<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/NCT03825835</url>
  </required_header>
  <id_info>
    <org_study_id>Pro00083931</org_study_id>
    <nct_id>NCT03825835</nct_id>
  </id_info>
  <brief_title>30% or 60% Oxygen at Birth to Improve Neurodevelopmental Outcomes in Very Low Birthweight Infants</brief_title>
  <acronym>HiLo</acronym>
  <official_title>Does the Use of Higher Versus Lower Oxygen Concentration Improve Neurodevelopmental Outcomes at 18-24 Months in Very Low Birthweight Infants - The HiLo-Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>University of Alberta</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>University of Toronto</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Sydney</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Valencia</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Dalhousie University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>McMaster University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>University of Manitoba</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>McGill University</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Alberta</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      Preterm birth, or birth before 37 weeks' gestation, is increasingly common, occurring in 8&#xD;
      percent of pregnancies in Canada. Preterm birth is associated with many health complications,&#xD;
      particularly when the birth happens before 29 weeks' gestation. At this gestational age, the&#xD;
      lungs are not fully developed and it is not uncommon for infants to have problems breathing&#xD;
      at the time of birth. One complication that can arise is when an infant stops breathing and&#xD;
      needs to be resuscitated. When preterm babies need to be resuscitated doctors must take&#xD;
      special care because of the small infant size and the immaturity of the brain and lungs.&#xD;
      Oxygen is used to resuscitate babies who need it, but unfortunately there is disagreement&#xD;
      about the best oxygen concentration to use. Oxygen concentration is important because both&#xD;
      too much and too little oxygen can cause brain injury. This research aims to fill this&#xD;
      knowledge gap by participating in an international clinical trial to compare the effects of&#xD;
      resuscitating babies less than 29 weeks' gestational age with either a low oxygen&#xD;
      concentration or a high oxygen concentration. The oxygen concentrations have been selected&#xD;
      using the best available knowledge.&#xD;
&#xD;
      This will be a cluster randomized trial where each participating hospital will be randomized&#xD;
      to either 30 or 60 percent oxygen for the recruitment of 30 infants, and afterwards&#xD;
      randomized to the other group for the recruitment of another 30 infants. After the trial, the&#xD;
      investigator will determine whether the babies resuscitated with low oxygen or those&#xD;
      resuscitated with high oxygen have better survival and long-term health outcomes. This&#xD;
      research fills a critical knowledge gap in the care of extremely preterm babies and will&#xD;
      impact their survival both here in Canada and internationally.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Purpose: Over the last 10 years, recommendations regarding the ideal level of oxygen for&#xD;
      resuscitation in preterm infants have changed from 100 percent, down to low levels of oxygen&#xD;
      (&lt;30 percent), up to moderate concentration (30-65 percent). In addition, in 2010, oxygen&#xD;
      saturation targeting was recommended as standard of care and this contributed to a change in&#xD;
      clinical practice as clinicians were more likely and comfortable to start resuscitation at&#xD;
      either 21percent (room air) or titrated levels of oxygen such as 30-40 percent. When the&#xD;
      guidelines were again revised in 2015, the International Liaison Committee on Resuscitation&#xD;
      (ILCOR) acknowledged that a critical knowledge gap continued to exist for the resuscitation&#xD;
      of the preterm infants &lt;37 weeks, highlighting the need to provide more concrete guidelines.&#xD;
      This leaves clinicians in a challenging position. Despite the advances that have been&#xD;
      achieved in perinatal and neonatal care, neonates are still vulnerable to the consequences of&#xD;
      the oxidative effects from hyperoxia as well as the deleterious effects from hypoxia. A&#xD;
      large, multi-centre international trial of sufficient sample size that is powered to look at&#xD;
      safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to&#xD;
      provide the necessary evidenced to guide clinical practice with confidence.&#xD;
&#xD;
      Hypothesis: the null hypothesis for this study is that the incidence of mortality or abnormal&#xD;
