<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/NCT02214290</url>
  </required_header>
  <id_info>
    <org_study_id>HSC2013.10514</org_study_id>
    <nct_id>NCT02214290</nct_id>
  </id_info>
  <brief_title>Effect of Oral Caffeine and L-Citrulline Supplementation on Arterial Function in Healthy Males</brief_title>
  <official_title>Effect of Oral Caffeine and L-Citrulline Supplementation on Arterial Function in Healthy Males</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Florida State University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Florida State University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Caffeine is an exceedingly popular and consumed pharmacological agent. Although caffeine is&#xD;
      primarily consumed from coffee and tea beverages, it is also available in other forms such as&#xD;
      sodas, energy drinks, tablets and capsules. Nevertheless, caffeine acutely increases brachial&#xD;
      and aortic systolic blood pressure (BP) and arterial stiffness. Arterial stiffness is an&#xD;
      independent predictor of cardiovascular disease (CVD) and assessed through pulse wave&#xD;
      velocity (PWV). Interestingly, previous studies have proposed that caffeine may increase&#xD;
      aortic BP through increases in aortic PWV and augmentation index (AIx), a measurement of wave&#xD;
      reflection. Yet, these effects were seen in middle-aged adults with treated hypertension and&#xD;
      a wide age range. Therefore, it is imperative to consider that caffeine may cause different&#xD;
      effects in young normotensive individuals than in older adults independently of BP levels.&#xD;
      Importantly, oral supplementation of the amino-acid, L-citrulline has been shown to enhance&#xD;
      the bioavailability of L-arginine levels and nitric oxide (NO) production and, therefore,&#xD;
      improve arterial function. L-citrulline supplementation for 7 days given at 6 g/day has shown&#xD;
      to increase NO levels while improving PWV. Previous studies by our group also demonstrated&#xD;
      that L-citrulline supplementation reduces the BP response to cold exposure; a condition with&#xD;
      an increased vasoconstriction. Therefore, the acute effects of caffeine on central and&#xD;
      peripheral PWV and BP in healthy young men are yet to be fully evaluated. We hypothesized&#xD;
      that acute caffeine intake would increase peripheral and aortic BP and PWV and that&#xD;
      L-citrulline supplementation would attenuate the effects induced by acute caffeine ingestion.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The specific aims of this study are:&#xD;
&#xD;
      AIM 1: To examine the effects of the acute ingestion of 200mg caffeine (tablets) on arterial&#xD;
      function in young adults. The working hypothesis is that acute caffeine intake would increase&#xD;
      brachial, ankle and aortic BP, PWV (aortic and leg), and wave reflection. In order to test&#xD;
      this hypothesis, the investigators will perform non-invasive measurements of arterial&#xD;
      stiffness (aortic and leg PWV) and pulse wave analysis (aortic BP and AIx) using applanation&#xD;
      tonometry of the radial artery 30, 45, and 60 minutes following caffeine ingestion.&#xD;
&#xD;
      AIM 2: To determine the effectiveness of L-citrulline supplementation to attenuate the acute&#xD;
      cardiovascular effects of caffeine ingestion. The working hypothesis is that 7 days of&#xD;
      L-citrulline supplementation will attenuate the unfavorable arterial responses (increases in&#xD;
      BP, PWV, and wave reflection) to acute caffeine ingestion. In order to test this hypothesis,&#xD;
      the investigators will perform the same procedures previously specified in AIM 1.&#xD;
&#xD;
      Description of the study:&#xD;
&#xD;
      Sixteen healthy young men 18-40 years of age will be enrolled in this study. Participants&#xD;
      with CVD history, resting BP (&gt; 160/100 mmHg), recent history of smoking, or considered&#xD;
      competitive athlete will be excluded from the study. All subjects will refrain from food and&#xD;
      caffeine for &gt; 8 hours and from exercise for &gt; 24 hours before testing.&#xD;
&#xD;
      Study design:&#xD;
&#xD;
      Following an initial screening, arterial function measurements will be collected.&#xD;
      Measurements will be assessed at baseline following 10 minutes of rest in the supine position&#xD;
      and then again at 30, 45, and 60 minutes after 200 mg caffeine or placebo ingestion.&#xD;
      Participants will receive caffeine or placebo supplementation on two separate visits with a&#xD;
      minimum of 48 hours in between sessions. Following the acute phase of the study, subjects&#xD;
      will be randomized to consume L-citrulline or placebo for 7 days given at 6 grams/day.&#xD;
      Following the same protocol as the acute phase with 200 mg caffeine, measurements will be&#xD;
      collected before and after the 7 day supplementation period.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">March 2014</completion_date>
  <primary_completion_date type="Actual">March 2014</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>
    <primary_purpose>Other</primary_purpose>
