<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/NCT01683383</url>
  </required_header>
  <id_info>
    <org_study_id>22993</org_study_id>
    <nct_id>NCT01683383</nct_id>
  </id_info>
  <brief_title>California Transport Cooling Trial</brief_title>
  <acronym>CTCT</acronym>
  <official_title>A Randomized Clinical Trial of Therapeutic Hypothermia During Transport for Hypoxic Ischemic Encephalopathy (HIE): Device-regulated Cooling Versus Standard Practice.</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Stanford University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Inspiration Healthcare</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Stanford University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      Hypoxic ischemic encephalopathy (HIE) remains a major cause of death and severe disability&#xD;
      despite advances in neonatal and perinatal medicine. Therapeutic hypothermia is the single&#xD;
      most promising intervention for HIE. Reduction of brain temperature by 2° to 5°C has shown to&#xD;
      be neuroprotective in newborn and adult animal models of brain ischemia. Therapeutic&#xD;
      hypothermia instituted within 6 hours of birth has been shown to significantly improve&#xD;
      survival and neurodevelopmental outcome in term newborns with HIE. Hypothermia is most&#xD;
      effective if begun during the latent period, before the secondary energy failure. It is not&#xD;
      known whether cooling initiated after 6 hours of age is effective.&#xD;
&#xD;
      The goal of this proposal is to test the efficacy of the cooling device in achieving the&#xD;
      target temperatures in patients with moderate to severe HIE during transport when compared&#xD;
      with current practices.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Statement of the Problem:&#xD;
&#xD;
      Hypoxic ischemic encephalopathy (HIE) remains a major cause of death and severe disability&#xD;
      despite advances in neonatal and perinatal medicine. Therapeutic hypothermia is the single&#xD;
      most promising intervention for HIE. Reduction of brain temperature by 2° to 5°C has shown to&#xD;
      be neuroprotective in newborn and adult animal models of brain ischemia. Therapeutic&#xD;
      hypothermia instituted within 6 hours of birth has been shown to significantly improve&#xD;
      survival and neurodevelopmental outcome in term newborns with HIE. Hypothermia is most&#xD;
      effective if begun during the latent period, before secondary energy failure. It is not known&#xD;
      whether cooling initiated after 6 hours of age is effective. Animal studies have shown that&#xD;
      the sooner the initiation of cooling, the better the outcome. They have also suggested that&#xD;
      the latent period may be shorter with a more severe insult. Cooling should be initiated as&#xD;
      soon as possible, preferably within 2 hours and not later than 6 hours. There have been six&#xD;
      large randomized clinical trials supporting the efficacy of therapeutic hypothermia for HIE&#xD;
      and it is now the standard of care in the U.S. and internationally.&#xD;
&#xD;
      Once a patient qualifies for cooling, whole body cooling or selective head cooling is&#xD;
      initiated. However, most birth hospitals do not have the ability to provide therapeutic&#xD;
      hypothermia; thus, patients must be transported to Level 3 NICUs specially equipped to&#xD;
      provide this therapy. As there is a limited therapeutic window for induction of hypothermia,&#xD;
      it would be ideal to initiate therapeutic hypothermia as soon as the patient qualifies for&#xD;
      cooling therapy. If cooling is initiated at the birth hospital, neuroprotective temperatures&#xD;
      can be achieved several hours prior to arrival in the cooling center.&#xD;
&#xD;
      At this time patients cooled in transport receive passive cooling (turning off the active&#xD;
      warming devices such as the transport isolette) or active cooling (ice packs placed around&#xD;
      the baby). These practices have been shown to present a significant risk for over-cooling and&#xD;
      under-cooling. The risks associated with excessive cooling include bradycardia, cardiac&#xD;
      arrest, and coagulation disturbances. Undercooling likely results in reduced efficacy of the&#xD;
      neuroprotective effects provided by therapeutic hypothermia.&#xD;
&#xD;
      Primary and secondary endpoints Primary end point: The percentage of temperatures in the&#xD;
      target range (33°-34°C) both within and between enrolled infants after cooling initiation by&#xD;
      the transport team.&#xD;
&#xD;
      Secondary end point: Time to the target temperature range (33°-34°C), percentage of newborns&#xD;
      in target temperature range one hour after cooling initiation by transport team, and&#xD;
      temperature ranges.&#xD;
&#xD;
      Study Design The proposed California Transport Cooling Trial (CTCT) is a prospective&#xD;
      randomized multi-center clinical trial to be conducted by nine transport teams based at level&#xD;
      III NICUs in California who perform therapeutic hypothermia for HIE. The on-call&#xD;
      neonatologist at the participating cooling center will determine if the infant qualifies for&#xD;
      cooling. Infants greater than or equal to 35 weeks and less than six hours of age who are&#xD;
      being transported to a cooling center will be eligible. The transport team will randomize the&#xD;
      infant to either cooling as per center practice (Arm 1) or device-regulated cooling (Arm 2).&#xD;
      Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal&#xD;
      temperatures being recorded every 15 minutes. Subjects in Arm 2 will be placed on cooling&#xD;
      blanket connected to the Tecotherm Neo. Temperature will be monitored continuously and&#xD;
      servo-regulated using a rectal temperature probe. Pertinent clinical data will be collected&#xD;
      using CPQCC/CPeTS data forms and CTCT data forms. Temperatures from initiation of cooling&#xD;
      until admission to the cooling center will be analyzed for percentage of temperatures in the&#xD;
      target range after cooling initiation by the transport team, time to target temperature&#xD;
      range, percentage of newborns in the target temperature range 1 hour after cooling initiation&#xD;
      by the transport team, and temperature ranges. ANOVA method will be used to compare the&#xD;
      temperature ranges across arms. Cox proportional hazard model will be used to compare time to&#xD;
      target temperature. Safety outcomes will be compared using standard logistic regression.&#xD;
&#xD;
      Study Methods Subjects assigned to Arm 1 will be cooled as per the usual center practice with&#xD;
      recording of rectal temperatures every 15 minutes. Arm 2 subjects will be cooled using a&#xD;
      portable servo-regulated cooling device using a rectal probe. Temperatures will be stored on&#xD;
      the memory card every minute. No PHI will be stored in the cooling device. Data will be&#xD;
      downloaded from the device at the conclusion of the transport.&#xD;
&#xD;
      Sample Size and Estimated Study Duration Power calculations for this study were based on&#xD;
      anticipated 140 patients requiring initiation of therapeutic hypothermia by nine transport&#xD;
      teams over a period of one year. A 70% consent rate and 50 patients per arm will provide 90%&#xD;
      power to detect 30% absolute difference in the percentage of temperatures in the target range&#xD;
      assuming a standard deviation for percentage of temperature in the target range of 45% based&#xD;
      on the Kendall study, published in Archives of Diseases of Childhood in 2010. All analyses&#xD;
      will adjust for center and will be two-sided and conducted at the 0.05 level of significance.&#xD;
&#xD;
      We estimate that patient enrollment will take approximately one year. Data analysis,&#xD;
      manuscript preparation, and submission will be completed within 6 months of completion of&#xD;
      enrollment.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>September 2012</start_date>
  <completion_date type="Actual">October 2013</completion_date>
  <primary_completion_date type="Actual">October 2013</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>Percentage of Temperatures in Target Range During Transport</measure>
    <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
    <description>The percentage of temperatures in the target range (33°-34°C) during transport after cooling initiation by the transport team.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to Target Temperature</measure>
    <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
    <description>Time to the target temperature range (33°-34°C) from initiation of cooling by the transport team</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Percentage of Participants in the Target Range at 1 Hour</measure>
    <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
    <description>Percentage of participants in target range (33°-34°C) one hour after cooling initiation by the transport team</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Participants in Target Temperature Range Anytime During Transport</measure>
