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    Summary
    EudraCT Number:2012-002009-23
    Sponsor's Protocol Code Number:GP15-301
    National Competent Authority:Estonia - SAM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2015-10-06
    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 ConcernedEstonia - SAM
    A.2EudraCT number2012-002009-23
    A.3Full title of the trial
    A randomized, double-blind, parallel-group Phase III study to demonstrate equivalent efficacy and to compare safety and immunogenicity of GP2015 and Enbrel® (EU-authorized) in patients with moderate to severe, active rheumatoid arthritis
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Clinical trial to demonstrate that treatments with GP2015 and Enbrel® are comparable in patients with rheumatoid arthritis
    A.3.2Name or abbreviated title of the trial where available
    EQUIRA
    A.4.1Sponsor's protocol code numberGP15-301
    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 SponsorHexal AG
    B.1.3.4CountryGermany
    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 supportHexal AG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationHexal AG
    B.5.2Functional name of contact pointClinical Trial Information Desk
    B.5.3 Address:
    B.5.3.1Street AddressIndustriestr. 25
    B.5.3.2Town/ cityHolzkirchen
    B.5.3.3Post code83607
    B.5.3.4CountryGermany
    B.5.5Fax number4980244764880
    B.5.6E-mailbiosimilar.clinicaltrials@sandoz.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 GP2015
    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 INNETANERCEPT
    D.3.9.1CAS number 185243-69-0
    D.3.9.4EV Substance CodeSUB01984MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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 Enbrel 50 mg solution for injection in pre-filled syringe
    D.2.1.1.2Name of the Marketing Authorisation holderPfizer 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 nameEnbrel 50 mg solution for injection in pre-filled syringe
    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 INNETANERCEPT
    D.3.9.1CAS number 185243-69-0
    D.3.9.4EV Substance CodeSUB01984MIG
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number50
    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
    Moderate to severe active rheumatoid arthritis
    E.1.1.1Medical condition in easily understood language
    Chronic inflammatory disease causing pain and swelling in the joints
    E.1.1.2Therapeutic area Diseases [C] - Musculoskeletal Diseases [C05]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 19.1
    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
    To demonstrate equivalence of change in DAS28-CRP score from baseline to week 24 between patients treated with GP2015 and patients treated with EU-authorized Enbrel
    E.2.2Secondary objectives of the trial
    Efficacy:
    In the first part of the study, GP2015 and EU-authorized Enbrel will be compared up to week 24. Continuous GP2015 treatment versus a treatment transition from EU-authorized Enbrel to GP2015 after week 24 up to week 48 of treatment will be compared in the second part of the study for following efficacy parameters:
    * DAS28-CRP and DAS28-ESR scores
    * Changes from baseline in DAS28-CRP and DAS28-ESR scores
    * Proportion of patients achieving EULAR good and moderate response and proportion of patients achieving DAS28 ≤2.6
    * For other objectives please see protocol

    Safety and tolerability:
    * Evaluation of the clinical safety of GP2015 and EU-authorized Enbrel.
    * Evaluation of the local tolerability at the injection sites of both products as assessed by the investigator.
    * Assessment of the immunogenicity of GP2015 and EU-authorized Enbrel by measuring the rate of anti-drug antibody (ADA) positive patients at baseline, and at weeks 2, 4, 12, 24, 30, 36 and 48.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Patients at least 18 years of age at screening with RA diagnosed according to the ACR 1987 or ACR/EULAR 2010 criteria for ≥ 6 months at the time of baseline visit.
    2. Patients must have active disease defined as DAS28-CRP ≥ 3.2.
    3. Patients must haveCRP level above upper limit of normal (> 5 mg/l) or erythrocyte sedimentation rate (ESR) ≥28 mm/h.
    4. Patients must have inadequate clinical response to MTX at a dose of 10 - 25 mg/week after proper dose escalation according to local standards. Patients are required to have been on MTX therapy for ≥ 3 months and to be on a stable dose for ≥ 4 weeks prior to baseline. Patients who failed a DMARD treatment other than MTX, and any other DMARD used in combination with MTX, will be allowed to enter into the study after an appropriate wash-out period prior to baseline (except for MTX).
