<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/NCT04471805</url>
  </required_header>
  <id_info>
    <org_study_id>202005124</org_study_id>
    <nct_id>NCT04471805</nct_id>
  </id_info>
  <brief_title>4 mA tDCS, Estrogen, and Leg Muscle Fatigability</brief_title>
  <official_title>Estrogen Levels and Leg Muscle Fatigability in Eumenorrheic Young Women After 4 mA Transcranial Direct Current Stimulation</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Iowa</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>University of Iowa</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>Yes</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      The majority of transcranial direct current stimulation (tDCS) studies have failed to&#xD;
      consider sex as a modulating factor. This neglect may partly account for the high&#xD;
      inter-subject variability bemoaned by many tDCS investigators (e.g., approximately 50% of&#xD;
      participants do not respond to tDCS) and has certainly delayed progress in the field.&#xD;
      Therefore, research into how sex influences stimulation-related outcomes is vital to fully&#xD;
      understand the underlying mechanisms of tDCS, which has shown great inconsistency.&#xD;
&#xD;
      Because of the menstrual cycle, the hormonal levels of women fluctuate considerably more than&#xD;
      in men. Importantly, these hormonal variations might impact the efficacy of neuromodulatory&#xD;
      tools, like tDCS. It is suggested that estrogen, which is high in the second follicular&#xD;
      phase, reinforces excitatory mechanisms in the motor cortex. However, because anodal tDCS&#xD;
      enhances cortical excitation there is also a possibility of excessive excitability. For&#xD;
      instance, anodal tDCS may lead to overexcitation and non-optimal performance when it is&#xD;
      applied in the second follicular phase of the menstrual cycle. Currently, there is a lack of&#xD;
      knowledge on how the phases of the menstrual cycle affect tDCS performance outcomes in&#xD;
      healthy young women because no studies have examined if and how the phases of the menstrual&#xD;
      cycle alter tDCS efficacy.&#xD;
&#xD;
      This study is critical for determining the optimal time to administer anodal tDCS, and the&#xD;
      ideal intensity for that administration, to achieve the most beneficial results. Furthermore,&#xD;
      this investigation will emphasize the need for future tDCS studies to test women during the&#xD;
      same menstrual cycle phase.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The majority of transcranial direct current stimulation (tDCS) studies have failed to&#xD;
      consider sex as a modulating factor. This neglect may partly account for the high&#xD;
      inter-subject variability bemoaned by many tDCS investigators (e.g., approximately 50% of&#xD;
      participants do not respond to tDCS) and has certainly delayed progress in the field.&#xD;
      Therefore, research into how sex influences stimulation-related outcomes is vital to fully&#xD;
      understand the underlying mechanisms of tDCS, which has shown great inconsistency.&#xD;
&#xD;
      Because of the menstrual cycle, the hormonal levels of women fluctuate considerably more than&#xD;
      in men. There are two main phases of the menstrual cycle: 1) the follicular phase,&#xD;
      characterized by low levels of estradiol and progesterone (first follicular phase, days 1-7)&#xD;
      followed by increased levels of estradiol and low levels of progesterone (second follicular&#xD;
      phase, days 7-14); and 2) the luteal phase (days 14-28), characterized by moderate estradiol&#xD;
      and high progesterone levels. Importantly, these hormonal variations might impact the&#xD;
      efficacy of neuromodulatory tools, like tDCS.&#xD;
&#xD;
      It is suggested that estrogen, which is high in the second follicular phase, reinforces&#xD;
      excitatory mechanisms in the motor cortex. Thus, it appears that higher levels of estradiol&#xD;
      increase cortical excitability. However, because anodal tDCS enhances cortical excitation&#xD;
      there is also a possibility of excessive excitability. For instance, anodal tDCS may lead to&#xD;
      overexcitation and nonoptimal performance when it is applied in the second follicular phase&#xD;
      of the menstrual cycle. Currently, there is a lack of knowledge on how the phases of the&#xD;
      menstrual cycle affect tDCS performance outcomes in healthy young women because no studies&#xD;
      have examined if and how the phases of the menstrual cycle alter tDCS efficacy.&#xD;
&#xD;
      This research will be significant because the changing hormone levels during the different&#xD;
      phases of menstruation in women is an especially important factor for minimizing response&#xD;
      variability from tDCS. Thus, this study is critical for determining the optimal time to&#xD;
      administer anodal tDCS, and the ideal intensity for that administration, to achieve the most&#xD;
