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    Summary
    EudraCT Number:2005-006165-14
    Sponsor's Protocol Code Number:C08005
    National Competent Authority:UK - MHRA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-05-11
    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 ConcernedUK - MHRA
    A.2EudraCT number2005-006165-14
    A.3Full title of the trial
    A Randomized, Double-Blind, Placebo-Controlled, Phase 2a Study of the Efficacy, Safety, and Pharmacokinetics of MLN3897 in Patients with Rheumatoid Arthritis Taking Methotrexate
    A.3.2Name or abbreviated title of the trial where available
    NA
    A.4.1Sponsor's protocol code numberC08005
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberNA
    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 SponsorMillennium Pharmaceuticals Inc,
    B.1.3.4CountryUnited States
    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 nameMLN3897
    D.3.2Product code N/A
    D.3.4Pharmaceutical form Capsule*
    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 INNN/A
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeMLN3897
    D.3.9.3Other descriptive nameAVE9897
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    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 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 No
    D.IMP: 2
    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 Methotrexate(MTX) administration is at the discretion of the rheumatologist and no tradename is fixed by the protocol.
    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 nameMethotrexate
    D.3.2Product code N/A
    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 INNMethotrexate
    D.3.9.1CAS number N/A
    D.3.9.2Current sponsor codeN/A
    D.3.9.3Other descriptive nameN/A
    D.3.10 Strength
    D.3.10.1Concentration unit mg milligram(s)
    D.3.10.2Concentration typerange
    D.3.10.3Concentration number7.5 to 25
    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 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 placeboCapsule*
    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
    This is the first study of MLN3897 in any disease population. It seeks to establish:
    • The ability of MLN3897 to modify the signs and symptoms of rheumatoid arthritis (RA)
    • The safety and tolerability of MLN3897 in combination with methotrexate (MTX)
    • The pharmacokinetic (PK)/pharmacodynamic (PD) profile of MLN3897 in the RA population, and comparison to that in the healthy volunteer population with respect to CCR1 receptor blockade
    • MTX PK and MLN3897 PK and PD when these drugs are used in combination
    E.2.2Secondary objectives of the trial
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    Each patient must meet all of the following inclusion criteria to be enrolled into the study:
    1. Be male or female aged 18 to 70 years (inclusive)
    2. Meet the ACR diagnostic criteria for RA (see section 16.1 for details). Patients with rheumatological disorders other than RA, where arthritis may be a prominent feature, such as systemic lupus erythematosus, mixed connective tissue disease, scleroderma, poly-dermatomytosis, Sjogren’s syndrome, etc, will be excluded. Patients with RA who have conditions associated secondarily with RA, such as osteoarthritis of affected joint(s) or sicca syndrome, may be enrolled.
    3. Have an RA Global Functional Class of I, II, or III (see section 16.2 for details).
    4. Be taking MTX for a minimum of 6 months before screening with a stable, once weekly oral dose of 7.5 to 25 mg for at least 3 months prior to screening and plan to continue that regimen for the duration of the study
    5. If taking oral corticosteroids, be taking no more than 10 mg/day of prednisone or its equivalent at a dose that has been unchanged for at least 4 weeks prior to screening
    6. If taking NSAIDs, be taking a stable regimen of NSAIDs that has been unchanged for at least 2 weeks prior to screening
    7. Be willing and able to comply with the protocol for the duration of the study
    8. If female of childbearing potential (less than one year post-menopausal or not surgically sterile [tubal ligation does not qualify]), must not be pregnant or breast-feeding. Confirmation that a female patient is not pregnant must be established by a negative serum βhCG pregnancy test at screening and a negative urine pregnancy test on Day 1, prior to study drug administration.
    9. Female patients of childbearing potential and all male patients must use two complementary methods of contraception while enrolled in the study (e.g. condoms plus diaphragm, condom plus oral contraceptives, etc). All patients should use appropriate contraceptives before and after the study as long as they continue taking the background drug, MTX, in accordance with their physician's advice. Abstinance will be considered as an acceptable method of contraception on a case-by-case basis upon discussion with the Millennium or Covance medical monitor.
    10. Have ≥6 swollen joints and ≥6 tender joints, plus at least 2 of the following:
    • CRP >1.5 mg/dL (measured twice, at least 10 days apart, during screening)
    • Morning stiffness with a duration of at least 45 minutes
    • ESR ≥28 mm/h (measured twice, at least 10 days apart, during screening)
    11. Provide written informed consent prior to any study-related procedures not conducted as part of normal medical care.
    E.4Principal exclusion criteria
    Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
    1. Be taking any DMARD other than MTX concomitantly or within 1 month prior to study enrollment (Note: If patient had previously been taking leflunomide [Arava®], his/her last dose must have been taken a minimum of 3 months prior to enrollment, or he/she must have undergone washout with cholestyramine). If patient has previously been taking hydroxychloroquine (Plaquenil®) or chloroquine, his/her last dose must have been a minimum of 3 months prior to enrollment.
    2. Currently being treated with TNF-antagonists (e.g., etanercept, infliximab, or adalimumab) or any other biologic anti-rheumatic agents. If a patient had previously been treated with etanercept, his/her last dose must have been taken a minimum of 4 weeks prior to enrollment. If a patient had previously been treated with infliximab or adalimumab, his/her last dose must have been taken a minimum of 12 weeks prior to enrollment.
    3. Have a tuberculosis (TB) infection of any kind (pulmonary or extra-pulmonary, active or latent), regardless of history of anti-TB treatment. Patients must be screened for TB by customary clinical measures (history, chest X-ray, and skin test as appropriate) at screening. Those patients who appear to be negative for TB must be confirmed free of TB by an ELISPOT blood test.
    4. Have received any investigational drug or experimental procedure in the 30 days before Day 1
    5. Have received intra-articular or systemic corticosteroid injections within 1month prior to screening
    6. Have an acute or chronic active infection or be at high risk of developing an infection due to a compromised immune system (with the exception of patients receiving corticosteroids or MTX as defined in the inclusion criteria)
    7. Have a known or suspected human immunodeficiency virus (HIV) infection, or be at high risk of being HIV-infected due to risk factors in medical or social history, including a known history of intravenous illicit drug use.
    8. Test positive for hepatitis B or hepatitis C infection at screening
    9. Have evidence of an infectious or acute cardiopulmonary process on chest X-ray completed at screening (or on chest X-ray performed within 6 months prior to screening, if available), or any other clinically significant finding that could confound study conduct or results, in the opinion of the investigator.
    10. Have baseline QTc duration >450 msec in males or >460 msec in females or have any other abnormality on a 12-lead ECG that is clinically significant in the opinion of the investigator
    11. Use medications that prolong QT/QTc interval 30 days prior to study drug administration.
    12. History of risk factors for Torsade de Pointes, including but not limited to:
    • family history of long QT syndrome
    • history of congestive heart failure, dilated cardiomyopathy, hypertrophic cardiomyopathy, myocarditis, or Kawasaki syndrome
    • significant electrolyte disorder, especially hypokalemia, hypocalcemia, or hypomagnesemia
    • bradycardia, atrioventricular (AV) block
    13. Have a creatinine clearance as calculated by the Cockcroft-Gault formula of <30 mL/min (see section 16.3 for details)
    14. Have AST, ALT, or total bilirubin values >1.5 x ULN)
    15. Have a creatine phosphokinase (CPK) value ≥1.5 x ULN
    16. Be diagnosed with any type of arthritis prior to the age of 16 years
    17. Have a rheumatological diagnosis other than RA
    18. Use of a potent CYP3A4 inhibitor drugs or foodstuffs (especially grapefruit/grapefruit juice) or any herbal supplements within 14 days prior to Day 1. (For reference list see section 16.6)
    19. Have a known history of cancer, except for a distant history of carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin (≥5 years prior to study entry)
    20. Have other serious concomitant disorders incompatible with the study (exceptions must be discussed and confirmed in writing with the Millennium Pharmaceuticals, Inc. [Millennium] medical monitor or designated delegate)
    21. Have an acute illness which, in the opinion of the investigator, could pose a threat or harm to the patient
    22. Have any planned surgeries or procedures during the course of the study
    23. Have any other factor that, in the opinion of the investigator, could confound the conduct or interpretation of the study
    24. Have received any live, attenuated vaccinations within 1 month prior to study drug administration. Note: Patients who receive study drug should not receive any type of these vaccinations within 1 month after receiving their final dose.
    25. Admit to illicit drug use within 6 months of enrollment, or participation in a drug or alcohol detoxification program within the past 5 years
    26. Currently consume >1 standard units/day of alcohol or admit to alcohol abuse. A standard unit of alcohol is defined as 360 mL beer, 30 mL of 80 proof alcohol, or one 180-mL glass of wine.
    E.5 End points
    E.5.1Primary end point(s)
    The primary endpoint for efficay will be the percentage of patients achieving ACR20 at Day 84 in MLN3897 versus placebo-treated patients.

