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    Summary
    EudraCT Number:2012-000979-17
    Sponsor's Protocol Code Number:rhLAMAN-05
    National Competent Authority:Germany - BfArM
    Clinical Trial Type:EEA CTA
    Trial Status:Completed
    Date on which this record was first entered in the EudraCT database:2012-07-09
    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 number2012-000979-17
    A.3Full title of the trial
    A Multi-Center, Double-Blind, Randomized, Placebo-Controlled, Parallel Group Trial, Investigating the Efficacy and Safety of Repeated Lamazym Treatment of Subjects with alpha-Mannosidosis
    Multizentrische, doppelblinde, randomisierte, placebokontrollierte Parallelgruppenstudie zur Untersuchung der Wirksamkeit und Unbedenklichkeit wiederholter Lamazym-Behandlungen von Patienten mit Alpha-Mannosidose
    A.3.1Title of the trial for lay people, in easily understood, i.e. non-technical, language
    A Placebo-Controlled phase 3 trial of repeated Lamazym treatment of subjects with Alpha-Mannosidosis
    A.3.2Name or abbreviated title of the trial where available
    Phase III
    A.4.1Sponsor's protocol code numberrhLAMAN-05
    A.5.4Other Identifiers
    Name:EudraCTNumber:2012-000979-17
    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 SponsorZymenex A/S
    B.1.3.4CountryDenmark
    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 supportEU FP7 ALPHA-MAN
    B.4.2CountryEuropean Union
    B.5 Contact point designated by the sponsor for further information on the trial
    B.5.1Name of organisationZymenex A/S
    B.5.2Functional name of contact pointCEO
    B.5.3 Address:
    B.5.3.1Street AddressRoskildevej 12C
    B.5.3.2Town/ cityHillerod
    B.5.3.3Post codeDK-3400
    B.5.3.4CountryDenmark
    B.5.4Telephone number+4548250054
    B.5.5Fax number+4548251054
    B.5.6E-mailzxmail@zymenex.com
    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/3/04/260
    D.3 Description of the IMP
    D.3.1Product nameLamazym
    D.3.2Product code rhLAMAN
    D.3.4Pharmaceutical form Powder for solution for infusion
    D.3.4.1Specific paediatric formulation No
    D.3.7Routes of administration for this IMPIntravenous use
    D.3.8 to D.3.10 IMP Identification Details (Active Substances)
    D.3.8INN - Proposed INNrhLAMAN
    D.3.9.2Current sponsor coderhLAMAN
    D.3.9.3Other descriptive namerecombinant human alpha-mannosidase
    D.3.10 Strength
    D.3.10.1Concentration unit mg/ml milligram(s)/millilitre
    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 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) No
    D.3.11.7Plasma derived medicinal product No
    D.3.11.8Extractive medicinal product No
    D.3.11.9Recombinant medicinal product Yes
    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 placeboPowder for solution for infusion
    D.8.4Route of administration of the placeboIntravenous use
    E. General Information on the Trial
    E.1 Medical condition or disease under investigation
    E.1.1Medical condition(s) being investigated
    Treatement of Alpha-Mannosidosis
    Behandlung von Alpha-Mannosidose
    E.1.1.1Medical condition in easily understood language
    Treatement of Alpha-Mannosidosis
    Behandlung von Alpha-Mannosidose
    E.1.1.2Therapeutic area Diseases [C] - Nutritional and Metabolic Diseases [C18]
    MedDRA Classification
    E.1.3Condition being studied is a rare disease Yes
    E.2 Objective of the trial
    E.2.1Main objective of the trial
    The overall objective of this trial is to evaluate the efficacy and safety of repeated Lamazym i.v. treatment, compared with placebo, in subjects 5-35 years of age with alpha-Mannosidosis
    Übergeordnetes Ziel dieser klinischen Studie ist die Beurteilung der Wirksamkeit und Unbedenklichkeit wiederholter i. v. Lamazym-Behandlungen im Vergleich zu Placebo bei Alpha-Mannosidose-Patienten im Alter von 5-35 Jahren.
