<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/NCT03838822</url>
  </required_header>
  <id_info>
    <org_study_id>Cofactor Calibration 1.0</org_study_id>
    <nct_id>NCT03838822</nct_id>
  </id_info>
  <brief_title>Kinetics of Metabolic Cofactors in NAFLD</brief_title>
  <acronym>NAFLDCOFCAL</acronym>
  <official_title>Kinetics of Metabolic Cofactors After Oral Supplementation in Healthy Subjects</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sahlgrenska University Hospital, Sweden</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Karolinska Institutet</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Chalmers University of Technology</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Sahlgrenska University Hospital, Sweden</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>
      There is a strong correlation between major adverse health consequences of obesity and&#xD;
      development of non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by abnormal&#xD;
      hepatic accumulation of triglycerides and other lipids. It has become a worldwide health&#xD;
      problem that accelerates cirrhosis, type 2 diabetes mellitus (T2DM), and especially premature&#xD;
      cardiovascular morbidity and mortality.&#xD;
&#xD;
      The plasma level of glutathione (GSH) is typically depleted in individuals with metabolism&#xD;
      related disorders. However, cellular GSH levels cannot be increased by supplementing GSH and&#xD;
      it must be synthesized within the liver either de novo or by salvation pathway. The level of&#xD;
      GSH is not enough to maintain and regulate the thiol redox status of the liver in subjects&#xD;
      with high hepatic steatosis at fasting stage due to the depletion of glycine. Glycine can be&#xD;
      synthesized via the interconversion of serine. It has been shown that the serine synthesis is&#xD;
      downregulated in patients with NAFLD and supplementation of serine has attenuated alcoholic&#xD;
      fatty liver by enhancing homocysteine metabolism in mice and rats. Depleted liver glutathione&#xD;
      is also restored by the administration of N-acetylcystein as in acetaminophen poising.&#xD;
      L-carnitine and nicotinamide that both stimulate the transfer of fatty acids from cytosol to&#xD;
      mitochondria have been identified as two additional cofactors that are depleted in patients&#xD;
      with NAFLD.&#xD;
&#xD;
      In this study, the kinetics in blood of pivotal metabolic cofactors, serine, L-carnitine,&#xD;
      N-acetylcystein and nicotinamide after single and simultaneous dietary supplementation, are&#xD;
      measured.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      In 10 healthy subjects with BMI &lt;30 kg/m2 the plasma concentrations of 4 natural compounds&#xD;
      (nicotinamide riboside, L-carnitine, L-serine and N-acetylcystein) are measured by&#xD;
      ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMSMS) after individual&#xD;
      and combined administration, on five consecutive days and at every hour during 9 hours after&#xD;
      administration. The study will start at 8:00 every morning and at each time point, blood&#xD;
      samples will be collected.&#xD;
&#xD;
      The taste and any potential sensing of the co-factors such as vertigo, nausea, bowel movement&#xD;
      will be recorded.&#xD;
&#xD;
      Each participant will receive one oral dose of Day 1: 1 g nicotinamide riboside; Day 2: 3 g&#xD;
      L-carnitine; Day 3: 5 g N-acetylcystein; Day 4: 20 g L-serine; Day 5: combined 1 g&#xD;
      nicotinamide riboside, 3 g L-carnitine, 5 g N-acetylcystein, and 20 g L-serine&#xD;
&#xD;
      In addition, untargeted metabolomics analysis as well as O-link proteomics analysis we be&#xD;
      performed to study effect of the administered cofactors.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 1, 2018</start_date>
  <completion_date type="Actual">December 1, 2018</completion_date>
  <primary_completion_date type="Actual">November 1, 2018</primary_completion_date>
  <phase>Early Phase 1</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>Changes of plasma levels of nicotinamide riboside measured by mass spectrometry</measure>
    <time_frame>Twenty-four hours after administration</time_frame>
    <description>Plasma levels of nicotinamide riboside by UPLCMSMS at 8 time points during 24h after administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes of plasma levels of L-carnitine measured by mass spectrometry</measure>
