<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/NCT03235882</url>
  </required_header>
  <id_info>
    <org_study_id>H-17013993</org_study_id>
    <nct_id>NCT03235882</nct_id>
  </id_info>
  <brief_title>Fast Assessment of Surfactant Deficiency to Speed up Treatment</brief_title>
  <acronym>FAST</acronym>
  <official_title>Fast Assessment of Surfactant Deficiency to Speed up Treatment: Assessment of Lung Maturity and Prediction of RDS by Determination of L/S-ratio in Fresh Gastric Aspirates by FTIR Spectroscopy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Rigshospitalet, Denmark</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Aalborg University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Aarhus University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Kolding Sygehus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Odense University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Herlev Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Hvidovre University Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Holbaek Sygehus</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Rigshospitalet, Denmark</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>No</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The aim is to validate a FTIR spectroscopy test for measuring lung maturity/Respiratory&#xD;
      Distress Syndrome (RDS) in terms of safety, usability, and efficacy.&#xD;
&#xD;
      The purpose is to accurately predict RDS using Lecithin/Sphingomyelin ratio (L/S ratio&#xD;
      determined by a rapid FTIR test on fresh gastric aspirates) using retrospective analysis.&#xD;
&#xD;
      Research question:&#xD;
&#xD;
      &quot;In very preterm newborn infants with (risk of) respiratory distress who have not received&#xD;
      prophylactic surfactant: does analysis of L/S-ratio in fresh gastric aspirates using a rapid&#xD;
      FTIR test predict RDS requiring exogenous surfactant with sufficient specificity and&#xD;
      sensitivity to be clinical useful?&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Respiratory distress syndrome (RDS) remains a major cause of mortality and morbidity in&#xD;
      premature infants despite the increased use of antenatal steroids and early nasal continuous&#xD;
      positive airway pressure (nCPAP) in addition to exogenous surfactant replacement&#xD;
      therapy(1,2). In recent years, there have been several improvements in treatment, reducing&#xD;
      the incidence and severity of RDS and bronchopulmonary dysplasia (BPD) including early&#xD;
      treatment with nCPAP, early targeted surfactant replacement therapy, increased used of lung&#xD;
      protective ventilation together with an overall reduced use of mechanical ventilation(1,3,4).&#xD;
&#xD;
      However, the majority of premature infants with a gestational age of less than 30 weeks have&#xD;
      immature lungs and approximately half still require treatment with exogenous surfactant(2).&#xD;
      Timing of surfactant treatment seems crucial. Prophylactic surfactant treatment followed by&#xD;
      mechanical ventilation has been widely used, but has now been shown to increase the combined&#xD;
      mortality and incidence of BPD, as opposed to early targeted rescue treatment, especially&#xD;
      when combined with nCPAP and avoidance of mechanical ventilation using the &quot;Intubation,&#xD;
      surfactant, extubation (INSURE) or &quot;Less Invasive Surfactant Administration &quot; (LISA)&#xD;
      approach(5-8). In addition, evidence shows that very early targeted surfactant treatment is&#xD;
      associated with a better outcome compared to later treatment(9).&#xD;
&#xD;
      Consequently, it is necessary to treat with surfactant selectively and very soon after birth,&#xD;
      preferably even before classical symptoms of RDS are present, in order to further improve&#xD;
      outcome from RDS. To be able to do so, we need a bedside test that can quickly identify which&#xD;
      infants have surfactant deﬁciency to target treatment effectively(1).&#xD;
&#xD;
      Biomarkers expressing lung maturity have been identiﬁed in amniotic ﬂuid, gastric aspirate,&#xD;
      and oropharyngeal secretions(10-12). These ﬂuids are partially produced in the foetal lungs&#xD;
      as well as in the kidneys and the amniotic sac and therefore contain lung surfactant(13). The&#xD;
      classic method to determine surfactant in amniotic ﬂuid has been measuring&#xD;
      lecithin/sphingomyelin ratio (L/S) with thin-layer chromatography(10,14). Sphingomyelin&#xD;