      neurodevelopmental outcomes at 18-24 months corrected age will be no different by using&#xD;
      either higher initial oxygen concentration of 60 percent compared to using lower initial&#xD;
      oxygen concentration of 30 percent for resuscitation of preterm infants of 23 0/7- 28 6/7&#xD;
      weeks gestation.&#xD;
&#xD;
      Justification:&#xD;
&#xD;
      The use of supplementary oxygen may be crucial, but also potentially detrimental to premature&#xD;
      infants at birth. High oxygen levels may lead to organ damage through oxidative stress, while&#xD;
      low oxygen levels may lead to increased mortality. Excess oxygen exposure during the early&#xD;
      post-birth period is associated with many complications and morbidities of preterm birth.&#xD;
      Preterm infants have lower levels of anti-oxidant pathways consistent with their expected&#xD;
      fetal environment of low oxygen exposure. Excess of oxygen free-radicals in infants&#xD;
      intrinsically deficient in enzymatic antioxidants and non-enzymatic antioxidants may&#xD;
      contribute to these morbidities. Pulmonary oxygen toxicity, through the generation of&#xD;
      reactive oxygen and nitrogen species in excess of antioxidant defenses, is believed to be a&#xD;
      major contributor to the development of bronchopulmonary dysplasia (BPD). Using lower oxygen&#xD;
      concentrations at birth results in decreased oxidative stress markers and a decrease risk of&#xD;
      developing BPD compared to higher oxygen concentrations. Other organs that may be damaged by&#xD;
      such oxidative stress include kidneys, myocardium and the retina.&#xD;
&#xD;
      There is equally growing evidence that using lower oxygen concentrations will lead to lower&#xD;
      oxygen saturation levels and bradycardia, which may lead to increased rates of mortality in&#xD;
      this vulnerable group of infants. An individual patient analysis of clinical trials reported&#xD;
      that 46% of preterm infants resuscitated with initial low oxygen concentration did not reach&#xD;
      SpO2 of 80% at 5 min. This was associated with increased risk of major intraventricular&#xD;
      hemorrhage (IVH), and an almost five times higher risk of death in this vulnerable group of&#xD;
      infants. These data provide a warning note for the use of higher vs. lower initial oxygen&#xD;
      concentration during delivery room resuscitation. As the investigator proceed in determining&#xD;
      a safe range for resuscitation of ELBW/ELGA infants, it is highly likely that the optimum&#xD;
      level of oxygen concentration is between the two extremes of 21 percent and 100 percent.&#xD;
&#xD;
      Objectives: To determine whether initial resuscitation of preterm neonates with 60 percent&#xD;
      versus 30 percent oxygen results in better neurodevelopmental outcomes at 18-24 months.&#xD;
&#xD;
      Research Method/Procedures: This will be a cluster crossover design, unmasked randomized&#xD;
      controlled trial (RCT) comparing two oxygen concentrations at initiation of resuscitation.&#xD;
      Infants will be placed on the resuscitation table with the initial steps of resuscitation&#xD;
      carried out as per standard of care at each centre which usually follows current&#xD;
      resuscitation guidelines. All centres will make every effort to establish adequate lung&#xD;
      expansion using CPAP or positive pressure ventilation as needed. Enrolled infants will have a&#xD;
      pulse oximeter sensor placed on the right arm in the first minute of life. Their&#xD;
      resuscitation will be initiated with an oxygen concentration of 30 or 60 percent depending on&#xD;
      the randomization sequence at the centre at the given time. Infants in the 30 percent group&#xD;
      will remain in 30 percent oxygen until 5 min of age unless the infant's heart rate (HR)&#xD;
      remains 100/min or less and does not show a tendency towards progressive increase before&#xD;
      reaching 5 min of age or infant needs chest compression and/or epinephrine. No alteration in&#xD;
      oxygen concentration will be made for an infant who is responding to resuscitation efforts&#xD;
      with HR progressively increasing as minutes go by. At 5 min of age, the clinical team will&#xD;
      assess oxygen saturation. If the saturation is less than 85 percent, oxygen should be&#xD;
      increased by 10-20 percent every 60 sec to achieve saturations of 85 percent or greater or a&#xD;
      saturation of 90-95 percent at 10 min of age. If saturations are greater than 95 percent at&#xD;
      or before 5 min of age, oxygen should be decreased stepwise (every 60 sec) with an aim to&#xD;
      maintain saturations of 85 percent or greater during 5-10 min of age or 90-95 percent at and&#xD;
      beyond 10 min of age. The procedure for infants in the 60 percent group will be identical.&#xD;
