<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/NCT03040687</url>
  </required_header>
  <id_info>
    <org_study_id>CIR 315 BSIgG</org_study_id>
    <nct_id>NCT03040687</nct_id>
  </id_info>
  <brief_title>Efficacy of B7A BSIgG Against E. Coli Strain B7A Challenge</brief_title>
  <official_title>Protective Efficacy of Orally Delivered Bovine Serum Immunoglobulin (BSIgG) Specific for the Colonization Factor CS6 Following Challenge With the CS6-expressing Enterotoxigenic E. Coli (ETEC) Strain B7A</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Johns Hopkins Bloomberg School of Public Health</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Naval Medical Research Center</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
    <collaborator>
      <agency>United States Department of Defense</agency>
      <agency_class>U.S. Fed</agency_class>
    </collaborator>
  </sponsors>
  <source>Johns Hopkins Bloomberg School of Public Health</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea worldwide. Vaccines and&#xD;
      therapeutics are under development to prevent ETEC disease in children and travelers. One&#xD;
      approach is to use passive protection (antibodies) to prevent infection. The purpose of this&#xD;
      study are to assess the safety of serum-derived bovine immunoglobulins in healthy adult&#xD;
      subjects when orally administered and to estimate protective efficacy of those preparations&#xD;
      against moderate-severe diarrhea upon challenge with the ETEC strain B7A.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of infectious&#xD;
      diarrhea in children in resource limited countries, and is also a frequent cause of&#xD;
      traveler's diarrhea in civilian and military travelers to endemic countries. ETEC strains&#xD;
      express a variety of colonization factors (CF) that help them attach to the intestinal wall.&#xD;
      Each colonization factor has one or more surface antigens (CS). One of the major surface&#xD;
      antigens of ETEC is CS6 (Coli surface antigen 6).&#xD;
&#xD;
      Vaccines and treatments to prevent ETEC disease are under development. Some of these target&#xD;
      specific enterotoxins or colonization factors. For over 40 years, we have used ETEC human&#xD;
      challenge studies to understand the ETEC disease process, immune response, and more recently,&#xD;
      to determine whether treatments or vaccines are protective or effective in mitigating&#xD;
      disease. B7A is the only CS6 expressing ETEC challenge strain currently used.&#xD;
&#xD;
      A modality that has shown some success in the prevention of diarrhea is passive, oral&#xD;
      administration of bovine milk IgG with specific activity against viral, bacterial and&#xD;
      parasitic enteropathogens. Passive oral administration of Bovine Serum Immunoglobulins&#xD;
      (BSIgG) may protect against ETEC-mediated infectious diarrhea. The hypothesized mechanism of&#xD;
      protection stems from the passive administration of bovine anti-tip adhesion or fimbriae&#xD;
      antibodies preventing their adherence in the human small intestine (the initial step in&#xD;
      pathogenesis), thereby preventing downstream pathogenic processes and symptomatic illness.&#xD;
      This study will establish the foundation for evaluating BSIgG products against numerous ETEC&#xD;
      CFs.&#xD;
&#xD;
      This study will explore if anti-B7A and anti- CS6 BSIgG provides protection against oral&#xD;
      challenge with B7A in healthy adult volunteers. There will be two inpatient admissions of&#xD;
      approximately 30 subjects (up to 60 total). They will receive one of three investigational&#xD;
      products (IP) three times daily following meals beginning 2 days prior to challenge. Each&#xD;
      volunteer will be challenged with CS6 expressing ETEC B7A on Day 0. The investigational&#xD;
      product/placebo will be administered for a total of 7 days, or until antibiotic treatment has&#xD;
      been administered. The investigators hypothesize that anti-CS6 BSIgG will provide protection&#xD;
      against B7A mediated moderate to severe diarrhea upon challenge.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 2017</start_date>
  <completion_date type="Actual">August 2017</completion_date>
  <primary_completion_date type="Actual">April 2017</primary_completion_date>
  <phase>Phase 1</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>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Safety of Serum Derived Bovine Immunoglobulins (BSIgG)</measure>
    <time_frame>28 days</time_frame>
    <description>Number of Participants with adverse events in groups receiving B7A- and CS6- hyperimmune (BSIgG) compared with the group receiving the nonhyperimmune product.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Efficacy of B7A and CS6- Hyperimmune Bovine Serum Immunoglobin to Protect Against Moderate to Severe Diarrhea After Challenge With the CS6 Expressing ETEC Strain B7A</measure>
    <time_frame>28 days</time_frame>
    <description>Comparison of the number and percentage of volunteers in the arms receiving the B7A- and CS6 BSIgG vs the arm receiving the nonhyperimmune BSIgG who develop moderate to severe diarrhea.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">60</enrollment>
