<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/NCT03284658</url>
  </required_header>
  <id_info>
    <org_study_id>BTY 06-2018</org_study_id>
    <nct_id>NCT03284658</nct_id>
  </id_info>
  <brief_title>Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 (BioTyrosin)</brief_title>
  <acronym>BioTyrosin</acronym>
  <official_title>BioTyrosin - Biomarker for the Early Diagnosis and Monitoring in Tyrosinemia Type 1 - An International, Multicenter, Epidemiological Protocol</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>CENTOGENE GmbH Rostock</agency>
      <agency_class>Industry</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>CENTOGENE GmbH Rostock</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Development of a new MS-based biomarker for the early and sensitive diagnosis of Tyrosinemia&#xD;
      type 1 from blood (plasma)&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Hereditary Tyrosinemia type 1 (HT-1) is a rare genetic disorder in which the newborn child&#xD;
      lacks the ability to break down the amino acid tyrosine. As a result of this deficiency,&#xD;
      toxic sub-stances build up in the blood and can cause liver failure, kidney dysfunction and&#xD;
      neurological problems. There are two different forms of the disease - acute and chronic. The&#xD;
      acute form is most common.&#xD;
&#xD;
      Worldwide, Tyrosinemia type 1 affects about one newborn child in 100,000, although&#xD;
      geo-graphical variation is seen.&#xD;
&#xD;
      Tyrosinemia type 1 is hereditary. The disorder is caused by a defect in the gene coding for&#xD;
      the enzyme responsible for breaking down tyrosine. For a child to be affected by the disease,&#xD;
      both parents have to carry a defective gene. The risk of being born with Tyrosinemia type 1,&#xD;
      i.e. receiving both genes from the parents, is thus 25%.&#xD;
&#xD;
      Children with Tyrosinemia type 1 can display symptoms such as failure to gain weight and grow&#xD;
      at the expected rate, diarrhea, vomiting, enlarged liver, liver failure, accumulation of&#xD;
      fluid in the peritoneal cavity, kidney failure, softening of the bones (rickets) and liver&#xD;
      tumors.&#xD;
&#xD;
      The acute form usually appears in the first few months of life. The child has a slow weight&#xD;
      gain plus fever, diarrhea, blood in the feces and vomiting. The liver is enlarged and&#xD;
      yellowing of the skin and the whites of the eyes (jaundice) with an increased tendency to&#xD;
      bleed (particularly nosebleeds) may be evident. The spleen and abdomen can also be enlarged&#xD;
      and the legs swollen. Without treatment, liver failure and clotting problems can arise.&#xD;
&#xD;
      Children with the chronic form of Tyrosinemia type 1 develop symptoms gradually. The child&#xD;
      can suffer from enlarged liver, distended abdomen (due to enlarged liver and spleen, acites&#xD;
      and excessive fluids), changes in skeleton, and liver and kidney failure. Symptoms such as&#xD;
      abdominal pain, damage to the peripheral nerves and high blood pressure appear. In addition,&#xD;
      symptoms common in acute intermittent porphyria can also occur. If the child is not treated,&#xD;
      it will develop liver failure and liver tumors.&#xD;
&#xD;
      The condition is also referred to as hepatorenal Tyrosinemia, and is the most critical&#xD;
      variant of Tyrosinemia. The main function of the FAH gene is to regulate the production of&#xD;
      the enzyme fumarylacetoacetase that is required to break down or metabolize amino acid&#xD;
      tyrosine. The mutations of FAH gene leads to a deficiency of the enzyme fumarylacetoacetase,&#xD;
      which then leads to a failure in breaking down tyrosine.&#xD;
&#xD;
      Tyrosinemia type 1 is suspected on the basis of clinical presentation. Diagnostic&#xD;
      investigations include analyses of amino acids, succinylacetone and alpha-fetoprotein.&#xD;
&#xD;
      Today, the condition can be treated by diet, medication and liver transplantation. Liver&#xD;
      trans-plantation was once the only treatment, but since a new drug was introduced in 1991,&#xD;
      survival has increased significantly. Nevertheless, diet and special protein replacements&#xD;
      remain an important part of life-long treatment.&#xD;
&#xD;
      New methods, like mass-spectrometry give a good chance to characterize specific metabolic&#xD;
      alterations in the blood (plasma) of affected patients that allow diagnosing in the future&#xD;
      the dis-ease earlier, with a higher sensitivity and specificity.&#xD;
&#xD;
      Therefore it is the goal of the study to identify and validate a new biochemical marker from&#xD;
      the plasma of the affected patients helping to benefit other patients by an early diagnose&#xD;
      and thereby with an earlier treatment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    Transition to BioMetabol&#xD;
  </why_stopped>
  <start_date type="Actual">August 20, 2018</start_date>
  <completion_date type="Actual">February 28, 2021</completion_date>
  <primary_completion_date type="Actual">February 28, 2021</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Sequencing of the Tyrosinemia Type 1 disease related gene</measure>
