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    Summary
    EudraCT Number:2019-004369-42
    Sponsor's Protocol Code Number:FKS456-001
    National Competent Authority:Czechia - SUKL
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2020-08-05
    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 ConcernedCzechia - SUKL
    A.2EudraCT number2019-004369-42
    A.3Full title of the trial
    A Randomized, Double-Blind, Multiple-Dose, Parallel-Group, Two-Arm Study to Evaluate the Efficacy, Safety and Immunogenicity of MSB11456 Compared to European Union approved RoActemra® in Patients with Moderately to Severely Active Rheumatoid Arthritis (APTURA I study)
    Randomizovaná, dvojitě zaslepená studie s více dávkami, paralelními skupinami a dvěma rameny pro stanovení účinnosti, bezpečnosti a imunogenicity přípravku MSB11456 ve srovnání s přípravkem RoActemra®, schváleném v Evropské unii u pacientů se středně těžkou až těžkou aktivní revmatoidní artritidou (studie APTURA I)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A study of MSB11456 compared to RoActemra in patients with moderately to severely active rheumatoid arthritis (APTURA I)
    A.3.2Name or abbreviated title of the trial where available
    APTURA I
    A.4.1Sponsor's protocol code numberFKS456-001
    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 SponsorFresenius Kabi SwissBioSim GmbH
    B.1.3.4CountrySwitzerland
    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 supportFresenius Kabi SwissBioSim GmbH
    B.4.2CountrySwitzerland
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationFresenius Kabi SwissBioSim GmbH
    B.5.2Functional name of contact pointClinical Development
    B.5.3 Address:
    B.5.3.1Street AddressTerre Bonne Business Park, Route de Crassier 23 – Bâtiment A3
    B.5.3.2Town/ cityEysins
    B.5.3.3Post codeCH-1262
    B.5.3.4CountrySwitzerland
    B.5.4Telephone number+41793075735
    B.5.6E-mailclinical.development@fresenius-kabi.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 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.3.2Product code MSB11456
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    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 codeMSB11456
    D.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    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.IMP: 2
    D.1.2 and D.1.3IMP RoleComparator
    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(R)
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    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 (R)
    D.3.4Pharmaceutical form Solution for injection in pre-filled syringe
    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.3.9.3Other descriptive nameTOCILIZUMAB
    D.3.9.4EV Substance CodeSUB20313
    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
    Moderately to severely active Rheumatoid Arthritis
    E.1.1.1Medical condition in easily understood language
    Moderately to severely active 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 23.1
    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
    The primary objective of the study is to demonstrate equivalent efficacy of proposed biosimilar tocilizumab MSB11456 and EU-approved RoActemra both administered subcutaneously to patients with moderately to severely active rheumatoid arthritis.
    E.2.2Secondary objectives of the trial
    To compare the safety, immunogenicity and long-term efficacy of MSB11456 to EU-approved RoActemra.
    E.2.3Trial contains a sub-study Yes
    E.2.3.1Full title, date and version of each sub-study and their related objectives
    Pharmacokinetics Sub-study (as detailed in the main study protocol)
    During the population pharmacokinetic sub-study additional blood samples will be taken for the measurement of tocilizumab concentrations in order to characterize pharmacokinetics of both products. The sample size for the population PK sub-study is approximately 30 patients per group, for a total of up to 60 patients.
    E.3Principal inclusion criteria
    1. Are ≥18 years of age.
    2. Diagnosis of rheumatoid arthritis according to the revised 1987 ACR/EULAR
    Classification 2010 criteria with disease duration of ≥6 months.
    3. Have moderately to severely active rheumatoid arthritis as defined by: a.Swollen Joint Count ≥6
    (66 joint count) and Tender Joint Count ≥6 (68 joint count)
    4. Must have been treated with methotrexate for at least 12 consecutive weeks immediately prior to
    randomization and are on a stable dose between 10 and 25 mg/week methotrexate for the last 8 weeks
    prior to screening.