    <masking>Double (Participant, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Aortic Blood Pressure</measure>
    <time_frame>Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)</time_frame>
    <description>Aortic blood pressure at rest and 30 minutes after acute ingestion of 200 mg of caffeine before and after 7 days of either 6g/day of Citrulline or 6 g/day of Placebo.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Changes in Reflected Wave Pressure (P2)</measure>
    <time_frame>Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)</time_frame>
    <description>Reflected wave pressure at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Changes in Femoral-ankle Pulse Wave Velocity After 7 Days of Either L-Citrulline or Placebo (6g/Day)</measure>
    <time_frame>Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)</time_frame>
    <description>Femoral-ankle pulse wave velocity at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">16</enrollment>
  <condition>Hypertension</condition>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Caffeine</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>200 mg caffeine tablet produced by CVS Pharmacy, USA</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo pill produced by NOW FOODS, USA</description>
  </arm_group>
  <arm_group>
    <arm_group_label>L-citrulline</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>L-citrulline capsule (750 mg) provided by NOW FOODS</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Caffeine</intervention_name>
    <description>A 200 mg caffeine tablet was given to subject to examine the drugs effect on arterial function.</description>
    <arm_group_label>Caffeine</arm_group_label>
    <other_name>Caffeine tablet (CVS Pharmacy)</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>A 750 mg placebo capsule (maltodextrin) was given to subjects to examine the effect of the drug on arterial function.</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo from NOW FOODS, USA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>L-citrulline</intervention_name>
    <description>L-citrulline was used to examine the effect of the supplement on arterial function.</description>
    <arm_group_label>L-citrulline</arm_group_label>
    <other_name>L-citrulline (750 mg/capsule)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Young healthy males&#xD;
&#xD;
          -  Non smoker&#xD;
&#xD;
          -  Non endurance trained athlete&#xD;
&#xD;
          -  No previous history of cardiovascular disease&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Female&#xD;
&#xD;
          -  Blood pressure greater than 160/100&#xD;
&#xD;
          -  Smoker&#xD;
      </textblock>
    </criteria>
    <gender>Male</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>40 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Arturo Figueroa, M.D. Ph.D</last_name>
    <role>Principal Investigator</role>
    <affiliation>Florida State University</affiliation>
  </overall_official>
  <verification_date>October 2020</verification_date>
  <study_first_submitted>August 4, 2014</study_first_submitted>
  <study_first_submitted_qc>August 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 12, 2014</study_first_posted>
  <results_first_submitted>November 30, 2018</results_first_submitted>
  <results_first_submitted_qc>December 2, 2020</results_first_submitted_qc>
  <results_first_posted type="Actual">December 29, 2020</results_first_posted>
  <last_update_submitted>December 2, 2020</last_update_submitted>
  <last_update_submitted_qc>December 2, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">December 29, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Florida State University</investigator_affiliation>
    <investigator_full_name>Arturo Figueroa</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Cardiovascular</keyword>
  <keyword>Caffeine</keyword>
  <keyword>L-citrulline</keyword>
  <keyword>Arterial Function</keyword>
  <keyword>Hemodynamics</keyword>
  <keyword>Blood Pressure</keyword>
  <keyword>Pulse Wave Velocity</keyword>
  <keyword>Pulse Wave Analysis</keyword>
  <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>Caffeine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Sixteen young healthy men participated in this study. All subjects were non-smokers, recreationally active, and free of apparent cardiovascular-metabolic diseases based on medical history.</recruitment_details>
      <pre_assignment_details>Of the 42 individuals screened, 16 individuals completed the intervention in its entirety.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Citrulline First, Then Placebo</title>
          <description>Each participant received L-Citrulline (6g/day) for a 7 day period. This was followed by a 14 day washout period. Finally, the same participants then received a Placebo (6g/day maltodextrin) for a 7 day period.</description>
        </group>
        <group group_id="P2">
          <title>Placebo First, Then L-Citrulline</title>
