<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/NCT02219165</url>
  </required_header>
  <id_info>
    <org_study_id>2013.841</org_study_id>
    <nct_id>NCT02219165</nct_id>
  </id_info>
  <brief_title>Efficacy of IntraVenous ImmunoGlobulins in Toxic Shock Syndromes: a Paediatric Pilot Study</brief_title>
  <acronym>IVIG</acronym>
  <official_title>Efficacy of IntraVenous ImmunoGlobulins (IVIG) in Toxic Shock Syndromes (Staphylococcal and Streptococcal): a Paediatric Pilot Study.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Hospices Civils de Lyon</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Hospices Civils de Lyon</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Staphylococcus aureus and Streptococcus pyogenes produce many virulence factors. Some of them&#xD;
      are responsible for severe infections in humans. Superantigen toxins synthesized by S. aureus&#xD;
      or by S. pyogenes, are responsible for toxic shock syndromes (TSS) which lethality can attain&#xD;
      25% in children with validated criteria of septic shock.&#xD;
&#xD;
      Previous studies, performed in vitro and in vivo in animals, have shown that Intravenous&#xD;
      immunoglobulins [IVIG] contain antibodies [Ab] against these toxins and, when used at high&#xD;
      concentration, IVIG are able to neutralize their toxicity. However, in all these studies,&#xD;
      IVIG administration has been preventive and there is no reliable data demonstrating their&#xD;
      therapeutic efficacy in vitro or in vivo in humans or in animals, once the disease is&#xD;
      present.&#xD;
&#xD;
      The efficacy of IVIG is established in other pathologies for which the role of the&#xD;
      superantigens [superAg] is suspected, like Kawasaki disease in children. The mechanism of&#xD;
      action, although not perfectly known, involves at the same time a direct effect on superAg&#xD;
      (Ag-Ab complex) and indirect effects like the neutralisation of superAg within the network of&#xD;
      anti-idiotype Ab or the neutralisation of the T-cells receptors. Staphylococcal and&#xD;
      streptococcal toxic shocks imply bacterial exotoxins that are superAg. It seems thus&#xD;
      consistent to imagine a same type of treatment with IVIG. However, there is currently no&#xD;
      evidence of the efficacy of IVIG in this indication. One of the explanations relies on the&#xD;
      lack of statistical power of previous adult studies, which principal objective was to show a&#xD;
      reduction of the mortality. Taking into account the low prevalence of TSS, it has been hard&#xD;
      to recruit enough patients to have the required statistical power. Moreover, some works have&#xD;
      been extracted from larger studies on septic shock and the definitions of the TSS were nor&#xD;
      always very reliable. Lastly, if the investigators consider the definition of the TSS as&#xD;
      mentioned by the &quot; Centre for Disease Control &quot; [CDC], for which any hypotension, even a&#xD;
      simple orthostatic hypotension, serves the diagnosis of TSS as long as the other symptoms are&#xD;
      present, it is obvious that many patients are likely to be recruited in a study although it&#xD;
      is highly probable that their health will get better with a &quot; standard &quot; treatment. The&#xD;
      definition of a &quot; real &quot; TSS can be refined, keeping the CDC criteria, but changing the&#xD;
      hypotension criterion in a more accurate criterion as described in the &quot; surviving sepsis&#xD;
      campaign &quot;, internationally accepted and based on norms adapted to the age for paediatric&#xD;
      forms.&#xD;
&#xD;
      IVIG therapy is very expensive and TSS is not recognized as indication of IVIG according to&#xD;
      their marketing authorization. The feasibility of a randomized controlled study with this&#xD;
      treatment needs to be assessed as it would be hazardous to conduct a large prospective RCT&#xD;
      without having first assessed this feasibility in terms of recruitment rates, consent rates&#xD;
      or compliance rates. Inclusion, randomisation and collect of inform consent in the context of&#xD;
      severe shock are challenging and require evaluation of feasibility. The sample size&#xD;
      calculation of the large study on mortality required estimations of the event in the specific&#xD;
      population of children with criteria of septic shock. Surrogates markers of outcome need to&#xD;
      be better defined. For example it would be useful to determine the evolution of organ&#xD;
      dysfunctions with and without IVIG treatment in this population.&#xD;
&#xD;
      Various organ failure scores, used upon admission and later on, have been validated in adults&#xD;
      and in children. The absence of improvement of the Paediatric logistic organ dysfunction&#xD;
      (Pelod) score over time is a good indicator of mortality in Paediatric intensive care unit&#xD;
      (PICU). It could be used as surrogate marker to evaluate the efficacy of IVIG.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">January 8, 2015</start_date>
  <completion_date type="Actual">April 19, 2019</completion_date>
  <primary_completion_date type="Actual">April 19, 2019</primary_completion_date>