    5. Have had previous inadequate clinical response to at least one modifying anti rheumatic drug.
    6. Women of childbearing potential (i.e., considered fertile following
    menarche and until becoming postmenopausal unless permanently sterile) can participate only if they
    have a negative serum pregnancy test at screening and a negative urine pregnancy test at Day -1
    before randomization. Women of childbearing potential must have used and agree to use a highly
    effective contraception (i.e., methods with a failure rate of less than 1% per year), for 4 weeks
    before randomization and must agree to continue to practice adequate contraception for 3 months
    after the last study drug administration.
    Note: A separate ICF will be provided to and signed by each patient to
    provide information on the general risks of study participation related to
    COVID-19 and to document that it is understood by the patient. Another
    separate Informed Consent Form will be required to be understood and
    signed by partners of male participating patients who become pregnant
    during the study or within 10 weeks after the participating patient's last
    dose of study drug.

    E.4Principal exclusion criteria
    1. American College of Rheumatology functional class IV as defined by
    the ACR classification of functional status or wheelchair/bedbound.
    2. Rheumatic autoimmune disease or history of/current inflammatory joint disease other than rheumatoid arthritis or significant systemic involvement secondary to rheumatoid arthritis. Sjögren's syndrome
    secondary to rheumatoid arthritis is allowed.
    3. Previously received tocilizumab, an investigational or licensed biosimilar of tocilizumab or any interleukin-6 acting drugs (approved or investigational).
    4. Prior use of targeted synthetic disease-modifying anti-rheumatic drugs like janus kinase inhibitors
    5. Prior use of any biological agent for a condition other than rheumatoid arthritis (e.g., ranibizumab, denosumab).
    6. Prior use of more than two biologic treatments for rheumatoid arthritis.
    7. Prior use of biologic investigational drugs (excluding biosimilars) for the treatment of rheumatoid arthritis.
    8. Received any investigational drugs within 12 weeks or five drug half lives prior to screening or planned intake of an investigational drug during the course of this trial including the Follow-Up Period.
    9. Previous treatment with any alkylating agents or cell-depleting therapies including investigational drugs or approved biosimilars, or has previously undergone total lymphoid irradiation.
    10. Use of non-steroidal anti-inflammatory drugs not at a stable dose for at least 4 weeks prior to randomization or exceeding the maximum recommended dose. Note: Patients are permitted to take aspirin at a dose of =325 mg daily for cardiac prophylaxis.
    11. Use of oral corticosteroids >10 mg/day prednisone or equivalent if the dose has not been stable for at least 6 weeks prior to randomization.
    12. Intra-articular or parenteral corticosteroids within 4 weeks prior to randomization.
    13. Use of high potency opioid analgesics
    14. Has been treated with intravenous gamma globulin or plasmapheresis within 6 months of randomization.
    15. Received a live or attenuated vaccine within 4 weeks prior to randomization.
    16. History of hypersensitivity or severe allergic reactions to monoclonal antibodies, any components of the study drug formulations,
    comparable drugs, or latex.
    17. Patient is considered by the Investigator, for any reason, to be an unsuitable candidate for the study. Investigator should specifically
    evaluate the patient's eligibility taking into consideration COVID-19 risk factors and situation.
    18. Has a serious and/or unstable and/or poorly controlled medical condition that, in the opinion of the Investigator, would put the patient at risk by participation in the study.
    19. History of diverticulosis requiring antibiotic treatment or any other GI condition that might predispose the patient to gastrointestinal
    perforations.
    20. Uncontrolled medical conditions for which flares are commonly treated with corticosteroids or systemic corticosteroid treatment for
    these conditions within the last 12 months prior to randomization.
