<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/NCT04432935</url>
  </required_header>
  <id_info>
    <org_study_id>2019-1955-5013</org_study_id>
    <nct_id>NCT04432935</nct_id>
  </id_info>
  <brief_title>Effect of Lactoferrin on Polio Seroconversion</brief_title>
  <official_title>Effect of Bovine Lactoferrin on Seroconversion Following Polio Vaccine Administration in Children: A Randomized Control Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Aga Khan University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centers for Disease Control and Prevention</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Aga Khan University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      A massive decline in cases of poliomyelitis was observed worldwide since 1988; however its&#xD;
      transmission continues in Pakistan and Afghanistan. In 2017, a total of 17 cases were&#xD;
      reported from these countries, which represent approximately half of the cases reported in&#xD;
      2016. This achievement was made possible by large scale use of oral polio vaccine (OPV) and&#xD;
      inactivated polio vaccine (IPV). Despite vigorous efforts to end poliovirus transmission in&#xD;
      endemic areas, several challenges including illiteracy, poverty, malnutrition, difficulty to&#xD;
      access health and immunization services adversely affect the effectiveness of the polio&#xD;
      eradication efforts. Innovations are thus needed to accomplish the goal of eradication as due&#xD;
      to limited funding, the sustainability of a program becomes questionable. The aim of this&#xD;
      study is to assess the effectiveness of lactoferrin in increasing mucosal and serum immunity&#xD;
      in children following administration of poliovirus vaccines.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Lactoferrin was first discovered in bovine milk which was later isolated in human milk as the&#xD;
      second most abundant protein; with high levels found in colostrum. Evidence suggests that&#xD;
      Lactoferrin enhances a child's immunity against gastrointestinal infections by inhibiting the&#xD;
      growth of bacteria through iron deprivation and by preventing attachment of the virus to the&#xD;
      intestinal cells thus children become less susceptible to virus replication in the gut.&#xD;
      Investigations of enhanced efficacy of the BCG (Bacillus Calmette-Guérin) vaccine after&#xD;
      administration of Lactoferrin showed promising results. The use of bovine Lactoferrin in&#xD;
      children is generally recognized as safe by the US Food and Drug Administration. Its&#xD;
      anti-infective properties creates a new window of opportunity to assess its effects on the&#xD;
      level of seroconversion following poliovirus vaccination in children.&#xD;
&#xD;
      This is a double-blinded two arm randomized placebo-controlled trial. A total of 377 neonates&#xD;
      will be enrolled in each group (754 neonates in both groups). Females ages 18-45 years in&#xD;
      their last trimester of pregnancy in Karachi, Pakistan will be recruited for the study by the&#xD;
      study team and consent will be obtained. Participants will be newborns (on day 1 of birth)&#xD;
      who will be followed through 6 months of age. Newborns who fulfill the inclusion criteria&#xD;
      will be randomly assigned to the control or intervention group in 1:1 ratio on the first day&#xD;
      of birth. Intervention group will receive a daily bovine lactoferrin supplementation whereas&#xD;
      Control group will receive a daily placebo supplementation along with breast milk from day 0&#xD;
      of birth to 6 weeks of life. Newborns will be followed up daily during the course of the&#xD;
      hospital stay.&#xD;
&#xD;
      After discharge from the hospital, mothers will be provided with a week's supply of&#xD;
      lactoferrin or placebo along with instructions on how and when to administer it to the baby.&#xD;
      Newborns will be followed up weekly. Compliance will be assessed by counting the used sachets&#xD;
      of lactoferrin or placebo because mothers will be instructed to keep the empty sachets in a&#xD;
      dedicated container issued by study staff. Mothers will be strictly advised to administer all&#xD;
      vaccinations according to the routine immunization schedule. For both groups, a blood sample&#xD;
      will be collected in the hospital and containers will be given to the mother for collections&#xD;
      of stool for the newborn.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 1, 2020</start_date>
  <completion_date type="Actual">June 30, 2022</completion_date>
  <primary_completion_date type="Actual">June 30, 2022</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>
    <intervention_model_description>Group 1:&#xD;
