<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/NCT03821623</url>
  </required_header>
  <id_info>
    <org_study_id>18-0644</org_study_id>
    <nct_id>NCT03821623</nct_id>
  </id_info>
  <brief_title>Nicotinamide Riboside for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Middle-aged and Older Adults</brief_title>
  <official_title>Nicotinamide Riboside Supplementation for Treating Elevated Systolic Blood Pressure and Arterial Stiffness in Middle-aged and Older Adults</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Douglas Seals</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Colorado, Boulder</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>
  </oversight_info>
  <brief_summary>
    <textblock>
      Aging is the primary risk factor for cardiovascular diseases (CVD), the number one cause of&#xD;
      death in developed societies. Systolic blood pressure (SBP) increase with age and is a key&#xD;
      intermediary factor linking aging to increased CVD risk. The primary mechanisms underlying&#xD;
      the age-associated increase in SBP is stiffening of the large elastic arteries, which is&#xD;
      mediated by increases in oxidative stress, inflammation, and vascular smooth muscle tone.&#xD;
      Regular caloric restriction is effective at lowering SBP in middle-aged and older adults;&#xD;
      however, adherence to caloric restriction is poor and may be detrimental to normal weight&#xD;
      older adults due to reduced skeletal muscle mass and bone mineral density. Therefore,&#xD;
      identification of more practical alternative interventions that mimic the beneficial effects&#xD;
      of caloric restriction, with stronger adherence and less risk of adverse consequences, is of&#xD;
      significant biomedical importance.&#xD;
&#xD;
      Nicotinamide riboside is a naturally occurring precursor of nicotinamide adenine dinucleotide&#xD;
      (NAD+), a critical mediator of the beneficial effects of caloric restriction, and therefore a&#xD;
      novel caloric restriction mimetic compound. We recently completed the first pilot study of&#xD;
      nicotinamide riboside supplementation in healthy middle-aged and older adults and&#xD;
      demonstrated that 6 weeks of supplementation decreased systolic blood pressure (SBP) by 8&#xD;
      mmHg in individuals with baseline SBP of 120-139 mmHg (elevated SBP/stage 1 hypertension)&#xD;
      compared with placebo, and lowered arterial stiffness, a strong independent predictor of CVD&#xD;
      and related morbidity and mortality.&#xD;
&#xD;
      As a next translational step, we will conduct a randomized, placebo-controlled, double-blind&#xD;
      clinical trial to further assess the safety and efficacy of oral nicotinamide riboside (3&#xD;
      months vs placebo) for decreasing SBP and arterial stiffness in middle-aged and older men and&#xD;
      women with SBP between 120 and 139 mmHg at baseline.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Study Overview: This is a randomized, double-blind, placebo-controlled, parallel design,&#xD;
      single site phase IIa clinical trial assessing the efficacy of nicotinamide riboside&#xD;
      supplementation to lower systolic blood pressure (SBP) and aortic stiffness in middle-aged to&#xD;
      older (MA/O) adults (50-79 years) with elevated to stage-1 systolic hypertension (SBP:&#xD;
      120-139 mmHg). Nicotinamide riboside is an endogenously occurring precursor of NAD+ and a&#xD;
      novel caloric restriction mimetic in humans that is now commercially available as a dietary&#xD;
      ingredient/supplement. We have recently demonstrated that chronic supplementation with&#xD;
      nicotinamide riboside lowers SBP and carotid-femoral pulse wave velocity (CFPWV;&#xD;
      gold-standard measure of aortic stiffness and independent risk factor for cardiovascular&#xD;
      diseases) in a small pilot study of healthy MA/O adults; the greatest reductions in SBP were&#xD;
      observed in a subgroup with baseline SBP in the elevated/stage-1 hypertension range. As a&#xD;
      next translational step, the present study proposes to assess the efficacy of 3 months of&#xD;
      nicotinamide riboside supplementation for decreasing SBP (primary outcome) and aortic&#xD;
      stiffness (secondary outcome) in a larger cohort of MA/O men and women with SBP in the&#xD;
      elevated/stage-1 hypertension range. As secondary aims, we will also assess safety and&#xD;
      tolerability of long-term nicotinamide riboside supplementation, and the effects of&#xD;
      nicotinamide riboside supplementation vs. placebo on NAD+ metabolites and circulating&#xD;
      biomarkers of vasoconstriction, oxidative stress and inflammation.&#xD;
&#xD;
      Subject Enrollment and Screening: Potential participants will be made aware of the proposed&#xD;
      study through described recruitment efforts (see Recruitment and Retention section).&#xD;
      Interested participants will contact a staff research assistant via phone or email (contact&#xD;
      information supplied with recruitment materials) and will complete a general screening form&#xD;
      online through the Research Electronic Data Capture (REDCap) system to determine eligibility.&#xD;
      REDCap is a secure web-based application designed to support data capture for research&#xD;
      studies.&#xD;
&#xD;
      After hearing a thorough study description and having all questions answered by the staff&#xD;
      research assistant, those eligible and interested in participating in the study will provide&#xD;
      written and verbal informed consent, and undergo in-person screening at the CU Boulder&#xD;
      Clinical Translational Research Center (CTRC). Informed consent will only be obtained by&#xD;
