<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/NCT03230812</url>
  </required_header>
  <id_info>
    <org_study_id>NL62791.068.17</org_study_id>
    <nct_id>NCT03230812</nct_id>
  </id_info>
  <brief_title>Carnitine Supplementation in Type 2 Diabetic Patients</brief_title>
  <official_title>Carnitine Supplementation as a Therapy to Improve Insulin Sensitivity in Type 2 Diabetic Patients With Low Carnitine Status</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Maastricht University Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Maastricht University Medical Center</source>
  <oversight_info>
    <has_dmc>Yes</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>
      the results from animal studies and preliminary human studies show that carnitine&#xD;
      availability and acetylcarnitine concentrations are low in insulin resistant states such as&#xD;
      with type 2 diabetes mellitus. However, in humans, carnitine supplementation is sometimes&#xD;
      beneficial, but not in everyone. We hypothesize that this variability in response might be&#xD;
      due to differences between individuals in the amount of carnitine in the muscle i.e. subjects&#xD;
      with a low initial carnitine status will benefit more from supplementation. The state of the&#xD;
      art non-invasive magnetic resonance spectroscopy method allows us to identify patients muscle&#xD;
      acetylcarnitine status. Here we aim to test whether carnitine improves insulin sensitivity,&#xD;
      furthermore, whether acetylcarnitine concentration at baseline or other characteristics are&#xD;
      associated with the response (in insulin sensitivity) to carnitine supplementation.&#xD;
      Furthermore, we will examine the potentially positive effect of carnitine supplementation in&#xD;
      type 2 diabetes patients on intrahepatic lipid content, acetylcarnitine formation, blood&#xD;
      plasma metabolites, body composition, physical performance and quality of life&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Rationale: Type 2 diabetic patients are characterized by a decreased metabolic flexibility: a&#xD;
      reduced capability to switch from fat oxidation in the basal state to carbohydrate oxidation&#xD;
      in the insulin-stimulated state. This metabolic inflexibility is an early hallmark in the&#xD;
      development of diabetes. Recent evidence suggests that a low carnitine availability may limit&#xD;
      acetylcarnitine formation, thereby reducing metabolic flexibility. Thus, when substrate flux&#xD;
      in the muscle is high, acetyl-CoA concentrations increase, leading to inhibition of pyruvate&#xD;
      dehydrogenase (PDH) and thereby reducing glucose oxidation. The conversion of acetyl-CoA to&#xD;
      acetylcarnitine relieves this acetyl-CoA pressure on PDH. In humans, carnitine&#xD;
      supplementation is sometimes also beneficial, but not in everyone. Here we aim to test&#xD;
      whether carnitine improves insulin sensitivity, furthermore, whether acetylcarnitine&#xD;
      concentration at baseline or other characteristics are associated with the response (in&#xD;
      insulin sensitivity) to carnitine supplementation. Furthermore, we will examine the&#xD;
      potentially positive effect of carnitine supplementation in type 2 diabetes patients on&#xD;
      intrahepatic lipid content, acetylcarnitine formation, blood plasma metabolites, body&#xD;
      composition, physical performance and quality of life Objective: The primary objective is to&#xD;
      investigate whether carnitine improves insulin sensitivity, furthermore, whether&#xD;
      acetylcarnitine concentration at baseline or other characteristics are associated with the&#xD;
      response (in insulin sensitivity) to carnitine supplementation. Furthermore, we will examine&#xD;
      the potentially positive effect of carnitine supplementation in type 2 diabetes patients on&#xD;
      intrahepatic lipid content, acetylcarnitine formation, blood plasma metabolites, body&#xD;
      composition, physical performance and quality of life Study design: The current study is an&#xD;
      interventional design with one study arm. Subjects will not be blinded for the intervention&#xD;
      since all subjects will receive oral carnitine supplementation.&#xD;
&#xD;
      Study population: n=32, patient with type 2 diabetes (BMI 25-38, age 40-75 years) male and&#xD;
      female will be included. Only subjects with relatively well-controlled non-insulin depended&#xD;
      diabetes will be included.&#xD;
&#xD;
      Intervention (if applicable): Participants will be asked to take three chewing tablets of&#xD;
      L-carnitine (330mg), three times a day (breakfast, lunch and dinner), for 96 days.&#xD;
&#xD;
      Main study parameters/endpoints: The primary study endpoints are insulin sensitivity and&#xD;
      metabolic flexibility, measured by the hyperinsulinemic-euglycemic clamp. Secondary endpoints&#xD;
      are maximal acetylcarnitine concentrations after exercise, Intrahepatic lipid content, body&#xD;
      composition, metabolites in the blood before (i.e. glucose, free fatty acids, triglycerides,&#xD;
      cholesterol, insulin), functional markers of physical performance, cognition, quality of life&#xD;
      and quality of sleep.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 1, 2018</start_date>
  <completion_date type="Actual">November 11, 2019</completion_date>
  <primary_completion_date type="Actual">November 11, 2019</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>