  <condition>Healthy Volunteer</condition>
  <arm_group>
    <arm_group_label>Anti-CS6 group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Anti-whole cell B7A</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>control Immunoglobulin group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A)</description>
  </arm_group>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Anti CS6 BSIgG product (Lot PD1601105CS)</intervention_name>
    <arm_group_label>Anti-CS6 group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Anti B7A BSIgG product (Lot PD1601132ET)</intervention_name>
    <arm_group_label>Anti-whole cell B7A</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>Bovine Immunoglobin Negative Control (Lot PD161071NC)</intervention_name>
    <arm_group_label>control Immunoglobulin group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Biological</intervention_type>
    <intervention_name>B7A- CS6-expressing ETEC challenge strain</intervention_name>
    <arm_group_label>Anti-CS6 group</arm_group_label>
    <arm_group_label>Anti-whole cell B7A</arm_group_label>
    <arm_group_label>control Immunoglobulin group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Male or female between 18 and 50 years of age, inclusive.&#xD;
&#xD;
          -  General good health, without significant medical illness, abnormal physical&#xD;
             examination findings or clinical laboratory abnormalities as determined by principal&#xD;
             investigator (PI) or PI in consultation with the research monitor and sponsor.&#xD;
&#xD;
          -  Demonstrate comprehension of the protocol procedures and knowledge of ETEC illness by&#xD;
             passing a written examination (pass grade ≥ 70%)&#xD;
&#xD;
          -  Willing to participate after informed consent obtained.&#xD;
&#xD;
          -  Available for all planned follow-up visits.&#xD;
&#xD;
          -  Negative serum pregnancy test at screening and negative serum and/or urine pregnancy&#xD;
             test on the day of admittance to the inpatient phase for female subjects of&#xD;
             childbearing potential. Females of childbearing potential must agree to use an&#xD;
             efficacious hormonal or barrier method of birth control during the study. Abstinence&#xD;
             is acceptable. Female subjects unable to bear children must have this documented&#xD;
             (e.g., tubal ligation or hysterectomy).&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
        General health criteria&#xD;
&#xD;
          -  Presence of a significant medical condition, (e.g. psychiatric conditions or&#xD;
             gastrointestinal disease, such as peptic ulcer, symptoms or evidence of active&#xD;
             gastritis or gastroesophageal reflux disease, inflammatory bowel disease, alcohol or&#xD;
             illicit drug abuse/dependency, or other laboratory abnormalities which in the opinion&#xD;
             of the investigator precludes participation in the study.&#xD;
&#xD;
          -  Immunosuppressive illness or Immunoglobulin A (IgA) deficiency (serum IgA &lt; 7 mg/dL or&#xD;
             below the limit of detection of assay)&#xD;
&#xD;
          -  Evidence of confirmed infection with HIV, HBsAg, or Hepatitis C Virus (HCV), with&#xD;
             confirmatory assays.&#xD;
&#xD;
          -  Use of any investigational product within 30 days preceding the receipt of the&#xD;
             investigational products, or planned use during the active study period&#xD;
&#xD;
          -  Significant abnormalities in screening lab hematology or serum chemistries, as&#xD;
             determined by PI or PI in consultation with the research monitor and sponsor.&#xD;
&#xD;
          -  Lactation or breastfeeding.&#xD;
&#xD;
        Research-related exclusions applicable to challenge&#xD;
&#xD;
          -  History of microbiologically confirmed ETEC or cholera infection in last 3 years.&#xD;
&#xD;
          -  Occupation involving handling of ETEC or Vibrio cholerae currently, or in the past 3&#xD;
             years.&#xD;
&#xD;
          -  Travel to countries where ETEC or cholera infection is endemic (most of the developing&#xD;
             world) within 3 years prior to dosing.&#xD;
&#xD;
          -  Symptoms consistent with Travelers' Diarrhea concurrent with travel to countries where&#xD;
             ETEC infection is endemic (most of the developing world) within 3 years prior to&#xD;
             dosing, OR planned travel to endemic countries during the length of the study.&#xD;
&#xD;
          -  Vaccination for or ingestion of ETEC, cholera, or E coli heat labile toxin within 3&#xD;
             years prior to dosing.&#xD;
&#xD;
          -  Any prior experimental infection with ETEC strain B7A.&#xD;
&#xD;
        Study-specific Exclusion Criteria (potential increased risk or complicating outcome&#xD;
        ascertainment)&#xD;
&#xD;
          -  Abnormal stool pattern (fewer than 3 per week or more than 3 per day).&#xD;
&#xD;
          -  History of diarrhea in the 2 weeks prior to planned inpatient phase.&#xD;
&#xD;
