<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/NCT04494074</url>
  </required_header>
  <id_info>
    <org_study_id>SEPSISCOOL II</org_study_id>
    <nct_id>NCT04494074</nct_id>
  </id_info>
  <brief_title>Fever Control Using External Cooling in Mechanically Ventilated Patients With Septic Shock</brief_title>
  <official_title>Intérêt du Traitement de la fièvre Par Refroidissement Externe Pour la Survie Des Patients ventilés en Choc Septique</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Centre Hospitalier Intercommunal Creteil</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Centre Hospitalier Intercommunal Creteil</source>
  <oversight_info>
    <has_dmc>Yes</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>
      The best strategy for managing fever in patients with septic shock remains unknown. In a&#xD;
      pilot study, the investigators showed that fever control at normothermia allowed a better&#xD;
      control of shock and evolution of organ failures. In this second trial the investigators will&#xD;
      conduct a multicentre, open-label, randomized controlled, superiority trial in which two&#xD;
      strategies will be compared:&#xD;
&#xD;
        1. Respect of fever&#xD;
&#xD;
        2. Fever control at normothermia using external cooling The primary end point will be d-60&#xD;
           mortality.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Sepsis is a common syndrome responsible for multiple organ failure. Septic shock, defined as&#xD;
      sepsis with hyperlactatemia and cardiovascular failure requiring vasopressor infusion despite&#xD;
      adequate fluid resuscitation has an extremely high mortality rate. Fever is a frequent&#xD;
      disease process during sepsis. Fever increases oxygen consumption and can worsen imbalance&#xD;
      between oxygen supply and oxygen requirements. Fever increases inflammation but reduces viral&#xD;
      and bacterial growth. The beneficial effects of active fever control on inflammation have&#xD;
      been mainly shown in a context of lung injury. Pneumonia represents the first cause of septic&#xD;
      shock in developed countries.&#xD;
&#xD;
      In a pilot study (SEPSISCOOL I), we showed that fever treatment using external cooling&#xD;
      significantly increased the resolution of shock, improved organ functions and decreased d-14&#xD;
      mortality. Although reduced, hospital mortality was not significantly different. This study&#xD;
      was underpowered to allow conclusion on mortality. A more pronounced beneficial effect was&#xD;
      observed among the most severely ill patients with elevated serum lactate level.&#xD;
&#xD;
      Fever treatment is commonly applied in septic patients but its impact on survival remains&#xD;
      undetermined.&#xD;
&#xD;
      The main objective of the study is to compare two strategies of fever management in febrile&#xD;
      (body temperature &gt; 38.3°C) septic shock patients requiring invasive mechanical ventilation&#xD;
      and sedation. These patients will be randomly allocated in two arms:&#xD;
&#xD;
        1. Fever respect&#xD;
&#xD;
        2. Fever control by external cooling to obtain normothermia during 48 hours&#xD;
&#xD;
      A covariate-adaptive randomization will be used to ensure the comparability of the two groups&#xD;
      at each stage of the study. We will use an adaptive multistage population-enrichment design&#xD;
      with a pre-specified subgroup of patients with ARDS identified at randomization.&#xD;
&#xD;
      An independent Safety and Data Monitoring Committee will review data on serious adverse&#xD;
      events. The decision of study stop for potential harmful effect of one strategy will be let&#xD;
      at the entire responsibility of the committee.&#xD;
&#xD;
      One interim analysis will be performed by independent observers after enrolment of half of&#xD;
      the population. The assumption that fever treatment is more effective in patients with ARDS&#xD;
      will be confirmed or not. According to pre-defined rules based on the conditional power&#xD;
      calculated in the two subgroups, the trial will be stopped for futility, continued as planned&#xD;
      or continued by enrolling only patients with ARDS.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">October 1, 2022</start_date>
  <completion_date type="Anticipated">December 1, 2024</completion_date>
  <primary_completion_date type="Actual">December 1, 2022</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>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Mortality</measure>
    <time_frame>Day 60</time_frame>
    <description>All causes mortality</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Evolution of SOFA Score</measure>
    <time_frame>Up to Day 7</time_frame>
    <description>Sequential Organ Failure Assessment (SOFA) score will be calculated at d1, d2, d3 and d7 and compared between the 2 arms.&#xD;
Higer the score higher the severity of organ dysfunctions. Min 0 Max 24</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of ventilator free days</measure>
    <time_frame>Day 28</time_frame>
    <description>Number of free days will be assessed as proposed by YEHYA et al. Patients who died before d28 will be considered as having 0 free day</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of renal replacement therapy free days</measure>
    <time_frame>Day 28</time_frame>
    <description>Number of free days will be assessed as proposed by YEHYA et al.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of vasopressor free days</measure>
    <time_frame>Day 28</time_frame>
    <description>Number of free days will be assessed as proposed by YEHYA et al. Shock resolution will be defined by vasopressor stop during at least 24h in the absence of care withdrawing</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Mortality</measure>
    <time_frame>Day 28</time_frame>
    <description>All causes mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with shivering</measure>
    <time_frame>Day 2</time_frame>
    <description>Shivering will be monitored according to a specific scale</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with seizure</measure>
    <time_frame>Day 3</time_frame>
    <description>Seizure will be clinically documented or reveal by EEG</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with hypothermia</measure>
    <time_frame>Day 2</time_frame>
