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    Summary
    EudraCT Number:2013-002007-34
    Sponsor's Protocol Code Number:ML28691
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-12-09
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2013-002007-34
    A.3Full title of the trial
    Tocilizumab SC in patients with active rheumatoid arthritis and inadequate response to DMARDs. A single-arm, open-label study to evaluate safety, tolerability and efficacy. In a sub-group of patients inflammation will be measured by ultasound
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Safety and efficacy study of tocilizumab injected under the skin in patients with active rheumatoid arthritis (RA) and inadequate response to disease modifying antirheumatic drugs.
    A.3.2Name or abbreviated title of the trial where available
    TOZULTRA
    A.4.1Sponsor's protocol code numberML28691
    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 SponsorRoche a/s
    B.1.3.4CountryDenmark
    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 supportRoche a/s
    B.4.2CountryDenmark
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoche a/s
    B.5.2Functional name of contact pointBirte Agular
    B.5.3 Address:
    B.5.3.1Street AddressIndustriholmen 59
    B.5.3.2Town/ cityHvidovre
    B.5.3.3Post code2650
    B.5.3.4CountryDenmark
    B.5.4Telephone number+453639 9999
    B.5.5Fax number+453639 9930
    B.5.6E-mailbirte.agular@roche.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 RoActemra
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration Limited
    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 nameTocilizumab SC
    D.3.2Product code Ro 487-7533/F10-04
    D.3.4Pharmaceutical form Solution for injection
    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 INNTocilizumab
    D.3.9.1CAS number 375823-41-9
    D.3.9.2Current sponsor codeRO4877533
    D.3.9.3Other descriptive nameRecombinant humanized anti-human monoclonal antibody directed against the IL-6R
    D.3.9.4EV Substance CodeSUB20313
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number180
    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
    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 19.0
    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
    Primary Objective:
    To evaluate early changes in clinical efficacy by measuring mean change in CDAI at 12 weeks after onset of treatment with SC TCZ, either in monotherapy or in combination with MTX or other non-biologic DMARDs, in patient with rheumatoid arthritis receiving their first biologic treatment.
    E.2.2Secondary objectives of the trial
    Secondary Objectives:
    1. To evaluate the safety and tolerability of subcutaneous (SC) tocilizumab (TCZ) in monotherapy or in combination with MTX or other non-biologic DMARDS, comprising adverse events (AEs), physical examination, vital signs, and clinical laboratory assessments, including immunogenicity, in patients with active rheumatoid arthritis (RA) during 24 weeks.
    2. To assess the efficacy of SC TCZ in monotherapy or in combination with MTX or other non-biologic DMARDs, over time using endpoints such as Disease Activity Score 28-erythrocyte sedimentation rate (DAS28-ESR), American College of Rheumatology (ACR) repsonse scores, European League Against Rheumatism (EULAR) response criteria, Simplified DIsease Activity Index (SDAI) or Clinical Disease Activity Index (CDAI), tender joint count (TJC)/swollen joint count (SJC), and patient reported outcome (PROs) at Week 24, including onset of action at Week 2.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Patients must meet the following criteria for study entry:
    1. Able and willing to give written informed consent and comply with the requirements of the study protocol
    2. Patients at least 18 years of age.
    3. Patients with a diagnosis of active RA according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria
    4. Oral corticosteroids (≤10 mg/day prednisone or equivalent) and nonsteroidal anti inflammatory drugs (NSAIDs; up to the maximum recommended dose) are permitted if on a stable dose regimen for ≥4 weeks prior to Baseline.
    5. Permitted non-biologic DMARDs are allowed if at a stable dose for at least 4 weeks prior to Baseline.
    6. Receiving treatment on an outpatient basis, not including TCZ.
    7. Females of childbearing potential and males with female partners of childbearing potential may participate in this study only if using a reliable means of contraception (e.g. physical barrier [patient or partner], contraceptive pill or patch, spermicide and barrier, or intrauterine device) during the study and for a least 5 months following the last dose ot TCZ
    8. If female of childbearing potential, the patient must have a negative pregnancy test at Screening and Baseline visits.
    9. Patient with inadequate response and/or intolerance to MTX or other non-biologic DMARDs and/or where MTX or other non-biologic DMARDs are inappropriate
    10. Have moderate to severe RA, DAS-28-ESR>3.2
    E.4Principal exclusion criteria
    General

    1. Major surgery (including joint surgery) within 8 weeks prior to Screening or planned major surgery within 6 months following Baseline
    2.Rheumatic autoimmune disease other than RA, including systemic lupus erythematosis, mixed connective tissue disorder, scleroderma, polymyositis, or significant systemic involvement secondary to RA (e.g vasculitis, pulmonary fibrosis or Felty´s syndorme). Secondary Sjögren´s syndrome with RA is permitted.
    3. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis.
    4. Diagnosis of juvenile idiopathic arthritis or juvenile RA and/or RA before the age of 16.
    5. Prior history of or current inflammatory joint disease other than RA (e.g. gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, and arthropathy of inflammatory bowel disease

