<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/NCT04430790</url>
  </required_header>
  <id_info>
    <org_study_id>NL72125.078.19</org_study_id>
    <secondary_id>80-84800-9843009</secondary_id>
    <secondary_id>2019-003666-41</secondary_id>
    <nct_id>NCT04430790</nct_id>
  </id_info>
  <brief_title>Doxapram Therapy in Preterm Infants (DOXA Trial)</brief_title>
  <official_title>Doxapram Versus Placebo in Preterm Newborns: An International Double Blinded Multicenter Randomized Controlled Trial</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Erasmus Medical Center</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Academisch Medisch Centrum - Universiteit van Amsterdam (AMC-UvA)</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Nederlands Neonataal Netwerk (N3), the Netherlands</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Universitaire Ziekenhuizen KU Leuven</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Erasmus Medical Center</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 infants often suffer from apnea of prematurity (AOP; a cessation of breathing) due to&#xD;
      immaturity of the respiratory system. AOP can lead to oxygen shortage and a low heart rate&#xD;
      which might harm the development of the newborn, especially the central nervous system. In&#xD;
      order to prevent oxygen shortage, infants are treated with non-invasive respiratory support&#xD;
      and caffeine. Despite these treatments, many preterm newborns still suffer from AOP and need&#xD;
      invasive mechanical ventilation. Although this will result in complete resolution of AOP,&#xD;
      invasive mechanical ventilation has the disadvantage of being a major risk of chronic lung&#xD;
      disease and impaired neurodevelopmental outcome. Restrictive invasive ventilation is&#xD;
      therefore advocated nowadays in preterm infants. Doxapram is a respiratory stimulant that has&#xD;
      been administered off-label to treat AOP. Doxapram, as add-on treatment, seems to be&#xD;
      effective in treating AOP and to prevent invasive mechanical ventilation. It is unclear if a&#xD;
      preterm infant benefit from doxapram treatment on the longer term. This study compares&#xD;
      doxapram to placebo and hypothesizes that doxapram will protect preterm infants from both&#xD;
      invasive ventilation (and related lung disease) and AOP related oxygen shortage (and related&#xD;
      impaired brain development).&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      The main objective of the trial is to investigate if doxapram is safe and effective in&#xD;
      reducing the composite outcome of death and neurodevelopmental impairment/severe disability&#xD;
      at 2 years corrected age as compared to placebo. This multicenter double blinded randomized&#xD;
      placebo-controlled superiority trial will be conducted in multiple neonatal intensive care&#xD;
      units in the Netherlands and Belgium, including 8 years follow-up. After written&#xD;
      informed-consent the patients will be randomized into the doxapram treatment group or the&#xD;
      placebo treatment group. Randomization will be stratified based on center and gestational age&#xD;
      &lt; or &gt;= 26 weeks.&#xD;
&#xD;
      The participating departments include Dutch and Belgian Neonatal Intensive care units. The&#xD;
      units include both academic and non-academic level III and IV units that are specialized in&#xD;
      the care for critically ill and preterm born infants. Postnatal ages of patients at doxapram&#xD;
      start vary from directly after birth up to months for the most-preterm born infants.&#xD;
&#xD;
      Blinded continuous doxapram or placebo (glucose 5%) will be infused as long as needed.&#xD;
      Therapy is down titrated or stopped based on the patients' condition. If endotracheal&#xD;
      intubation is needed study drug is stopped. After extubation study drug may be restarted.&#xD;
      Switch to gastro-enteral administration is allowed if no iv-access is needed for other&#xD;
      reasons. Next to study drug infusion, there will be no other study-related interventions. All&#xD;
      outcome variables are already collected as standard of care. In a subset of patients doxapram&#xD;
      plasma levels will be determined to validate the doxapram pharmacokinetic (PK) model. Blood&#xD;
      will only be collected during routine blood sampling, with a maximum amount of 0.6 ml.&#xD;
      Economic and cost-effectiveness evaluation will be performed. The national protocol for&#xD;
      preterm birth advices follow-up at 2, 5.5 and 8 years respectively, as in the current study.&#xD;
      Additional questionnaires will be used to collect data on the quality of life of patients and&#xD;
      their parents.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">June 15, 2020</start_date>
  <completion_date type="Anticipated">May 1, 2030</completion_date>
  <primary_completion_date type="Anticipated">May 1, 2024</primary_completion_date>
  <phase>Phase 3</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>
    <intervention_model_description>Doxapram versus placebo</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Death or severe disability</measure>
    <time_frame>2 years corrected age</time_frame>