      The intervention duration for the trial will be the first 5 min after birth followed by&#xD;
      initial monitoring/action for the next 5 min where titration in oxygen concentration will be&#xD;
      made to achieve stability making a total of 10 min for study intervention. Titration of&#xD;
      oxygen before 5 min after birth will only be made if the infant remains bradycardic (HR less&#xD;
      than 100) and does not show a tendency towards a sustained increase in HR or if the oxygen&#xD;
      saturation exceeds 95 percent. If the infant does not respond to ventilation with increasing&#xD;
      HR in the first 5 min after birth, steps to ensure effective ventilation should be done&#xD;
      before oxygen is titrated.&#xD;
&#xD;
      Plan for Data Analysis: Generalized linear mixed model with binary outcome and maximum&#xD;
      likelihood estimate will be used to evaluate the effect of an oxygen concentration on the&#xD;
      primary outcome (as a composite between 18 and 24 months corrected age of all-cause mortality&#xD;
      or the presence of a major neurodevelopmental outcome). To account for cluster crossover&#xD;
      design of the study, effects of centers (clusters) and a period (oxygen concentration) within&#xD;
      center will be considered random, and effects of a period (oxygen concentration) will be&#xD;
      entered as a fixed effect. This hierarchical model allows for the correlation of patients&#xD;
      within periods and within clusters. The model will be adjusted for gestational age and&#xD;
      whether or not infant required mask ventilation as potential confounding variables. Similar&#xD;
      generalized linear mixed models will be performed to evaluate the effect of group on&#xD;
      secondary outcomes. In addition, three subgroup analysis will be performed: i) Gestational&#xD;
      age will be categorized into 2 categories: 23+0- 25+6 vs. 26+0-28+6 weeks; ii) Breathing&#xD;
      support will be categorized by infants supported only with CPAP vs. received mask&#xD;
      ventilation; iii) Sex/Gender will be categorized into 2 categories: female vs. male. For&#xD;
      subgroup analysis baseline characteristics will be compared using linear and generalized&#xD;
      linear mixed models. Sensitivity analysis will be performed to analyze the missing data;&#xD;
      however, a very low number of missing values are expected due to the design of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 27, 2022</start_date>
  <completion_date type="Anticipated">December 30, 2027</completion_date>
  <primary_completion_date type="Anticipated">September 30, 2027</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>Prevention</primary_purpose>
    <masking>Single (Outcomes Assessor)</masking>
    <masking_description>Outcome assessed will be unaware of group allocation</masking_description>
  </study_design_info>
  <primary_outcome>
    <measure>Neurodevelopmental outcome at 18-24 months</measure>
    <time_frame>18-24 months of age</time_frame>
    <description>At 18-24 months corrected age, the infants will be assessed using the Bayley Scales of Infant Development-3rd edition (Bayley-III). A score 85-114 will be classified as normal, and scores &lt;70 (2 SD below the mean of 100) will define severe cognitive delay.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Healing loss</measure>
    <time_frame>18-24 months of age</time_frame>
    <description>Audiometry will be performed to assess the presence or absence of severe hearing loss.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Blindness</measure>
    <time_frame>18-24 months of age</time_frame>
    <description>Blindness will be defined as a corrected visual acuity of &lt;20/200.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Number of intubation in the delivery room</measure>
    <time_frame>first 15 minutes after birth</time_frame>
    <description>Number of infants intubated in the delivery room</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death in the Neonatal Intensive Care Unit</measure>
    <time_frame>During admission in the Neonatal Intensive Care Unit; no exact time frame can be given as this can happen after 1 day, 1 week, 1 months or up to 2-3 month. again deepening on gestational age and policy for transferring infants at participating centres.</time_frame>
    <description>Number of infants died after admission in the Neonatal Intensive Care Unit</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death in the delivery room</measure>
    <time_frame>During resuscitation in the delivery room; for lay people: this time frame might be 10min or 1-3 hours, depending on the approaching each participating hospital</time_frame>
    <description>Number of infants died in the delivery room during resuscitation</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">1200</enrollment>