Bovine lactoferrin (bLF) will be administered (300mg) from day 0 of birth to 6 weeks of life with a single daily dose mixed with milk (preferentially breast milk otherwise premature formula milk).&#xD;
Group 2:&#xD;
Placebo will be administered from day 0 of birth to 6 weeks of life. (Placebo will be physically identical to the bLF mixed with breast milk or premature formula milk).</intervention_model_description>
    <primary_purpose>Prevention</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
    <masking_description>Randomization will be carried out by Data management unit and all investigators /dispensers and participants will be masked to the randomization.</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Assessment of humoral immunity by seroconversion</measure>
    <time_frame>10 weeks</time_frame>
    <description>Presence of detectable antibodies to poliovirus types 1 and 3 in serum) after receipt of two doses of OPV</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Comparison of humoral immunity represented by seroconversion</measure>
    <time_frame>18 weeks</time_frame>
    <description>Presence of detectable antibodies to poliovirus types 1, 2 and 3 in serum) after completion of the routine immunization doses/schedule</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of intestinal immunity represented by shedding of poliovirus types 1 and 3</measure>
    <time_frame>19 weeks</time_frame>
    <description>If lactoferrin is effective in improving intestinal immunity, shedding is expected to be lower in the lactoferrin receiving group.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Comparison of duration of shedding among the two study arms</measure>
    <time_frame>20 and 22 weeks</time_frame>
    <description>Represented by shedding at 20 weeks of age and at 22 weeks of age after the challenge dose of bOPV administered</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">468</enrollment>
  <condition>Poliomyelitis</condition>
  <arm_group>
    <arm_group_label>Bovine Lactoferrin</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intervention group will receive bovine lactoferrin supplementation daily once a day from day 0 of birth to 6 weeks of life.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Glucon D</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Control group will receive Glucon-D supplementation daily once a day from day 0 of birth to 6 weeks of life.</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Bovine Lactoferrin</intervention_name>
    <description>Lactoferrin is a nutritional supplement which was first discovered in bovine milk which was later isolated in human milk as the second most abundant protein; with high levels found in colostrum. The use of bovine Lactoferrin in children is generally recognized as safe by the US Food and Drug Administration.</description>
    <arm_group_label>Bovine Lactoferrin</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Placebo Glucon D</intervention_name>
    <description>This group will be given 100mg Glucon-D (99.4% glucose) which will be similar in shape, color to the bLF.</description>
    <arm_group_label>Glucon D</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Pregnant females aged 18 to 45 years with no underlying complications or&#xD;
             co-morbidities&#xD;
&#xD;
          -  Residence less than 30 kms away from the study clinic and have resided there for at&#xD;
             least 1 year. Family MUST indicate that they will not move from their current&#xD;
             residence for the 5 months after birth of the child (study period)&#xD;
&#xD;
          -  Healthy singleton full-term births born to these mothers, regardless of birth weight&#xD;
             and an APGAR score of 7 or higher 5 minutes after delivery with no underlying&#xD;
             complication (randomization will take place at this stage)&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Females with health issues and high risk pregnancies&#xD;
&#xD;
          -  Neonates presenting with any morbidities and congenital anomalies will be excluded&#xD;
             from the study&#xD;
&#xD;
          -  Preterm birth (&lt;37 weeks of gestation)&#xD;
&#xD;
          -  Immunodeficiency disorder in immediate family member&#xD;
&#xD;
          -  Parents refusing to consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Hour</minimum_age>
    <maximum_age>23 Hours</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Sajid Soofi, MBBS, FCPS</last_name>
    <role>Principal Investigator</role>
    <affiliation>Aga Khan University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Kharadar Campus, Aga Khan University Hospital</name>
      <address>
        <city>Karachi</city>
        <zip>74800</zip>
        <country>Pakistan</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Pakistan</country>
  </location_countries>
  <link>
    <url>https://www.fda.gov/food/gras-notice-inventory/agency-response-letter-gras-notice-no-grn-000611</url>
