<clinical_study>
  <!-- This xml conforms to an XML Schema at:
    https://clinicaltrials.gov/ct2/html/images/info/public.xsd -->
  <required_header>
    <download_date>ClinicalTrials.gov processed this data on September 20, 2023</download_date>
    <link_text>Link to the current ClinicalTrials.gov record.</link_text>
    <url>https://clinicaltrials.gov/ct2/show/NCT01681953</url>
  </required_header>
  <id_info>
    <org_study_id>rhLAMAN-05</org_study_id>
    <secondary_id>2012-000979-17</secondary_id>
    <nct_id>NCT01681953</nct_id>
  </id_info>
  <brief_title>A Placebo-Controlled Phase 3 Trial of Repeated Lamazym Treatment of Subjects With Alpha-Mannosidosis</brief_title>
  <official_title>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.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Zymenex A/S</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>European Commission</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Chiesi Farmaceutici S.p.A.</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The overall objective of this trial is to evaluate the efficacy and safety of repeated&#xD;
      Lamazym i.v. treatment, compared with placebo, in subjects 5-35 years of age with&#xD;
      alpha-Mannosidosis&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date>August 2012</start_date>
  <completion_date type="Actual">May 2014</completion_date>
  <primary_completion_date type="Actual">May 2014</primary_completion_date>
  <phase>Phase 3</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Reduction of oligosaccharides in serum</measure>
    <time_frame>Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks</time_frame>
    <description>Primary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group</description>
  </primary_outcome>
  <primary_outcome>
    <measure>The number of steps climbed in 3 minutes (3-minute stair climb test)</measure>
    <time_frame>Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks</time_frame>
    <description>Primary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Forced Vital Capacity</measure>
    <time_frame>Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks</time_frame>
    <description>Secondary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>The distance walked in 6 minutes (6-minute walk test)</measure>
    <time_frame>Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks</time_frame>
    <description>Secondary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse Events</measure>
    <time_frame>1 week</time_frame>
    <description>Safety endpoint assessed weekly throughout the trial</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Development of clinically significant changes in vital signs and change in physical examination</measure>
    <time_frame>1 week</time_frame>
    <description>Safety endpoints assessed weekly throughout the trial</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Clinical laboratory parameters (hematology, biochemistry and urinalysis)</measure>
    <time_frame>1 week</time_frame>
    <description>Safety endpoints assessed weekly throughout the trial</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Development of Lamazym antibodies and neutralizing/inhibitory antibodies</measure>
    <time_frame>1 week</time_frame>
    <description>Safety endpoints assessed weekly throughout the trial</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Quantitative determination of rhLAMAN in plasma</measure>
    <time_frame>10 min, 60 min, 2 hours, 24 hours, 3 days, 7 days</time_frame>
    <description>Pharmacokinetic (PK) assessments. Blood samples are drawn pre-treatment and at various times post-treatment (see time frame above)</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">25</enrollment>
  <condition>Alpha-Mannosidosis</condition>
  <arm_group>
    <arm_group_label>Lamazym</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>1 mg Lamazym/kg body weight</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo is formulated as an isotonic phosphate buffer with glycine and mannitol</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Lamazym</intervention_name>
    <description>ERT, i.v. infusions weekly</description>
    <arm_group_label>Lamazym</arm_group_label>
    <other_name>rhLAMAN</other_name>
    <other_name>recombinant human alpha-mannosidase</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Infusions weekly</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Subject or subjects legally authorized guardian(s) must provide signed, informed&#xD;
             consent prior to performing any trial-related activities&#xD;
&#xD;
          -  The subject and his/her guardian(s) must have the ability to comply with the protocol&#xD;
&#xD;
          -  The subject must have a confirmed diagnosis of alpha-Mannosidosis as defined by&#xD;
             alpha-Mannosidase activity &lt; 10% of normal activity (historical data)&#xD;
&#xD;
          -  The subject must have an age at the time of screening ≥ 5 years and ≤ 35 years&#xD;
&#xD;
          -  The subject must have the ability to physically and mentally cooperate in the tests&#xD;
&#xD;
          -  The subject must have an ECHO without abnormalities that, in the opinion of the&#xD;
             Investigator, would preclude participation in the trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  The subjects diagnosis cannot be confirmed by alpha-Mannosidase activity &lt; 10% of&#xD;
