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    Summary
    EudraCT Number:2015-001246-28
    Sponsor's Protocol Code Number:P1200_14
    National Competent Authority:Belgium - FPS Health-DGM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-07-23
    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 ConcernedBelgium - FPS Health-DGM
    A.2EudraCT number2015-001246-28
    A.3Full title of the trial
    Ultrasound scores as imaging biomarkers of early response to subcutaneous tocilizumab in association with methotrexate in early rheumatoid arthritis (TOVERA study)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Ultrasound scores as imaging biomarkers of early response to subcutaneous tocilizumab in association with methotrexate in early rheumatoid arthritis (TOVERA study)
    A.3.2Name or abbreviated title of the trial where available
    TOVERA
    A.4.1Sponsor's protocol code numberP1200_14
    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 SponsorCliniques Universitaires Saint-Luc, Université catholique de Louvain
    B.1.3.4CountryBelgium
    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 supportCliniques Universitaires Saint-Luc, Université catholique de Louvain
    B.4.2CountryBelgium
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationCliniques Universitaires Saint-Luc, Université catholique de Louvain
    B.5.2Functional name of contact pointPôle de pathologies rhumatismales
    B.5.3 Address:
    B.5.3.1Street AddressAvenue Hippocrate 10
    B.5.3.2Town/ cityBrussels
    B.5.3.3Post code1200
    B.5.3.4CountryBelgium
    B.5.4Telephone number3227645391
    B.5.5Fax number3227645394
    B.5.6E-mailmaria.stoenoiu@uclouvain.be
    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 Ltd.
    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 nameRoActemra
    D.3.4Pharmaceutical form Solution for injection/infusion in pre-filled syringe
    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 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.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
    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 18.0
    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
    Main primary objectives
    Induction phase
    1. To investigate if an early US response at week 12 may be predictive of later clinical response (week 24 and week 48) and to identify a minimum set of joints to be monitored to adequately assess disease activity
    2. To investigate the mean change from baseline PD, SH, JE scores and global scoring system (GLOSS) assessing the MCP (2-5 joints of both hands) and wrists [time frame: baseline to weeks 2, 4, 8, 12, 16, 24]
    3. To define the earliest time point at which improvement in PD, SH, JE and GLOSS scores in MCP (2-5 joints of both hands) and wrists can be detected [time frame: weeks 2, 4, 8, 12, 16, 24]
    4. To investigate the mean change from baseline to the end of the induction phase in PD, SH, JE and GLOSS scores for the whole 32-US joint set [time frame: baseline to week 2, 4, 8, 12, 16, 24]