    5. Patients (male and female) who have been compliant and are willing to remain compliant throughout the study and after study completion with the safety precautions in accordance with the local MTX label, particularly in relation to contraception requirements to prevent fathering a child or becoming pregnant.
    6. Patients should be taking adequate folic acid supplementation in a stable dose (≥ 5 mg per week) during the last 4 weeks before baseline and until the end of the study.
    7. Patients taking systemic corticosteroids have to be on a stable dose of ≤ 7.5 mg/d prednisone or equivalent for at least 4 weeks before baseline and have to continue on this stable dose during the study.
    8. Patients taking regular NSAIDs, COX-2 inhibitors, paracetamol/acetaminophen or low strengths opioids as part of their RA therapy are required to be on stable dose for at least 4 weeks before baseline.
    9. Patients taking NSAIDs or COX-2 inhibitors or paracetamol/acetaminophen/low strength opioids on a PRN basis (as required, meaning not as a fixed dose schedule) within 4 weeks before randomization have to stop their medication at least 24 hours before a study vist.
    10. Patients must show the following laboratory results obtained at Visit 1:
    * Hemoglobin ≥ 8.5 g/dl
    * White blood cell count (WBC) ≥ 3,500/µl and neutrophils > 2,000/μL and platelets >100,000/μL
    * AST, ALT and AP ≤ 2.5 x ULN
    * Serum creatinine level ≤ 176.8 µmol/L (2.0 mg/dL)
    11. Patients must give written, signed and dated informed consent before any study-related assessment is performed.
    12. Must be able to understand and communicate with the investigator and comply with the requirements of the study. Where relevant, a legal representative will also sign the informed study consent according to local laws and regulations.
    13. Patient is affiliated to social security or equivalent system (France only).
    E.4Principal exclusion criteria
    1. Previous exposure to etanercept in the past.
    2. Treatment with any other biologic therapy for RA, including TNFα inhibitors, anti-CD20, immune-modulator drug(s), other investigational drug(s) and /or device(s) within three months or five half-lives at the time of enrollment whichever is longer.
    3. Previous use of >2 biologics.
    4. Primary and secondary biologic therapy failures in the opinion of the investigator (e.g. patients with biologic treatment stopped because of safety and/or efficacy issues).
    5. Subjects taking high potency opioid analgesics, or any intramuscular corticosteroid injection, or any therapy by intra-articular injection required for treatment of acute RA flare within 4 weeks before baseline.
    6. History of known hypersensitivity to any ingredients of the IMPs, to any recombinant human protein or any of the excipients used in GP2015 or Enbrel.
    7. Patients who are allergic to rubber or latex (the needle cover on the prefilled syringes for both GP2015 and Enbrel contains dry natural rubber).
    8. Patients with functional status class IV according to the ACR 1991 revised criteria.
    9. Systemic manifestation of RA, with the exception of Sjögren’s syndrome.
    10. Active ongoing inflammatory diseases other than RA that might confound the evaluation of the efficacy.
    11. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female after conception and until the termination of gestation, confirmed by a positive hCG laboratory test (> 5 mIU/mL).
    12. Women of child-bearing potential not willing to use highly effective contraception throughout.
    13. Pre-existing or recent-onset central or peripheral nervous system demyelinating disorders according to investigator's discretion and taking into account a neurological assessment; patients who are considered to have an increased risk of developing a demyelinating disease.
    14. Any serious illness or uncontrolled medical condition, including but not limited to significant hepatic or renal disease, uncontrolled hypertension (defined as ≥ 160/95), congestive heart failure (NYHA class III or IV), or other severe, uncontrolled cardiac disease.
    15. Patients who have body mass index (BMI) ≥ 29.9.
    16. History of active tuberculosis (TB) or presence of latent (inactive) TB detected by imaging (Chest X-ray [PA or PA and lateral according to local practice], Computerized Tomography [CT] scan or MRI) and/or by the QuantiFERON®-TB Gold test at screening.
    17. Chronic infectious disease or history of recurrent infectious disease or active systemic infection within 2 weeks prior to selection or during the screening period (except for common cold) and patients with a history or evidence of opportunistic infections (e.g. histoplasmosis, listeriosis, legionellosis).