          -  Regular use of laxatives, antacids, or other agents to lower stomach acidity (regular&#xD;
             defined as at least weekly).&#xD;
&#xD;
          -  Use of antibiotics during the 7 days before receipt of any investigational&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>50 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Kawsar R Talaat, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Johns Hopkins Center for Immunization Research</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Johns Hopkins Center for Immunization Research</name>
      <address>
        <city>Baltimore</city>
        <state>Maryland</state>
        <zip>21205</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Porter CK, Riddle MS, Alcala AN, Sack DA, Harro C, Chakraborty S, Gutierrez RL, Savarino SJ, Darsley M, McKenzie R, DeNearing B, Steinsland H, Tribble DR, Bourgeois AL. An Evidenced-Based Scale of Disease Severity following Human Challenge with Enteroxigenic Escherichia coli. PLoS One. 2016 Mar 3;11(3):e0149358. doi: 10.1371/journal.pone.0149358. eCollection 2016.</citation>
    <PMID>26938983</PMID>
  </reference>
  <reference>
    <citation>McKenzie R, Porter CK, Cantrell JA, Denearing B, O'Dowd A, Grahek SL, Sincock SA, Woods C, Sebeny P, Sack DA, Tribble DR, Bourgeois AL, Savarino SJ. Volunteer challenge with enterotoxigenic Escherichia coli that express intestinal colonization factor fimbriae CS17 and CS19. J Infect Dis. 2011 Jul 1;204(1):60-4. doi: 10.1093/infdis/jir220.</citation>
    <PMID>21628659</PMID>
  </reference>
  <reference>
    <citation>Freedman DJ, Tacket CO, Delehanty A, Maneval DR, Nataro J, Crabb JH. Milk immunoglobulin with specific activity against purified colonization factor antigens can protect against oral challenge with enterotoxigenic Escherichia coli. J Infect Dis. 1998 Mar;177(3):662-7. doi: 10.1086/514227.</citation>
    <PMID>9498445</PMID>
  </reference>
  <verification_date>March 2019</verification_date>
  <study_first_submitted>January 26, 2017</study_first_submitted>
  <study_first_submitted_qc>February 1, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">February 2, 2017</study_first_posted>
  <results_first_submitted>August 8, 2018</results_first_submitted>
  <results_first_submitted_qc>March 14, 2019</results_first_submitted_qc>
  <results_first_posted type="Actual">June 14, 2019</results_first_posted>
  <last_update_submitted>March 14, 2019</last_update_submitted>
  <last_update_submitted_qc>March 14, 2019</last_update_submitted_qc>
  <last_update_posted type="Actual">June 14, 2019</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>ETEC</keyword>
  <keyword>Escherichia coli</keyword>
  <keyword>enteritis</keyword>
  <keyword>challenge</keyword>
  <keyword>CS6</keyword>
  <keyword>B7A</keyword>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <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>November 22, 2016</document_date>
      <document_url>https://ClinicalTrials.gov/ProvidedDocs/87/NCT03040687/Prot_SAP_000.pdf</document_url>
    </provided_document>
  </provided_document_section>

  <clinical_results>

    <participant_flow>
      <recruitment_details>Sixty healthy adult naive subjects enrolled and received one of the three BSIgG products. Fifty-nine of those subjects were challenged with ETEC strain B7A.</recruitment_details>
      <pre_assignment_details>Study specific screening occurred prior to enrollment. Eighty-two subjects signed study specific consent forms. Nineteen subjects screened failed. Three subjects were randomized but did not receive BSIgG.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Anti-CS6 Group</title>
          <description>Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti CS6 BSIgG product (Lot PD1601105CS)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
        <group group_id="P2">
          <title>Anti-whole Cell B7A</title>
          <description>Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti B7A BSIgG product (Lot PD1601132ET)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
        <group group_id="P3">
          <title>Control Immunoglobulin Group</title>
          <description>Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A)&#xD;
Bovine Immunoglobin Negative Control (Lot PD161071NC)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="20"/>
                <participants group_id="P2" count="20"/>
                <participants group_id="P3" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="19"/>
                <participants group_id="P2" count="20"/>
                <participants group_id="P3" count="20"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Withdrawal by Subject</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
                <participants group_id="P3" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <group_list>
        <group group_id="B1">
          <title>Anti-CS6 Group</title>
          <description>Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti CS6 BSIgG product (Lot PD1601105CS)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
        <group group_id="B2">
          <title>Anti-whole Cell B7A</title>