    <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
    <description>Participants in target temperature range (33-34 C) anytime during transport</description>
  </secondary_outcome>
  <other_outcome>
    <measure>Safety Outcomes</measure>
    <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
    <description>The incidence, intervention and outcome of cardiac arrhythmia, major bleeding, altered skin integrity, pulmonary hypertension, device-related events, death, and other serious adverse events from the time of initiation of transport cooling to the time of completion will be monitored.</description>
  </other_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Actual">101</enrollment>
  <condition>Hypoxic Ischemic Encephalopathy</condition>
  <arm_group>
    <arm_group_label>Control (standard practice)</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Device (servo-regulated cooling)</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
  </arm_group>
  <intervention>
    <intervention_type>Device</intervention_type>
    <intervention_name>Device (servo-regulated cooling)</intervention_name>
    <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
    <arm_group_label>Device (servo-regulated cooling)</arm_group_label>
    <other_name>Tecotherm Neo</other_name>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Control (standard practice)</intervention_name>
    <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
    <arm_group_label>Control (standard practice)</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Term or near-term infants with gestational age ≥35 weeks who meet institutional&#xD;
             criteria for use of therapeutic hypothermia and in whom the decision has been made to&#xD;
             perform cooling during transport.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Presence of a congenital or lethal chromosomal anomaly&#xD;
&#xD;
          -  Decision to not provide full intensive care&#xD;
&#xD;
          -  Refusal to consent&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>6 Hours</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Krisa Van Meurs, M.D.</last_name>
    <role>Principal Investigator</role>
    <affiliation>Stanford University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Loma Linda University Children's Hospital</name>
      <address>
        <city>Loma Linda</city>
        <state>California</state>
        <zip>92354</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital Central California</name>
      <address>
        <city>Madera</city>
        <state>California</state>
        <zip>93636</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Children's Hospital &amp; Research Center</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94609</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Kaiser Permanente Oakland/Walnut Creek</name>
      <address>
        <city>Oakland</city>
        <state>California</state>
        <zip>94611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Stanford University</name>
      <address>
        <city>Palo Alto</city>
        <state>California</state>
        <zip>94305</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Sutter Medical Center</name>
      <address>
        <city>Sacramento</city>
        <state>California</state>
        <zip>95819</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Rady Childrens Hospital</name>
      <address>
        <city>San Diego</city>
        <state>California</state>
        <zip>92123</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>University of California San Francisco Medical Center</name>
      <address>
        <city>San Francisco</city>
        <state>California</state>
        <zip>94143</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Santa Clara Valley Medical Center</name>
      <address>
        <city>San Jose</city>
        <state>California</state>
        <zip>95128</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <reference>
    <citation>Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997 Jan 15;99(2):248-56. doi: 10.1172/JCI119153.</citation>
    <PMID>9005993</PMID>
  </reference>
  <reference>
    <citation>Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics. 1997 Dec;100(6):1004-14. doi: 10.1542/peds.100.6.1004. No abstract available.</citation>
    <PMID>9374573</PMID>
  </reference>
  <reference>
    <citation>Gluckman PD, Williams CE. When and why do brain cells die? Dev Med Child Neurol. 1992 Nov;34(11):1010-4. doi: 10.1111/j.1469-8749.1992.tb11407.x. No abstract available.</citation>
    <PMID>1358734</PMID>
  </reference>
  <reference>
    <citation>Iwata O, Iwata S, Thornton JS, De Vita E, Bainbridge A, Herbert L, Scaravilli F, Peebles D, Wyatt JS, Cady EB, Robertson NJ. &quot;Therapeutic time window&quot; duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets. Brain Res. 2007 Jun 18;1154:173-80. doi: 10.1016/j.brainres.2007.03.083. Epub 2007 Apr 1.</citation>
    <PMID>17475224</PMID>
  </reference>
  <reference>
    <citation>Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70. doi: 10.1016/S0140-6736(05)17946-X.</citation>
    <PMID>15721471</PMID>
  </reference>
  <reference>
    <citation>Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, Horgan MJ, Languani S, Bhatia JJ, Givelichian LM, Sankaran K, Yager JY. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005 Jan;32(1):11-7. doi: 10.1016/j.pediatrneurol.2004.06.014.</citation>
    <PMID>15607598</PMID>
  </reference>
  <reference>
    <citation>Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929.</citation>
    <PMID>16221780</PMID>
  </reference>
  <reference>
    <citation>Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854. Erratum In: N Engl J Med. 2010 Mar 18;362(11):1056.</citation>
    <PMID>19797281</PMID>
  </reference>
  <reference>
    <citation>Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010 Oct;126(4):e771-8. doi: 10.1542/peds.2009-2441. Epub 2010 Sep 20.</citation>
    <PMID>20855387</PMID>
  </reference>
  <reference>
    <citation>Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, Wright IM, Kirpalani HM, Darlow BA, Doyle LW; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011 Aug;165(8):692-700. doi: 10.1001/archpediatrics.2011.43. Epub 2011 Apr 4.</citation>
    <PMID>21464374</PMID>
  </reference>
  <reference>
    <citation>Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010 May;30(5):324-9. doi: 10.1038/jp.2009.168. Epub 2009 Oct 22.</citation>
    <PMID>19847186</PMID>
  </reference>
  <reference>
    <citation>Hallberg B, Olson L, Bartocci M, Edqvist I, Blennow M. Passive induction of hypothermia during transport of asphyxiated infants: a risk of excessive cooling. Acta Paediatr. 2009 Jun;98(6):942-6. doi: 10.1111/j.1651-2227.2009.01303.x.</citation>
    <PMID>19484830</PMID>
  </reference>
  <reference>
    <citation>Akula VP, Davis AS, Gould JB, Van Meurs K. Therapeutic hypothermia during neonatal transport: current practices in California. Am J Perinatol. 2012 May;29(5):319-26. doi: 10.1055/s-0031-1295661. Epub 2011 Dec 5.</citation>
    <PMID>22143969</PMID>
  </reference>
  <reference>
    <citation>Kendall GS, Kapetanakis A, Ratnavel N, Azzopardi D, Robertson NJ; Cooling on Retrieval Study Group. Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2010 Nov;95(6):F408-12. doi: 10.1136/adc.2010.187211. Epub 2010 Sep 24.</citation>
    <PMID>20870910</PMID>
  </reference>
  <reference>
    <citation>Akula VP, Gould JB, Davis AS, Hackel A, Oehlert J, Van Meurs KP. Therapeutic hypothermia during neonatal transport: data from the California Perinatal Quality Care Collaborative (CPQCC) and California Perinatal Transport System (CPeTS) for 2010. J Perinatol. 2013 Mar;33(3):194-7. doi: 10.1038/jp.2012.144. Epub 2012 Dec 6.</citation>
    <PMID>23223159</PMID>
  </reference>
  <verification_date>December 2014</verification_date>
  <study_first_submitted>September 6, 2012</study_first_submitted>
  <study_first_submitted_qc>September 7, 2012</study_first_submitted_qc>
  <study_first_posted type="Estimate">September 11, 2012</study_first_posted>
  <results_first_submitted>November 21, 2014</results_first_submitted>
  <results_first_submitted_qc>December 1, 2014</results_first_submitted_qc>
  <results_first_posted type="Estimate">December 8, 2014</results_first_posted>
  <last_update_submitted>December 1, 2014</last_update_submitted>
  <last_update_submitted_qc>December 1, 2014</last_update_submitted_qc>
  <last_update_posted type="Estimate">December 8, 2014</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Stanford University</investigator_affiliation>
    <investigator_full_name>Krisa P Van Meurs</investigator_full_name>
    <investigator_title>Professor of Pediatrics</investigator_title>
  </responsible_party>
  <keyword>Hypoxic ischemic encephalopathy</keyword>
  <keyword>Therapeutic hypothermia</keyword>
  <keyword>Whole body cooling</keyword>
  <keyword>Transport cooling</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Brain Diseases</mesh_term>
    <mesh_term>Brain Ischemia</mesh_term>
    <mesh_term>Hypoxia-Ischemia, Brain</mesh_term>
    <mesh_term>Ischemia</mesh_term>
    <mesh_term>Hypoxia</mesh_term>
  </condition_browse>

