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    Summary
    EudraCT Number:2016-001064-11
    Sponsor's Protocol Code Number:NI071F2
    National Competent Authority:Poland - Office for Medicinal Products
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2017-04-12
    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 ConcernedPoland - Office for Medicinal Products
    A.2EudraCT number2016-001064-11
    A.3Full title of the trial
    A Randomized, Double-Blind, Multicenter, 3-Stage, Efficacy and Safety Study of NI-071 and US-Licensed Remicade® (Infliximab) for the Treatment of Patients with Rheumatoid Arthritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Efficacy and safety study of Remicade® (infliximab) and NI-071 (a proposed infliximab biosimilar) for the treatment of patients with rheumatoid arthritis
    A.4.1Sponsor's protocol code numberNI071F2
    A.5.4Other Identifiers
    Name:IND numberNumber:126520
    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 SponsorNichi-Iko Pharmaceutical Co., Ltd.
    B.1.3.4CountryJapan
    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 supportNichi-Iko Pharmaceutical Co., Ltd.
    B.4.2CountryJapan
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationNichi-Iko Pharmaceutical Co., Ltd.
    B.5.2Functional name of contact pointBiosimilar Development Department
    B.5.3 Address:
    B.5.3.1Street Address11th Floor, Sumitomo Fudosan Nihonbashi Bldg
    B.5.3.2Town/ city5-4 Nihonbashi-Honcho 1-chome, Chuo-ku
    B.5.3.3Post code103-0023
    B.5.3.4CountryJapan
    B.5.6E-mailkenji-matsuyama@nichiiko.co.jp
    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 nameNI-071
    D.3.2Product code NI-071
    D.3.4Pharmaceutical form Powder for concentrate for solution for 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 INNINFLIXIMAB
    D.3.9.1CAS number 170277-31-3
    D.3.9.2Current sponsor codeNI-071
    D.3.9.4EV Substance CodeSUB02681MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 Remicade
    D.2.1.1.2Name of the Marketing Authorisation holderJanssen Biotech, Inc.
    D.2.1.2Country which granted the Marketing AuthorisationUnited States
    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 nameRemicade
    D.3.4Pharmaceutical form Powder for concentrate for solution for 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 INNINFLIXIMAB
    D.3.9.1CAS number 170277-31-3
    D.3.9.3Other descriptive nameRemicade
    D.3.9.4EV Substance CodeSUB02681MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number10
    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 20.0
    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
    Stage 1 (Biosimilarity Stage)
    Primary:
    • To investigate the biosimilarity of NI-071 (proposed infliximab biosimilar) and US-licensed Remicade® (infliximab; Remicade-US) in terms of efficacy in patients with rheumatoid arthritis (RA) not adequately responding to methotrexate (MTX), by determining the percentages of patients achieving ACR20-CRP (a 20% improvement from baseline in the American College of Rheumatology [ACR] core set criteria using C-reactive protein [CRP] as the acute-phase reactant)
    Stage 2 (Interchangeability Stage)
    Primary:
    • To investigate the interchangeability between NI-071 and Remicade-US by evaluating key pharmacokinetic (PK) parameters in each treatment group following treatment switches
    Stage 3 (Safety Follow-up Stage)
    Primary:
    • To evaluate the safety of long-term treatment (follow-up through Week 62)
    E.2.2Secondary objectives of the trial
    Stage 1 (Biosimilarity Stage)
    Secondary:
    • To evaluate safety and immunogenicity of NI-071 and Remicade-US
    • To evaluate efficacy based on other rates of improvement in the ACR criteria, on the DAS28 (disease activity score involving 28 joints) and the RAPID3 (routine assessment of patient index data 3), and on changes in health-related quality of life
    Stage 2 (Interchangeability Stage)
    Secondary:
    • To evaluate the safety, efficacy, and immunogenicity of NI-071 and Remicade-US
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    - Patients with a diagnosis of RA as defined by the 2010 ACR and European League Against Rheumatism (EULAR) classification criteria.
    - Patients have active RA, as confirmed by the following criteria:
    • ≥6 swollen joints and ≥6 tender joints at screening and baseline (28-joint count), and
    • Either CRP ≥0.7 mg/dL (≥7.0 mg/L) or erythrocyte sedimentation rate (ESR) ≥28 mm/h at screening
    - Patients taking MTX (oral or parenteral) for at least 3 months prior to screening and at a stable dose of between 10 and 25 mg/week for at
    least 8 weeks. Concomitant folic/folinic acid at a dose of at least 5 mg/week is to be taken during the study; patients can start treatment
    with folic/folinic acid at screening if not already receiving it.
    - If the patient is currently taking non-steroidal anti-inflammatory drugs (NSAIDs), the patient must be on a stable dose for at least 4 weeks prior
    to screening and during the study.
    - Patients with a body weight of ≥40 kg and ≤120 kg at screening.
    - Patients who are ≥18 and ≤75 years of age at screening.
    - Women of childbearing potential (WOCBP) and men (if their sexual partners are WOCBP) must use at least 1 highly effective form of birth
    control throughout the study and for 6 months after the last dose of study treatment. Highly effective methods of birth control include true
    sexual abstinence (defined as refraining from heterosexual intercourse during the entire period of risk, in line with the preferred and usual
    lifestyle of the patient), surgery (bilateral tubal ligation or occlusion, vasectomized partner), progestogen-only or estrogen/progestogen
    hormonal contraceptive associated with inhibition of ovulation (oral, patch, injectable, implantable, or intravaginal), intrauterine device
    (IUD), or intrauterine hormone-releasing system (IUS). See Section 8.7 for a definition of WOCBP and a complete description of contraceptive
    requirements.

