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    The EU Clinical Trials Register currently displays   43845   clinical trials with a EudraCT protocol, of which   7282   are clinical trials conducted with subjects less than 18 years old.   The register also displays information on   18700   older paediatric trials (in scope of Article 45 of the Paediatric Regulation (EC) No 1901/2006).

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    Summary
    EudraCT Number:2013-004604-19
    Sponsor's Protocol Code Number:CAR-ERA
    National Competent Authority:Germany - PEI
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2014-06-03
    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 ConcernedGermany - PEI
    A.2EudraCT number2013-004604-19
    A.3Full title of the trial
    Delayed Gadolinium-enhanced Magnetic resonance Imaging (MRI) of Cartilage - A pilot study to measure the effect of Adalimumab plus Methotrexat (MTX) versus Placebo plus MTX on cartilage in early rheumatoid arthritis (RA) patients
    Verzögerte Gadolinium-verstärkte Magnetresonanztomographie des Knorpelgewebes - Eine Pilotstudie zur Bestimmung der Wirkung von Adalimumab und Methotrexat (MTX) gegen Placebo und MTX auf Knorpelgewebe bei Patienten mit früher Rheumatoider Arthritis (RA)
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    Effect of Adalimumab plus Methortrexat (MTX) versus Placebo plus MTX on cartilage in early RA patients
    Therapieeffektes auf den Knorpel von Adalimumab und Methotrexat (MTX) im Vergleich zu Plazebo und Methotrexat bei Patienten mit früher rheumatoider Arthritis
    A.4.1Sponsor's protocol code numberCAR-ERA
    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 SponsorHeinrich-Heine-Universität Düsseldorf
    B.1.3.4CountryGermany
    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 supportAbbVie Deutschland GmbH&Co.KG
    B.4.2CountryGermany
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationUniversiätsklinikum Düsseldorf
    B.5.2Functional name of contact pointKoordinierungszentrum kl. Studien
    B.5.3 Address:
    B.5.3.1Street AddressMoorenstrasse 5
    B.5.3.2Town/ cityDuesseldorf
    B.5.3.3Post code40225
    B.5.3.4CountryGermany
    B.5.4Telephone number4902118119701
    B.5.5Fax number4902118119702
    B.5.6E-maildorothea.schilken@med.uni-duesseldorf.de
    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 Humira 40mg Injektionslösung
    D.2.1.1.2Name of the Marketing Authorisation holderAbbVie Ltd.
    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 nameHumira
    D.3.4Pharmaceutical form Injection
    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) Yes
    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
    D.8 Placebo: 1
    D.8.1Is a Placebo used in this Trial?Yes
    D.8.3Pharmaceutical form of the placeboInjection
    D.8.4Route of administration of the placeboSubcutaneous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    patients with early progressive rheumatoid arthritis
    E.1.1.1Medical condition in easily understood language
    patients with early progressive rheumatoid arthritis
    E.1.1.2Therapeutic area Body processes [G] - Bones and nerves physological processes [G11]
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 17.0
    E.1.2Level LLT
    E.1.2Classification code 10066578
    E.1.2Term Progression of rheumatoid arthritis
    E.1.2System Organ Class 100000004859
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To compare longitudinally the effect of adalimumab plus methotrexate (MTX) versus MTX monotherapy on cartilage Glycosaminglycan (GAG) content, reflected by delayed Gadolinium-enhanced magnetic resonance imaging of cartilage (dGEMRIC) index, in patients with early progressive rheumatoid arthritis (RA), who had not previously received any disease modifying antirheumatic drug (DMARD) or biolologic treatment.
    E.2.2Secondary objectives of the trial
    • To assess differences in cartilage thickness between patients initially treated with adalimumab plus MTX versus MTX monotherapy as measured by 3T (threetime) MRI at weeks 12 and 24 and correlate changes from baseline to week 24 in each treatment arm with changes in dGEMRIC index.
    • To assess differences of specific bio-respectively serum cartilage markers (e.g. C2c, Collagen Typ II, COMP, MMP-3, YKL-40) in patients initially treated with adalimumab plus MTX versus MTX monotherapy at week 0, 12 and 24 and to correlate changes in serum cartilage markers (e.g. C2c, Collagen Type II, COMP, MMP-3, YKL-40) from baseline in each treatment arm with changes in dGEMRIC index from baseline to week 24.
