<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/NCT03827005</url>
  </required_header>
  <id_info>
    <org_study_id>HE16235</org_study_id>
    <nct_id>NCT03827005</nct_id>
  </id_info>
  <brief_title>L-arginine Supplementation and Resistance Exercise</brief_title>
  <official_title>The Acute Effects of L-arginine Supplementation on Flow-mediated Dilation After Resistance Exercise to Fatigue</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>North Dakota State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>North Dakota State University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The purpose of this study was to examine the acute endothelial, cardiovascular, and&#xD;
      performance responses to L-arginine by assessing flow-mediated dilation (FMD) and heart rate&#xD;
      variability (HRV) both before and after resistance exercise to fatigue. Thirty (15 male, 15&#xD;
      female) physically active participants volunteered for a randomized, cross-over,&#xD;
      double-blind, placebo- controlled clinical trial. Participants completed five sets of elbow&#xD;
      extension-flexion exercise after consumption of either 3 g of placebo or 3 g L-arginine.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Participants Thirty healthy, physically active males (n=15) and females (n=15), 18-25 years&#xD;
      of age completed the study. Subjects had not participated in another clinical trial or&#xD;
      consumed another study related investigation product within 30 days of enrollment. If a&#xD;
      supplement containing L-arginine or other nitrate precursors was being taken, a three-week&#xD;
      washout period was conducted before participation. All procedures were approved in advance by&#xD;
      the North Dakota State University Institutional Review Board and written consent was&#xD;
      obtained.&#xD;
&#xD;
      Protocol A randomized, double-blind, placebo-controlled research design was implemented for&#xD;
      this investigation. Prior to the randomized testing sessions, participants completed a&#xD;
      anthropometric measurements and familiarization session which included:: collection of&#xD;
      participant age, height (Seca 213, Chino, CA), and body mass data (Detecto, Webb City, MO)&#xD;
      and familiarization with the Biodex Dynamometer (Biodex Medical Systems, Shirley, NY),&#xD;
      ultrasound (Philips Ultrasound, Bothell, WA), and electronic sphygmomanometer (Hokanson Rapid&#xD;
      Cuff Inflation System, Bellevue, WA) procedures. Participants then reported to the laboratory&#xD;
      for two testing sessions, each separated by at least a 48 hours washout period. Testing&#xD;
      sessions were conducted at the same time of day to account for circadian variation.&#xD;
      Participants entered the trial sessions on an 8-our fast, but were encouraged to arrive at&#xD;
      the session well-hydrated. The participants were instructed not to exercise or consume&#xD;
      caffeine 24 hours prior to trial time or use toothpaste, chewing gum, or mouthwash the&#xD;
      morning of the trials, due to the possible effects on nitric oxide absorption. All females&#xD;
      tested negative for pregnancy based on a urinary pregnancy test (Clinical Guard, Atlanta, GA)&#xD;
      prior to each trial session. At the start of the trial, participants rested for 5 minutes&#xD;
      while sitting.&#xD;
&#xD;
      Endothelial responses were measured by a technique termed flow mediated vasodilation (FMD)&#xD;
      which assessed the maximal vasodilatory response to shear stress. FMD was measured in&#xD;
      accordance with recommendations from the International Brachial Artery Reactivity Task Force.&#xD;
      A Philips HD11XE ultrasound system (Philips, Amsterdam, NL) equipped with 2D imaging, color&#xD;
      and spectral Doppler, and a high-frequency vascular transducer was used for the protocol. The&#xD;
      participants laid supine with the right arm inside a pillow for a stabilizer. Probe placement&#xD;
      was on the brachial artery, above the antecubital fossa in the longitudinal place. Continuous&#xD;
      2D imaging was used to take an initial brachial artery diameter for 10 seconds to determine&#xD;
      the resting artery diameter (to cover the full cardiac cycle). Probe placement was outlined&#xD;
      with a marker. A Hokanson E20 electronic sphygmomanometric cuff and rapid cuff inflation&#xD;
      system (Bellevue, WA) was placed on the middle of the forearm and inflated to 50 mmHg above&#xD;
      systolic blood pressure for five mins and cuff placement was marked with a marker. Upon&#xD;
      release of the cuff, the ultrasound probe was placed in the same area in which the first&#xD;
