<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/NCT04430517</url>
  </required_header>
  <id_info>
    <org_study_id>2020P001652</org_study_id>
    <secondary_id>1R01AG066670</secondary_id>
    <nct_id>NCT04430517</nct_id>
  </id_info>
  <brief_title>Effects of Nicotinamide Riboside on Bioenergetics and Oxidative Stress in Mild Cognitive Impairment/Alzheimer's Dementia</brief_title>
  <official_title>Effects of Orally Administered Nicotinamide Riboside on Bioenergetic Metabolism, Oxidative Stress and Cognition in Mild Cognitive Impairment and Mild Alzheimer's Dementia</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Mclean Hospital</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>National Institute on Aging (NIA)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>Mclean Hospital</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>Yes</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The primary aim of this study is to investigate the effects of exogenously administered&#xD;
      nicotinamide riboside (NR) on brain energy metabolism, oxidative stress, and cognitive&#xD;
      function in individuals with mild cognitive impairment (MCI) and mild Alzheimer's dementia&#xD;
      (AD).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Mitochondrial function is mediated, in part, by nicotinamide adenine dinucleotide (NAD).&#xD;
      Unfortunately, decreases in NAD+ levels are associated with normal aging, and also with&#xD;
      numerous diseases such as AD. Accumulating evidence suggests that NR can enhance&#xD;
      mitochondrial function and help slow or reverse these age-related abnormalities. Numerous&#xD;
      preclinical and clinical studies have been performed using NR and related compounds to boost&#xD;
      NAD+ level in human subjects with various diseases or animal models. However, no studies to&#xD;
      date have investigated in vivo metabolic and bioenergetic changes (target engagement)&#xD;
      associated with NR supplementation. In this project, we aim to investigate the&#xD;
      neurobiological mechanisms and clinical effects of NR in patients with MCI and mild AD using&#xD;
      in vivo novel neuroimaging techniques.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">March 2, 2022</start_date>
  <completion_date type="Anticipated">April 30, 2025</completion_date>
  <primary_completion_date type="Anticipated">April 30, 2025</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>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Changes in brain NAD+</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in brain NAD+ levels</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Changes in brain redox state</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in brain NAD+/NADH ratio</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in mitochondrial function</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in brain CK/ATPase activity</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in antioxidant glutathione (GSH) levels</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in brain GSH levels</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Changes in cognitive status</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores. The RBANS provides a total score from 40-160, with a higher score indicating a better outcome.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in functional status</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores. The ADCS-ADL provides a total score from 0-78, with a higher score indicating lower severity and a better outcome.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in mood</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in Patient Health Questionnaire (PHQ-9) scores. The PHQ-9 provides a total score from 0-27, with a higher score indicating more symptoms of depression.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in behavioral or psychiatric symptoms resulting from memory problem</measure>
    <time_frame>Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in The Neuropsychiatric Inventory Questionnaire (NPI-Q) responses. The NPI-Q is scored in 12 domains which assess the severity and distress of specific mood, behavioral, or psychiatric symptoms resulting from memory problems. Higher scores indicate greater severity or caregiver distress associated with each of the behavioral and psychiatric symptoms.</description>
  </other_outcome>
  <other_outcome>
    <measure>Changes in spirituality and religious beliefs</measure>
    <time_frame>Baseline and 12 weeks, pre- and post- 1000 mg NR daily</time_frame>
    <description>Changes in responses to series of brief psychometrically valid and reliable measures of spirituality/religion administered in order to evaluate spiritual/religious predictors of adjustment to AD as indexed by emotional, behavioral, neurocognitive, and neural assessments.</description>
  </other_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">50</enrollment>
  <condition>Mild Cognitive Impairment</condition>
  <condition>Mild Alzheimer Disease</condition>
  <arm_group>
