<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/NCT03307772</url>
  </required_header>
  <id_info>
    <org_study_id>08-SBUS-2-GRA-01 A</org_study_id>
    <nct_id>NCT03307772</nct_id>
  </id_info>
  <brief_title>Immune Response to the Consumption of Lactobacillus GG and FOS in Patients With Recurrent Herpes Labialis</brief_title>
  <acronym>EVIM</acronym>
  <official_title>A Randomized, Triple-blind Placebo-controlled Single Center Trial to Evaluate the Immune Response to the Consumption of a Minidrink Containing a Combination of Lactobacillus GG and Fructooligosaccharides in Patients With Recurrent Herpes Labialis</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Sprim Advanced Life Sciences</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Sprim Advanced Life Sciences</source>
  <oversight_info>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Background: Herpes labialis is the result of the presence of Herplex Simplex Virus -1 (HSV-1)&#xD;
      and is a common disease in the population. Because of its visibility it has a serious impact&#xD;
      on social life and the feeling of well-being in people who suffer from this disease. Until&#xD;
      now there is no effective treatment and no remedy for prevention of the virus outbreak.&#xD;
&#xD;
      Prebiotics and probiotics have both been shown to have a favorable and supportive effect on&#xD;
      the immune system in different health conditions such as influenza, atopic dermatitis and&#xD;
      diarrhea. So far no study has addressed the effect of the consumption of pre- and/or&#xD;
      probiotics in a population with recurrent herpes labialis.&#xD;
&#xD;
      Aim of the study: The present study investigated the effect of pre- or probiotics or a&#xD;
      combination of the two on the recurrence of herpes labialis lesions as well as on the immune&#xD;
      system in general.&#xD;
&#xD;
      Design: 78 Patients were eligible to participate in the study and after a run-in period of&#xD;
      two weeks consuming a placebo minidrink were randomized to one of the four experimental&#xD;
      groups, these were: placebo minidrink (n=), prebiotic (fructooligosaccharides) minidrink&#xD;
      (n=), probiotic (Lactobacillus rhamnosus GG or LGG) minidrink (n=) or a minidrink containing&#xD;
      a combination of a pre- and probiotic. These minidrinks were consumed for another 5 weeks. At&#xD;
      day 33 of the study the lip most prone to the development of a lesion was stimulated with UVB&#xD;
      in order to provoke a lesion. During the entire study period subjects were checked for any&#xD;
      clinical signs of a lesion, completed a self-assessment regarding the lesion and a quality of&#xD;
      life questionnaire at baseline (day 14) and the end of the study (day 49). In addition, a&#xD;
      blood sample was collected at baseline and at the end of the study to be analyzed for general&#xD;
      and HSV-specific antibodies, intracellular cytokine concentrations and parameters of the&#xD;
      innate immune response such as natural killer cell activity and phagocytosis.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The present study showed that the daily consumption of a minidrink containing either only&#xD;
      Lactobacillus rhamnosus or a combination of Lactobacillus rhamnosus and&#xD;
      fructooligosaccharides significantly decreased both the occurrence and the incidence of&#xD;
      Herpes labialis lesions after stimulation with UVR in a population with recurrent Herpes&#xD;
      labialis. No difference in the function of either CD8+ T lymphocytes or natural killer cells&#xD;
      was found, nevertheless a trend, that did not reach statistical significance, was observed&#xD;
      for some of the immunological analyses pointing out towards an immunemodulating effect of&#xD;
      probiotic or pre- and probiotic combination minidrink on the adaptive immune system. The end&#xD;
      of study results of immune analyses were slightly improved compared to the baseline values in&#xD;
      individuals using the probiotics or the pre- and probiotics combination minidrink, however&#xD;
      the differences between groups did not reach the significance level. Phagocytosis and killing&#xD;
      were clearly and statistically different in individuals that used either placebo or&#xD;
      probiotics or pre- and probiotics minidrinks. Therefore, the probiotics and the pre- and&#xD;
      probiotics minidrinks have an important effect on innate immunity, resulting in a significant&#xD;
      improvement of both phagocytosis and killing. No effect was found on the quality of life of&#xD;
      subjects. No special or unusual features of the safety evaluations were found. No serious&#xD;
      adverse events were reported during the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">December 15, 2008</start_date>
  <completion_date type="Actual">October 20, 2009</completion_date>
  <primary_completion_date type="Actual">September 16, 2009</primary_completion_date>
  <phase>N/A</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Randomized</allocation>
    <intervention_model>Parallel Assignment</intervention_model>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Double (Participant, Investigator)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Incidence rate of ultraviolet exposure-lesion</measure>
    <time_frame>Day 42</time_frame>
    <description>Incidence rate of ultraviolet exposure-lesion at at Day 42.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Incidence rate of ultraviolet exposure-lesion</measure>
    <time_frame>day 35</time_frame>