      measure was taken. A continuous 2D imaging was used from cuff release to 120 seconds&#xD;
      post-release. The average of three diameters measured using RadiAnt DICOM software was used&#xD;
      for determination of FMD (%), which was expressed as the change in post-stimulus diameter as&#xD;
      a percentage of baseline diameter.&#xD;
&#xD;
      Measures of the cardiovascular system included heart rate variability (HRV). HRV were&#xD;
      recorded using a Polar H7 Bluetooth strap (Polar, Bethpage, NY) combined Personal Pro Elite&#xD;
      HRV smartphone application (elitehrv.com) over 5 min intervals then further analyzed with&#xD;
      Kubios software using the &quot;very low&quot; artifact correction setting. HRV explored the&#xD;
      differences in beat-to-beat intervals based on the time (milliseconds) between adjacent R to&#xD;
      R (RR) peaks within a PQRST waveform. HRV provides a dynamic, sensitive meter of the balance&#xD;
      or tone between the two branches of the autonomic nervous system, sympathetic (SNS) and&#xD;
      parasympathetic (PNS), RMSSD and pNN50 are also the most commonly used HRV measures and were&#xD;
      used in this study.&#xD;
&#xD;
      After baseline measurements were collected, the participants consumed either 6 capsules (3 g)&#xD;
      of L-arginine (NOW Foods, Bloomingdale, IL) or 6 capsules of corn starch, placebo (3 g) which&#xD;
      had an identical appearance (InHealth Specialty Pharmacy, Fargo, ND). Each supplement was&#xD;
      consumed with 12 oz. of water. The participant then rested for 55 minutes to ensure enough&#xD;
      time for digestion, absorption and availability. At 55 minutes post-supplementation,&#xD;
      participants completed a 5 minutes warm up using a cycle ergometer (Monark 828E, Vansbro,&#xD;
      SV). Sixty minutes post-supplementation, participants completed elbow flexion and extension&#xD;
      exercise with their right arm on an isokinetic dynamometer to determine the elbow flexor and&#xD;
      extensor peak torque.The exercise protocol, designed to induce fatigue, consisted of five&#xD;
      sets of 10 maximal isokinetic extension repetitions of the elbow joint at 90º per second with&#xD;
      30 seconds of rest in between sets. Participants were instructed and encouraged to use&#xD;
      full-force for all sets. Isometric peak torque was measured prior to and thirty seconds after&#xD;
      exercise to determine the fatigue percentage. Dynamometer settings remained constant for each&#xD;
      testing session as recorded during the anthropometric and familiarization session. At 10&#xD;
      minutes post-exercise, which was 120 minutes after supplement consumption, FMD and HRV were&#xD;
      measured for the final time.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">July 16, 2016</start_date>
  <completion_date type="Actual">May 30, 2017</completion_date>
  <primary_completion_date type="Actual">April 30, 2017</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Crossover Assignment</intervention_model>
    <intervention_model_description>double blind, placebo, controlled -cross over</intervention_model_description>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
    <masking_description>blinding performed by co-investigator not involved with data collection</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Change in Flow mediated dilation 120 seconds post-cuff release</measure>
    <time_frame>Change from Baseline and 120 seconds</time_frame>
    <description>Flow mediated dilation was measured using a A Philips HD11XE ultrasound system (Philips, Amsterdam, NL) equipped with 2D imaging, color and spectral Doppler, and a high-frequency vascular transducer.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in Heart Rate Variability 10 minutes after intervention</measure>
    <time_frame>Change from Baseline and 10 minutes post-exercise</time_frame>
    <description>Hear rate variability was recorded using a Polar H7 Bluetooth strap (Polar, Bethpage, NY) combined Personal Pro Elite HRV smartphone application (elitehrv.com) over 5 minutes intervals then further analyzed with Kubios software</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Healthy Adult</condition>
  <arm_group>
    <arm_group_label>placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>3 grams cornstarch once per day for one day.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>L-arginine</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>3 g L-arginine once per day for one day.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L-arginine</intervention_name>
    <description>NOW Foods, Bloomingdale, IL</description>
