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    Summary
    EudraCT Number:2013-000359-42
    Sponsor's Protocol Code Number:ML28695
    National Competent Authority:Greece - EOF
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-08-27
    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 ConcernedGreece - EOF
    A.2EudraCT number2013-000359-42
    A.3Full title of the trial
    Multicenter, open label, phase IIIb study to evaluate the safety and tolerability of subcutaneous tocilizumab as monotherapy and/or in combination with methotrexate or other non-biologic disease modifying antirheumatic drugs in patients with Rheumatoid Arthritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Not applicable
    A.4.1Sponsor's protocol code numberML28695
    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 HELLAS S.A.
    B.1.3.4CountryGreece
    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 HELLAS S.A.
    B.4.2CountryGreece
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationROCHE HELLAS S.A.
    B.5.2Functional name of contact pointANNA MARIA KOURKOUTA
    B.5.3 Address:
    B.5.3.1Street AddressALAMANAS 4 & DELFON
    B.5.3.2Town/ cityMAROUSSI/ATTIKI
    B.5.3.3Post code15125
    B.5.3.4CountryGreece
    B.5.4Telephone number00302106166268
    B.5.5Fax number00302106100758
    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 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.3.11 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] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 16.0
    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
    To assess the efficacy of treatment with SC TCZ monotherapy and/or in combination with MTX or other non biologic DMARDs with regard to achievement of clinical remission as measured by Disease Activity Score 28 (DAS28) <2.6 at the end of 24 weeks of treatment in patients with active rheumatoid arthritis (RA)
    E.2.2Secondary objectives of the trial
    To assess the efficacy of treatment with SC TCZ monotherapy and/or in combination with MTX or other non-biol. DMARDs over time at wk 24 & 52, includ. onset of action at wk 2.To evaluate the ability to maintain the optimal therapeutic target (Remission or LDA) of SC TCZ monotherapy, following MTX/other non-biol.(nb) DMARDs discontinuation from SC TCZ in combination with MTX/other nb DMARDs from wk 24 to 52.To evaluate the proportions of patients who will flare while on SC TCZ monotherapy and will necessitate add-on of MTX/other NB DMARDs to maintain the optimal therapeutic target (Remission or LDA), achieved between wk 24 – 52.To evaluate the safety and tolerability of SC TCZ as monotherapy and/or in combination with MTX or other NB DMARDs comprising AEs, physical examination, vital signs, and clinical lab.assessments, includ. immunogenicity, in patients with active RA at wk 24 & 52.Proportion of patients and reasons for corticosteroid dose reductions and/or discontinuation over time
    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 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. Females of childbearing potential must use a reliable means of contraception for at least 3 month following the last dose of TCZ.
    8. If female of childbearing potential, the patient must have a negative pregnancy test at the Screening and Baseline visits.
    9. The target population for this study is adult men or women with active Rheumatoid Arthritis ,DAS28(ESR) >3.2, early RA of less than 6 month duration or established RA of more than 6 month duration , either naïve to MTX and /or other non biologic DMARD’s treatment, or having inadequate response (inefficacy/intolerance) to previous non biologic DMARDs ( MTX-IR, DMARD-IR) and/or having inadequate response (inefficacy/ intolerance) to previous biologic DMARDs (including Tumor necrosis factor-TNFiIR or Abatacept- when this was assigned as first line biologic-Abatacept IR IR). Patients who have experienced inadequate responses (inefficacy/intolerance) to previous biologics DMARDs could participate in this study with or without going through a biologic wash-out period. The time between the last dose of TNF inhibitor or Abatacept and the inclusion in the study could be between 1 and 8 weeks depending on the approved dosing interval as reported in the SmPC and according to the physician’s judgment.
    E.4Principal exclusion criteria
    A patient will be excluded if the answer to any of the following statements is “yes”.
    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 syndrome). Secondary Sjögren’s syndrome with RA is permitted.
    3. Functional Class IV as defined by the ACR Classification of Functional Status in Rheumatoid Arthritis (Appendix 2).
    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).
    6. Patients with lack of peripheral venous access.