    <intervention_model_description>One group with type 2 diabetic patients who will undergo oral L-carnitine supplementation for 96 days</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Insulin sensitivity</measure>
    <time_frame>2-step hyperinsulinemische-egulycemische clamp (5.5 hours)</time_frame>
    <description>Whole body insulin sensitivity measured as GIR in µmol/kg/min during the stable period of the insulin phase of the clamp.&#xD;
Hepatic insulin sensitivity measured as percent EGP supression in µmol/kg/min.&#xD;
Peripheral insulin sensitivity measured as Rd in µmol/kg/min.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Metabolic flexibility</measure>
    <time_frame>2-step hyperinsulinemische-egulycemische clamp (5.5 hours)</time_frame>
    <description>delta RER between basal and insulin stimulated state (both low (10mU) and high (40mU) insulin state</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Maximal acetylcarnitine concentrations after exercise</measure>
    <time_frame>45 minutes</time_frame>
    <description>Measured using 1H-MRS after 30 minutes of cycling at 70% Wmax</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Body composition (bod pod)</measure>
    <time_frame>30 minutes</time_frame>
    <description>determination fat mass and fat free mass</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Intrahepatic lipid content</measure>
    <time_frame>45 minutes</time_frame>
    <description>Measured using 1H-MRS</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>physical performance</measure>
    <time_frame>6 minutes</time_frame>
    <description>distance covered in 6 minutes by walking</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>physical performance</measure>
    <time_frame>5 minutes</time_frame>
    <description>10 sit-standing exercises</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of life</measure>
    <time_frame>15 minutes</time_frame>
    <description>32-item questionnaire about Quality of Life. Reporting happens via a score on the so called combined quality of life score scale. The survey ranges between 32-160 points, with a higher score indicating a better QoL</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quality of sleep</measure>
    <time_frame>15 minutes</time_frame>
    <description>The Pittsburgh Sleep Quality Index (PSQI) was used to estimate quality of sleep (QoS) over the previous month. Reporting happens via a score on the so quality of sleep score scale. The score ranges between 0-21, with a lower score indicating a better sleep quality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cognitive performance</measure>
    <time_frame>1 hour</time_frame>
    <description>CANTAB</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Maximal aerobic capacity</measure>
    <time_frame>20 minutes</time_frame>
    <description>(measured during a VO2max cycling test)</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Glucose Intolerance</condition>
  <arm_group>
    <arm_group_label>Experimental: carnitine intervention (in all participants)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>All subjects will undergo oral Carnitene (L-Carnitine or levocarnitine) supplementation for 96 days.The total dosage of L-carnitine per day will be 2970mg. Consumption of the chewing tablets will be divided over the day. Intake of these chewing tablets will be during breakfast (990mg), lunch (990mg) and during diner (990mg). Since the chewing tablets are only available in concentrations of 330mg, participants have to consume 3 chewing tablets per meal, a total of 9 chewing tablets each day.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Carnitene (L-Carnitine or Levocarnitine)</intervention_name>
    <description>All subjects will undergo oral Carnitene (L-Carnitine or levocarnitine) supplementation for 96 days.The total dosage of L-carnitine per day will be 2970mg. Consumption of the chewing tablets will be divided over the day. Intake of these chewing tablets will be during breakfast (990mg), lunch (990mg) and during diner (990mg). Since the chewing tablets are only available in concentrations of 330mg, participants have to consume 3 chewing tablets per meal, a total of 9 chewing tablets each day.</description>
    <arm_group_label>Experimental: carnitine intervention (in all participants)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Men and woman&#xD;
&#xD;
          -  Age: 40-75 years&#xD;
&#xD;
          -  Woman should be postmenopausal&#xD;
&#xD;
          -  BMI: 25-38 kg/m2&#xD;
&#xD;
          -  Stable dietary habits&#xD;
&#xD;
          -  No use of medication interfering with investigated study parameters (as determined by&#xD;
             responsible physician)&#xD;
&#xD;
          -  Use of oral glucose lowering medication (metformin only or in combination with&#xD;
             sulfonylurea agents)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Haemoglobin levels &lt; 7.8 mmol/L&#xD;
&#xD;
          -  Uncontrolled hypertension&#xD;
&#xD;
          -  Use of anticoagulants&#xD;
&#xD;
          -  Insulin dependent type 2 diabetic patients.&#xD;
&#xD;
          -  No signs of active liver or kidney malfunction.&#xD;
&#xD;
          -  Engagement in exercise &gt; 3 hours a week&#xD;
&#xD;
          -  Being vegetarian or vegan (because of altered whole body carnitine status)&#xD;
&#xD;
          -  Alcohol and/or drug abuse&#xD;
&#xD;
          -  Unstable body weight (weight gain or loss &gt; 5kg in the last 3 months)&#xD;