          <description>Each participant received a Placebo (6g/day maltodextrin) for a 7 day period. This was followed by a 14 day washout period. Finally, the same participants then received a L-Citrulline (6g/day) for a 7 day period.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>First Intervention (7 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Washout (14 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
        <period>
          <title>Second Intervention (7 Days)</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="8"/>
                <participants group_id="P2" count="8"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>L-Citrulline or Placebo</title>
          <description>Placebo and L-Citrulline pills produced by NOW FOODS, USA&#xD;
Citrulline or Placebo (both 6g/day) were given for a 7 day supplementation period. This was followed by a 14 day washout period and crossover to the other supplement (L-Citrulline or Placebo) for 7 days. Measurements of arterial function were performed to determine if the supplements had any significant effect on blood pressure control/pressure wave reflection at rest and immediately after ingestion of 200 milligrams of caffeine.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="16"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="16"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>&lt;=18 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Between 18 and 65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
                <category>
                  <title>&gt;=65 years</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Age</title>
          <description>ages of 18 to 40 years</description>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="16"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23" spread="3"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="16"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </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>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="16"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race and Ethnicity Not Collected</title>
          <population>Race and Ethnicity were not collected from any participant.</population>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <analyzed_list>
                <analyzed>
                  <units>Participants</units>
                  <scope>Class</scope>
                  <count_list>
                    <count group_id="B1" value="0"/>
                  </count_list>
                </analyzed>
              </analyzed_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Aortic Blood Pressure</title>
        <description>Aortic blood pressure at rest and 30 minutes after acute ingestion of 200 mg of caffeine before and after 7 days of either 6g/day of Citrulline or 6 g/day of Placebo.</description>
        <time_frame>Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)</time_frame>
        <population>Young, apparently healthy individuals, aged 18-40 years old.</population>
        <group_list>
          <group group_id="O1">
            <title>Citrulline</title>
            <description>Participants received 6g/day of Citrulline for 7 days</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants received 6 g/day of Maltodextrin for 7 days.</description>
          </group>
        </group_list>
        <measure>
          <title>Aortic Blood Pressure</title>
          <description>Aortic blood pressure at rest and 30 minutes after acute ingestion of 200 mg of caffeine before and after 7 days of either 6g/day of Citrulline or 6 g/day of Placebo.</description>
          <population>Young, apparently healthy individuals, aged 18-40 years old.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" spread="1"/>
                    <measurement group_id="O2" value="6" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>7 Days</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4" spread="1"/>
                    <measurement group_id="O2" value="4" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANOVA</method>
            <method_desc>post-hoc comparisons were used to determine within-group and between-group differences.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Reflected Wave Pressure (P2)</title>
        <description>Reflected wave pressure at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.</description>
        <time_frame>Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)</time_frame>
        <population>Young, apparently healthy adults, aged 18-40 years.</population>
        <group_list>
          <group group_id="O1">
            <title>Citrulline</title>
            <description>Participants received 6g/day of Citrulline for 7 days</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants received 6 g/day of Placebo</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Reflected Wave Pressure (P2)</title>
          <description>Reflected wave pressure at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.</description>
          <population>Young, apparently healthy adults, aged 18-40 years.</population>
          <units>mmHg</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="5" spread="1"/>
                    <measurement group_id="O2" value="5" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>7 Days</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="4" spread="1"/>
