between treatment arms in corticosteroid-associated toxicity as measured by the Glucocorticoid Toxicity Index (GTI)
    • To evaluate the safety and tolerability of every other week SC administration of XmAb5871 in subjects with active IgG4-RD
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female 12 years of age or older
    2. Able to provide written informed consent. For subjects 12 to 18 years of age, the adolescent signs a patient assent form, and the parent or the legal guardian must sign the ICF.
    3. Meet the ACR/EULAR classification criteria for IgG4-RD with a score of ≥ 20
    4. Must have active IgG4-RD signs/symptoms that require, as assessed by the Investigator, the initiation of corticosteroid therapy or the increase in background long-term corticosteroid therapy (if previously on a stable dose of ≤ 10 mg/day prednisone equivalent).
    5. An oral corticosteroid dose must be maintained at a stable dose for 14 to 28 days during the 28-day screening period prior to randomization.
    6. Must be able and willing to receive corticosteroid therapy during the induction phase of the trial and be able to taper off any systemic corticosteroid therapy per protocol
    7. Must be willing to stop other IgG4-RD directed medications during screening (eg. methotrexate, mycophenolate mofetil, 6-mercaptopurine or azathioprine).
    8. Female subjects of childbearing potential must agree to use a highly effective method of birth control from screening until 8 weeks after the last dose of XmAb5871/placebo is given. Women are considered to be of childbearing potential unless it is documented that they are premenarche OR over the age of 60 OR postmenopausal by history with no menses for 1 year and confirmed by follicle stimulating hormone (FSH) OR have a history of hysterectomy and/or bilateral oophorectomy OR have a history of bilateral tubal ligation. Highly effective methods of birth control include combined hormonal birth control (oral, intravaginal, transdermal) or progestogen-only hormonal contraception associated with inhibition of ovulation (oral, injectable, intrauterine), intrauterine devices (IUDs), intrauterine hormone-releasing system, bilateral tubal occlusion, vasectomy (in the male partner), or sexual abstinence. Sexual counseling of adolescent study subjects should take place prior to entrance into the study.
    9. No history of severe allergic reactions to monoclonal antibodies.
    10. Are able and willing to complete the entire study according to the study schedule.
    11. Are willing to forego other forms of experimental treatment during the study.
    E.4Principal exclusion criteria
    1. Any Exclusion Criteria as listed in the ACR/EULAR IgG4-RD Classification Criteria (see Appendix 1 of Protocol)
    2. Initiation of corticosteroid therapy (or increase in long-term corticosteroid therapy) for new or exacerbated signs/symptoms of IgG4-RD > 14 days before enrolment
    3. Corticosteroid dose has exceeded 60 mg/day prednisone equivalent given orally within 14 days prior to screening or will exceed 60 mg/day during the screening .period.
    4. Corticosteroids have been given by the IV or IM route within 14 days prior to screening or will be given by these routes of administration during the screening period.
    5. IgG4-RD requiring long-standing corticosteroid therapy at a dose of > 10 mg/day prednisone equivalent
    6. Subjects with disease in only 1 organ system whose primary manifestation is fibrosis (for example, neuro-meningeal involvement, retroperitoneal fibrosis, fibrosing or sclerosing mesenteritis) will be excluded.
    7. History or evidence of a clinically unstable/uncontrolled disorder, condition or disease (including but not limited to cardiopulmonary, oncologic, renal, hepatic, metabolic, hematologic or psychiatric) other than IgG4-RD that, in the opinion of the Investigator would pose a risk to subject safety or interfere with the study evaluation, procedures or completion.
    8. Malignancy within 5 years (except successfully treated in situ cervical cancer, resected squamous cell or basal cell carcinoma of the skin, breast cancer with no recurrence ≥ 5 years following therapy, or prostate cancer with no recurrence ≥3 years following prostatectomy).
    9. Presence of recurrent or chronic infections, defined as ≥3 infections requiring antimicrobials over the past 6 months prior to screening.
    10. Active infection requiring hospitalization or treatment with parenteral antimicrobials within the 30 days prior to randomization or oral antimicrobials within the 14 days prior to randomization.
    11. Prior use of rituximab (or other B cell depleting agents) within 5 months of randomization.
    12. Use of any investigational agent within 5 half-lives of the agent (or 3 months if the half-life is unknown) prior to randomization.
