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    Summary
    EudraCT Number:2004-002567-24
    Sponsor's Protocol Code Number:M120204-063
    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:2005-02-22
    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 number2004-002567-24
    A.3Full title of the trial
    A Phase 2a Magnetic Resonance Study of the Safety and Efficacy of MLN1202 in Patients with Multiple Sclerosis
    A.3.2Name or abbreviated title of the trial where available
    Not applicable
    A.4.1Sponsor's protocol code numberM120204-063
    A.5.1ISRCTN (International Standard Randomised Controlled Trial) NumberNot applicable
    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 Information not present in EudraCT
    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 nameMLN1202
    D.3.2Product code MLN1202
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous 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) 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) Yes
    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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    The purpose of this study is to investigate the safety, PK parameters, PD responses, and clinical responses of multiple dose administration of MLN1202 in patients with relapsing remitting multiple sclerosis (RRMS).
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 8.1
    E.1.2Level LLT
    E.1.2Classification code 10028245
    E.1.2Term Multiple sclerosis
    E.1.3Condition being studied is a rare disease No
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The primary objectives of this study are to:
    • Determine the safety and tolerability of MLN1202 in patients with RRMS.
    • Determine the efficacy of MLN1202 in patients with RRMS by comparing the mean number of new gadolinium-diethylenetriamine pentaacetic acid(Gd)-enhancing lesions on magnetic resonance imaging (MRI) during the pretreatment phase with the mean number of new Gd enhancing lesions found during the treatment phase.
    E.2.2Secondary objectives of the trial
    Secondary objectives :
    The secondary objective of this study is to:
    • Characterize the pharmacokinetics (PK) and observe the pharmacodynamics (PD) responses in relation to MLN1202 in patients with RRMS
    • To observe other MRI assessments in relation to MLN1202 in patients with RRMS

    The exploratory objectives of this study are to:
    •Use mRNA or protein expression patterns of genes known to be involved in MS pathophysiology or chemokine pathways to further understand the mechanism of action of MLN1202 in patients with MS
    •Determine if select mRNA or protein expression patterns of genes known to be involved in MS pathophysiology or chemokine pathways are potentially useful biomarkers of clinical outcome to MLN1202 treatment of patients with MS
    E.2.3Trial contains a sub-study Information not present in EudraCT
    E.3Principal inclusion criteria
    Each patient must meet all of the following inclusion criteria to be enrolled in the pre-treatment phase of the study:
    •Be 18 years of age or older
    •Have a diagnosis of RRMS
    •Have had at least 1 documented relapse of MS within 18 months prior to study entry
    •Have an Expanded Disability Status Score (EDSS) of 0 to 5.5, inclusive (see Study Manual for calculation details)
    •Be willing and able to comply with the protocol for the duration of the study period
    •Be willing to use adequate “double-barrier” contraceptive methods for the duration • If female, must be neither pregnant nor breast-feeding. Confirmation that the patient is not pregnant must be established by a negative serum hCG pregnancy test within 7 days of study entry and again within 7 days prior to the first administration of study drug.
    • Have given written informed consent prior to any study-related procedure not part of normal medical care, with the understanding that consent may be withdrawn by the patient at any time without prejudice to future medical care