                    <measurement group_id="O2" value="5" spread="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANOVA</method>
            <method_desc>post-hoc comparisons were used to determine within-group and between-group differences.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Changes in Femoral-ankle Pulse Wave Velocity After 7 Days of Either L-Citrulline or Placebo (6g/Day)</title>
        <description>Femoral-ankle pulse wave velocity at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.</description>
        <time_frame>Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)</time_frame>
        <population>young, apparently healthy adults, aged 18-40 years</population>
        <group_list>
          <group group_id="O1">
            <title>Citrulline</title>
            <description>Participants received a 6 g/day of Citrulline for 7 days</description>
          </group>
          <group group_id="O2">
            <title>Placebo</title>
            <description>Participants received a 200 mg maltodextrin tablet, and femoral-ankle pulse wave velocity was taken at 60 minutes post-ingestion.</description>
          </group>
        </group_list>
        <measure>
          <title>Changes in Femoral-ankle Pulse Wave Velocity After 7 Days of Either L-Citrulline or Placebo (6g/Day)</title>
          <description>Femoral-ankle pulse wave velocity at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.</description>
          <population>young, apparently healthy adults, aged 18-40 years</population>
          <units>m/s</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="16"/>
                <count group_id="O2" value="16"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Baseline</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.6" spread="0.4"/>
                    <measurement group_id="O2" value="0.7" spread="0.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>7 Days</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0.4" spread="0.4"/>
                    <measurement group_id="O2" value="0.6" spread="0.4"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>ANOVA</method>
            <method_desc>post-hoc comparisons were used to determine within-group and between-group differences.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
    </outcome_list>

    <reported_events>
      <desc>Adverse events were not monitored/assessed because the participants were young and healthy.</desc>
      <group_list>
        <group group_id="E1">
          <title>Citrulline</title>
          <description>Participants received 6g/day of Citrulline for 7 days</description>
        </group>
        <group group_id="E2">
          <title>Placebo</title>
          <description>Participants received 6g/day of Placebo (Maltodextrin) for 7 days</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="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="0"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="0"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT 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. Arturo Figueroa</name_or_title>
      <organization>Texas Tech University</organization>
      <phone>8068345587</phone>
      <email>arturo.figueroa@ttu.edu</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/NCT02214290
org study id: HSC2013.10514
nct id: NCT02214290
lead sponsor: 
has dmc: No
Caffeine is an exceedingly popular and consumed pharmacological agent. Although caffeine is
      primarily consumed from coffee and tea beverages, it is also available in other forms such as
      sodas, energy drinks, tablets and capsules. Nevertheless, caffeine acutely increases brachial
      and aortic systolic blood pressure (BP) and arterial stiffness. Arterial stiffness is an
      independent predictor of cardiovascular disease (CVD) and assessed through pulse wave
      velocity (PWV). Interestingly, previous studies have proposed that caffeine may increase
      aortic BP through increases in aortic PWV and augmentation index (AIx), a measurement of wave
      reflection. Yet, these effects were seen in middle-aged adults with treated hypertension and
      a wide age range. Therefore, it is imperative to consider that caffeine may cause different
      effects in young normotensive individuals than in older adults independently of BP levels.
      Importantly, oral supplementation of the amino-acid, L-citrulline has been shown to enhance
      the bioavailability of L-arginine levels and nitric oxide (NO) production and, therefore,
      improve arterial function. L-citrulline supplementation for 7 days given at 6 g/day has shown
      to increase NO levels while improving PWV. Previous studies by our group also demonstrated
      that L-citrulline supplementation reduces the BP response to cold exposure; a condition with
      an increased vasoconstriction. Therefore, the acute effects of caffeine on central and
      peripheral PWV and BP in healthy young men are yet to be fully evaluated. We hypothesized
      that acute caffeine intake would increase peripheral and aortic BP and PWV and that
      L-citrulline supplementation would attenuate the effects induced by acute caffeine ingestion.