    <arm_group_label>Mild Cognitive Impairment and Alzheimer's Dementia</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will take 4 pills every day, each containing 250 mg NR (NIAGEN® by Chromadex; www.chromadex.com), via the oral route, for 12 weeks.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nicotinamide riboside</intervention_name>
    <description>Participants will take 4 pills every day, each containing 250 mg NR (NIAGEN® by Chromadex; www.chromadex.com), via the oral route, for 12 weeks.</description>
    <arm_group_label>Mild Cognitive Impairment and Alzheimer's Dementia</arm_group_label>
    <other_name>Chromadex NIAGEN</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability of the participant and/or his/her legally authorized representative to&#xD;
             understand the purpose and risks of the study, to provide signed and dated informed&#xD;
             consent, and to authorize the use of confidential health information.&#xD;
&#xD;
          -  Ability to speak and read fluently in English&#xD;
&#xD;
          -  55-89 years old (inclusive)&#xD;
&#xD;
          -  Normal or corrected to normal hearing and vision&#xD;
&#xD;
          -  Meet clinical diagnostic criteria for MCI or Mild AD, according to the following&#xD;
             criteria:&#xD;
&#xD;
               1. CDR Global Score of 0.5 (MCI) or 1.0 (mild AD)&#xD;
&#xD;
               2. 2018 NIA-AA guidelines for MCI/mild AD&#xD;
&#xD;
          -  Study partner available for the duration of trial participation&#xD;
&#xD;
          -  At least one copy of the APOE ε4 allele or AD+ including Amyloid positive PET scan,&#xD;
             Tau positive PET Scan (MK6240 et al.), or CSF AD biomarkers [i.e., amyloid-beta beta&#xD;
             (Aβ42) total (T)-tau, and phosphorylated (P)-tau]&#xD;
&#xD;
          -  An aggregate risk score &gt; 4 according to the risk analysis method developed by Sabbagh&#xD;
             et al. (2017)&#xD;
&#xD;
          -  For individuals who are taking niacin (or a vitamin supplement with niacin) of &gt;200mg,&#xD;
             the completion of a two-week wash-out period&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Current serious or unstable medical or neurological condition that could affect&#xD;
             cognitive functioning, as determined by study clinician&#xD;
&#xD;
          -  Clinically unstable mood or anxiety disorder within 6 months prior to screening, as&#xD;
             determined by study clinician&#xD;
&#xD;
          -  Lifetime history of psychotic disorder (i.e. Schizophrenia, Schizoaffective Disorder),&#xD;
             as determined by study clinician&#xD;
&#xD;
          -  Diagnosis of a mitochondrial disorder&#xD;
&#xD;
          -  Any MRI safety contraindications&#xD;
&#xD;
          -  History of drug hypersensitivity or intolerance to NR&#xD;
&#xD;
          -  Transient ischemic attack or stroke within 1 year prior to screening&#xD;
&#xD;
          -  History of alcohol or substance abuse within prior year, as determined by study&#xD;
             clinician and urine toxicology screen&#xD;
&#xD;
          -  History of head injury rated as moderate or worse, per DSM-5 criteria&#xD;
&#xD;
          -  History of seizure within prior 10 years&#xD;
&#xD;
          -  Current use of medication with known adverse effects on cognition (benzodiazepines,&#xD;
             barbiturates, opiate analgesics, first generation antipsychotic medication, centrally&#xD;
             acting anticholinergics, sedating antihistamines, tricyclic anti-depressants)&#xD;
&#xD;
          -  Change in dose of any psychiatric medications within 4 weeks of screening visit&#xD;
&#xD;
          -  Prior use of L-DOPA, any anti-Parkinsonian medication, or prior treatment with&#xD;
             anti-amyloid immunotherapy&#xD;
&#xD;
          -  Current use of putative mitochondrial enhancers and antioxidants (e.g carnitine,&#xD;
             creatine Co-Q10, N-acetyl cysteine [NAC], pramipexole)&#xD;
&#xD;
          -  Initiation of treatment or change in dosing of acetylcholinesterase inhibitors&#xD;
             (AChEIs) and memantine within 4 weeks of baseline visit&#xD;
&#xD;
          -  Prior use of prescription narcotics 4 weeks before baseline visit&#xD;
&#xD;
          -  Female subjects who are pregnant or breastfeeding&#xD;
&#xD;
          -  The use of current use of niacin (or a vitamin supplement with niacin) &gt;200mg within&#xD;
             the last two weeks prior to study visit.&#xD;
&#xD;
          -  Current or lifetime history of cancer.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>55 Years</minimum_age>
    <maximum_age>89 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Fei Du, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mclean Hospital</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Brent Forester, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Mclean Hospital</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Fei Du, PhD</last_name>
    <phone>6178552710</phone>
    <email>fdu@mclean.harvard.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>McLean Hospital</name>
      <address>
        <city>Belmont</city>
        <state>Massachusetts</state>
        <zip>02478</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Fei Du, PhD</last_name>
      <phone>617-855-2710</phone>