    Previous or Concomitant Therapy
    6. Exposure to any biologic DMARDs, including TCZ (either intravenous [IV] or SC) at any time prior to Baseline.
    7. Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever is longer) of Screening.
    8.Previous treatment with any cell-depleting therapies, including investigational agents or approved therapies, some examples are CAMPATH, anti-CD4. anti-CD5, anti-CD3, anti-CD19 and anti-CD20.
    9. Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline
    10. Intraarticular or parenteral corticosteroids within 4 weeds prior to Baseline
    11. Immunization with a live/attenuated vaccine 4 weeks prior to Baseline
    12. Any previous treatment with alkylating agents such as chlorambucil or with total lymphoid irradation

    General Safety
    13. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies.
    14. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or gastrointestinal (GI) disease.
    15. History of diverticulitis, diverticulosis requiring antibiotic treatment, or chronic ulcerative lower GI diseases such as Crohn’s disease, ulcerative colitis or other symptomatic lower GI condition that might predispose to perforation
    16. 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 nail beds).
    17. Any major episode of infection requiring hospitalization or treatment with IV antibiotics within 4 weeks of Screening or oral antibiotics within 2 weeks of Screening,
    18. Active TB requiring treatment within the previous 3 years. Patient should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patient treated for TB with no recurrence in 3 years are permitted.
    19. Current liver disease as determined by the Investigator
    20. Positive hepatitis B surface antigen or hepatitis C antibody.
    21. Primary and secondary immunodeficiency (history of or currently active)
    22. Evidence of active malignant disease, malignancies diagnosed within the previous 10 years (including hematological malignancies and solid tumors, except basal and squamous cell carcinoma of the skin or carcinoma in situ of the cervix uteri that has been excised and cured), or breast cancer diagnosed within the previous 20 years.
    23. Pregnant women or nursing (breast feeding) mothers-
    24. Patients with reproductive potential not willing to use effective method of contraception.
    24. History of alcohol, drug or chemical abuse within 1 year prior to Screening.
    26. Neuropathies or other conditions that might interfere with pain evaluation.

    Laboratory
    27. Serum creatinine >1.4 mg/dL (124 μmol/L) in female patients and >1.6 mg/dL (141 μmol/L) in male patients.
    28. Alanine aminotransferase or aspartate aminotransferase >1.5 times upper limit of normal (ULN).
    29. Total bilirubin >ULN.
    30 .Platelet count <100 x 109/L (100,000/mm3).
    31. Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L).
    32. White blood cells <3.0 x 109/L (3000/mm3).
    33.Absolute neutrophil count <2.0 x 109/L (2000/mm3).
    34.Absolute lymphocyte count <0.5 x 109/L (500/mm3
    E.5 End points
    E.5.1Primary end point(s)
    Mean change in CDAIat week 12
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 12
    E.5.2Secondary end point(s)
    Efficacy Outcome
    1 Change in DAS28-ESR up to Week 24.
    2. ACR response scores up to Week 24.
    3. EULAR response criteria up to Week 24.
    4. Change in SDAI or CDAI up to Week 24.
    5. Change in total TJC and total SJC over time.

    Safety Outcome
    1.Incidence and severity of AEs, serious adverse events, and AEs of special interest over time up to Week 24.
    2.Rates of AEs leading to dose modification or study withdrawal up to Week 24.
    3.Assessment of physical examination and vital signs up to Week 24.
    4.Incidence of clinically significant laboratory abnormalities following TCZ SC administration up to Week 24.
    5.Assessment of immunogenicity following SC TCZ administration up to Week 24 and 8 weeks after last dose.

    Patient outcome
    1. Patient Global Assessment of disease activity visual analogue scale (VAS) up to Week 24.
    2. Patient Pain VAS up to Week 24.
    3. Health Assessment Questionnaire-Disability Index up to Week 24.
    4. Patient compliance (patient diary cards and return records) up to Week 24.
    5. Patient Functional Assessment of Chronic Illness Therapy – Fatigue (FACIT-F) up to week 24
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy outcome
    1. Week 24.
    2. Week 24.
    3. Week 24.
    4. Week 24.
    5. Over time.
    Safety outcome
    1. Over time up to Week 24.
    2. Over time up to Week 24.
    3. Over time up to Week 24.
    4. Over time up to Week 24.
    5. Over time up to Week 24 and 8 weeks after last dose.
    Patient outcome
    1. Over time to Week 24.
    2. Over time up to Week 24.
    3. Over time up to Week 24.
    4. Over time up to Week 24.
    5. Over time up to week 24
    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 No
    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 No
    E.8.1.1Randomised No
    E.8.1.2Open Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA22
    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 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
    LVLS is expected October 31st 2016
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years2
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years2
    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: 120
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 30
    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 state42
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 137
    F.4.2.2In the whole clinical trial 137
    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 Decision2013-12-09
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-12-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-09-13
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