    <time_frame>Twenty-four hours after administration</time_frame>
    <description>Plasma levels of L-carnitine (nM) measured by UPLCMSMS at 8 time points during 24h after administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes of plasma levels of L-serine measured by mass spectrometry</measure>
    <time_frame>Twenty-four hours after administration</time_frame>
    <description>Plasma levels of L-serine (nM) measured by UPLCMSMS at 8 times points during 24h after administration</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes of plasma levels of N-acetylcystein measured by mass spectrometry</measure>
    <time_frame>Twenty-four hours after administration</time_frame>
    <description>Plasma levels of N-acetylcystein (nM) measured by UPLCMSMS at 8 times points during 24h after administration</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in the plasma level of metabolites associated with the supplementation of metabolic co-factors.</measure>
    <time_frame>Twenty-four hours after administration of combined cofactors</time_frame>
    <description>Untargeted metabolomic analysis using mass spectrometry. (Untargeted = not pre-specified in terms of outcome)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in the plasma level of inflammation-related proteins associated with the supplementation of metabolic co-factors.</measure>
    <time_frame>Twenty-four hours after administration of combined cofactors</time_frame>
    <description>Changes in the plasma level of inflammation related proteins associated with the supplementation of metabolic co-factors.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Intervention</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Oral administration of cofactors, 1g nicotinamide riboside, 3g L-carnitine, 20g serine and 5g N-acetylcystein, first as single compounds, then combined, on 5 days</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Cofactors</intervention_name>
    <description>Oral administration of 1g nicotinamide riboside, 3g L-carnitine, 20g serine and 5g N-acetylcystein, first as single compounds, then combined, on 5 days</description>
    <arm_group_label>Intervention</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Healthy without any medication, no smokers, no obesity&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        Any known disease, obesity&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Hanns-Ulrich Marschall, Prof</last_name>
    <role>Principal Investigator</role>
    <affiliation>Sahlgrenska University Hospital, Sweden</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hanns-Ulrich Marschall</name>
      <address>
        <city>Göteborg</city>
        <zip>411 31</zip>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sahlgrenska Academy</name>
      <address>
        <city>Göteborg</city>
        <country>Sweden</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Sweden</country>
  </location_countries>
  <verification_date>February 2019</verification_date>
  <study_first_submitted>February 4, 2019</study_first_submitted>
  <study_first_submitted_qc>February 11, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 12, 2019</study_first_posted>
  <last_update_submitted>February 12, 2019</last_update_submitted>
  <last_update_submitted_qc>February 12, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 15, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Sahlgrenska University Hospital, Sweden</investigator_affiliation>
    <investigator_full_name>Hanns-Ulrich Marschall</investigator_full_name>
    <investigator_title>Professor, University Hospital Consultant</investigator_title>
  </responsible_party>
  <keyword>nicotinamid riboside</keyword>
  <keyword>L-carnitine</keyword>
  <keyword>L-serine</keyword>
  <keyword>N-acetylcystein</keyword>
  <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/NCT03838822
org study id: Cofactor Calibration 1.0
nct id: NCT03838822
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
There is a strong correlation between major adverse health consequences of obesity and
      development of non-alcoholic fatty liver disease (NAFLD). NAFLD is characterized by abnormal
      hepatic accumulation of triglycerides and other lipids. It has become a worldwide health
      problem that accelerates cirrhosis, type 2 diabetes mellitus (T2DM), and especially premature
      cardiovascular morbidity and mortality.

