<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/NCT02218632</url>
  </required_header>
  <id_info>
    <org_study_id>12020</org_study_id>
    <secondary_id>grant PAC number 12.64</secondary_id>
    <nct_id>NCT02218632</nct_id>
  </id_info>
  <brief_title>Glycosylation in Patients With Galactosaemia</brief_title>
  <official_title>Galactosaemia, a Modifiable Multi-system Glycosylation Disorder?</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Children's University Hospital, Ireland</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Health Research Board, Ireland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Medical Research Charities Group Ireland</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University College Dublin</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Children's University Hospital, Ireland</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Galactosaemia is an inherited condition caused by a lack of an enzyme (catalyst) which&#xD;
      normally breaks down galactose (the sugar found in milk products). This affects 1:19,000&#xD;
      births annually in Ireland (the highest incidence worldwide) and is screened for by the&#xD;
      National Newborn Screening Programme. When an affected infant is diagnosed, galactose is&#xD;
      immediately restricted from the diet. This prevents often fatal liver disease and other&#xD;
      immediate complications. However, despite early treatment the majority of affected patients&#xD;
      go on to develop long-term complications such as intellectual impairment, neurological&#xD;
      complications, speech difficulties and infertility in females. The underlying mechanisms for&#xD;
      these complications are unclear. The investigators have shown in detailed biochemical and&#xD;
      gene analysis studies that major abnormalities affecting the function of complex molecules in&#xD;
      the body, particularly glycoproteins, (consisting of sugar chains attached to proteins)&#xD;
      persist in treated individuals which may lead to disturbances of the body's intrinsic&#xD;
      cellular machinery and relate to the complications seen.&#xD;
&#xD;
      In this research the investigators expand on from their earlier studies to see if they can&#xD;
      identify biomarkers and parts of the galactose/glycosylation pathways which could be modified&#xD;
      or changed with new treatments to improve outcomes for this condition (i.e., IgG N glycans).&#xD;
&#xD;
      In more detail, the investigators test the use of the most abundant glycoprotein in human&#xD;
      plasma (IgG) as an improved clinical test for monitoring the galactose control needed in&#xD;
      patients and also to see if some patients (including children aged 5-12 yrs) might have a&#xD;
      better predicted outcome with moderate increases of galactose in the diet. The investigators&#xD;
      believe that these studies greatly improve the understanding of Galactosaemia with a view to&#xD;
      improving current treatment options and future outcomes.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Classical Galactosaemia is an inherited disorder of galactose metabolism caused by profound&#xD;
      deficiency of galactose-1-phosphate uridyltransferase (GALT: EC 2.7.712). This results in a&#xD;
      systemic accumulation of toxic galactose intermediates and a decrease in the level of&#xD;
      UDP-galactose, a required sugar for glycosylation. Galactosaemia has a relatively high&#xD;
      incidence in Ireland, (1:19,000 births) presenting a particular public health problem. The&#xD;
      neonatal life-threatening phenotype (liver disease, coagulopathy and sepsis) is rescued by&#xD;
      restriction of dietary galactose. However, outcomes of treatment are disappointing beyond the&#xD;
      neonatal period (even after successful newborn screening, early treatment and long term&#xD;
      compliance). The majority of Irish patients harbour the severe Q188R Galt mutation.&#xD;
&#xD;
      56.5% of Irish patients ≥ 6yrs have IQs ≤ 79; and 91.2% of Irish female patients ≥ 13yrs have&#xD;
      Premature Ovarian Insufficiency (POI). Unfortunately, the basic pathophysiology of this&#xD;
      condition remains enigmatic with limited treatment approaches.&#xD;
&#xD;
      In their earlier work, the investigators reported very considerable variation in patient&#xD;
      outcomes, even among siblings. The investigators have proposed that these differences are&#xD;
      determined by variation in galactose accessory pathways (beyond the GALT deficiency). This&#xD;
      may result in variable galactose tolerance in patients with linked variation in glycosylation&#xD;
      pathways which could allow for enhanced UDP-galactose bioavailability essential for&#xD;