      beneficial results. Furthermore, this investigation will emphasize the need for future tDCS&#xD;
      studies to test women during the same menstrual cycle phase.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2020</start_date>
  <completion_date type="Actual">November 1, 2021</completion_date>
  <primary_completion_date type="Actual">November 1, 2021</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Fatigue Index From the Isokinetic Fatigue Test</measure>
    <time_frame>Completed at each visit, spaced approximately 14 days apart for 2 consecutive months</time_frame>
    <description>Perform 40 consecutive flexion and extension repetitions of the knee on the dominant leg. After a 10 minute rest, do the same task on the non-dominant leg.&#xD;
The fatigue index was calculated using the greatest torque from the relevant repetitions of the fatigue test as follows: ([mean of reps 3 through 7-mean of last five reps]/mean of reps 3 through 7) X 100 and is expressed as a percentage of decline in torque production.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Muscle Activity During the Strength and Fatigue Tests</measure>
    <time_frame>Completed at each visit, spaced approximately 14 days apart for 2 consecutive months</time_frame>
    <description>Collect electromyographic (EMG; muscle activity) information during the fatigue tests. Muscle activity is measured as electrical signals/voltages.&#xD;
The muscle activity of the knee extensors (rectus femoris, vastus medialis, and vastus lateralis) was averaged to represent the cumulative activity of this muscle group. The first two repetitions of the fatigue test were considered adaptation repetitions and were removed. Therefore, the remaining 38 repetitions were used for the average EMG analyses. The subsequent 38 repetitions were also organized into 8 windows. The first seven windows consisted of five consecutive and non-overlapping repetitions (e.g., window 2 = reps 8-12; window 3 = reps 13-17, etc.) while the last (eighth) window was comprised of the final three repetitions.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Estrogen Level</measure>
    <time_frame>Completed at each visit, spaced approximately 14 days apart for 2 consecutive months</time_frame>
    <description>Staff nurses collected 4.5 mL of blood from the median cubital vein of the left arm (total volume collected per subject = 9 mL) for the estrogen assay. Samples were immediately analyzed for serum estrogen levels after the blood draws by University of Iowa Hospitals and Clinics Pathology technicians using an Electrochemiluminescence Assay (Roche Diagnostics, Basel, Switzerland). The estrogen assay had a lower limit of detection of 5 pg/mL and a coefficient of variation of 8%.&#xD;
Because menstrual cycles have great inter- and intrasubject variability, the peak estrogen levels of the subjects were not consistently found in the late-follicular phase, which is a common failing of menstrual cycle phase calendar estimation. Thus, estrogen levels were grouped as high or low according to each individual subject's estrogen serum levels, irrespective of the anticipated/targeted phase.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">10</enrollment>
  <condition>Healthy</condition>
  <arm_group>
    <arm_group_label>Eumenorrheic Women</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Participants will have the anode (active electrode) placed over the brain area that controls their dominant leg and the cathode (return electrode) above the ipsilateral eyebrow. tDCS is administered in the early follicular phase, late follicular phase, and mid-luteal phase of their menstrual cycle.&#xD;
tDCS: Stimulation is ramped up to 4 mA over the first 30 seconds and stays at 4 mA for the remainder of the simulation time.&#xD;
Sham: Stimulation is turned on (4 mA) for 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Sham transcranial direct current stimulation 4 mA</intervention_name>
    <description>Uses weak electrical current (4 mA intensity) at the beginning and the end of a given stimulation period to control for potential placebo-like effects or participant expectation bias.</description>
    <arm_group_label>Eumenorrheic Women</arm_group_label>
    <other_name>Sham tDCS 2 mA</other_name>
  </intervention>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Transcranial direct current stimulation 4 mA</intervention_name>
    <description>Uses weak electrical current (4 mA intensity) to either increase or decrease brain excitability and improve functional or cognitive outcomes.</description>
    <arm_group_label>Eumenorrheic Women</arm_group_label>
    <other_name>tDCS 4 mA</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Has a regular menstrual cycle&#xD;
&#xD;
          2. Young adult (18-35 years)&#xD;
&#xD;
          3. Right-side dominant&#xD;
&#xD;
          4. At least 30 min of moderate-intensity, physical activity on at least 3 days of the&#xD;
             week for at least the last 3 months&#xD;
&#xD;
          5. Without chronic neurological, psychiatric, or medical conditions&#xD;
&#xD;
