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    Summary
    EudraCT Number:2013-002429-52
    Sponsor's Protocol Code Number:ML28709
    National Competent Authority:Ireland - HPRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2013-08-15
    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 ConcernedIreland - HPRA
    A.2EudraCT number2013-002429-52
    A.3Full title of the trial
    A PHASE IIIb STUDY TO EVALUATE THE EFFICACY, SAFETY AND TOLERABILITY OF SUBCUTANEOUS (SC) TOCILIZUMAB (TCZ) GIVEN AS MONOTHERAPY OR IN COMBINATION WITH METHOTREXATE (MTX) OR OTHER NON-BIOLOGICS DMARDs IN SUBJECTS WITH RHEUMATOID ARTHRITIS
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    STUDY TO EVALUATE THE EFFICACY, SAFETY AND TOLERABILITY OF SUBCUTANEOUS (SC) TOCILIZUMAB (TCZ) IN SUBJECTS WITH RHEUMATOID ARTHRITIS
    A.4.1Sponsor's protocol code numberML28709
    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 Farma S.A
    B.1.3.4CountrySpain
    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 Farma S.A
    B.4.2CountrySpain
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationRoche Farma S.A
    B.5.2Functional name of contact pointCarmen Codina/Sol Rodriguez Soriano
    B.5.3 Address:
    B.5.3.1Street AddressC/Eucalipto nº 33
    B.5.3.2Town/ cityMadrid
    B.5.3.3Post code28016
    B.5.3.4CountrySpain
    B.5.4Telephone number34913248145-
    B.5.5Fax number34913248154-
    B.5.6E-mailsoledad.rodriguez-soriano@oche.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 SC
    D.3.9.1CAS number 375823-41-9
    D.3.9.2Current sponsor codeRO4877533
    D.3.9.3Other descriptive nameTOCILIZUMAB SC
    D.3.9.4EV Substance CodeSUB122597
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 (RA) in adults. RA is a long-term disease that leads to inflammation of the joints and surrounding tissues. It can also affect other organs.
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    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
    To assess the efficacy of SC TCZ monotherapy or in combination with oral/SC MTX or other non-biologic (nb) DMARDs using sustained clinical remission activity (DAS-28-ESR<2.6) at week 20 and week 24, in patients with active RA with inadequate response to non-biologic DMARDs or to one anti-TNF.
    E.2.2Secondary objectives of the trial
    Safety and efficacy of SC TCZ monotherapy or in combination with oral/SC MTX or other nbDMARDs given every q2w compared with SC TCZ given qw, in the subgroup of patients who achieve sustained clinical remission based on DAS28<2.6 at weeks 20 and 24, in a 48-week study
    The mean change in disease activity based on DAS28-ESR and the rate of flares (change in DAS28-ESR >1.2)
    Efficacy of SC TCZ monotherapy or in combination with oral/SC MTX or other nb DMARDs using endpoints: DAS 28 ESR, ACR response scores, EULAR response criteria, Simplified Disease Activity Index or Clinical Disease Activity Index, tender joint count/swollen joint count, and patient reported outcomes at Week 24 and 48, onset of action at Week 2
    Proportion of patients who maintained remission (DAS-28ESR<2.6) after switching from SC TCZ qw to SC TCZ q2w, from week 24 to 48
    Safety and tolerability, comprising AEs, physical examination, vital signs, clinical laboratory assessments, imunogenicity, at Week 24 and up to 56.
    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 (DAS28-ESR > 3.2), according to the revised (1987) ACR criteria or EULAR/ACR (2010) criteria of > 6 months duration.
    4. Oral corticosteroids (≤10 mg/day prednisone or equivalent) and non-steroidal 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
    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 at least 3 months following the last dose of TCZ.
    8. If female is of childbearing potential, the patient must have a negative pregnancy test at screening and baseline visits.
    9. Patients with intolerance or inadequate response to MTX or other nb DMARDs or inadequate response to a first anti-TNF agent.
    E.4Principal exclusion criteria
    A patient will be excluded if the answer to any of the following statements is "yes":
    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.
