<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/NCT03779360</url>
  </required_header>
  <id_info>
    <org_study_id>CHDR1752-B</org_study_id>
    <nct_id>NCT03779360</nct_id>
  </id_info>
  <brief_title>Intradermal LPS and Antibiotics</brief_title>
  <official_title>Investigating Anti-inflammatory Effects of Topical Antibiotics in an LPS Skin Challenge Model</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre for Human Drug Research, Netherlands</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Maruho Co., Ltd.</agency>
      <agency_class>Industry</agency_class>
    </collaborator>
  </sponsors>
  <source>Centre for Human Drug Research, Netherlands</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Erythromycin and clindamycin are believed to have anti-inflammatory aspects. This study&#xD;
      investigates the possible anti-inflammatory effects of erythromycin and clindamycin.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Convincing mechanistic reports on the immunomodulatory action of erythromycin and clindamycin&#xD;
      are scarce, rarely based on experiments in freshly isolated human immune cells, and&#xD;
      potentially contradicting. Moreover, direct immunomodulatory effects of both antibiotics have&#xD;
      never been demonstrated in vivo. The Centre for Human Drug Research Biomarker lab has studied&#xD;
      in depth the immunomodulatory actions of erythromycin and clindamycin in vitro. These in&#xD;
      vitro experiments on primary human immune cells demonstrated that both erythromycin and&#xD;
      clindamycin are able to modulate the immune response of peripheral blood mononuclear cells&#xD;
      upon stimulation with different immune triggers such as lipopolysaccharide (LPS) and polyI:C.&#xD;
      In this current study the in vitro work will be translated to an in vivo study where it will&#xD;
      be made into an intradermal LPS skin challenge model in healthy volunteers.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">October 12, 2018</start_date>
  <completion_date type="Actual">February 23, 2019</completion_date>
  <primary_completion_date type="Actual">February 23, 2019</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Factorial Assignment</intervention_model>
    <intervention_model_description>An interventional, open-label, comparator controlled study to investigate the immunomodulatory effects of erythromycin and clindamycin in an LPS skin challenge model in healthy volunteers.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Change in perfusion by Laser speckle contrast imaging (LSCI)</measure>
    <time_frame>Baseline, 3, 6, 10, 24 and 48 hours post LPS injection</time_frame>
    <description>Cutaneous microcirculation between pre and post-dose will be assessed using the laser speckle imager.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in erythema by Antera 3D camera and 2D camera</measure>
    <time_frame>Baseline, 3, 6, 10, 24 and 48 hours post LPS injection</time_frame>
    <description>Standardized photographs will be taken using the Antera camera (Antera 3D, Miravex, Ireland).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in erythema by clinical evaluation (erythema grading scale)</measure>
    <time_frame>Baseline, 3, 6, 10, 24 and 48 hours post LPS injection</time_frame>
    <description>At the specific time points pre and post dose the colour of the injected area is scored (erythema index), on a 4 point scale; normal, mild, moderate, severe.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in temperature by thermography in celsius</measure>
    <time_frame>Baseline, 3, 6, 10, 24 and 48 hours post LPS injection</time_frame>
    <description>Skin temperature will be measured using a thermal imaging camera.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Change in skin microbiome</measure>
    <time_frame>Baseline, 3, 6, 10, 24 and 48 hours post LPS injection</time_frame>
    <description>Collection of skin culture samples is a non-invasive procedure where a sterile polyester flock tip per site is passed along the surface of treated and non-treated areas.&#xD;
bacteria studied include but are not limited to: Acinetobacter Anaerococcus Corynebacterium Enhydrobacter Finegoldia Lactobacillus Micrococcus Paracoccus Peptoniphilus Prevotella Propionibacterium Staphylococcus Streptococcus</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">32</enrollment>
  <condition>Inflammation; Skin</condition>
  <arm_group>
    <arm_group_label>Subjects 1-6</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>7 day treatment of erythromycin and clindamycin twice daily on indicated skin areas prior to Clobetasol treatment; randomized either on the left or right arm for 2 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Subjects 7-24</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>7 day treatment of erythromycin and clindamycin twice daily on indicated skin area prior to 4 Lipopolysaccharide injections and Clobetasol treatment; randomized either on the left or right arm for 2 days.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Subjects 25-30</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>0.5mg/kg prednisolone two days prior to Lipopolysaccharide injections</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Erythromycin 4% topical gel formulation:</intervention_name>