    <description>Incidence rate of ultraviolet exposure-lesion at at Day 35.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Incidence rate of ultraviolet exposure-lesion</measure>
    <time_frame>day 49</time_frame>
    <description>Incidence rate of ultraviolet exposure-lesion at at Day 49</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measurement of lesion size (mm2).</measure>
    <time_frame>Day 35 day 42 Day 49</time_frame>
    <description>Measurement of lesion size as a product of the length and the width of the lesion (measured in mm2) at Day 35 / 42 / 49.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Time to healing (days).</measure>
    <time_frame>Day 35 day 42 Day 49</time_frame>
    <description>Time to healing defined as either loss of the hard crust or return to normal skin (measured in days) at Day 35 / 42 / 49</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Lesion development by classification of lesion stage.</measure>
    <time_frame>Day 35 day 42 Day 49</time_frame>
    <description>Lesion development by classification of lesion stage. The lesion stages are shown in table 2 of the clinical protocol (adapted from Spruance et al, 2002). In addition, a photo was made at every visit. At Day 35 / 42 / 49</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Duration and intensity of pain (10 cm Vas Analogue Scale).</measure>
    <time_frame>Day 35 day 42 Day 49</time_frame>
    <description>Duration and intensity of pain as recorded by the patient on a visual analogue scale (VAS) of 100 mm, at Day 35 / 42 / 49.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in HSV-specific IgG, IgG3, IgG4 and IgE concentrations</measure>
    <time_frame>Day 49</time_frame>
    <description>HSV-specific IgG1 and IgG3 (Th1) and IgG4 and IgE (Th2) concentrations were analyzed by ELISA at day 49.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in HSV-specific CD8+ T cells by pentamers</measure>
    <time_frame>Day 49</time_frame>
    <description>Immunologic evaluation of HSV-specific CD8+ T cells by pentamers (only on HLA A2-01+ individuals: an estimated 35-40% of individuals fit this criterion) at day 49.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in HSV-specific CD8+ T cells by IFN-gamma ELISPOT</measure>
    <time_frame>day 49</time_frame>
    <description>Immunologic evaluation of HSV-specific CD8+ T cells by IFN-gamma ELISPOT (only on HLA A2-01+ individuals: an estimated 35-40% of individuals fit this criterion) at day 49.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in lytic ability of CD8+ T cells</measure>
    <time_frame>day 49</time_frame>
    <description>Immunologic evaluation of the lytic ability of CD8+ T cells by FACS analyses (perforin, granzymes) (all individuals).</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in IL-2, IFN-γ, IL10</measure>
    <time_frame>day 49</time_frame>
    <description>The following intracellular cytokine concentrations in HSV-stimulated CD4+ cells at day 49:&#xD;
Interleukin-2;&#xD;
Interferon-γ;&#xD;
Interleukin-10.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in SF-36 QoL questionnaire.</measure>
    <time_frame>day 49</time_frame>
    <description>The quality of life was determined by the SF-36 quality of life questionnaire at day 49.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in Phagocyte number and activity</measure>
    <time_frame>day 49</time_frame>
    <description>Phagocyte number and activity as measured by flow cytometry;</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Change in NK cell number and activity</measure>
    <time_frame>day 49</time_frame>
    <description>Natural killer cell number and activity as measured by flow cytometry.</description>
  </secondary_outcome>
  <number_of_arms>4</number_of_arms>
  <enrollment type="Actual">78</enrollment>
  <condition>Herpes Labialis</condition>
  <arm_group>
    <arm_group_label>placebo drink</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>The placebo drink consists of fermented low-fat milk with no added Lactobacillus GG.(placebo)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LGG Drink (</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The probiotic drink consists of fermented low-fat milk with added Lactobacillus GG. (probiotics)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>FOS Drink</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The prebiotics drink consists of fermented low-fat milk with fructooligosaccharides. (prebiotics)</description>
  </arm_group>
  <arm_group>
    <arm_group_label>LGG e FOS Drink</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>The probiotics and prebiotics drink consists of acidified low-fat milk with added Lactobacillus GG and fructooligosaccharides (prebiotics and probiotics)</description>
  </arm_group>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Probiotics</intervention_name>
    <arm_group_label>LGG Drink (</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Prebiotics</intervention_name>
    <arm_group_label>FOS Drink</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Prebiotics and Probiotics</intervention_name>
    <arm_group_label>LGG e FOS Drink</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Dietary Supplement</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <arm_group_label>placebo drink</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Healthy free-living men and women aged 18 to 65 years-old&#xD;
&#xD;
          -  History of recurrent herpes labialis at most 3 episodes after exposure to sunlight in&#xD;
             the previous 12 months&#xD;
&#xD;
          -  Fitzpatrick skin type 1 to 4&#xD;
&#xD;
          -  No presence of herpes labialis lesion at the time of recruitment&#xD;