    <arm_group_label>L-arginine</arm_group_label>
    <arm_group_label>placebo</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>InHealth Specialty Pharmacy, Fargo, ND</description>
    <arm_group_label>L-arginine</arm_group_label>
    <arm_group_label>placebo</arm_group_label>
    <other_name>cornstarch</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  generally healthy&#xD;
&#xD;
          -  physically active&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  previous clinical trial&#xD;
&#xD;
          -  pregnancy&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <gender_based>Yes</gender_based>
    <gender_description>self reported</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>25 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <reference>
    <citation>Alvares TS, Conte CA, Paschoalin VM, Silva JT, Meirelles Cde M, Bhambhani YN, Gomes PS. Acute l-arginine supplementation increases muscle blood volume but not strength performance. Appl Physiol Nutr Metab. 2012 Feb;37(1):115-26. doi: 10.1139/h11-144. Epub 2012 Jan 17.</citation>
    <PMID>22251130</PMID>
  </reference>
  <reference>
    <citation>Alvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS. L-Arginine as a potential ergogenic aid in healthy subjects. Sports Med. 2011 Mar 1;41(3):233-48. doi: 10.2165/11538590-000000000-00000.</citation>
    <PMID>21395365</PMID>
  </reference>
  <reference>
    <citation>Bondonno CP, Croft KD, Hodgson JM. Dietary Nitrate, Nitric Oxide, and Cardiovascular Health. Crit Rev Food Sci Nutr. 2016 Sep 9;56(12):2036-52. doi: 10.1080/10408398.2013.811212.</citation>
    <PMID>25976309</PMID>
  </reference>
  <reference>
    <citation>Bai Y, Sun L, Yang T, Sun K, Chen J, Hui R. Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow-mediated dilation is low: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2009 Jan;89(1):77-84. doi: 10.3945/ajcn.2008.26544. Epub 2008 Dec 3.</citation>
    <PMID>19056561</PMID>
  </reference>
  <reference>
    <citation>Kapadia MR, Eng JW, Jiang Q, Stoyanovsky DA, Kibbe MR. Nitric oxide regulates the 26S proteasome in vascular smooth muscle cells. Nitric Oxide. 2009 Jun;20(4):279-88. doi: 10.1016/j.niox.2009.02.005. Epub 2009 Feb 20.</citation>
    <PMID>19233305</PMID>
  </reference>
  <reference>
    <citation>Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci. 1999 Jul;55(8-9):1078-87. doi: 10.1007/s000180050358.</citation>
    <PMID>10442089</PMID>
  </reference>
  <reference>
    <citation>Fahs CA, Heffernan KS, Fernhall B. Hemodynamic and vascular response to resistance exercise with L-arginine. Med Sci Sports Exerc. 2009 Apr;41(4):773-9. doi: 10.1249/MSS.0b013e3181909d9d.</citation>
    <PMID>19276857</PMID>
  </reference>
  <verification_date>January 2019</verification_date>
  <study_first_submitted>July 1, 2018</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 1, 2019</study_first_posted>
  <last_update_submitted>January 30, 2019</last_update_submitted>
  <last_update_submitted_qc>January 30, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">February 1, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>North Dakota State University</investigator_affiliation>
    <investigator_full_name>Kyle Hackney</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>L-arginine</keyword>
  <keyword>flow mediated dilation</keyword>
  <keyword>resistance exercise</keyword>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03827005
org study id: HE16235
nct id: NCT03827005
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The purpose of this study was to examine the acute endothelial, cardiovascular, and
      performance responses to L-arginine by assessing flow-mediated dilation (FMD) and heart rate
      variability (HRV) both before and after resistance exercise to fatigue. Thirty (15 male, 15
      female) physically active participants volunteered for a randomized, cross-over,
      double-blind, placebo- controlled clinical trial. Participants completed five sets of elbow
      extension-flexion exercise after consumption of either 3 g of placebo or 3 g L-arginine.
Participants Thirty healthy, physically active males (n=15) and females (n=15), 18-25 years
      of age completed the study. Subjects had not participated in another clinical trial or
      consumed another study related investigation product within 30 days of enrollment. If a
      supplement containing L-arginine or other nitrate precursors was being taken, a three-week
      washout period was conducted before participation. All procedures were approved in advance by
      the North Dakota State University Institutional Review Board and written consent was
      obtained.

