<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/NCT03786991</url>
  </required_header>
  <id_info>
    <org_study_id>MP-31-2019-2960</org_study_id>
    <nct_id>NCT03786991</nct_id>
  </id_info>
  <brief_title>EPI-STORM: Cytokine Storm in Organ Donors</brief_title>
  <acronym>EPI-STORM</acronym>
  <official_title>EPI-STORM Cytokine Storm in Organ Donors: A Translational Study Linking Donor Epigenetic to Transplantation Success in Recipient</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Université de Sherbrooke</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Centre de recherche du CHUS</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Université de Sherbrooke</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>
      Kidney and liver transplantation are the treatment of choice and are often the last&#xD;
      therapeutic option offered to patients with chronic renal and liver failure. More than 70% of&#xD;
      kidneys and liver available for transplantation are obtained from donors following&#xD;
      neurological death. Unfortunately, compared to living donation, transplant function, graft&#xD;
      survival, and recipient survival are consistently inferior with kidneys and liver from&#xD;
      neurologically deceased donors. This difference lies with the exacerbated pro-inflammatory&#xD;
      state characteristic of deceased donors. Indeed, when neurologic death occurs, the immune&#xD;
      system releases substances in the blood that could harm organs and particularly the liver and&#xD;
      the kidneys. We believe that achieving a better understanding of the inflammatory processes&#xD;
      of organ donors could be greatly informative to design future randomized controlled trial&#xD;
      assessing the effect of personalized immunosuppressive therapy on organ donors to ultimately&#xD;
      improve the care provided to donors so as to increase the number of organs available for&#xD;
      transplantation and enhancing the survival of received grafts&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Severe neurological injuries, such as those observed in neurologically deceased donors,&#xD;
      trigger a pro-inflammatory state that activates the immune system, increases vascular&#xD;
      permeability, and recruits and activates immune cells in solid organs. The rapid and intense&#xD;
      increase in circulating pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) following&#xD;
      neurological death, has been referred to as the cytokine storm, one condition that is not&#xD;
      seen among living donors. Interestingly, increased expression of TNF-α in the kidney and&#xD;
      liver at the time of transplantation has been associated with reduced graft survival and&#xD;
      acute rejection. Moreover, numerous studies have suggested that miRNA biomarkers can be&#xD;
      targeted as diagnostic or therapeutic molecules in the field of organ transplantation.&#xD;
      However, current models of graft injury fail to consider the epigenetic effects of&#xD;
      physiological stressors that occurred in neurologically deceased donors. Although several&#xD;
      biomarkers have been associated with graft dysfunction, the changes within the donor's&#xD;
      inflammatory state, the mechanism underlying these events in donors, and the impacts on&#xD;
      recipients are only poorly understood.&#xD;
&#xD;
      The investigators propose a multicenter prospective cohort study with the main objective of&#xD;
      assessing the pro-inflammatory status of neurologically deceased donors by examining both&#xD;
      miRNAs and circulatory cytokines and investigating its association with graft function in the&#xD;
      recipient. Blood specimens will be collected at various time points in neurologically&#xD;
      deceased liver and kidney donors in 5 organ recovery centres. The investigators hypothesize&#xD;
      that in donors, Peak plasma concentration of pro-inflammatory cytokines and&#xD;
      inflammatory-associated miRNAs targets (between consent and recovery) are associated with an&#xD;
      increase in kidney delayed graft function and liver early graft dysfunction in the&#xD;
      recipients. Considering that there is a therapeutic arsenal for treating donor cytokine&#xD;
      storms( e.g., immunosuppressants) and that new targets based on a highly personalized&#xD;
      mechanism could be developed we believe that the knowledge acquired in this research program&#xD;
      will make it possible to improve the rate of livers and kidneys recovered from potential&#xD;
      donors as well as enhance graft function in recipients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">December 16, 2018</start_date>
  <completion_date type="Anticipated">December 1, 2023</completion_date>
  <primary_completion_date type="Anticipated">December 1, 2023</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>Kidney delayed graft function</measure>