  <phase>Phase 2</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>Other</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Recruitment rate</measure>
    <time_frame>up to 12 months</time_frame>
    <description>Measured in overall and in the different centers (eligibility, recruitment, refusal, non-respect of the inclusion/non-inclusion criteria)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Compliance with the protocol design</measure>
    <time_frame>up to 15 months</time_frame>
    <description>timing of randomization, respect of randomization and the interventions, respect of the blinding)</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Practical feasibility</measure>
    <time_frame>up to 15 months</time_frame>
    <description>time required for the Case Report Forms completion, length of the interventions, missing data, difficulties met</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Financial feasibility</measure>
    <time_frame>up to 15 months</time_frame>
    <description>budget per patient, personnel required</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evolution of organ failure score (PELOD 2)</measure>
    <time_frame>Day 1, day 2 and day 5</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>D 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Measure of the Cumulative vasopressor index (CVI) .</measure>
    <time_frame>(a) before treatment (day 1) and after treatment (day 2) and (b) over the 24h following drug administration</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Adverse events (AE) and serious AE</measure>
    <time_frame>Day 1, day 2, day 3, day 4, day 5, PICU discharge, day 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mechanism of superantigens (ancillary biological study: immune response: HLA-DR, Treg pool)</measure>
    <time_frame>Day 1, day 3/5, day 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>In vivo mechanism of IVIG (ancillary biological study: Vbêta, Ig dosage)</measure>
    <time_frame>Day 1, day 3/5, day 60</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>measure of lactate clearance</measure>
    <time_frame>(a) before treatment (day 1) and after treatment (day 2) and (b) over the 24h following drug administration</time_frame>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">30</enrollment>
  <condition>Toxic Shock Syndrome</condition>
  <arm_group>
    <arm_group_label>IVIG 2 g/kg</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Intravenous human immunoglobulin Day 1: As soon as there is suspicion of TSS, randomisation will be performed in order for the study treatment to be administered within the 12h following PICU admission (or following the manifestation of the first signs of shock). Concurrently, the TSS antibiotherapy following Surviving Sepsis Campaign recommendations is given</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Albumin 4%</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Same study scheduling as the first arm. Only the study treatment given is different (albumin instead of IGIV)</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Intravenous human immunoglobulin</intervention_name>
    <description>Single administration of IVIG 2 g/kg within the 12 hours following PICU admission (or following the manifestation of the first signs of shock). The bottles of IVIG used will contain 10 g of proteins in 100 ml of solution. Thus, to reach a concentration of 2 g/kg, will be administered 1 bottle per 5 kg of body weight (with a maximum of 14 bottles for 70 kg patients and over).</description>
    <arm_group_label>IVIG 2 g/kg</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Albumin</intervention_name>
    <description>Single administration of albumin 4% within the 12 hours following PICU admission (or following the manifestation of the first signs of shock). The solution will be given at the same volume as IVIG (that is: 1 bottle / 5 kg of body weight).</description>
    <arm_group_label>Albumin 4%</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  1 month &lt;Age &lt; 18 years&#xD;
&#xD;
          -  Admitted to PICU, with a strong suspicion of staphylococcal or streptococcal infection&#xD;
             (at least one of the following criteria):&#xD;
&#xD;
          -  Diagnostic of TSS according to CDC (Centre for Disease Control) criteria or Group A&#xD;
             streptococcus necrotizing fasciitis (positive streptest) or Varicella with infected&#xD;
             lesions and erythroderma or positive streptest or Erythroderma in menstrual period or&#xD;
             Pleuropneumopathy with erythroderma or positive streptest in pleural fluid or&#xD;
             Erythroderma and biological fluid positive to type A streptococcus ou staphylococcus&#xD;
             (articular, pericardial, bronchopulmonar, pharynx…)&#xD;
&#xD;
          -  with shock resistant to fluid resuscitation defined as the presence, despite 40 ml/kg&#xD;
             of fluid volume in 1 hour, of: hypotension (&lt;5th percentile) or systolic arterial&#xD;
             pressure &lt; 2 SD for age or need for vasoactive drugs in order to maintain AP at a&#xD;
             normal level (dopamine &gt; 5µg/kg/min or dobutamine, adrenaline, noradrenaline,&#xD;
