<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/NCT02998879</url>
  </required_header>
  <id_info>
    <org_study_id>CCD-LMZYMAA1-08</org_study_id>
    <secondary_id>2016-001988-36</secondary_id>
    <nct_id>NCT02998879</nct_id>
  </id_info>
  <brief_title>Trial on Safety and Efficacy of Velmanase Alfa Treatment in Pediatric Patients With Alpha-Mannosidosis</brief_title>
  <acronym>rhLaman-08</acronym>
  <official_title>A 24-month Multicenter, Open-label Phase II Trial Investigating the Safety and Efficacy of Repeated Velmanase Alfa (Recombinant Human Alpha-mannosidase) Treatment in Pediatric Patients Below 6 Years of Age With Alpha-Mannosidosis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Chiesi Farmaceutici S.p.A.</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Cromsource</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Chiesi Farmaceutici S.p.A.</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The main objectives of the study are to evaluate safety and efficacy of repeated treatment&#xD;
      with recombinant human alfa-mannosidase of patients with alfa-mannosidosis aged less than 6&#xD;
      years&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The Primary endpoints of the study include:&#xD;
&#xD;
        -  Safety and tolerability of velmanase alfa as per Adverse events (AEs, including IRR),&#xD;
           vital signs, laboratory parameters (hematology, biochemistry and urinanalysis)&#xD;
&#xD;
        -  Detection of anti-velmanase alfa antibodies and neutralizing/inhibitory antibodies&#xD;
&#xD;
      The Secondary endpoints include changes from baseline to 24 months for the following&#xD;
      parameters. Efficacy outcomes:&#xD;
&#xD;
        -  Serum oligosaccharides&#xD;
&#xD;
        -  Functional capacity: Peabody Developmental Motor Scale - 2nd edition (PDMS-2) scores,&#xD;
           Mullen's Scale of Early Learning (MSEL) scores, Bruininks-Oseretsky Test Of Motor&#xD;
           Proficiency-2nd Edition (BOT-2), when applicable by age (from 4 years) or upon the&#xD;
           judgment of the physician&#xD;
&#xD;
        -  Endurance: 3-Minute Stair Climb Test (3MSCT) and 6-Minute Walk Test (6MWT) in pediatric&#xD;
           patients from 4 years of age, or when applicable according to the judgment of the&#xD;
           physician, 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age, or when&#xD;
           applicable according to the judgment of the physician&#xD;
&#xD;
        -  Hearing evaluation: Otoacoustic Emissions (OAE) testing, Automatic Auditory Brainstem&#xD;
           Response (A-ABR) audiometry&#xD;
&#xD;
        -  Immunological profile, when applicable upon the judgment of the physician:&#xD;
&#xD;
        -  CSF biomarkers: Tau protein (Tau), Neurofilament Protein Light (NFL), Glial Fibrillary&#xD;
           Acidic Protein (GFAp), Oligosaccharides&#xD;
&#xD;
        -  Assessment of quality of life via Questionnaire to parents&#xD;
&#xD;
        -  Assessment of mannose-rich oligosaccharides in brain tissue, MRI&#xD;
&#xD;
        -  Pharmacokinetic parameters&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>December 2016</start_date>
  <completion_date type="Actual">July 2020</completion_date>
  <primary_completion_date type="Actual">July 2020</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety and tolerability of velmanase alfa as per Adverse events</measure>
    <time_frame>From baseline throughout study completion, at least of 2 years</time_frame>
    <description>Safety and tolerability assessed as per AEs including infusion-related reactions [IRRs]</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety and tolerability of velmanase alfa as per vital signs</measure>
    <time_frame>From baseline throughout study completion, at least of 2 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per hematology</measure>
    <time_frame>From baseline throughout study completion, at least of 2 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per blood biochemistry</measure>
    <time_frame>From baseline throughout study completion, at least of 2 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per urinalysis</measure>
    <time_frame>From baseline throughout study completion, at least of 2 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Detection of anti-velmanase alfa-IgG antibodies (ADA) and neutralizing/inhibitory antibodies</measure>
    <time_frame>From baseline throughout study completion, at least of 2 years</time_frame>
    <description>Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evaluation of levels of Serum oligosaccharides</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
    <description>Assessment of change from baseline in levels of Serum oligosaccharides</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional capacity: The Peabody Developmental Motor Scale test (PDMS-2)</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
