<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/NCT03801161</url>
  </required_header>
  <id_info>
    <org_study_id>PR-18006</org_study_id>
    <nct_id>NCT03801161</nct_id>
  </id_info>
  <brief_title>Influence of Inflammation on Micronutrient Status Assessment</brief_title>
  <official_title>Influence of Inflammation on Micronutrient Status Assessment</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>International Centre for Diarrhoeal Disease Research, Bangladesh</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Newcastle University, UK</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>International Centre for Diarrhoeal Disease Research, Bangladesh</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Inflammation can influence several biochemical measurements those commonly used to interpret&#xD;
      micronutrient status in children. Our primary objective is to investigate the effects of&#xD;
      inflammation on several biochemical measurements used to interpret micronutrient status in&#xD;
      children. A total of 40 infants (9-18 mo of age) will participate in this study.&#xD;
      Investigators will use PENTA vaccines as a means to induce controlled inflammation (closely&#xD;
      mimic to natural infection). PENTA is a combination of five different vaccine antigens&#xD;
      (Hepatitis B (HBV)/ Haemophilus influenza type b (Hib) / Tetanus-Diphtheria-whole cell&#xD;
      Pertussis (TDwP)). The investigators will also use two different stable isotopic retinols for&#xD;
      the assessment of total body vitamin A stores. Baseline blood samples (5 mL) will be obtained&#xD;
      from all infants and then randomly selected 30 infants will receive PENTA vaccines, while the&#xD;
      other 10 infants will receive no vaccines. 24 hours after vaccination a finger-prick blood&#xD;
      sample will be obtained from the infants in the vaccinated group to measure CRP and on the&#xD;
      same day, blood samples (5 mL) will be obtained from infants who develop inflammation (CRP&gt;&#xD;
      5mg/L) in the vaccine group and also from infants in the control group. Thus estimated plasma&#xD;
      micronutrients and vitamin A stores before and after inflammation will calculate the effects&#xD;
      of inflammation on the interpretation of micronutrient deficiencies based on biochemical&#xD;
      indicator assessment.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Background:&#xD;
&#xD;
      Subclinical micronutrient deficiencies remain a hidden aspect of malnutrition for which&#xD;
      comprehensive data are lacking. Defining subclinical micronutrient deficiencies requires&#xD;
      considering the prevalence of inflammation and its implications for the interpretation of&#xD;
      micronutrient deficiencies based on biochemical indicator assessment. This study will provide&#xD;
      a comprehensive profile of micronutrient status and antimicrobial resistance in a cohort of&#xD;
      young children living in the densely populated urban slum.&#xD;
&#xD;
      Hypothesis:&#xD;
&#xD;
      I. Inflammation can influence several biochemical measurements those commonly used to&#xD;
      interpret micronutrient status in children II. Micronutrient assessments can be performed&#xD;
      successfully using finger/heel prick blood samples with microsamplers, thus increasing the&#xD;
      ease of blood collection and reducing costs for cold storage and transport to the analytical&#xD;
      laboratory.&#xD;
&#xD;
      Specific Objectives:&#xD;
&#xD;
      Our primary objective is to investigate the effects of inflammation on several biochemical&#xD;
      measurements used to interpret micronutrient status in children. Our secondary aim is to test&#xD;
      the applicability of a blood spot device allowing the determination of micronutrient status&#xD;
      in field settings. Our exploratory objective is to make a comparative analysis of gut&#xD;
      antimicrobial resistance genes (AMR) and resistome profile in children.&#xD;
&#xD;
      Methods:&#xD;
&#xD;
      A total of 40 infants (9-18 mo of age) will participate in this study. In this study,&#xD;
      investigators will use two different stable isotopic vitamin A e.g., 13C10-retinyl acetate&#xD;
      and 13C4-retinyl acetate. 400 μg of these isotopes, dissolved in 0.5 mL of sunflower oil,&#xD;
      will be provided directly into the infant's mouth by using a direct replacement pipette.&#xD;
      Mothers will be asked to breastfeed their infant after oral dosing to enhance absorption of&#xD;
      the labeled vitamin A. Specific activity of 13C10- and 13C4- retinyl acetate in the blood&#xD;
      samples will be measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS). On the&#xD;
      day of blood collection, a 24-h dietary recall and weekly morbidity questionnaires will be&#xD;
      used. Investigators will also use PENTA vaccines as a means to induce controlled inflammation&#xD;
      (closely mimic to natural infection). PENTA is a combination of five different vaccine&#xD;
      antigens (Hepatitis B (HBV)/ Haemophilus influenza type b (Hib) / Tetanus-Diphtheria-whole&#xD;
      cell Pertussis (TDwP)). This vaccination is beneficial to the infants since the World Health&#xD;