    18. Known immunodeficiency, history of positive serology to human immunodeficiency virus (HIV), or is immunocompromised.
    19. Positive serology to hepatitis B (HBsAg or anti-HBc) or hepatitis C (HCV RNA) at screening or baseline
    20. History of lymphoproliferative disease or any known malignancy or history of malignancy of any organ system (except for basal cell carcinoma or actinic keratosis that have been treated with no evidence of recurrence in the past 3 months, and except for carcinoma in situ of the cervix or non-invasive malignant colon polyps that have been removed with no evidence of recurrence), treated or untreated, within the past 5 years.
    21. Any medical or psychiatric condition which, in the Investigator’s opinion, would preclude the participant from adhering to the protocol or completing the study per protocol.
    22. History or evidence of ongoing alcohol or drug abuse, within the last six months before baseline.
    23. Plans for administration of live vaccines during the study period or vaccination within 3 months prior to baseline.
    24. Patients who are legally institutionalized, or patients under judicial protection (France and any other country where stipulated by local regulations).
    25. Patients with an immediate family member (i.e., spouse, parent/legal guardian, sibling or a child) being a member of study site staff or being a member of the sponsor’s study team.
    E.5 End points
    E.5.1Primary end point(s)
    Change from baseline in DAS28-CRP
    E.5.1.1Timepoint(s) of evaluation of this end point
    Week 24
    E.5.2Secondary end point(s)
    Efficacy endpoints:
    1) DAS28-CRP and DAS28-ESR scores
    2) DAS28-CRP and DAS28-ESR score change from baseline
    3) EULAR good and moderate response and proportion of patients achieving DAS28 ≤2.6
    4) EULAR/ACR boolean remission criteria
    5) ACR20/50/70 response
    6) ACR-N scores
    7) SDAI and CDAI: high, moderate, low disease activity and remission
    8) Health-related Quality of life (HAQ)
    9) Functional Assessment of Chronic Illness Therapy (FACIT) Fatigue scale
    10) CRP/ESR levels

    Safety endpoints:
    11) Physical examination and vital signs
    12) Laboratory assessments: hematology, clinical chemistry, urine analysis
    13) ECG
    14) Immunogenicity (development of anti-drug-antibodies (ADA))
    15) Assessment of injection site reactions (ISRs)
    16) AEs and SAEs
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy endpoints:
    1) Weeks 0, 4, 12, 24 and up to week 48
    2) Weeks 4, 12, 24 and up to week 48
    3) Weeks 4, 12 and 24, 36 and 48
    4) Weeks 4, 12 and 24, 36 and 48
    5) Weeks 4, 12, 24, 36 and 48
    6) Weeks 0, 4, 12, 24, 36 and 48
    7) Weeks 4, 12, 24, 36 and 48
    8) Weeks 0, 4, 12, 24, 36 and 48
    9) Weeks 4, 12, 24, 36 and 48
    10) Weeks 0, 4, 12, 24, 36 and 48

    Safety and tolerability endpoints:
    11) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48
    12) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48
    13) Weeks 24 and 48
    14) Weeks 0, 2, 4, 12, 24, 30, 36 and 48
    15) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48
    16) Weeks 0, 2, 4, 8, 12, 18, 24, 30, 36, 42 and 48
    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 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 Yes
    E.8.1.6Cross over No
    E.8.1.7Other Yes
    E.8.1.7.1Other trial design description
    Parallel group with open label phase after week 24
    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 Information not present in EudraCT
    E.8.4 The trial involves multiple sites in the Member State concerned Information not present in EudraCT
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA74
    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
    Czech Republic
    Estonia
    Germany
    Hungary
    Italy
    Latvia
    Lithuania
    Mexico
    Poland
    Russian Federation
    Serbia
    Slovakia
    Spain
    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
    LSLV
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years
    E.8.9.1In the Member State concerned months
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial years1
    E.8.9.2In all countries concerned by the trial months8
    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: 293
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 73
    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 state55
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 206
    F.4.2.2In the whole clinical trial 366
    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)
    Standard of care
    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 Decision2015-10-12
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2015-10-02
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2017-06-12
    As of 1.2.2020, the UK is no longer an EU Member State. However, EU law still applies to the UK during the transition period
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