      glycosylation. In their previous and current work the investigators have identified ongoing&#xD;
      dysregulation of glycoprotein formation and expression of genes involved in glycan&#xD;
      biosynthesis and cell signalling pathways in treated Galactosaemia patients.&#xD;
&#xD;
      The present proposal, which builds on published previous work, enables the investigators to&#xD;
      establish that Galactosaemia is a modifiable, multi-systemic glycosylation defect. The&#xD;
      overall objectives of the work are to progress the development of biochemical markers (IgG&#xD;
      N-glycan analysis) as prognostic indices for potentially modifiable relevant pathways. The&#xD;
      investigators consider how the phenotype could be relaxed in some patients with Classical&#xD;
      Galactosaemia, initially by studies of modification of exogenous galactose requirements to&#xD;
      identify if the ongoing glycan processing defects identified may be improved reflecting&#xD;
      accessory pathways of galactose disposal.&#xD;
&#xD;
      Study Aim: Expand previous and published work using IgG N-glycan analysis to examine the&#xD;
      glycosylation status of treated adult Galactosaemia patients in a larger study and develop&#xD;
      this test as a reliable diagnostic tool. The investigators also carry out a pilot study to&#xD;
      examine the effects of diet relaxation in paediatric patients (5-12 yrs) aiming to determine&#xD;
      optimum galactose intake levels for this cohort with the hope of preventing long-term&#xD;
      complications later in life. The investigators propose that this research offers new insights&#xD;
      into the ongoing pathophysiology of this rare disorder with the possibility of developing new&#xD;
      treatment targets, which over time could be cost-effective by preventing major disability.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>July 2012</start_date>
  <completion_date type="Actual">August 2014</completion_date>
  <primary_completion_date type="Actual">August 2014</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Number of patients with Classical Galactosaemia on a lactose-free diet in Ireland with disease specific complications</measure>
    <time_frame>2 years</time_frame>
    <description>clinical monitoring and biochemical assessment to determine the number of patients with classical galactsaemia in Ireland with disease specific complications</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of participants with Classical Galactosaemia with variations in their glycosylation status in the Irish cohort</measure>
    <time_frame>2 years</time_frame>
    <description>Glycosylation analysis: IgG N-glycan analysis (serum test)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">26</enrollment>
  <condition>Classical Galactosaemia</condition>
  <arm_group>
    <arm_group_label>lactose-free diet</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>lactose-free diet (standard therapy) vs. lactose-free diet plus temporary oral galactose supplements</description>
  </arm_group>
  <arm_group>
    <arm_group_label>lactose free diet</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>lactose-free diet (standard therapy)</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>lactose-free diet</intervention_name>
    <description>standard diet</description>
    <arm_group_label>lactose-free diet</arm_group_label>
    <other_name>On established lactose-free diet</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Temporary oral galactose supplements</intervention_name>
    <description>galactose supplements in the range of physiological galactose production</description>
    <arm_group_label>lactose free diet</arm_group_label>
    <other_name>In addition to lactose-free diet</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Classical galactosaemia&#xD;
&#xD;
          -  Q188R Genotype&#xD;
&#xD;
          -  On lactose-free diet&#xD;
&#xD;
          -  No complications, condition well controlled&#xD;
&#xD;
          -  Male/femal adults and children aged between 5-12 yrs.&#xD;
&#xD;
          -  Informed consent /assent&#xD;
&#xD;
          -  Patient attend the Galactosaemia Clinic, NCIMD Dublin&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Complications, such as cataracts&#xD;
&#xD;
          -  Galactosaemia varaint, no Q188R-Genotype&#xD;
&#xD;
          -  Poor compliance&#xD;
&#xD;
          -  Intercurrent illness&#xD;
&#xD;
          -  Individual may not complete follow up&#xD;
&#xD;
          -  Children below 5 years of age&#xD;
&#xD;
          -  Unable to provide informed consent&#xD;
&#xD;