      members of the research team who have been observed and approved by the CTRC Research Subject&#xD;
      Advocate (see Protection of Human Subjects). We plan to consent 148 subjects in order to meet&#xD;
      our enrollment targets (to account for an ~25% rate of exclusion base on in-person&#xD;
      screening).&#xD;
&#xD;
      In-person screening will include: review of medical history; physical exam; resting heart&#xD;
      rate; resting blood pressure; blood draw for metabolic profile, lipid profile, complete blood&#xD;
      count, and thyroid stimulating hormone; measurement of ankle-brachial index; and a 12-lead&#xD;
      ECG at rest and during graded exercise testing (see the Eligibility Criteria section for&#xD;
      detailed inclusion/exclusion criteria).&#xD;
&#xD;
      Resting blood pressure will be measured on a second occasion within one week of the initial&#xD;
      screening to establish baseline blood pressure status; SBP measured on the two separate days&#xD;
      will be averaged and must be in the elevated to stage-1 hypertension range (120-139 mmHg) for&#xD;
      enrollment into the study.&#xD;
&#xD;
      Participant Randomization and Subject/Investigator Blinding: After completing screening,&#xD;
      eligible subjects will be randomized to either the nicotinamide riboside or placebo group. A&#xD;
      randomized block design will be used to balance groups for sex, age (mid-life: 50-64 years&#xD;
      vs. older: 65-79 years) and hypertension status (elevated vs. stage-1 systolic hypertension).&#xD;
      Randomization will be carried out by an unblinded staff research assistant who is not&#xD;
      involved in data collection or analysis. Subjects will be categorized based on the block&#xD;
      randomization scheme and then a random number generator will be used to assign subjects to&#xD;
      either nicotinamide riboside or placebo treatment. Researchers involved in collection of&#xD;
      outcome data will be blinded to the assigned intervention. Subjects will be blinded to their&#xD;
      assigned intervention and will receive capsules in coded blister packs; nicotinamide riboside&#xD;
      and placebo capsules will appear identical. CTRC clinical staff involved with subject&#xD;
      check-in visits and/or data collection will also be blinded (in the case of a serious adverse&#xD;
      event, blinding of the CTRC staff will be broken, as necessary to ensure appropriate medical&#xD;
      treatment).&#xD;
&#xD;
      Assessment of Study Outcomes: All subjects will undergo baseline testing for all primary,&#xD;
      secondary, and other outcome measures. All measurements will be made after a 12 hour fast&#xD;
      from food and caffeine (water allowed) and 24 hours after abstaining from alcohol and&#xD;
      exercise. All tests will take place in the CU Boulder CTRC.&#xD;
&#xD;
      The protocol for baseline testing is as follows:&#xD;
&#xD;
        -  Urine sample collection;&#xD;
&#xD;
        -  Assessment of casual SBP;&#xD;
&#xD;
        -  Placement of IV in an antecubital vein followed by 30 minutes of rest in a supine&#xD;
           position; - Collection of blood samples by a trained CTRC provider;&#xD;
&#xD;
        -  Assessment of aortic stiffness by CFPWV.&#xD;
&#xD;
      Following completion of outcome measure testing, the below non-outcome measures will be made&#xD;
      in order to ensure that participant characteristics known to affect cardiovascular function&#xD;
      are unaltered during the intervention:&#xD;
&#xD;
        -  3-day diet records to ensure that daily fluid and caloric intake remain stable;&#xD;
&#xD;
        -  The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire will&#xD;
           be completed and physical activity will be assessed by accelerometers (ActiGraph, 3-day&#xD;
           recordings) to document stability of physical activity levels;&#xD;
&#xD;
        -  Maximal oxygen consumption using indirect calorimetry during incremental treadmill&#xD;
           exercise (Balke protocol) will be measured to document unchanged aerobic fitness; and&#xD;
&#xD;
        -  Body composition will be assessed by dual energy x-ray absorptiometry (DEXA) and&#xD;
           anthropometry to confirm unaltered body composition; body mass will also be determined&#xD;
           during safety and check in visits with CTRC nursing staff.&#xD;
&#xD;
      Following all CTRC testing procedures, subjects will be outfitted with an ambulatory blood&#xD;
      pressure monitor pre-programmed to automatically measure blood pressure every 20 minutes. A&#xD;
      study team member will provide the subject with written and verbal instructions on how to&#xD;
      operate the monitor. Subjects will wear the monitor for 24 hours before returning it to the&#xD;
      investigators. Ambulatory blood pressure data will be evaluated for completeness immediately&#xD;
      upon return of the monitor; if an inadequate number of blood pressure measurements (&lt;67% of&#xD;
      expected) were made to properly characterize 24-hour SBP the subject will be re-outfitted&#xD;
      with the ambulatory monitor, be re-instructed on its use, and wear it for a second 24-hour&#xD;
      period.&#xD;
&#xD;
      The Research Strategy and Outcome Measures sections provide a more detailed description of&#xD;
      these procedures. Similar protocols and procedures are well established in the Seals&#xD;
      laboratory and the CU Boulder CTRC.&#xD;
&#xD;
      Delivery of the Intervention: After completing baseline testing, subjects will begin their&#xD;
      assigned intervention (nicotinamide riboside or placebo). Subjects will be instructed to take&#xD;