  <condition>Premature Infant</condition>
  <condition>Respiratory Distress Syndrome in Premature Infant</condition>
  <condition>Neurodevelopmental Outcome</condition>
  <arm_group>
    <arm_group_label>30% group</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Infants in the 30% oxygen group will remain in 30% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is &lt;85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.&#xD;
Intervention: Infants randomized to the 30% oxygen group will receive 30% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>60% group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Infants in the 60% oxygen group will remain in 60% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is &lt;85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.&#xD;
Intervention: Infants randomized to the 60% oxygen group will receive 60% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>30% oxygen group</intervention_name>
    <description>Infants in the 30% oxygen group will remain in 30% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is &lt;85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.&#xD;
Intervention: Infants randomized to the 30% oxygen group will receive 30% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.</description>
    <arm_group_label>30% group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>60% oxygen group</intervention_name>
    <description>Infants in the 60% oxygen group will remain in 60% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is &lt;85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.&#xD;
Intervention: Infants randomized to the 60% oxygen group will receive 60% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.</description>
    <arm_group_label>60% group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Infants born at 23 0/7 weeks to 28 6/7 weeks' gestational age who will receive full&#xD;
             resuscitation and are without major congenital abnormalities&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Infants who are outborn - initial resuscitation not performed at the study centre&#xD;
&#xD;
          -  Infants who are not born within the eligible gestational age range- this trial is&#xD;
             specific to preterm infants&#xD;
&#xD;
          -  Infants who are born with a major congenital abnormality- congenital abnormalities may&#xD;
             affect oxygenation or neurodevelopmental outcomes&#xD;
&#xD;
          -  Infants who will not receive full resuscitation at birth- these infants will not&#xD;
             receive resuscitation&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>0 Minutes</minimum_age>
    <maximum_age>10 Minutes</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Georg Schmolzer, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Alberta</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Georg Schmolzer, MD, PhD</last_name>
    <phone>7807354647</phone>
    <email>schmolze@ualberta.ca</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Barb Kamstra, RN</last_name>
    <phone>7807354647</phone>
    <email>Barb Kamstra &lt;Barbara.Kamstra@albertahealthservices.ca&gt;</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Foothills Hospital</name>
      <address>
        <city>Calgary</city>
        <state>Alberta</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amuchou Soraisham</last_name>
      <email>Amuchou.Soraisham@albertahealthservices.ca</email>
    </contact>
    <investigator>
      <last_name>Amuchou Soraisham</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Royal Alexandra Hospital</name>
      <address>
        <city>Edmonton</city>
        <state>Alberta</state>
        <zip>T5H 3V9</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Georg SCHMOLZER</last_name>
      <phone>7807354660</phone>
      <email>georg.schmoelzer@me.com</email>
    </contact>
    <investigator>
      <last_name>Georg Schmolzer</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Brenda Law</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Health Sciences</name>
      <address>
        <city>Winnipeg</city>
        <state>Manitoba</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Ayman Sheta</last_name>
      <email>asheta@hsc.mb.ca</email>
    </contact>
    <investigator>
      <last_name>Ayman Sheta</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Newborn Health - IWK Health Centre</name>
      <address>
        <city>Halifax</city>
        <state>Nova Scotia</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Walid EL-NAGGAR</last_name>
      <email>Walid.El-Naggar@iwk.nshealth.ca</email>
    </contact>
    <investigator>
      <last_name>Walid EL-NAGGAR</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Neonatal Intensive Care Unit - Hamilton Health Sciences</name>
