<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/NCT03002090</url>
  </required_header>
  <id_info>
    <org_study_id>IRB #: 1402004495</org_study_id>
    <nct_id>NCT03002090</nct_id>
  </id_info>
  <brief_title>Defining the Functional Role of Iron in Aerobic Training and Physical Performance</brief_title>
  <official_title>Defining the Functional and Metabolic Role of Iron in Aerobic Training and Physical Performance</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Cornell University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Cornell University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Iron deficiency is known to negatively impact physical performance, attention, and time spent&#xD;
      doing physical activity. As a result, an iron deficient person must expend more energy to&#xD;
      complete the same amount of work as someone who is healthy. Another interesting relationship&#xD;
      has been observed between exercise training and iron status in that women who participate in&#xD;
      exercise training often have higher rates of iron deficiency than sedentary women. ID is&#xD;
      commonly treated using daily iron supplementation. However, it is currently unknown whether&#xD;
      participating in regular exercise somehow impacts the effectiveness of iron supplementation.&#xD;
      Iron deficient women who participate in exercise programs may potentially benefit less from&#xD;
      iron supplementation than those who do not. Another common treatment for the symptoms of iron&#xD;
      deficiency is the traditional Chinese herbal treatment, Ba-Zhen-Ke-Li (BZKL). While studies&#xD;
      have shown that BZKL impacts expression of some iron-related proteins and increases endurance&#xD;
      performance in rats, no studies have examined the efficacy of BZKL in improving iron markers&#xD;
      or physical performance in humans. This study will compare the efficacy of BZKL in improving&#xD;
      iron status and physical performance with that of ferrous sulfate supplementation. The&#xD;
      Cornell research team will achieve these objectives in collaboration with colleagues at&#xD;
      Kunming Medical University (KMU) in Kunming, China. A double-blind, randomized, placebo&#xD;
      controlled study will be conducted by a Cornell graduate student at KMU. The subjects will be&#xD;
      healthy women, age 18-26 years, attending KMU. Blood samples will be collected and analyzed&#xD;
      for measures of iron).&#xD;
&#xD;
      Subjects will be randomly assigned to receive 50 mg of ferrous sulfate (10 mg of elemental&#xD;
      iron), 6mg of BZKL, or an identical placebo pill twice daily for 8 weeks. Subjects will be&#xD;
      further randomly sub-divided to receive aerobic exercise training or no training during the&#xD;
      8-week supplementation period. At weeks 4 and 8, subjects will perform the same series of&#xD;
      tests as was performed at baseline. The investigators hypothesize that: 1. the women who&#xD;
      train and received iron will have smaller improvements in iron status than those who do not&#xD;
      train 2. The women who receive iron and train will have greater improvements in physical&#xD;
      performance than those who train and do not receive iron, and 3. The women who receive BZKL&#xD;
      will improve their iron status or physical performance more than those who receive placebo.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background: Despite the overall improvements in malnutrition in the Chinese population, iron&#xD;
      deficiency (ID) and iron deficiency anemia (low iron and low hemoglobin, IDA) are still&#xD;
      widely prevalent in China. According to recent studies, the prevalence of anemia in Chinese&#xD;
      women of childbearing age is 20% and can be as high as 30% in rural areas, with 85% of anemia&#xD;
      cases resulting from ID. Diabetes, heart disease, and obesity are also highly prevalent in&#xD;
      China - though the Chinese government is taking actions against these epidemics, often via&#xD;
      interventions promoting physical activity. Iron deficiency without anemia (IDNA) can impair&#xD;
      adult physical performance and lowers time spent doing voluntary physical activities.&#xD;
      However, iron supplementation intended to alleviate IDNA may be less effective in those who&#xD;
      are physically active, suggesting an intricate, but currently undefined, relationship between&#xD;
      iron status, exercise, and physical performance capacity. A combined analysis of iron status,&#xD;
      exercise training, and physical performance in Chinese women could illuminate interactions&#xD;
      between these factors and their role in diabetes and obesity reduction.&#xD;
&#xD;
      One common treatment for the symptoms of iron deficiency is the traditional Chinese herbal&#xD;
      treatment, Ba-Zhen-Ke-Li (BZKL). While studies have shown that BZKL impacts expression of&#xD;
      some iron-related proteins and increases endurance performance in rats, no studies have&#xD;
      examined the efficacy of BZKL in improving iron markers or physical performance in humans.&#xD;
      This study will compare the efficacy of BZKL in improving iron status and physical&#xD;