      secretion remains fairly constant during pregnancy, whereas lecithin secretion increases in&#xD;
      parallel with lung maturation. Consequently, L/S-ratio reﬂects lung maturity independently of&#xD;
      dilution sampling effects(10)&#xD;
&#xD;
      Gastric aspirate (GAS) and oropharyngeal (OPS) secretion are easier to obtain and measure&#xD;
      than amniotic ﬂuid, and can be obtained within minutes from birth using routine neonatal care&#xD;
      measures(15,16). Previously, we have measured the surfactant content in gastric aspirate with&#xD;
      microbubble stability tests and with lamellar body counts(17,18). In a recent randomized&#xD;
      clinical trial in very preterm infants we compared early surfactant treatment guided by&#xD;
      lamellar body counts in gastric aspirate with traditional surfactant treatment, and found a&#xD;
      significant reduction in the need of oxygen at six hours of age and by day 28, in addition to&#xD;
      reduced duration of oxygen-dependency and a trend towards a lower incidence of&#xD;
      bronchopulmonary dysplasia(19).&#xD;
&#xD;
      However, both the microbubble stability test and lamellar body counts are work and laboratory&#xD;
      intensive and require a minimum of two to three hours for analysis.&#xD;
&#xD;
      The investigators have developed a fast method based on Fourier Transform Infrared (FTIR)&#xD;
      Spectroscopy for determining the L/S ratio in gastric aspirate and secretion from the&#xD;
      oropharynx. In a recent study, the algorithms for FTIR L/S analyses were developed and&#xD;
      improved 20). Concentrations were measured of the most surface-active lung phospholipid&#xD;
      dipalmitoylphosphatidylcholine and sphingomyelin in frozen gastric aspirates from 89&#xD;
      premature infants expressed as lecithin/sphingomyelin ratio (L/S) by mass spectrometry as the&#xD;
      reference method. The same aspirates were analyzed with FTIR spectroscopy. An L/S algorithm&#xD;
      was developed based on the 89 aspirates. Subsequently gastric aspirates were sampled in 136&#xD;
      infants of 24-31 weeks of gestation. L/S was measured in these frozen gastric aspirates using&#xD;
      FTIR spectroscopy and the results were compared with RDS development. Of 136 infants 61 (45%)&#xD;
      developed RDS. The cut-off value of L/S was 2.2, sensitivity was 92% and specificity was 73%.&#xD;
      The FTIR spectroscopy analysis required 10 μL of aspirate and took 10 minutes.&#xD;
&#xD;
      In an effort to increase accuracy and reproducibility, the investigators have continued to&#xD;
      improve the FTIR spectroscopy method and algorithms by making comparative measurements with&#xD;
      mass spectrometry using fresh non-frozen aspirates from newborn infants. These improvements&#xD;
      may also have affected the optimal cut-off value in our test.&#xD;
&#xD;
      The investigators are in the process of planning a large multicenter randomized clinical&#xD;
      trial of FTIR spectroscopy guided surfactant treatment using a point of care (POC) device&#xD;
      based on the FTIR algorithms and techinique using fresh aspirates that can be analyzed&#xD;
      immidiately in birth suite or the NICU. Before embarking on an interventional study however,&#xD;
      it is needed to re-validate the updated and improved FTIR spectroscopy test by again&#xD;
      comparing clinical appearance of RDS with L/S-ratio measured by FTIR spectroscopy on fresh&#xD;
      non-frozen gastric aspirates froma new population of preterm infants.&#xD;
&#xD;
      Hypothesis: Fast determination of Lecithin/Sphingomyelin-ratio (L/S-ratio) in gastric&#xD;
      aspirates by FTIR Spectroscopy, can accurately and consistently predict RDS based on clinical&#xD;
      criteria.&#xD;
&#xD;
      Trial design The trial is designed as prospective non-intervention observational cohort&#xD;
      study, with the aim to assess the efficacy in predicting RDS by a LS-test on fresh gastric&#xD;
      aspirates and oral secretions based on FTIR spectroscopy, by comparing clinical progress with&#xD;
      the LS-ratio. Included infants will be treated according to routine guidelines and at the&#xD;
      discretion of the attending neonatologist. No interventions are planned to be based on the&#xD;
      result of the L/S test.&#xD;
&#xD;
      AMMENTMENT:&#xD;
&#xD;
      We have ammended the project with an attempt to use the same method and AI combined with&#xD;
      clinical data to predict development of BPD, defined as continued requirements for&#xD;