      <address>
        <city>Hamilton</city>
        <state>Ontario</state>
        <zip>L8S 4K1</zip>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Amit MUKERJI</last_name>
      <email>mukerji@mcmaster.ca</email>
    </contact>
    <investigator>
      <last_name>Amit MUKERJI</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Neonatal Intensive Care Unit - Mount Sinai Hospital</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Prakesh SHAH</last_name>
      <email>Prakeshkumar.Shah@sinaihealth.ca</email>
    </contact>
    <investigator>
      <last_name>Prakesh SHAH</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Sunnybrook Health Sciences Centre</name>
      <address>
        <city>Toronto</city>
        <state>Ontario</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Elizabeth Asztalos</last_name>
      <email>elizabeth.asztalos@sunnybrook.ca</email>
    </contact>
    <contact_backup>
      <last_name>Afsheen Ayaz</last_name>
      <email>afsheen.ayaz@sunnybrook.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Elizabeth Asztalos</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>McGill Univeristy</name>
      <address>
        <city>Montréal</city>
        <state>Quebec</state>
        <country>Canada</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marc Beltempo</last_name>
      <email>marc.beltempo@mcgill.ca</email>
    </contact>
    <contact_backup>
      <last_name>Francois Olivier</last_name>
      <email>francois.olivier@mcgill.ca</email>
    </contact_backup>
    <investigator>
      <last_name>Marc Beltempo</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Francois Olivier</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location_countries>
    <country>Canada</country>
  </location_countries>
  <verification_date>July 2023</verification_date>
  <study_first_submitted>January 25, 2019</study_first_submitted>
  <study_first_submitted_qc>January 30, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">January 31, 2019</study_first_posted>
  <last_update_submitted>July 20, 2023</last_update_submitted>
  <last_update_submitted_qc>July 20, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">July 21, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor</responsible_party_type>
  </responsible_party>
  <keyword>Delivery Room</keyword>
  <keyword>Resuscitation</keyword>
  <keyword>Premature Infant</keyword>
  <keyword>Oxygen</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Distress Syndrome</mesh_term>
    <mesh_term>Respiratory Distress Syndrome, Newborn</mesh_term>
    <mesh_term>Premature Birth</mesh_term>
    <mesh_term>Birth Weight</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>The data will be included in a prospectively planned IPD, which is called PROMOTION Other researchers can email the PI for more information at georg.schmoelzer@me.com</ipd_description>
    <ipd_info_type>Study Protocol</ipd_info_type>
    <ipd_info_type>Statistical Analysis Plan (SAP)</ipd_info_type>
    <ipd_info_type>Informed Consent Form (ICF)</ipd_info_type>
    <ipd_info_type>Clinical Study Report (CSR)</ipd_info_type>
    <ipd_info_type>Analytic Code</ipd_info_type>
    <ipd_time_frame>after the publication of the primary results indefinitely</ipd_time_frame>
    <ipd_access_criteria>Other researchers can email the PI for more information at georg.schmoelzer@me.com</ipd_access_criteria>
  </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/NCT03825835
org study id: Pro00083931
nct id: NCT03825835
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Preterm birth, or birth before 37 weeks' gestation, is increasingly common, occurring in 8
      percent of pregnancies in Canada. Preterm birth is associated with many health complications,
      particularly when the birth happens before 29 weeks' gestation. At this gestational age, the
      lungs are not fully developed and it is not uncommon for infants to have problems breathing
      at the time of birth. One complication that can arise is when an infant stops breathing and
      needs to be resuscitated. When preterm babies need to be resuscitated doctors must take
      special care because of the small infant size and the immaturity of the brain and lungs.
      Oxygen is used to resuscitate babies who need it, but unfortunately there is disagreement
      about the best oxygen concentration to use. Oxygen concentration is important because both
      too much and too little oxygen can cause brain injury. This research aims to fill this
      knowledge gap by participating in an international clinical trial to compare the effects of
      resuscitating babies less than 29 weeks' gestational age with either a low oxygen
      concentration or a high oxygen concentration. The oxygen concentrations have been selected
      using the best available knowledge.