             milrinone whatever the dose) or 2 signs of hypo perfusion among: metabolic acidosis&#xD;
             with a base deficit &gt; 5 lactate x 2 laboratory normal value diuresis &lt; 0,5 ml/kg/h&#xD;
             capillary refill time &gt; 5 sec difference skin/central temperature &gt; 3°C&#xD;
&#xD;
          -  Consent to participation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  First signs of shock appeared more than 24h ago&#xD;
&#xD;
          -  Known hypersensitivity to one of the components (study treatment or placebo)&#xD;
&#xD;
          -  Hypersensitivity to homologous immunoglobulins, specifically in very rare cases of Ig&#xD;
             A deficit, when the patient has anti-IgA antibodies&#xD;
&#xD;
          -  Known hyperprolinemia&#xD;
&#xD;
          -  Immunodeficiency (acquired or not)&#xD;
&#xD;
          -  Immunosuppressive drugs&#xD;
&#xD;
          -  No health cover&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>1 Month</minimum_age>
    <maximum_age>17 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Etienne Javouhey</last_name>
    <role>Principal Investigator</role>
    <affiliation>Service de réanimation pédiatrique, Hôpital Femme Mère Enfant, Groupement Hospitalier Est, 59 Boulevard Pinel, 69677 BRON, FRANCE</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Hôpital Femme Mère Enfant</name>
      <address>
        <city>Bron</city>
        <zip>69677</zip>
        <country>France</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>June 2021</verification_date>
  <study_first_submitted>August 6, 2014</study_first_submitted>
  <study_first_submitted_qc>August 15, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 18, 2014</study_first_posted>
  <last_update_submitted>June 7, 2021</last_update_submitted>
  <last_update_submitted_qc>June 7, 2021</last_update_submitted_qc>
  <last_update_posted type="Actual">June 8, 2021</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Paediatrics</keyword>
  <keyword>Toxic Shock Syndrome</keyword>
  <keyword>Intravenous human immunoglobulin</keyword>
  <keyword>feasibility</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock, Septic</mesh_term>
    <mesh_term>Syndrome</mesh_term>
    <mesh_term>Shock</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Immunoglobulins</mesh_term>
    <mesh_term>Immunoglobulins, Intravenous</mesh_term>
    <mesh_term>Antibodies</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/NCT02219165
org study id: 2013.841
nct id: NCT02219165
lead sponsor: 
has dmc: Yes
Staphylococcus aureus and Streptococcus pyogenes produce many virulence factors. Some of them
      are responsible for severe infections in humans. Superantigen toxins synthesized by S. aureus
      or by S. pyogenes, are responsible for toxic shock syndromes (TSS) which lethality can attain
      25% in children with validated criteria of septic shock.

      Previous studies, performed in vitro and in vivo in animals, have shown that Intravenous
      immunoglobulins [IVIG] contain antibodies [Ab] against these toxins and, when used at high
      concentration, IVIG are able to neutralize their toxicity. However, in all these studies,
      IVIG administration has been preventive and there is no reliable data demonstrating their
      therapeutic efficacy in vitro or in vivo in humans or in animals, once the disease is
      present.

      The efficacy of IVIG is established in other pathologies for which the role of the
      superantigens [superAg] is suspected, like Kawasaki disease in children. The mechanism of
      action, although not perfectly known, involves at the same time a direct effect on superAg
      (Ag-Ab complex) and indirect effects like the neutralisation of superAg within the network of
      anti-idiotype Ab or the neutralisation of the T-cells receptors. Staphylococcal and
      streptococcal toxic shocks imply bacterial exotoxins that are superAg. It seems thus
      consistent to imagine a same type of treatment with IVIG. However, there is currently no
      evidence of the efficacy of IVIG in this indication. One of the explanations relies on the
      lack of statistical power of previous adult studies, which principal objective was to show a
      reduction of the mortality. Taking into account the low prevalence of TSS, it has been hard
      to recruit enough patients to have the required statistical power. Moreover, some works have
      been extracted from larger studies on septic shock and the definitions of the TSS were nor
      always very reliable. Lastly, if the investigators consider the definition of the TSS as
      mentioned by the " Centre for Disease Control " [CDC], for which any hypotension, even a
      simple orthostatic hypotension, serves the diagnosis of TSS as long as the other symptoms are
      present, it is obvious that many patients are likely to be recruited in a study although it
      is highly probable that their health will get better with a " standard " treatment. The
      definition of a " real " TSS can be refined, keeping the CDC criteria, but changing the
      hypotension criterion in a more accurate criterion as described in the " surviving sepsis
      campaign ", internationally accepted and based on norms adapted to the age for paediatric
      forms.