      performance with that of ferrous sulfate supplementation.&#xD;
&#xD;
      Significance and Specific Aims:&#xD;
&#xD;
      The goal of the proposed research is to clarify the relationship between iron status,&#xD;
      physical performance, and aerobic exercise training. By conducting an iron intervention study&#xD;
      in combination with an exercise training program, the investigators can examine the modifying&#xD;
      effect of iron status on the physical performance changes from aerobic exercise training as&#xD;
      well as the modifying effect of participation in aerobic exercise in maintenance of iron&#xD;
      status. To achieve this goal, a randomized double-blind, placebo controlled trial will be&#xD;
      conducted with Chinese collegiate women.&#xD;
&#xD;
      The proposed work will be organized along three specific aims:&#xD;
&#xD;
      Aim I: To determine how changes in iron status, alone or in combination with exercise&#xD;
      training, influence physical performance. Hypothesis: Subjects who both improve iron status&#xD;
      and receive exercise training will show improvements in physical performance greater than the&#xD;
      additive improvements resulting from either treatment alone. This result would suggest iron&#xD;
      replete individuals benefit more from exercise training than those who are iron deficient.&#xD;
&#xD;
      Aim II: To determine how aerobic exercise training affects the maintenance of iron&#xD;
      homeostasis. Hypothesis: Subjects participating in exercise training will show smaller&#xD;
      improvements in iron status from iron supplementation than sedentary subjects who receive the&#xD;
      same iron supplementation. This would suggest regular exercise training negatively impacts&#xD;
      iron absorption, iron excretion and/or iron homeostasis.&#xD;
&#xD;
      Aim III: To determine whether BZKL can be used as an alternative to iron supplementation for&#xD;
      improving iron status or physical performance of iron deficient, non-anemic women.&#xD;
      Hypothesis: Those women who receive BZKL will improve in iron status and physical performance&#xD;
      measures more than those who receive placebo.&#xD;
&#xD;
      The proposed research in Aims 1 and 2 is important because there is no known explanation for&#xD;
      the observed relationships between iron, exercise training, and physical performance in IDNA.&#xD;
      This research will allow clarification of the role that iron status plays in modifying the&#xD;
      effects of exercise training on physical performance as well as whether participation in&#xD;
      exercise impacts effectiveness of iron supplementation in improving iron status.&#xD;
&#xD;
      The long-term significance of this research is that establishing these relationships will&#xD;
      further the current understanding of how iron status impacts and is impacted by aerobic&#xD;
      exercise and physical performance. This knowledge could lead to improved physical activity&#xD;
      interventions, which help reduce chronic diseases like obesity and diabetes in populations&#xD;
      with high prevalence of ID, such as the U.S. and China. It will also help to inform iron&#xD;
      interventions designed to alleviate ID in physically active populations, such as rural&#xD;
      Chinese laborers and women in developed countries who participate in aerobic training to&#xD;
      improve fitness.&#xD;
&#xD;
      Research Design and Methods:&#xD;
&#xD;
      Participants will be female subjects between the ages of 18-26 years with low body iron but&#xD;
      normal hemoglobin (Hb) levels, (ferritin &lt;20 μg/L and Hb &gt; 120 g/L) who are otherwise&#xD;
      healthy.&#xD;
&#xD;
      The study will be a randomized double-blind, placebo controlled trial with a 3x2 design.&#xD;
      Power calculations were based on the pilot study performed by the investigators in Shanghai&#xD;
      in 2013 and a study by Brownlie et al. Sample size was calculated to require 24 women per&#xD;
      group, which was expanded to 29 subjects per group to allow for sample dropout. Subjects will&#xD;
      be randomized to receive either 50mg of ferrous sulfate capsule twice a day (20mg elemental&#xD;
      iron/day), 6 mg of BaZhen KeLi, or identical placebo capsules for 8 weeks. Half of each&#xD;
      supplement group will also be randomly assigned to receive 8 weeks of aerobic exercise&#xD;
      training (5 days/week, 25 minutes/day) or no training.&#xD;
&#xD;
      At weeks 0, 4, and 8 subjects will complete the following:&#xD;
&#xD;
        1. Anthropometric measurements (height, weight, skinfold thickness)&#xD;
&#xD;
        2. Physical activity and 4-day dietary intake questionnaires&#xD;
&#xD;
        3. Resting venous blood draw for iron status assessment&#xD;
&#xD;
        4. Exercise testing (VO2max test and energetic efficiency test)&#xD;
&#xD;
      To address Aims 1 and 2, the investigators will compare energetic efficiency, maximum ability&#xD;
      to use oxygen, ventilatory threshold, and blood lactate concentrations at baseline, after&#xD;
      supplementation (or placebo), and after exercise training (or no training). The 3x2 study&#xD;
      design will allow for the determination of whether subjects receiving iron benefit more from&#xD;
