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    Summary
    EudraCT Number:2018-002202-31
    Sponsor's Protocol Code Number:BAT-1806-002-CR
    National Competent Authority:Bulgarian Drug Agency
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2018-11-30
    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 ConcernedBulgarian Drug Agency
    A.2EudraCT number2018-002202-31
    A.3Full title of the trial
    A Randomized, Double-Blind, Parallel-Group, Active-Control Study to Compare the Efficacy and Safety of BAT1806 to RoActemra® in Rheumatoid Arthritis Patients With Inadequate Response to Methotrexate
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Phase 3 study to compare BAT1806 with RoActemra in patients with Rheumatoid Arthritis
    A.4.1Sponsor's protocol code numberBAT-1806-002-CR
    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 SponsorBio-Thera Solutions, Ltd.
    B.1.3.4CountryChina
    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 supportBio-Thera Solutions, Ltd.
    B.4.2CountryChina
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationBio-Thera Solutions, Ltd.
    B.5.2Functional name of contact pointClinical Development Department
    B.5.3 Address:
    B.5.3.1Street AddressFloor 5, Building A6, Science Enterprise Accelerator, 11 Kaiyuan Avenue, Science City
    B.5.3.2Town/ cityHuangpu District, Guangzhou, Guangdong Province
    B.5.3.3Post code510000
    B.5.3.4CountryChina
    B.5.4Telephone number862022233607
    B.5.5Fax number862022233613
    B.5.6E-mailCT_Registration@bio-thera.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 BAT1806
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNBAT1806
    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 number20
    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
    D.2.1.1.2Name of the Marketing Authorisation holderRoche Registration GmbH
    D.2.1.2Country which granted the Marketing AuthorisationGermany
    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 nameRoActerma
    D.3.4Pharmaceutical form Infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNRoActemra
    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 number20
    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 Patients With Inadequate Response to Methotrexate
    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 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 BAT1806 and RoActemra in subjects with rheumatoid arthritis (RA)
    that is inadequately controlled by methotrexate (MTX).
    E.2.2Secondary objectives of the trial
    - To evaluate the efficacy profile ofBAT1806 compared with RoActemra over time based on secondary efficacy endpoints.
    - To evaluate the safety and tolerability profile ofBAT1806 compared with RoActemra over the entire study period.
    - To evaluate the irnmunogenicityprofile ofBAT1806 in terms of anti-drug antibody (ADAs) production compared with RoActemra.
    - To evaluate the steady-state pharmacokinetics (PK) ofBATl 806 compared with RoActemra
    - To assess safety and imrnunogenicity following transition from RoActemra to BAT1806.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Male or female subjects 18 years of age or older who fulfil the American College of Rheumatology (ACR)/European League Against Rheumatism (EULAR) 2010 revised classification criteria for RA diagnosis for at least 6 months before screening, based on the medical history record.
    2. Subject presents with active RA, as defined by:
    a. 2: 6 out of 68 tender joints (at screening and randomization) AND
    b. 2: 6 out of 66 swollen joints (at screening and randomization) AND
    c. Serum C-reactive protein (CRP) >upper limit of normal (ULN) value or erythrocyte sedimentation rate (ESR) 2: 28 mm/hour at screening.
    3. Subject must be receiving MTX therapy according to the following:
    a. MTX treatment by any route of administration for 2: 12 weeks prior to randomization, with at least the last 4 consecutive weeks prior to randomization on a stable dose ranging between 10 to 25 mg/week.
    b. Subjects will continue on their stable MTX dose and route of administration throughout the study.
    4. If using oral corticosteroids, subject must be on a stable::=:: 10 mg dose ofprednisone/day equivalent for at least 4 consecutive weeks prior to randomization and willing to continue at this level throughout the study.
    5. If taking nonsteroidal anti-inflammatory drugs, subject must be on a stable dose for at least 2 consecutive weeks prior to randomization and willing to continue at this level throughout the study.
    6. Subjects are eligible if they have received not more than 2 biological agents other than interleukin-6 inhibitors or targeted synthetic DMARDs ( eg, tofacitinib) in total for RA treatment.