             normal activity&#xD;
&#xD;
          -  The subject cannot walk without support&#xD;
&#xD;
          -  Presence of known chromosomal abnormality and syndromes affecting psychomotor&#xD;
             development, other than alpha-Mannosidosis&#xD;
&#xD;
          -  History of BMT&#xD;
&#xD;
          -  Presence of known clinically significant cardiovascular, hepatic, pulmonary, or renal&#xD;
             disease or other medical conditions that, in the opinion of the Investigator, would&#xD;
             preclude participation in the trial&#xD;
&#xD;
          -  Any other medical condition or serious intercurrent illness, or extenuating&#xD;
             circumstance that, in the opinion of the Investigator, would preclude participation in&#xD;
             the trial&#xD;
&#xD;
          -  Pregnancy: Pregnant woman is excluded. Before start of the treatment the investigators&#xD;
             will for women of childbearing potential perform a pregnancy test and decide whether&#xD;
             or not there is a need for contraception&#xD;
&#xD;
          -  Psychosis; any psychotic disease, also in remission, is an exclusion criteria&#xD;
&#xD;
          -  Planned major surgery that, in the opinion of the Investigator, would preclude&#xD;
             participation in the trial&#xD;
&#xD;
          -  Participation in other interventional trials testing IMP (including Lamazym) within&#xD;
             the last 3 months&#xD;
&#xD;
          -  Adult patients who, in the opinion of the Investigator, would be unable to give&#xD;
             consent, and who does not have any legal protection or guardianship&#xD;
&#xD;
          -  Total IgE &gt;800 IU/ml&#xD;
&#xD;
          -  Known allergy to the IMP or any excipients (Sodium-Phosphate, Glycine, Mannitol)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Allan M Lund, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Copenhagen University Hospital, Center for Metabolic Diseases, Department for Clinical Genetics</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Jens Fogh</last_name>
    <role>Study Chair</role>
    <affiliation>Zymenex A/S</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Center for Metabolic Diseases, Department of Clinical Genetics, Juliane Marie Centre, Copenhagen University Hospital, Blegdamsvej 9</name>
      <address>
        <city>Copenhagen</city>
        <zip>DK-2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Femme Mère Enfant, Lyon, 59 boulevard Pinel</name>
      <address>
        <city>Bron</city>
        <zip>69677</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Hôpital Trousseau, Service de neuropédiatrie, Centre Référence des Maladies Lysosomales, 26 avenue du Docteur Arnold Netter</name>
      <address>
        <city>PARIS Cedex 12</city>
        <zip>75 571</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Universitätsmedizin Mainz, Zentrum für Kinder- und Jugendmedizin, Langenbeckstrasse 1</name>
      <address>
        <city>Mainz</city>
        <zip>55131</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>The Children's Memorial Health Institute Warsaw, Department of Metabolic Diseases, Al Dzieci Polskich 20</name>
      <address>
        <city>Warszawa</city>
        <zip>04 730</zip>
        <country>Poland</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Genetic Medicine, 6th floor, St Mary's Hospital, Oxford Road,</name>
      <address>
        <city>Manchester</city>
        <zip>M13 9WL</zip>
        <country>United Kingdom</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
    <country>France</country>
    <country>Germany</country>
    <country>Poland</country>
    <country>United Kingdom</country>
  </location_countries>
  <link>
    <url>https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-000979-17</url>
    <description>Study Record on EU Clinical Trials Register including results</description>
  </link>
  <reference>
    <citation>Borgwardt L, Stensland HM, Olsen KJ, Wibrand F, Klenow HB, Beck M, Amraoui Y, Arash L, Fogh J, Nilssen O, Dali CI, Lund AM. Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation. Orphanet J Rare Dis. 2015 Jun 6;10:70. doi: 10.1186/s13023-015-0286-x.</citation>
    <PMID>26048034</PMID>
  </reference>
  <reference>
    <citation>Borgwardt L, Thuesen AM, Olsen KJ, Fogh J, Dali CI, Lund AM. Cognitive profile and activities of daily living: 35 patients with alpha-mannosidosis. J Inherit Metab Dis. 2015 Nov;38(6):1119-27. doi: 10.1007/s10545-015-9862-4. Epub 2015 May 28.</citation>
    <PMID>26016802</PMID>
  </reference>
  <reference>
    <citation>Harmatz P, Cattaneo F, Ardigo D, Geraci S, Hennermann JB, Guffon N, Lund A, Hendriksz CJ, Borgwardt L. Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis. Mol Genet Metab. 2018 Jun;124(2):152-160. doi: 10.1016/j.ymgme.2018.04.003. Epub 2018 Apr 18.</citation>
    <PMID>29716835</PMID>
  </reference>
  <results_reference>
    <citation>Borgwardt L, Guffon N, Amraoui Y, Dali CI, De Meirleir L, Gil-Campos M, Heron B, Geraci S, Ardigo D, Cattaneo F, Fogh J, Van den Hout JMH, Beck M, Jones SA, Tylki-Szymanska A, Haugsted U, Lund AM. Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial. J Inherit Metab Dis. 2018 Nov;41(6):1215-1223. doi: 10.1007/s10545-018-0185-0. Epub 2018 May 30.</citation>