          6. Not taking any psychoactive medications.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Pregnant&#xD;
&#xD;
          2. Known holes or fissures in the skull&#xD;
&#xD;
          3. Metallic objects or implanted devices in the skull (e.g., metal plate)&#xD;
&#xD;
          4. Women on hormonal contraceptives/supplements.&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>35 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Thorsten Rudroff, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Health and Human Physiology</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Iowa</name>
      <address>
        <city>Iowa City</city>
        <state>Iowa</state>
        <zip>52242</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>July 10, 2020</study_first_submitted>
  <study_first_submitted_qc>July 10, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 15, 2020</study_first_posted>
  <results_first_submitted>March 19, 2023</results_first_submitted>
  <results_first_submitted_qc>April 17, 2023</results_first_submitted_qc>
  <results_first_posted type="Actual">May 10, 2023</results_first_posted>
  <last_update_submitted>April 17, 2023</last_update_submitted>
  <last_update_submitted_qc>April 17, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">May 10, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>University of Iowa</investigator_affiliation>
    <investigator_full_name>Thorsten Rudroff</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>transcranial direct current stimulation</keyword>
  <keyword>muscle fatigue</keyword>
  <keyword>brain stimulation</keyword>
  <provided_document_section>
    <provided_document>
      <document_type>Study Protocol and Statistical Analysis Plan</document_type>
      <document_has_protocol>Yes</document_has_protocol>
      <document_has_icf>No</document_has_icf>
      <document_has_sap>Yes</document_has_sap>
      <document_date>July 8, 2021</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/05/NCT04471805/Prot_SAP_001.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <group_list>
        <group group_id="P1">
          <title>Eumenorrheic Women</title>
          <description>Participants will have the anode (active electrode) placed over the brain area that controls their dominant leg and the cathode (return electrode) above the ipsilateral eyebrow. tDCS is administered in the early follicular phase, late follicular phase, and mid-luteal phase of their menstrual cycle.&#xD;
tDCS: Stimulation is ramped up to 4 mA over the first 30 seconds and stays at 4 mA for the remainder of the simulation time.&#xD;
Sham: Stimulation is turned on (4 mA) for 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>tDCS, Early Follicular Phase</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Sham, Early Follicular Phase</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>tDCS, Late Follicular Phase</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Sham, Late Follicular Phase</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>tDCS, Mid-Luteal Phase</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Sham, Mid-Luteal Phase</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="10"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Eumenorrheic Women</title>
          <description>Biological women will have the anode (active electrode) placed over the brain area the controls their dominant leg and the cathode (return electrode) above the eyebrow on the opposite side of the head.&#xD;
Transcranial direct current stimulation 2 mA: Uses weak electrical current (2 mA intensity) to either increase or decrease brain excitability and improve functional or cognitive outcomes. Stimulation is ramped up to 2 mA over the first 30 seconds and stays at 2 mA for the remainder of the stimulation time.&#xD;
Sham transcranial direct current stimulation 2 mA/4mA: Uses weak electrical current (2 mA or 4 mA intensity) at the beginning and the end of a given stimulation period to control for potential placebo-like effects or participant expectation bias. Stimulation is turned on (2 mA or 4 mA) for the 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="10"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="24.3" spread="5.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Race (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>American Indian or Alaska Native</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Region of Enrollment</title>
          <units>participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>United States</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="10"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Fatigue Index From the Isokinetic Fatigue Test</title>
        <description>Perform 40 consecutive flexion and extension repetitions of the knee on the dominant leg. After a 10 minute rest, do the same task on the non-dominant leg.&#xD;
The fatigue index was calculated using the greatest torque from the relevant repetitions of the fatigue test as follows: ([mean of reps 3 through 7-mean of last five reps]/mean of reps 3 through 7) X 100 and is expressed as a percentage of decline in torque production.</description>