      exercise training. The investigators will also examine whether participating in exercise&#xD;
      training affects iron homeostasis or lowers iron status.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>August 2014</start_date>
  <completion_date type="Actual">June 2015</completion_date>
  <primary_completion_date type="Actual">June 2015</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>Factorial Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Concentration of serum ferritin in µg/L</measure>
    <time_frame>Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.</time_frame>
    <description>Changes from week 0 to weeks 4 and 8 measured both within and between groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of soluble transferrin receptor in mg/L</measure>
    <time_frame>Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.</time_frame>
    <description>Changes from week 0 to weeks 4 and 8 measured both within and between groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of hemoglobin g/L</measure>
    <time_frame>Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.</time_frame>
    <description>Changes from week 0 to weeks 4 and 8 measured both within and between groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of alpha-1-acid glycoprotein in g/L</measure>
    <time_frame>Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.</time_frame>
    <description>Changes from week 0 to weeks 4 and 8 measured both within and between groups.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Concentration of C-reactive protein in mg/L</measure>
    <time_frame>Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.</time_frame>
    <description>Changes from week 0 to weeks 4 and 8 measured both within and between groups.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Human performance as assessed by maximal capacity for oxygen uptake (mL/min/kg body weight)</measure>
    <time_frame>Change from weeks 0 to 8. Change from weeks 0 to 4.</time_frame>
    <description>Changes from week 0 to weeks 4 and 8 measured both within and between groups.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Human performance as assessed by energetic efficiency (in %)</measure>
    <time_frame>Change from weeks 0 to 8. Change from weeks 0 to 4.</time_frame>
    <description>Changes from week 0 to weeks 4 and 8 measured both within and between groups.</description>
  </secondary_outcome>
  <number_of_arms>6</number_of_arms>
  <enrollment type="Actual">109</enrollment>
  <condition>Iron Deficiency Without Anemia</condition>
  <arm_group>
    <arm_group_label>Iron trained</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Iron Untrained</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>BZKL Trained</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>BZKL Untrained</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Trained</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo Untrained</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Iron trained</intervention_name>
    <description>Ferrous sulfate: 100 mg/day of FeSO4 dosed in 2 capsules taken individually by mouth with breakfast and dinner. Capsules were made with FeSO4 and dextrose. Analysis has shown that each capsule contains 11mg of elemental iron, which is expected to be absorbed at roughly 33% bioavailability.&#xD;
Aerobic Training: 25 minutes/day, 5 days/week for 8 weeks working at an intensity between 75-85% of age-predicted maximum heart rate.</description>
    <arm_group_label>Iron trained</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Iron Untrained</intervention_name>
    <description>1. Ferrous sulfate: 100 mg/day of FeSO4 dosed in 2 capsules taken individually by mouth with breakfast and dinner. Capsules were made with FeSO4 and dextrose. Analysis has shown that each capsule contains 11mg of elemental iron, which is expected to be absorbed at roughly 33% bioavailability.</description>
    <arm_group_label>Iron Untrained</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>BZKL Trained</intervention_name>
    <description>BaZhen KeLi capsules: Traditional Chinese herbal supplement composed of: Radix Paeoniae Alba (White peony root), Rhizoma Atractylodis (Atractylodes), Rhizoma Chuanxiong (Chuanxiong), Radix Angelicae Sinensis (Angelica), Radix Codonopsis Pilosula (Codonopsis), Poria cocos (Poria), licorice, and Rehmannia glutinosa Each pill contained 5g of licorice and 10g of all other ingredients. Dosed in 2 capsules taken individually by mouth with breakfast and dinner. Analysis has shown that each capsule contained 0.5mg of elemental iron.&#xD;
Aerobic Training: 25 minutes/day, 5 days/week for 8 weeks working at an intensity between 75-85% of age-predicted maximum heart rate.</description>
    <arm_group_label>BZKL Trained</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>BZKL Untrained</intervention_name>
    <description>1. BaZhen KeLi capsules: Traditional Chinese herbal supplement composed of: Radix Paeoniae Alba (White peony root), Rhizoma Atractylodis (Atractylodes), Rhizoma Chuanxiong (Chuanxiong), Radix Angelicae Sinensis (Angelica), Radix Codonopsis Pilosula (Codonopsis), Poria cocos (Poria), licorice, and Rehmannia glutinosa Each pill contained 5g of licorice and 10g of all other ingredients. Dosed in 2 capsules taken individually by mouth with breakfast and dinner. Analysis has shown that each capsule contained 0.5mg of elemental iron.</description>