  <clinical_results>

    <participant_flow>
      <recruitment_details>131 infants were screened for eligibility at nine participating NICUs between October 1, 2012 and September 27th, 2013. Eligible infants had a gestational age of at least 35 weeks, met institutional criteria for use of therapeutic hypothermia, and a decision had been made to initiate cooling in transport.</recruitment_details>
      <pre_assignment_details>Infants were excluded if they had a lethal congenital or chromosomal anomaly, the decision had been made to not provide full intensive care, or there was refusal of consent. Of 131 infants screened for eligibility, 30 were excluded, and 101 consented and were randomized.</pre_assignment_details>
      <group_list>
        <group group_id="P1">
          <title>Control (Standard Cooling)</title>
          <description>Infants were cooled as per the birth hospital practice either passively (turning the radiant warmer /incubator off) and/or actively (ice or gel packs).</description>
        </group>
        <group group_id="P2">
          <title>Device (Servo-regulated Cooling)</title>
          <description>Infants were placed on a servo-controlled cooling blanket after a rectal or esophageal probe was inserted. The temperature was servo-controlled using the Tecotherm Neo (Inspiration Medical LTD, Leicester, UK) (Appendix 1; online only) with the target temperature set to 33.5°C.</description>
        </group>
      </group_list>
      <period_list>
        <period>
          <title>Overall Study</title>
          <milestone_list>
            <milestone>
              <title>STARTED</title>
              <participants_list>
                <participants group_id="P1" count="50"/>
                <participants group_id="P2" count="51"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>Transported and Treated</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
                <participants group_id="P2" count="51"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="49"/>
                <participants group_id="P2" count="51"/>
              </participants_list>
            </milestone>
            <milestone>
              <title>NOT COMPLETED</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </milestone>
          </milestone_list>
          <drop_withdraw_reason_list>
            <drop_withdraw_reason>
              <title>Infant was not transported</title>
              <participants_list>
                <participants group_id="P1" count="1"/>
                <participants group_id="P2" count="0"/>
              </participants_list>
            </drop_withdraw_reason>
          </drop_withdraw_reason_list>
        </period>
      </period_list>
    </participant_flow>