    Study Endpoints:-

    Efficacy: ACR response criteria assessment, DAS28-CRP assessment, time to
    ACR20 response, HAQ-DI, European League Against Rheumatism (EULAR)
    response criteria, and duration of morning stiffness will be evaluated.

    Safety: AEs, vital signs, clinical laboratory assessments, physical examinations,
    vision examinations, ECGs, peripheral blood leukocyte immunophenotyping

    Pharmacokinetics: MTX, 7-hydroxy MTX, and MLN3897 PK parameters including
    maximum plasma concentration (Cmax), time to reach maximum plasma concentration
    (Tmax), and area under the plasma concentration-time curve from 0 to 24 hours
    (AUC0-24) will be estimated from plasma concentration data using noncompartmental
    methods. Additional PK parameters may be estimated and reported as appropriate. PK parameters for the 2 treatment groups will be compared statistically to assess whether concurrent use of MLN3897 has any effect on MTX and 7-hydroxy MTX PK, and also to determine whether MTX has any effect on the steady-state PK of MLN3897.

    Pharmacodynamics: C-C chemokine receptor-1 (CCR1) internalization will be
    assessed.
    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 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) 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 EEA28
    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 Information not present in EudraCT
    E.8.6.3If E.8.6.1 or E.8.6.2 are Yes, specify the regions in which trial sites are planned
    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
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years1
    E.8.9.1In the Member State concerned months1
    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 months1
    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.1.3Elderly (>=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 For clinical trials recorded in the database before the 10th March 2011 this question read: "Women of childbearing potential" and did not include the words "not using contraception". An answer of yes could have included women of child bearing potential whether or not they would be using contraception. The answer should therefore be understood in that context. This trial was recorded in the database on 2006-05-11. Yes
    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 state28
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 186
    F.4.2.2In the whole clinical trial 186
    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 Decision2006-06-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-08-03
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-08-21
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