<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/NCT02262819</url>
  </required_header>
  <id_info>
    <org_study_id>140199</org_study_id>
    <secondary_id>14-I-0199</secondary_id>
    <nct_id>NCT02262819</nct_id>
  </id_info>
  <brief_title>Human Immunity Against Staphylococcus Aureus Skin Infection</brief_title>
  <official_title>Human Immunity Against Staphylococcus Aureus Skin Infection</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>National Institute of Allergy and Infectious Diseases (NIAID)</agency>
      <agency_class>NIH</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>National Institutes of Health Clinical Center (CC)</source>
  <oversight_info>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background:&#xD;
&#xD;
      - Staphylococcus aureus, or staph, is commonly found on the skin and in the respiratory&#xD;
      system. Sometimes people who get sick with staph infection do not get better with standard&#xD;
      treatment. These staph infections can be serious and even deadly. Researchers want to find&#xD;
      out why some people are more likely to get the infection.&#xD;
&#xD;
      Objectives:&#xD;
&#xD;
      - To look at the immune response of the skin when it is exposed to bacteria.&#xD;
&#xD;
      Eligibility:&#xD;
&#xD;
        -  People age 2 65 with hyper IgE syndrome (HIES) and those with recurrent staph&#xD;
           infections.&#xD;
&#xD;
        -  Healthy volunteers.&#xD;
&#xD;
      Design:&#xD;
&#xD;
        -  Participants will be screened with medical history, physical exam, and blood tests.&#xD;
&#xD;
        -  Over 1 5 days, participants may have blood tests and a skin and nasal swab. They may&#xD;
           have additional tests if needed. If they had a recent biopsy, researchers may ask for a&#xD;
           sample from it.&#xD;
&#xD;
        -  Some participants will spend the night at the clinic. Their vital signs will be taken&#xD;
           and they will have blood drawn. Some participants will take aspirin or ibuprofen&#xD;
           starting 2 days before their stay.&#xD;
&#xD;
        -  Some participants will have blisters created on the inside of their forearm. Suction&#xD;
           will pull a layer of skin from their arm. Skin will be removed. Different solutions will&#xD;
           be applied to the blisters. Up to 3 biopsies may be taken.&#xD;
&#xD;
        -  Children will not have blood tests or biopsies.&#xD;
&#xD;
        -  Participants will be called every day for 10 days, then at 30 days after the procedure.&#xD;
&#xD;
        -  Participants will have a follow-up visit 10 days after the procedure.&#xD;
&#xD;
        -  Participants who did not get blisters or biopsies will not have any follow-up&#xD;
           appointments.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The incidence of community-associated (CA) staphylococcal infections, especially those caused&#xD;
      by methicillin-resistant Staphylococcus aureus (MRSA), has increased dramatically in recent&#xD;
      years. Skin and soft tissues are the primary site for most of these infections, and skin or&#xD;
      mucosal colonization increases the risk of disseminated disease. Many patients without&#xD;
      apparent underlying immune dysfunction suffer from recurrent and persistent skin infections&#xD;
      with MRSA. Additionally, patients with conditions such as atopic dermatitis and Hyper IgE (or&#xD;
      Job s) Syndrome (HIES) are disproportionately affected. Although underlying host molecular&#xD;
      defects responsible for some of these predisposing conditions have been uncovered in recent&#xD;
      years (e.g. STAT3 mutations in HIES), the skin immune response to S. aureus infections has&#xD;
      not been elucidated in either healthy controls or susceptible populations. In this protocol,&#xD;
      we will perform exploratory evaluations of anti-staphylococcal immune responses in healthy&#xD;
      subjects, subjects with STAT3 mutations, and otherwise healthy subjects with a history of&#xD;
      recurrent staphylococcal skin infections. An additional group of subjects with other&#xD;
      underlying conditions of interest may be included.&#xD;
&#xD;
      The primary objective of this research is to perform in vivo and ex vivo challenges with&#xD;
      killed bacteria through the use of the skin blister model and keratinocyte cultures to&#xD;
      evaluate skin immune responses. Occasionally, a commensal fungi, such as Candida species may&#xD;
      also be used. We will use three experimental approaches to complete this objective: 1)&#xD;
      evaluation of in vivo responses in skin blisters to killed microbe exposure, 2) ex vivo&#xD;
      evaluation of anti-microbial responses through derivation of keratinocyte cultures from skin&#xD;
      blisters or biopsies, and 3) evaluation of function and immune-stimulatory ability of&#xD;
      commensal organisms.&#xD;
&#xD;
      Specifically, a suction blister device will be used to induce a skin blister on the forearm.&#xD;
      The tops of the blisters will be removed, and solutions of killed S. aureus, commensal&#xD;
      coagulase-negative staphylococcal species, or other Gram-negative commensals as well as&#xD;
      commensal fungi, such as Candida species will be applied to the blisters to stimulate&#xD;
      inflammatory responses. The blister fluid will then be collected at various time points over&#xD;
      24 hours for laboratory analysis. Baseline skin and/or nasal swabs, skin biopsies, and blood&#xD;
      draws will also be performed (The skin and nasal swabs may be performed at the screening or&#xD;
      baseline visit.). Pediatric participants may be enrolled for baseline skin and/or nasal&#xD;
      swabs. All research procedures will be performed at the National Institutes of Health&#xD;
      Clinical Center. We anticipate that the research will provide critical new information on the&#xD;
      human skin immune response to S. aureus that has direct relevance for the development of&#xD;