    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).
    Excluded Previous or Concomitant Therapy:
    6. Exposure to 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 (IA) or parenteral corticosteroids within 4 weeks prior to baseline.
    11. Immunisation with a live/attenuated vaccine within 4 weeks prior to baseline.
    12. Any previous treatment with alkylating agents such as chlorambucil, or with total lymphoid irradiation.
    13. Previous treatment with Abatacept
    Exclusions for General Safety:
    14. History of severe allergic or anaphylactic reactions to human, humanised, 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 gastrointestinal (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 hospitalisation 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 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 haematological malignancies and solid tumours, 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. Alanine aminotransferase or aspartate aminotransferase >1.5 times upper limit of normal (ULN).
    30. Total bilirubin >ULN.
    31. Platelet count <100 x 10^9/L (100,000/mm^3).
    32. Haemoglobin <85 g/L (8.5 g/dL; 5.3 mmol/L).
    33. White blood cells <3.0 x 10^9/L (3000/mm^3).
    34. Absolute neutrophil count <2.0 x 10^9/L (2000/mm^3).
    35. Absolute lymphocyte count <0.5 x 10^9/L (500/mm^3).
    E.5 End points
    E.5.1Primary end point(s)
    The proportion of patients who achieve sustained clinical remission at week 24 (i.e. DAS28-ESR <2.6 at week 20 and 24).
    E.5.1.1Timepoint(s) of evaluation of this end point
    At week 20 and 24
    E.5.2Secondary end point(s)
    - Safety and efficacy in the subgroup of patients who achieve sustained clinical remission based on DAS28<2.6
    - The mean change in disease activity based on DAS28-ESR and the rate of flares (change in DAS28-ESR >1.2)
    - Efficacy of SC TCZ monotherapy or in combination with oral/SC MTX or other nb DMARDs using endpoints: DAS 28 ESR, ACR response scores, EULAR response criteria, Simplified Disease Activity Index or Clinical Disease Activity Index, tender joint count /swollen joint count
    - Proportion of patients who maintained remission (DAS-28ESR<2.6) after switching from SC TCZ qw to SC TCZ q2w
    - Safety and tolerability, comprising AE, physical examination, vital signs, clinical laboratory assessments, imunogenicity
    E.5.2.1Timepoint(s) of evaluation of this end point
    Safety-efficacy of SC TCZ in patients who achieve sustained clinical remission based on DAS28<2.6 at weeks 20 and 24, in a 48-week
    Change in disease activity (DAS28-ESR) and rate of flares (change in DAS28-ESR>1.2), in patients who achieve sustained clinical remission based on DAS 28-ESR score (DAS28<2.6) at week 20 and week 24, in a 48-week
    Efficacy of SC TCZ with endpoints:DAS28 ESR, ACR, EULAR, SDAI or CDAI, tender/swollen joint count, patient reported outcomes at Week 24 and Week 48, including onset of action at Week 2
    Patients who maintained remission (DAS-28ESR<2.6) after switching from SC TCZ qw to SC TCZ q2w, from week 24 to week 48
    Safety-tolerability, comprising AEs, physical examination, vital signs, clinical laboratory assessments, immunogenicity, at Week 24 up to week 56
    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) 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 Yes
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    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 No
    E.8.2.3Other Yes
    E.8.2.3.1Comparator description
    Different dose administration
    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 concerned4
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA50
    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
    The end of the study will occur when the last patient last visit (LPLV) occurs. The LPLV is either the date of the last visit of the last patient to complete the study or the date at which the last data point from the last patient, which is required for the statistical analysis, is received, whichever is the later date.
    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 months0
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial 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.1.2.1Number of subjects for this age range: 420
    F.1.3Elderly (>=65 years) No
    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 state70
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 420
    F.4.2.2In the whole clinical trial 420
    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)
    Roche will determine the best way of providing medication to patient thats end the teatment period before market the new formulation of the study drug
    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 Decision2013-10-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2013-10-23
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2016-03-09
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