          <description>Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti B7A BSIgG product (Lot PD1601132ET)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
        <group group_id="B3">
          <title>Control Immunoglobulin Group</title>
          <description>Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A)&#xD;
Bovine Immunoglobin Negative Control (Lot PD161071NC)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
        <group group_id="B4">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="20"/>
            <count group_id="B2" value="20"/>
            <count group_id="B3" value="20"/>
            <count group_id="B4" value="60"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age</title>
          <units>years</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="33.5" lower_limit="25.0" upper_limit="37.5"/>
                    <measurement group_id="B2" value="35.0" lower_limit="31.0" upper_limit="43.0"/>
                    <measurement group_id="B3" value="35.5" lower_limit="26.8" upper_limit="41.8"/>
                    <measurement group_id="B4" value="34" lower_limit="26.8" upper_limit="42"/>
                  </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="9"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="9"/>
                    <measurement group_id="B4" value="22"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="11"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="11"/>
                    <measurement group_id="B4" value="38"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Ethnicity (NIH/OMB)</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="1"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="7"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Not Hispanic or Latino</title>
                  <measurement_list>
                    <measurement group_id="B1" value="17"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="17"/>
                    <measurement group_id="B4" value="53"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" 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 group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Asian</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Native Hawaiian or Other Pacific Islander</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Black or African American</title>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="18"/>
                    <measurement group_id="B3" value="15"/>
                    <measurement group_id="B4" value="48"/>
                  </measurement_list>
                </category>
                <category>
                  <title>White</title>
                  <measurement_list>
                    <measurement group_id="B1" value="5"/>
                    <measurement group_id="B2" value="2"/>
                    <measurement group_id="B3" value="3"/>
                    <measurement group_id="B4" value="10"/>
                  </measurement_list>
                </category>
                <category>
                  <title>More than one race</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="2"/>
                    <measurement group_id="B4" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Unknown or Not Reported</title>
                  <measurement_list>
                    <measurement group_id="B1" value="0"/>
                    <measurement group_id="B2" value="0"/>
                    <measurement group_id="B3" value="0"/>
                    <measurement group_id="B4" 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="20"/>
                    <measurement group_id="B2" value="20"/>
                    <measurement group_id="B3" value="20"/>
                    <measurement group_id="B4" value="60"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Safety of Serum Derived Bovine Immunoglobulins (BSIgG)</title>
        <description>Number of Participants with adverse events in groups receiving B7A- and CS6- hyperimmune (BSIgG) compared with the group receiving the nonhyperimmune product.</description>
        <time_frame>28 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Anti-CS6 Group</title>
            <description>Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti CS6 BSIgG product (Lot PD1601105CS)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
          </group>
          <group group_id="O2">
            <title>Anti-whole Cell B7A</title>
            <description>Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti B7A BSIgG product (Lot PD1601132ET)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
          </group>
          <group group_id="O3">
            <title>Control Immunoglobulin Group</title>
            <description>Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A)&#xD;
Bovine Immunoglobin Negative Control (Lot PD161071NC)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
          </group>
        </group_list>
        <measure>
          <title>Safety of Serum Derived Bovine Immunoglobulins (BSIgG)</title>
          <description>Number of Participants with adverse events in groups receiving B7A- and CS6- hyperimmune (BSIgG) compared with the group receiving the nonhyperimmune product.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="20"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Abdominal Distension</title>
