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    Summary
    EudraCT Number:2012-003644-71
    Sponsor's Protocol Code Number:B1801355
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2013-02-06
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2012-003644-71
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled Study of the Safety and Efficacy of Etanercept in Subjects with Rheumatoid Arthritis Who Have Had and Inadequate Response to Adalimumab or Infliximab Plus Methotrexate.
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Randomized, Double-Blind, Placebo-Controlled Trial of etanercept plus methotrexate in monoclonal antibody (mAb) anti-TNF failure
    A.4.1Sponsor's protocol code numberB1801355
    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 SponsorPfizer 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 supportPfizer Inc.
    B.4.2CountryUnited States
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationPfizer Inc.
    B.5.2Functional name of contact pointClinicalTrials.gov Call Center
    B.5.3 Address:
    B.5.3.1Street Address235 East 42nd Street
    B.5.3.2Town/ cityNew York
    B.5.3.3Post codeNY 10017
    B.5.3.4CountryUnited States
    B.5.4Telephone number+1800718 1021
    B.5.5Fax number+1303739 1119
    B.5.6E-mailClinicalTrials.gov_Inquiries@pfizer.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 Enbrel
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer Ltd., Sandwich, Kent, UK
    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 nameEnbrel
    D.3.4Pharmaceutical form Solution 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 INNETANERCEPT
    D.3.9.1CAS number 185243-69-0
    D.3.9.4EV Substance CodeSUB01984MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 infusion 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
    Rheumatoid Arthritis
    E.1.1.1Medical condition in easily understood language
    Rheumatoid Arthritis
    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 16.1
    E.1.2Level PT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    E.1.2System Organ Class 10028395 - Musculoskeletal and connective tissue 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 compare the efficacy of etanercept to placebo in inadequate responders to infliximab or adalimumab plus methotrexate (MTX) in all subjects and in subjects who are anti-drug antibody positive (ADA+) to one of these monoclonal antibodies (mAbs).
    E.2.2Secondary objectives of the trial
    • To assess the effect of ADA status on the efficacy of etanercept in inadequate responders to infliximab or adalimumab plus MTX
    • To evaluate the safety of etanercept in inadequate responders to infliximab or adalimumab plus MTX.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Subject eligibility should be reviewed and documented by an
    appropriately qualified member of the investigator's study team before
    subjects are included in the study.
    Subjects must meet all of the following inclusion criteria to be eligible
    for enrollment into the study:
    1. Evidence of a personally signed and dated informed consent document indicating that the subject (or a legal representative) has been informed of all pertinent aspects of the study.
    2. Subjects who are willing and able to comply with scheduled visits,
    treatment plan, laboratory tests, and other study procedures.
    3. Subject is literate and able to complete the protocol-specified
    questionnaires.

    Period 1 Inclusion Criteria
    In addition to the criteria in Section 4.1, subjects must meet all of the
    following inclusion criteria to be eligible for enrollment into Period 1 of the study:
    1. Male or female ≥ 18 years and <80 years of age at the time of
    consent.
    2. Male and female subjects of childbearing potential must agree to use a highly effective method of contraception throughout the study and for at least 12 weeks after the last dose of assigned treatment. A subject is of childbearing potential if, in the opinion of the investigator, he/she is biologically capable of having children and is sexually active (see Section 4.5 Life Style Guidelines)..
    3. Met the 1987 ACR Revised Criteria for RA (see Appendix 1).
    4. A history of inadequate efficacy response to at least a 6-month course of either infliximab or adalimumab with at least the last 4 weeks before the screening visit receiving a combination of either infliximab plus MTX or adalimumab plus MTX.
    5. For subjects receiving infliximab, the last dose of infliximab must have
    been received ≥ 6 weeks before the screening mAb ADA test.
    6. For subjects receiving adalimumab, the last dose of adalimumab must have been taken ≥ 11 days before the screening mAb ADA test.
    7. Stable dose of oral MTX (10 mg QW to 25 mg QW) for ≥6 weeks
    before the baseline visit.
    8. Active RA at the screening visit, defined as all of the following:
    a. high-sensitivity C-reactive protein (hs-CRP) ≥ 1.0 mg/L
    b. ≥ 6 tender joints based on the 28 joint assessment (see Section
    7.1.5)
    c. ≥ 6 swollen joints based on the 28 joint assessment (see Section
    7.1.5)
    9. Active RA at the baseline visit, defined as all of the following:
    a. ≥ 6 tender joints based on the 28 joint assessment (see Section
    7.1.5)
    b. ≥ 6 swollen joints based on the 28 joint assessment (see Section
    7.1.5)
    10.In the opinion of the investigator, subject is a reasonable candidate
    for treatment with etanercept plus MTX.