      2 x 250 mg capsules in the morning and 2 x 250 mg capsules in the evening (4 capsules/day).&#xD;
      This will result in a dosing of 500 mg nicotinamide riboside 2x/day in the nicotinamide&#xD;
      riboside group (1000 mg/day total).&#xD;
&#xD;
      Subjects will return to the CU Boulder CTRC once every two weeks for check-in and to receive&#xD;
      capsules. Capsules will be prepared by the manufacturer in blister packs to promote adherence&#xD;
      and will be stored and dispensed by the CTRC pharmacist (unblinded) and distributed by a CTRC&#xD;
      nurse (blinded). Subjects will return their blister packs at each check-in visit and after&#xD;
      follow-up testing to assess adherence to the intervention. During each visit to the CTRC,&#xD;
      subjects will be monitored for treatment-emergent adverse events by blinded CTRC clinical&#xD;
      staff.&#xD;
&#xD;
      Post-Testing: After completing 3 months of treatment with either nicotinamide riboside or&#xD;
      placebo, subjects will return to the CU Boulder CTRC for reassessment of all outcome&#xD;
      measures, including: casual SBP, 24-h ambulatory SBP, CFPWV, venous blood draw, and urine&#xD;
      sample. Non-outcome control measures (3-day diet record, CHAMPS survey, activity monitor,&#xD;
      maximal oxygen consumption test, body composition) will also be reassessed. These measures&#xD;
      will be made under the same experimental conditions, in the same order, and with the same&#xD;
      techniques as baseline testing.&#xD;
&#xD;
      Intervention Duration and Study Sample Size: The expected duration for a participant to&#xD;
      complete the entire protocol from screening to follow-up testing is 18 weeks. Based on our&#xD;
      power analysis, we need to complete the entire protocol on a total of 94 participants&#xD;
      (47/group) to detect a significant difference between treatment conditions in our primary&#xD;
      outcome measure (SBP). We intend to enroll 118 subjects (59/group) to account for an ~20%&#xD;
      dropout rate. Based on this, we will enroll 2-3 subjects per month, which will allow for&#xD;
      completion of data collection by month 55 of this award; this rate of testing is achievable&#xD;
      based on previous pharmacological interventions carried out in the Seals laboratory and the&#xD;
      availability of the CTRC facilities and staff.&#xD;
&#xD;
      Data Collection and Analysis (including blinding): Collection of primary and secondary&#xD;
      outcome measures will be performed by postdoctoral fellow, Dr. Craighead, with the assistance&#xD;
      of members of the laboratory. IV placement and blood draws will be performed by experienced&#xD;
      CTRC clinical staff. Data analysis will be performed by Dr. Craighead. Having a single&#xD;
      investigator perform all data collection and analysis will remove the potential for&#xD;
      inter-investigator variation. Dr. Craighead and other research and clinical staff involved in&#xD;
      data acquisition will remain blinded throughout data collection and analysis. All data will&#xD;
      be analyzed as outlined in the Research Strategy section and Outcome Measures section; data&#xD;
      analysis and dissemination of results will be completed by the end of this award.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">May 10, 2019</start_date>
  <completion_date type="Anticipated">December 31, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 31, 2023</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Triple (Participant, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Systolic blood pressure</measure>
    <time_frame>3 months</time_frame>
    <description>Resting systolic blood pressure</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Ambulatory blood pressure</measure>
    <time_frame>3 months</time_frame>
    <description>24-hour mean blood pressure</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Arterial stiffness</measure>
    <time_frame>3 months</time_frame>
    <description>Carotid-femoral pulse wave velocity</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Number and severity of adverse events (safety)</measure>
    <time_frame>3 months</time_frame>
    <description>Monitoring and documentation of number and type of adverse events</description>
  </other_outcome>
  <other_outcome>
    <measure>Number of participants that dropout due to adverse events (tolerability)</measure>
    <time_frame>3 months</time_frame>
    <description>Monitoring subject dropout due to adverse events</description>
  </other_outcome>
  <other_outcome>
    <measure>Adherence to the intervention (percentage of prescribed pills consumed)</measure>
    <time_frame>3 months</time_frame>
    <description>Counting returned pills on a bi-weekly basis to determine what percentage of prescribed pills subjects take.</description>
  </other_outcome>
  <other_outcome>
    <measure>NAD+ and related metabolite blood levels</measure>
    <time_frame>3 months</time_frame>
    <description>Blood samples will be analysed using high performance liquid chromatography-mass spectronomy analysis for levels of NAD+ and related metabolites including: NADP+, nicotinic acid adeniene dinucleotide, nicotinamide, and nicotinamide mononucleotide.</description>
  </other_outcome>
  <other_outcome>
    <measure>Sympathetic activity</measure>
    <time_frame>3 months</time_frame>
    <description>Plasma norepinephrine, a marker of sympathetic activity, will be measured by high performance liquid chromatography</description>
  </other_outcome>
  <other_outcome>
    <measure>Oxidative stress</measure>
    <time_frame>3 months</time_frame>
    <description>Plasma oxidized LDL, a marker of oxidative stress, will be measured by ELISA</description>