    <description>Disability will be defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness. Cognitive delay will be defined as a Mental Development Index score of less than 85 on the Bayley Scales of Infant and Toddler Development, Bayley Score of Infant Development (BSID) III scores. Cerebral palsy will be diagnosed if the child had a non-progressive motor impairment characterized by abnormal muscle tone and decreased range or control of movements. The level of gross motor function will be determined with the use of the Gross Motor Function Classification System. Audiometry will be performed to determine the presence or absence of hearing loss. Blindness will be defined as a corrected visual acuity less than 20/200</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Broncho pulmonary dysplasia</measure>
    <time_frame>36 weeks post menstrual age</time_frame>
    <description>Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Death</measure>
    <time_frame>until 36 weeks post menstrual age and until hospital discharge</time_frame>
    <description>Death at 36 weeks post menstrual age and hospital mortality</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Admission period</measure>
    <time_frame>through study completion and until discharge home, average 3 months</time_frame>
    <description>Length of stay at the intensive care, length of stay in hospital</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Endotracheal intubations</measure>
    <time_frame>Day 3, 7, 14, and 21 after start of study medication</time_frame>
    <description>Incidence of endotracheal intubations</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Oxygenation days and complications</measure>
    <time_frame>During first hospital admittance and through study completion, average of 3 months</time_frame>
    <description>Number of days on invasive ventilation, number of days on ventilatory support (non-invasive ventilation, CPAP, humidified high flow, low flow), number of days with supplemental oxygen, respiratory complications (airleak, pneumonia, etc), use of (rescue) corticosteroids for respiratory reasons.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Gastro-intestinal outcome measures</measure>
    <time_frame>During first hospital admittance and until 36 weeks post menstrual age</time_frame>
    <description>solitary intestinal perforation, necrotizing enterocolitis &gt; stage 2 according to Bell, feeding problems with need for parental feeding (days with parental feeding after inclusion), body weight (gain, length), head circumference</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Neurological outcome measures</measure>
    <time_frame>During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months</time_frame>
    <description>Intraventricular hemorhage(IVH) (all grades, grade III-IV, venous infarction), clinical seizures, periventricular leucomalacia (PVL) &gt; gr 1)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Complications during neonatal period</measure>
    <time_frame>During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months</time_frame>
    <description>Incidence of late onset sepsis (culture proven or clinical suspected) and meningitis after inclusion, need for inotropes/circulatory support</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Retinopathy of prematurity</measure>
    <time_frame>During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months</time_frame>
    <description>Grade of retinopathy (including plus disease and need for therapy)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Hearing</measure>
    <time_frame>At term equivalent age, 37-42 weeks postmenstrual age, average 3 months</time_frame>
    <description>Hearing test</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Additional long term outcomes</measure>
    <time_frame>2 years corrected age</time_frame>
    <description>Readmissions since first discharge home, weight/length/head circumference, behavioral problems (Child Behavior Checklist)</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Parent reported outcome</measure>
    <time_frame>2 years corrected age</time_frame>
    <description>Parent reported outcome with the PARCA-R (Parent Report of Children's Abilities-Revised) questionnaire (expected mean standardised scores 100 (SD 15), higher score is better outcome)</description>
  </secondary_outcome>
  <number_of_arms>2</number_of_arms>
  <enrollment type="Anticipated">398</enrollment>
  <condition>Apnea of Prematurity</condition>
  <condition>Respiratory Insufficiency</condition>
  <arm_group>
    <arm_group_label>Doxapram</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Blinded doxapram (2mg/ml, in glucose 5%) loading dose of 2.0 to 2.5 mg/kg administered in 5 to 10 minutes, followed by a continuous infusion of 0.5 - 1.0 mg/kg/hr ('www.kinderformularium.nl') as long as needed. Therapy is down titrated or stopped based on the patients' respiratory condition. If endotracheal intubation is needed study drug is stopped. After extubation study drug may be restarted. Switch to gastro-enteral administration is allowed if no iv-access is needed for other reasons.</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Placebo</arm_group_label>
    <arm_group_type>Placebo Comparator</arm_group_type>
    <description>Placebo (glucose 5%) will also be administered with a loading dose and continuous infusion (in equal amounts of fluid as in experimental arm) by intravenous or gastro-intestinal infusion. The treatment protocol will be equal to the protocol in the doxapram arm.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Doxapram</intervention_name>
    <description>Loading dose and continuous doxapram infusion.</description>
    <arm_group_label>Doxapram</arm_group_label>
    <other_name>Dopram</other_name>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Placebo</intervention_name>
