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    Summary
    EudraCT Number:2005-003436-21
    Sponsor's Protocol Code Number:D2450174
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Prematurely Ended
    Date on which this record was first entered in the EudraCT database:2005-10-24
    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 ConcernedGermany - BfArM
    A.2EudraCT number2005-003436-21
    A.3Full title of the trial
    A phase 2, multi-centre, randomised, double blind, placebo controlled study evaluating the efficacy, safety and pharmacokinetics of two doses of a candidate Disease Modifying Anti-Rheumatic Drug (DMARD), (SMP-114 120 mg and 240 mg once daily), administered in combination with ongoing methotrexate treatment in patients with active rheumatoid arthritis.
    A.3.2Name or abbreviated title of the trial where available
    ASPECTS- Assessment of Safety, Pharmacokinetics and Efficacy in a Combination Treatment with SMP-114
    A.4.1Sponsor's protocol code numberD2450174
    A.7Trial is part of a Paediatric Investigation Plan Information not present in EudraCT
    A.8EMA Decision number of Paediatric Investigation Plan
    B. Sponsor Information
    B.Sponsor: 1
    B.1.1Name of SponsorDainippon Sumitomo Pharma Europe Ltd.
    B.1.3.4CountryUnited Kingdom
    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 support
    B.4.2Country
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisation
    B.5.2Functional name of contact point
    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 nameSMP-114
    D.3.2Product code SMP-114
    D.3.4Pharmaceutical form Tablet
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPOral use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNrimacalib
    D.3.9.1CAS number 215174-50-8
    D.3.9.2Current sponsor codeSMP-114
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typeequal
    D.3.10.3Concentration number40
    D.3.11 The IMP contains an:
    D.3.11.1Active substance of chemical origin Yes
    D.3.11.2Active substance of biological/ biotechnological origin (other than Advanced Therapy IMP (ATIMP) No
    The IMP is a:
    D.3.11.3Advanced Therapy IMP (ATIMP) Information not present in EudraCT
    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 Information not present in EudraCT
    D.3.11.3.4Combination ATIMP (i.e. one involving a medical device) Information not present in EudraCT
    D.3.11.3.5Committee on Advanced therapies (CAT) has issued a classification for this product Information not present in EudraCT
    D.3.11.4Combination product that includes a device, but does not involve an Advanced Therapy Information not present in EudraCT
    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 Information not present in EudraCT
    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 Yes
    D.3.11.13.1Other medicinal product typedisease modifying anti-rheumatic drug
    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 placeboTablet
    D.8.4Route of administration of the placeboOral use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Rheumatoid Arthritis
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level LLT
    E.1.2Classification code 10039073
    E.1.2Term Rheumatoid arthritis
    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 the efficacy of SMP-114 (120 mg and 240 mg) versus placebo in terms of the percentage of patients meeting the American College of Rheumatology criteria for 20% improvement in Rheumatoid arthritis (ACR20) at Week 24.
    E.2.2Secondary objectives of the trial
    To compare the efficacy of SMP-114 (120 mg and 240 mg) versus placebo in terms of the % of patients who:
    - Meet the ACR criteria for 50% and 70% improvement in RA at Week 24
    - Obtain ‘good’ or ‘moderate’ or ‘none’ response according to the EULAR criteria using a calculation of DAS at Week 24
    To compare the efficacy of SMP-114 (120 mg and 240 mg) versus placebo with respect to:
    - The mean change and the mean % change from baseline in core set variable results, the mean change from baseline in Quality of Life (short form - 36) measure and in DAS28 at Week 24
    - The mean time to first response (time to ACR20, EULAR and DAS28 responses)
    - The actual change in radiological joint damage as assessed by x-ray: from Week 24 to Week 48 and from baseline at Week 24 and at Week 48
    To assess safety and tolerability of each regimen during the study
    To describe the PK profile of SMP-114 and the metabolite flurbiprofen
    To explore the relationship of SMP-114 drug concentration with PD effect
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Is at least 18 years of age
    2. Has given his/her written informed consent to participate in the study
    3. Has had a diagnosis of RA (based on the ACR criteria) for at least 6 months
    4. Has RA disease classified as ACR functional class I, II or III
    5. Has active RA disease as defined by:
    · ≥ 6 swollen joints (using 28-joint counts)
    · ≥ 6 tender joints (using 28-joint counts)
    · and at least one of the following: ESR ≥ 28 mm/hr, CRP ≥ 10 mg/L
    6. Has been receiving methotrexate at weekly doses of 10 to 25 mg for ≥ 12 weeks prior to study drug administration. Methotrexate use must have been in accordance with its product labelling (SmPC)
    7. The dose of methotrexate has been stable for at least 8 weeks prior to randomisation and is anticipated to remain constant during the study period Individuals previously treated with methotrexate can be enrolled provided they have not had clinically significant toxic effects or lack of response, at the discretion of the Investigator
    8. Has been on a stable dose of folate (or leucovorin) for at least 4 weeks prior to randomisation and the dose of folate (or leucovorin) is anticipated to remain constant during the study period. If not currently prescribed, is willing to start receiving folate (or leucovorin) at screening
    9. If on a stable dose of NSAID and/or COX-2 inhibitor, the doses of these concomitant medications must have been stable for at least 2 weeks prior to randomisation. The dose(s) must be anticipated to remain constant during the study
    10. If taking oral corticosteroid at a permissible dose (eg ≤ 10 mg prednisolone) then the dose of the oral corticosteroid must have been stable for at least 4 weeks prior to randomisation and must be anticipated to remain constant during the study
    E.4Principal exclusion criteria
    Patients are not eligible for this study if they fulfil any of the following criteria:

    1. Is a pregnant or lactating woman
    2. Is a woman of childbearing potential not prepared to use a reliable form of contraception during the study. An effective form of birth control includes contraception such as a barrier method (condom with spermicidal) in conjunction with hormone-based contraceptives or certain intra-uterine devices, or alternatively abstinence or surgical methods.