    • To compare clinical and functional outcome (American college of rheumatology (ACR) response, Disease-activity-score (DAS)28, (HAQ)) between treatment groups at week 12 and 24 and assess changes of these parameters from baseline up to weeks 12 and 24 in each treatment group.
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject is ≥ 18 years of age.
    2. Subject has a diagnosis of early RA (ERA) fulfilling the 2010 ACR criteria for classification of RA) and has disease duration less than 12 months from symptoms onset.
    3. MCP II and/or MCP III arthritis at the clinically dominant – selected for MRI- hand indicated by joint tenderness.
    4. DAS28 > 3.2.
    5. Anti-citrullinated peptide antibodies (ACPA) and/or RF positive.
    6. Discrete low-grade erosions (Sharp van der Heijde (SHS) Score 0-2) but no larger erosions at MCP II/III joints of the clinically dominant hand are allowed.
    7. Therapy-naive for disease modifying drugs (DMARD).
    8. Oral Prednisone or prednisone equivalent at ≤ 10 mg/day is allowed during the study and should be kept at a stable dose. The dose must not be changed at least 4 weeks prior to the baseline visit and at least 6 weeks prior to the Week 24 visit. One prednisone pulse not exceeding the duration of 14 days for acute medical conditions other than RA with an indication for steroid pulse treatment is allowed. The prednisone pulse is not permitted within 6 weeks prior to the Week 24.
    9. Subject is judged to be in good general health as determined by the Coordinating Investigator based upon the results of medical history, laboratory profile, physical examination, chest X-ray (CXR), and 12-lead electrocardiogram (ECG) performed at Screening.
    10. Subjects must be able and willing to self-administer SC injections or have a qualified person available to administer SC injections.
    E.4Principal exclusion criteria
    1. Subject has previous exposure to any systemic biologic therapy (e.g. abatacept, tocilizumab) including anti-TNF therapy (e.g., infliximab, golimumab, certolizumab pegol, etanercept) including adalimumab.
    2. Subject has been previously treated with DMARDs or MTX.
    3. Joint injections into the reference joint (MCP II) are not allowed. Two joint injections of corticosteroids, not exceeding the equivalent of 40 mg prednisone
    in other joints are allowed. Joint injections are not permitted 6 weeks prior to the Week 24 assessment. Two joints may be injected at the same visit and will be counted as two injections. For the analysis of the Tender joint count (TJC) and Swollen joint count (SJC) these joints will be considered "not assessable" for three months from the time of the intra-articular injection.
    4. Subject has undergone joint surgery within the preceding two months (at joints to be assessed within the study).
    5. Subject has a history of acute inflammatory joint disease of different origin other than RA (e.g., mixed connective tissue disease, seronegative spondyloarthropathy, psoriatic arthritis, Reiter's syndrome, fibromyalgia, systemic lupus erythematosus or any arthritis with onset prior to age 17 years)
    6. Subject has been treated with any investigational drug of a "chemical" nature within two months prior to study entry (screening visit).
    7. Subject has a poorly controlled medical condition, such as uncontrolled diabetes, unstable heart disease, congestive heart failure, recent cerebrovascular accidents and any other condition which, in the opinion of the Investigator, would put the subject at risk by participation in the study.
    8. Subject has a history of clinically significant hematologic (e.g., severe anemia, leukopenia, thrombocytopenia), renal, liver disease (e.g., fibrosis, cirrhosis, hepatitis B and C), or gastroenteric ulcer.
    9. Subject has a history or a present renal dysfunction (GFR < 30 ml/min/1.73m2) [Kaewlai R et al. 2012].
    10. Subject has history of neurologic symptoms suggestive of central nervous system (CNS) demyelinating disease and/or diagnosis of central demyelinating disease.
    11. Subject has history of cancer or lymphoproliferative disease other than a successfully treated non-metastatic cutaneous squamous cell or basal cell carcinoma and/or localized carcinoma in situ of the cervix.