      This will be a cluster randomized trial where each participating hospital will be randomized
      to either 30 or 60 percent oxygen for the recruitment of 30 infants, and afterwards
      randomized to the other group for the recruitment of another 30 infants. After the trial, the
      investigator will determine whether the babies resuscitated with low oxygen or those
      resuscitated with high oxygen have better survival and long-term health outcomes. This
      research fills a critical knowledge gap in the care of extremely preterm babies and will
      impact their survival both here in Canada and internationally.
Purpose: Over the last 10 years, recommendations regarding the ideal level of oxygen for
      resuscitation in preterm infants have changed from 100 percent, down to low levels of oxygen
      (<30 percent), up to moderate concentration (30-65 percent). In addition, in 2010, oxygen
      saturation targeting was recommended as standard of care and this contributed to a change in
      clinical practice as clinicians were more likely and comfortable to start resuscitation at
      either 21percent (room air) or titrated levels of oxygen such as 30-40 percent. When the
      guidelines were again revised in 2015, the International Liaison Committee on Resuscitation
      (ILCOR) acknowledged that a critical knowledge gap continued to exist for the resuscitation
      of the preterm infants <37 weeks, highlighting the need to provide more concrete guidelines.
      This leaves clinicians in a challenging position. Despite the advances that have been
      achieved in perinatal and neonatal care, neonates are still vulnerable to the consequences of
      the oxidative effects from hyperoxia as well as the deleterious effects from hypoxia. A
      large, multi-centre international trial of sufficient sample size that is powered to look at
      safety outcomes such as mortality and adverse neurodevelopmental outcomes is required to
      provide the necessary evidenced to guide clinical practice with confidence.

      Hypothesis: the null hypothesis for this study is that the incidence of mortality or abnormal
      neurodevelopmental outcomes at 18-24 months corrected age will be no different by using
      either higher initial oxygen concentration of 60 percent compared to using lower initial
      oxygen concentration of 30 percent for resuscitation of preterm infants of 23 0/7- 28 6/7
      weeks gestation.

      Justification:

      The use of supplementary oxygen may be crucial, but also potentially detrimental to premature
      infants at birth. High oxygen levels may lead to organ damage through oxidative stress, while
      low oxygen levels may lead to increased mortality. Excess oxygen exposure during the early
      post-birth period is associated with many complications and morbidities of preterm birth.
      Preterm infants have lower levels of anti-oxidant pathways consistent with their expected
      fetal environment of low oxygen exposure. Excess of oxygen free-radicals in infants
      intrinsically deficient in enzymatic antioxidants and non-enzymatic antioxidants may
      contribute to these morbidities. Pulmonary oxygen toxicity, through the generation of
      reactive oxygen and nitrogen species in excess of antioxidant defenses, is believed to be a
      major contributor to the development of bronchopulmonary dysplasia (BPD). Using lower oxygen
      concentrations at birth results in decreased oxidative stress markers and a decrease risk of
      developing BPD compared to higher oxygen concentrations. Other organs that may be damaged by
      such oxidative stress include kidneys, myocardium and the retina.

      There is equally growing evidence that using lower oxygen concentrations will lead to lower
      oxygen saturation levels and bradycardia, which may lead to increased rates of mortality in
      this vulnerable group of infants. An individual patient analysis of clinical trials reported
      that 46% of preterm infants resuscitated with initial low oxygen concentration did not reach
      SpO2 of 80% at 5 min. This was associated with increased risk of major intraventricular
      hemorrhage (IVH), and an almost five times higher risk of death in this vulnerable group of
      infants. These data provide a warning note for the use of higher vs. lower initial oxygen
      concentration during delivery room resuscitation. As the investigator proceed in determining
      a safe range for resuscitation of ELBW/ELGA infants, it is highly likely that the optimum
      level of oxygen concentration is between the two extremes of 21 percent and 100 percent.

