<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/NCT02226419</url>
  </required_header>
  <id_info>
    <org_study_id>H-1-2012-130</org_study_id>
    <nct_id>NCT02226419</nct_id>
  </id_info>
  <brief_title>Fat and Sugar Metabolism During Exercise, With and Without L-carnitine in Patients With Carnitine Transporter Deficiency</brief_title>
  <acronym>CTD</acronym>
  <official_title>Fat and Carbohydrate Metabolism During Exercise, With and Without L-carnitine Supplementation in Patients With Carnitine Transporter Deficiency</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Karen Lindhardt Madsen</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The investigators wish to investigate fat and sugar metabolism during exercise with and&#xD;
      without L-carnitine supplementation in patients with carnitine transporter deficiency (CTD).&#xD;
&#xD;
      Patients with CTD have low plasma- and muscle concentrations of carnitine, which is believed&#xD;
      to lead to an impaired fat oxidation. Presently there is no cure available for these&#xD;
      patients, but daily intake of L-carnitine has been shown to limit the amount of symptoms.&#xD;
      Little is known about the metabolism during exercise and the pathophysiological mechanisms&#xD;
      causing the symptoms.&#xD;
&#xD;
      Studying the fat and sugar metabolism in CTD patients will contribute to the understanding of&#xD;
      the role of the carnitine transporter in the development of symptoms in these patients.&#xD;
      Furthermore, knowledge about the fat and sugar metabolism in these patients can increase the&#xD;
      understanding of the role of the carnitine transporter in the metabolism healthy persons.&#xD;
&#xD;
      The investigators have included 8 patients with genetically verified CTD in the study and a&#xD;
      group of 10 age- and sex-matched controls. Subjects will perform a 1h cycling test,&#xD;
      exercising at a moderate intensity. By measuring the expiration of carbon dioxide (CO2) and&#xD;
      consumption of oxygen (O2), the investigators can determine the total fatty acid and&#xD;
      carbohydrate oxidation during cycling. At the same time the investigators will measure the&#xD;
      patients' whole body palmitate (fat) and glucose (sugar) oxidation rates using stable isotope&#xD;
      technique.&#xD;
&#xD;
      The patient group will repeat the cycling test after 4 days without taking their usual&#xD;
      L-carnitine treatment. During the treatment break, patients will be admitted to be&#xD;
      continuously monitored for heart rhythm disturbances, which is a known but rarely occurring&#xD;
      complication to untreated CTD.&#xD;
&#xD;
      Since the patients have a defect in their fat metabolism, the investigators expect to find&#xD;
      that they have a reduced ability to burn fat, which is the major source of energy during low&#xD;
      intensity exercise. It is therefore likely, that the CTD patients will benefit from&#xD;
      adjustments in their daily diet, whenever they have to perform physically. By learning about&#xD;
      the metabolism of different dietary substances, fat and sugar, these studies can help to&#xD;
      improve the treatment in terms of dietary recommendations for CTD patients. This will have a&#xD;
      direct impact on the daily life of the patients.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      8 Patients with verified CTD have been included&#xD;
&#xD;
        -  All patients have performed an incremental load exercise test to exhaustion on a cycle&#xD;
           ergometer to determine maximal oxygen comsumption rate (VO2 max)&#xD;
&#xD;
        -  One-hour exercise test: Measurement of the total fat and sugar oxidation rates during&#xD;
           exercise using stable isotope tracers.&#xD;
&#xD;
      Subjects arrive at the laboratory after 3-9 hours fasting. One IV-catheter is inserted in the&#xD;
      cubital vein in one arm and another in a peripheral vein in the other hand. The stable&#xD;
      isotope tracers will be given in the cubital vein as a constant infusion of solutions of:&#xD;
&#xD;
        -  [U-13C]-palmitate (0.0026 mg x kg-1 x min-1, after a priming bolus of 0.085 mg x kg-1&#xD;
           NaH13CO3)&#xD;
&#xD;
        -  [1,1,2,3,3-2H5]-glycerol (0.0049 mg x kg-1 x min-1 )&#xD;
&#xD;
        -  [6.6-2H2]-glucose (0.0728 mg x kg-1 x min-1 ) 5 days before the study, subjects must&#xD;
           avoid eating food containing corn. Corn contains larger amounts of C13, which we use as&#xD;
           a tracer, and can therefore disturb the measurements.&#xD;
&#xD;
      For two hours the subjects rest while receiving the infusions until the tracers have&#xD;
      distributed in the body and reached a steady state. After the rest, the subjects exercise on&#xD;
      the cycle-ergometer until exhaustion or for a maximum of 1 hour at an intensity that&#xD;
      corresponds to 60-70% of VO2max.&#xD;
&#xD;
      Every other minute during exercise, the heart rate is recorded and the subject evaluates&#xD;
      his/her degree of exertion (Rate of Perceived Exertion, RPE) on a Borg scale.&#xD;
&#xD;
      Blood and breath samples:&#xD;
&#xD;
      From 20 minutes before exercise until the end of exercise, blood samples are drawn through&#xD;