  </other_outcome>
  <other_outcome>
    <measure>Inflammation</measure>
    <time_frame>3 months</time_frame>
    <description>Plasma interleukin-6, a marker of inflammation, will be measured by ELISA</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">118</enrollment>
  <condition>Hypertension</condition>
  <condition>Aging</condition>
  <arm_group>
    <arm_group_label>Nicotinamide riboside</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will take 500 mg of the vitamin B3-precursor, nicotinamide riboside (NIAGEN) twice per day (1,000 mg per day total) for 3 months.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Subjects will take placebo pills twice a day for 3 months.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Nicotinamide riboside</intervention_name>
    <description>Nicotinamide riboside, a dietary supplement available over the counter under the name NIAGEN®, (ChromaDex Inc) is an exogenous NAD+ precursor that reverses age-related arterial dysfunction in aged mice, suggesting that declining NAD+ may play a key role in cardiovascular aging.</description>
    <arm_group_label>Nicotinamide riboside</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Subjects will take placebo pills twice a day for 3 months</description>
    <arm_group_label>Placebo</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Ability to provide informed consent&#xD;
&#xD;
          -  Willing to accept random assignment to condition&#xD;
&#xD;
          -  Systolic blood pressure between 120 and 159 mmHg&#xD;
&#xD;
          -  Body mass index &lt;40 kg/m2&#xD;
&#xD;
          -  Weight stable in the prior 3 months (&lt;2 kg weight change) and willing to remain weight&#xD;
             stable throughout the study&#xD;
&#xD;
          -  Absence of other clinical disease as determined by medical history, physical&#xD;
             examination, blood chemistries, ankle-brachial index, and 12-lead ECG at rest and&#xD;
             during graded treadmill exercise&#xD;
&#xD;
               -  Ankle-brachial index &gt;0.7&#xD;
&#xD;
               -  Total cholesterol &lt;240 mg/dL&#xD;
&#xD;
               -  Fasting plasma glucose &lt;126 mg/dL&#xD;
&#xD;
               -  Normal 12-lead ECG at rest and during graded treadmill exercise to fatigue&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Systolic blood pressure &lt;120 or &gt;/= 160 mmHg&#xD;
&#xD;
          -  Currently taking antihypertensive medications&#xD;
&#xD;
          -  Other chronic medical condition (e.g., diabetes, chronic kidney disease, cancer)&#xD;
&#xD;
          -  Current smoker&#xD;
&#xD;
          -  Alcohol dependence or abuse&#xD;
&#xD;
          -  Uncontrolled thyroid disease or change in thyroid medication within previous 3 months&#xD;
&#xD;
          -  Abnormal blood pressure response to exercise (drop in SBP below resting pressure or&#xD;
             SBP &gt;160 mmHg or DBP &gt;115 mmHg)&#xD;
&#xD;
          -  Regular vigorous aerobic/endurance exercise (&gt;4 bouts/weeks, &gt;30 min/bout at a&#xD;
             workload &gt;6 METS)&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>50 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Daniel H Craighead, PhD</last_name>
    <phone>303-492-7702</phone>
    <email>daniel.craighead@colorado.edu</email>
  </overall_contact>
  <location>
    <facility>
      <name>Integrative Physiology of Aging Laboratory</name>
      <address>
        <city>Boulder</city>
        <state>Colorado</state>
        <zip>80309</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Melanie R Zigler, MS</last_name>
      <phone>303-492-2485</phone>
      <email>melanie.connell@colorado.edu</email>
    </contact>
    <investigator>
      <last_name>Douglas R Seals, PhD</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7.</citation>
    <PMID>29599478</PMID>
  </reference>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 14, 2019</study_first_submitted>
  <study_first_submitted_qc>January 28, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 30, 2019</study_first_posted>
  <last_update_submitted>June 21, 2023</last_update_submitted>
  <last_update_submitted_qc>June 21, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 22, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Colorado, Boulder</investigator_affiliation>
    <investigator_full_name>Douglas Seals</investigator_full_name>
    <investigator_title>Principal Investigator</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Hypertension</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>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/NCT03821623
org study id: 18-0644
nct id: NCT03821623
lead sponsor: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
Aging is the primary risk factor for cardiovascular diseases (CVD), the number one cause of
      death in developed societies. Systolic blood pressure (SBP) increase with age and is a key
      intermediary factor linking aging to increased CVD risk. The primary mechanisms underlying
      the age-associated increase in SBP is stiffening of the large elastic arteries, which is
      mediated by increases in oxidative stress, inflammation, and vascular smooth muscle tone.
      Regular caloric restriction is effective at lowering SBP in middle-aged and older adults;
      however, adherence to caloric restriction is poor and may be detrimental to normal weight
      older adults due to reduced skeletal muscle mass and bone mineral density. Therefore,
      identification of more practical alternative interventions that mimic the beneficial effects
      of caloric restriction, with stronger adherence and less risk of adverse consequences, is of
      significant biomedical importance.