      Objectives: To determine whether initial resuscitation of preterm neonates with 60 percent
      versus 30 percent oxygen results in better neurodevelopmental outcomes at 18-24 months.

      Research Method/Procedures: This will be a cluster crossover design, unmasked randomized
      controlled trial (RCT) comparing two oxygen concentrations at initiation of resuscitation.
      Infants will be placed on the resuscitation table with the initial steps of resuscitation
      carried out as per standard of care at each centre which usually follows current
      resuscitation guidelines. All centres will make every effort to establish adequate lung
      expansion using CPAP or positive pressure ventilation as needed. Enrolled infants will have a
      pulse oximeter sensor placed on the right arm in the first minute of life. Their
      resuscitation will be initiated with an oxygen concentration of 30 or 60 percent depending on
      the randomization sequence at the centre at the given time. Infants in the 30 percent group
      will remain in 30 percent oxygen until 5 min of age unless the infant's heart rate (HR)
      remains 100/min or less and does not show a tendency towards progressive increase before
      reaching 5 min of age or infant needs chest compression and/or epinephrine. No alteration in
      oxygen concentration will be made for an infant who is responding to resuscitation efforts
      with HR progressively increasing as minutes go by. At 5 min of age, the clinical team will
      assess oxygen saturation. If the saturation is less than 85 percent, oxygen should be
      increased by 10-20 percent every 60 sec to achieve saturations of 85 percent or greater or a
      saturation of 90-95 percent at 10 min of age. If saturations are greater than 95 percent at
      or before 5 min of age, oxygen should be decreased stepwise (every 60 sec) with an aim to
      maintain saturations of 85 percent or greater during 5-10 min of age or 90-95 percent at and
      beyond 10 min of age. The procedure for infants in the 60 percent group will be identical.
      The intervention duration for the trial will be the first 5 min after birth followed by
      initial monitoring/action for the next 5 min where titration in oxygen concentration will be
      made to achieve stability making a total of 10 min for study intervention. Titration of
      oxygen before 5 min after birth will only be made if the infant remains bradycardic (HR less
      than 100) and does not show a tendency towards a sustained increase in HR or if the oxygen
      saturation exceeds 95 percent. If the infant does not respond to ventilation with increasing
      HR in the first 5 min after birth, steps to ensure effective ventilation should be done
      before oxygen is titrated.

      Plan for Data Analysis: Generalized linear mixed model with binary outcome and maximum
      likelihood estimate will be used to evaluate the effect of an oxygen concentration on the
      primary outcome (as a composite between 18 and 24 months corrected age of all-cause mortality
      or the presence of a major neurodevelopmental outcome). To account for cluster crossover
      design of the study, effects of centers (clusters) and a period (oxygen concentration) within
      center will be considered random, and effects of a period (oxygen concentration) will be
      entered as a fixed effect. This hierarchical model allows for the correlation of patients
      within periods and within clusters. The model will be adjusted for gestational age and
      whether or not infant required mask ventilation as potential confounding variables. Similar
      generalized linear mixed models will be performed to evaluate the effect of group on
      secondary outcomes. In addition, three subgroup analysis will be performed: i) Gestational
      age will be categorized into 2 categories: 23+0- 25+6 vs. 26+0-28+6 weeks; ii) Breathing
      support will be categorized by infants supported only with CPAP vs. received mask
      ventilation; iii) Sex/Gender will be categorized into 2 categories: female vs. male. For
      subgroup analysis baseline characteristics will be compared using linear and generalized
      linear mixed models. Sensitivity analysis will be performed to analyze the missing data;
      however, a very low number of missing values are expected due to the design of the study.
allocation: Randomized
intervention model: Parallel Assignment
primary purpose: Prevention
masking: Single (Outcomes Assessor)
masking description: Outcome assessed will be unaware of group allocation
measure: Neurodevelopmental outcome at 18-24 months
time frame: 18-24 months of age
description: At 18-24 months corrected age, the infants will be assessed using the Bayley Scales of Infant Development-3rd edition (Bayley-III). A score 85-114 will be classified as normal, and scores <70 (2 SD below the mean of 100) will define severe cognitive delay.