&#xD;
          -  Consent to the study and to comply with study product&#xD;
&#xD;
          -  Agreement to adhere to the prescribed list of food and nutrients as provided at the&#xD;
             start of the study&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of acute/terminal disease&#xD;
&#xD;
          -  Intolerance for milk protein or lactose&#xD;
&#xD;
          -  Daily consumption of probiotic products 1 month before start of the study&#xD;
&#xD;
          -  Treatment with acyclovir or other medication believed to interfere with immune&#xD;
             responses at the time of the study&#xD;
&#xD;
          -  Participation in any herpes UVB reactivation study within the previous three months&#xD;
&#xD;
          -  Episode of herpes labialis within 30 days before enrolment in the study&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>65 Years</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>October 2017</verification_date>
  <study_first_submitted>October 3, 2017</study_first_submitted>
  <study_first_submitted_qc>October 6, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">October 12, 2017</study_first_posted>
  <last_update_submitted>October 6, 2017</last_update_submitted>
  <last_update_submitted_qc>October 6, 2017</last_update_submitted_qc>
  <last_update_posted type="Actual">October 12, 2017</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>lactobacillus</keyword>
  <keyword>Herpes Labialis</keyword>
  <keyword>immune response</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Herpes Simplex</mesh_term>
    <mesh_term>Herpes Labialis</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/NCT03307772
org study id: 08-SBUS-2-GRA-01 A
nct id: NCT03307772
lead sponsor: 
is fda regulated drug: No
is fda regulated device: No
Background: Herpes labialis is the result of the presence of Herplex Simplex Virus -1 (HSV-1)
      and is a common disease in the population. Because of its visibility it has a serious impact
      on social life and the feeling of well-being in people who suffer from this disease. Until
      now there is no effective treatment and no remedy for prevention of the virus outbreak.

      Prebiotics and probiotics have both been shown to have a favorable and supportive effect on
      the immune system in different health conditions such as influenza, atopic dermatitis and
      diarrhea. So far no study has addressed the effect of the consumption of pre- and/or
      probiotics in a population with recurrent herpes labialis.

      Aim of the study: The present study investigated the effect of pre- or probiotics or a
      combination of the two on the recurrence of herpes labialis lesions as well as on the immune
      system in general.

      Design: 78 Patients were eligible to participate in the study and after a run-in period of
      two weeks consuming a placebo minidrink were randomized to one of the four experimental
      groups, these were: placebo minidrink (n=), prebiotic (fructooligosaccharides) minidrink
      (n=), probiotic (Lactobacillus rhamnosus GG or LGG) minidrink (n=) or a minidrink containing
      a combination of a pre- and probiotic. These minidrinks were consumed for another 5 weeks. At
      day 33 of the study the lip most prone to the development of a lesion was stimulated with UVB
      in order to provoke a lesion. During the entire study period subjects were checked for any
      clinical signs of a lesion, completed a self-assessment regarding the lesion and a quality of
      life questionnaire at baseline (day 14) and the end of the study (day 49). In addition, a
      blood sample was collected at baseline and at the end of the study to be analyzed for general
      and HSV-specific antibodies, intracellular cytokine concentrations and parameters of the
      innate immune response such as natural killer cell activity and phagocytosis.
The present study showed that the daily consumption of a minidrink containing either only
      Lactobacillus rhamnosus or a combination of Lactobacillus rhamnosus and
      fructooligosaccharides significantly decreased both the occurrence and the incidence of
      Herpes labialis lesions after stimulation with UVR in a population with recurrent Herpes
      labialis. No difference in the function of either CD8+ T lymphocytes or natural killer cells
      was found, nevertheless a trend, that did not reach statistical significance, was observed
      for some of the immunological analyses pointing out towards an immunemodulating effect of
      probiotic or pre- and probiotic combination minidrink on the adaptive immune system. The end
      of study results of immune analyses were slightly improved compared to the baseline values in
      individuals using the probiotics or the pre- and probiotics combination minidrink, however
      the differences between groups did not reach the significance level. Phagocytosis and killing
      were clearly and statistically different in individuals that used either placebo or
      probiotics or pre- and probiotics minidrinks. Therefore, the probiotics and the pre- and
      probiotics minidrinks have an important effect on innate immunity, resulting in a significant
      improvement of both phagocytosis and killing. No effect was found on the quality of life of
      subjects. No special or unusual features of the safety evaluations were found. No serious
      adverse events were reported during the study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: Double (Participant, Investigator)
measure: Incidence rate of ultraviolet exposure-lesion
time frame: Day 42
description: Incidence rate of ultraviolet exposure-lesion at at Day 42.