    <arm_group_label>BZKL Untrained</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo Trained</intervention_name>
    <description>1. Aerobic Training: 25 minutes/day, 5 days/week for 8 weeks working at an intensity between 75-85% of age-predicted maximum heart rate.</description>
    <arm_group_label>Placebo Trained</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo Untrained</intervention_name>
    <description>No intervention</description>
    <arm_group_label>Placebo Untrained</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-26&#xD;
&#xD;
          -  Must be able to complete exercise on a stationary bicycle&#xD;
&#xD;
          -  Clinical diagnosis of iron depletion without severe anemia (sFer&lt; 25µg/L, Hb&gt;110g/L)&#xD;
&#xD;
          -  Willing to comply with the 8-week supplementation and if assigned, training program&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  age less than 18&#xD;
&#xD;
          -  severe anemia (Hb&lt;90g/L in blood analyses)&#xD;
&#xD;
          -  current pregnancy or pregnancy within the previous year&#xD;
&#xD;
          -  recent infectious illness or fever&#xD;
&#xD;
          -  current inflammation or chronic inflammatory diseases (AGP &gt; 1.0 g/L in blood&#xD;
             analyses)&#xD;
&#xD;
          -  hemolytic anemia&#xD;
&#xD;
          -  chronic respiratory disease&#xD;
&#xD;
          -  musculoskeletal problems&#xD;
&#xD;
          -  history of eating disorders&#xD;
&#xD;
          -  smoking, BMI &lt; 18 or &gt;24 kg/m2&#xD;
&#xD;
          -  consumption of medications that may affect dietary iron intake or absorption or that&#xD;
             have anticoagulant properties&#xD;
&#xD;
          -  participation in varsity sports team&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>26 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jere Haas, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Cornell University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kunming Medical University, Department of Nursing,</name>
      <address>
        <city>Chenggong</city>
        <state>Yunnan</state>
        <country>China</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>China</country>
  </location_countries>
  <verification_date>December 2016</verification_date>
  <study_first_submitted>December 14, 2016</study_first_submitted>
  <study_first_submitted_qc>December 20, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 23, 2016</study_first_posted>
  <last_update_submitted>December 20, 2016</last_update_submitted>
  <last_update_submitted_qc>December 20, 2016</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 23, 2016</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>iron deficiency</keyword>
  <keyword>anemia</keyword>
  <keyword>exercise training</keyword>
  <keyword>aerobic</keyword>
  <keyword>performance</keyword>
  <keyword>Chinese medicine</keyword>
  <keyword>BaZhen KeLi</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Anemia, Iron-Deficiency</mesh_term>
    <mesh_term>Iron Deficiencies</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Iron</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03002090
org study id: IRB #: 1402004495
nct id: NCT03002090
lead sponsor: 
has dmc: No
Iron deficiency is known to negatively impact physical performance, attention, and time spent
      doing physical activity. As a result, an iron deficient person must expend more energy to
      complete the same amount of work as someone who is healthy. Another interesting relationship
      has been observed between exercise training and iron status in that women who participate in
      exercise training often have higher rates of iron deficiency than sedentary women. ID is
      commonly treated using daily iron supplementation. However, it is currently unknown whether
      participating in regular exercise somehow impacts the effectiveness of iron supplementation.
      Iron deficient women who participate in exercise programs may potentially benefit less from
      iron supplementation than those who do not. Another common treatment for the symptoms of iron
      deficiency is the traditional Chinese herbal treatment, Ba-Zhen-Ke-Li (BZKL). While studies
      have shown that BZKL impacts expression of some iron-related proteins and increases endurance
      performance in rats, no studies have examined the efficacy of BZKL in improving iron markers
      or physical performance in humans. This study will compare the efficacy of BZKL in improving
      iron status and physical performance with that of ferrous sulfate supplementation. The
      Cornell research team will achieve these objectives in collaboration with colleagues at
      Kunming Medical University (KMU) in Kunming, China. A double-blind, randomized, placebo
      controlled study will be conducted by a Cornell graduate student at KMU. The subjects will be
      healthy women, age 18-26 years, attending KMU. Blood samples will be collected and analyzed
      for measures of iron).