      Nicotinamide riboside is a naturally occurring precursor of nicotinamide adenine dinucleotide
      (NAD+), a critical mediator of the beneficial effects of caloric restriction, and therefore a
      novel caloric restriction mimetic compound. We recently completed the first pilot study of
      nicotinamide riboside supplementation in healthy middle-aged and older adults and
      demonstrated that 6 weeks of supplementation decreased systolic blood pressure (SBP) by 8
      mmHg in individuals with baseline SBP of 120-139 mmHg (elevated SBP/stage 1 hypertension)
      compared with placebo, and lowered arterial stiffness, a strong independent predictor of CVD
      and related morbidity and mortality.

      As a next translational step, we will conduct a randomized, placebo-controlled, double-blind
      clinical trial to further assess the safety and efficacy of oral nicotinamide riboside (3
      months vs placebo) for decreasing SBP and arterial stiffness in middle-aged and older men and
      women with SBP between 120 and 139 mmHg at baseline.
Study Overview: This is a randomized, double-blind, placebo-controlled, parallel design,
      single site phase IIa clinical trial assessing the efficacy of nicotinamide riboside
      supplementation to lower systolic blood pressure (SBP) and aortic stiffness in middle-aged to
      older (MA/O) adults (50-79 years) with elevated to stage-1 systolic hypertension (SBP:
      120-139 mmHg). Nicotinamide riboside is an endogenously occurring precursor of NAD+ and a
      novel caloric restriction mimetic in humans that is now commercially available as a dietary
      ingredient/supplement. We have recently demonstrated that chronic supplementation with
      nicotinamide riboside lowers SBP and carotid-femoral pulse wave velocity (CFPWV;
      gold-standard measure of aortic stiffness and independent risk factor for cardiovascular
      diseases) in a small pilot study of healthy MA/O adults; the greatest reductions in SBP were
      observed in a subgroup with baseline SBP in the elevated/stage-1 hypertension range. As a
      next translational step, the present study proposes to assess the efficacy of 3 months of
      nicotinamide riboside supplementation for decreasing SBP (primary outcome) and aortic
      stiffness (secondary outcome) in a larger cohort of MA/O men and women with SBP in the
      elevated/stage-1 hypertension range. As secondary aims, we will also assess safety and
      tolerability of long-term nicotinamide riboside supplementation, and the effects of
      nicotinamide riboside supplementation vs. placebo on NAD+ metabolites and circulating
      biomarkers of vasoconstriction, oxidative stress and inflammation.