    13. White blood cell count < 2.5 x 103/μL.
    14. Absolute neutrophil count (ANC) < 1.0 x 103/μL.
    15. Elevated serum creatinine > 2.5 x upper limit of normal (ULN) OR estimated creatinine clearance < 40 mL/minutes calculated by the Cockroft-Gault formula at screening.
    16. Hemoglobin < 10 g/dL.
    17. Platelet count < 75 x 109/L.
    18. Positive test result for human immunodeficiency virus (HIV) I and II antibody, hepatitis B surface antigen, (HBsAg), hepatitis B core antibody (HBcAb), or hepatitis C virus antibody (HCV Ab).
    19. Has received live vaccines within 4 weeks before randomization.
    20. Inability to communicate reliably with the Investigator.
    21. Subject is pregnant or breast feeding or planning to become pregnant while enrolled in the study.
    22. Positive urine pregnancy test at screening or during the study.
    23. Subjects who do not agree to use medically acceptable methods of contraception.
    24. Known or suspected sensitivity to mammalian cell-derived products or any components of the study drug.
    25. Unable or unwilling to partake in follow-up assessments or required protocol procedures.
    E.5 End points
    E.5.1Primary end point(s)
    Time to IgG4-RD disease flare (TDF), defined as the reappearance of signs/symptoms of IgG4-RD or the appearance of new signs/symptoms of IgG4-RD, that requires IgG4-RD rescue therapy. Subjects will have met the following criteria for IgG4-RD disease flare if at any time point during the study, after randomization, up to and including Study Day 701 (Week 101):
    1. There has been a worsening of IgG4-RD RI of at least 1, AND
    2. There is evidence of worsening of disease by change in physical exam, change in imaging, or change in biochemical parameters, AND
    3. The Investigator assesses that there is a need for the institution of rescue therapy (ie, any IgG4-RD directed therapy, including but not limited to, additional corticosteroid dose or duration other than protocol-specified amounts, methotrexate, azathioprine, mycophenylate mofetil, B-cell depleting therapy, or other investigational therapy)
    E.5.1.1Timepoint(s) of evaluation of this end point
    any time point
    E.5.2Secondary end point(s)
    Secondary Efficacy:
    • The proportion of subjects that remain free of IgG4-RD disease flares from randomization to Study Day 701 (Week 101)
    • Type and cumulative amount of IgG4-RD rescue therapy usage from randomization to Study Day 701 (Week 101)
    • Number and frequency of IgG4-RD disease flares from randomization to Study Day 701 (Week 101) or study withdrawal

    Secondary Safety:
    • Incidence of AEs
    • Incidence of AEs related to corticosteroids or other rescue therapies
    • Glucocorticoid Toxicity Index (GTI)Vital signs assessment
    • Clinical laboratory assessments
    • ECG assessments
    Secondary Immunogenicity:
    • Frequency and titer of serum anti-XmAb5871 antibodies (ADA); association with AEs and changes in effective exposure
    Secondary Pharmacokinetic:
    • Trough serum concentrations of XmAb5871
    Secondary Pharmacodynamic:
    • Change from baseline in ABC count
    • Change from baseline in B cell CD19 RO
    • Change from baseline in serum IgG4 concentration
    • Change from baseline in B cell qPCR IgG4/IgG BCR RNA ratio (exploratory studies may be done on this sample to elucidate B- and T-cell receptor repertoires and major histocompatibility complex alleles; if done, these may be reported in a separate report)
    • Change from baseline in circulating plasmablast count (may be performed at selected sites)
    • Change from baseline in circulating CD4+ CTLs (may be performed at selected sites)
    • Change from baseline pancreatic endocrine and exocrine function
    Secondary Pharmacogenomics:
    • Incidence of FcγRIIa R131H polymorphism
    • Incidence of FcγRIIb I232T polymorphism
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 101, for other time points see protocol
    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 EEA40
    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
    Canada
    Czech Republic
    France
    Germany
    Hungary
    Israel
    Italy
    Netherlands
    Poland
    Spain
    Sweden
    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
    LVLS
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years6
    E.8.9.1In the Member State concerned months5
    E.8.9.1In the Member State concerned days2
    E.8.9.2In all countries concerned by the trial years6
    E.8.9.2In all countries concerned by the trial months5
    E.8.9.2In all countries concerned by the trial days2
    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: 2
    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) Yes
    F.1.1.6.1Number of subjects for this age range: 2
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 143
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 95
    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 state8
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 143
    F.4.2.2In the whole clinical trial 240
    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)
    None
    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 Decision2018-08-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-07-23
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2020-01-14
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