      Organization recommends a booster vaccination dose. At the end of the study, PENTA vaccines&#xD;
      will also be provided to the study infants in the &quot;no-vaccine&quot; group.&#xD;
&#xD;
      On day 0, all infants (n=40) will receive an oral dose of 13C10-retinyl acetate, and blood&#xD;
      samples (5 mL) will be taken on day 4. On day 7 all infants (n=40) will also receive another&#xD;
      oral dose of 13C4-retinyl acetate. 3-day later randomly selected 30 infants will receive&#xD;
      PENTA vaccines (day 10), while the other 10 infants will receive no vaccines. 24 hours after&#xD;
      vaccination a finger-prick blood sample will be obtained from the infants in the vaccinated&#xD;
      group to measure CRP (QuikRead go, Orion, Finland). On the same day (day 11), blood samples&#xD;
      (5 mL) will be obtained from infants who develop inflammation (CRP&gt; 5mg/L) in the vaccine&#xD;
      group and also from infants in the control group (day 11). Thus plasma micronutrients and&#xD;
      vitamin A stores estimates on day 4 and day 11 will evaluate the effects of inflammation on&#xD;
      the plasma micronutrient status indicators and total body vitamin A store. Blood&#xD;
      microsamplers will be tested alongside venous blood collection to assess the feasibility of&#xD;
      finger/heel prick sampling. Fecal samples, local surface water, and wastewater samples will&#xD;
      be collected to test the prevalence of AMR resitomes in children and their environment.&#xD;
&#xD;
      Outcome measures/variables:&#xD;
&#xD;
        1. The following plasma biomarkers will be estimated before inflammation and 24 hours after&#xD;
           inflammation&#xD;
&#xD;
             -  Inflammation markers: C-reactive protein (CRP) (mg/L) and α1-acid glycoprotein&#xD;
                (AGP) (g/L)&#xD;
&#xD;
             -  Vitamin A status indicators: retinol (nmol/L), total body vitamin A stores (nmol),&#xD;
                Retinol binding protein (RBP) (mg/L) and beta-carotene (nmol/L)&#xD;
&#xD;
             -  Iron status indicators: ferritin (ug/L) and soluble transferrin receptor (mg/L)&#xD;
&#xD;
             -  Folate/B12 status indicators: folate (nmol/L), methylmalonic acid (umol/L) and&#xD;
                cobalamin (pmol/L)&#xD;
&#xD;
             -  Trace element status indicators: selenium (ug/L), copper (ug/L) and thyroglobulin&#xD;
                (ug/L).&#xD;
&#xD;
        2. The usefulness of a microsampler device to collect blood samples for future&#xD;
           micronutrient assessments.&#xD;
&#xD;
        3. Assessment and contrast of AMR gene abundances and diversity to develop resistomes&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">June 1, 2018</start_date>
  <completion_date type="Actual">June 30, 2019</completion_date>
  <primary_completion_date type="Actual">March 31, 2019</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>Parallel Assignment</intervention_model>
    <primary_purpose>Diagnostic</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Inflammation marker C-reactive protein (CRP) levels in infants before and 1-day after inflammation</measure>
    <time_frame>24 hours</time_frame>
    <description>In infants (9-18 mo) plasma CRP levels (mg/L) will be estimated by ELISA before and 24 hours after inflammation. Paired t-test will be used to evaluate the difference.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Vitamin A status in infants before and 1-day after inflammation</measure>
    <time_frame>24 hours</time_frame>
    <description>In infants (9-18 mo) plasma retinol levels (nmol/L) will be estimated by HPLC before and 24 hours after inflammation.Paired t-test will be used to evaluate the difference.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Total body stores (TBS) of vitamin A in infants before and 1-day after inflammation</measure>
    <time_frame>24 hours</time_frame>
    <description>In infants (9-18 mo) TBS of vitamin A (nmol) will be estimated before and 24 hours after inflammation. TBS will be measured by calculating the specific activities of 13C10- and 13C4- retinyl acetate in the blood samples by using liquid chromatography-tandem mass spectrometry (LC/MS/MS) method. Paired t-test will be used to evaluate the difference.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Iron status in infants before and 1-day after inflammation</measure>
    <time_frame>24 hours</time_frame>
    <description>In infants (9-18 mo) plasma ferritin levels (ug/L) will be estimated by ELISA before and 24 hours after inflammation. Paired t-test will be used to evaluate the difference.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Iron status in infants before and 1-day after inflammation</measure>
    <time_frame>24 hours</time_frame>
    <description>In infants (9-18 mo) plasma soluble transferrin receptor (sTfR) concentration (mg/L) will be estimated by ELISA before and 24 hours after inflammation. Paired t-test will be used to evaluate the difference.</description>
  </primary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">75</enrollment>
  <condition>Healthy Infants</condition>
  <arm_group>
    <arm_group_label>Healthy infants</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