    <time_frame>4 weeks</time_frame>
    <description>Next-Generation Sequencing (NGS) of the FAH gene will be performed. The mutation will be confirmed by Sanger sequencing.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The Tyrosinemia type 1 specific biomarker candidates finding</measure>
    <time_frame>24 months</time_frame>
    <description>The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">0</enrollment>
  <condition>Tyrosinosis</condition>
  <condition>Hepatorenal Tyrosinemia</condition>
  <condition>Fumarylacetoacetase Deficiency</condition>
  <condition>Fah Deficiency</condition>
  <condition>Metabolic Disorders</condition>
  <arm_group>
    <arm_group_label>Observation</arm_group_label>
    <description>Patients with a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1</description>
  </arm_group>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      For the development of the new biomarkers using the technique of Mass-spectrometry, a blood&#xD;
      sample of maximal 7,5 ml blood will be taken from the patient via using a dry blood spot&#xD;
      filter card. To proof the correct diagnosis a Tyrosinemia type 1, in those patients where up&#xD;
      to the enrollment in the study no genetic testing has been done, sequencing of a Tyrosinemia&#xD;
      type 1 will be done.&#xD;
&#xD;
      The analyses will be done at:&#xD;
&#xD;
      Centogene AG Am Strande 7 18055 Rostock Germany&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Patients with a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Informed consent will be obtained from the patient or the parents before any study&#xD;
             related procedures.&#xD;
&#xD;
          -  Patients of both genders older than 2 months&#xD;
&#xD;
          -  The patient has a diagnosis of Tyrosinemia type 1 or a high-grade suspicion for&#xD;
             Tyrosinemia type 1&#xD;
&#xD;
        High-grade suspicion present, if one or more inclusion criteria are valid:&#xD;
&#xD;
          -  Positive family anamnesis for Tyrosinemia type 1&#xD;
&#xD;
          -  Hepatomegaly&#xD;
&#xD;
          -  Splenomegaly&#xD;
&#xD;
          -  Ascites&#xD;
&#xD;
          -  Coagulopathy&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  No Informed consent from the patient or the parents before any study related&#xD;
             procedures.&#xD;
&#xD;
          -  Patients of both gender younger than 2 months&#xD;
&#xD;
          -  No diagnosis of Tyrosinemia type 1 or no valid criteria for profound suspicion of&#xD;
             Tyrosinemia type 1&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Months</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Peter Bauer, Prof.</last_name>
    <role>Study Chair</role>
    <affiliation>Centogene GmbH</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centogene AG</name>
      <address>
        <city>Rostock</city>
        <zip>18055</zip>
        <country>Germany</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>NIRMAN Navi Mumbai Institute of Research In Mental And Neurological Handicap/Pediatric Geneticist</name>
      <address>
        <city>Mumbai</city>
        <zip>400705</zip>
        <country>India</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Lady Ridgeway Hospital for Children</name>
      <address>
        <city>Colombo 8</city>
        <zip>00800c</zip>
        <country>Sri Lanka</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Germany</country>
    <country>India</country>
    <country>Sri Lanka</country>
  </location_countries>
  <removed_countries>
    <country>Egypt</country>
  </removed_countries>
  <link>
    <url>http://centogene.com</url>
    <description>Centogene is one of the leading laboratories focusing on genetic testing for rare hereditary disorders. We now offer more than 2200 routine genetic and biochemical tests.</description>
  </link>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>September 13, 2017</study_first_submitted>
  <study_first_submitted_qc>September 13, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">September 15, 2017</study_first_posted>
  <last_update_submitted>February 9, 2023</last_update_submitted>
  <last_update_submitted_qc>February 9, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 13, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Tyrosinemia Type 1</keyword>
  <keyword>Biomarker</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Tyrosinemias</mesh_term>
    <mesh_term>Metabolic Diseases</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03284658
org study id: BTY 06-2018
nct id: NCT03284658
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Development of a new MS-based biomarker for the early and sensitive diagnosis of Tyrosinemia
      type 1 from blood (plasma)
Hereditary Tyrosinemia type 1 (HT-1) is a rare genetic disorder in which the newborn child
      lacks the ability to break down the amino acid tyrosine. As a result of this deficiency,
      toxic sub-stances build up in the blood and can cause liver failure, kidney dysfunction and
      neurological problems. There are two different forms of the disease - acute and chronic. The
      acute form is most common.