      Subject Enrollment and Screening: Potential participants will be made aware of the proposed
      study through described recruitment efforts (see Recruitment and Retention section).
      Interested participants will contact a staff research assistant via phone or email (contact
      information supplied with recruitment materials) and will complete a general screening form
      online through the Research Electronic Data Capture (REDCap) system to determine eligibility.
      REDCap is a secure web-based application designed to support data capture for research
      studies.

      After hearing a thorough study description and having all questions answered by the staff
      research assistant, those eligible and interested in participating in the study will provide
      written and verbal informed consent, and undergo in-person screening at the CU Boulder
      Clinical Translational Research Center (CTRC). Informed consent will only be obtained by
      members of the research team who have been observed and approved by the CTRC Research Subject
      Advocate (see Protection of Human Subjects). We plan to consent 148 subjects in order to meet
      our enrollment targets (to account for an ~25% rate of exclusion base on in-person
      screening).

      In-person screening will include: review of medical history; physical exam; resting heart
      rate; resting blood pressure; blood draw for metabolic profile, lipid profile, complete blood
      count, and thyroid stimulating hormone; measurement of ankle-brachial index; and a 12-lead
      ECG at rest and during graded exercise testing (see the Eligibility Criteria section for
      detailed inclusion/exclusion criteria).

      Resting blood pressure will be measured on a second occasion within one week of the initial
      screening to establish baseline blood pressure status; SBP measured on the two separate days
      will be averaged and must be in the elevated to stage-1 hypertension range (120-139 mmHg) for
      enrollment into the study.

      Participant Randomization and Subject/Investigator Blinding: After completing screening,
      eligible subjects will be randomized to either the nicotinamide riboside or placebo group. A
      randomized block design will be used to balance groups for sex, age (mid-life: 50-64 years
      vs. older: 65-79 years) and hypertension status (elevated vs. stage-1 systolic hypertension).
      Randomization will be carried out by an unblinded staff research assistant who is not
      involved in data collection or analysis. Subjects will be categorized based on the block
      randomization scheme and then a random number generator will be used to assign subjects to
      either nicotinamide riboside or placebo treatment. Researchers involved in collection of
      outcome data will be blinded to the assigned intervention. Subjects will be blinded to their
      assigned intervention and will receive capsules in coded blister packs; nicotinamide riboside
      and placebo capsules will appear identical. CTRC clinical staff involved with subject
      check-in visits and/or data collection will also be blinded (in the case of a serious adverse
      event, blinding of the CTRC staff will be broken, as necessary to ensure appropriate medical
      treatment).