      the IV-catheter in the hand vein (10-12 mL per sample) and samples of the expired breath are&#xD;
      collected in a Douglas bag (Hans Rudolph inc.) every ten minutes. The breath is transferred&#xD;
      into Vaccutainer-glas for analysis of 13CO2 -enrichment (10 mL). The plasma samples are&#xD;
      anayzed for concentrations of hormones, metabolites, carnitine and acyl-carnitines.&#xD;
&#xD;
      Muscle biopsy:&#xD;
&#xD;
      On this day a muscle biopsy is taken from the vastus lateralis of the thigh to measure the&#xD;
      intramuscular concentrations of carnitine and acylcarnitines.&#xD;
&#xD;
        -  Wash-out period: For 4 days patients were admitted for telemetric cardiac monitoring&#xD;
           while they pause their daily oral L-carnitine treatment.&#xD;
&#xD;
        -  After the washout period, patients repeat the one-hour exercise test with the stable&#xD;
           isotope tracers. Also the muscle biopsy for intramuscular carnitine and acyl-carnitine&#xD;
           concentrations are repeated-&#xD;
&#xD;
      TRACERS In this study we will use infusions of stable isotopes incorporated into metabolites&#xD;
      as tracers of whole body metabolism. We will use small amounts of fat (palmitate and&#xD;
      glycerol) and sugar (glucose) labelled with stable isotopes of carbon (13C) and hydrogen&#xD;
      (2H). The palmitate and glycerol tracers (98 % enriched, Cambrigde Isotope Laboratories,&#xD;
      Andover, MA, USA) will be dissolved in sterile water and infused through a bacterial filter&#xD;
      into human serum albumin. The glucose tracer (99 % enriched, Cambrigde Isotope Laboratories,&#xD;
      Andover, MA, USA) will be dissolved and injected into a solution of 0.9% saline (NaCl)&#xD;
      through a bacterial filter as well.&#xD;
&#xD;
      These tracers are naturally occurring in food (e.g. in corn) and in the human body. They are&#xD;
      harmless and will be handled and given to the subjects under sterile conditions.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2013</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>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>The whole body palmitate and carbohydrate oxidation rate in CTD patients during exercise</measure>
    <time_frame>With and without L-carnitine treatment</time_frame>
    <description>The whole body palmitate and carbohydrate oxidation will be assessed during 1h exercise test performed on a cycle-ergometer using stable isotope technique combined with indirect calorimetry.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>The maximal oxidative capacity (VO2max) as an indicator of exercise tolerance and performance in CTD patients</measure>
    <time_frame>During a 15 min incremental intensity exercise test and during a 1h moderate intensity cycling test</time_frame>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">14</enrollment>
  <condition>Carnitine Transporter, Plasma-membrane, Deficiency of</condition>
  <arm_group>
    <arm_group_label>Break in L-carnitine treatment</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Patients do not take their L-carnitine (Levocarnitine) treatment for 2-4 days until plasma carnitine and acylcarnitine have fallen. While patients abstain from taking the treatment, they are admitted for cardiac telemetry monitoring.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Break in L-carnitine treatment</intervention_name>
    <description>Levocarnitine oral tablet supplement at individual doses</description>
    <arm_group_label>Break in L-carnitine treatment</arm_group_label>
    <other_name>Levocarnitine</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Verified diagnosis of CTD&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Other conditions or diseases that may compromise the outcome of the study&#xD;
&#xD;
          -  Pregnancy or lactation&#xD;
&#xD;
          -  Inability to cooperate carrying out the experiments&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Karen L Madsen, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Neuromuscular Research Unit, Rigshospitalet</affiliation>
  </overall_official>
  <verification_date>May 2015</verification_date>
  <study_first_submitted>August 5, 2013</study_first_submitted>
  <study_first_submitted_qc>August 26, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 27, 2014</study_first_posted>
  <last_update_submitted>May 4, 2015</last_update_submitted>
  <last_update_submitted_qc>May 4, 2015</last_update_submitted_qc>
  <last_update_posted type="Estimate">May 5, 2015</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Karen Lindhardt Madsen</investigator_full_name>
    <investigator_title>MD</investigator_title>
  </responsible_party>
  <keyword>Fatty acid oxidation disorder</keyword>
  <keyword>Primary carnitine deficiency</keyword>
  <keyword>Exercise</keyword>
  <keyword>L-carnitine treatment</keyword>
  <keyword>Stable isotopes</keyword>
  <keyword>Carnitine transporter deficiency</keyword>
  <!-- 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/NCT02226419
org study id: H-1-2012-130
nct id: NCT02226419
lead sponsor: 
collaborator: 
has dmc: No
The investigators wish to investigate fat and sugar metabolism during exercise with and
      without L-carnitine supplementation in patients with carnitine transporter deficiency (CTD).