      <email>fdu@mclean.harvard.edu</email>
    </contact>
    <contact_backup>
      <last_name>Brent Forester, MD, MSc</last_name>
      <phone>(617) 855-3622</phone>
      <email>bforester@partners.org</email>
    </contact_backup>
    <investigator>
      <last_name>Fei Du, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Brent Forester, MD, MSc</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>May 29, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>April 3, 2023</last_update_submitted>
  <last_update_submitted_qc>April 3, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 4, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Mclean Hospital</investigator_affiliation>
    <investigator_full_name>Fei Du</investigator_full_name>
    <investigator_title>Director, Laboratory for High-Field Imaging and Translational Neuroscience</investigator_title>
  </responsible_party>
  <keyword>Mild Cognitive Impairment</keyword>
  <keyword>Bioenergetics</keyword>
  <keyword>Mild Alzheimer's Dementia</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Alzheimer Disease</mesh_term>
    <mesh_term>Dementia</mesh_term>
    <mesh_term>Cognitive Dysfunction</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>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The proposed research will include data and biosamples from 50 subjects who will receive open-label treatment with nicotinamide riboside (NR) throughout the duration of the 12-week study. At the time of publication of the primary results or within 9 months of database lock, whichever comes first, we will create deidentified datasets, which could be available for research purposes to qualified individuals within the scientific community.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_time_frame>At the time of publication of the primary results or within 9 months of database lock, whichever comes first, we will create deidentified datasets, which could be available for research purposes to qualified individuals within the scientific community.</ipd_time_frame>
    <ipd_access_criteria>Data are available to users only under a data-sharing agreement. All users will provide to PIs a proposal of hypotheses, variables needed to test these hypotheses, and plans for dissemination of findings. All users will indicate in a signed document: (1) a commitment to using the data only for research purposes and not to identify any participant, clinician, or plan; (2) a plan for securing the data using appropriate technology/data use protocols; (3) an agreement to either destroy or return the data once analyses are completed or by a specific negotiated date; (4) appropriate IRB approval; (5) a commitment that the information provided to users will not be used for commercial purposes, will not be redistributed to third parties, or shared with any others not on the research team; (6) adequate funding/resources to analyze the data and publish results. All findings generated will be described via peer-reviewed articles in scientific journals made available via PubMed Central.</ipd_access_criteria>
  </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/NCT04430517
org study id: 2020P001652
secondary id: 1R01AG066670
nct id: NCT04430517
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
is us export: Yes
The primary aim of this study is to investigate the effects of exogenously administered
      nicotinamide riboside (NR) on brain energy metabolism, oxidative stress, and cognitive
      function in individuals with mild cognitive impairment (MCI) and mild Alzheimer's dementia
      (AD).
Mitochondrial function is mediated, in part, by nicotinamide adenine dinucleotide (NAD).
      Unfortunately, decreases in NAD+ levels are associated with normal aging, and also with
      numerous diseases such as AD. Accumulating evidence suggests that NR can enhance
      mitochondrial function and help slow or reverse these age-related abnormalities. Numerous
      preclinical and clinical studies have been performed using NR and related compounds to boost
      NAD+ level in human subjects with various diseases or animal models. However, no studies to
      date have investigated in vivo metabolic and bioenergetic changes (target engagement)
      associated with NR supplementation. In this project, we aim to investigate the
      neurobiological mechanisms and clinical effects of NR in patients with MCI and mild AD using
      in vivo novel neuroimaging techniques.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Changes in brain NAD+
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in brain NAD+ levels
measure: Changes in brain redox state
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in brain NAD+/NADH ratio
measure: Changes in mitochondrial function
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in brain CK/ATPase activity
measure: Changes in antioxidant glutathione (GSH) levels
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in brain GSH levels
measure: Changes in cognitive status
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in Repeatable Battery for the Assessment of Neuropsychological Status (RBANS) scores. The RBANS provides a total score from 40-160, with a higher score indicating a better outcome.