        <time_frame>Completed at each visit, spaced approximately 14 days apart for 2 consecutive months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Eumenorrheic Women</title>
            <description>Participants will have the anode (active electrode) placed over the brain area that controls their dominant leg and the cathode (return electrode) above the ipsilateral eyebrow. tDCS is administered in the early follicular phase, late follicular phase, and mid-luteal phase of their menstrual cycle.&#xD;
tDCS: Stimulation is ramped up to 4 mA over the first 30 seconds and stays at 4 mA for the remainder of the simulation time.&#xD;
Sham: Stimulation is turned on (4 mA) for 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.</description>
          </group>
        </group_list>
        <measure>
          <title>Fatigue Index From the Isokinetic Fatigue Test</title>
          <description>Perform 40 consecutive flexion and extension repetitions of the knee on the dominant leg. After a 10 minute rest, do the same task on the non-dominant leg.&#xD;
The fatigue index was calculated using the greatest torque from the relevant repetitions of the fatigue test as follows: ([mean of reps 3 through 7-mean of last five reps]/mean of reps 3 through 7) X 100 and is expressed as a percentage of decline in torque production.</description>
          <units>Percent decline</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>tDCS High Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="61.7" spread="10.6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sham High Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="46.7" spread="20.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>tDCS Low Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="57.28" spread="11.57"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sham Low Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="55.90" spread="8.67"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <p_value_desc>Post hoc analyses (paired t-tests and Bonferroni correction) and effect size (Cohen's d) were calculated to clarify significant main effects and interactions.</p_value_desc>
            <method>ANOVA</method>
            <method_desc>Normality and sphericity evaluated with Shapiro-Wilk test and Mauchly's test. Greenhouse-Geisser corrections used when sphericity was violated.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Muscle Activity During the Strength and Fatigue Tests</title>
        <description>Collect electromyographic (EMG; muscle activity) information during the fatigue tests. Muscle activity is measured as electrical signals/voltages.&#xD;
The muscle activity of the knee extensors (rectus femoris, vastus medialis, and vastus lateralis) was averaged to represent the cumulative activity of this muscle group. The first two repetitions of the fatigue test were considered adaptation repetitions and were removed. Therefore, the remaining 38 repetitions were used for the average EMG analyses. The subsequent 38 repetitions were also organized into 8 windows. The first seven windows consisted of five consecutive and non-overlapping repetitions (e.g., window 2 = reps 8-12; window 3 = reps 13-17, etc.) while the last (eighth) window was comprised of the final three repetitions.</description>
        <time_frame>Completed at each visit, spaced approximately 14 days apart for 2 consecutive months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Eumenorrheic Women</title>
            <description>Participants will have the anode (active electrode) placed over the brain area that controls their dominant leg and the cathode (return electrode) above the ipsilateral eyebrow. tDCS is administered in the early follicular phase, late follicular phase, and mid-luteal phase of their menstrual cycle.&#xD;
tDCS: Stimulation is ramped up to 4 mA over the first 30 seconds and stays at 4 mA for the remainder of the simulation time.&#xD;
Sham: Stimulation is turned on (4 mA) for 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.</description>
          </group>
        </group_list>
        <measure>
          <title>Muscle Activity During the Strength and Fatigue Tests</title>
          <description>Collect electromyographic (EMG; muscle activity) information during the fatigue tests. Muscle activity is measured as electrical signals/voltages.&#xD;
The muscle activity of the knee extensors (rectus femoris, vastus medialis, and vastus lateralis) was averaged to represent the cumulative activity of this muscle group. The first two repetitions of the fatigue test were considered adaptation repetitions and were removed. Therefore, the remaining 38 repetitions were used for the average EMG analyses. The subsequent 38 repetitions were also organized into 8 windows. The first seven windows consisted of five consecutive and non-overlapping repetitions (e.g., window 2 = reps 8-12; window 3 = reps 13-17, etc.) while the last (eighth) window was comprised of the final three repetitions.</description>