      vaccines, diagnostics, and therapeutics.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>October 10, 2014</start_date>
  <completion_date type="Actual">April 24, 2019</completion_date>
  <primary_completion_date type="Actual">April 24, 2019</primary_completion_date>
  <phase>Phase 1</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Evaluate the local in vivo skin immune response to bacteria.</measure>
    <time_frame>4 years</time_frame>
  </primary_outcome>
  <primary_outcome>
    <measure>Evaluate the keratinocyte responses to bacterial challenge.</measure>
    <time_frame>4 years</time_frame>
  </primary_outcome>
  <secondary_outcome>
    <measure>Determine if abnormalities in specific immune pathways, such as IL-17 and vitamin D metabolism, are present in subjects with recognized susceptibility to S. aureus infections.</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Characterize cultured skin bacteria (S. aureus, S. epidermidis, and other skin commensals) with molecular and functional studies.</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Assess the impact of non-steroidal anti-inflammatory drugs (NSAIDs) on skin immune function.</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Characterize blood immune parameters in a cohort of patients with invasive and/or recurrent skin and soft tissue S. aureus infections.</measure>
    <time_frame>4 years</time_frame>
  </secondary_outcome>
  <enrollment type="Actual">49</enrollment>
  <condition>Staphylococcus Aureus Skin Infection</condition>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>S. aureus</intervention_name>
    <description>S. aureus, commensal coagulase-negative staphylococcal species, and Gram-negative commensals, such as Roseomonas and Pseudomonas species</description>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        -  INCLUSION CRITERIA:&#xD;
&#xD;
        Participants must either:&#xD;
&#xD;
          1. Have documentation of a proven or suspected immune defect or a history of invasive&#xD;
             infection or recurrent (2 or more) skin infections with S. aureus (patient&#xD;
             population); or&#xD;
&#xD;
          2. Not have evidence of an immune defect or history of invasive or recurrent S. aureus&#xD;
             infections (healthy volunteers).&#xD;
&#xD;
               -  Participants must be between 2 and 65 years old (inclusive).&#xD;
&#xD;
               -  Participants must be willing to allow storage of blood, DNA, RNA, bacterial and&#xD;
                  fungal cultures, and other tissue samples for future research. Some research&#xD;
                  blood may not be required of healthy volunteers, except at the discretion of the&#xD;
                  Principal Investigator (PI).&#xD;
&#xD;
        EXCLUSION CRITERIA:&#xD;
&#xD;
        The following exclusion criteria apply to all participants:&#xD;
&#xD;
          -  Current chemotherapy or underlying malignancy.&#xD;
&#xD;
          -  Current oral steroids.&#xD;
&#xD;
          -  Individuals with any condition that, in the opinion of the investigator,&#xD;
             contraindicates participation in the study will be excluded.&#xD;
&#xD;
        The following exclusion criteria apply to adult participants in the blister portion of the&#xD;
        study (Arm 1) only:&#xD;
&#xD;
          -  Viral hepatitis B or C. Test results, including those from an outside facility or lab,&#xD;
             within the prior 6 months will be accepted.&#xD;
&#xD;
          -  HIV positive. Test results, including those from an outside facility or lab, within&#xD;
             the prior 6 months will be accepted.&#xD;
&#xD;
          -  Individuals on anticoagulant or anti-platelet therapy (other than aspirin or NSAIDs as&#xD;
             described in the protocol).&#xD;
&#xD;
          -  Pregnancy.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>2 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Ian A Myles, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>National Institute of Allergy and Infectious Diseases (NIAID)</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>National Institutes of Health Clinical Center, 9000 Rockville Pike</name>
      <address>
        <city>Bethesda</city>
        <state>Maryland</state>
        <zip>20892</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Gough P, Ganesan S, Datta SK. IL-20 Signaling in Activated Human Neutrophils Inhibits Neutrophil Migration and Function. J Immunol. 2017 Jun 1;198(11):4373-4382. doi: 10.4049/jimmunol.1700253. Epub 2017 Apr 19.</citation>
    <PMID>28424238</PMID>
  </reference>
  <reference>
    <citation>Sastalla I, Williams KW, Anderson ED, Myles IA, Reckhow JD, Espinoza-Moraga M, Freeman AF, Datta SK. Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome. Pathogens. 2017 Jun 6;6(2):23. doi: 10.3390/pathogens6020023.</citation>
    <PMID>28587312</PMID>
  </reference>
  <verification_date>April 24, 2019</verification_date>
  <study_first_submitted>October 10, 2014</study_first_submitted>
  <study_first_submitted_qc>October 10, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">October 13, 2014</study_first_posted>
  <last_update_submitted>March 29, 2021</last_update_submitted>
  <last_update_submitted_qc>March 29, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">March 30, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Skin Blister</keyword>
  <keyword>Immune Response</keyword>
  <keyword>Suction Device</keyword>
  <keyword>Anti-Microbial</keyword>
  <keyword>Killed Microbe</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Infections</mesh_term>
    <mesh_term>Communicable Diseases</mesh_term>
    <mesh_term>Staphylococcal Infections</mesh_term>
    <mesh_term>Cellulitis</mesh_term>
    <mesh_term>Skin Diseases, Infectious</mesh_term>
    <mesh_term>Staphylococcal Skin Infections</mesh_term>
  </condition_browse>
  <!-- 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/NCT02262819
org study id: 140199
secondary id: 14-I-0199
nct id: NCT02262819
lead sponsor: 
is fda regulated drug: Yes
Background:

      - Staphylococcus aureus, or staph, is commonly found on the skin and in the respiratory
      system. Sometimes people who get sick with staph infection do not get better with standard
      treatment. These staph infections can be serious and even deadly. Researchers want to find
      out why some people are more likely to get the infection.

      Objectives:

      - To look at the immune response of the skin when it is exposed to bacteria.

      Eligibility:

        -  People age 2 65 with hyper IgE syndrome (HIES) and those with recurrent staph
           infections.

        -  Healthy volunteers.

      Design:

        -  Participants will be screened with medical history, physical exam, and blood tests.

        -  Over 1 5 days, participants may have blood tests and a skin and nasal swab. They may
           have additional tests if needed. If they had a recent biopsy, researchers may ask for a
           sample from it.

        -  Some participants will spend the night at the clinic. Their vital signs will be taken
           and they will have blood drawn. Some participants will take aspirin or ibuprofen
           starting 2 days before their stay.

        -  Some participants will have blisters created on the inside of their forearm. Suction
           will pull a layer of skin from their arm. Skin will be removed. Different solutions will
           be applied to the blisters. Up to 3 biopsies may be taken.

        -  Children will not have blood tests or biopsies.

        -  Participants will be called every day for 10 days, then at 30 days after the procedure.

        -  Participants will have a follow-up visit 10 days after the procedure.