                  <measurement_list>
                    <measurement group_id="O1" value="1"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Abdominal Pain</title>
                  <measurement_list>
                    <measurement group_id="O1" value="2"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Defecation Urgency</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                    <measurement group_id="O3" value="1"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Flatulence</title>
                  <measurement_list>
                    <measurement group_id="O1" value="3"/>
                    <measurement group_id="O2" value="4"/>
                    <measurement group_id="O3" value="2"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Headache</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Nausea</title>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                    <measurement group_id="O3" value="0"/>
                  </measurement_list>
                </category>
                <category>
                  <title>None</title>
                  <measurement_list>
                    <measurement group_id="O1" value="14"/>
                    <measurement group_id="O2" value="11"/>
                    <measurement group_id="O3" value="16"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Primary</type>
        <title>Efficacy of B7A and CS6- Hyperimmune Bovine Serum Immunoglobin to Protect Against Moderate to Severe Diarrhea After Challenge With the CS6 Expressing ETEC Strain B7A</title>
        <description>Comparison of the number and percentage of volunteers in the arms receiving the B7A- and CS6 BSIgG vs the arm receiving the nonhyperimmune BSIgG who develop moderate to severe diarrhea.</description>
        <time_frame>28 days</time_frame>
        <group_list>
          <group group_id="O1">
            <title>Anti-CS6 Group</title>
            <description>Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti CS6 BSIgG product (Lot PD1601105CS)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
          </group>
          <group group_id="O2">
            <title>Anti-whole Cell B7A</title>
            <description>Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti B7A BSIgG product (Lot PD1601132ET)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
          </group>
          <group group_id="O3">
            <title>Control Immunoglobulin Group</title>
            <description>Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A)&#xD;
Bovine Immunoglobin Negative Control (Lot PD161071NC)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
          </group>
        </group_list>
        <measure>
          <title>Efficacy of B7A and CS6- Hyperimmune Bovine Serum Immunoglobin to Protect Against Moderate to Severe Diarrhea After Challenge With the CS6 Expressing ETEC Strain B7A</title>
          <description>Comparison of the number and percentage of volunteers in the arms receiving the B7A- and CS6 BSIgG vs the arm receiving the nonhyperimmune BSIgG who develop moderate to severe diarrhea.</description>
          <units>Participants</units>
          <param>Count of Participants</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="19"/>
                <count group_id="O2" value="20"/>
                <count group_id="O3" value="20"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="12"/>
                    <measurement group_id="O2" value="7"/>
                    <measurement group_id="O3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>6 months</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Anti-CS6 Group</title>
          <description>Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti CS6 BSIgG product (Lot PD1601105CS)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
        <group group_id="E2">
          <title>Anti-whole Cell B7A</title>
          <description>Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A)&#xD;
Anti B7A BSIgG product (Lot PD1601132ET)&#xD;
B7A- CS6-expressing ETEC challenge strain</description>
        </group>
        <group group_id="E3">
          <title>Control Immunoglobulin Group</title>
          <description>Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A)&#xD;
Bovine Immunoglobin Negative Control (Lot PD161071NC)&#xD;
B7A- CS6-expressing ETEC challenge strain</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="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="19" subjects_at_risk="20"/>
                <counts group_id="E2" subjects_affected="17" subjects_at_risk="20"/>
                <counts group_id="E3" subjects_affected="20" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Cardiac disorders</title>
            <event_list>
              <event>
                <sub_title>Bradycardia</sub_title>
                <counts group_id="E1" events="1" subjects_affected="1" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="0" subjects_affected="0" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Gastrointestinal disorders</title>
            <event_list>
              <event>