    <description>7 day pre-treatment with erythromycin and clindamycin applied twice daily on marked area on left (erythromycin) and right side (clindamycin) of the volar lower arm. Erythromycin is a bacteriostatic antibiotic that belongs to the macrolide group of antibiotics. Macrolides act as bacteriostatic by reversibly binding to the P site on the 50S subunit of bacterial ribosomes. A topical gel formulation with hyprolose and ethanol.</description>
    <arm_group_label>Subjects 1-6</arm_group_label>
    <arm_group_label>Subjects 7-24</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clindamycin 1% lotion formulation:</intervention_name>
    <description>7 day pre-treatment with erythromycin and clindamycin applied twice daily on marked area on left (erythromycin) and right side (clindamycin) of the volar lower arm. Clindamcin is a bacteriostatic antibiotic that belongs to the lincosamide group of antibiotics. Lincosamides act as bacteriostatic by reversibly binding to the P site on the 50S subunit of bacterial ribosomes. A topical lotion formulation with ethanol.</description>
    <arm_group_label>Subjects 1-6</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Prednisolone tablet (0.5mg/kg; parallel comparison):</intervention_name>
    <description>2 day pre-treatment with prednisolone daily dose 0.5mg/kg (0.25mg/kg in the morning and 0.25mg/kg in the evening). Prednisolone tablet (0.5mg/kg; parallel comparison): Prednisolone is a synthetic corticosteroid with predominant glucocorticoid activity and as such it is widely used in the treatment for inflammatory and autoimmune diseases. Prednisolone exerts its effect by binding to cytoplasmic glucocorticoid receptors and subsequently activates glucocorticoid receptor mediated gene expression. This results in synthesis of certain anti-inflammatory proteins, while inhibiting the synthesis of certain inflammatory mediators.</description>
    <arm_group_label>Subjects 25-30</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Clobetasol propionate 0.05% topical formulation (crossover comparison):</intervention_name>
    <description>2 day pre-treatment with clobetasol propionate 0.05% topical formulation applied twice daily on marked area on left or right side of the volar lower arm.&#xD;
Clobetasol propionate 0.05% topical formulation (crossover comparison):&#xD;
Clobetasol propionate is a potent synthetic corticosteroid with anti-inflammatory, anti-pruritic, and vasoconstrictive properties. Clobetasol propionate exerts its effect by binding to cytoplasmic glucocorticoid receptors and subsequently activates glucocorticoid receptor mediated gene expression. This results in synthesis of certain anti-inflammatory proteins, while inhibiting the synthesis of certain inflammatory mediators. Specifically, clobetasol propionate appears to induce phospholipase A2 inhibitory proteins, thereby controlling the release of the inflammatory precursor arachidonic acid from membrane phospholipids by phospholipase A2.</description>
    <arm_group_label>Subjects 1-6</arm_group_label>
    <arm_group_label>Subjects 7-24</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Lipopolysaccharide</intervention_name>
    <description>As TLR4 agonist, purified lipopolysaccharide prepared from Escherichia Coli: 113: H10:K negative (U.S. Standard Reference Endotoxin) will be used. This LPS batch is manufactured in the US by the National Institute of Health (NIH). Subjects will receive two intradermal doses of LPS in each forearm on day 0 (4 LPS injections in total, except for subjects 1-6 who receive none and subjects 25-27 will receive 2 LPS injections, only in the right arm). The dose per injection is 10 ng.</description>
    <arm_group_label>Subjects 25-30</arm_group_label>
    <arm_group_label>Subjects 7-24</arm_group_label>
    <other_name>LPS</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          1. Healthy male or female subjects, 18 to 45 years of age, inclusive. Healthy status is&#xD;
             defined by absence of evidence of any active or chronic disease following a detailed&#xD;
             medical and surgical history, a complete physical examination including vital signs,&#xD;
             12-lead ECG, hematology, blood chemistry, blood serology and urinalysis;&#xD;
&#xD;
          2. Body mass index (BMI) between 18 and 30 kg/m2, inclusive, and with a minimum weight of&#xD;
             50 kg;&#xD;
&#xD;
          3. Fitzpatrick skin type I-III (Caucasian);&#xD;
&#xD;
          4. Able and willing to give written informed consent and to comply with the study&#xD;
             restrictions.&#xD;
&#xD;
          5. Able to work with the eDiary app.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Any disease associated with immune system impairment, including auto-immune diseases,&#xD;
             HIV and transplantation patients;&#xD;
&#xD;
          2. Type 1 or type 2 diabetes mellitus;&#xD;
&#xD;
          3. Any vaccination within the last 3 months;&#xD;
&#xD;
          4. Family history of psoriasis;&#xD;
&#xD;
          5. History of pathological scar formation (keloid, hypertrophic scar);&#xD;
&#xD;
          6. Have any current and / or recurrent pathologically, clinical significant skin&#xD;
             condition at the treatment area (i.e. atopic dermatitis);&#xD;
