<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/NCT03789175</url>
  </required_header>
  <id_info>
    <org_study_id>190034</org_study_id>
    <secondary_id>19-H-0034</secondary_id>
    <nct_id>NCT03789175</nct_id>
  </id_info>
  <brief_title>Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome</brief_title>
  <official_title>Exploratory Study of Nicotinamide Riboside on Mitochondrial Function in Li-Fraumeni Syndrome</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Heart, Lung, and Blood Institute (NHLBI)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      Nicotinamide riboside (NR) is a vitamin B3 dietary supplement. It may help improve muscle&#xD;
      function, that may in turn may improve a person s exercise capacity. Researchers want to&#xD;
      study how skeletal muscle responds to NR in an individual who has Li-Fraumeni Syndrome and&#xD;
      slow muscle energy recovery after exercise.&#xD;
&#xD;
      Objective:&#xD;
&#xD;
      To study how nicotinamide riboside affects skeletal muscle after exercise.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
      One person at least 18 years old with Li-Fraumeni syndrome and a certain gene mutation&#xD;
&#xD;
      Design:&#xD;
&#xD;
      The participant will be screened with a medical history, physical exam, and blood and urine&#xD;
      tests.&#xD;
&#xD;
      The participant may also have a heart test.&#xD;
&#xD;
      The participant will maintain their regular diet and supplements during the study.&#xD;
&#xD;
      The participant will take the study drug as 1-4 tablets twice a day for 12 weeks. The&#xD;
      participant may be contacted with reminders and questions about side effects.&#xD;
&#xD;
      The participant will have 4-5 visits over 18-30 weeks. At visits, the participant will repeat&#xD;
      screening tests. At some visits they will also have:&#xD;
&#xD;
        -  Ultrasound of the heart with a wand placed on the chest.&#xD;
&#xD;
        -  Test of oxygen used at rest and exercise, while wearing a face mask.&#xD;
&#xD;
        -  Exercise test on a treadmill or bicycle with electrodes on the skin.&#xD;
&#xD;
        -  Magnetic resonance spectroscopy. The participant will have no caffeine for 12 hours.&#xD;
           Then they will lie in a machine for about 2 hours. Sometimes they will lie still.&#xD;
           Sometimes they will be asked to move.&#xD;
&#xD;
      Health questionnaire&#xD;
&#xD;
      The participant may have a skin sample taken by needle.&#xD;
&#xD;
      The participant will be withdrawn from the study if they become pregnant.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      We have previously reported that inherited mutations of TP53, which causes the premature&#xD;
      cancer disorder Li-Fraumeni syndrome (LFS), can promote mitochondrial function both in&#xD;
      patients and mouse models. In the course of our follow up studies, we encountered a LFS&#xD;
      patient with a long-standing history of fatigue and muscle weakness of unclear etiology.&#xD;
      Notably, we observed in vivo evidence of markedly decreased mitochondrial function in her leg&#xD;
      skeletal muscle during exercise using noninvasive phosphorus-31 magnetic resonance&#xD;
      spectroscopy (31P-MRS), a technique that has previously been used to study patients with&#xD;
      primary mitochondrial disorders. The decrease in mitochondrial function was also confirmed by&#xD;
      the patients skin fibroblasts in vitro using standard biochemical measurements.&#xD;
&#xD;
      There is growing evidence that nicotinamide adenine dinucleotide (NAD+) homeostasis plays a&#xD;
      significant role in maintaining the mitochondria through various mechanisms and that it is&#xD;
      possible to improve mitochondrial function by dietary supplementation with the vitamin B3&#xD;
      analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. Remarkably,&#xD;
      we observed that culturing the LFS patients fibroblasts in medium containing NR rescued the&#xD;
      severe deficit in mitochondrial respiration. While continuing our investigations into the&#xD;
      molecular mechanism(s) underlying the mitochondrial dysfunction observed in this patient, the&#xD;
      in vitro rescue of the respiratory deficiency by NR presents a unique opportunity to&#xD;
      investigate whether it can also be observed in vivo using skeletal muscle 31P-MRS. We propose&#xD;
      to explore the effect of NR, currently available as a dietary supplement, on in vivo&#xD;
      mitochondrial function in this LFS patient.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">March 25, 2019</start_date>
  <completion_date type="Actual">November 1, 2019</completion_date>
  <primary_completion_date type="Actual">November 1, 2019</primary_completion_date>
  <phase>Phase 1/Phase 2</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in PCr Recovery Tc Measurement From Baseline to 12 Week NR Supplementation Using the 31P-MRS Skeletal Muscle Submaximal Exercise.</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>The effect of nicotinamide riboside (NR) supplementation on the phosphocreatine (PCr) recovery time constant (Tc) of skeletal muscle after exercise as a marker of mitochondrial oxidative phosphorylation capacity.&#xD;