    11.Either the subject or a designee must be capable (according to the
    investigator's judgment) of administering the SC investigational product
    and must be able to store all investigational product under required
    storage conditions or must be able to come to the study site for
    administrations where the investigational product may be stored on
    behalf of the subject.
    12.Active and latent tuberculosis (TB) must be ruled out by screening for TB in accordance with local country guidelines; subjects with recent
    exposure to active TB must be evaluated by a qualified physician to rule
    out TB (see Period 1 Exclusion Criteria 20).
    13.Female subjects of childbearing potential per the investigator's
    opinion must have negative urine pregnancy test results based on the
    screening visit and baseline visit tests (see Section 7.4.1 Pregnancy
    Testing). This includes subjects who are menstruating at the time of the
    visit and/or who are not sexually active.

    Escape Arm Inclusion Criteria
    The subject must meet all of the following criteria to be included in the
    Escape Arm of the study:
    1. The subject has completed the week 8 visit of the study.
    2. Less than 10% improvement in either the tender/painful joint count
    or the swollen joint count at the week 8 visit as compared to the
    baseline joint counts (see Appendix 1 for examples).
    Subject must be willing to continue stable dose of all RA medications
    that the subject is using at Week 8 through Week 24 (except when dose
    adjustment is allowed according to Section 5.5 Concomitant
    Medications).

    Period 2 Inclusion Criteria
    The subject must meet all of the following criteria to be included in
    Period 2 of the study:
    1. Subject has completed Period 1 (ie, the week 12 visit) of the study.
    2. Subject must be willing to continue stable dose of all RA medications
    that the subject is using at Week 12 through Week 24 (except when
    dose adjustment is allowed according to Section 5.5 Concomitant
    Medications).
    E.4Principal exclusion criteria
    Period 1:
    1.Subjects who are investigational site staff members directly involved in conduct of trial and their family members, site staff members otherwise supervised by Investigator or subjects who are Pfizer employees directly involved in conduct of trial
    2.ACR functional class IV
    3.Prior treatment with etanercept any immunosuppressive biologic
    agent other than infliximab or adalimumab or both infliximab and
    adalimumab
    4.Discontinuation of infliximab or adalimumab for primary reason other than inadequate efficacy response
    5.Subjects receiving infliximab, dose >10 mg/kg every 4 weeks within 12 weeks before baseline
    6.Subjects receiving adalimumab, dose >40 mg every other week within 12 weeks before baseline
    7.Subject with known or suspected allergy, hypersensitivity or contraindication to MTX or its components or to etanercept, its excipients or other compounds related to this class of medication including biopharmaceutical proteins
    8.Receipt >1 permitted non-biologic DMARD other than MTX or change in total daily dose of the additional permitted non-biologic DMARD within 4 weeks before baseline
    9.Cyclophosphamide, cyclosporine or azathioprine within 6 months before baseline
    10.Leflunomide without elimination procedure within 8 weeks before baseline or within 4 weeks of baseline if protocol-specified elimination procedure is followed.
    11.Any invest. non-biologic drugs or devices within 12 weeks before baseline and/or during study B1801355
    12.Non-biologic DMARDs other than those permitted during study or which are not listed under other excl. criteria within 8 weeks before baseline
    13.Receipt >10 mg/day of oral prednisone (or equivalent) or change in dose within 2 weeks before baseline
    14.IA or soft tissue corticosteroid injection or bolus IM or IV corticosteroids within 4 weeks before baseline
    15.Receipt >1 NSAID or change in dose or type of NSAID within 2 weeks before baseline
    16.Any live (attenuated) vaccines within 4 weeks before baseline
    17.Any of following hematology or chemistry lab.abnormalities based on screening test results
    a.WBC count ≤3.5 x 109/L
    b.Hemoglobin level ≤85 g/L or ≤5.3 mmol/L
    c.Hematocrit ≤27%
    d.Platelet count ≤125 x 109/L
    e.Serum creatinine level ≥175 µmol/L or ≥1.98 mg/dL
    f.AST or ALT level ≥2 times upper limit of normal (X ULN)
    18.Any other clinically significant lab. results or vital sign measurements
    19.Active TB or evidence of untreated latent or active TB
    20.Received TB chemoprophylaxis between the screening and baseline visits and has had ALT≥2X ULN and/or AST≥2X ULN during this period 21.Any infection assoc. with hospitalization and/or parenteral anti-infective agents within 4 weeks before baseline
    22.Active infection at screening and/or baseline including systemic fungal infections
    23.Any clinically relevant concurrent medical conditions, incl.: a.Uncompensated congestive heart failure, Class III or IV heart failure or any episode of acute congestive heart failure within 6 months before screening
    b.Uncontrolled hypertension
    c.Myocardial infarction within 12 months before screening