      IVIG therapy is very expensive and TSS is not recognized as indication of IVIG according to
      their marketing authorization. The feasibility of a randomized controlled study with this
      treatment needs to be assessed as it would be hazardous to conduct a large prospective RCT
      without having first assessed this feasibility in terms of recruitment rates, consent rates
      or compliance rates. Inclusion, randomisation and collect of inform consent in the context of
      severe shock are challenging and require evaluation of feasibility. The sample size
      calculation of the large study on mortality required estimations of the event in the specific
      population of children with criteria of septic shock. Surrogates markers of outcome need to
      be better defined. For example it would be useful to determine the evolution of organ
      dysfunctions with and without IVIG treatment in this population.

      Various organ failure scores, used upon admission and later on, have been validated in adults
      and in children. The absence of improvement of the Paediatric logistic organ dysfunction
      (Pelod) score over time is a good indicator of mortality in Paediatric intensive care unit
      (PICU). It could be used as surrogate marker to evaluate the efficacy of IVIG.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Other
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Recruitment rate
time frame: up to 12 months
description: Measured in overall and in the different centers (eligibility, recruitment, refusal, non-respect of the inclusion/non-inclusion criteria)
measure: Compliance with the protocol design
time frame: up to 15 months
description: timing of randomization, respect of randomization and the interventions, respect of the blinding)
measure: Practical feasibility
time frame: up to 15 months
description: time required for the Case Report Forms completion, length of the interventions, missing data, difficulties met
measure: Financial feasibility
time frame: up to 15 months
description: budget per patient, personnel required
measure: Evolution of organ failure score (PELOD 2)
time frame: Day 1, day 2 and day 5
measure: Mortality
time frame: D 60
measure: Measure of the Cumulative vasopressor index (CVI) .
time frame: (a) before treatment (day 1) and after treatment (day 2) and (b) over the 24h following drug administration
measure: Adverse events (AE) and serious AE
time frame: Day 1, day 2, day 3, day 4, day 5, PICU discharge, day 60
measure: Mechanism of superantigens (ancillary biological study: immune response: HLA-DR, Treg pool)
time frame: Day 1, day 3/5, day 60
measure: In vivo mechanism of IVIG (ancillary biological study: Vbêta, Ig dosage)
time frame: Day 1, day 3/5, day 60
measure: measure of lactate clearance
time frame: (a) before treatment (day 1) and after treatment (day 2) and (b) over the 24h following drug administration
arm group label: IVIG 2 g/kg
arm group type: Experimental
description: Intravenous human immunoglobulin Day 1: As soon as there is suspicion of TSS, randomisation will be performed in order for the study treatment to be administered within the 12h following PICU admission (or following the manifestation of the first signs of shock). Concurrently, the TSS antibiotherapy following Surviving Sepsis Campaign recommendations is given
arm group label: Albumin 4%
arm group type: Placebo Comparator
description: Same study scheduling as the first arm. Only the study treatment given is different (albumin instead of IGIV)
intervention type: Drug
intervention name: Intravenous human immunoglobulin
description: Single administration of IVIG 2 g/kg within the 12 hours following PICU admission (or following the manifestation of the first signs of shock). The bottles of IVIG used will contain 10 g of proteins in 100 ml of solution. Thus, to reach a concentration of 2 g/kg, will be administered 1 bottle per 5 kg of body weight (with a maximum of 14 bottles for 70 kg patients and over).
arm group label: IVIG 2 g/kg
intervention type: Drug
intervention name: Albumin
description: Single administration of albumin 4% within the 12 hours following PICU admission (or following the manifestation of the first signs of shock). The solution will be given at the same volume as IVIG (that is: 1 bottle / 5 kg of body weight).
arm group label: Albumin 4%
criteria: 
gender: All
minimum age: 1 Month
maximum age: 17 Years
healthy volunteers: No
last name: Etienne Javouhey
role: Principal Investigator
affiliation: Service de réanimation pédiatrique, Hôpital Femme Mère Enfant, Groupement Hospitalier Est, 59 Boulevard Pinel, 69677 BRON, FRANCE
facility: 
country: France
responsible party type: Sponsor
mesh term: Shock, Septic
mesh term: Syndrome
mesh term: Shock
mesh term: Immunoglobulins
mesh term: Immunoglobulins, Intravenous
mesh term: Antibodies