      supplemental oxygen to DOL28. Spectroscopic measurements were done again using stored gastric&#xD;
      aspirate from the first part of the study.&#xD;
&#xD;
      This amendment has been approved by HREC and measurements were only done after parents gave&#xD;
      informed consent for participation of this additional part of the study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">September 1, 2017</start_date>
  <completion_date type="Actual">April 26, 2019</completion_date>
  <primary_completion_date type="Actual">April 26, 2019</primary_completion_date>
  <study_type>Observational</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <observational_model>Cohort</observational_model>
    <time_perspective>Prospective</time_perspective>
  </study_design_info>
  <primary_outcome>
    <measure>development of RDS</measure>
    <time_frame>5 days from delivery</time_frame>
  </primary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">72</enrollment>
  <condition>RDS of Prematurity</condition>
  <condition>Prematurity</condition>
  <arm_group>
    <arm_group_label>observational group</arm_group_label>
    <description>Infants born 24-32 weeks.&#xD;
Inclusion criteria:&#xD;
Have gastric aspirate and oral secretions obtained within 45 minutes from birth via:&#xD;
a naso- or orogastric tube inserted in the delivery room if clinically indicated as part of resuscitation or&#xD;
a nasogastric tube inserted as part of routine management of preterm infants.&#xD;
Written informed consent has been obtained</description>
  </arm_group>
  <intervention>
    <intervention_type>Diagnostic Test</intervention_type>
    <intervention_name>LS-ratio</intervention_name>
    <description>Accurately predict RDS using Lecithin/Sphingomyelin ratio (L/S ratio determined by a rapid FTIR test on fresh gastric aspirates) using retrospective analysis</description>
    <arm_group_label>observational group</arm_group_label>
  </intervention>
  <eligibility>
    <study_pop>
      <textblock>
        Preterm newborn babies that have gastric/oral secretions sampled before 45 minutes of age&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
        Inclusion criteria:&#xD;
&#xD;
          -  Have GAS obtained within 45 minutes from birth via:&#xD;
&#xD;
               -  a naso- or orogastric tube inserted in the delivery room if clinically indicated&#xD;
                  as part of resuscitation or&#xD;
&#xD;
               -  a nasogastric tube inserted as part of routine management of preterm infants.&#xD;
&#xD;
          -  Written informed consent has been obtained&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Intubated and treated with surfactant before obtaining GAS&#xD;
&#xD;
          -  Diagnosis of lethal malformations&#xD;
&#xD;
          -  Antenatal diagnosis of lung hypoplasia&#xD;
&#xD;
          -  Therapeutic infusion given in the amniotic cavity&#xD;
&#xD;
          -  GAS unavailable or significantly contaminated by meconium/pus&#xD;
&#xD;
          -  Sepsis&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>45 Minutes</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Department of Neonatology, Rigshospitalet</name>
      <address>
        <city>Copenhagen</city>
        <zip>2100</zip>
        <country>Denmark</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>Denmark</country>
  </location_countries>
  <link>
    <url>https://www.ncbi.nlm.nih.gov/pubmed/31038796</url>
    <description>Publication of the completed study</description>
  </link>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>July 27, 2017</study_first_submitted>
  <study_first_submitted_qc>July 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Actual">August 1, 2017</study_first_posted>
  <last_update_submitted>March 12, 2020</last_update_submitted>
  <last_update_submitted_qc>March 12, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">March 16, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Rigshospitalet, Denmark</investigator_affiliation>
    <investigator_full_name>Christian Heiring</investigator_full_name>
    <investigator_title>Consultant</investigator_title>
  </responsible_party>
  <keyword>Lung surfactant</keyword>
  <keyword>Mid-infrared spectroscopy</keyword>
  <keyword>Prematurity</keyword>
  <keyword>Respiratory distress syndrome</keyword>
  <keyword>gastric aspirate</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Premature Birth</mesh_term>
  </condition_browse>
  <patient_data>
    <sharing_ipd>Undecided</sharing_ipd>
  </patient_data>
  <!-- Results have not yet been posted for this study                                          -->
</clinical_study>


