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    Summary
    EudraCT Number:2006-005341-11
    Sponsor's Protocol Code Number:rhASA-01
    National Competent Authority:Denmark - DHMA
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2006-11-08
    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 ConcernedDenmark - DHMA
    A.2EudraCT number2006-005341-11
    A.3Full title of the trial
    A single center, open-label, non-randomized, uncontrolled, multiple-dose, dose escalation study of the safety, pharmacokinetics and efficacy of Metazym (recombinant human arylsulfatase A or rhASA) for the treatment of patients with late infantile metachromatic leukodystrophy (MLD)
    A.4.1Sponsor's protocol code numberrhASA-01
    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 SponsorShire Pharmaceuticals Ireland Limited
    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 Yes
    D.2.5.1Orphan drug designation numberEU/3/03/158
    D.3 Description of the IMP
    D.3.1Product nameMetazym
    D.3.2Product code rhASA
    D.3.4Pharmaceutical form Injection*
    D.3.4.1Specific paediatric formulation Information not present in EudraCT
    D.3.7Routes of administration for this IMPIntravenous use
    Intravenous drip use (Noncurrent)
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNArylsulfatase A
    D.3.9.2Current sponsor coderhASA
    D.3.9.3Other descriptive nameMetazym
    D.3.10 Strength
    D.3.10.1Concentration unit IU/ml international unit(s)/millilitre
    D.3.10.2Concentration typenot less then
    D.3.10.3Concentration number125
    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) 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
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Late infantile metachromatic leukodystrophy (MLD)
    MedDRA Classification
    E.1.2 Medical condition or disease under investigation
    E.1.2Version 9.1
    E.1.2Level LLT
    E.1.2Classification code 10024381
    E.1.2Term Leukodystrophy
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    To evaluate the safety profile of Metazym
    To determine the PK profile of Metazym in patients with late infantile MLD as measured by rhASA levels in plasma and ASA activity in leukocytes
    E.2.2Secondary objectives of the trial
    Efficacy of Metazym on the biochemical level, by assessing sulfatide concentrations in urine and cerebrospinal fluid, and changes in cerebrospinal fluid biomarkers
    Efficacy of Metazym on functional capacity (disability level), by assessing gross and fine motor function, adaptive and cognitive development
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject’s legally authorized guardian(s) must provide signed, informed consent prior to performing any study-related activities (Trial-related activities are any procedures that would not have been performed during normal management of the subject).
    2. The patient must have a confirmed diagnosis of MLD as defined by:
    -ASA activity < 10 nmol/h/mg in leukocytes
    -Presence of elevated sulfatide in urine
    3. The patient must have a confirmed nerve conduction velocity < 2 standard deviations (from the appropriate age level)
    4. The patient must have a residual level of voluntary function (as judged by the investigator), including presence of residual cognitive function (attention, executive and visual functions) as well as the presence of residual voluntary motor function in one upper or lower limb as a minimum.
    5. The patient must have an age at the time of screening ≥ 1 year and < 6 years
    6. The patient must have had onset of symptoms before the age of 4 years
    7. The subject and his/her guardian(s) must have the ability to comply with the clinical protocol
    8. The patients’ medical record must document that the legal guardian(s) has had independent counselling or a consultation regarding stem cell transplantation in order to assure that the guardian(s) is fully informed regarding the risks and benefits of this alternative
    E.4Principal exclusion criteria
    1. Presence of a gross motor function measure (GMFM < 10)
    2. Presence of severe pseudo-bulbar signs (weakness and disco-ordination of tongue and swallowing muscles leading to severe difficulty with swallowing)
    3. Spasticity so severe to inhibit transportation
    4. Known multiple sulfatase deficiency
    5. Presence of major congenital abnormality
    6. Presence of known chromosomal abnormality and syndromes affecting psychomotor development
    7. History of stem cell transplantation
    8. Presence of known clinically significant cardiovascular, hepatic, pulmonary or renal disease or other medical condition
    9. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
    10. Use of any investigational product within 30 days prior to study enrolment or currently enrolled in another study which involves clinical investigations.
    11. Received ERT with rhASA from any source
    12. Planned or anticipated initiation of antispastic treatment after trial initiation
    E.5 End points
    E.5.1Primary end point(s)
    From the safety evaluation a maximum tolerated dose (MTD) is determined by a DMC (on the basis of evaluation after each dose group) and this is the primary safety endpoint.

    All adverse events will be summarized overall by use of system organ class and preferred terms in MEDDRA code summarized by dose level. Adverse events will be accounted for in relation to the dose level used at the time for onset of the event. Serious adverse events will be summarized separately in similar form.
    All adverse events will in addition be summarized according to dose level, severity and according to relationship to study drug as assessed by investigator.

    Changes from normal to abnormal will be presented in shift tables for all laboratory variables for whom reference ranges are available. Urine-analysis, ECG and physical examination will be presented descriptively by dose level, only.

    The following PK endpoints are derived and will be analyzed:
    rhASA in blood and ASA activity in leukocytes will be presented graphically.
    AUC, Cmax, Tmax, T½ (if applicable) will be derived by trapzodial method and presented descriptively by dose level.

    Functional capacity
    GMFM is the primary efficacy endpoint. Item scores can be summed to calculate raw and percent score for each of the five GMFM dimensions.

    Biochemical markers
    Urinary sulfatide, CSF sulfatide, chitotriosidase, NFp, GFAp, tau protein are all measured on a continuous scale.

    Nerve conduction velocity
    NCV, AMP and DL are all measured on a continuous scale.
    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 No
    E.6.8Bioequivalence No
    E.6.9Dose response Yes
    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) Yes
    E.7.1.1First administration to humans Yes
    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) No
    E.7.4Therapeutic use (Phase IV) No
    E.8 Design of the trial
    E.8.1Controlled No
    E.8.1.1Randomised No
    E.8.1.2Open No
    E.8.1.3Single blind No
    E.8.1.4Double blind No
    E.8.1.5Parallel group No
    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) Information not present in EudraCT
    E.8.2.2Placebo Information not present in EudraCT
    E.8.2.3Other Information not present in EudraCT
    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 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 patient last visit (end of trial visit) in cohort 3.
    E.8.9 Initial estimate of the duration of the trial
    E.8.9.1In the Member State concerned years0
    E.8.9.1In the Member State concerned months10
    E.8.9.1In the Member State concerned days0
    F. Population of Trial Subjects
    F.1 Age Range
    F.1.1Trial has subjects under 18 Yes
    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) Yes
    F.1.1.5Children (2-11years) Yes
    F.1.1.6Adolescents (12-17 years) No
    F.1.2Adults (18-64 years) No
    F.1.3Elderly (>=65 years) No
    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 state12
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 12
    F.4.2.2In the whole clinical trial 12
    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 Decision2006-12-21
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2006-12-28
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2008-03-25
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