measure: Incidence rate of ultraviolet exposure-lesion
time frame: day 35
description: Incidence rate of ultraviolet exposure-lesion at at Day 35.
measure: Incidence rate of ultraviolet exposure-lesion
time frame: day 49
description: Incidence rate of ultraviolet exposure-lesion at at Day 49
measure: Measurement of lesion size (mm2).
time frame: Day 35 day 42 Day 49
description: Measurement of lesion size as a product of the length and the width of the lesion (measured in mm2) at Day 35 / 42 / 49.
measure: Time to healing (days).
time frame: Day 35 day 42 Day 49
description: Time to healing defined as either loss of the hard crust or return to normal skin (measured in days) at Day 35 / 42 / 49
measure: Lesion development by classification of lesion stage.
time frame: Day 35 day 42 Day 49
description: Lesion development by classification of lesion stage. The lesion stages are shown in table 2 of the clinical protocol (adapted from Spruance et al, 2002). In addition, a photo was made at every visit. At Day 35 / 42 / 49
measure: Duration and intensity of pain (10 cm Vas Analogue Scale).
time frame: Day 35 day 42 Day 49
description: Duration and intensity of pain as recorded by the patient on a visual analogue scale (VAS) of 100 mm, at Day 35 / 42 / 49.
measure: Change in HSV-specific IgG, IgG3, IgG4 and IgE concentrations
time frame: Day 49
description: HSV-specific IgG1 and IgG3 (Th1) and IgG4 and IgE (Th2) concentrations were analyzed by ELISA at day 49.
measure: Change in HSV-specific CD8+ T cells by pentamers
time frame: Day 49
description: Immunologic evaluation of HSV-specific CD8+ T cells by pentamers (only on HLA A2-01+ individuals: an estimated 35-40% of individuals fit this criterion) at day 49.
measure: Change in HSV-specific CD8+ T cells by IFN-gamma ELISPOT
time frame: day 49
description: Immunologic evaluation of HSV-specific CD8+ T cells by IFN-gamma ELISPOT (only on HLA A2-01+ individuals: an estimated 35-40% of individuals fit this criterion) at day 49.
measure: Change in lytic ability of CD8+ T cells
time frame: day 49
description: Immunologic evaluation of the lytic ability of CD8+ T cells by FACS analyses (perforin, granzymes) (all individuals).
measure: Change in IL-2, IFN-γ, IL10
time frame: day 49
description: The following intracellular cytokine concentrations in HSV-stimulated CD4+ cells at day 49:
Interleukin-2;
Interferon-γ;
Interleukin-10.
measure: Change in SF-36 QoL questionnaire.
time frame: day 49
description: The quality of life was determined by the SF-36 quality of life questionnaire at day 49.
measure: Change in Phagocyte number and activity
time frame: day 49
description: Phagocyte number and activity as measured by flow cytometry;
measure: Change in NK cell number and activity
time frame: day 49
description: Natural killer cell number and activity as measured by flow cytometry.
arm group label: placebo drink
arm group type: Placebo Comparator
description: The placebo drink consists of fermented low-fat milk with no added Lactobacillus GG.(placebo)
arm group label: LGG Drink (
arm group type: Active Comparator
description: The probiotic drink consists of fermented low-fat milk with added Lactobacillus GG. (probiotics)
arm group label: FOS Drink
arm group type: Active Comparator
description: The prebiotics drink consists of fermented low-fat milk with fructooligosaccharides. (prebiotics)
arm group label: LGG e FOS Drink
arm group type: Active Comparator
description: The probiotics and prebiotics drink consists of acidified low-fat milk with added Lactobacillus GG and fructooligosaccharides (prebiotics and probiotics)
intervention type: Dietary Supplement
intervention name: Probiotics
arm group label: LGG Drink (
intervention type: Dietary Supplement
intervention name: Prebiotics
arm group label: FOS Drink
intervention type: Dietary Supplement
intervention name: Prebiotics and Probiotics
arm group label: LGG e FOS Drink
intervention type: Dietary Supplement
intervention name: Placebo
arm group label: placebo drink
criteria: 
gender: All
minimum age: 18 Years
maximum age: 65 Years
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Sponsor
mesh term: Herpes Simplex
mesh term: Herpes Labialis