    E.2.2Secondary objectives of the trial
    PK evaluation
    E.2.3Trial contains a sub-study No
    E.3Principal inclusion criteria
    1. Subject or subjects legally authorized guardian(s) must provide signed, informed consent prior to performing any trial-related activities
    2. The subject and his/her guardian(s) must have the ability to comply with the protocol
    3. The subject must have a confirmed diagnosis of alpha-mannosidosis as defined by alpha-mannosidase activity < 10% of normal activity (historical data)
    4. The subject must have an age at the time of screening ≥ 5 years and ≤ 35 years
    5. The subject must have the ability to physically and mentally cooperate in the tests
    6. The subject must have an ECHO without abnormalities that, in the opinion of the Investigator, would preclude participation in the trial
    1. Der Patient bzw. dessen gesetzliche(r) Vertreter müssen vor der Durchführung studienbezogener Maßnahmen eine unterzeichnete Einwilligungserklärung vorlegen.
    2. Der Patient bzw. dessen gesetzliche(r) Vertreter müssen in der Lage sein, den Studienplan zu befolgen.
    3. Die Diagnose Alpha-Mannosidose, definiert als Alpha-Mannosidase-Aktivität < 10 % der normalen Aktivität (anamnestische Werte) muss bestätigt sein.
    4. Der Patient muss zum Screening-Zeitpunkt mindestens fünf und höchstens 35 Jahre alt sein.
    5. Der Patient muss körperlich und geistig in der Lage sein, die verschiedenen Untersuchungen durchzuführen.
    6. Die Echokardiografie des Patienten darf keine Zustände zeigen, die nach Auffassung des Prüfarztes eine Teilnahme an der Studie ausschließen.
    E.4Principal exclusion criteria
    1. The subjects diagnosis cannot be confirmed by alpha-mannosidase activity < 10% of normal activity
    2. The subject cannot walk without support
    3. Presence of known chromosomal abnormality and syndromes affecting psychomotor development, other than alpha-mannosidosis
    4. History of BMT
    5. Presence of known clinically significant cardiovascular, hepatic, pulmonary, or renal disease or other medical conditions that, in the opinion of the Investigator, would preclude participation in the trial
    6. Any other medical condition or serious intercurrent illness, or extenuating circumstance that, in the opinion of the Investigator, would preclude participation in the trial
    7. Pregnancy: Pregnant woman are excluded. Before start of the treatment the investigators will for women of childbearing potential perform a pregnancy test and decide whether or not there is a need for contraception
    8. Psychosis; any psychotic disease, also in remission, is an exclusion criteria
    9. Planned major surgery that, in the opinion of the Investigator, would preclude participation in the trial
    10. Participation in other interventional trials testing IMP (including Lamazym) within the last 3 months
    11. 11. Adult patients who, in the opinion of the Investigator, would be unable to give consent, and who does not have any legal protection or guardianship
    12. Total IgE >800IU/ml
    13. 13. Known allergy to the IMP or any excipients (Sodium-Phosphate, Glycine, Mannitol)
    1. Die Diagnose Alpha-Mannosidose kann nicht durch eine Alpha-Mannosidase-Aktivität < 10 % der normalen Aktivität bestätigt werden.
    2. Der Patient kann nur mit Unterstützung gehen.
    3. Bekannte Chromosomenanomalie und Syndrome (angeborene Krankheiten) abgesehen von Alpha-Mannosidose, die die psychische und motorische Entwicklung hemmen.
    4. Zurückliegende Stammzelltherapie.
    5. Bekannte klinisch relevante kardiovaskuläre, hepatische, pulmonale oder renale Krankheit oder andere Erkrankung, die nach Meinung des Prüfarztes eine Nichtteilnahme an der Studie begründen.
    6. Mögliche andere medizinische Zustände oder schwere interkurrente Krankheiten oder andere Umstände, der bzw. die nach Meinung des Prüfarztes eine Nichtteilnahme an der Studie begründen.