    12. Subject has a history of listeriosis, histoplasmosis, untreated TB, persistent chronic infections, or recent active infections requiring hospitalization or treatment with intravenous (IV) anti-infectives within 30 days or oral anti-infectives within 14 days prior to the Baseline visit.
    13. Subject currently uses or plans to use anti-retroviral therapy at any time during the study.
    14. Subject is known to have immune deficiency, history of HIV or is immunocompromised.
    15. Female subject who is pregnant or breast-feeding or considering becoming pregnant during the study or for 150 days after the last dose of study medication.
    16. Subject has a history of clinically significant drug or alcohol usage in the last year or cannot maintain an alcohol intake of 30 g a day or less throughout the study.
    17. Subject has a positive Tb Screening test.
    18. Subject with evidence of earlier or present hepatitis B or C infection.
    19. Subjects with a pacemaker, defibrillator, or cerebral aneurysm clip or planning to receive any such device within the duration of the study
    20. Subjects with a previous history of kidney failure, dialysis, or liver transplant
    21. Subjects with Claustrophobia (preventing them from taking the MRI exam)
    22. Female subject is either of childbearing potential or is of childbearing potential and is not practicing a reliable method of birth control throughout the study and for 150 days after study completion:
    23. Female subjects of childbearing potential who have a positive serum pregnancy test at the Screening visit and a positive urine pregnancy test at Baseline.
    24. Subjects who are not able and willing to provide written informed consent and comply with the requirements of this study protocol.
    E.5 End points
    E.5.1Primary end point(s)
    Mean Intergroup difference of pooled (per patient) dGEMRIC index (T1 [ms]) of the MCP II and MCP III joints of the clinically dominant hand, measured by variable flip-angle imaging 3T MRI at week 24 versus baseline.
    E.5.1.1Timepoint(s) of evaluation of this end point
    after 24 weeks (End of Study)
    E.5.2Secondary end point(s)
    •Proportion of patients showing no decrease in dGEMRIC index from week 0 to week 24 in each treatment group
    •Proportion of patients in each treatment group showing an increase of dGEMRIC index from week 0 to weeks 12 and 24
    •Difference of cartilage thickness / Joint space narrowing (JSN) at MCP II and MCP III joints of the clinically dominant hand from baseline to weeks 12 and 24 in each treatment group, determined by 3T MRI using T1 weighed gradient echo images
    •Total rheumatoid arthritis magnetic resonance Imaging (RAMRI) score and subscores for synovitis, osteitis and bone erosions at MCP II/III joints of the clinically dominant hand in each treatment group at 0, 12 and 24 weeks and intergroup difference of changes from week 0 to weeks 12 and 24
    •Proportion of subjects showing no decrease of cartilage thickness / JSN in 3T MRI at week 24 compared to baseline
    •Proportion of subjects with improvement in RAMRI score for synovitis, osteitis and bone erosion in each treatment group at week 24 compared to baseline
    •Proportion of subjects with decrease in rate of early enhancement in perfusion MRI in each treatment group
    •Mean and median concentration of cartilage markers (e.g. Collagen Typ II, COMP, MMP-3, YKL-40) at week 0, 12 and 24 and changes from baseline to week 12 and 24 in each treatment arm
    •Proportion of subjects in each treatment group who are in clinical remission (DAS 28 < 2.6) or low disease activity (DAS 28 >2.6 <3.2) at 12 and 24 weeks
    •Mean and median DAS28 at 0, 12 and 24 weeks and changes in DAS28 from baseline to week 12 and 24 in each treatment arm
    •ACR 20, 50 and 70 response at 12 and 24 weeks in each treatment arm
    •Mean and median total health assessment question (HAQ) at 0, 12 and 24 weeks and changes in total HAQ from baseline to week 12 and 24 in each treatment group
    E.5.2.1Timepoint(s) of evaluation of this end point
    after 24 weeks (End of Study)
    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.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) No
    E.8.2.2Placebo Yes
    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 Yes
    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 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 years2
    E.8.9.1In the Member State concerned months0
    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 months0
    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: 27
    F.1.3Elderly (>=65 years) Yes
    F.1.3.1Number of subjects for this age range: 3
    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 state30
    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 special treatment planned. After finishing the study the patients will be offered the standard of care for their disease.
    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 Decision2014-08-06
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2014-08-05
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
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