The phosphocreatine level will be measured using 31P-magnetic resonance spectroscopy (MRS) during the following sequence of 3-minute rest, 2-minute exercise, and 6-minute recovery periods. The 31P spectra will be obtained during these periods and analyzed with the use of SAGE 7 (GE Healthcare) and IDL, version 6.4 (Exelis Visual Information Solutions), software. The single exponential recovery time constant (Tc) is calculated from the post-exercise recovery period data.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Change in Time of CPET Time as a Measure of Exercise Tolerance From Baseline to 12 Weeks of NR Supplementation.</measure>
    <time_frame>Baseline to 12 weeks</time_frame>
    <description>Measure change in time of cardiopulmonary exercise test (CPET) to determine exercise tolerance from baseline to 12 weeks of NR supplementation.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">1</enrollment>
  <condition>Cancer</condition>
  <condition>Skin Fibroblasts</condition>
  <condition>Muscle Weakness</condition>
  <arm_group>
    <arm_group_label>Nicotinamide riboside (NR) in Li-Fraumeni syndrome</arm_group_label>
    <arm_group_type>Other</arm_group_type>
    <description>Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Nicotinamide Riboside (NR)</intervention_name>
    <description>Niacin is a form of vitamin B3 and has been used to treat hypercholesterolemia for many years. There is growing evidence that nicotinamide adenine dinucleotide (NAD+ can maintain mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. We have observed that culturing the fibroblasts of a LFS patient with mitochondrial deficiency in medium containing NR rescues the defect in mitochondrial respiration.</description>
    <arm_group_label>Nicotinamide riboside (NR) in Li-Fraumeni syndrome</arm_group_label>
    <other_name>Niagen; Nicotinamide Riboside (NR)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
          -  At least 18-years of age and able to give informed consent&#xD;
&#xD;
          -  Have delayed phosphocreatine (PCr) recovery time constant &gt;45 sec by 31P-magnetic&#xD;
             resonance spectroscopy (MRS) testing and a history of fatigue symptoms&#xD;
&#xD;
          -  Ability to undergo study procedures, including scheduled visits, blood draws and&#xD;
             skeletal muscle exercise Nuclear Magnetic Resonance (NMR)&#xD;
&#xD;
          -  Have Li-Fraumeni syndrome and confirmed TP53 mutation by genetic testing&#xD;
&#xD;
          -  Committed to using reliable contraception which may include abstinence during study&#xD;
             participation&#xD;
&#xD;
          -  Female participants of child-bearing ability and potential willing to commit to&#xD;
             reliable contraception while participating in the study&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
          -  Current systemic treatment for cancer&#xD;
&#xD;
          -  Unable to perform required study visits or procedures&#xD;
&#xD;
          -  Magnetic resonance imaging (MRI) incompatible hardware&#xD;
&#xD;
          -  Pregnant or breastfeeding women&#xD;
&#xD;
          -  History of intolerance to NR precursor compounds, including niacin or nicotinamide&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>70 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Paul M Hwang, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Heart, Lung, and Blood Institute (NHLBI)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <link>
    <url>https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-H-0034.html</url>
    <description>NIH Clinical Center Detailed Web Page</description>
  </link>
  <verification_date>November 26, 2019</verification_date>
  <study_first_submitted>December 27, 2018</study_first_submitted>
  <study_first_submitted_qc>December 27, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 28, 2018</study_first_posted>
  <results_first_submitted>October 14, 2020</results_first_submitted>
  <results_first_submitted_qc>November 16, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">December 8, 2020</results_first_posted>
  <last_update_submitted>November 16, 2020</last_update_submitted>
  <last_update_submitted_qc>November 16, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 8, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Oxidative Phosphorylation Capacity</keyword>
  <keyword>Increased Oxidative Metabolism</keyword>
  <keyword>Regeneration of Phosphocreatine (PCr)</keyword>
  <keyword>Inherited Mutation of TP53 Tumor Suppressor Gene</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Li-Fraumeni Syndrome</mesh_term>
    <mesh_term>Muscle Weakness</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Niacinamide</mesh_term>
    <mesh_term>Niacin</mesh_term>
    <mesh_term>Nicotinic Acids</mesh_term>
  </intervention_browse>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>December 12, 2018</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/75/NCT03789175/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>This is a one-subject study so there are no recruitment or screening of other subjects.</recruitment_details>
      <group_list>
        <group group_id="P1">
          <title>Nicotinamide Riboside (NR) in Li-Fraumeni Syndrome</title>
          <description>Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Week 0 to Week 12 of NR</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Week 12 to Week 24 of NR</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1">Participant did not meet primary endpoint and completed study at week 24</participants>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Nicotinamide Riboside (NR) in Li-Fraumeni Syndrome</title>