                <sub_title>Abdominal Distention</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E3" events="9" subjects_affected="9" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Abdominal Pain</sub_title>
                <counts group_id="E1" events="12" subjects_affected="12" subjects_at_risk="20"/>
                <counts group_id="E2" events="7" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E3" events="12" subjects_affected="12" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Abdominal Pain lower</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Abdominal tenderness</sub_title>
                <counts group_id="E1" events="5" subjects_affected="5" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="7" subjects_affected="7" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Decreased appetite</sub_title>
                <counts group_id="E1" events="10" subjects_affected="10" subjects_at_risk="20"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
                <counts group_id="E3" events="10" subjects_affected="10" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Defecation Urgency</sub_title>
                <counts group_id="E1" events="9" subjects_affected="9" subjects_at_risk="20"/>
                <counts group_id="E2" events="4" subjects_affected="4" subjects_at_risk="20"/>
                <counts group_id="E3" events="9" subjects_affected="9" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Immune system disorders</title>
            <event_list>
              <event>
                <sub_title>Apthous ulcer</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Chills</sub_title>
                <counts group_id="E1" events="7" subjects_affected="7" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="10" subjects_affected="5" subjects_at_risk="20"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Musculoskeletal and connective tissue disorders</title>
            <event_list>
              <event>
                <sub_title>Arthraligia</sub_title>
                <counts group_id="E1" events="2" subjects_affected="2" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="5" subjects_affected="5" subjects_at_risk="20"/>
              </event>
              <event>
                <sub_title>Back pain</sub_title>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E2" events="0" subjects_affected="0" subjects_at_risk="20"/>
                <counts group_id="E3" events="1" subjects_affected="1" subjects_at_risk="20"/>
              </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>Kawsar Talaat</name_or_title>
      <organization>Johns Hopkins University</organization>
      <phone>410-502-9627</phone>
      <email>ktalaat@jhu.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/NCT03040687
org study id: CIR 315 BSIgG
nct id: NCT03040687
lead sponsor: 
collaborator: 
collaborator: 
has dmc: No
Enterotoxigenic Escherichia coli (ETEC) is a major cause of diarrhea worldwide. Vaccines and
      therapeutics are under development to prevent ETEC disease in children and travelers. One
      approach is to use passive protection (antibodies) to prevent infection. The purpose of this
      study are to assess the safety of serum-derived bovine immunoglobulins in healthy adult
      subjects when orally administered and to estimate protective efficacy of those preparations
      against moderate-severe diarrhea upon challenge with the ETEC strain B7A.
Enterotoxigenic Escherichia coli (ETEC) is one of the most common causes of infectious
      diarrhea in children in resource limited countries, and is also a frequent cause of
      traveler's diarrhea in civilian and military travelers to endemic countries. ETEC strains
      express a variety of colonization factors (CF) that help them attach to the intestinal wall.
      Each colonization factor has one or more surface antigens (CS). One of the major surface
      antigens of ETEC is CS6 (Coli surface antigen 6).

      Vaccines and treatments to prevent ETEC disease are under development. Some of these target
      specific enterotoxins or colonization factors. For over 40 years, we have used ETEC human
      challenge studies to understand the ETEC disease process, immune response, and more recently,
      to determine whether treatments or vaccines are protective or effective in mitigating
      disease. B7A is the only CS6 expressing ETEC challenge strain currently used.

      A modality that has shown some success in the prevention of diarrhea is passive, oral
      administration of bovine milk IgG with specific activity against viral, bacterial and
      parasitic enteropathogens. Passive oral administration of Bovine Serum Immunoglobulins
      (BSIgG) may protect against ETEC-mediated infectious diarrhea. The hypothesized mechanism of
      protection stems from the passive administration of bovine anti-tip adhesion or fimbriae
      antibodies preventing their adherence in the human small intestine (the initial step in
      pathogenesis), thereby preventing downstream pathogenic processes and symptomatic illness.
      This study will establish the foundation for evaluating BSIgG products against numerous ETEC
      CFs.