    <description>Agency Response Letter GRAS Notice No. GRN 000611</description>
  </link>
  <reference>
    <citation>Hussain SF, Boyle P, Patel P, Sullivan R. Eradicating polio in Pakistan: an analysis of the challenges and solutions to this security and health issue. Global Health. 2016 Oct 12;12(1):63. doi: 10.1186/s12992-016-0195-3.</citation>
    <PMID>27729081</PMID>
  </reference>
  <reference>
    <citation>Roseanu A, Brock JH. What are the structure and the biological function of lactoferrin in human breast milk? IUBMB Life. 2006 Apr;58(4):235-7. doi: 10.1080/15216540600577897. No abstract available.</citation>
    <PMID>16754302</PMID>
  </reference>
  <reference>
    <citation>Seganti L, Di Biase AM, Marchetti M, Pietrantoni A, Tinari A, Superti F. Antiviral activity of lactoferrin towards naked viruses. Biometals. 2004 Jun;17(3):295-9. doi: 10.1023/b:biom.0000027708.27142.bc.</citation>
    <PMID>15222481</PMID>
  </reference>
  <reference>
    <citation>Ochoa TJ, Cleary TG. Effect of lactoferrin on enteric pathogens. Biochimie. 2009 Jan;91(1):30-4. doi: 10.1016/j.biochi.2008.04.006. Epub 2008 Apr 18.</citation>
    <PMID>18472012</PMID>
  </reference>
  <reference>
    <citation>Superti F, Ammendolia MG, Valenti P, Seganti L. Antirotaviral activity of milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like cell line HT-29. Med Microbiol Immunol. 1997 Oct;186(2-3):83-91. doi: 10.1007/s004300050049.</citation>
    <PMID>9403835</PMID>
  </reference>
  <reference>
    <citation>Hwang SA, Wilk KM, Budnicka M, Olsen M, Bangale YA, Hunter RL, Kruzel ML, Actor JK. Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis. Vaccine. 2007 Sep 17;25(37-38):6730-43. doi: 10.1016/j.vaccine.2007.07.005. Epub 2007 Jul 27.</citation>
    <PMID>17698261</PMID>
  </reference>
  <reference>
    <citation>Hwang SA, Arora R, Kruzel ML, Actor JK. Lactoferrin enhances efficacy of the BCG vaccine: comparison between two inbred mice strains (C57BL/6 and BALB/c). Tuberculosis (Edinb). 2009 Dec;89 Suppl 1:S49-54. doi: 10.1016/S1472-9792(09)70012-5.</citation>
    <PMID>20006305</PMID>
  </reference>
  <verification_date>August 2023</verification_date>
  <study_first_submitted>December 11, 2019</study_first_submitted>
  <study_first_submitted_qc>June 15, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 16, 2020</study_first_posted>
  <last_update_submitted>August 15, 2023</last_update_submitted>
  <last_update_submitted_qc>August 15, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">August 16, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Aga Khan University</investigator_affiliation>
    <investigator_full_name>Dr Sajid Bashir Soofi</investigator_full_name>
    <investigator_title>Associate Professor</investigator_title>
  </responsible_party>
  <keyword>Bovine Lactoferrin</keyword>
  <keyword>Poliovirus</keyword>
  <keyword>Routine immunization</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Poliomyelitis</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Lactoferrin</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Study findings will be disseminated through presentations at scientific conferences and educational practice workshops and will be published in an international peer-reviewed scientific journal.</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>After the manuscript has been prepared and published.</ipd_time_frame>
    <ipd_access_criteria>A formal application to the PI will be required requesting him about the accessibility of the data. This should include the rationale and expected use of the study data.</ipd_access_criteria>
  </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/NCT04432935
org study id: 2019-1955-5013
nct id: NCT04432935
lead sponsor: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
is us export: No
A massive decline in cases of poliomyelitis was observed worldwide since 1988; however its
      transmission continues in Pakistan and Afghanistan. In 2017, a total of 17 cases were
      reported from these countries, which represent approximately half of the cases reported in
      2016. This achievement was made possible by large scale use of oral polio vaccine (OPV) and
      inactivated polio vaccine (IPV). Despite vigorous efforts to end poliovirus transmission in
      endemic areas, several challenges including illiteracy, poverty, malnutrition, difficulty to
      access health and immunization services adversely affect the effectiveness of the polio
      eradication efforts. Innovations are thus needed to accomplish the goal of eradication as due
      to limited funding, the sustainability of a program becomes questionable. The aim of this
      study is to assess the effectiveness of lactoferrin in increasing mucosal and serum immunity
      in children following administration of poliovirus vaccines.