      Subjects will be randomly assigned to receive 50 mg of ferrous sulfate (10 mg of elemental
      iron), 6mg of BZKL, or an identical placebo pill twice daily for 8 weeks. Subjects will be
      further randomly sub-divided to receive aerobic exercise training or no training during the
      8-week supplementation period. At weeks 4 and 8, subjects will perform the same series of
      tests as was performed at baseline. The investigators hypothesize that: 1. the women who
      train and received iron will have smaller improvements in iron status than those who do not
      train 2. The women who receive iron and train will have greater improvements in physical
      performance than those who train and do not receive iron, and 3. The women who receive BZKL
      will improve their iron status or physical performance more than those who receive placebo.
Background: Despite the overall improvements in malnutrition in the Chinese population, iron
      deficiency (ID) and iron deficiency anemia (low iron and low hemoglobin, IDA) are still
      widely prevalent in China. According to recent studies, the prevalence of anemia in Chinese
      women of childbearing age is 20% and can be as high as 30% in rural areas, with 85% of anemia
      cases resulting from ID. Diabetes, heart disease, and obesity are also highly prevalent in
      China - though the Chinese government is taking actions against these epidemics, often via
      interventions promoting physical activity. Iron deficiency without anemia (IDNA) can impair
      adult physical performance and lowers time spent doing voluntary physical activities.
      However, iron supplementation intended to alleviate IDNA may be less effective in those who
      are physically active, suggesting an intricate, but currently undefined, relationship between
      iron status, exercise, and physical performance capacity. A combined analysis of iron status,
      exercise training, and physical performance in Chinese women could illuminate interactions
      between these factors and their role in diabetes and obesity reduction.