          <description>Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="1"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="40" spread="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Change in PCr Recovery Tc Measurement From Baseline to 12 Week NR Supplementation Using the 31P-MRS Skeletal Muscle Submaximal Exercise.</title>
        <description>The effect of nicotinamide riboside (NR) supplementation on the phosphocreatine (PCr) recovery time constant (Tc) of skeletal muscle after exercise as a marker of mitochondrial oxidative phosphorylation capacity.&#xD;
The phosphocreatine level will be measured using 31P-magnetic resonance spectroscopy (MRS) during the following sequence of 3-minute rest, 2-minute exercise, and 6-minute recovery periods. The 31P spectra will be obtained during these periods and analyzed with the use of SAGE 7 (GE Healthcare) and IDL, version 6.4 (Exelis Visual Information Solutions), software. The single exponential recovery time constant (Tc) is calculated from the post-exercise recovery period data.</description>
        <time_frame>Baseline to 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Baseline Phosphocreatine (PCr) Recovery Tc Measurement</title>
            <description>All participants prior to initiation of nicotinamide riboside (NR).</description>
          </group>
          <group group_id="O2">
            <title>Nicotinamide Riboside (NR) in Li-Fraumeni Syndrome</title>
            <description>Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in PCr Recovery Tc Measurement From Baseline to 12 Week NR Supplementation Using the 31P-MRS Skeletal Muscle Submaximal Exercise.</title>
          <description>The effect of nicotinamide riboside (NR) supplementation on the phosphocreatine (PCr) recovery time constant (Tc) of skeletal muscle after exercise as a marker of mitochondrial oxidative phosphorylation capacity.&#xD;
The phosphocreatine level will be measured using 31P-magnetic resonance spectroscopy (MRS) during the following sequence of 3-minute rest, 2-minute exercise, and 6-minute recovery periods. The 31P spectra will be obtained during these periods and analyzed with the use of SAGE 7 (GE Healthcare) and IDL, version 6.4 (Exelis Visual Information Solutions), software. The single exponential recovery time constant (Tc) is calculated from the post-exercise recovery period data.</description>
          <units>Seconds</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="60"/>
                    <measurement group_id="O2" value="73"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Change in Time of CPET Time as a Measure of Exercise Tolerance From Baseline to 12 Weeks of NR Supplementation.</title>
        <description>Measure change in time of cardiopulmonary exercise test (CPET) to determine exercise tolerance from baseline to 12 weeks of NR supplementation.</description>
        <time_frame>Baseline to 12 weeks</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Baseline CPET Exercise Endurance Time</title>
            <description>All participants prior to initiation of nicotinamide riboside (NR).</description>
          </group>
          <group group_id="O2">
            <title>Nicotinamide Riboside (NR) in Li-Fraumeni Syndrome</title>
            <description>Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.</description>
          </group>
        </group_list>
        <measure>
          <title>Change in Time of CPET Time as a Measure of Exercise Tolerance From Baseline to 12 Weeks of NR Supplementation.</title>
          <description>Measure change in time of cardiopulmonary exercise test (CPET) to determine exercise tolerance from baseline to 12 weeks of NR supplementation.</description>
          <units>Minutes</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="1"/>
                <count group_id="O2" value="1"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12.1"/>
                    <measurement group_id="O2" value="11.68"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>24 weeks</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Nicotinamide Riboside (NR) in Li-Fraumeni Syndrome</title>
          <description>Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.</description>
        </group>
      </group_list>
      <serious_events>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, all-cause mortality</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_vocab>CTCAE (5.0)</default_vocab>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Metabolism and nutrition disorders</title>
            <event_list>
              <event>
                <sub_title>Muscle cramp</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Generalized muscle weakness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
              <event>
                <sub_title>Muscle Tightness</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="1"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>All Principal Investigators ARE employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <point_of_contact>
      <name_or_title>Dr. Paul Hwang</name_or_title>
      <organization>NHLBI, NIH</organization>
      <phone>3014353068</phone>
      <email>hwangp@mail.nih.gov</email>
    </point_of_contact>
  </clinical_results>
</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/NCT03789175
org study id: 190034
secondary id: 19-H-0034
nct id: NCT03789175
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Background:

      Nicotinamide riboside (NR) is a vitamin B3 dietary supplement. It may help improve muscle
      function, that may in turn may improve a person s exercise capacity. Researchers want to
      study how skeletal muscle responds to NR in an individual who has Li-Fraumeni Syndrome and
      slow muscle energy recovery after exercise.

      Objective:

      To study how nicotinamide riboside affects skeletal muscle after exercise.

      Eligibility:

      One person at least 18 years old with Li-Fraumeni syndrome and a certain gene mutation

      Design:

      The participant will be screened with a medical history, physical exam, and blood and urine
      tests.

      The participant may also have a heart test.

      The participant will maintain their regular diet and supplements during the study.

      The participant will take the study drug as 1-4 tablets twice a day for 12 weeks. The
      participant may be contacted with reminders and questions about side effects.

      The participant will have 4-5 visits over 18-30 weeks. At visits, the participant will repeat
      screening tests. At some visits they will also have:

        -  Ultrasound of the heart with a wand placed on the chest.

        -  Test of oxygen used at rest and exercise, while wearing a face mask.

        -  Exercise test on a treadmill or bicycle with electrodes on the skin.

        -  Magnetic resonance spectroscopy. The participant will have no caffeine for 12 hours.
           Then they will lie in a machine for about 2 hours. Sometimes they will lie still.
           Sometimes they will be asked to move.

      Health questionnaire

      The participant may have a skin sample taken by needle.

      The participant will be withdrawn from the study if they become pregnant.
We have previously reported that inherited mutations of TP53, which causes the premature
      cancer disorder Li-Fraumeni syndrome (LFS), can promote mitochondrial function both in
      patients and mouse models. In the course of our follow up studies, we encountered a LFS
      patient with a long-standing history of fatigue and muscle weakness of unclear etiology.
      Notably, we observed in vivo evidence of markedly decreased mitochondrial function in her leg
      skeletal muscle during exercise using noninvasive phosphorus-31 magnetic resonance
      spectroscopy (31P-MRS), a technique that has previously been used to study patients with
      primary mitochondrial disorders. The decrease in mitochondrial function was also confirmed by
      the patients skin fibroblasts in vitro using standard biochemical measurements.