    21. Major surgery within 8 weeks prior to screening or planned major surgery during the study.
    22. History of, or current myeloproliferative or lymphoproliferative disease or malignancy.
    23. Medical evidence of current or history of primary or secondary immunodeficiency as per Investigator's judgment.
    24. Pre-existing or recent-onset central or peripheral nervous system demyelinating disorder, or symptoms suggestive of such a disorder as per Investigator's judgment.
    25. Confirmed or, based on the signs and symptoms observed at the time of assessment, suspected active COVID-19 infection at the time of screening and/or randomization.
    26. Has had any infection as follows:
    a. Herpes zoster or any opportunistic invasive infection within 6 months
    of screening.
    b. Frequent chronic or recurrent infections
    c. A positive test for human immunodeficiency virus subtype 1 or 2,
    hepatitis C antibody, hepatitis B surface antigen and/or core antibody
    for immunoglobulin G and/or immunoglobulin M or total immunoglobulin
    at screening.
    d. A serious infection within 8 weeks prior to randomization.
    e. Treatment with oral antibiotics and/or anti-fungal drugs within 14
    days prior to randomization.
    27. Medical evidence of active or latent tuberculosis or has had active or latent tuberculosis disease at any time in the past.
    28. History of clinically significant drug or alcohol abuse within the last year prior to randomization.
    29. Laboratory abnormalities (excluding erythrocyte sedimentation and C reactive protein values) that were considered clinically significant by the Investigator
    30. Received a COVID 19 vaccine within 4 weeks prior to randomization, are receiving ongoing COVID-19 vaccination at the time
    of screening or plan to receive COVID-19 vaccination before the completion of the Week 30 visit of the study. COVID-19 vaccination is
    considered ongoing if a multidose regimen has been started but has not been completed.
    E.5 End points
    E.5.1Primary end point(s)
    The primary efficacy endpoint is the mean absolute change from baseline in Disease Activity Score 28-Erythrocyte Sedimentation Rate (DAS28-ESR) at Week 24.
    E.5.1.1Timepoint(s) of evaluation of this end point
    From baseline to Week 24.
    E.5.2Secondary end point(s)
    Efficacy:
    - DAS28-ESR mean absolute change from baseline at all assessment
    visits (except Week 1)
    - ACR20 (20% improvement in ACR Core Set Measurements) response
    rate at Week 24.
    Safety:
    - Occurrence of treatment-emergent adverse events
    - Occurrence of serious adverse events
    Immunogenicity:
    - Antidrug antibody incidence
    - Antidrug antibody titer
    - Neutralizing antibody incidence
    E.5.2.1Timepoint(s) of evaluation of this end point
    DAS28-ESR mean absolute change from baseline at all assessment visits
    excl. Week 1 and 24.
    ACR20 response rate at Week 24.
    Occurrence of treatment-emergent AEs up to Week 24, Week 30, Week
    55 and Week 63.
    Occurrence of SAEs up to Week 24, Week 30, Week 55 and Week 63.
    Antidrug antibody incidence at Weeks 2, 12, 24, 30, 52 and 55.
    Antidrug antibody titer at Weeks 2, 12, 24, 30, 52 and 55.
    Neutralizing antibody incidence at Weeks 2, 12, 24, 30, 52 and 55.
    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 Yes
    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 Yes
    E.6.13.1Other scope of the trial description
    Immunogenicity
    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) Yes
    E.8.2.2Placebo No
    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 concerned6
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA64
    E.8.6 Trial involving sites outside the EEA
    E.8.6.1Trial being conducted both within and outside the EEA Yes
    E.8.6.2Trial being conducted completely outside of the EEA No
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    Georgia
    Moldova, Republic of
    Russian Federation
    Serbia
    Bulgaria
    Germany
    Hungary
    Poland
    Slovakia
    Czechia
    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 years1
    E.8.9.1In the Member State concerned months11
    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 months11
    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: 298
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 244
    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 state38
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 284
    F.4.2.2In the whole clinical trial 542
    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)
    No post-trial treatment is given to the patients.
    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 Decision2020-09-01
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2020-04-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2022-06-06
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