    d.Coronary artery bypass graft or percutaneous transluminal coronary angioplasty within 12 months before screening
    e.Unstable angina pectoris within 6 months before screening f.Presence or history of severe pulmonary disease requiring recurrent hospitalizations or supplemental oxygen
    g.Presence or history of confirmed blood dyscrasias
    h.Diagnosis of multiple sclerosis or other central or peripheral nervous system demyelinating diseases
    i.Malignancy or history of malignancy (except non metastatic basal cell or squamous cell skin carcinoma; or cervical carcinoma in situ) j.Uncontrolled diabetes mellitus
    k.Diagnosis of systemic lupus erythematosus, scleroderma or polymyositis
    l.Open cutaneous ulcers
    m.History of clinically significant drug induced liver injury, cirrhosis or fibrosis
    n.Known history or presence of hepatitis C or chronic hepatitis B infection; or positive test result at screening for hepatitis C virus or chronic hepatitis B
    o.Known history, presence of, or positive test result history for HIV 24.Other severe acute or chronic medical or psychiatric condition or lab abnormality that may increase the risk associated with study participation or invest. product administration or may interfere with interpretation of study results and, in the investigator’s judgment, would make subject inappropriate for entry into this study.
    25.Any anticipated or planned surgical procedure during study period 26.Pregnant or breastfeeding females 27.Sexually active males and females of childbearing potential not using highly effective contraception or not agreeing to continue highly effective contraception for at least 12 weeks after last dose of invest. product Escape Arm:
    1.Discontinuation of invest. product for any reason prior to completion of week 8 visit
    Period 2: 1.Discontinuation of invest. product for any reason prior to completion of week 12 visit
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in the disease activity score based on a 28 joint count (DAS28-CRP) at week 12
    The primary study comparison is between etanercept 50 mg QW and placebo in all subjects, as determined by the change from baseline in DAS28-CRP scores at week 12.
    The conditional primary study comparison is between etanercept 50 mg QW and placebo in subjects who are mAb ADA+, as determined by the change from baseline in DAS28-CRP scores at week 12.
    E.5.1.1Timepoint(s) of evaluation of this end point
    12 weeks
    E.5.2Secondary end point(s)
    Key Secondary Efficacy Endpoint
    Change from baseline in the DAS28-CRP at week 24
    The key secondary study comparison will be between subjects who are mAb ADA+ and mAb ADA- and are randomized to etanercept, as determined by the change from baseline in DAS28-CRP scores at week 24.

    Additional Secondary Efficacy Endpoints
    The following endpoints will be assessed at all timepoints unless otherwise noted:
    • Change from baseline in DAS28-CRP
    • DAS28-CRP < 3.2 and DAS28-CRP < 2.6
    • American College of Rheumatology (ACR) 20, ACR50, ACR70, and ACR90
    • European League Against Rheumatism (EULAR) good response and EULAR good/moderate response
    • Simplified Disease Activity Index (SDAI) and Clinical Disease Activity Index (CDAI)
    • Individual components of the ACR and DAS
    • Etanercept ADA status (at week 12 and week 24, or upon early withdrawal). Samples which are positive for etanercept ADAs will also be tested for etanercept neutralizing antibodies.
    • Vectra disease activity (DA) levels (at baseline, week 4, week 12, and week 24, or upon early withdrawal)
    E.5.2.1Timepoint(s) of evaluation of this end point
    24 weeks
    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 No
    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) No
    E.7.4Therapeutic use (Phase IV) Yes
    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 trial4
    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 EEA14
    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
    Belgium
    Chile
    Colombia
    France
    Hong Kong
    Israel
    Netherlands
    New Zealand
    Poland
    Russian Federation
    Spain
    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
    End of Trial in all participating countries is defined as the Last Subject Last Visit.
    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 months6
    E.8.9.1In the Member State concerned days15
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months9
    E.8.9.2In all countries concerned by the trial days6
    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: 100
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 20
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 56
    F.4.2.2In the whole clinical trial 120
    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)
    No administration of Enbrel is planned after the subject has ended the participation in the trial. Subject is expected to receive normal treatment of that condition.
    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 Decision2013-02-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-07-08
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    The status of studies in GB is no longer updated from 1.1.2021
    For the UK, as from 1.1.2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI
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