    7. Female subjects of childbearing potential and male subjects with a female partner of childbearing potential must be willing to take reliable contraceptive precautions throughout the study period and continuing for at least 3 months after the last dose of study drug. Reliable methods of contraception include: intrauterine device, hormonal contraceptives (eg, oral, patch, or injectable), male vasectomy (if vasectomy was medically confirmed), a barrier protection method ( eg, condom or diaphragm) in association with spermicide cream, foam, or gel. Abstinence from heterosexual intercourses is accepted when this is the usual lifestyle of the subject and must be continued for at least 3 months after the last dose of study drug. A female subject is considered not of child-bearing potential when postmenopausal (at least 12 consecutive months without menses without an alternative medical cause) or surgically sterilized (bilateral tubal ligation, bilateral oophorectomy with or without hysterectomy).
    8. If female of childbearing potential, subject should have a negative pregnancy test result at Screening and Baseline visit.
    9. Subjects must be willing to provide written consent and to comply with the requirements of the study protocol.
    E.4Principal exclusion criteria
    1. Has RA of ACR functional class IV or is wheelchair/bed bound.
    2. Known hypersensitivity to tocilizumab or to study treatment excipients.
    3. Previous exposure to any authorized or investigational interleukin-6 inhibitor
    4. Subject has received any biological agents other than those prohibited or any targeted synthetic DMARDs
    5. Subject has received any cell-depleting therapy (eg, rituximab) ::=:: 12 months prior to randomization.
    6. Subject has been treated with an investigational drug other than those prohibited or device :S 8 weeks or 5 half-lives of the drug (whichever is longer) prior to randomization.
    7. Subject has received any conventional DMARDs other than MTX (eg, hydroxychloroquine, sulfasalazine, iguratimod, etc.)::=:: 4 weeks prior to randomization. For leflunomide, the washout period before randomization must be a minimum of 12 weeks or a minimum of 4 weeks is accepted
    after documented completion of standard cholestyramine or activated charcoal washout procedure.
    8. Previous exposure to alkylating agents such as cyclophosphamide or chlorambucil.
    9. Subject has received IV imrnunoglobulins or plasmapheresis ::=:: 6 months prior to randomization.
    10. Subject has been treated with intra-articular or parenteral corticosteroids ::=:: 4 weeks prior to randomization (inhaled corticosteroids for stable medical conditions are allowed).
    11. Subject has received any herbal remedies, traditional medicines, or other not approved medications for RA :S 4 weeks prior to randomization.
    12. Subject has undergone joint surgery :S 12 weeks prior to randomization (on any joint to be assessed during the study) or has any surgery planned during the study.
    13. Evidence of malignancy, lung infection, or abnormalities suggestive of active tuberculosis (TB) on chest radiography performed within 12 weeks prior to the Screening Visit or during the screening period.
    14. Subject meets any of the following criteria relative to latent or active TB infection:
    a. History of active TB :S 3 years prior to screening. If> 3 years, documentation of completion of adequate therapy must be available.
    b. Presence of signs or symptoms suggestive of active TB upon medical history and/or physical examination during screening.
    c. Recent close contact with a person with active TB.
    d. Positive interferon-gamma release assay (IGRA) result at screening.
    15. History of invasive infection (eg, histoplasmosis, coccidioidomycosis, blastomycosis).
    16. Presence of active infection at screening, or history of infection requiring intravenous antibiotics and/or hospitalization :S 4 weeks prior to randomization or oral antibiotics :S 2 weeks prior to randomization. Minor fungal infections (eg, minor nail infections) will be allowed.
    17. Any recurrent bacterial, fungal, or viral infection that based on the investigator's clinical assessment makes the subject unsuitable for the study, including recurrent/disseminated herpes zoster.
    18. Current or history of diverticulitis, complications of diverticulitis, history of diverticulosis requiring antibiotic treatment, current or history of chronic ulcerative lower gastrointestinal tract diseases or any other lower gastrointestinal condition that may predispose to perforation.
    19. Any history of malignancy or lymphoproliferative disease at any tin1e, except curative treatment for nonmelanoma skin cancer or resected carcinoma in situ of the cervix.
    20. Have a transplanted organ/tissue or stem cell transplantation.
    21. Significant medical problems, including but not limited to the following: uncontrolled hypertension (systolic pressure 2: 160 and/or diastolic pressure 2: 95 mmHg), congestive heart failure (New York Heart Association status of class III or IV), history of unstable angina pectoris, myocardial infarction, or cerebrovascular accident within the past 12 months, uncontrolled diabetes, renal or liver disease.
    22. Presence of any of the following abnormal laboratory test results at screening:
    a. Abnormal liver function.
    b. Serum total bilirubin > 1.5 x ULN.
    c. Abnormal renal function defined as serum creatinine level 2: 1.5 x ULN.
    d. Total white blood cell count :S 3,000/μL, absolute neutrophil count :S 2,000/μL, platelet count < 100,000/μL, or hemoglobin < 8.5 g/dL.
    e. Positive HIV, hepatitis B, or hepatitis C serological result.
    For European sites, HBsAg-positive AND I OR HBcAb-positive subjects will be excluded.