    <baseline>
      <population>Eligible newborns</population>
      <group_list>
        <group group_id="B1">
          <title>Control (Standard Cooling)</title>
          <description>Infants were cooled as per the birth hospital practice either passively (turning the radiant warmer /incubator off) and/or actively (ice or gel packs).</description>
        </group>
        <group group_id="B2">
          <title>Device (Servo-regulated Cooling)</title>
          <description>Infants were placed on a servo-controlled cooling blanket after a rectal or esophageal probe was inserted. The temperature was servo-controlled using the Tecotherm Neo (Inspiration Medical LTD, Leicester, UK) (Appendix 1; online only) with the target temperature set to 33.5°C.</description>
        </group>
        <group group_id="B3">
          <title>Total</title>
          <description>Total of all reporting groups</description>
        </group>
      </group_list>
      <analyzed_list>
        <analyzed>
          <units>Participants</units>
          <scope>Overall</scope>
          <count_list>
            <count group_id="B1" value="49"/>
            <count group_id="B2" value="51"/>
            <count group_id="B3" value="100"/>
          </count_list>
        </analyzed>
      </analyzed_list>
      <measure_list>
        <measure>
          <title>Age, Customized</title>
          <description>Chronological age at cooling initiation at birth hospital (hours)</description>
          <units>Hours</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <title>Chron. age at cooling initiation at birth hospital</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26" spread="6"/>
                    <measurement group_id="B2" value="28" spread="6"/>
                    <measurement group_id="B3" value="27" spread="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Sex: Female, Male</title>
          <units>Participants</units>
          <param>Count of Participants</param>
          <class_list>
            <class>
              <category_list>
                <category>
                  <title>Female</title>
                  <measurement_list>
                    <measurement group_id="B1" value="25"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="47"/>
                  </measurement_list>
                </category>
                <category>
                  <title>Male</title>
                  <measurement_list>
                    <measurement group_id="B1" value="24"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="53"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Birth weight</title>
          <units>Grams</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3397" spread="627"/>
                    <measurement group_id="B2" value="3321" spread="523"/>
                    <measurement group_id="B3" value="3358" spread="610"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Gestational age</title>
          <units>Weeks</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="39.1" spread="1.7"/>
                    <measurement group_id="B2" value="39.1" spread="1.7"/>
                    <measurement group_id="B3" value="39.1" spread="1.7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Apgar scores @ 1 minute</title>
          <description>Apgar scores ≤5 at either 5 or 10 minutes can be due to acute hypoxia ischemia in the intrapartum period and as such are often one of the eligibility criteria for therapeutic hypothermia to treat HIE.</description>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Apgar @ 1 min ≤ 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="89"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Apgar @ 1 min &gt; 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="11"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Apgar scores @ 5 minutes</title>
          <description>Apgar scores ≤5 at either 5 or 10 minutes can be due to acute hypoxia ischemia in the intrapartum period and as such are often one of the eligibility criteria for therapeutic hypothermia to treat HIE.</description>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Apgar @ 5 min ≤ 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="42"/>
                    <measurement group_id="B2" value="38"/>
                    <measurement group_id="B3" value="80"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Apgar @ 5 min &gt; 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7"/>
                    <measurement group_id="B2" value="13"/>
                    <measurement group_id="B3" value="20"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Apgar scores @ 10 minutes</title>
          <description>Apgar scores ≤5 at either 5 or 10 minutes can be due to acute hypoxia ischemia in the intrapartum period and as such are often one of the eligibility criteria for therapeutic hypothermia to treat HIE.</description>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Apgar @ 10 min ≤ 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="27"/>
                    <measurement group_id="B2" value="24"/>
                    <measurement group_id="B3" value="51"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Apgar @ 10 min &gt; 5</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="22"/>
                    <measurement group_id="B2" value="27"/>
                    <measurement group_id="B3" value="49"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Delivery room resuscitation: Oxygen</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Oxygen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No oxygen</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Delivery room resuscitation: CPAP</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>CPAP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="18"/>
                    <measurement group_id="B2" value="16"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No CPAP</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="31"/>
                    <measurement group_id="B2" value="35"/>
                    <measurement group_id="B3" value="66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Delivery room resuscitation: Bag and mask</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Bag and mask</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="43"/>
                    <measurement group_id="B2" value="43"/>
                    <measurement group_id="B3" value="86"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No bag and mask</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6"/>
                    <measurement group_id="B2" value="8"/>
                    <measurement group_id="B3" value="14"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Delivery room resuscitation: Intubation with ventilation</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Intubation with ventilation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="32"/>
                    <measurement group_id="B3" value="66"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No intubation with ventilation</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="19"/>
                    <measurement group_id="B3" value="34"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Delivery room resuscitation: Epinephrine</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Epinephrine</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="13"/>
                    <measurement group_id="B2" value="10"/>
                    <measurement group_id="B3" value="23"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No epinephrine</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="36"/>
                    <measurement group_id="B2" value="41"/>
                    <measurement group_id="B3" value="77"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Delivery room resuscitation: Chest compressions</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Chest compressions</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="20"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="42"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No chest compressions</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="29"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="58"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Respiratory support @ randomization: Non-invasive ventilation</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Non-invasive ventilation: Yes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15"/>
                    <measurement group_id="B2" value="9"/>
                    <measurement group_id="B3" value="24"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Non-invasive ventilation: No</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="34"/>
                    <measurement group_id="B2" value="42"/>
                    <measurement group_id="B3" value="76"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Respiratory support @ randomization: Conventional mechanical ventilation</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Conventional mechanical ventilation: Yes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="26"/>
                    <measurement group_id="B2" value="29"/>
                    <measurement group_id="B3" value="55"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Conventional mechanical ventilation: No</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="23"/>
                    <measurement group_id="B2" value="22"/>
                    <measurement group_id="B3" value="45"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Respiratory support @ randomization: High-frequency ventilation</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>High-frequency ventilation: Yes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>High-frequency ventilation: No</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Respiratory support @ randomization: Inhaled nitric oxide</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Inhaled nitric oxide: Yes</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="2"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="6"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Inhaled nitric oxide: No</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="47"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="94"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Pressors at randomization</title>
          <units>Participants</units>
          <param>Number</param>
          <class_list>
            <class>
              <title>Pressors used</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="3"/>
                    <measurement group_id="B2" value="4"/>
                    <measurement group_id="B3" value="7"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>No pressors used</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="46"/>
                    <measurement group_id="B2" value="47"/>
                    <measurement group_id="B3" value="93"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cord gas: pH</title>
          <units>pH</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="6.91" spread="0.20"/>
                    <measurement group_id="B2" value="7.01" spread="0.15"/>
                    <measurement group_id="B3" value="6.96" spread="0.18"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>Cord gas: base deficit</title>
          <units>mEq/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="15.6" spread="7.1"/>
                    <measurement group_id="B2" value="14.0" spread="4.7"/>
                    <measurement group_id="B3" value="14.8" spread="6.0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>First postnatal gas: pH</title>
          <units>pH</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="7.06" spread="0.20"/>
                    <measurement group_id="B2" value="7.02" spread="0.19"/>
                    <measurement group_id="B3" value="7.04" spread="0.19"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <measure>
          <title>First postnatal gas: base deficit</title>
          <units>mEq/L</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="B1" value="17.0" spread="6.7"/>
                    <measurement group_id="B2" value="17.5" spread="6.9"/>
                    <measurement group_id="B3" value="17.3" spread="6.8"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </measure_list>
    </baseline>