    7. Schwangerschaft: Schwangere Frau sind ausgeschlossen. Vor Beginn der Behandlung lässt der Prüfarzt bei Frauen im gebärfähigen Alter einen Schwangerschaftstest durchführen und entscheidet, ob eine Verhütungsmethode angebracht ist oder nicht.
    8. Psychose; eine psychotische Erkrankung, auch in Remission ist ein Ausschlusskriterium
    9. Geplante größere Operation, die nach Meinung des Prüfarztes eine Nichtteilnahme an der Studie begründet.
    10. Teilnahme an einer anderen Interventionsstudie zur Untersuchung eines Arzneimittels (auch Lamazym) innerhalb der letzten drei Monate.
    11. Erwachsene Patienten, die in der Stellungnahme des Investigator, nicht in der Lage, die Einwilligung, und die geben würde keinen rechtlichen Schutz oder Vormundschaft
    12. Total IgE >800 IU/ml
    13. Bekannte Allergie gegen das IMP oder einen der sonstigen Bestandteile (Natrium-Phosphat, Glycin, Mannitol)
    E.5 End points
    E.5.1Primary end point(s)
    Primary Efficacy Endpoints is change from baseline in the active treated group versus the placebo group:
    • The level of oligosaccharides in serum
    • 3-minute stair climb test (3MSCT)
    Bewertung der primären Endpunkte der Wirksamkeit als Veränderung zur Baseline bei der mit dem Wirkstoff behandelten Gruppe verglichen mit der Placebo-Gruppe:
    • Oligosaccharidgehalt im Serum
    • 3-Minuten-Treppensteigentest (3MTT)
    E.5.1.1Timepoint(s) of evaluation of this end point
    Efficacy will be assessed at the Danish site at baseline (prior to first dose), as midterm evaluation (after 26±3 weeks, referred to as midterm evaluation or visit 26a), and as end evaluation (after 52±3 weeks, referred to as end evaluation or visit 52a).
    Die Wirksamkeit wird am dänischen Prüfzentrum in Verbindung mit dem Baseline-Besuch (vor der ersten Dosis), der Halbzeituntersuchung (nach 26±3 Wochen, als Halbzeituntersuchung oder Besuch 26a bezeichnet) und der Abschlussuntersuchung (nach 52±3 Wochen, als Abschlussuntersuchung oder Besuch 52a bezeichnet) bewertet.
    E.5.2Secondary end point(s)
    Prioritized Secondary Efficacy Endpoints:
    • Forced Vital Capacity (FVC)
    • 6 minute walk test (6MWT)

    Other Secondary Efficacy Endpoints:
    • Bruininks-Oseretsky test of Motor Proficiency (BOT2)
    • Leiter R
    • Cerebrospinal fluid biomarkers incl oligosaccharide and standard tests
    • Pulmonary Function Tests
    • Pure tone audiometry (PTA)
    • Questionnaires (CHAQ and EQ-5D)

    Safety Endpoints:
    • Adverse events (AEs)
    • Vital signs and change in physical examination
    • Clinical laboratory parameters (hematology, biochemistry and urinalysis)
    • Development of Lamazym antibodies and neutralizing/inhibitory antibodies

    Pharmacokinetic endpoints:
    • Pharmacokinetics (PK)
    Wichtigste sekundäre Endpunkte der Wirksamkeit:
    • Forcierte Vitalkapazität (Forced Vital Capacity)
    • 6-Minuten-Gehtest (6MGT)

    Andere sekundäre Endpunkte der Wirksamkeit:
    • Bruininks-Oseretsky-Test motorischer Kompetenzen (BOT2)
    • Leiter R
    • Biomarker in der Rückenmarkflüssigkeit, einschl. Oligosaccharide und Standardtests
    • Lungenfunktionsprüfungen
    • Reintonaudiometrie
    • Fragebogen (CHAQ und EQ-5D)

    Endpunkte der Unbedenklichkeit:
    • Unerwünschte Ereignisse (UE)
    • Vitalzeichen und Veränderungen bei der körperlichen Untersuchung
    • Klinische Laborwerte (Hämatologie, Blutchemie und Urin)
    • Auftreten von Lamazym-Antikörpern und neutralisierenden/inhibitorischen Antikörpern

    Pharmakokinetische Endpunkte:
    • Pharmakokinetik (PK)
    E.5.2.1Timepoint(s) of evaluation of this end point
    Efficacy will be assessed at the Danish site at baseline (prior to first dose), as midterm evaluation (after 26±23 weeks, referred to as midterm evaluation or visit 26a), and as end evaluation (after 52±3 weeks, referred to as end evaluation or visit 52a).