    <description>Loading dose and continuous placebo infusion.</description>
    <arm_group_label>Placebo</arm_group_label>
    <other_name>Placebo (for Doxapram)</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Admitted to the neonatal intensvie care unit (NICU) of one of the participating&#xD;
             centres&#xD;
&#xD;
          -  Written informed consent of both parents or legal representatives&#xD;
&#xD;
          -  Gestational age at birth &lt; 29 weeks&#xD;
&#xD;
          -  Caffeine therapy, adequately dosed (see also under co-medication)&#xD;
&#xD;
          -  Optimal Non-invasively supported with nasal Continuous Positive Airway Pressure (CPAP)&#xD;
             or ventilation ((S)NIPPV, NIV-NAVA, BIPAP/Duopap, SIPAP)&#xD;
&#xD;
          -  Apnea that require a medical intervention as judged by the attending physician&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Previous use of open label doxapram&#xD;
&#xD;
          -  Use of theophylline (to replace doxapram)&#xD;
&#xD;
          -  Chromosomal defects (e.g. trisomy 13, 18, or 21)&#xD;
&#xD;
          -  Major congenital malformations that: compromise lung function (e.g. surfactant protein&#xD;
             deficiencies, congenital diaphragmatic hernia); result in chronic ventilation (e.g.&#xD;
             Pierre Robin sequence); increase the risk of death or adverse neurodevelopmental&#xD;
             outcome (congenital cerebral malformations, chromosomal abnormalities);&#xD;
&#xD;
          -  Palliative care or treatment limitations because of high risk of impaired outcome.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>23 Weeks</minimum_age>
    <maximum_age>29 Weeks</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Anne Smits, MD, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Universitair Ziekenhuis Leuven</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Karel Allegaert, MD, PhD</last_name>
    <role>Study Director</role>
    <affiliation>Universitair Ziekenhuis Leuven</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Sinno HP Simons, MD, PhD</last_name>
    <phone>+31641376695</phone>
    <email>s.simons@erasmusmc.nl</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Jeroen J Hutten, MD, PhD</last_name>
    <email>g.j.hutten@amsterdamumc.nl</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>St Luc Louvain</name>
      <address>
        <city>Brussels</city>
        <state>Avenaue Hippocrate 10</state>
        <zip>1200</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Katherine Carkeek</last_name>
      <email>katherine.carkeek@saintluc.uclouvain.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Delta Hospital Brussels</name>
      <address>
        <city>Brussels</city>
        <state>Brussels Hoofdstedelijk Gewest</state>
        <zip>1160</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Dorottya Kelen</last_name>
      <email>Dorottya.Kelen@erasme.ulb.ac.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Brussels</name>
      <address>
        <city>Jette</city>
        <state>Brussels Hoofdstedelijk Gewest</state>
        <zip>1090</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ingrid van limberghen</last_name>
      <email>ingrid.vanlimberghen@uzbrussel.be</email>
    </contact>
    <investigator>
      <last_name>Julie Lefevere</last_name>
      <role>Principal Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>Grand Hospital de Charleroi</name>
      <address>
        <city>Charleroi</city>
        <state>Henegouwen</state>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Vincent Cassart</last_name>
      <email>Vincent.cassart@ghdc.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Clinique Saint-Vincent Liege</name>
      <address>
        <city>Liège</city>
        <state>Liege</state>
        <zip>4000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Suspended</status>
  </location>
  <location>
    <facility>
      <name>Academisch Ziekenhuis Sint-Jan</name>
      <address>
        <city>Brugge</city>
        <state>West-Vlaanderen</state>
        <zip>8000</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Luc Cornette</last_name>
      <email>Luc.Cornette@azsintjan.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Sint Augustinus Hospital Antwerp</name>
      <address>
        <city>Antwerp</city>
        <zip>2610</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Katleen Plaskie</last_name>
      <email>Katleen.Plaskie@gza.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospital Antwerp</name>
      <address>
        <city>Antwerp</city>
        <zip>2650</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>michiel Voeten</last_name>
      <email>michiel.voeten@uza.be</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Chirec-Delta Hospital</name>
      <address>
        <city>Brussels</city>
        <zip>1160</zip>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Not yet recruiting</status>
    <contact>
      <last_name>Olivia Williams</last_name>
      <email>brussels.doc@gmail.com</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Hospitals Leuven</name>
      <address>
        <city>Leuven</city>
        <country>Belgium</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Anne Smits</last_name>
      <email>anne.smits@uzleuven.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Radboudumc Amalia Children's Hospital Nijmegen</name>
      <address>
        <city>Nijmegen</city>
        <state>Gelderland</state>
        <zip>6525 GA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Willem de Boode</last_name>