          -  Patient not under the care of Galactosaemia Clinic, NCIMD Dublin&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>5 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Eileen Treacy, MD, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>University Children's Hospital Dublin Irleland</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Centre for Inherited Metabolic Disorders, Children's University Hospital, Temple Street</name>
      <address>
        <city>Dublin</city>
        <zip>1</zip>
        <country>Ireland</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Ireland</country>
  </location_countries>
  <results_reference>
    <citation>Coss KP, Hawkes CP, Adamczyk B, Stockmann H, Crushell E, Saldova R, Knerr I, Rubio-Gozalbo ME, Monavari AA, Rudd PM, Treacy EP. N-glycan abnormalities in children with galactosemia. J Proteome Res. 2014 Feb 7;13(2):385-94. doi: 10.1021/pr4008305. Epub 2013 Dec 20.</citation>
    <PMID>24359113</PMID>
  </results_reference>
  <results_reference>
    <citation>Knerr I, Coss KP, Doran PP, Hughes J, Wareham N, Burling K, Treacy EP. Leptin levels in children and adults with classic galactosaemia. JIMD Rep. 2013;9:125-131. doi: 10.1007/8904_2012_191. Epub 2012 Nov 7.</citation>
    <PMID>23430559</PMID>
  </results_reference>
  <verification_date>August 2014</verification_date>
  <study_first_submitted>August 7, 2014</study_first_submitted>
  <study_first_submitted_qc>August 14, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 18, 2014</study_first_posted>
  <last_update_submitted>August 14, 2014</last_update_submitted>
  <last_update_submitted_qc>August 14, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">August 18, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Galactosaemia</keyword>
  <keyword>Dysglycosylation</keyword>
  <keyword>Diet</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Galactosemias</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/NCT02218632
org study id: 12020
secondary id: grant PAC number 12.64
nct id: NCT02218632
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
Galactosaemia is an inherited condition caused by a lack of an enzyme (catalyst) which
      normally breaks down galactose (the sugar found in milk products). This affects 1:19,000
      births annually in Ireland (the highest incidence worldwide) and is screened for by the
      National Newborn Screening Programme. When an affected infant is diagnosed, galactose is
      immediately restricted from the diet. This prevents often fatal liver disease and other
      immediate complications. However, despite early treatment the majority of affected patients
      go on to develop long-term complications such as intellectual impairment, neurological
      complications, speech difficulties and infertility in females. The underlying mechanisms for
      these complications are unclear. The investigators have shown in detailed biochemical and
      gene analysis studies that major abnormalities affecting the function of complex molecules in
      the body, particularly glycoproteins, (consisting of sugar chains attached to proteins)
      persist in treated individuals which may lead to disturbances of the body's intrinsic
      cellular machinery and relate to the complications seen.

      In this research the investigators expand on from their earlier studies to see if they can
      identify biomarkers and parts of the galactose/glycosylation pathways which could be modified
      or changed with new treatments to improve outcomes for this condition (i.e., IgG N glycans).

      In more detail, the investigators test the use of the most abundant glycoprotein in human
      plasma (IgG) as an improved clinical test for monitoring the galactose control needed in
      patients and also to see if some patients (including children aged 5-12 yrs) might have a
      better predicted outcome with moderate increases of galactose in the diet. The investigators
      believe that these studies greatly improve the understanding of Galactosaemia with a view to
      improving current treatment options and future outcomes.
Classical Galactosaemia is an inherited disorder of galactose metabolism caused by profound
      deficiency of galactose-1-phosphate uridyltransferase (GALT: EC 2.7.712). This results in a
      systemic accumulation of toxic galactose intermediates and a decrease in the level of
      UDP-galactose, a required sugar for glycosylation. Galactosaemia has a relatively high
      incidence in Ireland, (1:19,000 births) presenting a particular public health problem. The
      neonatal life-threatening phenotype (liver disease, coagulopathy and sepsis) is rescued by
      restriction of dietary galactose. However, outcomes of treatment are disappointing beyond the
      neonatal period (even after successful newborn screening, early treatment and long term
      compliance). The majority of Irish patients harbour the severe Q188R Galt mutation.