    Safety will be assessed at every visit.
    PK will be analyzed at visit 1.
    Die Wirksamkeit wird am dänischen Prüfzentrum in Verbindung mit dem Baseline-Besuch (vor der ersten Dosis), der Halbzeituntersuchung (nach 26±3 Wochen, als Halbzeituntersuchung oder Besuch 26a bezeichnet) und der Abschlussuntersuchung (nach 52±3 Wochen, als Abschlussuntersuchung oder Besuch 52a bezeichnet) bewertet. Die Unbedenklichkeit wird bei jedem Besuch beurteilt. PK wird bei Besuch 1 analysiert.
    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 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 Yes
    E.8.5.1Number of sites anticipated in the EEA6
    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 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 is the date when all subjects have completed their EOT visit and this is defined as the End of Trial date.
    Der letzte Besuch des letzten Patienten ist der Zeitpunkt, zu dem alle Patienten die Studie beendet haben (EOT-Besuch) und ist damit als Studienende definiert.
    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 months12
    E.8.9.1In the Member State concerned days0
    E.8.9.2In all countries concerned by the trial years0
    E.8.9.2In all countries concerned by the trial months12
    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 Yes
    F.1.1Number of subjects for this age range: 10
    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) Yes
    F.1.1.5.1Number of subjects for this age range: 5
    F.1.1.6Adolescents (12-17 years) Yes
    F.1.1.6.1Number of subjects for this age range: 5
    F.1.2Adults (18-64 years) Yes
    F.1.2.1Number of subjects for this age range: 10
    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 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 Yes
    F.3.3.6.1Details of subjects incapable of giving consent
    Due to the disease related mental retardation the subjects are under gardianship of the parents
    Aufgrund der krankheitsbedingten intellektuellen Defizite stehen die Patienten unter der Vormundschaft ihrer Eltern.
    F.3.3.7Others No
    F.4 Planned number of subjects to be included
    F.4.1In the member state7
    F.4.2 For a multinational trial
    F.4.2.1In the EEA 20
    F.4.2.2In the whole clinical trial 20
    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)
    When the trial is completed, given no safety concerns have arisen, all subjects, including the subjects randomized to placebo, will be offered to receive Lamazym as post study therapy in the home country. This will last until the product is available on the market or until the sponsor decides to terminate the project. If the project is terminated, Zymenex has no further obligation to provide the study drug, even for post study therapy
    Nach Abschluss der Studie und unter der Voraussetzung, dass keine Sicherheitsbedenken laut werden, wird allen Patienten, d. h. auch denen, die in die Placebo-Gruppe randomisiert wurden, eine Lamazym-Behandlung in ihrem Heimatland angeboten, bis das Arzneimittel im Handel erhältlich ist oder der Sponsor einen Abbruch des Projekts beschließt. Wird das Projekt abgebrochen, ist Zymenex nicht länger verpflichtet, die Prüfmedikation zur Verfügung zu stellen, auch nicht im Rahmen des Nachsorgeprogramms
    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 Decision2012-09-25
    N.Ethics Committee Opinion of the trial applicationFavourable
    N.Ethics Committee Opinion: Reason(s) for unfavourable opinion
    N.Date of Ethics Committee Opinion2012-12-17
    P. End of Trial
    P.End of Trial StatusCompleted
    P.Date of the global end of the trial2014-05-02
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