&#xD;
          7. Hypersensitivity for dermatological marker at screening;&#xD;
&#xD;
          8. Requirement of immunosuppressive or immunomodulatory medication within 30 days prior&#xD;
             to enrollment or planned to use during the course of the study;&#xD;
&#xD;
          9. Excessive sun exposure or a tanning booth within 3 weeks of enrollment;&#xD;
&#xD;
         10. Participation in an investigational drug or device study within 3 months prior to&#xD;
             screening or more than 4 times a year;&#xD;
&#xD;
         11. Loss or donation of blood over 500 mL within three months prior to screening. Or the&#xD;
             donation of plasma within 14 days prior to screening;&#xD;
&#xD;
         12. Current smoker and/or regular user of other nicotine-containing products (e.g.,&#xD;
             patches);&#xD;
&#xD;
         13. History of or current drug or substance abuse considered significant by the PI (or&#xD;
             medically qualified designee), including a positive urine drug screen.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Matthijs Moerland, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Researc Director</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Centre for Human Drug Research</name>
      <address>
        <city>Leiden</city>
        <state>Zuid-Holland</state>
        <zip>2333 CL</zip>
        <country>Netherlands</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>August 2021</verification_date>
  <study_first_submitted>December 10, 2018</study_first_submitted>
  <study_first_submitted_qc>December 17, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 19, 2018</study_first_posted>
  <last_update_submitted>August 2, 2021</last_update_submitted>
  <last_update_submitted_qc>August 2, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">August 3, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Dermatitis</mesh_term>
    <mesh_term>Inflammation</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Clindamycin</mesh_term>
    <mesh_term>Clindamycin palmitate</mesh_term>
    <mesh_term>Clindamycin phosphate</mesh_term>
    <mesh_term>Erythromycin</mesh_term>
    <mesh_term>Erythromycin Estolate</mesh_term>
    <mesh_term>Erythromycin Ethylsuccinate</mesh_term>
    <mesh_term>Erythromycin stearate</mesh_term>
    <mesh_term>Prednisolone</mesh_term>
    <mesh_term>Clobetasol</mesh_term>
  </intervention_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/NCT03779360
org study id: CHDR1752-B
nct id: NCT03779360
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Erythromycin and clindamycin are believed to have anti-inflammatory aspects. This study
      investigates the possible anti-inflammatory effects of erythromycin and clindamycin.
Convincing mechanistic reports on the immunomodulatory action of erythromycin and clindamycin
      are scarce, rarely based on experiments in freshly isolated human immune cells, and
      potentially contradicting. Moreover, direct immunomodulatory effects of both antibiotics have
      never been demonstrated in vivo. The Centre for Human Drug Research Biomarker lab has studied
      in depth the immunomodulatory actions of erythromycin and clindamycin in vitro. These in
      vitro experiments on primary human immune cells demonstrated that both erythromycin and
      clindamycin are able to modulate the immune response of peripheral blood mononuclear cells
      upon stimulation with different immune triggers such as lipopolysaccharide (LPS) and polyI:C.
      In this current study the in vitro work will be translated to an in vivo study where it will
      be made into an intradermal LPS skin challenge model in healthy volunteers.
allocation: Non-Randomized
intervention model: Factorial Assignment
intervention model description: An interventional, open-label, comparator controlled study to investigate the immunomodulatory effects of erythromycin and clindamycin in an LPS skin challenge model in healthy volunteers.
primary purpose: Basic Science
masking: None (Open Label)
measure: Change in perfusion by Laser speckle contrast imaging (LSCI)
time frame: Baseline, 3, 6, 10, 24 and 48 hours post LPS injection
description: Cutaneous microcirculation between pre and post-dose will be assessed using the laser speckle imager.
measure: Change in erythema by Antera 3D camera and 2D camera
time frame: Baseline, 3, 6, 10, 24 and 48 hours post LPS injection
description: Standardized photographs will be taken using the Antera camera (Antera 3D, Miravex, Ireland).
measure: Change in erythema by clinical evaluation (erythema grading scale)
time frame: Baseline, 3, 6, 10, 24 and 48 hours post LPS injection
description: At the specific time points pre and post dose the colour of the injected area is scored (erythema index), on a 4 point scale; normal, mild, moderate, severe.
measure: Change in temperature by thermography in celsius
time frame: Baseline, 3, 6, 10, 24 and 48 hours post LPS injection
description: Skin temperature will be measured using a thermal imaging camera.
measure: Change in skin microbiome
time frame: Baseline, 3, 6, 10, 24 and 48 hours post LPS injection
description: Collection of skin culture samples is a non-invasive procedure where a sterile polyester flock tip per site is passed along the surface of treated and non-treated areas.