    3. Has previously discontinued DMARD therapy due to hepatic intolerance.
    4. Has received any DMARD in addition to methotrexate during the 4 weeks prior to randomisation. All DMARD’s, with the exception of methotrexate must have been discontinued at least 4 weeks before randomisation, unless requiring a longer washout period
    5. Is receiving more than 2 DMARDs in addition to methotrexate at the time of screening
    6. Is receiving or has received Gold, leflunomide or biological agents including TNF/IL-1 inhibitors within the 8 weeks prior to randomisation. Leflunomide washout can be completed with colestyramine according to the manufacturer’s instructions
    7. Has previously failed ≥2 DMARDS. Failure is defined as removal of the administration of a DMARD due to inadequate efficacy response rather than discontinuation of DMARD therapy due to intolerance. A patient who has been removed from biological DMARD therapy due to non-clinical reasons can enter the study
    8. Will require any treatments contraindicated for methotrexate
    9. Is currently taking flurbiprofen
    10. Has used intra-articular, intra-muscular or intravenous corticosteroids within 8 weeks prior to randomisation
    11. Requires ongoing treatment with warfarin, cimetidine, phenytoin, trimethoprim, quinolones or dextropropoxyphenes (including co-proxamol) during the study
    12. Persistent or severe infections within 3 months before randomisation
    13. Has any known or suspected hypersensitivity to leflunomide or any other isoxazole compounds or any ingredients contained within the study drug (mannitol, corn starch, croscarmellose sodium, hypromellose, magnesium stearate, titanium dioxide, macrogol, carnuba wax, gelatine, sodium metabisulphite)
    14. Has pre-existing hepatic disease, or co morbid illness predisposing to hepatic complications and/or the following laboratory parameters at screening:
    · AST ≥ 2 X ULN on two consecutive occasions and/or
    · ALT ≥ 2 X ULN on two consecutive occasions
    15. Has any pre-existing renal disease, or co morbid illness predisposing to renal complications, or the following laboratory parameter at screening:
    · Serum creatinine ≥ 1.5 mg/dL
    16. Has current blood dyscrasias such as bone marrow hypoplasia, leukopenia, thrombocytopenia or significant anaemia including Haemoglobin <10 g/dL at screening
    17. Has any other significant systemic, cardiac, neurological, psychiatric or other illness that in the Investigator’s opinion would preclude the patient from participating in the study
    18. Has a known or had a known malignancy of any type in the previous 5 years with the exception of basal or squamous cell carcinoma of the skin if no recurrence during the 1 year prior to screening
    19. Has a current history of known or in the opinion of the Principal Investigator, suspected drug and/or alcohol abuse
    20. Has participated in another clinical trial with an investigational agent (including named patient or compassionate use protocols) 8 weeks prior to randomisation (or longer if 8 weeks does not provide a reasonable wash-out period for the drug)
    21. Has previously participated in a clinical trial of SMP-114
    E.5 End points
    E.5.1Primary end point(s)
    A patient will be classified as a responder as per ACR20 if all of the following criteria are met after 24 weeks of treatment, when compared to baseline:
    ≥20% improvement in tender joint count (TJC)
    AND
    ≥20% improvement in swollen joint count (SJC)
    AND
    ≥20% improvement in three of the five following ACR core set measures:
    1. Patient assessment of pain (Visual Analogue Scale[VAS])
    2. Patient global assessment of disease activity (VAS)
    3. Physician global assessment of disease activity (VAS)
    4. Patient self-assessed disability (disability index of the Health Assessment Questionnaire [HAQ])
    5. Acute phase reactant C-reactive protein (CRP) or ESR
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic No
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Biomarker analysis
    E.7Trial type and phase
    E.7.1Human pharmacology (Phase I) No
    E.7.1.1First administration to humans Information not present in EudraCT
    E.7.1.2Bioequivalence study Information not present in EudraCT
    E.7.1.3Other Information not present in EudraCT
    E.7.1.3.1Other trial type description
    E.7.2Therapeutic exploratory (Phase II) Yes
    E.7.3Therapeutic confirmatory (Phase III) No
    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.8.3 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 EEA49
    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 Information not present in EudraCT
    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 patient undergoing the trial.
    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 months25
    E.8.9.1In the Member State concerned days
    E.8.9.2In all countries concerned by the trial months25
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 No
    F.1.1.1In Utero Information not present in EudraCT
    F.1.1.2Preterm newborn infants (up to gestational age < 37 weeks) Information not present in EudraCT
    F.1.1.3Newborns (0-27 days) Information not present in EudraCT
    F.1.1.4Infants and toddlers (28 days-23 months) Information not present in EudraCT
    F.1.1.5Children (2-11years) Information not present in EudraCT
    F.1.1.6Adolescents (12-17 years) Information not present in EudraCT
    F.1.2Adults (18-64 years) Yes
    F.1.3Elderly (>=65 years) Yes
    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 state30
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 300
    F.4.2.2In the whole clinical trial 300
    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 Decision2006-01-02
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-01-18
    P. End of Trial
    P.End of Trial StatusPrematurely Ended
    P.Date of the global end of the trial2008-04-30
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