    <outcome_list>
      <outcome>
        <type>Primary</type>
        <title>Percentage of Temperatures in Target Range During Transport</title>
        <description>The percentage of temperatures in the target range (33°-34°C) during transport after cooling initiation by the transport team.</description>
        <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
        <population>Total patients in each study arm</population>
        <group_list>
          <group group_id="O1">
            <title>Control (Standard Cooling)</title>
            <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
          </group>
          <group group_id="O2">
            <title>Device (Servo-regulated Cooling)</title>
            <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Temperatures in Target Range During Transport</title>
          <description>The percentage of temperatures in the target range (33°-34°C) during transport after cooling initiation by the transport team.</description>
          <population>Total patients in each study arm</population>
          <units>Percentage of temperatures</units>
          <param>Median</param>
          <dispersion>Inter-Quartile Range</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0" lower_limit="0" upper_limit="52"/>
                    <measurement group_id="O2" value="73" lower_limit="17" upper_limit="88"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>Adjusted Wald estimation</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Time to Target Temperature</title>
        <description>Time to the target temperature range (33°-34°C) from initiation of cooling by the transport team</description>
        <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
        <population>Total patients in each study arm</population>
        <group_list>
          <group group_id="O1">
            <title>Control (Standard Cooling)</title>
            <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
          </group>
          <group group_id="O2">
            <title>Device (Servo-regulated Cooling)</title>
            <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
          </group>
        </group_list>
        <measure>
          <title>Time to Target Temperature</title>
          <description>Time to the target temperature range (33°-34°C) from initiation of cooling by the transport team</description>
          <population>Total patients in each study arm</population>
          <units>Minutes</units>
          <param>Mean</param>
          <dispersion>Standard Deviation</dispersion>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="63" spread="37"/>
                    <measurement group_id="O2" value="44" spread="31"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>0.04</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Percentage of Participants in the Target Range at 1 Hour</title>
        <description>Percentage of participants in target range (33°-34°C) one hour after cooling initiation by the transport team</description>
        <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
        <population>Total participants in each study arm, excluding 8 participants in the control arm and 12 participants in the device arm who completed transport in &lt; 1 hour.</population>
        <group_list>
          <group group_id="O1">
            <title>Control (Standard Cooling)</title>
            <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
          </group>
          <group group_id="O2">
            <title>Device (Servo-regulated Cooling)</title>
            <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
          </group>
        </group_list>
        <measure>
          <title>Percentage of Participants in the Target Range at 1 Hour</title>
          <description>Percentage of participants in target range (33°-34°C) one hour after cooling initiation by the transport team</description>
          <population>Total participants in each study arm, excluding 8 participants in the control arm and 12 participants in the device arm who completed transport in &lt; 1 hour.</population>
          <units>Percentage of participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="41"/>
                <count group_id="O2" value="39"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="8"/>
                    <measurement group_id="O2" value="28"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
      <outcome>
        <type>Secondary</type>
        <title>Participants in Target Temperature Range Anytime During Transport</title>
        <description>Participants in target temperature range (33-34 C) anytime during transport</description>
        <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
        <population>Total participants in each study arm</population>
        <group_list>
          <group group_id="O1">
            <title>Control (Standard Cooling)</title>
            <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
          </group>
          <group group_id="O2">
            <title>Device (Servo-regulated Cooling)</title>
            <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
          </group>
        </group_list>
        <measure>
          <title>Participants in Target Temperature Range Anytime During Transport</title>
          <description>Participants in target temperature range (33-34 C) anytime during transport</description>
          <population>Total participants in each study arm</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="24"/>
                    <measurement group_id="O2" value="41"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
        <analysis_list>
          <analysis>
            <group_id_list>
              <group_id>O1</group_id>
              <group_id>O2</group_id>
            </group_id_list>
            <non_inferiority_type>Superiority or Other</non_inferiority_type>
            <p_value>&lt;0.001</p_value>
            <method>Wilcoxon (Mann-Whitney)</method>
          </analysis>
        </analysis_list>
      </outcome>
      <outcome>
        <type>Other Pre-specified</type>
        <title>Safety Outcomes</title>
        <description>The incidence, intervention and outcome of cardiac arrhythmia, major bleeding, altered skin integrity, pulmonary hypertension, device-related events, death, and other serious adverse events from the time of initiation of transport cooling to the time of completion will be monitored.</description>
        <time_frame>Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours</time_frame>
        <population>Total participants in each study arm</population>
        <group_list>
          <group group_id="O1">
            <title>Control (Standard Cooling)</title>
            <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
          </group>
          <group group_id="O2">
            <title>Device (Servo-regulated Cooling)</title>
            <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
          </group>
        </group_list>
        <measure>
          <title>Safety Outcomes</title>
          <description>The incidence, intervention and outcome of cardiac arrhythmia, major bleeding, altered skin integrity, pulmonary hypertension, device-related events, death, and other serious adverse events from the time of initiation of transport cooling to the time of completion will be monitored.</description>
          <population>Total participants in each study arm</population>
          <units>Participants</units>
          <param>Number</param>
          <analyzed_list>
            <analyzed>
              <units>Participants</units>
              <scope>Measure</scope>
              <count_list>
                <count group_id="O1" value="49"/>
                <count group_id="O2" value="51"/>
              </count_list>
            </analyzed>
          </analyzed_list>
          <class_list>
            <class>
              <title>Cardiac arrhythmia</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Major bleeding (pulmonary hemorrhage)</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="1"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Altered skin integrity</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Pulmonary hypertension</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="0"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Device-related events</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="0"/>
                    <measurement group_id="O2" value="2"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
            <class>
              <title>Death</title>
              <category_list>
                <category>
                  <measurement_list>
                    <measurement group_id="O1" value="6"/>
                    <measurement group_id="O2" value="9"/>
                  </measurement_list>
                </category>
              </category_list>
            </class>
          </class_list>
        </measure>
      </outcome>
    </outcome_list>