      Patients with CTD have low plasma- and muscle concentrations of carnitine, which is believed
      to lead to an impaired fat oxidation. Presently there is no cure available for these
      patients, but daily intake of L-carnitine has been shown to limit the amount of symptoms.
      Little is known about the metabolism during exercise and the pathophysiological mechanisms
      causing the symptoms.

      Studying the fat and sugar metabolism in CTD patients will contribute to the understanding of
      the role of the carnitine transporter in the development of symptoms in these patients.
      Furthermore, knowledge about the fat and sugar metabolism in these patients can increase the
      understanding of the role of the carnitine transporter in the metabolism healthy persons.

      The investigators have included 8 patients with genetically verified CTD in the study and a
      group of 10 age- and sex-matched controls. Subjects will perform a 1h cycling test,
      exercising at a moderate intensity. By measuring the expiration of carbon dioxide (CO2) and
      consumption of oxygen (O2), the investigators can determine the total fatty acid and
      carbohydrate oxidation during cycling. At the same time the investigators will measure the
      patients' whole body palmitate (fat) and glucose (sugar) oxidation rates using stable isotope
      technique.

      The patient group will repeat the cycling test after 4 days without taking their usual
      L-carnitine treatment. During the treatment break, patients will be admitted to be
      continuously monitored for heart rhythm disturbances, which is a known but rarely occurring
      complication to untreated CTD.

      Since the patients have a defect in their fat metabolism, the investigators expect to find
      that they have a reduced ability to burn fat, which is the major source of energy during low
      intensity exercise. It is therefore likely, that the CTD patients will benefit from
      adjustments in their daily diet, whenever they have to perform physically. By learning about
      the metabolism of different dietary substances, fat and sugar, these studies can help to
      improve the treatment in terms of dietary recommendations for CTD patients. This will have a
      direct impact on the daily life of the patients.
8 Patients with verified CTD have been included

        -  All patients have performed an incremental load exercise test to exhaustion on a cycle
           ergometer to determine maximal oxygen comsumption rate (VO2 max)

        -  One-hour exercise test: Measurement of the total fat and sugar oxidation rates during
           exercise using stable isotope tracers.