&#xD;
          -  Significant food allergies/intolerances (seriously hampering study meals)&#xD;
&#xD;
          -  Participation in another biomedical study within 1 month before the first study visit,&#xD;
             which would possibly hamper our study results&#xD;
&#xD;
          -  Medication use known to hamper subject's safety during the study procedures&#xD;
&#xD;
          -  Subjects with contra-indications for MRI&#xD;
&#xD;
          -  Subjects who intend to donate blood during the intervention or subjects who have&#xD;
             donated blood less than three months before the start of the study&#xD;
&#xD;
          -  Subjects who do not want to be informed about unexpected medical findings&#xD;
&#xD;
          -  No signs of active diabetes-related co-morbidities like active cardiovascular&#xD;
             diseases, active diabetic foot, polyneuropathy or retinopathy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>40 Years</minimum_age>
    <maximum_age>75 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Vera Schrauwen, Dr</last_name>
    <role>Principal Investigator</role>
    <affiliation>Maastricht University Medical Center</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Maastricht University</name>
      <address>
        <city>Maastricht</city>
        <state>Limburg</state>
        <zip>6229ER</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>December 2020</verification_date>
  <study_first_submitted>July 24, 2017</study_first_submitted>
  <study_first_submitted_qc>July 25, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">July 26, 2017</study_first_posted>
  <last_update_submitted>December 3, 2020</last_update_submitted>
  <last_update_submitted_qc>December 3, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 7, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Insulin sensitivity</keyword>
  <keyword>Metabolic flexibility</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Glucose Intolerance</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/NCT03230812
org study id: NL62791.068.17
nct id: NCT03230812
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
the results from animal studies and preliminary human studies show that carnitine
      availability and acetylcarnitine concentrations are low in insulin resistant states such as
      with type 2 diabetes mellitus. However, in humans, carnitine supplementation is sometimes
      beneficial, but not in everyone. We hypothesize that this variability in response might be
      due to differences between individuals in the amount of carnitine in the muscle i.e. subjects
      with a low initial carnitine status will benefit more from supplementation. The state of the
      art non-invasive magnetic resonance spectroscopy method allows us to identify patients muscle
      acetylcarnitine status. Here we aim to test whether carnitine improves insulin sensitivity,
      furthermore, whether acetylcarnitine concentration at baseline or other characteristics are
      associated with the response (in insulin sensitivity) to carnitine supplementation.
      Furthermore, we will examine the potentially positive effect of carnitine supplementation in
      type 2 diabetes patients on intrahepatic lipid content, acetylcarnitine formation, blood
      plasma metabolites, body composition, physical performance and quality of life
Rationale: Type 2 diabetic patients are characterized by a decreased metabolic flexibility: a
      reduced capability to switch from fat oxidation in the basal state to carbohydrate oxidation
      in the insulin-stimulated state. This metabolic inflexibility is an early hallmark in the
      development of diabetes. Recent evidence suggests that a low carnitine availability may limit
      acetylcarnitine formation, thereby reducing metabolic flexibility. Thus, when substrate flux
      in the muscle is high, acetyl-CoA concentrations increase, leading to inhibition of pyruvate
      dehydrogenase (PDH) and thereby reducing glucose oxidation. The conversion of acetyl-CoA to
      acetylcarnitine relieves this acetyl-CoA pressure on PDH. In humans, carnitine
      supplementation is sometimes also beneficial, but not in everyone. Here we aim to test
      whether carnitine improves insulin sensitivity, furthermore, whether acetylcarnitine
      concentration at baseline or other characteristics are associated with the response (in
      insulin sensitivity) to carnitine supplementation. Furthermore, we will examine the
      potentially positive effect of carnitine supplementation in type 2 diabetes patients on
      intrahepatic lipid content, acetylcarnitine formation, blood plasma metabolites, body
      composition, physical performance and quality of life Objective: The primary objective is to
      investigate whether carnitine improves insulin sensitivity, furthermore, whether
      acetylcarnitine concentration at baseline or other characteristics are associated with the
      response (in insulin sensitivity) to carnitine supplementation. Furthermore, we will examine
      the potentially positive effect of carnitine supplementation in type 2 diabetes patients on
      intrahepatic lipid content, acetylcarnitine formation, blood plasma metabolites, body
      composition, physical performance and quality of life Study design: The current study is an
      interventional design with one study arm. Subjects will not be blinded for the intervention
      since all subjects will receive oral carnitine supplementation.