    E.2.2Secondary objectives of the trial
    Main secondary objectives
    1. To investigate the mean change from the beginning of maintenance phase to 54 weeks in PD, SH, JE and GLOSS scores for the whole 32-US joint set [time frame: baseline to week 2, 4, 8, 12, 16, 24]
    2. To investigate the mean change from the beginning of maintenance phase to 54 weeks in PD, SH, JE, GLOSS scores assessing the MCP (2-5 joints of both hands) [time frame: week 24 to 32, 40, 54]
    3. To assess if PD score at 12 weeks is predictive of clinical response at 24 and at 48 weeks
    4. To assess the predictive value of PD findings in relation to radiologic outcome at 54 weeks.
    5. ACR and EULAR core data set response during the induction and maintenance phase.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Inclusion criteria
    1. Diagnosis of RA fulfilling the 2010 EULAR/ACR (European League Against Rheumatism/ American College of Rheumatology classification criteria)
    2. Disease duration no longer than 12 months from the time of initial diagnosis
    3. Age : 18-70 years
    4. Disease activity defined by a disease activity score DAS28-CRP > 3.2 or all must be met: tender joint count (TJC) of ≥4 and swollen joint count (SJC) ≥4
    5. US SH or PD synovitis scores >1 for at least 2 metacarpophalangeal (MCP) joints (2-5) and US SH or PD synovitis scores ≥1
    6. Naïve to DMARD (methotrexate, leflunomide, sulphasalazine) and biologics (TNF-, IL6-, CD20-, IL1-blockers)
    E.4Principal exclusion criteria
    Exclusion criteria
    1. History of other concomitant autoimmune disease such as lupus or psoriatic arthritis
    2. Meeting diagnostic criteria for any other rheumatic disease than RA (e.g. gout, Lyme disease, seronegative spondyloarthropathy including reactive arthritis, psoriatic arthritis, arthropathy or inflammatory bowel disease)
    3. Any previous treatment with :
    a. Etanercept, infliximab, certolizumab, golimumab, abatacept or adalimumab, anakinra
    b. 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
    c. Intravenous gamma globulin, plasmapheresis or Prosorba column within 6 months of baseline.
    d. Alkylating agents such as chlorambucil, or with total lymphoid irradiation
    4. Previous MCP arthroplasty or wrist arthrodesis. Participants who have undergone or are scheduled to undergo joint arthroplasties other than the MCP joints can be recruited in the study provided all other eligibility criteria are met.
    5. Current liver disease requiring medication
    6. Current symptoms of severe progressive or uncontrolled renal, hematologic, gastro-intestinal, pulmonary, cardiac, neurologic or cerebral disease whether or not related to rheumatoid arthritis, that would jeopardize inclusion in the protocol as judged by the clinician
    7. History of malignancy or lymphoproliferative disease, within the last 5 years, with the exception of basal cell or squamous cell carcinoma of the skin or carcinoma in situ of cervix which that has been fully excised/cured with no evidence of recurrence
    8. Concomitant diagnosis or history of diverticulitis, peptic ulcer disease, 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 perforations
    9. Evidence of active or latent bacterial, viral, fungal (except for fungal infections of nail beds), mycobacterial or other opportunistic infections at the time of potential enrolment
    10. Any major episode of infection requiring hospitalisation or treatment with IV antibiotics within 4 weeks or oral antibiotics within 2 weeks of screening’
    11. Herpes zoster or cytomegalovirus infection that resolved less than 2 months before the informed consent was signed
    12. Subjects at risk of tuberculosis (TB) are excluded if any of the following is present:
    - A history of active TB within the last 3 years, even if treated
    - Latent TB that was not successfully treated ≥ 4 weeks
    - Current clinical radiographic, or laboratory evidence of active TB
    13. Subjects who received live vaccines within 4 weeks of the anticipated first dose of study medication. Live and live attenuated vaccines should not be given concurrently
    14. Subjects must agree not to take live attenuated vaccines (including seasonal nasal flu vaccine, varicella vaccine for shingles or chickenpox, MMR or MMRV, oral polio vaccine and vaccines for yellow fever, measles, mumps or rubella) thirty (30) days before the Screening Visit, throughout the duration of the trial and for sixty (60) days following the subject’s last dose of study drug
    15. Subjects with positive test results for hepatitis B surface antigen or hepatitis C, or HIV detected with polymerase chain reaction or immunoblot assay
    16. Subjects with primary or secondary immunodeficiency
    17. History of severe allergic or anaphylactic reactions to human, humanized or murine monoclonal antibodies
    18. Major surgery within 8 weeks
    19. Patients with lack of peripheral venous access
    20. Pregnancy or breast-feeding
    21. Females of childbearing potential can only participate if using reliable contraception
    22. Intra-articular steroid injection in the joints assessed by US less than four weeks before screening
    23. Anticipated non-compliance with the protocol
    E.5 End points
    E.5.1Primary end point(s)
    Primary end points
    Induction phase
    Area under the curve of the US parameters (SH, JE, PD, GLOSS) assessing the MCP joints
    (2nd to 5th of both hands) and wrists from baseline through 24 weeks

    Time to change in US parameters (SH, JE, PD, GLOSS) defined as US improvement (20%, 50%, 70%) of the sum scores of individual joints, from baseline through 24 weeks

    US response at week 12 may be predictive of later clinical response at week 24 and week 48



    Maintenance phase
    4. Area under the curve of the US parameters (SH, JE, PD, GLOSS) assessing MCP joints (2nd to 5th of both hands) from 24 weeks to 54 weeks
    5. Area under the curve in PD, SH, JE and GLOSS scores assessing the MCP joints (2nd to 5th of both hands) and wrists from baseline to weeks 54
    6. Percentage of patients which have an US improvement (20%, 50%, 70%) in US parameters (SH, JE, PD, GLOSS) of the sum scores of individual joints, at 24 weeks and 48 weeks
    E.5.1.1Timepoint(s) of evaluation of this end point
    To identify the minimum set of joint to be monitored to adequately assess disease activity by comparing the sensitivity to change of different reduced ultrasound joint counts.
    E.5.2Secondary end point(s)
    Main secondary end points
    1. Area under the curve of the US parameters (SH, JE, PD, GLOSS) for the whole 32-US joint set, from 24 weeks to 54 weeks
    2. Area under the curve of the US parameters (SH, JE, PD, GLOSS) for the for the whole 32-US joint set, from baseline to 54 weeks
    3. ACR and EULAR core data set response during the induction and maintenance phase.
    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.6.13.1Other scope of the trial description
    ????????????
    to be completed
    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 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 Yes
    E.8.1.7.1Other trial design description
    standard of care
    E.8.2 Comparator of controlled trial
    E.8.2.1Other medicinal product(s) Yes
    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 No
    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 years3
    E.8.9.1In the Member State concerned months0
    E.8.9.1In the Member State concerned days30
    E.8.9.2In all countries concerned by the trial years3
    E.8.9.2In all countries concerned by the trial months0
    E.8.9.2In all countries concerned by the trial days30
    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: 35
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 10
    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 state45
    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)
    TO BE COMPLETED
    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 Decision2015-09-04
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-19
    P. End of Trial
    P.End of Trial StatusCompleted
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    The status and protocol content of GB trials is no longer updated since 1 January 2021. For the UK, as of 31 January 2021, EU Law applies only to the territory of Northern Ireland (NI) to the extent foreseen in the Protocol on Ireland/NI. Legal notice
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