The specific aims of this study are:

      AIM 1: To examine the effects of the acute ingestion of 200mg caffeine (tablets) on arterial
      function in young adults. The working hypothesis is that acute caffeine intake would increase
      brachial, ankle and aortic BP, PWV (aortic and leg), and wave reflection. In order to test
      this hypothesis, the investigators will perform non-invasive measurements of arterial
      stiffness (aortic and leg PWV) and pulse wave analysis (aortic BP and AIx) using applanation
      tonometry of the radial artery 30, 45, and 60 minutes following caffeine ingestion.

      AIM 2: To determine the effectiveness of L-citrulline supplementation to attenuate the acute
      cardiovascular effects of caffeine ingestion. The working hypothesis is that 7 days of
      L-citrulline supplementation will attenuate the unfavorable arterial responses (increases in
      BP, PWV, and wave reflection) to acute caffeine ingestion. In order to test this hypothesis,
      the investigators will perform the same procedures previously specified in AIM 1.

      Description of the study:

      Sixteen healthy young men 18-40 years of age will be enrolled in this study. Participants
      with CVD history, resting BP (> 160/100 mmHg), recent history of smoking, or considered
      competitive athlete will be excluded from the study. All subjects will refrain from food and
      caffeine for > 8 hours and from exercise for > 24 hours before testing.

      Study design:

      Following an initial screening, arterial function measurements will be collected.
      Measurements will be assessed at baseline following 10 minutes of rest in the supine position
      and then again at 30, 45, and 60 minutes after 200 mg caffeine or placebo ingestion.
      Participants will receive caffeine or placebo supplementation on two separate visits with a
      minimum of 48 hours in between sessions. Following the acute phase of the study, subjects
      will be randomized to consume L-citrulline or placebo for 7 days given at 6 grams/day.
      Following the same protocol as the acute phase with 200 mg caffeine, measurements will be
      collected before and after the 7 day supplementation period.
allocation: Randomized
intervention model: Crossover Assignment
primary purpose: Other
masking: Double (Participant, Outcomes Assessor)
measure: Aortic Blood Pressure
time frame: Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)
description: Aortic blood pressure at rest and 30 minutes after acute ingestion of 200 mg of caffeine before and after 7 days of either 6g/day of Citrulline or 6 g/day of Placebo.
measure: Changes in Reflected Wave Pressure (P2)
time frame: Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)
description: Reflected wave pressure at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.
measure: Changes in Femoral-ankle Pulse Wave Velocity After 7 Days of Either L-Citrulline or Placebo (6g/Day)
time frame: Baseline and Day 7 (Calculated change between rest and 30 minutes post-caffeine ingestion at these time points)
description: Femoral-ankle pulse wave velocity at rest and 30 minutes after ingestion of 200mg of caffeine after 7 days supplementation of 6g/day of either L-Citrulline or Placebo.
arm group label: Caffeine
arm group type: Active Comparator
description: 200 mg caffeine tablet produced by CVS Pharmacy, USA
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo pill produced by NOW FOODS, USA
arm group label: L-citrulline
arm group type: Experimental
description: L-citrulline capsule (750 mg) provided by NOW FOODS
intervention type: Drug
intervention name: Caffeine
description: A 200 mg caffeine tablet was given to subject to examine the drugs effect on arterial function.
arm group label: Caffeine
other name: Caffeine tablet (CVS Pharmacy)
intervention type: Drug
intervention name: Placebo
description: A 750 mg placebo capsule (maltodextrin) was given to subjects to examine the effect of the drug on arterial function.
arm group label: Placebo
other name: Placebo from NOW FOODS, USA
intervention type: Dietary Supplement
intervention name: L-citrulline
description: L-citrulline was used to examine the effect of the supplement on arterial function.
arm group label: L-citrulline
other name: L-citrulline (750 mg/capsule)
criteria: 
gender: Male
minimum age: 18 Years
maximum age: 40 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Arturo Figueroa, M.D. Ph.D
role: Principal Investigator
affiliation: Florida State University
responsible party type: Principal Investigator
investigator affiliation: Florida State University
investigator full name: Arturo Figueroa
investigator title: Associate Professor
mesh term: Hypertension
mesh term: Caffeine
sharing ipd: No
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 