    <description>Number of patients with body temperature lower than 36°C</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with at least 1 episode of cardiac arrhythmia</measure>
    <time_frame>Day 3</time_frame>
    <description>Patient with new episode of supraventricular or ventricular arrhythmia</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Secondary acquired nosocomial infections</measure>
    <time_frame>Day 28</time_frame>
    <description>Only the first episode will be taken into account</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Number of patients with ARDS development among patients free of ARDS at inclusion</measure>
    <time_frame>Up to Day 3</time_frame>
    <description>Secondary acquired ARDS according to Berlin definition</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Acute kidney injury</measure>
    <time_frame>Up to Day7</time_frame>
    <description>Maximal stage of AKI according to the KDIGO definition</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">820</enrollment>
  <condition>Septic Shock</condition>
  <arm_group>
    <arm_group_label>Fever Control by external cooling</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>External cooling during 48 hours to obtain normothermia</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Fever respected, no cooling</arm_group_label>
    <arm_group_type>No Intervention</arm_group_type>
    <description>Fever respect without any antipyretic therapy</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>External Cooling</intervention_name>
    <description>External Cooling</description>
    <arm_group_label>Fever Control by external cooling</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Septic shock defined by the need for vasopressor and lactate&gt;2 mmol/l despite adequate&#xD;
             fluid resuscitation (sepsis-3 definition)&#xD;
&#xD;
          -  Patients under invasive mechanical ventilation&#xD;
&#xD;
          -  Body core temperature&gt;38.3°C&#xD;
&#xD;
          -  Intravenous sedation or opioids&#xD;
&#xD;
          -  Ongoing antimicrobial treatment and/or intervention for infection source control&#xD;
&#xD;
          -  Attending physician confirms clinical equipoise without substantial risk if the&#xD;
             patient participates in the trial&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Cardiac arrest within previous 7 days&#xD;
&#xD;
          -  Acute brain injury within previous 7 days&#xD;
&#xD;
          -  Extensive burns or epidermal necrolysis&#xD;
&#xD;
          -  &lt;18 years old&#xD;
&#xD;
          -  Body core temperature &gt;41°C&#xD;
&#xD;
          -  Under legal guardianship&#xD;
&#xD;
          -  No affiliation with the French health-care system&#xD;
&#xD;
          -  Pregnancy&#xD;
&#xD;
          -  Participation in another interventional study with mortality as the primary endpoint&#xD;
&#xD;
          -  An investigator's decision not to resuscitate&#xD;
&#xD;
          -  Patient already recruited in the trial&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>N/A</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_contact>
    <last_name>Frédérique SCHORTGEN, MD</last_name>
    <phone>01 45 17 56 83</phone>
    <email>Frederique.schortgen@chicreteil.fr</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Camille JUNG, MD</last_name>
    <phone>0157022268</phone>
    <email>camille.jung@chicreteil.fr</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>CHU Angers</name>
      <address>
        <city>Angers</city>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>ASFAR Pierre, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre hospitalier intercommunal de Créteil</name>
      <address>
        <city>Créteil</city>
        <zip>94000</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>SCHORTGEN Frédérique, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHD Dijon</name>
      <address>
        <city>Dijon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>QUENOT Jean Pierre, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHD Vendée</name>
      <address>
        <city>La Roche sur Yon</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>LACHARADE Jean Claude, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU Kremlin Bicetre</name>
      <address>
        <city>Le Kremlin-Bicêtre</city>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>ANGUEL Nadia, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>CHU Hotel Dieu</name>
      <address>
        <city>Nantes</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>REIGNIER Jean, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hopital Lariboisière - Réanimation Médicale</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>DEYE Nicolas, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Hôpital Lariboisière -Réanimation chirurgicale</name>
      <address>
        <city>Paris</city>
        <zip>75010</zip>
        <country>France</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>CHOUSTERMAN Benjamin, MD</last_name>
    </contact>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Mignot</name>
      <address>
        <city>Versailles</city>
        <country>France</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>LEGRIEL Stéphane, MD</last_name>
    </contact>
  </location>
  <location_countries>
    <country>France</country>
  </location_countries>
  <verification_date>February 2023</verification_date>
  <study_first_submitted>July 28, 2020</study_first_submitted>
  <study_first_submitted_qc>July 28, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">July 31, 2020</study_first_posted>
  <last_update_submitted>February 23, 2023</last_update_submitted>
  <last_update_submitted_qc>February 23, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">February 24, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>External cooling,</keyword>
  <keyword>Fever</keyword>
  <keyword>ARDS</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Shock, Septic</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/NCT04494074
org study id: SEPSISCOOL II
nct id: NCT04494074
lead sponsor: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
The best strategy for managing fever in patients with septic shock remains unknown. In a
      pilot study, the investigators showed that fever control at normothermia allowed a better
      control of shock and evolution of organ failures. In this second trial the investigators will
      conduct a multicentre, open-label, randomized controlled, superiority trial in which two
      strategies will be compared:

        1. Respect of fever

        2. Fever control at normothermia using external cooling The primary end point will be d-60
           mortality.
Sepsis is a common syndrome responsible for multiple organ failure. Septic shock, defined as
      sepsis with hyperlactatemia and cardiovascular failure requiring vasopressor infusion despite
      adequate fluid resuscitation has an extremely high mortality rate. Fever is a frequent
      disease process during sepsis. Fever increases oxygen consumption and can worsen imbalance
      between oxygen supply and oxygen requirements. Fever increases inflammation but reduces viral
      and bacterial growth. The beneficial effects of active fever control on inflammation have
      been mainly shown in a context of lung injury. Pneumonia represents the first cause of septic
      shock in developed countries.

      In a pilot study (SEPSISCOOL I), we showed that fever treatment using external cooling
      significantly increased the resolution of shock, improved organ functions and decreased d-14
      mortality. Although reduced, hospital mortality was not significantly different. This study
      was underpowered to allow conclusion on mortality. A more pronounced beneficial effect was
      observed among the most severely ill patients with elevated serum lactate level.

      Fever treatment is commonly applied in septic patients but its impact on survival remains
      undetermined.

      The main objective of the study is to compare two strategies of fever management in febrile
      (body temperature > 38.3°C) septic shock patients requiring invasive mechanical ventilation
      and sedation. These patients will be randomly allocated in two arms:

        1. Fever respect

        2. Fever control by external cooling to obtain normothermia during 48 hours

      A covariate-adaptive randomization will be used to ensure the comparability of the two groups
      at each stage of the study. We will use an adaptive multistage population-enrichment design
      with a pre-specified subgroup of patients with ARDS identified at randomization.

      An independent Safety and Data Monitoring Committee will review data on serious adverse
      events. The decision of study stop for potential harmful effect of one strategy will be let
      at the entire responsibility of the committee.

      One interim analysis will be performed by independent observers after enrolment of half of
      the population. The assumption that fever treatment is more effective in patients with ARDS
      will be confirmed or not. According to pre-defined rules based on the conditional power
      calculated in the two subgroups, the trial will be stopped for futility, continued as planned
      or continued by enrolling only patients with ARDS.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Mortality
time frame: Day 60
description: All causes mortality
measure: Evolution of SOFA Score
time frame: Up to Day 7
description: Sequential Organ Failure Assessment (SOFA) score will be calculated at d1, d2, d3 and d7 and compared between the 2 arms.
Higer the score higher the severity of organ dysfunctions. Min 0 Max 24
measure: Number of ventilator free days
time frame: Day 28
description: Number of free days will be assessed as proposed by YEHYA et al. Patients who died before d28 will be considered as having 0 free day
measure: Number of renal replacement therapy free days
time frame: Day 28
description: Number of free days will be assessed as proposed by YEHYA et al.
measure: Number of vasopressor free days
time frame: Day 28
description: Number of free days will be assessed as proposed by YEHYA et al. Shock resolution will be defined by vasopressor stop during at least 24h in the absence of care withdrawing
measure: Mortality
time frame: Day 28
description: All causes mortality
measure: Number of patients with shivering
time frame: Day 2
description: Shivering will be monitored according to a specific scale
measure: Number of patients with seizure
time frame: Day 3
description: Seizure will be clinically documented or reveal by EEG
measure: Number of patients with hypothermia
time frame: Day 2
description: Number of patients with body temperature lower than 36°C
measure: Number of patients with at least 1 episode of cardiac arrhythmia
time frame: Day 3
description: Patient with new episode of supraventricular or ventricular arrhythmia
measure: Secondary acquired nosocomial infections
time frame: Day 28
description: Only the first episode will be taken into account
measure: Number of patients with ARDS development among patients free of ARDS at inclusion
time frame: Up to Day 3
description: Secondary acquired ARDS according to Berlin definition
measure: Acute kidney injury
time frame: Up to Day7
description: Maximal stage of AKI according to the KDIGO definition
arm group label: Fever Control by external cooling
arm group type: Experimental
description: External cooling during 48 hours to obtain normothermia
arm group label: Fever respected, no cooling
arm group type: No Intervention
description: Fever respect without any antipyretic therapy
intervention type: Other
intervention name: External Cooling
description: External Cooling
arm group label: Fever Control by external cooling
criteria: 
gender: All
minimum age: 18 Years
maximum age: N/A
healthy volunteers: No
last name: Frédérique SCHORTGEN, MD
phone: 01 45 17 56 83
email: Frederique.schortgen@chicreteil.fr
last name: Camille JUNG, MD
phone: 0157022268
email: camille.jung@chicreteil.fr
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: France
responsible party type: Sponsor
mesh term: Shock, Septic