      Assessment of Study Outcomes: All subjects will undergo baseline testing for all primary,
      secondary, and other outcome measures. All measurements will be made after a 12 hour fast
      from food and caffeine (water allowed) and 24 hours after abstaining from alcohol and
      exercise. All tests will take place in the CU Boulder CTRC.

      The protocol for baseline testing is as follows:

        -  Urine sample collection;

        -  Assessment of casual SBP;

        -  Placement of IV in an antecubital vein followed by 30 minutes of rest in a supine
           position; - Collection of blood samples by a trained CTRC provider;

        -  Assessment of aortic stiffness by CFPWV.

      Following completion of outcome measure testing, the below non-outcome measures will be made
      in order to ensure that participant characteristics known to affect cardiovascular function
      are unaltered during the intervention:

        -  3-day diet records to ensure that daily fluid and caloric intake remain stable;

        -  The Community Healthy Activities Model Program for Seniors (CHAMPS) questionnaire will
           be completed and physical activity will be assessed by accelerometers (ActiGraph, 3-day
           recordings) to document stability of physical activity levels;

        -  Maximal oxygen consumption using indirect calorimetry during incremental treadmill
           exercise (Balke protocol) will be measured to document unchanged aerobic fitness; and

        -  Body composition will be assessed by dual energy x-ray absorptiometry (DEXA) and
           anthropometry to confirm unaltered body composition; body mass will also be determined
           during safety and check in visits with CTRC nursing staff.

      Following all CTRC testing procedures, subjects will be outfitted with an ambulatory blood
      pressure monitor pre-programmed to automatically measure blood pressure every 20 minutes. A
      study team member will provide the subject with written and verbal instructions on how to
      operate the monitor. Subjects will wear the monitor for 24 hours before returning it to the
      investigators. Ambulatory blood pressure data will be evaluated for completeness immediately
      upon return of the monitor; if an inadequate number of blood pressure measurements (<67% of
      expected) were made to properly characterize 24-hour SBP the subject will be re-outfitted
      with the ambulatory monitor, be re-instructed on its use, and wear it for a second 24-hour
      period.

      The Research Strategy and Outcome Measures sections provide a more detailed description of
      these procedures. Similar protocols and procedures are well established in the Seals
      laboratory and the CU Boulder CTRC.

      Delivery of the Intervention: After completing baseline testing, subjects will begin their
      assigned intervention (nicotinamide riboside or placebo). Subjects will be instructed to take
      2 x 250 mg capsules in the morning and 2 x 250 mg capsules in the evening (4 capsules/day).
      This will result in a dosing of 500 mg nicotinamide riboside 2x/day in the nicotinamide
      riboside group (1000 mg/day total).

      Subjects will return to the CU Boulder CTRC once every two weeks for check-in and to receive
      capsules. Capsules will be prepared by the manufacturer in blister packs to promote adherence
      and will be stored and dispensed by the CTRC pharmacist (unblinded) and distributed by a CTRC
      nurse (blinded). Subjects will return their blister packs at each check-in visit and after
      follow-up testing to assess adherence to the intervention. During each visit to the CTRC,
      subjects will be monitored for treatment-emergent adverse events by blinded CTRC clinical
      staff.

      Post-Testing: After completing 3 months of treatment with either nicotinamide riboside or
      placebo, subjects will return to the CU Boulder CTRC for reassessment of all outcome
      measures, including: casual SBP, 24-h ambulatory SBP, CFPWV, venous blood draw, and urine
      sample. Non-outcome control measures (3-day diet record, CHAMPS survey, activity monitor,
      maximal oxygen consumption test, body composition) will also be reassessed. These measures
      will be made under the same experimental conditions, in the same order, and with the same
      techniques as baseline testing.

      Intervention Duration and Study Sample Size: The expected duration for a participant to
      complete the entire protocol from screening to follow-up testing is 18 weeks. Based on our
      power analysis, we need to complete the entire protocol on a total of 94 participants
      (47/group) to detect a significant difference between treatment conditions in our primary
      outcome measure (SBP). We intend to enroll 118 subjects (59/group) to account for an ~20%
      dropout rate. Based on this, we will enroll 2-3 subjects per month, which will allow for
      completion of data collection by month 55 of this award; this rate of testing is achievable
      based on previous pharmacological interventions carried out in the Seals laboratory and the
      availability of the CTRC facilities and staff.