          <units>Microvolts</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>tDCS High Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="95.15" spread="26.46"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>tDCS Low Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="91.83" spread="16.48"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sham High Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="77.53" spread="19.71"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sham Low Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="82.35" spread="21.44"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority</non_inferiority_type>
            <p_value>&lt;0.05</p_value>
            <p_value_desc>Post hoc analyses (paired t-tests and Bonferroni correction) and effect size (Cohen's d) were calculated to clarify significant main effects and interactions.</p_value_desc>
            <method>ANOVA</method>
            <method_desc>Normality and sphericity evaluated with Shapiro-Wilk test and Mauchly's test. Greenhouse-Geisser corrections used when sphericity was violated.</method_desc>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Estrogen Level</title>
        <description>Staff nurses collected 4.5 mL of blood from the median cubital vein of the left arm (total volume collected per subject = 9 mL) for the estrogen assay. Samples were immediately analyzed for serum estrogen levels after the blood draws by University of Iowa Hospitals and Clinics Pathology technicians using an Electrochemiluminescence Assay (Roche Diagnostics, Basel, Switzerland). The estrogen assay had a lower limit of detection of 5 pg/mL and a coefficient of variation of 8%.&#xD;
Because menstrual cycles have great inter- and intrasubject variability, the peak estrogen levels of the subjects were not consistently found in the late-follicular phase, which is a common failing of menstrual cycle phase calendar estimation. Thus, estrogen levels were grouped as high or low according to each individual subject's estrogen serum levels, irrespective of the anticipated/targeted phase.</description>
        <time_frame>Completed at each visit, spaced approximately 14 days apart for 2 consecutive months</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Eumenorrheic Women</title>
            <description>Participants will have the anode (active electrode) placed over the brain area that controls their dominant leg and the cathode (return electrode) above the ipsilateral eyebrow. tDCS is administered in the early follicular phase, late follicular phase, and mid-luteal phase of their menstrual cycle.&#xD;
tDCS: Stimulation is ramped up to 4 mA over the first 30 seconds and stays at 4 mA for the remainder of the simulation time.&#xD;
Sham: Stimulation is turned on (4 mA) for 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.</description>
          </group>
        </group_list>
        <measure>
          <title>Estrogen Level</title>
          <description>Staff nurses collected 4.5 mL of blood from the median cubital vein of the left arm (total volume collected per subject = 9 mL) for the estrogen assay. Samples were immediately analyzed for serum estrogen levels after the blood draws by University of Iowa Hospitals and Clinics Pathology technicians using an Electrochemiluminescence Assay (Roche Diagnostics, Basel, Switzerland). The estrogen assay had a lower limit of detection of 5 pg/mL and a coefficient of variation of 8%.&#xD;
Because menstrual cycles have great inter- and intrasubject variability, the peak estrogen levels of the subjects were not consistently found in the late-follicular phase, which is a common failing of menstrual cycle phase calendar estimation. Thus, estrogen levels were grouped as high or low according to each individual subject's estrogen serum levels, irrespective of the anticipated/targeted phase.</description>
          <units>(pg/mL)</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="10"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>tDCS High Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="157.7" spread="101.5"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>tDCS Low Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="31.9" spread="10.9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sham High Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="137.2" spread="114.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Sham Low Estrogen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="42.9" spread="25.1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Completed at each visit, spaced approximately 14 days apart for 2 consecutive months</time_frame>
      <desc>This study was deemed to be of non-significant risk. This type of brain stimulation has established safety and tolerability data in both human and animal models.</desc>
      <group_list>
        <group group_id="E1">
          <title>Eumenorrheic Women</title>
          <description>Biological women will have the anode (active electrode) placed over the brain area the controls their dominant leg and the cathode (return electrode) above the eyebrow on the opposite side of the head.&#xD;