      <email>Willem.deBoode@radboudumc.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Maastricht University Medical Center</name>
      <address>
        <city>Maastricht</city>
        <state>Limburg</state>
        <zip>6229 HX</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Matthias Hutten</last_name>
      <email>matthias.hutten@mumc.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Maxima Medical Center Veldhoven</name>
      <address>
        <city>Veldhoven</city>
        <state>Noord-Brabant</state>
        <zip>5504 DB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Ellen de Kort</last_name>
      <email>e.dekort@mmc.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Amsterdam University Medical Center</name>
      <address>
        <city>Amsterdam</city>
        <state>Noord-Holland</state>
        <zip>1105 AZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Jeroen Hutten</last_name>
      <email>g.j.hutten@amsterdam.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Isala Clinics Zwolle</name>
      <address>
        <city>Zwolle</city>
        <state>Overijssel</state>
        <zip>8025 AB</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Marieke Hemels</last_name>
      <email>m.a.c.hemels@isala.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Leiden University Medical Center</name>
      <address>
        <city>Leiden</city>
        <state>Zuid-Holland</state>
        <zip>2333 ZA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Arjan te Pas</last_name>
      <email>a.b.te_pas@lumc.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>Erasmus Medical Center - Sophia Children's Hospital</name>
      <address>
        <city>Rotterdam</city>
        <state>Zuid-Holland</state>
        <zip>3015 GD</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Andre Kroon</last_name>
      <email>a.a.kroon@erasmusmc.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>University Medical Center Groningen</name>
      <address>
        <city>Groningen</city>
        <zip>9713 GZ</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Peter Dijk</last_name>
      <email>p.h.dijk@umcg.nl</email>
    </contact>
  </location>
  <location>
    <facility>
      <name>UMC Utrecht - Wilhelmina Kinderziekenhuis</name>
      <address>
        <city>Utrecht</city>
        <zip>3584 EA</zip>
        <country>Netherlands</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Inge Zonnenberg</last_name>
      <email>i.a.zonnenberg-2@umcutrecht.nk</email>
    </contact>
  </location>
  <location_countries>
    <country>Belgium</country>
    <country>Netherlands</country>
  </location_countries>
  <verification_date>June 2022</verification_date>
  <study_first_submitted>January 8, 2020</study_first_submitted>
  <study_first_submitted_qc>June 11, 2020</study_first_submitted_qc>
  <study_first_posted type="Actual">June 12, 2020</study_first_posted>
  <last_update_submitted>June 21, 2022</last_update_submitted>
  <last_update_submitted_qc>June 21, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">June 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Erasmus Medical Center</investigator_affiliation>
    <investigator_full_name>Sinno H.P. Simons</investigator_full_name>
    <investigator_title>Principal investigator</investigator_title>
  </responsible_party>
  <keyword>Preterm infants</keyword>
  <keyword>Hypoxia</keyword>
  <keyword>Doxapram</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Respiratory Insufficiency</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Doxapram</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>Yes</sharing_ipd>
    <ipd_description>Yes</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>study protocol, sap and icf will be available at start of recruitment</ipd_time_frame>
    <ipd_access_criteria>data will be available on request. Requests will be discussed by the steering committee</ipd_access_criteria>
    <ipd_url>https://dmp.radboudumc.nl/plans/31885/export.pdf?export%5Bquestion_headings%5D=true</ipd_url>
  </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/NCT04430790
org study id: NL72125.078.19
secondary id: 80-84800-9843009
secondary id: 2019-003666-41
nct id: NCT04430790
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: No
is fda regulated device: No
Preterm infants often suffer from apnea of prematurity (AOP; a cessation of breathing) due to
      immaturity of the respiratory system. AOP can lead to oxygen shortage and a low heart rate
      which might harm the development of the newborn, especially the central nervous system. In
      order to prevent oxygen shortage, infants are treated with non-invasive respiratory support
      and caffeine. Despite these treatments, many preterm newborns still suffer from AOP and need
      invasive mechanical ventilation. Although this will result in complete resolution of AOP,
      invasive mechanical ventilation has the disadvantage of being a major risk of chronic lung
      disease and impaired neurodevelopmental outcome. Restrictive invasive ventilation is
      therefore advocated nowadays in preterm infants. Doxapram is a respiratory stimulant that has
      been administered off-label to treat AOP. Doxapram, as add-on treatment, seems to be
      effective in treating AOP and to prevent invasive mechanical ventilation. It is unclear if a
      preterm infant benefit from doxapram treatment on the longer term. This study compares
      doxapram to placebo and hypothesizes that doxapram will protect preterm infants from both
      invasive ventilation (and related lung disease) and AOP related oxygen shortage (and related
      impaired brain development).