      Data Collection and Analysis (including blinding): Collection of primary and secondary
      outcome measures will be performed by postdoctoral fellow, Dr. Craighead, with the assistance
      of members of the laboratory. IV placement and blood draws will be performed by experienced
      CTRC clinical staff. Data analysis will be performed by Dr. Craighead. Having a single
      investigator perform all data collection and analysis will remove the potential for
      inter-investigator variation. Dr. Craighead and other research and clinical staff involved in
      data acquisition will remain blinded throughout data collection and analysis. All data will
      be analyzed as outlined in the Research Strategy section and Outcome Measures section; data
      analysis and dissemination of results will be completed by the end of this award.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Triple (Participant, Investigator, Outcomes Assessor)
measure: Systolic blood pressure
time frame: 3 months
description: Resting systolic blood pressure
measure: Ambulatory blood pressure
time frame: 3 months
description: 24-hour mean blood pressure
measure: Arterial stiffness
time frame: 3 months
description: Carotid-femoral pulse wave velocity
measure: Number and severity of adverse events (safety)
time frame: 3 months
description: Monitoring and documentation of number and type of adverse events
measure: Number of participants that dropout due to adverse events (tolerability)
time frame: 3 months
description: Monitoring subject dropout due to adverse events
measure: Adherence to the intervention (percentage of prescribed pills consumed)
time frame: 3 months
description: Counting returned pills on a bi-weekly basis to determine what percentage of prescribed pills subjects take.
measure: NAD+ and related metabolite blood levels
time frame: 3 months
description: Blood samples will be analysed using high performance liquid chromatography-mass spectronomy analysis for levels of NAD+ and related metabolites including: NADP+, nicotinic acid adeniene dinucleotide, nicotinamide, and nicotinamide mononucleotide.
measure: Sympathetic activity
time frame: 3 months
description: Plasma norepinephrine, a marker of sympathetic activity, will be measured by high performance liquid chromatography
measure: Oxidative stress
time frame: 3 months
description: Plasma oxidized LDL, a marker of oxidative stress, will be measured by ELISA
measure: Inflammation
time frame: 3 months
description: Plasma interleukin-6, a marker of inflammation, will be measured by ELISA
arm group label: Nicotinamide riboside
arm group type: Experimental
description: Subjects will take 500 mg of the vitamin B3-precursor, nicotinamide riboside (NIAGEN) twice per day (1,000 mg per day total) for 3 months.
arm group label: Placebo
arm group type: Placebo Comparator
description: Subjects will take placebo pills twice a day for 3 months.
intervention type: Drug
intervention name: Nicotinamide riboside
description: Nicotinamide riboside, a dietary supplement available over the counter under the name NIAGEN®, (ChromaDex Inc) is an exogenous NAD+ precursor that reverses age-related arterial dysfunction in aged mice, suggesting that declining NAD+ may play a key role in cardiovascular aging.
arm group label: Nicotinamide riboside
intervention type: Other
intervention name: Placebo
description: Subjects will take placebo pills twice a day for 3 months
arm group label: Placebo
criteria: 
gender: All
minimum age: 50 Years
maximum age: N/A
healthy volunteers: Accepts Healthy Volunteers
last name: Daniel H Craighead, PhD
phone: 303-492-7702
email: daniel.craighead@colorado.edu
facility: 
status: Recruiting
contact: 
investigator: 
country: United States
citation: Martens CR, Denman BA, Mazzo MR, Armstrong ML, Reisdorph N, McQueen MB, Chonchol M, Seals DR. Chronic nicotinamide riboside supplementation is well-tolerated and elevates NAD+ in healthy middle-aged and older adults. Nat Commun. 2018 Mar 29;9(1):1286. doi: 10.1038/s41467-018-03421-7.
PMID: 29599478
responsible party type: Sponsor-Investigator
investigator affiliation: University of Colorado, Boulder
investigator full name: Douglas Seals
investigator title: Principal Investigator
mesh term: Hypertension
mesh term: Niacinamide
mesh term: Niacin
mesh term: Nicotinic Acids
sharing ipd: No