Transcranial direct current stimulation 2 mA: Uses weak electrical current (2 mA intensity) to either increase or decrease brain excitability and improve functional or cognitive outcomes. Stimulation is ramped up to 2 mA over the first 30 seconds and stays at 2 mA for the remainder of the stimulation time.&#xD;
Sham transcranial direct current stimulation 2 mA/4mA: Uses weak electrical current (2 mA or 4 mA intensity) at the beginning and the end of a given stimulation period to control for potential placebo-like effects or participant expectation bias. Stimulation is turned on (2 mA or 4 mA) for the 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.</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="10"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="10"/>
              </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="10"/>
              </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>Thorsten Rudroff, PhD</name_or_title>
      <organization>University of Iowa, Department of Health and Human Physiology</organization>
      <phone>(319)467-0363</phone>
      <email>thorsten-rudroff@uiowa.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/NCT04471805
org study id: 202005124
nct id: NCT04471805
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: Yes
is us export: No
The majority of transcranial direct current stimulation (tDCS) studies have failed to
      consider sex as a modulating factor. This neglect may partly account for the high
      inter-subject variability bemoaned by many tDCS investigators (e.g., approximately 50% of
      participants do not respond to tDCS) and has certainly delayed progress in the field.
      Therefore, research into how sex influences stimulation-related outcomes is vital to fully
      understand the underlying mechanisms of tDCS, which has shown great inconsistency.

      Because of the menstrual cycle, the hormonal levels of women fluctuate considerably more than
      in men. Importantly, these hormonal variations might impact the efficacy of neuromodulatory
      tools, like tDCS. It is suggested that estrogen, which is high in the second follicular
      phase, reinforces excitatory mechanisms in the motor cortex. However, because anodal tDCS
      enhances cortical excitation there is also a possibility of excessive excitability. For
      instance, anodal tDCS may lead to overexcitation and non-optimal performance when it is
      applied in the second follicular phase of the menstrual cycle. Currently, there is a lack of
      knowledge on how the phases of the menstrual cycle affect tDCS performance outcomes in
      healthy young women because no studies have examined if and how the phases of the menstrual
      cycle alter tDCS efficacy.

      This study is critical for determining the optimal time to administer anodal tDCS, and the
      ideal intensity for that administration, to achieve the most beneficial results. Furthermore,
      this investigation will emphasize the need for future tDCS studies to test women during the
      same menstrual cycle phase.
The majority of transcranial direct current stimulation (tDCS) studies have failed to
      consider sex as a modulating factor. This neglect may partly account for the high
      inter-subject variability bemoaned by many tDCS investigators (e.g., approximately 50% of
      participants do not respond to tDCS) and has certainly delayed progress in the field.
      Therefore, research into how sex influences stimulation-related outcomes is vital to fully
      understand the underlying mechanisms of tDCS, which has shown great inconsistency.

      Because of the menstrual cycle, the hormonal levels of women fluctuate considerably more than
      in men. There are two main phases of the menstrual cycle: 1) the follicular phase,
      characterized by low levels of estradiol and progesterone (first follicular phase, days 1-7)
      followed by increased levels of estradiol and low levels of progesterone (second follicular
      phase, days 7-14); and 2) the luteal phase (days 14-28), characterized by moderate estradiol
      and high progesterone levels. Importantly, these hormonal variations might impact the
      efficacy of neuromodulatory tools, like tDCS.

      It is suggested that estrogen, which is high in the second follicular phase, reinforces
      excitatory mechanisms in the motor cortex. Thus, it appears that higher levels of estradiol
      increase cortical excitability. However, because anodal tDCS enhances cortical excitation
      there is also a possibility of excessive excitability. For instance, anodal tDCS may lead to
      overexcitation and nonoptimal performance when it is applied in the second follicular phase
      of the menstrual cycle. Currently, there is a lack of knowledge on how the phases of the
      menstrual cycle affect tDCS performance outcomes in healthy young women because no studies
      have examined if and how the phases of the menstrual cycle alter tDCS efficacy.