The main objective of the trial is to investigate if doxapram is safe and effective in
      reducing the composite outcome of death and neurodevelopmental impairment/severe disability
      at 2 years corrected age as compared to placebo. This multicenter double blinded randomized
      placebo-controlled superiority trial will be conducted in multiple neonatal intensive care
      units in the Netherlands and Belgium, including 8 years follow-up. After written
      informed-consent the patients will be randomized into the doxapram treatment group or the
      placebo treatment group. Randomization will be stratified based on center and gestational age
      < or >= 26 weeks.

      The participating departments include Dutch and Belgian Neonatal Intensive care units. The
      units include both academic and non-academic level III and IV units that are specialized in
      the care for critically ill and preterm born infants. Postnatal ages of patients at doxapram
      start vary from directly after birth up to months for the most-preterm born infants.

      Blinded continuous doxapram or placebo (glucose 5%) will be infused as long as needed.
      Therapy is down titrated or stopped based on the patients' condition. If endotracheal
      intubation is needed study drug is stopped. After extubation study drug may be restarted.
      Switch to gastro-enteral administration is allowed if no iv-access is needed for other
      reasons. Next to study drug infusion, there will be no other study-related interventions. All
      outcome variables are already collected as standard of care. In a subset of patients doxapram
      plasma levels will be determined to validate the doxapram pharmacokinetic (PK) model. Blood
      will only be collected during routine blood sampling, with a maximum amount of 0.6 ml.
      Economic and cost-effectiveness evaluation will be performed. The national protocol for
      preterm birth advices follow-up at 2, 5.5 and 8 years respectively, as in the current study.
      Additional questionnaires will be used to collect data on the quality of life of patients and
      their parents.
allocation: Randomized
intervention model: Parallel Assignment
intervention model description: Doxapram versus placebo
primary purpose: Treatment
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Death or severe disability
time frame: 2 years corrected age
description: Disability will be defined as cognitive delay, cerebral palsy, severe hearing loss, or bilateral blindness. Cognitive delay will be defined as a Mental Development Index score of less than 85 on the Bayley Scales of Infant and Toddler Development, Bayley Score of Infant Development (BSID) III scores. Cerebral palsy will be diagnosed if the child had a non-progressive motor impairment characterized by abnormal muscle tone and decreased range or control of movements. The level of gross motor function will be determined with the use of the Gross Motor Function Classification System. Audiometry will be performed to determine the presence or absence of hearing loss. Blindness will be defined as a corrected visual acuity less than 20/200
measure: Broncho pulmonary dysplasia
time frame: 36 weeks post menstrual age
description: Diagnosed according to the National Institute of Child Health and Human Development (NICHD) criteria
measure: Death
time frame: until 36 weeks post menstrual age and until hospital discharge
description: Death at 36 weeks post menstrual age and hospital mortality
measure: Admission period
time frame: through study completion and until discharge home, average 3 months
description: Length of stay at the intensive care, length of stay in hospital
measure: Endotracheal intubations
time frame: Day 3, 7, 14, and 21 after start of study medication
description: Incidence of endotracheal intubations
measure: Oxygenation days and complications
time frame: During first hospital admittance and through study completion, average of 3 months
description: Number of days on invasive ventilation, number of days on ventilatory support (non-invasive ventilation, CPAP, humidified high flow, low flow), number of days with supplemental oxygen, respiratory complications (airleak, pneumonia, etc), use of (rescue) corticosteroids for respiratory reasons.