      Protocol A randomized, double-blind, placebo-controlled research design was implemented for
      this investigation. Prior to the randomized testing sessions, participants completed a
      anthropometric measurements and familiarization session which included:: collection of
      participant age, height (Seca 213, Chino, CA), and body mass data (Detecto, Webb City, MO)
      and familiarization with the Biodex Dynamometer (Biodex Medical Systems, Shirley, NY),
      ultrasound (Philips Ultrasound, Bothell, WA), and electronic sphygmomanometer (Hokanson Rapid
      Cuff Inflation System, Bellevue, WA) procedures. Participants then reported to the laboratory
      for two testing sessions, each separated by at least a 48 hours washout period. Testing
      sessions were conducted at the same time of day to account for circadian variation.
      Participants entered the trial sessions on an 8-our fast, but were encouraged to arrive at
      the session well-hydrated. The participants were instructed not to exercise or consume
      caffeine 24 hours prior to trial time or use toothpaste, chewing gum, or mouthwash the
      morning of the trials, due to the possible effects on nitric oxide absorption. All females
      tested negative for pregnancy based on a urinary pregnancy test (Clinical Guard, Atlanta, GA)
      prior to each trial session. At the start of the trial, participants rested for 5 minutes
      while sitting.

      Endothelial responses were measured by a technique termed flow mediated vasodilation (FMD)
      which assessed the maximal vasodilatory response to shear stress. FMD was measured in
      accordance with recommendations from the International Brachial Artery Reactivity Task Force.
      A Philips HD11XE ultrasound system (Philips, Amsterdam, NL) equipped with 2D imaging, color
      and spectral Doppler, and a high-frequency vascular transducer was used for the protocol. The
      participants laid supine with the right arm inside a pillow for a stabilizer. Probe placement
      was on the brachial artery, above the antecubital fossa in the longitudinal place. Continuous
      2D imaging was used to take an initial brachial artery diameter for 10 seconds to determine
      the resting artery diameter (to cover the full cardiac cycle). Probe placement was outlined
      with a marker. A Hokanson E20 electronic sphygmomanometric cuff and rapid cuff inflation
      system (Bellevue, WA) was placed on the middle of the forearm and inflated to 50 mmHg above
      systolic blood pressure for five mins and cuff placement was marked with a marker. Upon
      release of the cuff, the ultrasound probe was placed in the same area in which the first
      measure was taken. A continuous 2D imaging was used from cuff release to 120 seconds
      post-release. The average of three diameters measured using RadiAnt DICOM software was used
      for determination of FMD (%), which was expressed as the change in post-stimulus diameter as
      a percentage of baseline diameter.

      Measures of the cardiovascular system included heart rate variability (HRV). HRV were
      recorded using a Polar H7 Bluetooth strap (Polar, Bethpage, NY) combined Personal Pro Elite
      HRV smartphone application (elitehrv.com) over 5 min intervals then further analyzed with
      Kubios software using the "very low" artifact correction setting. HRV explored the
      differences in beat-to-beat intervals based on the time (milliseconds) between adjacent R to
      R (RR) peaks within a PQRST waveform. HRV provides a dynamic, sensitive meter of the balance
      or tone between the two branches of the autonomic nervous system, sympathetic (SNS) and
      parasympathetic (PNS), RMSSD and pNN50 are also the most commonly used HRV measures and were
      used in this study.

      After baseline measurements were collected, the participants consumed either 6 capsules (3 g)
      of L-arginine (NOW Foods, Bloomingdale, IL) or 6 capsules of corn starch, placebo (3 g) which
      had an identical appearance (InHealth Specialty Pharmacy, Fargo, ND). Each supplement was
      consumed with 12 oz. of water. The participant then rested for 55 minutes to ensure enough
      time for digestion, absorption and availability. At 55 minutes post-supplementation,
      participants completed a 5 minutes warm up using a cycle ergometer (Monark 828E, Vansbro,
      SV). Sixty minutes post-supplementation, participants completed elbow flexion and extension
      exercise with their right arm on an isokinetic dynamometer to determine the elbow flexor and
      extensor peak torque.The exercise protocol, designed to induce fatigue, consisted of five
      sets of 10 maximal isokinetic extension repetitions of the elbow joint at 90º per second with
      30 seconds of rest in between sets. Participants were instructed and encouraged to use
      full-force for all sets. Isometric peak torque was measured prior to and thirty seconds after
      exercise to determine the fatigue percentage. Dynamometer settings remained constant for each
      testing session as recorded during the anthropometric and familiarization session. At 10
      minutes post-exercise, which was 120 minutes after supplement consumption, FMD and HRV were
      measured for the final time.