    <time_frame>7-days post-transplantation</time_frame>
    <description>Requirement for renal replacement therapy within the first 7 days following transplantation or decrease of &lt; 10% of creatinine after 3 days after transplantation, or creatinine &gt; 250 µmol/l at day 5 with evidence of delayed graft function by renal scintigraphy</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Liver early graft dysfunction</measure>
    <time_frame>7-days post-transplantation</time_frame>
    <description>Presence of one of the following three criteria: (i) peak AST or ALT &gt; 2000 U/L during the first 7 days, (ii) bilirubin ≥ 10 mg/dL on day 7 postoperatively, or (iii) INR ≥ 1.6 on day 7 postoperatively</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Quantification of circulatory cytokines</measure>
    <time_frame>From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 25 donors).</time_frame>
    <description>Quantification of IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 (p70), IL-13, IFN-γ, and TNF-α by Luminex (Multiplex human cytokine panel, Millipore)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Identification of inflammatory-related miRNA targets using micro-transcriptome analyses</measure>
    <time_frame>From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room) ;25 donors).</time_frame>
    <description>Sequencing on an Illumina NovaSeq 6000 sequencing platform</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Validation of inflammatory-related miRNA targets using targeted quantification</measure>
    <time_frame>From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).</time_frame>
    <description>Quantification by RT-qPCR using TaqMan Advanced miRNA Assays</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Validation of circulatory cytokines</measure>
    <time_frame>From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).</time_frame>
    <description>Quantification of identified cytokines (in the 25 donors cohort) by Luminex (Multiplex, Millipore)</description>
  </secondary_outcome>
  <number_of_groups>2</number_of_groups>
  <enrollment type="Anticipated">105</enrollment>
  <condition>Organ Donation</condition>
  <condition>Liver Transplantation</condition>
  <condition>Kidney Transplantation</condition>
  <condition>Graft Dysfunction</condition>
  <arm_group>
    <arm_group_label>Organ donors</arm_group_label>
    <description>Organ donors after neurologic death (NDD) of 18 years old and older for whom consent to organ donation has been obtained.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Liver and kidney Recipients</arm_group_label>
    <description>Liver and kidney recipients of 18 years old and older.</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>No intervention</intervention_name>
    <description>No intervention</description>
    <arm_group_label>Liver and kidney Recipients</arm_group_label>
    <arm_group_label>Organ donors</arm_group_label>
  </intervention>
  <biospec_retention>Samples With DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood samples (including miRNA and buffy coat) will be drawn at 5 specific time points:&#xD;
      following ICU admission when patient has a serious neurological lesion, as soon as possible&#xD;
      after consent to organ donation, as well as 4 to 8 hours and 24 hours after the first sample&#xD;
      of phase 2 has been drawn. A final draw will be made prior to transfer from the ICU to&#xD;
      operating room for organ recovery. A substudy will be conducted in some centers and we will&#xD;
      collect samples at time of aortic cross clamp during surgery&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Organ donors by neurologic death and liver and kidney recipients&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Phase 1 of the study:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Patient admitted to the intensive care unit with a serious neurologic lesion&#xD;
&#xD;
          -  Glasgow Coma Scale score ≤ 4&#xD;
&#xD;
          -  Absence of sedation for the last 6 hours&#xD;
&#xD;
          -  Age ≥ 18 years old&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  S. aureus bacteremia&#xD;
&#xD;
          -  Active neoplasia&#xD;
&#xD;
          -  Receiving immunosuppressive therapy (including steroids) for &gt; 3 months&#xD;
&#xD;
        Specific to potential liver donors:&#xD;
&#xD;
          -  Hepatic insufficiency defined as i) INR &gt; 1.5, ii) hepatic encephalopathy, iii) AST,&#xD;
             ALT &gt; 2 times normal value&#xD;
&#xD;
        Specific to potential kidney donors:&#xD;
&#xD;
          -  Polycystic kidney disease&#xD;
&#xD;
          -  Chronic renal failure (i.e., eGFR &lt; 60 ml/min)&#xD;
&#xD;
        Phase 2 of the study:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          -  Organ donor after neurologic death (DND) declaration as determined by the attending&#xD;
             physician&#xD;
&#xD;