measure: Healing loss
time frame: 18-24 months of age
description: Audiometry will be performed to assess the presence or absence of severe hearing loss.
measure: Blindness
time frame: 18-24 months of age
description: Blindness will be defined as a corrected visual acuity of <20/200.
measure: Number of intubation in the delivery room
time frame: first 15 minutes after birth
description: Number of infants intubated in the delivery room
measure: Death in the Neonatal Intensive Care Unit
time frame: During admission in the Neonatal Intensive Care Unit; no exact time frame can be given as this can happen after 1 day, 1 week, 1 months or up to 2-3 month. again deepening on gestational age and policy for transferring infants at participating centres.
description: Number of infants died after admission in the Neonatal Intensive Care Unit
measure: Death in the delivery room
time frame: During resuscitation in the delivery room; for lay people: this time frame might be 10min or 1-3 hours, depending on the approaching each participating hospital
description: Number of infants died in the delivery room during resuscitation
arm group label: 30% group
arm group type: Active Comparator
description: Infants in the 30% oxygen group will remain in 30% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is <85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.
Intervention: Infants randomized to the 30% oxygen group will receive 30% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.
arm group label: 60% group
arm group type: Experimental
description: Infants in the 60% oxygen group will remain in 60% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is <85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.
Intervention: Infants randomized to the 60% oxygen group will receive 60% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.
intervention type: Drug
intervention name: 30% oxygen group
description: Infants in the 30% oxygen group will remain in 30% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is <85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.
Intervention: Infants randomized to the 30% oxygen group will receive 30% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.
arm group label: 30% group
intervention type: Drug
intervention name: 60% oxygen group
description: Infants in the 60% oxygen group will remain in 60% oxygen (O2) until 5 min of age. At 5 min of age, the clinical team will assess oxygen saturation (SpO2). If SpO2 is <85%, O2 should be increased by 10-20% every 60 sec to achieve SpO2 of 85% or greater or a SpO2 of 90-95% at 10 min of age. If SpO2 are greater than 95% at or before 5 min of age, O2 should be decreased stepwise (every 60 sec) with an aim to maintain SpO2 of 85% or greater during 5-10 min of age or 90-95% at and beyond 10 min of age.
Intervention: Infants randomized to the 60% oxygen group will receive 60% oxygen at birth for the first 5 minutes. At 5 minutes oxygen can be adjusted as needed.
arm group label: 60% group
criteria: 
gender: All
minimum age: 0 Minutes
maximum age: 10 Minutes
healthy volunteers: No
last name: Georg Schmolzer, MD, PhD
role: Principal Investigator
affiliation: University of Alberta
last name: Georg Schmolzer, MD, PhD
phone: 7807354647
email: schmolze@ualberta.ca
last name: Barb Kamstra, RN
phone: 7807354647
email: Barb Kamstra <Barbara.Kamstra@albertahealthservices.ca>
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
facility: 
status: Not yet recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
facility: 
status: Recruiting
contact: 
contact backup: 
investigator: 
investigator: 
country: Canada
responsible party type: Sponsor
mesh term: Respiratory Distress Syndrome
mesh term: Respiratory Distress Syndrome, Newborn
mesh term: Premature Birth
mesh term: Birth Weight
sharing ipd: Yes
ipd description: The data will be included in a prospectively planned IPD, which is called PROMOTION Other researchers can email the PI for more information at georg.schmoelzer@me.com
ipd info type: Study Protocol
ipd info type: Statistical Analysis Plan (SAP)
ipd info type: Informed Consent Form (ICF)
ipd info type: Clinical Study Report (CSR)
ipd info type: Analytic Code
ipd time frame: after the publication of the primary results indefinitely
ipd access criteria: Other researchers can email the PI for more information at georg.schmoelzer@me.com