    <reported_events>
      <time_frame>Data were collected from the time of initiation of cooling (Arm 1 or Arm 2) to admission at the cooling center</time_frame>
      <group_list>
        <group group_id="E1">
          <title>Control (Standard Cooling)</title>
          <description>Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.</description>
        </group>
        <group group_id="E2">
          <title>Device (Servo-regulated Cooling)</title>
          <description>Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.</description>
        </group>
      </group_list>
      <serious_events>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, serious adverse events</sub_title>
                <counts group_id="E1" subjects_affected="6" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="10" subjects_at_risk="51"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Death</sub_title>
                <description>Note: These deaths were all attributed to disease complications and were not attributable to the study intervention.</description>
                <counts group_id="E1" events="6" subjects_affected="6" subjects_at_risk="49"/>
                <counts group_id="E2" events="9" subjects_affected="9" subjects_at_risk="51"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>Vascular disorders</title>
            <event_list>
              <event>
                <sub_title>Pulmonary hemorrhage</sub_title>
                <description>Note: Pulmonary hemorrhage was present prior to randomization and was not attributable to the study intervention.</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="1" subjects_affected="1" subjects_at_risk="51"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </serious_events>
      <other_events>
        <frequency_threshold>0</frequency_threshold>
        <default_assessment>Non-systematic Assessment</default_assessment>
        <category_list>
          <category>
            <title>Total</title>
            <event_list>
              <event>
                <sub_title>Total, other adverse events</sub_title>
                <counts group_id="E1" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" subjects_affected="2" subjects_at_risk="51"/>
              </event>
            </event_list>
          </category>
          <category>
            <title>General disorders</title>
            <event_list>
              <event>
                <sub_title>Equipment alarms</sub_title>
                <description>Brief equipment alarms when non-physiologic changes in temperature were registered by the device</description>
                <counts group_id="E1" events="0" subjects_affected="0" subjects_at_risk="49"/>
                <counts group_id="E2" events="2" subjects_affected="2" subjects_at_risk="51"/>
              </event>
            </event_list>
          </category>
        </category_list>
      </other_events>
    </reported_events>

    <certain_agreements>
      <pi_employee>Principal Investigators are NOT employed by the organization sponsoring the study.</pi_employee>
      <restrictive_agreement>There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed. </restrictive_agreement>
    </certain_agreements>
    <limitations_and_caveats>1, The criteria used to initiate hypothermia varied. 2, Operational errors occurred in 9 newborns during device regulated cooling. 3, 9.6% of temperatures in the control arm were missing.</limitations_and_caveats>
    <point_of_contact>
      <name_or_title>Krisa P. Van Meurs, M.D.</name_or_title>
      <organization>Stanford University School of Medicine</organization>
      <phone>+1 650 723 5711</phone>
      <email>vanmeurs@stanford.edu</email>
    </point_of_contact>
  </clinical_results>
</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/NCT01683383
org study id: 22993
nct id: NCT01683383
lead sponsor: 
collaborator: 
has dmc: Yes
Hypoxic ischemic encephalopathy (HIE) remains a major cause of death and severe disability
      despite advances in neonatal and perinatal medicine. Therapeutic hypothermia is the single
      most promising intervention for HIE. Reduction of brain temperature by 2° to 5°C has shown to
      be neuroprotective in newborn and adult animal models of brain ischemia. Therapeutic
      hypothermia instituted within 6 hours of birth has been shown to significantly improve
      survival and neurodevelopmental outcome in term newborns with HIE. Hypothermia is most
      effective if begun during the latent period, before the secondary energy failure. It is not
      known whether cooling initiated after 6 hours of age is effective.

      The goal of this proposal is to test the efficacy of the cooling device in achieving the
      target temperatures in patients with moderate to severe HIE during transport when compared
      with current practices.
Statement of the Problem:

      Hypoxic ischemic encephalopathy (HIE) remains a major cause of death and severe disability
      despite advances in neonatal and perinatal medicine. Therapeutic hypothermia is the single
      most promising intervention for HIE. Reduction of brain temperature by 2° to 5°C has shown to
      be neuroprotective in newborn and adult animal models of brain ischemia. Therapeutic
      hypothermia instituted within 6 hours of birth has been shown to significantly improve
      survival and neurodevelopmental outcome in term newborns with HIE. Hypothermia is most
      effective if begun during the latent period, before secondary energy failure. It is not known
      whether cooling initiated after 6 hours of age is effective. Animal studies have shown that
      the sooner the initiation of cooling, the better the outcome. They have also suggested that
      the latent period may be shorter with a more severe insult. Cooling should be initiated as
      soon as possible, preferably within 2 hours and not later than 6 hours. There have been six
      large randomized clinical trials supporting the efficacy of therapeutic hypothermia for HIE
      and it is now the standard of care in the U.S. and internationally.