Lactoferrin was first discovered in bovine milk which was later isolated in human milk as the
      second most abundant protein; with high levels found in colostrum. Evidence suggests that
      Lactoferrin enhances a child's immunity against gastrointestinal infections by inhibiting the
      growth of bacteria through iron deprivation and by preventing attachment of the virus to the
      intestinal cells thus children become less susceptible to virus replication in the gut.
      Investigations of enhanced efficacy of the BCG (Bacillus Calmette-Guérin) vaccine after
      administration of Lactoferrin showed promising results. The use of bovine Lactoferrin in
      children is generally recognized as safe by the US Food and Drug Administration. Its
      anti-infective properties creates a new window of opportunity to assess its effects on the
      level of seroconversion following poliovirus vaccination in children.

      This is a double-blinded two arm randomized placebo-controlled trial. A total of 377 neonates
      will be enrolled in each group (754 neonates in both groups). Females ages 18-45 years in
      their last trimester of pregnancy in Karachi, Pakistan will be recruited for the study by the
      study team and consent will be obtained. Participants will be newborns (on day 1 of birth)
      who will be followed through 6 months of age. Newborns who fulfill the inclusion criteria
      will be randomly assigned to the control or intervention group in 1:1 ratio on the first day
      of birth. Intervention group will receive a daily bovine lactoferrin supplementation whereas
      Control group will receive a daily placebo supplementation along with breast milk from day 0
      of birth to 6 weeks of life. Newborns will be followed up daily during the course of the
      hospital stay.

      After discharge from the hospital, mothers will be provided with a week's supply of
      lactoferrin or placebo along with instructions on how and when to administer it to the baby.
      Newborns will be followed up weekly. Compliance will be assessed by counting the used sachets
      of lactoferrin or placebo because mothers will be instructed to keep the empty sachets in a
      dedicated container issued by study staff. Mothers will be strictly advised to administer all
      vaccinations according to the routine immunization schedule. For both groups, a blood sample
      will be collected in the hospital and containers will be given to the mother for collections
      of stool for the newborn.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Group 1:
Bovine lactoferrin (bLF) will be administered (300mg) from day 0 of birth to 6 weeks of life with a single daily dose mixed with milk (preferentially breast milk otherwise premature formula milk).
Group 2:
Placebo will be administered from day 0 of birth to 6 weeks of life. (Placebo will be physically identical to the bLF mixed with breast milk or premature formula milk).
primary purpose: Prevention
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
masking description: Randomization will be carried out by Data management unit and all investigators /dispensers and participants will be masked to the randomization.
measure: Assessment of humoral immunity by seroconversion
time frame: 10 weeks
description: Presence of detectable antibodies to poliovirus types 1 and 3 in serum) after receipt of two doses of OPV
measure: Comparison of humoral immunity represented by seroconversion
time frame: 18 weeks
description: Presence of detectable antibodies to poliovirus types 1, 2 and 3 in serum) after completion of the routine immunization doses/schedule
measure: Comparison of intestinal immunity represented by shedding of poliovirus types 1 and 3
time frame: 19 weeks
description: If lactoferrin is effective in improving intestinal immunity, shedding is expected to be lower in the lactoferrin receiving group.
measure: Comparison of duration of shedding among the two study arms
time frame: 20 and 22 weeks
description: Represented by shedding at 20 weeks of age and at 22 weeks of age after the challenge dose of bOPV administered
arm group label: Bovine Lactoferrin
arm group type: Experimental
description: Intervention group will receive bovine lactoferrin supplementation daily once a day from day 0 of birth to 6 weeks of life.