      This study will explore if anti-B7A and anti- CS6 BSIgG provides protection against oral
      challenge with B7A in healthy adult volunteers. There will be two inpatient admissions of
      approximately 30 subjects (up to 60 total). They will receive one of three investigational
      products (IP) three times daily following meals beginning 2 days prior to challenge. Each
      volunteer will be challenged with CS6 expressing ETEC B7A on Day 0. The investigational
      product/placebo will be administered for a total of 7 days, or until antibiotic treatment has
      been administered. The investigators hypothesize that anti-CS6 BSIgG will provide protection
      against B7A mediated moderate to severe diarrhea upon challenge.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Safety of Serum Derived Bovine Immunoglobulins (BSIgG)
time frame: 28 days
description: Number of Participants with adverse events in groups receiving B7A- and CS6- hyperimmune (BSIgG) compared with the group receiving the nonhyperimmune product.
measure: Efficacy of B7A and CS6- Hyperimmune Bovine Serum Immunoglobin to Protect Against Moderate to Severe Diarrhea After Challenge With the CS6 Expressing ETEC Strain B7A
time frame: 28 days
description: Comparison of the number and percentage of volunteers in the arms receiving the B7A- and CS6 BSIgG vs the arm receiving the nonhyperimmune BSIgG who develop moderate to severe diarrhea.
arm group label: Anti-CS6 group
arm group type: Experimental
description: Anti-CS6 BSIgG and challenge strain CS6-expressing ETEC (B7A)
arm group label: Anti-whole cell B7A
arm group type: Experimental
description: Anti- whole cell B7A (killed) BSIgG and challenge strain CS6-expressing ETEC (B7A)
arm group label: control Immunoglobulin group
arm group type: Experimental
description: Negative Control (Nonhyperimmune BSIgG placebo) and challenge strain CS6-expressing ETEC (B7A)
intervention type: Biological
intervention name: Anti CS6 BSIgG product (Lot PD1601105CS)
arm group label: Anti-CS6 group
intervention type: Biological
intervention name: Anti B7A BSIgG product (Lot PD1601132ET)
arm group label: Anti-whole cell B7A
intervention type: Biological
intervention name: Bovine Immunoglobin Negative Control (Lot PD161071NC)
arm group label: control Immunoglobulin group
intervention type: Biological
intervention name: B7A- CS6-expressing ETEC challenge strain
arm group label: Anti-CS6 group
arm group label: Anti-whole cell B7A
arm group label: control Immunoglobulin group
criteria: 
gender: All
minimum age: 18 Years
maximum age: 50 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Kawsar R Talaat, MD
role: Principal Investigator
affiliation: Johns Hopkins Center for Immunization Research
facility: 
country: United States
citation: Porter CK, Riddle MS, Alcala AN, Sack DA, Harro C, Chakraborty S, Gutierrez RL, Savarino SJ, Darsley M, McKenzie R, DeNearing B, Steinsland H, Tribble DR, Bourgeois AL. An Evidenced-Based Scale of Disease Severity following Human Challenge with Enteroxigenic Escherichia coli. PLoS One. 2016 Mar 3;11(3):e0149358. doi: 10.1371/journal.pone.0149358. eCollection 2016.
PMID: 26938983
citation: McKenzie R, Porter CK, Cantrell JA, Denearing B, O'Dowd A, Grahek SL, Sincock SA, Woods C, Sebeny P, Sack DA, Tribble DR, Bourgeois AL, Savarino SJ. Volunteer challenge with enterotoxigenic Escherichia coli that express intestinal colonization factor fimbriae CS17 and CS19. J Infect Dis. 2011 Jul 1;204(1):60-4. doi: 10.1093/infdis/jir220.
PMID: 21628659
citation: Freedman DJ, Tacket CO, Delehanty A, Maneval DR, Nataro J, Crabb JH. Milk immunoglobulin with specific activity against purified colonization factor antigens can protect against oral challenge with enterotoxigenic Escherichia coli. J Infect Dis. 1998 Mar;177(3):662-7. doi: 10.1086/514227.
PMID: 9498445
responsible party type: Sponsor
sharing ipd: Undecided
provided document: 
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
point of contact: 