      Study population: n=32, patient with type 2 diabetes (BMI 25-38, age 40-75 years) male and
      female will be included. Only subjects with relatively well-controlled non-insulin depended
      diabetes will be included.

      Intervention (if applicable): Participants will be asked to take three chewing tablets of
      L-carnitine (330mg), three times a day (breakfast, lunch and dinner), for 96 days.

      Main study parameters/endpoints: The primary study endpoints are insulin sensitivity and
      metabolic flexibility, measured by the hyperinsulinemic-euglycemic clamp. Secondary endpoints
      are maximal acetylcarnitine concentrations after exercise, Intrahepatic lipid content, body
      composition, metabolites in the blood before (i.e. glucose, free fatty acids, triglycerides,
      cholesterol, insulin), functional markers of physical performance, cognition, quality of life
      and quality of sleep.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: One group with type 2 diabetic patients who will undergo oral L-carnitine supplementation for 96 days
primary purpose: Prevention
masking: None (Open Label)
measure: Insulin sensitivity
time frame: 2-step hyperinsulinemische-egulycemische clamp (5.5 hours)
description: Whole body insulin sensitivity measured as GIR in µmol/kg/min during the stable period of the insulin phase of the clamp.
Hepatic insulin sensitivity measured as percent EGP supression in µmol/kg/min.
Peripheral insulin sensitivity measured as Rd in µmol/kg/min.
measure: Metabolic flexibility
time frame: 2-step hyperinsulinemische-egulycemische clamp (5.5 hours)
description: delta RER between basal and insulin stimulated state (both low (10mU) and high (40mU) insulin state
measure: Maximal acetylcarnitine concentrations after exercise
time frame: 45 minutes
description: Measured using 1H-MRS after 30 minutes of cycling at 70% Wmax
measure: Body composition (bod pod)
time frame: 30 minutes
description: determination fat mass and fat free mass
measure: Intrahepatic lipid content
time frame: 45 minutes
description: Measured using 1H-MRS
measure: physical performance
time frame: 6 minutes
description: distance covered in 6 minutes by walking
measure: physical performance
time frame: 5 minutes
description: 10 sit-standing exercises
measure: Quality of life
time frame: 15 minutes
description: 32-item questionnaire about Quality of Life. Reporting happens via a score on the so called combined quality of life score scale. The survey ranges between 32-160 points, with a higher score indicating a better QoL
measure: Quality of sleep
time frame: 15 minutes
description: The Pittsburgh Sleep Quality Index (PSQI) was used to estimate quality of sleep (QoS) over the previous month. Reporting happens via a score on the so quality of sleep score scale. The score ranges between 0-21, with a lower score indicating a better sleep quality
measure: Cognitive performance
time frame: 1 hour
description: CANTAB
measure: Maximal aerobic capacity
time frame: 20 minutes
description: (measured during a VO2max cycling test)
arm group label: Experimental: carnitine intervention (in all participants)
arm group type: Experimental
description: All subjects will undergo oral Carnitene (L-Carnitine or levocarnitine) supplementation for 96 days.The total dosage of L-carnitine per day will be 2970mg. Consumption of the chewing tablets will be divided over the day. Intake of these chewing tablets will be during breakfast (990mg), lunch (990mg) and during diner (990mg). Since the chewing tablets are only available in concentrations of 330mg, participants have to consume 3 chewing tablets per meal, a total of 9 chewing tablets each day.
intervention type: Drug
intervention name: Carnitene (L-Carnitine or Levocarnitine)
description: All subjects will undergo oral Carnitene (L-Carnitine or levocarnitine) supplementation for 96 days.The total dosage of L-carnitine per day will be 2970mg. Consumption of the chewing tablets will be divided over the day. Intake of these chewing tablets will be during breakfast (990mg), lunch (990mg) and during diner (990mg). Since the chewing tablets are only available in concentrations of 330mg, participants have to consume 3 chewing tablets per meal, a total of 9 chewing tablets each day.
arm group label: Experimental: carnitine intervention (in all participants)
criteria: 
gender: All
minimum age: 40 Years
maximum age: 75 Years
healthy volunteers: No
last name: Vera Schrauwen, Dr
role: Principal Investigator
affiliation: Maastricht University Medical Center
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Glucose Intolerance