          -  Consent to organ donation obtained&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>80 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Dr Frédérick D'Aragon, MD FRCPC MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Université de Sherbrooke</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Marie-Hélène Masse, RRT, M.Sc.</last_name>
    <phone>819-346-1110</phone>
    <phone_ext>14173</phone_ext>
    <email>marie-helene.masse3@usherbrooke.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Daphnée Lamarche, PhD</last_name>
    <phone>819-821-8000</phone>
    <phone_ext>70106</phone_ext>
    <email>daphnee.lamarche@usherbrooke.ca</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Hôpital Maisonneuve-Rosemont</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H1T 2M4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Montréal</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <zip>H2X 3E4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>Centre Hospitalier Universitaire de Québec- Université Laval</name>
      <address>
        <city>Quebec city</city>
        <state>Quebec</state>
        <zip>G1V 4G2</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
  </location>
  <location>
    <facility>
      <name>CIUSSS de l'Estrie-CHUS</name>
      <address>
        <city>Sherbrooke</city>
        <state>Quebec</state>
        <zip>J1H 5N4</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marie-Hélène Masse, RRT, MSc</last_name>
      <phone>819-346-1110</phone>
      <phone_ext>14173</phone_ext>
      <email>marie-helene.masse3@usherbrooke.ca</email>
    </contact>
    <contact_backup>
      <last_name>Daphnée Lamarche, PhD</last_name>
      <phone>819-821-8000</phone>
      <phone_ext>70106</phone_ext>
      <email>daphnee.lamarche@usherbrooke.ca</email>
    </contact_backup>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>November 30, 2018</study_first_submitted>
  <study_first_submitted_qc>December 19, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 26, 2018</study_first_posted>
  <last_update_submitted>April 18, 2023</last_update_submitted>
  <last_update_submitted_qc>April 18, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 19, 2023</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>Cytokine Release Syndrome</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- 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/NCT03786991
org study id: MP-31-2019-2960
nct id: NCT03786991
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
Kidney and liver transplantation are the treatment of choice and are often the last
      therapeutic option offered to patients with chronic renal and liver failure. More than 70% of
      kidneys and liver available for transplantation are obtained from donors following
      neurological death. Unfortunately, compared to living donation, transplant function, graft
      survival, and recipient survival are consistently inferior with kidneys and liver from
      neurologically deceased donors. This difference lies with the exacerbated pro-inflammatory
      state characteristic of deceased donors. Indeed, when neurologic death occurs, the immune
      system releases substances in the blood that could harm organs and particularly the liver and
      the kidneys. We believe that achieving a better understanding of the inflammatory processes
      of organ donors could be greatly informative to design future randomized controlled trial
      assessing the effect of personalized immunosuppressive therapy on organ donors to ultimately
      improve the care provided to donors so as to increase the number of organs available for
      transplantation and enhancing the survival of received grafts
Severe neurological injuries, such as those observed in neurologically deceased donors,
      trigger a pro-inflammatory state that activates the immune system, increases vascular
      permeability, and recruits and activates immune cells in solid organs. The rapid and intense
      increase in circulating pro-inflammatory cytokines (e.g., IL-1, IL-6, TNF-α) following
      neurological death, has been referred to as the cytokine storm, one condition that is not
      seen among living donors. Interestingly, increased expression of TNF-α in the kidney and
      liver at the time of transplantation has been associated with reduced graft survival and
      acute rejection. Moreover, numerous studies have suggested that miRNA biomarkers can be
      targeted as diagnostic or therapeutic molecules in the field of organ transplantation.
      However, current models of graft injury fail to consider the epigenetic effects of
      physiological stressors that occurred in neurologically deceased donors. Although several
      biomarkers have been associated with graft dysfunction, the changes within the donor's
      inflammatory state, the mechanism underlying these events in donors, and the impacts on
      recipients are only poorly understood.