      One common treatment for the symptoms of iron deficiency is the traditional Chinese herbal
      treatment, Ba-Zhen-Ke-Li (BZKL). While studies have shown that BZKL impacts expression of
      some iron-related proteins and increases endurance performance in rats, no studies have
      examined the efficacy of BZKL in improving iron markers or physical performance in humans.
      This study will compare the efficacy of BZKL in improving iron status and physical
      performance with that of ferrous sulfate supplementation.

      Significance and Specific Aims:

      The goal of the proposed research is to clarify the relationship between iron status,
      physical performance, and aerobic exercise training. By conducting an iron intervention study
      in combination with an exercise training program, the investigators can examine the modifying
      effect of iron status on the physical performance changes from aerobic exercise training as
      well as the modifying effect of participation in aerobic exercise in maintenance of iron
      status. To achieve this goal, a randomized double-blind, placebo controlled trial will be
      conducted with Chinese collegiate women.

      The proposed work will be organized along three specific aims:

      Aim I: To determine how changes in iron status, alone or in combination with exercise
      training, influence physical performance. Hypothesis: Subjects who both improve iron status
      and receive exercise training will show improvements in physical performance greater than the
      additive improvements resulting from either treatment alone. This result would suggest iron
      replete individuals benefit more from exercise training than those who are iron deficient.

      Aim II: To determine how aerobic exercise training affects the maintenance of iron
      homeostasis. Hypothesis: Subjects participating in exercise training will show smaller
      improvements in iron status from iron supplementation than sedentary subjects who receive the
      same iron supplementation. This would suggest regular exercise training negatively impacts
      iron absorption, iron excretion and/or iron homeostasis.

      Aim III: To determine whether BZKL can be used as an alternative to iron supplementation for
      improving iron status or physical performance of iron deficient, non-anemic women.
      Hypothesis: Those women who receive BZKL will improve in iron status and physical performance
      measures more than those who receive placebo.

      The proposed research in Aims 1 and 2 is important because there is no known explanation for
      the observed relationships between iron, exercise training, and physical performance in IDNA.
      This research will allow clarification of the role that iron status plays in modifying the
      effects of exercise training on physical performance as well as whether participation in
      exercise impacts effectiveness of iron supplementation in improving iron status.

      The long-term significance of this research is that establishing these relationships will
      further the current understanding of how iron status impacts and is impacted by aerobic
      exercise and physical performance. This knowledge could lead to improved physical activity
      interventions, which help reduce chronic diseases like obesity and diabetes in populations
      with high prevalence of ID, such as the U.S. and China. It will also help to inform iron
      interventions designed to alleviate ID in physically active populations, such as rural
      Chinese laborers and women in developed countries who participate in aerobic training to
      improve fitness.

      Research Design and Methods:

      Participants will be female subjects between the ages of 18-26 years with low body iron but
      normal hemoglobin (Hb) levels, (ferritin <20 μg/L and Hb > 120 g/L) who are otherwise
      healthy.

      The study will be a randomized double-blind, placebo controlled trial with a 3x2 design.
      Power calculations were based on the pilot study performed by the investigators in Shanghai
      in 2013 and a study by Brownlie et al. Sample size was calculated to require 24 women per
      group, which was expanded to 29 subjects per group to allow for sample dropout. Subjects will
      be randomized to receive either 50mg of ferrous sulfate capsule twice a day (20mg elemental
      iron/day), 6 mg of BaZhen KeLi, or identical placebo capsules for 8 weeks. Half of each
      supplement group will also be randomly assigned to receive 8 weeks of aerobic exercise
      training (5 days/week, 25 minutes/day) or no training.

      At weeks 0, 4, and 8 subjects will complete the following:

        1. Anthropometric measurements (height, weight, skinfold thickness)

        2. Physical activity and 4-day dietary intake questionnaires

        3. Resting venous blood draw for iron status assessment

        4. Exercise testing (VO2max test and energetic efficiency test)

      To address Aims 1 and 2, the investigators will compare energetic efficiency, maximum ability
      to use oxygen, ventilatory threshold, and blood lactate concentrations at baseline, after
      supplementation (or placebo), and after exercise training (or no training). The 3x2 study
      design will allow for the determination of whether subjects receiving iron benefit more from
      exercise training. The investigators will also examine whether participating in exercise
      training affects iron homeostasis or lowers iron status.
allocation: Randomized
intervention model: Factorial Assignment
primary purpose: Basic Science
masking: Double (Participant, Investigator)
measure: Concentration of serum ferritin in µg/L
time frame: Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.
description: Changes from week 0 to weeks 4 and 8 measured both within and between groups.
measure: Concentration of soluble transferrin receptor in mg/L
time frame: Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.
description: Changes from week 0 to weeks 4 and 8 measured both within and between groups.
measure: Concentration of hemoglobin g/L
time frame: Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.
description: Changes from week 0 to weeks 4 and 8 measured both within and between groups.
measure: Concentration of alpha-1-acid glycoprotein in g/L
time frame: Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.
description: Changes from week 0 to weeks 4 and 8 measured both within and between groups.
measure: Concentration of C-reactive protein in mg/L
time frame: Change in concentration of the 5 biomarkers from weeks 0 to 8. Change in concentration of the 5 biomarkers from weeks 0 to 4.
description: Changes from week 0 to weeks 4 and 8 measured both within and between groups.
measure: Human performance as assessed by maximal capacity for oxygen uptake (mL/min/kg body weight)
time frame: Change from weeks 0 to 8. Change from weeks 0 to 4.
description: Changes from week 0 to weeks 4 and 8 measured both within and between groups.
measure: Human performance as assessed by energetic efficiency (in %)
time frame: Change from weeks 0 to 8. Change from weeks 0 to 4.
description: Changes from week 0 to weeks 4 and 8 measured both within and between groups.
arm group label: Iron trained
arm group type: Experimental
arm group label: Iron Untrained
arm group type: Experimental
arm group label: BZKL Trained
arm group type: Experimental
arm group label: BZKL Untrained
arm group type: Experimental
arm group label: Placebo Trained
arm group type: Experimental
arm group label: Placebo Untrained
arm group type: Placebo Comparator
intervention type: Dietary Supplement
intervention name: Iron trained
description: Ferrous sulfate: 100 mg/day of FeSO4 dosed in 2 capsules taken individually by mouth with breakfast and dinner. Capsules were made with FeSO4 and dextrose. Analysis has shown that each capsule contains 11mg of elemental iron, which is expected to be absorbed at roughly 33% bioavailability.
Aerobic Training: 25 minutes/day, 5 days/week for 8 weeks working at an intensity between 75-85% of age-predicted maximum heart rate.
arm group label: Iron trained
intervention type: Dietary Supplement
intervention name: Iron Untrained
description: 1. Ferrous sulfate: 100 mg/day of FeSO4 dosed in 2 capsules taken individually by mouth with breakfast and dinner. Capsules were made with FeSO4 and dextrose. Analysis has shown that each capsule contains 11mg of elemental iron, which is expected to be absorbed at roughly 33% bioavailability.
arm group label: Iron Untrained
intervention type: Dietary Supplement
intervention name: BZKL Trained
description: BaZhen KeLi capsules: Traditional Chinese herbal supplement composed of: Radix Paeoniae Alba (White peony root), Rhizoma Atractylodis (Atractylodes), Rhizoma Chuanxiong (Chuanxiong), Radix Angelicae Sinensis (Angelica), Radix Codonopsis Pilosula (Codonopsis), Poria cocos (Poria), licorice, and Rehmannia glutinosa Each pill contained 5g of licorice and 10g of all other ingredients. Dosed in 2 capsules taken individually by mouth with breakfast and dinner. Analysis has shown that each capsule contained 0.5mg of elemental iron.
Aerobic Training: 25 minutes/day, 5 days/week for 8 weeks working at an intensity between 75-85% of age-predicted maximum heart rate.
arm group label: BZKL Trained
intervention type: Dietary Supplement
intervention name: BZKL Untrained
description: 1. BaZhen KeLi capsules: Traditional Chinese herbal supplement composed of: Radix Paeoniae Alba (White peony root), Rhizoma Atractylodis (Atractylodes), Rhizoma Chuanxiong (Chuanxiong), Radix Angelicae Sinensis (Angelica), Radix Codonopsis Pilosula (Codonopsis), Poria cocos (Poria), licorice, and Rehmannia glutinosa Each pill contained 5g of licorice and 10g of all other ingredients. Dosed in 2 capsules taken individually by mouth with breakfast and dinner. Analysis has shown that each capsule contained 0.5mg of elemental iron.
arm group label: BZKL Untrained
intervention type: Dietary Supplement
intervention name: Placebo Trained
description: 1. Aerobic Training: 25 minutes/day, 5 days/week for 8 weeks working at an intensity between 75-85% of age-predicted maximum heart rate.
arm group label: Placebo Trained
intervention type: Dietary Supplement
intervention name: Placebo Untrained
description: No intervention
arm group label: Placebo Untrained
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 26 Years
healthy volunteers: No
last name: Jere Haas, PhD
role: Principal Investigator
affiliation: Cornell University
facility: 
country: China
responsible party type: Sponsor
mesh term: Anemia, Iron-Deficiency
mesh term: Iron Deficiencies
mesh term: Iron
sharing ipd: No