measure: Changes in functional status
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in Alzheimer's Disease Cooperative Study-Activities of Daily Living (ADCS-ADL) scores. The ADCS-ADL provides a total score from 0-78, with a higher score indicating lower severity and a better outcome.
measure: Changes in mood
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in Patient Health Questionnaire (PHQ-9) scores. The PHQ-9 provides a total score from 0-27, with a higher score indicating more symptoms of depression.
measure: Changes in behavioral or psychiatric symptoms resulting from memory problem
time frame: Baseline, 6 and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in The Neuropsychiatric Inventory Questionnaire (NPI-Q) responses. The NPI-Q is scored in 12 domains which assess the severity and distress of specific mood, behavioral, or psychiatric symptoms resulting from memory problems. Higher scores indicate greater severity or caregiver distress associated with each of the behavioral and psychiatric symptoms.
measure: Changes in spirituality and religious beliefs
time frame: Baseline and 12 weeks, pre- and post- 1000 mg NR daily
description: Changes in responses to series of brief psychometrically valid and reliable measures of spirituality/religion administered in order to evaluate spiritual/religious predictors of adjustment to AD as indexed by emotional, behavioral, neurocognitive, and neural assessments.
arm group label: Mild Cognitive Impairment and Alzheimer's Dementia
arm group type: Experimental
description: Participants will take 4 pills every day, each containing 250 mg NR (NIAGEN® by Chromadex; www.chromadex.com), via the oral route, for 12 weeks.
intervention type: Drug
intervention name: Nicotinamide riboside
description: Participants will take 4 pills every day, each containing 250 mg NR (NIAGEN® by Chromadex; www.chromadex.com), via the oral route, for 12 weeks.
arm group label: Mild Cognitive Impairment and Alzheimer's Dementia
other name: Chromadex NIAGEN
criteria: 
gender: All
minimum age: 55 Years
maximum age: 89 Years
healthy volunteers: No
last name: Fei Du, PhD
role: Principal Investigator
affiliation: Mclean Hospital
last name: Brent Forester, MD, MSc
role: Principal Investigator
affiliation: Mclean Hospital
last name: Fei Du, PhD
phone: 6178552710
email: fdu@mclean.harvard.edu
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Mclean Hospital
investigator full name: Fei Du
investigator title: Director, Laboratory for High-Field Imaging and Translational Neuroscience
mesh term: Alzheimer Disease
mesh term: Dementia
mesh term: Cognitive Dysfunction
mesh term: Niacinamide
mesh term: Niacin
mesh term: Nicotinic Acids
sharing ipd: Yes
ipd description: The proposed research will include data and biosamples from 50 subjects who will receive open-label treatment with nicotinamide riboside (NR) throughout the duration of the 12-week study. At the time of publication of the primary results or within 9 months of database lock, whichever comes first, we will create deidentified datasets, which could be available for research purposes to qualified individuals within the scientific community.
ipd info type: Study Protocol
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd time frame: At the time of publication of the primary results or within 9 months of database lock, whichever comes first, we will create deidentified datasets, which could be available for research purposes to qualified individuals within the scientific community.
ipd access criteria: Data are available to users only under a data-sharing agreement. All users will provide to PIs a proposal of hypotheses, variables needed to test these hypotheses, and plans for dissemination of findings. All users will indicate in a signed document: (1) a commitment to using the data only for research purposes and not to identify any participant, clinician, or plan; (2) a plan for securing the data using appropriate technology/data use protocols; (3) an agreement to either destroy or return the data once analyses are completed or by a specific negotiated date; (4) appropriate IRB approval; (5) a commitment that the information provided to users will not be used for commercial purposes, will not be redistributed to third parties, or shared with any others not on the research team; (6) adequate funding/resources to analyze the data and publish results. All findings generated will be described via peer-reviewed articles in scientific journals made available via PubMed Central.