      The plasma level of glutathione (GSH) is typically depleted in individuals with metabolism
      related disorders. However, cellular GSH levels cannot be increased by supplementing GSH and
      it must be synthesized within the liver either de novo or by salvation pathway. The level of
      GSH is not enough to maintain and regulate the thiol redox status of the liver in subjects
      with high hepatic steatosis at fasting stage due to the depletion of glycine. Glycine can be
      synthesized via the interconversion of serine. It has been shown that the serine synthesis is
      downregulated in patients with NAFLD and supplementation of serine has attenuated alcoholic
      fatty liver by enhancing homocysteine metabolism in mice and rats. Depleted liver glutathione
      is also restored by the administration of N-acetylcystein as in acetaminophen poising.
      L-carnitine and nicotinamide that both stimulate the transfer of fatty acids from cytosol to
      mitochondria have been identified as two additional cofactors that are depleted in patients
      with NAFLD.

      In this study, the kinetics in blood of pivotal metabolic cofactors, serine, L-carnitine,
      N-acetylcystein and nicotinamide after single and simultaneous dietary supplementation, are
      measured.
In 10 healthy subjects with BMI <30 kg/m2 the plasma concentrations of 4 natural compounds
      (nicotinamide riboside, L-carnitine, L-serine and N-acetylcystein) are measured by
      ultra-performance liquid chromatography-tandem mass spectrometry (UPLCMSMS) after individual
      and combined administration, on five consecutive days and at every hour during 9 hours after
      administration. The study will start at 8:00 every morning and at each time point, blood
      samples will be collected.

      The taste and any potential sensing of the co-factors such as vertigo, nausea, bowel movement
      will be recorded.

      Each participant will receive one oral dose of Day 1: 1 g nicotinamide riboside; Day 2: 3 g
      L-carnitine; Day 3: 5 g N-acetylcystein; Day 4: 20 g L-serine; Day 5: combined 1 g
      nicotinamide riboside, 3 g L-carnitine, 5 g N-acetylcystein, and 20 g L-serine

      In addition, untargeted metabolomics analysis as well as O-link proteomics analysis we be
      performed to study effect of the administered cofactors.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Changes of plasma levels of nicotinamide riboside measured by mass spectrometry
time frame: Twenty-four hours after administration
description: Plasma levels of nicotinamide riboside by UPLCMSMS at 8 time points during 24h after administration
measure: Changes of plasma levels of L-carnitine measured by mass spectrometry
time frame: Twenty-four hours after administration
description: Plasma levels of L-carnitine (nM) measured by UPLCMSMS at 8 time points during 24h after administration
measure: Changes of plasma levels of L-serine measured by mass spectrometry
time frame: Twenty-four hours after administration
description: Plasma levels of L-serine (nM) measured by UPLCMSMS at 8 times points during 24h after administration
measure: Changes of plasma levels of N-acetylcystein measured by mass spectrometry
time frame: Twenty-four hours after administration
description: Plasma levels of N-acetylcystein (nM) measured by UPLCMSMS at 8 times points during 24h after administration
measure: Changes in the plasma level of metabolites associated with the supplementation of metabolic co-factors.
time frame: Twenty-four hours after administration of combined cofactors
description: Untargeted metabolomic analysis using mass spectrometry. (Untargeted = not pre-specified in terms of outcome)
measure: Changes in the plasma level of inflammation-related proteins associated with the supplementation of metabolic co-factors.
time frame: Twenty-four hours after administration of combined cofactors
description: Changes in the plasma level of inflammation related proteins associated with the supplementation of metabolic co-factors.
arm group label: Intervention
arm group type: Experimental
description: Oral administration of cofactors, 1g nicotinamide riboside, 3g L-carnitine, 20g serine and 5g N-acetylcystein, first as single compounds, then combined, on 5 days
intervention type: Dietary Supplement
intervention name: Cofactors
description: Oral administration of 1g nicotinamide riboside, 3g L-carnitine, 20g serine and 5g N-acetylcystein, first as single compounds, then combined, on 5 days
arm group label: Intervention
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Hanns-Ulrich Marschall, Prof
role: Principal Investigator
affiliation: Sahlgrenska University Hospital, Sweden
facility: 
facility: 
country: Sweden
responsible party type: Principal Investigator
investigator affiliation: Sahlgrenska University Hospital, Sweden
investigator full name: Hanns-Ulrich Marschall
investigator title: Professor, University Hospital Consultant
sharing ipd: No