      There is growing evidence that nicotinamide adenine dinucleotide (NAD+) homeostasis plays a
      significant role in maintaining the mitochondria through various mechanisms and that it is
      possible to improve mitochondrial function by dietary supplementation with the vitamin B3
      analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. Remarkably,
      we observed that culturing the LFS patients fibroblasts in medium containing NR rescued the
      severe deficit in mitochondrial respiration. While continuing our investigations into the
      molecular mechanism(s) underlying the mitochondrial dysfunction observed in this patient, the
      in vitro rescue of the respiratory deficiency by NR presents a unique opportunity to
      investigate whether it can also be observed in vivo using skeletal muscle 31P-MRS. We propose
      to explore the effect of NR, currently available as a dietary supplement, on in vivo
      mitochondrial function in this LFS patient.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in PCr Recovery Tc Measurement From Baseline to 12 Week NR Supplementation Using the 31P-MRS Skeletal Muscle Submaximal Exercise.
time frame: Baseline to 12 weeks
description: The effect of nicotinamide riboside (NR) supplementation on the phosphocreatine (PCr) recovery time constant (Tc) of skeletal muscle after exercise as a marker of mitochondrial oxidative phosphorylation capacity.
The phosphocreatine level will be measured using 31P-magnetic resonance spectroscopy (MRS) during the following sequence of 3-minute rest, 2-minute exercise, and 6-minute recovery periods. The 31P spectra will be obtained during these periods and analyzed with the use of SAGE 7 (GE Healthcare) and IDL, version 6.4 (Exelis Visual Information Solutions), software. The single exponential recovery time constant (Tc) is calculated from the post-exercise recovery period data.
measure: Change in Time of CPET Time as a Measure of Exercise Tolerance From Baseline to 12 Weeks of NR Supplementation.
time frame: Baseline to 12 weeks
description: Measure change in time of cardiopulmonary exercise test (CPET) to determine exercise tolerance from baseline to 12 weeks of NR supplementation.
arm group label: Nicotinamide riboside (NR) in Li-Fraumeni syndrome
arm group type: Other
description: Nicotinamide riboside (NR) to be initiated at week 0 at dose of 250 mg twice a day. At Week 1, NR will be titrated to 500 mg twice a day. At Week 6, NR will be titrated to 750 mg twice a day. At Week 7, NR will be titrated to 1000 mg twice a day or as tolerated until end of week 12. At week 12, if participant responds to primary endpoint, participant will washout of NR at week 18 then restart NR at week 24 until week 30. If there is not response to NR treatment at week 12, the participant may continue taking NR at a tolerated dose until week 24 and the primary endpoint will be re-measured. If participant has a positive response to NR treatment at week 24, then the participant will washout of NR until week 30, at which time the primary endpoint will be re-measured to ensure return to baseline. If there is no response to continued NR treatment at week 24, the study will be ended.
intervention type: Dietary Supplement
intervention name: Nicotinamide Riboside (NR)
description: Niacin is a form of vitamin B3 and has been used to treat hypercholesterolemia for many years. There is growing evidence that nicotinamide adenine dinucleotide (NAD+ can maintain mitochondria through various mechanisms and that it is possible to improve mitochondrial function by dietary supplementation with the vitamin B3 analogue nicotinamide riboside (NR), an intermediate in the NAD+ salvage pathway. We have observed that culturing the fibroblasts of a LFS patient with mitochondrial deficiency in medium containing NR rescues the defect in mitochondrial respiration.
arm group label: Nicotinamide riboside (NR) in Li-Fraumeni syndrome
other name: Niagen; Nicotinamide Riboside (NR)
criteria: 
gender: All
minimum age: 18 Years
maximum age: 70 Years
healthy volunteers: No
last name: Paul M Hwang, M.D.
role: Principal Investigator
affiliation: National Heart, Lung, and Blood Institute (NHLBI)
facility: 
country: United States
url: https://clinicalstudies.info.nih.gov/cgi/detail.cgi?B_2019-H-0034.html
description: NIH Clinical Center Detailed Web Page
responsible party type: Sponsor
mesh term: Li-Fraumeni Syndrome
mesh term: Muscle Weakness
mesh term: Niacinamide
mesh term: Niacin
mesh term: Nicotinic Acids
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 