    Excluded Previous or Concomitant Therapy:
    7. Exposure to TCZ (either IV or SC) at any time prior to Baseline.
    8. Treatment with any investigational agent within 4 weeks (or five half-lives of the investigational drug, whichever is longer) of Screening.
    9. 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.
    10. Treatment with IV gamma globulin, plasmapheresis within 6 months of Baseline.
    11. Intraarticular (IA) or parenteral corticosteroids within 4 weeks prior to Baseline.
    12. Immunization with a live/attenuated vaccine within 4 weeks prior to Baseline.
    13. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.

    Exclusions for General Safety:
    14. History of severe allergic or anaphylactic reactions to human, humanized, or murine monoclonal antibodies.
    15. Evidence of serious uncontrolled concomitant cardiovascular, nervous system, pulmonary (including obstructive pulmonary disease), renal, hepatic, endocrine (including uncontrolled diabetes mellitus), or GI disease.
    16. 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 to perforation.
    17. 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).
    18. 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.
    19. Active TB requiring treatment within the previous 3 years. Patients should be screened for latent TB and, if positive, treated following local practice guidelines prior to initiating TCZ. Patients treated for TB with no recurrence in 3 years are permitted.
    20. Current liver disease as determined by the Investigator.
    21. Positive hepatitis B surface antigen (HbsAg) or hepatitis C antibody.
    22. Primary or secondary immunodeficiency (history of or currently active).
    23. 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.
    24. Pregnant women or nursing (breast feeding) mothers.
    25. Patients with reproductive potential not willing to use an effective method of contraception.
    26. History of alcohol, drug, or chemical abuse within 1 year prior to Screening.
    27. Neuropathies or other conditions that might interfere with pain evaluation.

    Laboratory Exclusion Criteria (at Screening):
    28. Serum creatinine >1.4 mg/dL (124 μmol/L) in female patients and >1.6 mg/dL (141 μmol/L) in male patients.
    29. ALT or AST >1.5 times ULN.
    30. Total bilirubin >ULN.
    31. Platelet count <100 x 109/L (100,000/mm3).
    32. Hemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L).
    33. White blood cells <3.0 x 109/L (3000/mm3).
    34. Absolute neutrophil count (ANC) <2.0 x 109/L (2000/mm3).
    35. Absolute lymphocyte count <0.5 x 109/L (500/mm3).
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint is to estimate the proportion of patients who will achieve DAS28 remission at Week 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    E.5.2Secondary end point(s)
    Efficacy Outcome Measures
    · Proportions of patients that achieve DAS28 Remission up to Week 24

    · Proportions of patients that maintain DAS28 Remission/LDA from Week 24 up to week 52, for the patients on SC TCZ monotherapy since Week 24

    · Proportions of patients that achieve DAS28 Remission/LDA up to week 52 for the patients with intensification of MTX/non biologic DMARD treatment in combination with SC TCZ since Week 24.

    · Change in DAS28-ESR over time up to Week 52
    · ACR response scores over time up to Week 52

    · EULAR response criteria over time up to Week 52

    · Change in SDAI or CDAI over time up to Week 52

    · Change in total TJC and total SJC over time up to Week 52

    · Proportion of patients and reasons for corticosteroid dose reductions and/or discontinuation over time.




    Safety Outcome Measures

    1. Incidence and severity of AEs, SAEs, and AEs of special interest over time up to Week 52.
    2. Rates of AEs leading to dose modification or study withdrawal up to Week 52
    3. Assessment of physical examination and vital signs up to Week 52.
    4. Incidence of clinically significant laboratory abnormalities following TCZ SC administration up to Week 52 .
    5. Assessment of immunogenicity following SC TCZ administration up to Week 52 and 8 weeks after the last dose.
    E.5.2.1Timepoint(s) of evaluation of this end point
    Week 52
    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 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 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 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
    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 months6
    E.8.9.1In the Member State concerned days0
    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 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 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)
    The Sponsor does not intend to provide tocilizumab to patients following the completion of the trial.
    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 Decision2013-09-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-09-12
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-07-11
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