      Once a patient qualifies for cooling, whole body cooling or selective head cooling is
      initiated. However, most birth hospitals do not have the ability to provide therapeutic
      hypothermia; thus, patients must be transported to Level 3 NICUs specially equipped to
      provide this therapy. As there is a limited therapeutic window for induction of hypothermia,
      it would be ideal to initiate therapeutic hypothermia as soon as the patient qualifies for
      cooling therapy. If cooling is initiated at the birth hospital, neuroprotective temperatures
      can be achieved several hours prior to arrival in the cooling center.

      At this time patients cooled in transport receive passive cooling (turning off the active
      warming devices such as the transport isolette) or active cooling (ice packs placed around
      the baby). These practices have been shown to present a significant risk for over-cooling and
      under-cooling. The risks associated with excessive cooling include bradycardia, cardiac
      arrest, and coagulation disturbances. Undercooling likely results in reduced efficacy of the
      neuroprotective effects provided by therapeutic hypothermia.

      Primary and secondary endpoints Primary end point: The percentage of temperatures in the
      target range (33°-34°C) both within and between enrolled infants after cooling initiation by
      the transport team.

      Secondary end point: Time to the target temperature range (33°-34°C), percentage of newborns
      in target temperature range one hour after cooling initiation by transport team, and
      temperature ranges.

      Study Design The proposed California Transport Cooling Trial (CTCT) is a prospective
      randomized multi-center clinical trial to be conducted by nine transport teams based at level
      III NICUs in California who perform therapeutic hypothermia for HIE. The on-call
      neonatologist at the participating cooling center will determine if the infant qualifies for
      cooling. Infants greater than or equal to 35 weeks and less than six hours of age who are
      being transported to a cooling center will be eligible. The transport team will randomize the
      infant to either cooling as per center practice (Arm 1) or device-regulated cooling (Arm 2).
      Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal
      temperatures being recorded every 15 minutes. Subjects in Arm 2 will be placed on cooling
      blanket connected to the Tecotherm Neo. Temperature will be monitored continuously and
      servo-regulated using a rectal temperature probe. Pertinent clinical data will be collected
      using CPQCC/CPeTS data forms and CTCT data forms. Temperatures from initiation of cooling
      until admission to the cooling center will be analyzed for percentage of temperatures in the
      target range after cooling initiation by the transport team, time to target temperature
      range, percentage of newborns in the target temperature range 1 hour after cooling initiation
      by the transport team, and temperature ranges. ANOVA method will be used to compare the
      temperature ranges across arms. Cox proportional hazard model will be used to compare time to
      target temperature. Safety outcomes will be compared using standard logistic regression.

      Study Methods Subjects assigned to Arm 1 will be cooled as per the usual center practice with
      recording of rectal temperatures every 15 minutes. Arm 2 subjects will be cooled using a
      portable servo-regulated cooling device using a rectal probe. Temperatures will be stored on
      the memory card every minute. No PHI will be stored in the cooling device. Data will be
      downloaded from the device at the conclusion of the transport.

      Sample Size and Estimated Study Duration Power calculations for this study were based on
      anticipated 140 patients requiring initiation of therapeutic hypothermia by nine transport
      teams over a period of one year. A 70% consent rate and 50 patients per arm will provide 90%
      power to detect 30% absolute difference in the percentage of temperatures in the target range
      assuming a standard deviation for percentage of temperature in the target range of 45% based
      on the Kendall study, published in Archives of Diseases of Childhood in 2010. All analyses
      will adjust for center and will be two-sided and conducted at the 0.05 level of significance.