      Worldwide, Tyrosinemia type 1 affects about one newborn child in 100,000, although
      geo-graphical variation is seen.

      Tyrosinemia type 1 is hereditary. The disorder is caused by a defect in the gene coding for
      the enzyme responsible for breaking down tyrosine. For a child to be affected by the disease,
      both parents have to carry a defective gene. The risk of being born with Tyrosinemia type 1,
      i.e. receiving both genes from the parents, is thus 25%.

      Children with Tyrosinemia type 1 can display symptoms such as failure to gain weight and grow
      at the expected rate, diarrhea, vomiting, enlarged liver, liver failure, accumulation of
      fluid in the peritoneal cavity, kidney failure, softening of the bones (rickets) and liver
      tumors.

      The acute form usually appears in the first few months of life. The child has a slow weight
      gain plus fever, diarrhea, blood in the feces and vomiting. The liver is enlarged and
      yellowing of the skin and the whites of the eyes (jaundice) with an increased tendency to
      bleed (particularly nosebleeds) may be evident. The spleen and abdomen can also be enlarged
      and the legs swollen. Without treatment, liver failure and clotting problems can arise.

      Children with the chronic form of Tyrosinemia type 1 develop symptoms gradually. The child
      can suffer from enlarged liver, distended abdomen (due to enlarged liver and spleen, acites
      and excessive fluids), changes in skeleton, and liver and kidney failure. Symptoms such as
      abdominal pain, damage to the peripheral nerves and high blood pressure appear. In addition,
      symptoms common in acute intermittent porphyria can also occur. If the child is not treated,
      it will develop liver failure and liver tumors.

      The condition is also referred to as hepatorenal Tyrosinemia, and is the most critical
      variant of Tyrosinemia. The main function of the FAH gene is to regulate the production of
      the enzyme fumarylacetoacetase that is required to break down or metabolize amino acid
      tyrosine. The mutations of FAH gene leads to a deficiency of the enzyme fumarylacetoacetase,
      which then leads to a failure in breaking down tyrosine.

      Tyrosinemia type 1 is suspected on the basis of clinical presentation. Diagnostic
      investigations include analyses of amino acids, succinylacetone and alpha-fetoprotein.

      Today, the condition can be treated by diet, medication and liver transplantation. Liver
      trans-plantation was once the only treatment, but since a new drug was introduced in 1991,
      survival has increased significantly. Nevertheless, diet and special protein replacements
      remain an important part of life-long treatment.

      New methods, like mass-spectrometry give a good chance to characterize specific metabolic
      alterations in the blood (plasma) of affected patients that allow diagnosing in the future
      the dis-ease earlier, with a higher sensitivity and specificity.

      Therefore it is the goal of the study to identify and validate a new biochemical marker from
      the plasma of the affected patients helping to benefit other patients by an early diagnose
      and thereby with an earlier treatment.
observational model: Cohort
time perspective: Prospective
measure: Sequencing of the Tyrosinemia Type 1 disease related gene
time frame: 4 weeks
description: Next-Generation Sequencing (NGS) of the FAH gene will be performed. The mutation will be confirmed by Sanger sequencing.
measure: The Tyrosinemia type 1 specific biomarker candidates finding
time frame: 24 months
description: The quantitative determination of small molecules (molecular weight 150-700 kD, given as ng/μl) within a dried blood spot sample will be validated via liquid chromatography multiple reaction-monitoring mass spectrometry (LC/MRM-MS) and compared with a merged control cohort. The statistically best validated molecule will be considered as a disease specific biomarker.
arm group label: Observation
description: Patients with a Tyrosinemia type 1 or high-grade suspi-cion for Tyrosinemia type 1
For the development of the new biomarkers using the technique of Mass-spectrometry, a blood
      sample of maximal 7,5 ml blood will be taken from the patient via using a dry blood spot
      filter card. To proof the correct diagnosis a Tyrosinemia type 1, in those patients where up
      to the enrollment in the study no genetic testing has been done, sequencing of a Tyrosinemia
      type 1 will be done.

      The analyses will be done at:

      Centogene AG Am Strande 7 18055 Rostock Germany
study pop: 
sampling method: Probability Sample
criteria: 
gender: All
minimum age: 2 Months
maximum age: N/A
healthy volunteers: No
last name: Peter Bauer, Prof.
role: Study Chair
affiliation: Centogene GmbH
facility: 
facility: 
facility: 
country: Germany
country: India
country: Sri Lanka
country: Egypt
url: http://centogene.com
description: Centogene is one of the leading laboratories focusing on genetic testing for rare hereditary disorders. We now offer more than 2200 routine genetic and biochemical tests.
responsible party type: Sponsor
mesh term: Tyrosinemias
mesh term: Metabolic Diseases
sharing ipd: Undecided