    Each patient must meet the following inclusion criteria to be enrolled in the treatment phase of the study:
    •Have a total of at least 2 new Gd-enhancing lesions seen over the series of 3 pre-treatment MRIs. (Note: If a patient experiences a flare of disease during the pre-treatment period requiring the use of corticosteriods according to the exclusion criteria below, MRIs will not be performed for 2 months after completion of corticosteroids, at which time pre-screening monthly MRIs will then continue until the patient has completed 3 scans. The patient’s schedule of visits will be adjusted accordingly. The use of corticosteroids during the pre-treatment period will be limited to a 3 to 5 day course of IV methylprednisolone without subsequent oral corticosteroids.) of the study period
    E.4Principal exclusion criteria
    Patients meeting any of the following exclusion criteria are not to be enrolled in the study:
    •Have a diagnosis of PPMS or SPMS
    •Have received any investigational drug or experimental procedure within 3 months prior to Study Day 0
    •If the patient has received disease-modifying cyclophosphamide (Cytoxan®) or mitoxantrone [Novantrone®] for MS, that treatment must have discontinued 6 months prior to study Day 0.
    •If the patient has received the following prior disease modifying treatments: (interferons [Avonex®, Rebif®, Betaseron/®Betaferon®], glatiramer acetate [Copaxone®], azathioprine [Imuran®]) for MS, that treatment must have discontinued at least 12 weeks prior to study Day 0.
    •If the patient has received disease-modifying methotrexate, IV immunoglobulin, cyclosporin, or plasma exchange for MS, that treatment must have discontinued at least 8 weeks prior to study Day 0.
    •If the patient has received prior treatment with corticosteroids for MS, the patient must have discontinued that treatment at least 8 weeks prior to Study Day 0.
    •If the patient has ever been exposed to Tysabri® (natalizumab) or any other VLA-4 (a4b1) antagonist.
    •Have an active infection or be considered to be at high risk for developing an infection, including reactivation of latent tuberculosis, in the opinion of the investigator.
    •Have a history of hepatitis B, C, or human immunodeficiency virus (HIV)
    •Have a chest X-ray within 6 months of Study Day 0 with clinically significant findings or abnormalities, in the opinion of the investigator
    •Have inadequate renal (serum creatinine >1.5 times the upper limit of normal [ULN]) or hepatic function (aspartate transaminase [AST] or alanine transaminase [ALT] >2 times the ULN)
    •Have a known history of cancer, except for distant history (>10 years) of carcinoma in situ of the cervix or adequately treated basal cell carcinoma of the skin
    •Received any live, attenuated vaccinations within 30 days prior to Study Day 0
    •Have a history of illicit drug or alcohol abuse within 5 years of Study Day 0
    •Have a history of hypersensitivity to prior mAb treatment
    •Have a history of allergy or sensitivity to Gd
    •Have a history that would preclude serial MRI scans (eg, known implanted devices, claustrophobia, chronic low back pain, involuntary movements, poor venous access)
    E.5 End points
    E.5.1Primary end point(s)
    •Safety: Safety will be assessed by vital sign measurement, physical examinations, MS relapses, changes in EDSS scores and standard laboratory test results, as well as the incidence of adverse events (AEs) and serious adverse events (SAEs). In addition, MRI scans will be monitored on a continuous basis throughout the study for any change from the pre-treatment phase. Immunogenicity will be assessed through monitoring human anti-human (anti-MLN1202) antibodies (HAHA). Delayed-type hypersensitivity (DTH) response to purified protein derivative (PPD)/tuberculin (TB) antigen will also be assessed.

    •Efficacy: The primary efficacy endpoint will be the comparison of the mean number of new Gd enhancing lesions on MRI during the pre-treatment phase with the mean number of new Gd enhancing lesions found during the treatment phase as assessed by the central blinded MRI reader. Additional MRI assessments will include the T2-weighted lesion load, the volume of Gd-enhancing lesions, and volume of T1 weighted hypo-intense lesions.

    •Pharmacokinetics: Initially, serum concentration-time data will be analysed using noncompartmental methods. Parameters such as maximum concentration (Cmax), clearance (CL), volume of distribution at steady state Vss, and half-life (t1/2) will be reported. Compartmental methods will be used to calculate maximum elimination rate (Vm), and Michaelis-Menten rate constant (Km), in addition to other PK parameters. Graphical methods will be used to relate these measures.

    •Pharmacodynamics: The PD endpoints will be assessed by measuring free C-C chemokine receptor 2 (CCR2) receptors on CD14+ cells using a fluorescent-labelled antibody to CCR2 (free site assay) and by utilizing the fluorescent-labelled ligand, monocyte chemoattractant protein (MCP-1), to measure free CCR2 receptors on monocytes and memory CD4+ T cells (ligand internalization assay). PD measures will include percent positive cells (percentage of cells positive for the parameter being examined) and/or the molecule equivalence of soluble fluorochrome, often expressed and referred to as the mean equivalence of soluble fluorochrome (MESF).

    •Exploratory Biomarkers: The exploratory biomarker endpoints will be assessed by correlating changes in protein or gene expression patterns at baseline and following MLN1202 treatment with changes in Gd-enhanced MRI brain lesions.
    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 Yes
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    E.6.10Pharmacogenetic Yes
    E.6.11Pharmacogenomic Yes
    E.6.12Pharmacoeconomic No
    E.6.13Others Yes
    E.6.13.1Other scope of the trial description
    Exploratory Biomarkers
    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 No
    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 concerned5
    E.8.5The trial involves multiple Member States Yes
    E.8.5.1Number of sites anticipated in the EEA8
    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 months7
    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 months7
    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 Information not present in EudraCT
    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 2005-02-22. 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Written informed consent will be obtained from either the patient or his/her guardian or legal representative prior to study participation. The consent will comply with ICH-GCP and all applicable regulatory requirement(s).
    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 40
    F.4.2.2In the whole clinical trial 160
    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)
    Not applicable
    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 Decision2005-03-11
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-10-09
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2007-04-04
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