bacteria studied include but are not limited to: Acinetobacter Anaerococcus Corynebacterium Enhydrobacter Finegoldia Lactobacillus Micrococcus Paracoccus Peptoniphilus Prevotella Propionibacterium Staphylococcus Streptococcus
arm group label: Subjects 1-6
arm group type: Active Comparator
description: 7 day treatment of erythromycin and clindamycin twice daily on indicated skin areas prior to Clobetasol treatment; randomized either on the left or right arm for 2 days.
arm group label: Subjects 7-24
arm group type: Experimental
description: 7 day treatment of erythromycin and clindamycin twice daily on indicated skin area prior to 4 Lipopolysaccharide injections and Clobetasol treatment; randomized either on the left or right arm for 2 days.
arm group label: Subjects 25-30
arm group type: Active Comparator
description: 0.5mg/kg prednisolone two days prior to Lipopolysaccharide injections
intervention type: Drug
intervention name: Erythromycin 4% topical gel formulation:
description: 7 day pre-treatment with erythromycin and clindamycin applied twice daily on marked area on left (erythromycin) and right side (clindamycin) of the volar lower arm. Erythromycin is a bacteriostatic antibiotic that belongs to the macrolide group of antibiotics. Macrolides act as bacteriostatic by reversibly binding to the P site on the 50S subunit of bacterial ribosomes. A topical gel formulation with hyprolose and ethanol.
arm group label: Subjects 1-6
arm group label: Subjects 7-24
intervention type: Drug
intervention name: Clindamycin 1% lotion formulation:
description: 7 day pre-treatment with erythromycin and clindamycin applied twice daily on marked area on left (erythromycin) and right side (clindamycin) of the volar lower arm. Clindamcin is a bacteriostatic antibiotic that belongs to the lincosamide group of antibiotics. Lincosamides act as bacteriostatic by reversibly binding to the P site on the 50S subunit of bacterial ribosomes. A topical lotion formulation with ethanol.
arm group label: Subjects 1-6
intervention type: Drug
intervention name: Prednisolone tablet (0.5mg/kg; parallel comparison):
description: 2 day pre-treatment with prednisolone daily dose 0.5mg/kg (0.25mg/kg in the morning and 0.25mg/kg in the evening). Prednisolone tablet (0.5mg/kg; parallel comparison): Prednisolone is a synthetic corticosteroid with predominant glucocorticoid activity and as such it is widely used in the treatment for inflammatory and autoimmune diseases. Prednisolone exerts its effect by binding to cytoplasmic glucocorticoid receptors and subsequently activates glucocorticoid receptor mediated gene expression. This results in synthesis of certain anti-inflammatory proteins, while inhibiting the synthesis of certain inflammatory mediators.
arm group label: Subjects 25-30
intervention type: Drug
intervention name: Clobetasol propionate 0.05% topical formulation (crossover comparison):
description: 2 day pre-treatment with clobetasol propionate 0.05% topical formulation applied twice daily on marked area on left or right side of the volar lower arm.
Clobetasol propionate 0.05% topical formulation (crossover comparison):
Clobetasol propionate is a potent synthetic corticosteroid with anti-inflammatory, anti-pruritic, and vasoconstrictive properties. Clobetasol propionate exerts its effect by binding to cytoplasmic glucocorticoid receptors and subsequently activates glucocorticoid receptor mediated gene expression. This results in synthesis of certain anti-inflammatory proteins, while inhibiting the synthesis of certain inflammatory mediators. Specifically, clobetasol propionate appears to induce phospholipase A2 inhibitory proteins, thereby controlling the release of the inflammatory precursor arachidonic acid from membrane phospholipids by phospholipase A2.
arm group label: Subjects 1-6
arm group label: Subjects 7-24
intervention type: Other
intervention name: Lipopolysaccharide
description: As TLR4 agonist, purified lipopolysaccharide prepared from Escherichia Coli: 113: H10:K negative (U.S. Standard Reference Endotoxin) will be used. This LPS batch is manufactured in the US by the National Institute of Health (NIH). Subjects will receive two intradermal doses of LPS in each forearm on day 0 (4 LPS injections in total, except for subjects 1-6 who receive none and subjects 25-27 will receive 2 LPS injections, only in the right arm). The dose per injection is 10 ng.
arm group label: Subjects 25-30
arm group label: Subjects 7-24
other name: LPS
criteria: 
gender: All
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: Accepts Healthy Volunteers
last name: Matthijs Moerland, PhD
role: Principal Investigator
affiliation: Researc Director
facility: 
country: Netherlands
responsible party type: Sponsor
mesh term: Dermatitis
mesh term: Inflammation
mesh term: Clindamycin
mesh term: Clindamycin palmitate
mesh term: Clindamycin phosphate
mesh term: Erythromycin
mesh term: Erythromycin Estolate
mesh term: Erythromycin Ethylsuccinate
mesh term: Erythromycin stearate
mesh term: Prednisolone
mesh term: Clobetasol