      This research will be significant because the changing hormone levels during the different
      phases of menstruation in women is an especially important factor for minimizing response
      variability from tDCS. Thus, this study is critical for determining the optimal time to
      administer anodal tDCS, and the ideal intensity for that administration, to achieve the most
      beneficial results. Furthermore, this investigation will emphasize the need for future tDCS
      studies to test women during the same menstrual cycle phase.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Fatigue Index From the Isokinetic Fatigue Test
time frame: Completed at each visit, spaced approximately 14 days apart for 2 consecutive months
description: Perform 40 consecutive flexion and extension repetitions of the knee on the dominant leg. After a 10 minute rest, do the same task on the non-dominant leg.
The fatigue index was calculated using the greatest torque from the relevant repetitions of the fatigue test as follows: ([mean of reps 3 through 7-mean of last five reps]/mean of reps 3 through 7) X 100 and is expressed as a percentage of decline in torque production.
measure: Muscle Activity During the Strength and Fatigue Tests
time frame: Completed at each visit, spaced approximately 14 days apart for 2 consecutive months
description: Collect electromyographic (EMG; muscle activity) information during the fatigue tests. Muscle activity is measured as electrical signals/voltages.
The muscle activity of the knee extensors (rectus femoris, vastus medialis, and vastus lateralis) was averaged to represent the cumulative activity of this muscle group. The first two repetitions of the fatigue test were considered adaptation repetitions and were removed. Therefore, the remaining 38 repetitions were used for the average EMG analyses. The subsequent 38 repetitions were also organized into 8 windows. The first seven windows consisted of five consecutive and non-overlapping repetitions (e.g., window 2 = reps 8-12; window 3 = reps 13-17, etc.) while the last (eighth) window was comprised of the final three repetitions.
measure: Estrogen Level
time frame: Completed at each visit, spaced approximately 14 days apart for 2 consecutive months
description: Staff nurses collected 4.5 mL of blood from the median cubital vein of the left arm (total volume collected per subject = 9 mL) for the estrogen assay. Samples were immediately analyzed for serum estrogen levels after the blood draws by University of Iowa Hospitals and Clinics Pathology technicians using an Electrochemiluminescence Assay (Roche Diagnostics, Basel, Switzerland). The estrogen assay had a lower limit of detection of 5 pg/mL and a coefficient of variation of 8%.
Because menstrual cycles have great inter- and intrasubject variability, the peak estrogen levels of the subjects were not consistently found in the late-follicular phase, which is a common failing of menstrual cycle phase calendar estimation. Thus, estrogen levels were grouped as high or low according to each individual subject's estrogen serum levels, irrespective of the anticipated/targeted phase.
arm group label: Eumenorrheic Women
arm group type: Experimental
description: Participants will have the anode (active electrode) placed over the brain area that controls their dominant leg and the cathode (return electrode) above the ipsilateral eyebrow. tDCS is administered in the early follicular phase, late follicular phase, and mid-luteal phase of their menstrual cycle.
tDCS: Stimulation is ramped up to 4 mA over the first 30 seconds and stays at 4 mA for the remainder of the simulation time.
Sham: Stimulation is turned on (4 mA) for 30 seconds at the beginning and the end of the trial but stays at 0 mA in the intervening time.
intervention type: Device
intervention name: Sham transcranial direct current stimulation 4 mA
description: Uses weak electrical current (4 mA intensity) at the beginning and the end of a given stimulation period to control for potential placebo-like effects or participant expectation bias.
arm group label: Eumenorrheic Women
other name: Sham tDCS 2 mA
intervention type: Device
intervention name: Transcranial direct current stimulation 4 mA
description: Uses weak electrical current (4 mA intensity) to either increase or decrease brain excitability and improve functional or cognitive outcomes.
arm group label: Eumenorrheic Women
other name: tDCS 4 mA
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 35 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Thorsten Rudroff, PhD
role: Principal Investigator
affiliation: Health and Human Physiology
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: University of Iowa
investigator full name: Thorsten Rudroff
investigator title: Assistant Professor
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 