  </arm_group>
  <arm_group>
    <arm_group_label>Infants with an inflammatory condition</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Investigators will also use pentavalent (PENTA) vaccine as a means to induce controlled inflammation (closely mimic to natural infection). PENTA is a combination of five different vaccine antigens (Hepatitis B (HBV)/ Haemophilus influenza type b (Hib) / Tetanus-Diphtheria-whole cell Pertussis (TDwP)).</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Pentavalent vaccine. It is a combination of five different antigens (Hepatitis B (HBV)/ Haemophilus influenzae type b (HiB) / Tetanus-Diphtheria-whole cell Pertussis (TDwP)).</intervention_name>
    <description>Pentavalent vaccine is being recommended to provide infants at 6wk, 10wk and 14wk of age. This vaccine also induces plasma CRP &gt;5 mg/L in infants within 24 hours of immunization.</description>
    <arm_group_label>Infants with an inflammatory condition</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion criteria:&#xD;
&#xD;
          1. 9 - 18 months of age&#xD;
&#xD;
          2. Infants with normal body temperature and normal CRP (&lt;5 mg/L)&#xD;
&#xD;
          3. Infants receive breast milk from the mother at least once per day&#xD;
&#xD;
          4. Mothers produce a breast milk containing 30-40 nmol vitamin A /g milk fat&#xD;
&#xD;
          5. Infants received a high-dose vitamin A capsules at the time of the most recent&#xD;
             national distribution campaign (within the last 2-4 months)&#xD;
&#xD;
          6. Mother is 18 - 45 years of age&#xD;
&#xD;
          7. Mother and her infant plan to stay in the study area for the duration of the study&#xD;
&#xD;
        Exclusion criteria:&#xD;
&#xD;
          1. Mother or infant has chronic disease&#xD;
&#xD;
          2. Mother or infant has acute illness on the day of data collection&#xD;
&#xD;
          3. Infant is anemic (Hb &lt;90 g/L)&#xD;
&#xD;
          4. Infant has weight for length &lt;80% of the reference median&#xD;
&#xD;
          5. Infants do not develop inflammation (CRP ≥5 mg/L) after PENTA vaccination&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>9 Months</minimum_age>
    <maximum_age>18 Months</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Clinical Trail Unit (CTU), icddr,b.</name>
      <address>
        <city>Dhaka</city>
        <zip>1212</zip>
        <country>Bangladesh</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Shaikh M Ahmad</name>
      <address>
        <city>Dhaka</city>
        <zip>1212</zip>
        <country>Bangladesh</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Bangladesh</country>
  </location_countries>
  <verification_date>September 2018</verification_date>
  <study_first_submitted>March 29, 2018</study_first_submitted>
  <study_first_submitted_qc>January 10, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 11, 2019</study_first_posted>
  <last_update_submitted>August 21, 2019</last_update_submitted>
  <last_update_submitted_qc>August 21, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">August 26, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>vitamin A</keyword>
  <keyword>vitamin A isotope</keyword>
  <keyword>vitamin D</keyword>
  <keyword>ferritin</keyword>
  <keyword>transferrin receptor</keyword>
  <keyword>folate</keyword>
  <keyword>cobalamin</keyword>
  <keyword>beta-carotene</keyword>
  <keyword>Inflammation</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</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/NCT03801161
org study id: PR-18006
nct id: NCT03801161
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Inflammation can influence several biochemical measurements those commonly used to interpret
      micronutrient status in children. Our primary objective is to investigate the effects of
      inflammation on several biochemical measurements used to interpret micronutrient status in
      children. A total of 40 infants (9-18 mo of age) will participate in this study.
      Investigators will use PENTA vaccines as a means to induce controlled inflammation (closely
      mimic to natural infection). PENTA is a combination of five different vaccine antigens
      (Hepatitis B (HBV)/ Haemophilus influenza type b (Hib) / Tetanus-Diphtheria-whole cell
      Pertussis (TDwP)). The investigators will also use two different stable isotopic retinols for
      the assessment of total body vitamin A stores. Baseline blood samples (5 mL) will be obtained
      from all infants and then randomly selected 30 infants will receive PENTA vaccines, while the
      other 10 infants will receive no vaccines. 24 hours after vaccination a finger-prick blood
      sample will be obtained from the infants in the vaccinated group to measure CRP and on the
      same day, blood samples (5 mL) will be obtained from infants who develop inflammation (CRP>
      5mg/L) in the vaccine group and also from infants in the control group. Thus estimated plasma
      micronutrients and vitamin A stores before and after inflammation will calculate the effects
      of inflammation on the interpretation of micronutrient deficiencies based on biochemical
      indicator assessment.
Background:

      Subclinical micronutrient deficiencies remain a hidden aspect of malnutrition for which
      comprehensive data are lacking. Defining subclinical micronutrient deficiencies requires
      considering the prevalence of inflammation and its implications for the interpretation of
      micronutrient deficiencies based on biochemical indicator assessment. This study will provide
      a comprehensive profile of micronutrient status and antimicrobial resistance in a cohort of
      young children living in the densely populated urban slum.

      Hypothesis:

      I. Inflammation can influence several biochemical measurements those commonly used to
      interpret micronutrient status in children II. Micronutrient assessments can be performed
      successfully using finger/heel prick blood samples with microsamplers, thus increasing the
      ease of blood collection and reducing costs for cold storage and transport to the analytical
      laboratory.

      Specific Objectives:

      Our primary objective is to investigate the effects of inflammation on several biochemical
      measurements used to interpret micronutrient status in children. Our secondary aim is to test
      the applicability of a blood spot device allowing the determination of micronutrient status
      in field settings. Our exploratory objective is to make a comparative analysis of gut
      antimicrobial resistance genes (AMR) and resistome profile in children.

      Methods:

      A total of 40 infants (9-18 mo of age) will participate in this study. In this study,
      investigators will use two different stable isotopic vitamin A e.g., 13C10-retinyl acetate
      and 13C4-retinyl acetate. 400 μg of these isotopes, dissolved in 0.5 mL of sunflower oil,
      will be provided directly into the infant's mouth by using a direct replacement pipette.
      Mothers will be asked to breastfeed their infant after oral dosing to enhance absorption of
      the labeled vitamin A. Specific activity of 13C10- and 13C4- retinyl acetate in the blood
      samples will be measured by liquid chromatography-tandem mass spectrometry (LC/MS/MS). On the
      day of blood collection, a 24-h dietary recall and weekly morbidity questionnaires will be
      used. Investigators will also use PENTA vaccines as a means to induce controlled inflammation
      (closely mimic to natural infection). PENTA is a combination of five different vaccine
      antigens (Hepatitis B (HBV)/ Haemophilus influenza type b (Hib) / Tetanus-Diphtheria-whole
      cell Pertussis (TDwP)). This vaccination is beneficial to the infants since the World Health
      Organization recommends a booster vaccination dose. At the end of the study, PENTA vaccines
      will also be provided to the study infants in the "no-vaccine" group.

      On day 0, all infants (n=40) will receive an oral dose of 13C10-retinyl acetate, and blood
      samples (5 mL) will be taken on day 4. On day 7 all infants (n=40) will also receive another
      oral dose of 13C4-retinyl acetate. 3-day later randomly selected 30 infants will receive
      PENTA vaccines (day 10), while the other 10 infants will receive no vaccines. 24 hours after
      vaccination a finger-prick blood sample will be obtained from the infants in the vaccinated
      group to measure CRP (QuikRead go, Orion, Finland). On the same day (day 11), blood samples
      (5 mL) will be obtained from infants who develop inflammation (CRP> 5mg/L) in the vaccine
      group and also from infants in the control group (day 11). Thus plasma micronutrients and
      vitamin A stores estimates on day 4 and day 11 will evaluate the effects of inflammation on
      the plasma micronutrient status indicators and total body vitamin A store. Blood
      microsamplers will be tested alongside venous blood collection to assess the feasibility of
      finger/heel prick sampling. Fecal samples, local surface water, and wastewater samples will
      be collected to test the prevalence of AMR resitomes in children and their environment.