      We estimate that patient enrollment will take approximately one year. Data analysis,
      manuscript preparation, and submission will be completed within 6 months of completion of
      enrollment.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Treatment
masking: None (Open Label)
measure: Percentage of Temperatures in Target Range During Transport
time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
description: The percentage of temperatures in the target range (33°-34°C) during transport after cooling initiation by the transport team.
measure: Time to Target Temperature
time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
description: Time to the target temperature range (33°-34°C) from initiation of cooling by the transport team
measure: Percentage of Participants in the Target Range at 1 Hour
time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
description: Percentage of participants in target range (33°-34°C) one hour after cooling initiation by the transport team
measure: Participants in Target Temperature Range Anytime During Transport
time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
description: Participants in target temperature range (33-34 C) anytime during transport
measure: Safety Outcomes
time frame: Participants will be followed for the duration of neonatal transport from the birth hospital to the cooling center, an expected average of 4 hours
description: The incidence, intervention and outcome of cardiac arrhythmia, major bleeding, altered skin integrity, pulmonary hypertension, device-related events, death, and other serious adverse events from the time of initiation of transport cooling to the time of completion will be monitored.
arm group label: Control (standard practice)
arm group type: Active Comparator
description: Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.
arm group label: Device (servo-regulated cooling)
arm group type: Experimental
description: Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.
intervention type: Device
intervention name: Device (servo-regulated cooling)
description: Subjects in Arm 2 will be placed on cooling blanket connected to the Tecotherm Neo (Inspiration Healthcare LTD UK). Temperature will be monitored continuously and servo-regulated using a rectal temperature probe.
arm group label: Device (servo-regulated cooling)
other name: Tecotherm Neo
intervention type: Other
intervention name: Control (standard practice)
description: Subjects in Arm 1 will receive passive or active cooling as per center practice with rectal temperatures being recorded every 15 minutes.
arm group label: Control (standard practice)
criteria: 
gender: All
minimum age: N/A
maximum age: 6 Hours
healthy volunteers: No
last name: Krisa Van Meurs, M.D.
role: Principal Investigator
affiliation: Stanford University
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
facility: 
country: United States
citation: Gunn AJ, Gunn TR, de Haan HH, Williams CE, Gluckman PD. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal lambs. J Clin Invest. 1997 Jan 15;99(2):248-56. doi: 10.1172/JCI119153.
PMID: 9005993
citation: Vannucci RC, Perlman JM. Interventions for perinatal hypoxic-ischemic encephalopathy. Pediatrics. 1997 Dec;100(6):1004-14. doi: 10.1542/peds.100.6.1004. No abstract available.
PMID: 9374573
citation: Gluckman PD, Williams CE. When and why do brain cells die? Dev Med Child Neurol. 1992 Nov;34(11):1010-4. doi: 10.1111/j.1469-8749.1992.tb11407.x. No abstract available.
PMID: 1358734
citation: Iwata O, Iwata S, Thornton JS, De Vita E, Bainbridge A, Herbert L, Scaravilli F, Peebles D, Wyatt JS, Cady EB, Robertson NJ. "Therapeutic time window" duration decreases with increasing severity of cerebral hypoxia-ischaemia under normothermia and delayed hypothermia in newborn piglets. Brain Res. 2007 Jun 18;1154:173-80. doi: 10.1016/j.brainres.2007.03.083. Epub 2007 Apr 1.
PMID: 17475224
citation: Gluckman PD, Wyatt JS, Azzopardi D, Ballard R, Edwards AD, Ferriero DM, Polin RA, Robertson CM, Thoresen M, Whitelaw A, Gunn AJ. Selective head cooling with mild systemic hypothermia after neonatal encephalopathy: multicentre randomised trial. Lancet. 2005 Feb 19-25;365(9460):663-70. doi: 10.1016/S0140-6736(05)17946-X.
PMID: 15721471
citation: Eicher DJ, Wagner CL, Katikaneni LP, Hulsey TC, Bass WT, Kaufman DA, Horgan MJ, Languani S, Bhatia JJ, Givelichian LM, Sankaran K, Yager JY. Moderate hypothermia in neonatal encephalopathy: efficacy outcomes. Pediatr Neurol. 2005 Jan;32(1):11-7. doi: 10.1016/j.pediatrneurol.2004.06.014.
PMID: 15607598
citation: Shankaran S, Laptook AR, Ehrenkranz RA, Tyson JE, McDonald SA, Donovan EF, Fanaroff AA, Poole WK, Wright LL, Higgins RD, Finer NN, Carlo WA, Duara S, Oh W, Cotten CM, Stevenson DK, Stoll BJ, Lemons JA, Guillet R, Jobe AH; National Institute of Child Health and Human Development Neonatal Research Network. Whole-body hypothermia for neonates with hypoxic-ischemic encephalopathy. N Engl J Med. 2005 Oct 13;353(15):1574-84. doi: 10.1056/NEJMcps050929.
PMID: 16221780
citation: Azzopardi DV, Strohm B, Edwards AD, Dyet L, Halliday HL, Juszczak E, Kapellou O, Levene M, Marlow N, Porter E, Thoresen M, Whitelaw A, Brocklehurst P; TOBY Study Group. Moderate hypothermia to treat perinatal asphyxial encephalopathy. N Engl J Med. 2009 Oct 1;361(14):1349-58. doi: 10.1056/NEJMoa0900854. Erratum In: N Engl J Med. 2010 Mar 18;362(11):1056.
PMID: 19797281
citation: Simbruner G, Mittal RA, Rohlmann F, Muche R; neo.nEURO.network Trial Participants. Systemic hypothermia after neonatal encephalopathy: outcomes of neo.nEURO.network RCT. Pediatrics. 2010 Oct;126(4):e771-8. doi: 10.1542/peds.2009-2441. Epub 2010 Sep 20.
PMID: 20855387
citation: Jacobs SE, Morley CJ, Inder TE, Stewart MJ, Smith KR, McNamara PJ, Wright IM, Kirpalani HM, Darlow BA, Doyle LW; Infant Cooling Evaluation Collaboration. Whole-body hypothermia for term and near-term newborns with hypoxic-ischemic encephalopathy: a randomized controlled trial. Arch Pediatr Adolesc Med. 2011 Aug;165(8):692-700. doi: 10.1001/archpediatrics.2011.43. Epub 2011 Apr 4.
PMID: 21464374
citation: Fairchild K, Sokora D, Scott J, Zanelli S. Therapeutic hypothermia on neonatal transport: 4-year experience in a single NICU. J Perinatol. 2010 May;30(5):324-9. doi: 10.1038/jp.2009.168. Epub 2009 Oct 22.
PMID: 19847186
citation: Hallberg B, Olson L, Bartocci M, Edqvist I, Blennow M. Passive induction of hypothermia during transport of asphyxiated infants: a risk of excessive cooling. Acta Paediatr. 2009 Jun;98(6):942-6. doi: 10.1111/j.1651-2227.2009.01303.x.
PMID: 19484830
citation: Akula VP, Davis AS, Gould JB, Van Meurs K. Therapeutic hypothermia during neonatal transport: current practices in California. Am J Perinatol. 2012 May;29(5):319-26. doi: 10.1055/s-0031-1295661. Epub 2011 Dec 5.
PMID: 22143969
citation: Kendall GS, Kapetanakis A, Ratnavel N, Azzopardi D, Robertson NJ; Cooling on Retrieval Study Group. Passive cooling for initiation of therapeutic hypothermia in neonatal encephalopathy. Arch Dis Child Fetal Neonatal Ed. 2010 Nov;95(6):F408-12. doi: 10.1136/adc.2010.187211. Epub 2010 Sep 24.
PMID: 20870910
citation: Akula VP, Gould JB, Davis AS, Hackel A, Oehlert J, Van Meurs KP. Therapeutic hypothermia during neonatal transport: data from the California Perinatal Quality Care Collaborative (CPQCC) and California Perinatal Transport System (CPeTS) for 2010. J Perinatol. 2013 Mar;33(3):194-7. doi: 10.1038/jp.2012.144. Epub 2012 Dec 6.
PMID: 23223159
responsible party type: Principal Investigator
investigator affiliation: Stanford University
investigator full name: Krisa P Van Meurs
investigator title: Professor of Pediatrics
mesh term: Brain Diseases
mesh term: Brain Ischemia
mesh term: Hypoxia-Ischemia, Brain
mesh term: Ischemia
mesh term: Hypoxia
participant flow: 
baseline: 
outcome list: 
reported events: 
certain agreements: 
limitations and caveats: 1, The criteria used to initiate hypothermia varied. 2, Operational errors occurred in 9 newborns during device regulated cooling. 3, 9.6% of temperatures in the control arm were missing.
point of contact: 