measure: Gastro-intestinal outcome measures
time frame: During first hospital admittance and until 36 weeks post menstrual age
description: solitary intestinal perforation, necrotizing enterocolitis > stage 2 according to Bell, feeding problems with need for parental feeding (days with parental feeding after inclusion), body weight (gain, length), head circumference
measure: Neurological outcome measures
time frame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months
description: Intraventricular hemorhage(IVH) (all grades, grade III-IV, venous infarction), clinical seizures, periventricular leucomalacia (PVL) > gr 1)
measure: Complications during neonatal period
time frame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months
description: Incidence of late onset sepsis (culture proven or clinical suspected) and meningitis after inclusion, need for inotropes/circulatory support
measure: Retinopathy of prematurity
time frame: During first hospital admittance or at term equivalent age (37-42 weeks postmenstrual age), average 3 months
description: Grade of retinopathy (including plus disease and need for therapy)
measure: Hearing
time frame: At term equivalent age, 37-42 weeks postmenstrual age, average 3 months
description: Hearing test
measure: Additional long term outcomes
time frame: 2 years corrected age
description: Readmissions since first discharge home, weight/length/head circumference, behavioral problems (Child Behavior Checklist)
measure: Parent reported outcome
time frame: 2 years corrected age
description: Parent reported outcome with the PARCA-R (Parent Report of Children's Abilities-Revised) questionnaire (expected mean standardised scores 100 (SD 15), higher score is better outcome)
arm group label: Doxapram
arm group type: Experimental
description: Blinded doxapram (2mg/ml, in glucose 5%) loading dose of 2.0 to 2.5 mg/kg administered in 5 to 10 minutes, followed by a continuous infusion of 0.5 - 1.0 mg/kg/hr ('www.kinderformularium.nl') as long as needed. Therapy is down titrated or stopped based on the patients' respiratory condition. If endotracheal intubation is needed study drug is stopped. After extubation study drug may be restarted. Switch to gastro-enteral administration is allowed if no iv-access is needed for other reasons.
arm group label: Placebo
arm group type: Placebo Comparator
description: Placebo (glucose 5%) will also be administered with a loading dose and continuous infusion (in equal amounts of fluid as in experimental arm) by intravenous or gastro-intestinal infusion. The treatment protocol will be equal to the protocol in the doxapram arm.
intervention type: Drug
intervention name: Doxapram
description: Loading dose and continuous doxapram infusion.
arm group label: Doxapram
other name: Dopram
intervention type: Drug
intervention name: Placebo
description: Loading dose and continuous placebo infusion.
arm group label: Placebo
other name: Placebo (for Doxapram)
criteria: 
gender: All
minimum age: 23 Weeks
maximum age: 29 Weeks
healthy volunteers: No
last name: Anne Smits, MD, PhD
role: Principal Investigator
affiliation: Universitair Ziekenhuis Leuven
last name: Karel Allegaert, MD, PhD
role: Study Director
affiliation: Universitair Ziekenhuis Leuven
last name: Sinno HP Simons, MD, PhD
phone: +31641376695
email: s.simons@erasmusmc.nl
last name: Jeroen J Hutten, MD, PhD
email: g.j.hutten@amsterdamumc.nl
facility: 
status: Not yet recruiting
contact: 
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status: Not yet recruiting
contact: 
facility: 
status: Recruiting
contact: 
investigator: 
facility: 
status: Recruiting
contact: 
facility: 
status: Suspended
facility: 
status: Recruiting
contact: 
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status: Recruiting
contact: 
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status: Recruiting
contact: 
facility: 
status: Not yet recruiting
contact: 
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status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
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status: Recruiting
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status: Recruiting
contact: 
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status: Recruiting
contact: 
facility: 
status: Recruiting
contact: 
country: Belgium
country: Netherlands
responsible party type: Principal Investigator
investigator affiliation: Erasmus Medical Center
investigator full name: Sinno H.P. Simons
investigator title: Principal investigator
mesh term: Respiratory Insufficiency
mesh term: Doxapram
sharing ipd: Yes
ipd description: Yes
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: study protocol, sap and icf will be available at start of recruitment
ipd access criteria: data will be available on request. Requests will be discussed by the steering committee
ipd url: https://dmp.radboudumc.nl/plans/31885/export.pdf?export%5Bquestion_headings%5D=true