download date: ClinicalTrials.gov processed this data on September 20, 2023
link text: Link to the current ClinicalTrials.gov record.
url: https://clinicaltrials.gov/ct2/show/NCT03235882
org study id: H-17013993
nct id: NCT03235882
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
The aim is to validate a FTIR spectroscopy test for measuring lung maturity/Respiratory
      Distress Syndrome (RDS) in terms of safety, usability, and efficacy.

      The purpose is to accurately predict RDS using Lecithin/Sphingomyelin ratio (L/S ratio
      determined by a rapid FTIR test on fresh gastric aspirates) using retrospective analysis.

      Research question:

      "In very preterm newborn infants with (risk of) respiratory distress who have not received
      prophylactic surfactant: does analysis of L/S-ratio in fresh gastric aspirates using a rapid
      FTIR test predict RDS requiring exogenous surfactant with sufficient specificity and
      sensitivity to be clinical useful?
Respiratory distress syndrome (RDS) remains a major cause of mortality and morbidity in
      premature infants despite the increased use of antenatal steroids and early nasal continuous
      positive airway pressure (nCPAP) in addition to exogenous surfactant replacement
      therapy(1,2). In recent years, there have been several improvements in treatment, reducing
      the incidence and severity of RDS and bronchopulmonary dysplasia (BPD) including early
      treatment with nCPAP, early targeted surfactant replacement therapy, increased used of lung
      protective ventilation together with an overall reduced use of mechanical ventilation(1,3,4).

      However, the majority of premature infants with a gestational age of less than 30 weeks have
      immature lungs and approximately half still require treatment with exogenous surfactant(2).
      Timing of surfactant treatment seems crucial. Prophylactic surfactant treatment followed by
      mechanical ventilation has been widely used, but has now been shown to increase the combined
      mortality and incidence of BPD, as opposed to early targeted rescue treatment, especially
      when combined with nCPAP and avoidance of mechanical ventilation using the "Intubation,
      surfactant, extubation (INSURE) or "Less Invasive Surfactant Administration " (LISA)
      approach(5-8). In addition, evidence shows that very early targeted surfactant treatment is
      associated with a better outcome compared to later treatment(9).

      Consequently, it is necessary to treat with surfactant selectively and very soon after birth,
      preferably even before classical symptoms of RDS are present, in order to further improve
      outcome from RDS. To be able to do so, we need a bedside test that can quickly identify which
      infants have surfactant deﬁciency to target treatment effectively(1).

      Biomarkers expressing lung maturity have been identiﬁed in amniotic ﬂuid, gastric aspirate,
      and oropharyngeal secretions(10-12). These ﬂuids are partially produced in the foetal lungs
      as well as in the kidneys and the amniotic sac and therefore contain lung surfactant(13). The
      classic method to determine surfactant in amniotic ﬂuid has been measuring
      lecithin/sphingomyelin ratio (L/S) with thin-layer chromatography(10,14). Sphingomyelin
      secretion remains fairly constant during pregnancy, whereas lecithin secretion increases in
      parallel with lung maturation. Consequently, L/S-ratio reﬂects lung maturity independently of
      dilution sampling effects(10)

      Gastric aspirate (GAS) and oropharyngeal (OPS) secretion are easier to obtain and measure
      than amniotic ﬂuid, and can be obtained within minutes from birth using routine neonatal care
      measures(15,16). Previously, we have measured the surfactant content in gastric aspirate with
      microbubble stability tests and with lamellar body counts(17,18). In a recent randomized
      clinical trial in very preterm infants we compared early surfactant treatment guided by
      lamellar body counts in gastric aspirate with traditional surfactant treatment, and found a
      significant reduction in the need of oxygen at six hours of age and by day 28, in addition to
      reduced duration of oxygen-dependency and a trend towards a lower incidence of
      bronchopulmonary dysplasia(19).

      However, both the microbubble stability test and lamellar body counts are work and laboratory
      intensive and require a minimum of two to three hours for analysis.