      Outcome measures/variables:

        1. The following plasma biomarkers will be estimated before inflammation and 24 hours after
           inflammation

             -  Inflammation markers: C-reactive protein (CRP) (mg/L) and α1-acid glycoprotein
                (AGP) (g/L)

             -  Vitamin A status indicators: retinol (nmol/L), total body vitamin A stores (nmol),
                Retinol binding protein (RBP) (mg/L) and beta-carotene (nmol/L)

             -  Iron status indicators: ferritin (ug/L) and soluble transferrin receptor (mg/L)

             -  Folate/B12 status indicators: folate (nmol/L), methylmalonic acid (umol/L) and
                cobalamin (pmol/L)

             -  Trace element status indicators: selenium (ug/L), copper (ug/L) and thyroglobulin
                (ug/L).

        2. The usefulness of a microsampler device to collect blood samples for future
           micronutrient assessments.

        3. Assessment and contrast of AMR gene abundances and diversity to develop resistomes
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Diagnostic
masking: None (Open Label)
measure: Inflammation marker C-reactive protein (CRP) levels in infants before and 1-day after inflammation
time frame: 24 hours
description: In infants (9-18 mo) plasma CRP levels (mg/L) will be estimated by ELISA before and 24 hours after inflammation. Paired t-test will be used to evaluate the difference.
measure: Vitamin A status in infants before and 1-day after inflammation
time frame: 24 hours
description: In infants (9-18 mo) plasma retinol levels (nmol/L) will be estimated by HPLC before and 24 hours after inflammation.Paired t-test will be used to evaluate the difference.
measure: Total body stores (TBS) of vitamin A in infants before and 1-day after inflammation
time frame: 24 hours
description: In infants (9-18 mo) TBS of vitamin A (nmol) will be estimated before and 24 hours after inflammation. TBS will be measured by calculating the specific activities of 13C10- and 13C4- retinyl acetate in the blood samples by using liquid chromatography-tandem mass spectrometry (LC/MS/MS) method. Paired t-test will be used to evaluate the difference.
measure: Iron status in infants before and 1-day after inflammation
time frame: 24 hours
description: In infants (9-18 mo) plasma ferritin levels (ug/L) will be estimated by ELISA before and 24 hours after inflammation. Paired t-test will be used to evaluate the difference.
measure: Iron status in infants before and 1-day after inflammation
time frame: 24 hours
description: In infants (9-18 mo) plasma soluble transferrin receptor (sTfR) concentration (mg/L) will be estimated by ELISA before and 24 hours after inflammation. Paired t-test will be used to evaluate the difference.
arm group label: Healthy infants
arm group type: No Intervention
arm group label: Infants with an inflammatory condition
arm group type: Experimental
description: Investigators will also use pentavalent (PENTA) vaccine as a means to induce controlled inflammation (closely mimic to natural infection). PENTA is a combination of five different vaccine antigens (Hepatitis B (HBV)/ Haemophilus influenza type b (Hib) / Tetanus-Diphtheria-whole cell Pertussis (TDwP)).
intervention type: Biological
intervention name: Pentavalent vaccine. It is a combination of five different antigens (Hepatitis B (HBV)/ Haemophilus influenzae type b (HiB) / Tetanus-Diphtheria-whole cell Pertussis (TDwP)).
description: Pentavalent vaccine is being recommended to provide infants at 6wk, 10wk and 14wk of age. This vaccine also induces plasma CRP >5 mg/L in infants within 24 hours of immunization.
arm group label: Infants with an inflammatory condition
criteria: 
gender: All
minimum age: 9 Months
maximum age: 18 Months
healthy volunteers: Accepts Healthy Volunteers
facility: 
facility: 
country: Bangladesh
responsible party type: Sponsor
mesh term: Inflammation
sharing ipd: Undecided