      The investigators propose a multicenter prospective cohort study with the main objective of
      assessing the pro-inflammatory status of neurologically deceased donors by examining both
      miRNAs and circulatory cytokines and investigating its association with graft function in the
      recipient. Blood specimens will be collected at various time points in neurologically
      deceased liver and kidney donors in 5 organ recovery centres. The investigators hypothesize
      that in donors, Peak plasma concentration of pro-inflammatory cytokines and
      inflammatory-associated miRNAs targets (between consent and recovery) are associated with an
      increase in kidney delayed graft function and liver early graft dysfunction in the
      recipients. Considering that there is a therapeutic arsenal for treating donor cytokine
      storms( e.g., immunosuppressants) and that new targets based on a highly personalized
      mechanism could be developed we believe that the knowledge acquired in this research program
      will make it possible to improve the rate of livers and kidneys recovered from potential
      donors as well as enhance graft function in recipients.
observational model: Cohort
time perspective: Prospective
measure: Kidney delayed graft function
time frame: 7-days post-transplantation
description: Requirement for renal replacement therapy within the first 7 days following transplantation or decrease of < 10% of creatinine after 3 days after transplantation, or creatinine > 250 µmol/l at day 5 with evidence of delayed graft function by renal scintigraphy
measure: Liver early graft dysfunction
time frame: 7-days post-transplantation
description: Presence of one of the following three criteria: (i) peak AST or ALT > 2000 U/L during the first 7 days, (ii) bilirubin ≥ 10 mg/dL on day 7 postoperatively, or (iii) INR ≥ 1.6 on day 7 postoperatively
measure: Quantification of circulatory cytokines
time frame: From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 25 donors).
description: Quantification of IL-1β, IL-2, IL-4, IL-6, IL-10, IL-12 (p70), IL-13, IFN-γ, and TNF-α by Luminex (Multiplex human cytokine panel, Millipore)
measure: Identification of inflammatory-related miRNA targets using micro-transcriptome analyses
time frame: From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room) ;25 donors).
description: Sequencing on an Illumina NovaSeq 6000 sequencing platform
measure: Validation of inflammatory-related miRNA targets using targeted quantification
time frame: From ICU admission up to organ recovery (5 timepoints(1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).
description: Quantification by RT-qPCR using TaqMan Advanced miRNA Assays
measure: Validation of circulatory cytokines
time frame: From ICU admission up to organ recovery (5 timepoints (1:ICU admission; 2: consent to organ donation, 3: 4 to 8 hours after sample #2, 4: 24 hours after sample #2; 5: prior to transfer from ICU to operating room); 105 donors).
description: Quantification of identified cytokines (in the 25 donors cohort) by Luminex (Multiplex, Millipore)
arm group label: Organ donors
description: Organ donors after neurologic death (NDD) of 18 years old and older for whom consent to organ donation has been obtained.
arm group label: Liver and kidney Recipients
description: Liver and kidney recipients of 18 years old and older.
intervention type: Other
intervention name: No intervention
description: No intervention
arm group label: Liver and kidney Recipients
arm group label: Organ donors
Blood samples (including miRNA and buffy coat) will be drawn at 5 specific time points:
      following ICU admission when patient has a serious neurological lesion, as soon as possible
      after consent to organ donation, as well as 4 to 8 hours and 24 hours after the first sample
      of phase 2 has been drawn. A final draw will be made prior to transfer from the ICU to
      operating room for organ recovery. A substudy will be conducted in some centers and we will
      collect samples at time of aortic cross clamp during surgery
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: 18 Years
maximum age: 80 Years
healthy volunteers: No
last name: Dr Frédérick D'Aragon, MD FRCPC MSc
role: Principal Investigator
affiliation: Université de Sherbrooke
last name: Marie-Hélène Masse, RRT, M.Sc.
phone: 819-346-1110
phone ext: 14173
email: marie-helene.masse3@usherbrooke.ca
last name: Daphnée Lamarche, PhD
phone: 819-821-8000
phone ext: 70106
email: daphnee.lamarche@usherbrooke.ca
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
facility: 
status: Recruiting
contact: 
contact backup: 
country: Canada
responsible party type: Sponsor
mesh term: Cytokine Release Syndrome
sharing ipd: Undecided