        -  Participants who did not get blisters or biopsies will not have any follow-up
           appointments.
The incidence of community-associated (CA) staphylococcal infections, especially those caused
      by methicillin-resistant Staphylococcus aureus (MRSA), has increased dramatically in recent
      years. Skin and soft tissues are the primary site for most of these infections, and skin or
      mucosal colonization increases the risk of disseminated disease. Many patients without
      apparent underlying immune dysfunction suffer from recurrent and persistent skin infections
      with MRSA. Additionally, patients with conditions such as atopic dermatitis and Hyper IgE (or
      Job s) Syndrome (HIES) are disproportionately affected. Although underlying host molecular
      defects responsible for some of these predisposing conditions have been uncovered in recent
      years (e.g. STAT3 mutations in HIES), the skin immune response to S. aureus infections has
      not been elucidated in either healthy controls or susceptible populations. In this protocol,
      we will perform exploratory evaluations of anti-staphylococcal immune responses in healthy
      subjects, subjects with STAT3 mutations, and otherwise healthy subjects with a history of
      recurrent staphylococcal skin infections. An additional group of subjects with other
      underlying conditions of interest may be included.

      The primary objective of this research is to perform in vivo and ex vivo challenges with
      killed bacteria through the use of the skin blister model and keratinocyte cultures to
      evaluate skin immune responses. Occasionally, a commensal fungi, such as Candida species may
      also be used. We will use three experimental approaches to complete this objective: 1)
      evaluation of in vivo responses in skin blisters to killed microbe exposure, 2) ex vivo
      evaluation of anti-microbial responses through derivation of keratinocyte cultures from skin
      blisters or biopsies, and 3) evaluation of function and immune-stimulatory ability of
      commensal organisms.

      Specifically, a suction blister device will be used to induce a skin blister on the forearm.
      The tops of the blisters will be removed, and solutions of killed S. aureus, commensal
      coagulase-negative staphylococcal species, or other Gram-negative commensals as well as
      commensal fungi, such as Candida species will be applied to the blisters to stimulate
      inflammatory responses. The blister fluid will then be collected at various time points over
      24 hours for laboratory analysis. Baseline skin and/or nasal swabs, skin biopsies, and blood
      draws will also be performed (The skin and nasal swabs may be performed at the screening or
      baseline visit.). Pediatric participants may be enrolled for baseline skin and/or nasal
      swabs. All research procedures will be performed at the National Institutes of Health
      Clinical Center. We anticipate that the research will provide critical new information on the
      human skin immune response to S. aureus that has direct relevance for the development of
      vaccines, diagnostics, and therapeutics.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Evaluate the local in vivo skin immune response to bacteria.
time frame: 4 years
measure: Evaluate the keratinocyte responses to bacterial challenge.
time frame: 4 years
measure: Determine if abnormalities in specific immune pathways, such as IL-17 and vitamin D metabolism, are present in subjects with recognized susceptibility to S. aureus infections.
time frame: 4 years
measure: Characterize cultured skin bacteria (S. aureus, S. epidermidis, and other skin commensals) with molecular and functional studies.
time frame: 4 years
measure: Assess the impact of non-steroidal anti-inflammatory drugs (NSAIDs) on skin immune function.
time frame: 4 years
measure: Characterize blood immune parameters in a cohort of patients with invasive and/or recurrent skin and soft tissue S. aureus infections.
time frame: 4 years
intervention type: Drug
intervention name: S. aureus
description: S. aureus, commensal coagulase-negative staphylococcal species, and Gram-negative commensals, such as Roseomonas and Pseudomonas species
criteria: 
gender: All
minimum age: 2 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Ian A Myles, M.D.
role: Principal Investigator
affiliation: National Institute of Allergy and Infectious Diseases (NIAID)
facility: 
country: United States
citation: Gough P, Ganesan S, Datta SK. IL-20 Signaling in Activated Human Neutrophils Inhibits Neutrophil Migration and Function. J Immunol. 2017 Jun 1;198(11):4373-4382. doi: 10.4049/jimmunol.1700253. Epub 2017 Apr 19.
PMID: 28424238
citation: Sastalla I, Williams KW, Anderson ED, Myles IA, Reckhow JD, Espinoza-Moraga M, Freeman AF, Datta SK. Molecular Typing of Staphylococcus aureus Isolated from Patients with Autosomal Dominant Hyper IgE Syndrome. Pathogens. 2017 Jun 6;6(2):23. doi: 10.3390/pathogens6020023.
PMID: 28587312
responsible party type: Sponsor
mesh term: Infections
mesh term: Communicable Diseases
mesh term: Staphylococcal Infections
mesh term: Cellulitis
mesh term: Skin Diseases, Infectious
mesh term: Staphylococcal Skin Infections