      56.5% of Irish patients ≥ 6yrs have IQs ≤ 79; and 91.2% of Irish female patients ≥ 13yrs have
      Premature Ovarian Insufficiency (POI). Unfortunately, the basic pathophysiology of this
      condition remains enigmatic with limited treatment approaches.

      In their earlier work, the investigators reported very considerable variation in patient
      outcomes, even among siblings. The investigators have proposed that these differences are
      determined by variation in galactose accessory pathways (beyond the GALT deficiency). This
      may result in variable galactose tolerance in patients with linked variation in glycosylation
      pathways which could allow for enhanced UDP-galactose bioavailability essential for
      glycosylation. In their previous and current work the investigators have identified ongoing
      dysregulation of glycoprotein formation and expression of genes involved in glycan
      biosynthesis and cell signalling pathways in treated Galactosaemia patients.

      The present proposal, which builds on published previous work, enables the investigators to
      establish that Galactosaemia is a modifiable, multi-systemic glycosylation defect. The
      overall objectives of the work are to progress the development of biochemical markers (IgG
      N-glycan analysis) as prognostic indices for potentially modifiable relevant pathways. The
      investigators consider how the phenotype could be relaxed in some patients with Classical
      Galactosaemia, initially by studies of modification of exogenous galactose requirements to
      identify if the ongoing glycan processing defects identified may be improved reflecting
      accessory pathways of galactose disposal.

      Study Aim: Expand previous and published work using IgG N-glycan analysis to examine the
      glycosylation status of treated adult Galactosaemia patients in a larger study and develop
      this test as a reliable diagnostic tool. The investigators also carry out a pilot study to
      examine the effects of diet relaxation in paediatric patients (5-12 yrs) aiming to determine
      optimum galactose intake levels for this cohort with the hope of preventing long-term
      complications later in life. The investigators propose that this research offers new insights
      into the ongoing pathophysiology of this rare disorder with the possibility of developing new
      treatment targets, which over time could be cost-effective by preventing major disability.
allocation: Non-Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Number of patients with Classical Galactosaemia on a lactose-free diet in Ireland with disease specific complications
time frame: 2 years
description: clinical monitoring and biochemical assessment to determine the number of patients with classical galactsaemia in Ireland with disease specific complications
measure: Number of participants with Classical Galactosaemia with variations in their glycosylation status in the Irish cohort
time frame: 2 years
description: Glycosylation analysis: IgG N-glycan analysis (serum test)
arm group label: lactose-free diet
arm group type: Active Comparator
description: lactose-free diet (standard therapy) vs. lactose-free diet plus temporary oral galactose supplements
arm group label: lactose free diet
arm group type: Active Comparator
description: lactose-free diet (standard therapy)
intervention type: Other
intervention name: lactose-free diet
description: standard diet
arm group label: lactose-free diet
other name: On established lactose-free diet
intervention type: Dietary Supplement
intervention name: Temporary oral galactose supplements
description: galactose supplements in the range of physiological galactose production
arm group label: lactose free diet
other name: In addition to lactose-free diet
criteria: 
gender: All
minimum age: 5 Years
maximum age: 40 Years
healthy volunteers: No
last name: Eileen Treacy, MD, Prof
role: Principal Investigator
affiliation: University Children's Hospital Dublin Irleland
facility: 
country: Ireland
citation: Coss KP, Hawkes CP, Adamczyk B, Stockmann H, Crushell E, Saldova R, Knerr I, Rubio-Gozalbo ME, Monavari AA, Rudd PM, Treacy EP. N-glycan abnormalities in children with galactosemia. J Proteome Res. 2014 Feb 7;13(2):385-94. doi: 10.1021/pr4008305. Epub 2013 Dec 20.
PMID: 24359113
citation: Knerr I, Coss KP, Doran PP, Hughes J, Wareham N, Burling K, Treacy EP. Leptin levels in children and adults with classic galactosaemia. JIMD Rep. 2013;9:125-131. doi: 10.1007/8904_2012_191. Epub 2012 Nov 7.
PMID: 23430559
responsible party type: Sponsor
mesh term: Galactosemias