      The investigators have developed a fast method based on Fourier Transform Infrared (FTIR)
      Spectroscopy for determining the L/S ratio in gastric aspirate and secretion from the
      oropharynx. In a recent study, the algorithms for FTIR L/S analyses were developed and
      improved 20). Concentrations were measured of the most surface-active lung phospholipid
      dipalmitoylphosphatidylcholine and sphingomyelin in frozen gastric aspirates from 89
      premature infants expressed as lecithin/sphingomyelin ratio (L/S) by mass spectrometry as the
      reference method. The same aspirates were analyzed with FTIR spectroscopy. An L/S algorithm
      was developed based on the 89 aspirates. Subsequently gastric aspirates were sampled in 136
      infants of 24-31 weeks of gestation. L/S was measured in these frozen gastric aspirates using
      FTIR spectroscopy and the results were compared with RDS development. Of 136 infants 61 (45%)
      developed RDS. The cut-off value of L/S was 2.2, sensitivity was 92% and specificity was 73%.
      The FTIR spectroscopy analysis required 10 μL of aspirate and took 10 minutes.

      In an effort to increase accuracy and reproducibility, the investigators have continued to
      improve the FTIR spectroscopy method and algorithms by making comparative measurements with
      mass spectrometry using fresh non-frozen aspirates from newborn infants. These improvements
      may also have affected the optimal cut-off value in our test.

      The investigators are in the process of planning a large multicenter randomized clinical
      trial of FTIR spectroscopy guided surfactant treatment using a point of care (POC) device
      based on the FTIR algorithms and techinique using fresh aspirates that can be analyzed
      immidiately in birth suite or the NICU. Before embarking on an interventional study however,
      it is needed to re-validate the updated and improved FTIR spectroscopy test by again
      comparing clinical appearance of RDS with L/S-ratio measured by FTIR spectroscopy on fresh
      non-frozen gastric aspirates froma new population of preterm infants.

      Hypothesis: Fast determination of Lecithin/Sphingomyelin-ratio (L/S-ratio) in gastric
      aspirates by FTIR Spectroscopy, can accurately and consistently predict RDS based on clinical
      criteria.

      Trial design The trial is designed as prospective non-intervention observational cohort
      study, with the aim to assess the efficacy in predicting RDS by a LS-test on fresh gastric
      aspirates and oral secretions based on FTIR spectroscopy, by comparing clinical progress with
      the LS-ratio. Included infants will be treated according to routine guidelines and at the
      discretion of the attending neonatologist. No interventions are planned to be based on the
      result of the L/S test.

      AMMENTMENT:

      We have ammended the project with an attempt to use the same method and AI combined with
      clinical data to predict development of BPD, defined as continued requirements for
      supplemental oxygen to DOL28. Spectroscopic measurements were done again using stored gastric
      aspirate from the first part of the study.

      This amendment has been approved by HREC and measurements were only done after parents gave
      informed consent for participation of this additional part of the study.
observational model: Cohort
time perspective: Prospective
measure: development of RDS
time frame: 5 days from delivery
arm group label: observational group
description: Infants born 24-32 weeks.
Inclusion criteria:
Have gastric aspirate and oral secretions obtained within 45 minutes from birth via:
a naso- or orogastric tube inserted in the delivery room if clinically indicated as part of resuscitation or
a nasogastric tube inserted as part of routine management of preterm infants.
Written informed consent has been obtained
intervention type: Diagnostic Test
intervention name: LS-ratio
description: Accurately predict RDS using Lecithin/Sphingomyelin ratio (L/S ratio determined by a rapid FTIR test on fresh gastric aspirates) using retrospective analysis
arm group label: observational group
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: All
minimum age: N/A
maximum age: 45 Minutes
healthy volunteers: No
facility: 
country: Denmark
url: https://www.ncbi.nlm.nih.gov/pubmed/31038796
description: Publication of the completed study
responsible party type: Principal Investigator
investigator affiliation: Rigshospitalet, Denmark
investigator full name: Christian Heiring
investigator title: Consultant
mesh term: Premature Birth
sharing ipd: Undecided