    <PMID>29846843</PMID>
  </results_reference>
  <verification_date>July 2020</verification_date>
  <study_first_submitted>August 22, 2012</study_first_submitted>
  <study_first_submitted_qc>September 5, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 10, 2012</study_first_posted>
  <last_update_submitted>July 30, 2020</last_update_submitted>
  <last_update_submitted_qc>July 30, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Mannosidase Deficiency Diseases</mesh_term>
    <mesh_term>alpha-Mannosidosis</mesh_term>
  </condition_browse>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT01681953
org study id: rhLAMAN-05
secondary id: 2012-000979-17
nct id: NCT01681953
lead sponsor: 
collaborator: 
has dmc: Yes
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
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Reduction of oligosaccharides in serum
time frame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
description: Primary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group
measure: The number of steps climbed in 3 minutes (3-minute stair climb test)
time frame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
description: Primary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group
measure: Forced Vital Capacity
time frame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
description: Secondary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group
measure: The distance walked in 6 minutes (6-minute walk test)
time frame: Baseline evaluation prior to first dose, midterm evaluation after 26 weeks, and end evaluation after 52 weeks
description: Secondary efficacy endpoint evaluated as change from baseline in the active group versus the placebo group
measure: Adverse Events
time frame: 1 week
description: Safety endpoint assessed weekly throughout the trial
measure: Development of clinically significant changes in vital signs and change in physical examination
time frame: 1 week
description: Safety endpoints assessed weekly throughout the trial
measure: Clinical laboratory parameters (hematology, biochemistry and urinalysis)
time frame: 1 week
description: Safety endpoints assessed weekly throughout the trial
measure: Development of Lamazym antibodies and neutralizing/inhibitory antibodies
time frame: 1 week
description: Safety endpoints assessed weekly throughout the trial
measure: Quantitative determination of rhLAMAN in plasma
time frame: 10 min, 60 min, 2 hours, 24 hours, 3 days, 7 days
description: Pharmacokinetic (PK) assessments. Blood samples are drawn pre-treatment and at various times post-treatment (see time frame above)
arm group label: Lamazym
arm group type: Active Comparator
description: 1 mg Lamazym/kg body weight
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo is formulated as an isotonic phosphate buffer with glycine and mannitol
intervention type: Drug
intervention name: Lamazym
description: ERT, i.v. infusions weekly
arm group label: Lamazym
other name: rhLAMAN
other name: recombinant human alpha-mannosidase
intervention type: Drug
intervention name: Placebo
description: Infusions weekly
arm group label: Placebo
criteria: 
gender: All
minimum age: 5 Years
maximum age: 35 Years
healthy volunteers: No
last name: Allan M Lund, MD
role: Principal Investigator
affiliation: Copenhagen University Hospital, Center for Metabolic Diseases, Department for Clinical Genetics
last name: Jens Fogh
role: Study Chair
affiliation: Zymenex A/S
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Denmark
country: France
country: Germany
country: Poland
country: United Kingdom
url: https://www.clinicaltrialsregister.eu/ctr-search/search?query=2012-000979-17
description: Study Record on EU Clinical Trials Register including results
citation: Borgwardt L, Stensland HM, Olsen KJ, Wibrand F, Klenow HB, Beck M, Amraoui Y, Arash L, Fogh J, Nilssen O, Dali CI, Lund AM. Alpha-mannosidosis: correlation between phenotype, genotype and mutant MAN2B1 subcellular localisation. Orphanet J Rare Dis. 2015 Jun 6;10:70. doi: 10.1186/s13023-015-0286-x.
PMID: 26048034
citation: Borgwardt L, Thuesen AM, Olsen KJ, Fogh J, Dali CI, Lund AM. Cognitive profile and activities of daily living: 35 patients with alpha-mannosidosis. J Inherit Metab Dis. 2015 Nov;38(6):1119-27. doi: 10.1007/s10545-015-9862-4. Epub 2015 May 28.
PMID: 26016802
citation: Harmatz P, Cattaneo F, Ardigo D, Geraci S, Hennermann JB, Guffon N, Lund A, Hendriksz CJ, Borgwardt L. Enzyme replacement therapy with velmanase alfa (human recombinant alpha-mannosidase): Novel global treatment response model and outcomes in patients with alpha-mannosidosis. Mol Genet Metab. 2018 Jun;124(2):152-160. doi: 10.1016/j.ymgme.2018.04.003. Epub 2018 Apr 18.
PMID: 29716835
citation: Borgwardt L, Guffon N, Amraoui Y, Dali CI, De Meirleir L, Gil-Campos M, Heron B, Geraci S, Ardigo D, Cattaneo F, Fogh J, Van den Hout JMH, Beck M, Jones SA, Tylki-Szymanska A, Haugsted U, Lund AM. Efficacy and safety of Velmanase alfa in the treatment of patients with alpha-mannosidosis: results from the core and extension phase analysis of a phase III multicentre, double-blind, randomised, placebo-controlled trial. J Inherit Metab Dis. 2018 Nov;41(6):1215-1223. doi: 10.1007/s10545-018-0185-0. Epub 2018 May 30.
PMID: 29846843
responsible party type: Sponsor
mesh term: Mannosidase Deficiency Diseases
mesh term: alpha-Mannosidosis