      Subjects arrive at the laboratory after 3-9 hours fasting. One IV-catheter is inserted in the
      cubital vein in one arm and another in a peripheral vein in the other hand. The stable
      isotope tracers will be given in the cubital vein as a constant infusion of solutions of:

        -  [U-13C]-palmitate (0.0026 mg x kg-1 x min-1, after a priming bolus of 0.085 mg x kg-1
           NaH13CO3)

        -  [1,1,2,3,3-2H5]-glycerol (0.0049 mg x kg-1 x min-1 )

        -  [6.6-2H2]-glucose (0.0728 mg x kg-1 x min-1 ) 5 days before the study, subjects must
           avoid eating food containing corn. Corn contains larger amounts of C13, which we use as
           a tracer, and can therefore disturb the measurements.

      For two hours the subjects rest while receiving the infusions until the tracers have
      distributed in the body and reached a steady state. After the rest, the subjects exercise on
      the cycle-ergometer until exhaustion or for a maximum of 1 hour at an intensity that
      corresponds to 60-70% of VO2max.

      Every other minute during exercise, the heart rate is recorded and the subject evaluates
      his/her degree of exertion (Rate of Perceived Exertion, RPE) on a Borg scale.

      Blood and breath samples:

      From 20 minutes before exercise until the end of exercise, blood samples are drawn through
      the IV-catheter in the hand vein (10-12 mL per sample) and samples of the expired breath are
      collected in a Douglas bag (Hans Rudolph inc.) every ten minutes. The breath is transferred
      into Vaccutainer-glas for analysis of 13CO2 -enrichment (10 mL). The plasma samples are
      anayzed for concentrations of hormones, metabolites, carnitine and acyl-carnitines.

      Muscle biopsy:

      On this day a muscle biopsy is taken from the vastus lateralis of the thigh to measure the
      intramuscular concentrations of carnitine and acylcarnitines.

        -  Wash-out period: For 4 days patients were admitted for telemetric cardiac monitoring
           while they pause their daily oral L-carnitine treatment.

        -  After the washout period, patients repeat the one-hour exercise test with the stable
           isotope tracers. Also the muscle biopsy for intramuscular carnitine and acyl-carnitine
           concentrations are repeated-

      TRACERS In this study we will use infusions of stable isotopes incorporated into metabolites
      as tracers of whole body metabolism. We will use small amounts of fat (palmitate and
      glycerol) and sugar (glucose) labelled with stable isotopes of carbon (13C) and hydrogen
      (2H). The palmitate and glycerol tracers (98 % enriched, Cambrigde Isotope Laboratories,
      Andover, MA, USA) will be dissolved in sterile water and infused through a bacterial filter
      into human serum albumin. The glucose tracer (99 % enriched, Cambrigde Isotope Laboratories,
      Andover, MA, USA) will be dissolved and injected into a solution of 0.9% saline (NaCl)
      through a bacterial filter as well.

      These tracers are naturally occurring in food (e.g. in corn) and in the human body. They are
      harmless and will be handled and given to the subjects under sterile conditions.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: The whole body palmitate and carbohydrate oxidation rate in CTD patients during exercise
time frame: With and without L-carnitine treatment
description: The whole body palmitate and carbohydrate oxidation will be assessed during 1h exercise test performed on a cycle-ergometer using stable isotope technique combined with indirect calorimetry.
measure: The maximal oxidative capacity (VO2max) as an indicator of exercise tolerance and performance in CTD patients
time frame: During a 15 min incremental intensity exercise test and during a 1h moderate intensity cycling test
arm group label: Break in L-carnitine treatment
arm group type: Experimental
description: Patients do not take their L-carnitine (Levocarnitine) treatment for 2-4 days until plasma carnitine and acylcarnitine have fallen. While patients abstain from taking the treatment, they are admitted for cardiac telemetry monitoring.
intervention type: Dietary Supplement
intervention name: Break in L-carnitine treatment
description: Levocarnitine oral tablet supplement at individual doses
arm group label: Break in L-carnitine treatment
other name: Levocarnitine
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Karen L Madsen, MD
role: Principal Investigator
affiliation: Neuromuscular Research Unit, Rigshospitalet
responsible party type: Sponsor-Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Karen Lindhardt Madsen
investigator title: MD