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    Summary
    EudraCT Number:2015-005389-51
    Sponsor's Protocol Code Number:RB15.210
    National Competent Authority:France - ANSM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2016-06-27
    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 ConcernedFrance - ANSM
    A.2EudraCT number2015-005389-51
    A.3Full title of the trial
    Safety and Efficacy of tocilizuMAb versus placebo in Polymyalgia rHeumatica with glucocORticoid dEpendence SEMAPHORE
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and Efficacy of tocilizuMAb versus placebo in Polymyalgia rHeumatica with glucocORticoid dEpendence SEMAPHORE
    A.4.1Sponsor's protocol code numberRB15.210
    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 SponsorCHRU DE BREST
    B.1.3.4CountryFrance
    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 supportLaboratoire CHUGAI
    B.4.2CountryFrance
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCHRU DE BREST
    B.5.2Functional name of contact pointSPONSOR
    B.5.3 Address:
    B.5.3.1Street Address2 Avenue Foch
    B.5.3.2Town/ cityBREST
    B.5.3.3Post code29609
    B.5.3.4CountryFrance
    B.5.4Telephone number0033298223979
    B.5.5Fax number0033298223183
    B.5.6E-mailaudrey.legoff-coquet@chu-brest.fr
    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 Tocilizumab
    D.2.1.1.2Name of the Marketing Authorisation holderROCHE
    D.2.1.2Country which granted the Marketing AuthorisationFrance
    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 nameRoActemra
    D.3.4Pharmaceutical form Concentrate and solvent for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    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.3.11.13.1Other medicinal product type recombinant humanized, anti-human monoclonal antibody of the immunoglobulin G1 (IgG1) sub-class
    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
    Polymyalgia rHeumatica
    E.1.1.1Medical condition in easily understood language
    Inflammatory disease in the elderly
    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 19.0
    E.1.2Level PT
    E.1.2Classification code 10036099
    E.1.2Term Polymyalgia rheumatica
    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 demonstrate the ability of tocilizumab in comparison to placebo to decrease GCs (prednisone or prednisolone) and to maintain low disease activity at week 24 in steroid dependent PMR patients
    E.2.2Secondary objectives of the trial
    - Tolerance of tocilizumab and GCs
    - Absence of flare (PMR-AS>17) and remission from W24 to W32 in both arms
    - PMR-AS in tocilizumab arm versus placebo
    - PMR-AS using ESR in tocilizumab arm versus placebo
    - Cost/efficacy of tocilizumab arm in comparison to placebo and GCs
    - Quality of life (SF-36) and HAD in tocilizumab arm versus placebo
    - Cumulative doses of GCs in tocilizumab and placebo arms
    - Evaluation of synovitis and tenosynovitis in shoulders and hips using ultrasound in mode B and Doppler
    -Osteodensitometry (lumbar and hip sites) in Tocilizumab arm versus placebo
    - Biological markers in tocilizumab and placebo arms: Interleukin-6, TGF-β, B cells subpopulations, CRP, pyridinoline, telopeptide
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    -Age older than 50 years
    -Having previously
    -Fulfilled the Chuang criteria
    -Be successfully treated with GCs ≥ 15mg (CRP ≥ 10 mg/l or ESR ≥ 20 mm before GCs treatment and < 10 mg/dl (or ESR < 20 mm/h) after)
    - And currently
    -Being treated with schedule close to the 2015 ACR/EULAR recommendation and Unable to taper GCs < 10mg
    -PMR-AS > 10
    -Absence of signs or symptoms of other musculoskeletal or connective tissue conditions
    -Able to give informed consent
    -Concomitant treatments with méthotrexate or hydroxychloroquine are permitted if stable dose since 3 months.
    E.4Principal exclusion criteria
    General Exclusion Criteria:

    - Clinical symptoms of giant cell arteritis
    - Uncontrolled dyslipidemia, high blood pressure or cardiovascular disease
    - History of major organ or haematopoietic stem cell/marrow transplant
    - Clinical evidence of significant unstable or uncontrolled acute or chronic diseases not due to PMR
    - Planned surgical procedure within 12 months after randomization.
    - History of malignant neoplasm within the last 5 years.
    - Current active infection

    Detailed exclusion criteria related to prior or concomitant therapy, general safety and laboratory data:

    Exclusions Related to Prior or Concomitant Therapy

    - Previous treatment with cell-depleting therapies, including investigational agents, including
    but not limited to Campath (alemtuzumab), anti-CD4, anti-CD5, anti-CD3, anti-CD19, and anti-CD20
    - Treatment with IV gamma globulin or plasmapheresis within 6 months of baseline
    - Previous treatment with alkylating agents, such as chlorambucil, or with total lymphoid irradiation
    - Previous treatment with TCZ
    - Immunization with a live/attenuated vaccine within ≤ 4 weeks prior to baseline
    - Treatment with cyclosporine A, azathioprine, or MMF within 4 weeks of baseline
    - Treatment with etanercept within 2 weeks; infliximab, certolizumab, golimumab, abatacept, or adalimumab within 8 weeks; or anakinra within 1 week of baseline
    - Previous treatment with tofacitinib
    - Treatment with cyclophosphamide within 6 months of baseline
    Exclusions Related to General Safety

    - History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies or to prednisone
    - Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary
    (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled
    diabetes mellitus), psychiatric, osteoporosis/osteomalacia, glaucoma, corneal ulcers/injuries,
    or gastrointestinal (GI) disease
    - History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative
    lower GI disease such as Crohn's disease, ulcerative colitis, or other symptomatic lower GI
    conditions that might predispose a patient to perforations
    - Known active current or history of recurrent bacterial, viral, fungal, mycobacterial, or other
    infections (including but not limited to tuberculosis [TB] and atypical mycobacterial disease,
    hepatitis B and C, and herpes zoster, but excluding fungal infections of the nail beds)
    - Active TB requiring treatment within the previous 3 years Patients should be screened for latent TB and, if positive, treated according to local practice guidelines prior to initiating TCZ treatment. Patients treated for TB with no recurrence within 3 years and patients treated for latent TB within 3 years are eligible.
    - Primary or secondary immunodeficiency (history of or currently active)
    - Pregnant women and females who are breastfeeding
    - Female of childbearing potential must have a negative serum pregnancy test within 28 days of randomization. Females of child-bearing potential may participate in this trial only if using a reliable means of contraception (e.g. physical barrier (patient and partner), contraceptive pill or patch, spermicide and barrier, or IUD) during study treatment and for minimum of 3 months after last dose of TCZ.
    - Males of reproductive potential who are not willing to use an effective method of
    contraception, such as condom, sterilization, or true abstinence throughout study and for a
    minimum of 6 months after study drug therapy
    - History of alcohol, drug, or chemical abuse within 1 year prior to screening
    - Any medical or psychological condition that in the opinion of the principal investigator would interfere with safe completion of the trial.
    - Patients with lack of peripheral venous access
    - Pre-existing CNS demyelination or seizure disorders

    Laboratory Exclusions (at Screening)

    - Serum creatinine > 1.4 mg/dL (124 μmol/L) in female patients and> 1.6 mg/dL (141 μmol/L)
    in male patients
    - Total bilirubin >ULN
    - Platelet count < 100× 109/L (100,000/mm3)
    - Hemoglobin < 85 g/L (8.5 g/dL; 5.3 mmol/L)
    - White blood cells < 3.0 × 109/L (3000/mm3)
    - Absolute neutrophil count < 2.0 × 109/L (2000/mm3)
    - Absolute lymphocyte count < 0.5 × 109/L (500/mm3)
    - Positive hepatitis B surface antigen or hepatitis C antibody
    E.5 End points
    E.5.1Primary end point(s)
    Low disease activity (PMR-AS<10) with steroid independence (GCs ≤5 mg (absolute value) or decrease ≥ 10 mg from week 0 to week 24).
    E.5.1.1Timepoint(s) of evaluation of this end point
    week 24
    E.5.2Secondary end point(s)
    - Adverse events following SOC classification in both arms
    - Proportion of patients with (PMR-AS>17) from W24 to W32 in both arm
    - PMR-AS (inclusion and W0, W4, W8, W12, W16, W20, W24 and W32) and proportion of patients with PMR-AS < 1.5; 10;17.
    - Cost/efficacy of tocilizumab
    - Cumulative dosages of GCs at Week 32
    - Ultrasound Scoring of synovitis and tenosynovitis (mode B and Doppler) at inclusion and W 12, 24 and 32
    - bone mass density (lumbar and hip sites) (at inclusion and W32)
    - Level of biological markers in tocilizumab and placebo arms: Interleukine-6, TGF-ß, B cells sub populations, pyridinolins and telopeptides (at inclusion, W8, W16, W24, W32)
    E.5.2.1Timepoint(s) of evaluation of this end point
    week 32
    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 No
    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 Yes
    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 concerned9
    E.8.5The trial involves multiple Member States No
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA No
    E.8.6.2Trial being conducted completely outside of the EEA No
    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 years
    E.8.9.1In the Member State concerned months33
    E.8.9.1In the Member State concerned days
    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.1.3Elderly (>=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 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 state100
    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 Decision2017-10-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2016-06-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2020-11-12
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