    For Chinese sites:
    • HBsAg-positive subjects will be excluded;
    • IfHBsAg is negative:
    - HBcAb is also negative, subjects will be included;
    - HBcAb is positive:
    • HBsAb-positive subjects will be included;
    • HBsAb-negative subjects will be tested for HBV DNA:
    - IfHBV DNA is negative, the subjects will be included.
    - If HBV DNA is positive, the subjects will be excluded.
    23. Subject has a history of acute inflammatory joint disease of different origin other than RA.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for the study is the percentage of subjects
    achieving an American College of Rheumatology 20% (ACR20) response
    E.5.1.1Timepoint(s) of evaluation of this end point
    Two timepoints (Week 12 or Week 24) will be analyzed independently as
    primary for this measure, depending on the regulatory agency for
    submission (ie, for the European Medicines Agency [EMA] this will be
    Week 12 and for the US Food and Drug Administration [FDA] and China
    National Medical Products Administration [NMPA] this will be Week 24
    during TP1).
    E.5.2Secondary end point(s)
    The following secondary endpoints will be assessed.

    Efficacy
    • Change from baseline in Disease Activity Score on 28 Joints (DAS28; C- reactive protein [CRP]) and DAS28 (erythrocyte sedimentation rate [ESR]) over the course of the study
    • Percentage of subjects achieving ACR20, ACR50, and ACR 70 response over the course of the study
    • Change from baseline in ACR and DAS28 individual components over the course of the study, including Swollen Joint Count in 66 joints (SJC66), Tender Joint Count in 68 joints (TJC68), pain VAS, total Health Assessment Questionnaire - Disability Index (HAQ-DI), Subject's Global Assessment of Disease Activity visual analogue scale (VAS), Physician's Global Assessment of Disease Activity VAS, CRP, and ESR

    Pharmacokinetics
    • Trough serum concentration of tocilizumab at predose over the course of the study for both arms

    Immunogenicity
    • Proportion of subjects developing ADAs to RoActemra or BAT1806 over the course of the study

    Safety:
    • Adverse events (AEs), including treatment-emergent AEs (TEAEs), SAEs, related AEs and related SAEs
    • Laboratory parameters, including hematology, chemistry with lipids panel, and urinalysis
    • Vital signs
    • Physical examination
    • 12-lead ECG
    E.5.2.1Timepoint(s) of evaluation of this end point
    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 No
    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 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 No
    E.8.1.3Single blind No
    E.8.1.4Double blind Yes
    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) 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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA15
    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
    Bulgaria
    China
    Georgia
    Poland
    Ukraine
    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
    Last Visit of Last Subject will be end of trial.
    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 months11
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years2
    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: 553
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 68
    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 state48
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 211
    F.4.2.2In the whole clinical trial 621
    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 separate plans for treatment or care after the subject has ended the participation in 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 Decision2019-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2019-03-27
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2021-01-05
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