    Refer to protocol for more inclusion criteria.
    E.4Principal exclusion criteria
    - Patients who have had prior treatment with infliximab.
    - Patients who have had prior treatment with more than 1 biological drug other than infliximab (e.g., adalimumab, rituximab, abatacept,
    etanercept) for RA either as part of clinical management or during a clinical study. Patients who have had prior treatment with more than 1
    protein kinase inhibitor (e.g., tofacitinib) for RA either as part of clinical management or during a clinical study. Patients who have had prior
    treatment with 1 biological drug AND 1 protein kinase inhibitor are allowed in the study.
    - Patients who have had prior treatment with a tumor necrosis factor alpha (TNF-α) inhibitor for RA who had lack of efficacy as per clinical
    judgment (primary failure). Primary failure is defined as never having achieved an adequate response, whereas secondary failure is the loss of
    response over time. Patients who have received prior treatment with no more than 1 biological DMARD and who have received not more than 1
    prior TNF-α inhibitor (other than infliximab) and have failed it because of loss of efficacy (secondary failure) or intolerance (e.g., mild injection
    site reactions) are allowed in the study. Patients who have discontinued TNF-α inhibitors for RA (other than infliximab) because their insurance
    no longer covered the cost of treatment or they could no longer afford the cost or copays for the treatment are allowed in the study.
    - Patients who had prior treatment with cyclophosphamide or other cytotoxic agents.
    - Patients with a concomitant or past history of autoimmune connective tissue diseases other than RA, for example, systemic lupus
    erythematosus, Sjogren's syndrome, polymyositis, dermatomyositis, and mixed connective tissue disease.
    - Patients with a history of hypersensitivity to the components of NI-071 or mouse-derived protein (e.g., mouse, chimeric, and humanized
    antibody)
    - Patients with the following concomitant or past history:
    • Chronic or recurrent infectious disease (e.g., bronchiectasis, sinusitis)
    • Demyelinating disease (e.g., multiple sclerosis)
    • Presence of New York Heart Association (NYHA) Class III/IV heart failure (see Section 12.5)
    • Lymphoproliferative disorder (e.g., Epstein-Barr virus [EBV]-related lymphoproliferative disorder, lymphoma, or leukemia) or myelodysplastic syndrome
    • Cancer other than successfully treated non-melanoma skin cancer or localized carcinoma in situ of the cervix
    • Interstitial lung disease
    - Patients with mycobacterial infection or opportunistic infection (e.g., cytomegalovirus infection or invasive fungal infection such as histoplasmosis, blastomycosis, or coccidiomycosis) or who have resided in or traveled to regions where such infections are prevalent within 6 months prior to the initial administration of the investigational drug.
    - Patients who received a live vaccine within 12 weeks prior to study dosing, or who plan to receive a live vaccine during the study period or within 6 months after the last dose of study treatment. (If received prior to study dosing, these patients may be re-screened after the appropriate washout period.)
    - Female patients who are pregnant, wish to become pregnant, or are breastfeeding.
    - Male patients who plan to donate sperm during the study or within 6 months after the last dose. Female patients who plan to donate eggs or
    undergo in vitro fertilization treatment during the study or within 6 months after the last dose.

    Refer to protocol for more exclusion criteria.
    E.5 End points
    E.5.1Primary end point(s)
    Clinical Efficacy
    Primary endpoint:
    • ACR20-CRP at Week 22

    Pharmacokinetics
    Primary endpoints:
    • AUCtau and Cmax during the dosing interval of Weeks 46 to 54
    E.5.1.1Timepoint(s) of evaluation of this end point
    Clinical Efficacy
    • ACR20-CRP at Week 22

    Pharmacokinetics
    • AUCtau and Cmax during the dosing interval of Weeks 46 to 54



    Please refer to the Schedule of Assessments in the protocol.
    E.5.2Secondary end point(s)
    Clinical Efficacy
    Secondary endpoints:
    • Change from baseline in DAS28-CRP and DAS28-ESR scores
    • ACR20-CRP (at time points other than Week 22), ACR20-ESR, ACR50-CRP, ACR50-ESR, ACR70-CRP, and ACR70-ESR
    • Change from baseline in each item of ACR core set
    • Change from baseline in RAPID3 scores
    • Change from baseline in SF-36 domain subscores and summary scores

    Pharmacokinetics
    Secondary endpoints:
    • Minimum concentration (Cmin) and time at maximum concentration (tmax) during the dosing interval of Weeks 46 to 54
    E.5.2.1Timepoint(s) of evaluation of this end point
    Please refer to the Schedule of Assessments in the protocol.
    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 Yes
    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 trial3
    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 concerned14
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA46
    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
    Czech Republic
    Poland
    Puerto Rico
    Russian Federation
    Spain
    Ukraine
    United Kingdom
    United States
    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
    Last Visit of the Last Subject (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 months2
    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 months3
    E.8.9.2In all countries concerned by the trial days19
    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: 497
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 88
    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 state230
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 319
    F.4.2.2In the whole clinical trial 585
    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)
    Investigators will explain the safest way to end subject´s participation, which may involve the completion of some final key safety and efficacy assessments. Investigators will provide subjects with the best course of continuing care.
    G. Investigator Networks to be involved in the Trial
    G.4 Investigator Network to be involved in the Trial: 1
    G.4.1Name of Organisation National Institute for Health Research
    G.4.3.4Network Country United Kingdom
    N. Review by the Competent Authority or Ethics Committee in the country concerned
    N.Competent Authority Decision Authorised
    N.Date of Competent Authority Decision2017-04-13
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2017-03-01
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2019-05-10
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