allocation: Randomized
intervention model: Crossover Assignment
intervention model description: double blind, placebo, controlled -cross over
primary purpose: Other
masking: Double (Participant, Investigator)
masking description: blinding performed by co-investigator not involved with data collection
measure: Change in Flow mediated dilation 120 seconds post-cuff release
time frame: Change from Baseline and 120 seconds
description: Flow mediated dilation was measured using a A Philips HD11XE ultrasound system (Philips, Amsterdam, NL) equipped with 2D imaging, color and spectral Doppler, and a high-frequency vascular transducer.
measure: Change in Heart Rate Variability 10 minutes after intervention
time frame: Change from Baseline and 10 minutes post-exercise
description: Hear rate variability was recorded using a Polar H7 Bluetooth strap (Polar, Bethpage, NY) combined Personal Pro Elite HRV smartphone application (elitehrv.com) over 5 minutes intervals then further analyzed with Kubios software
arm group label: placebo
arm group type: Placebo Comparator
description: 3 grams cornstarch once per day for one day.
arm group label: L-arginine
arm group type: Experimental
description: 3 g L-arginine once per day for one day.
intervention type: Dietary Supplement
intervention name: L-arginine
description: NOW Foods, Bloomingdale, IL
arm group label: L-arginine
arm group label: placebo
intervention type: Dietary Supplement
intervention name: Placebo
description: InHealth Specialty Pharmacy, Fargo, ND
arm group label: L-arginine
arm group label: placebo
other name: cornstarch
criteria: 
gender: All
gender based: Yes
gender description: self reported
minimum age: 18 Years
maximum age: 25 Years
healthy volunteers: Accepts Healthy Volunteers
citation: Alvares TS, Conte CA, Paschoalin VM, Silva JT, Meirelles Cde M, Bhambhani YN, Gomes PS. Acute l-arginine supplementation increases muscle blood volume but not strength performance. Appl Physiol Nutr Metab. 2012 Feb;37(1):115-26. doi: 10.1139/h11-144. Epub 2012 Jan 17.
PMID: 22251130
citation: Alvares TS, Meirelles CM, Bhambhani YN, Paschoalin VM, Gomes PS. L-Arginine as a potential ergogenic aid in healthy subjects. Sports Med. 2011 Mar 1;41(3):233-48. doi: 10.2165/11538590-000000000-00000.
PMID: 21395365
citation: Bondonno CP, Croft KD, Hodgson JM. Dietary Nitrate, Nitric Oxide, and Cardiovascular Health. Crit Rev Food Sci Nutr. 2016 Sep 9;56(12):2036-52. doi: 10.1080/10408398.2013.811212.
PMID: 25976309
citation: Bai Y, Sun L, Yang T, Sun K, Chen J, Hui R. Increase in fasting vascular endothelial function after short-term oral L-arginine is effective when baseline flow-mediated dilation is low: a meta-analysis of randomized controlled trials. Am J Clin Nutr. 2009 Jan;89(1):77-84. doi: 10.3945/ajcn.2008.26544. Epub 2008 Dec 3.
PMID: 19056561
citation: Kapadia MR, Eng JW, Jiang Q, Stoyanovsky DA, Kibbe MR. Nitric oxide regulates the 26S proteasome in vascular smooth muscle cells. Nitric Oxide. 2009 Jun;20(4):279-88. doi: 10.1016/j.niox.2009.02.005. Epub 2009 Feb 20.
PMID: 19233305
citation: Arnal JF, Dinh-Xuan AT, Pueyo M, Darblade B, Rami J. Endothelium-derived nitric oxide and vascular physiology and pathology. Cell Mol Life Sci. 1999 Jul;55(8-9):1078-87. doi: 10.1007/s000180050358.
PMID: 10442089
citation: Fahs CA, Heffernan KS, Fernhall B. Hemodynamic and vascular response to resistance exercise with L-arginine. Med Sci Sports Exerc. 2009 Apr;41(4):773-9. doi: 10.1249/MSS.0b013e3181909d9d.
PMID: 19276857
responsible party type: Principal Investigator
investigator affiliation: North Dakota State University
investigator full name: Kyle Hackney
investigator title: Assistant Professor
sharing ipd: No