    <description>Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional capacity: Bruininks-Oseretsky test of Motor Proficiency (BOT-2) when applicable by age (from 4 years) or upon the judgment of the physician</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Functional capacity: Mullen Scales of Early Learning (MSEL)</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endurance: 3-Minute Stair Climb Test (3MSCT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endurance: 6-Minute Walk Test (6MWT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hearing evaluation: Otoacoustic Emissions (OAE) testing</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hearing evaluation: Automatic Auditory Brainstem Response (A-ABR) audiometry</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Immunological profile when applicable upon the judgement of the physician (Serum IgG, IgA, IgM; in vitro synthesis of IgG; in vitro proliferative response and Immunophenotype)</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>CSF biomarkers: Tau protein (Tau) § Neurofilament Protein Light (NFL) § Glial Fibrillary Acidic Protein (GFAp) § Oligosaccharides</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of quality of life via Questionnaire</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assessment of mannose-rich oligosaccharides in brain tissue, as measured by Magnetic Resonance Spectroscopy (MRS)</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Magnetic Resonance Imaging (MRI) in white matter, gray matter and in centrum semi ovale, and diffusion-MRI of the brain,</measure>
    <time_frame>From baseline throughout study completion, at least for 2 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine Cmax (Peak Concentration)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine Ctrough (Trough Plasma Concentration)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine Area Under Curve (AUC24)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine AUClast (Area Under Curve After The Last Count)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine AUCinf (Area Under Curve From Time Zero To Infinity)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine tmax (Time To Peak Concentration)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine CL (Clearance)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine t1/2 (Elimination Half-Life)</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Pharmacokinetic parameters to determine Rac (Obs) Observed Accumulation Ratio</measure>
    <time_frame>At first dose (visit 1) and after 6 months (visit 26)</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">5</enrollment>
  <condition>Alpha-Mannosidosis</condition>
  <arm_group>
    <arm_group_label>Velmanase Alfa</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>velmanase alfa 1mg/kg body weight infusion</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Velmanase Alfa (e.g. Lamazym)</intervention_name>
    <description>iv infusion treatment</description>
    <arm_group_label>Velmanase Alfa</arm_group_label>
    <other_name>Lamazym</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Patient's custodial parent(s) must provide signed ICF prior to the involvement of the&#xD;
             patient in any trial-related activities&#xD;
&#xD;
          2. The subject's custodial parent(s) must have the ability to comply with the protocol&#xD;
&#xD;
          3. The subject must have a confirmed diagnosis of alpha-mannosidosis as defined by&#xD;
             alpha-mannosidase activity in leukocytes or fibroblasts &lt; 10% of normal activity&#xD;
             (historical data)&#xD;
&#xD;
          4. The subject must have an age at the time of screening &lt; 6 years.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. The subject's diagnosis cannot be confirmed by alpha-mannosidase activity &lt; 10% of&#xD;
             normal activity&#xD;
&#xD;
          2. Presence of known chromosomal abnormality and syndromes affecting psychomotor&#xD;
             development, other than alpha-mannosidosis&#xD;
&#xD;
          3. History of BMT&#xD;
&#xD;
          4. 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;
          5. 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;
          6. Planned major surgery that, in the opinion of the Investigator, would preclude&#xD;
             participation in the trial&#xD;
&#xD;
          7. Participation in other interventional trials testing the IMP within the last 3 months.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>6 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <address>
        <city>Wien</city>
        <country>Austria</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Copenhagen</city>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Lyon</city>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Hamburg</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Mainz</city>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <address>
        <city>Trieste</city>
        <country>Italy</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Austria</country>
    <country>Denmark</country>
    <country>France</country>
    <country>Germany</country>
    <country>Italy</country>
  </location_countries>
  <link>
    <url>https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001988-36/results</url>
    <description>Study Record on EU Clinical Trials Register including results</description>
  </link>
  <verification_date>October 2021</verification_date>
  <study_first_submitted>November 25, 2016</study_first_submitted>
  <study_first_submitted_qc>December 16, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 21, 2016</study_first_posted>
  <last_update_submitted>October 18, 2021</last_update_submitted>
  <last_update_submitted_qc>October 18, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">October 26, 2021</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>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- 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/NCT02998879
org study id: CCD-LMZYMAA1-08
secondary id: 2016-001988-36
nct id: NCT02998879
lead sponsor: 
collaborator: 
has dmc: No
The main objectives of the study are to evaluate safety and efficacy of repeated treatment
      with recombinant human alfa-mannosidase of patients with alfa-mannosidosis aged less than 6
      years
The Primary endpoints of the study include:

        -  Safety and tolerability of velmanase alfa as per Adverse events (AEs, including IRR),
           vital signs, laboratory parameters (hematology, biochemistry and urinanalysis)

        -  Detection of anti-velmanase alfa antibodies and neutralizing/inhibitory antibodies

      The Secondary endpoints include changes from baseline to 24 months for the following
      parameters. Efficacy outcomes:

        -  Serum oligosaccharides

        -  Functional capacity: Peabody Developmental Motor Scale - 2nd edition (PDMS-2) scores,
           Mullen's Scale of Early Learning (MSEL) scores, Bruininks-Oseretsky Test Of Motor
           Proficiency-2nd Edition (BOT-2), when applicable by age (from 4 years) or upon the
           judgment of the physician

        -  Endurance: 3-Minute Stair Climb Test (3MSCT) and 6-Minute Walk Test (6MWT) in pediatric
           patients from 4 years of age, or when applicable according to the judgment of the
           physician, 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age, or when
           applicable according to the judgment of the physician

        -  Hearing evaluation: Otoacoustic Emissions (OAE) testing, Automatic Auditory Brainstem
           Response (A-ABR) audiometry

        -  Immunological profile, when applicable upon the judgment of the physician:

        -  CSF biomarkers: Tau protein (Tau), Neurofilament Protein Light (NFL), Glial Fibrillary
           Acidic Protein (GFAp), Oligosaccharides

        -  Assessment of quality of life via Questionnaire to parents

        -  Assessment of mannose-rich oligosaccharides in brain tissue, MRI

        -  Pharmacokinetic parameters
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Safety and tolerability of velmanase alfa as per Adverse events
time frame: From baseline throughout study completion, at least of 2 years
description: Safety and tolerability assessed as per AEs including infusion-related reactions [IRRs]
measure: Safety and tolerability of velmanase alfa as per vital signs
time frame: From baseline throughout study completion, at least of 2 years
measure: Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per hematology
time frame: From baseline throughout study completion, at least of 2 years
measure: Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per blood biochemistry
time frame: From baseline throughout study completion, at least of 2 years
measure: Safety and tolerability of velmanase alfa as per clinical laboratory parameters as per urinalysis
time frame: From baseline throughout study completion, at least of 2 years
measure: Detection of anti-velmanase alfa-IgG antibodies (ADA) and neutralizing/inhibitory antibodies
time frame: From baseline throughout study completion, at least of 2 years
description: Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained
measure: Evaluation of levels of Serum oligosaccharides
time frame: From baseline throughout study completion, at least for 2 years
description: Assessment of change from baseline in levels of Serum oligosaccharides
measure: Functional capacity: The Peabody Developmental Motor Scale test (PDMS-2)
time frame: From baseline throughout study completion, at least for 2 years
description: Serum samples for anti-velmanase alfa-IgG antibody (ADA) testing will be obtained
measure: Functional capacity: Bruininks-Oseretsky test of Motor Proficiency (BOT-2) when applicable by age (from 4 years) or upon the judgment of the physician
time frame: From baseline throughout study completion, at least for 2 years
measure: Functional capacity: Mullen Scales of Early Learning (MSEL)
time frame: From baseline throughout study completion, at least for 2 years
measure: Endurance: 3-Minute Stair Climb Test (3MSCT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician
time frame: From baseline throughout study completion, at least for 2 years
measure: Endurance: 6-Minute Walk Test (6MWT) in pediatric patients from 4 years of age, or when applicable according to the judgment of the physician 2-Minute Walk Test (2MWT) in pediatric patients below 4 years of age
time frame: From baseline throughout study completion, at least for 2 years
measure: Hearing evaluation: Otoacoustic Emissions (OAE) testing
time frame: From baseline throughout study completion, at least for 2 years
measure: Hearing evaluation: Automatic Auditory Brainstem Response (A-ABR) audiometry
time frame: From baseline throughout study completion, at least for 2 years
measure: Immunological profile when applicable upon the judgement of the physician (Serum IgG, IgA, IgM; in vitro synthesis of IgG; in vitro proliferative response and Immunophenotype)
time frame: From baseline throughout study completion, at least for 2 years
measure: CSF biomarkers: Tau protein (Tau) § Neurofilament Protein Light (NFL) § Glial Fibrillary Acidic Protein (GFAp) § Oligosaccharides
time frame: From baseline throughout study completion, at least for 2 years
measure: Assessment of quality of life via Questionnaire
time frame: From baseline throughout study completion, at least for 2 years
measure: Assessment of mannose-rich oligosaccharides in brain tissue, as measured by Magnetic Resonance Spectroscopy (MRS)
time frame: From baseline throughout study completion, at least for 2 years
measure: Magnetic Resonance Imaging (MRI) in white matter, gray matter and in centrum semi ovale, and diffusion-MRI of the brain,
time frame: From baseline throughout study completion, at least for 2 years
measure: Pharmacokinetic parameters to determine Cmax (Peak Concentration)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine Ctrough (Trough Plasma Concentration)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine Area Under Curve (AUC24)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine AUClast (Area Under Curve After The Last Count)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine AUCinf (Area Under Curve From Time Zero To Infinity)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine tmax (Time To Peak Concentration)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine CL (Clearance)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine t1/2 (Elimination Half-Life)
time frame: At first dose (visit 1) and after 6 months (visit 26)
measure: Pharmacokinetic parameters to determine Rac (Obs) Observed Accumulation Ratio
time frame: At first dose (visit 1) and after 6 months (visit 26)
arm group label: Velmanase Alfa
arm group type: Experimental
description: velmanase alfa 1mg/kg body weight infusion
intervention type: Drug
intervention name: Velmanase Alfa (e.g. Lamazym)
description: iv infusion treatment
arm group label: Velmanase Alfa
other name: Lamazym
criteria: 
gender: All
minimum age: N/A
maximum age: 6 Years
healthy volunteers: No
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: Austria
country: Denmark
country: France
country: Germany
country: Italy
url: https://www.clinicaltrialsregister.eu/ctr-search/trial/2016-001988-36/results
description: Study Record on EU Clinical Trials Register including results
responsible party type: Sponsor
mesh term: Mannosidase Deficiency Diseases
mesh term: alpha-Mannosidosis
sharing ipd: No