arm group label: Glucon D
arm group type: Placebo Comparator
description: Control group will receive Glucon-D supplementation daily once a day from day 0 of birth to 6 weeks of life.
intervention type: Dietary Supplement
intervention name: Bovine Lactoferrin
description: Lactoferrin is a nutritional supplement which was first discovered in bovine milk which was later isolated in human milk as the second most abundant protein; with high levels found in colostrum. The use of bovine Lactoferrin in children is generally recognized as safe by the US Food and Drug Administration.
arm group label: Bovine Lactoferrin
intervention type: Other
intervention name: Placebo Glucon D
description: This group will be given 100mg Glucon-D (99.4% glucose) which will be similar in shape, color to the bLF.
arm group label: Glucon D
criteria: 
gender: All
minimum age: 1 Hour
maximum age: 23 Hours
healthy volunteers: Accepts Healthy Volunteers
last name: Sajid Soofi, MBBS, FCPS
role: Principal Investigator
affiliation: Aga Khan University
facility: 
country: Pakistan
url: https://www.fda.gov/food/gras-notice-inventory/agency-response-letter-gras-notice-no-grn-000611
description: Agency Response Letter GRAS Notice No. GRN 000611
citation: Hussain SF, Boyle P, Patel P, Sullivan R. Eradicating polio in Pakistan: an analysis of the challenges and solutions to this security and health issue. Global Health. 2016 Oct 12;12(1):63. doi: 10.1186/s12992-016-0195-3.
PMID: 27729081
citation: Roseanu A, Brock JH. What are the structure and the biological function of lactoferrin in human breast milk? IUBMB Life. 2006 Apr;58(4):235-7. doi: 10.1080/15216540600577897. No abstract available.
PMID: 16754302
citation: Seganti L, Di Biase AM, Marchetti M, Pietrantoni A, Tinari A, Superti F. Antiviral activity of lactoferrin towards naked viruses. Biometals. 2004 Jun;17(3):295-9. doi: 10.1023/b:biom.0000027708.27142.bc.
PMID: 15222481
citation: Ochoa TJ, Cleary TG. Effect of lactoferrin on enteric pathogens. Biochimie. 2009 Jan;91(1):30-4. doi: 10.1016/j.biochi.2008.04.006. Epub 2008 Apr 18.
PMID: 18472012
citation: Superti F, Ammendolia MG, Valenti P, Seganti L. Antirotaviral activity of milk proteins: lactoferrin prevents rotavirus infection in the enterocyte-like cell line HT-29. Med Microbiol Immunol. 1997 Oct;186(2-3):83-91. doi: 10.1007/s004300050049.
PMID: 9403835
citation: Hwang SA, Wilk KM, Budnicka M, Olsen M, Bangale YA, Hunter RL, Kruzel ML, Actor JK. Lactoferrin enhanced efficacy of the BCG vaccine to generate host protective responses against challenge with virulent Mycobacterium tuberculosis. Vaccine. 2007 Sep 17;25(37-38):6730-43. doi: 10.1016/j.vaccine.2007.07.005. Epub 2007 Jul 27.
PMID: 17698261
citation: Hwang SA, Arora R, Kruzel ML, Actor JK. Lactoferrin enhances efficacy of the BCG vaccine: comparison between two inbred mice strains (C57BL/6 and BALB/c). Tuberculosis (Edinb). 2009 Dec;89 Suppl 1:S49-54. doi: 10.1016/S1472-9792(09)70012-5.
PMID: 20006305
responsible party type: Principal Investigator
investigator affiliation: Aga Khan University
investigator full name: Dr Sajid Bashir Soofi
investigator title: Associate Professor
mesh term: Poliomyelitis
mesh term: Lactoferrin
sharing ipd: Yes
ipd description: Study findings will be disseminated through presentations at scientific conferences and educational practice workshops and will be published in an international peer-reviewed scientific journal.
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: After the manuscript has been prepared and published.
ipd access criteria: A formal application to the PI will be required requesting him about the accessibility of the data. This should include the rationale and expected use of the study data.