<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/NCT02214589</url>
  </required_header>
  <id_info>
    <org_study_id>IRB5140027</org_study_id>
    <nct_id>NCT02214589</nct_id>
  </id_info>
  <brief_title>Non-pharmacological Interventions for Procedural Pain in Premature Neonates</brief_title>
  <official_title>Non-pharmacological Interventions for Procedural Pain in Premature Neonates</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Loma Linda University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Loma Linda University</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      A. Specific Aims Premature infants admitted to the neonatal intensive care unit (NICU)&#xD;
      require up to several hundred procedures during their hospitalization. Many of these are&#xD;
      tissue-damaging procedures (TDPs) known to cause pain [1]. Through funding from NINR, the&#xD;
      investigators found that TDPs not only caused pain but also increased markers of ATP&#xD;
      degradation and oxidative stress[2[. The TDP was tape removal, a commonly performed procedure&#xD;
      in the NICU2.&#xD;
&#xD;
      Based on this finding, the investigators sought to determine if interventions that relieve&#xD;
      pain also reduce biochemical markers of ATP degradation and oxidative stress. The&#xD;
      investigators first examined the effect of oral sucrose, a commonly used intervention, when&#xD;
      given before a heel lance. The investigators chose heel lance because it is the most&#xD;
      predominant painful procedure in the NICU, as shown in 29 different clinical trials[3]. The&#xD;
      investigators hypothesized that since oral sucrose is documented to significantly reduce pain&#xD;
      scores, then administration of this analgesic will also decrease markers of ATP degradation&#xD;
      and oxidative stress. However,the investigators observed the opposite effect. Although a&#xD;
      single dose of oral sucrose reduced behavioral markers of pain, it significantly increased&#xD;
      biochemical markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress&#xD;
      (allantoin) over time[4]. More importantly, the effect of oral sucrose on breakdown markers&#xD;
      of ATP were enhanced and were significantly higher in neonates that were intubated or were&#xD;
      receiving more than 30% FiO25. These findings lead to the question: If oral sucrose does not&#xD;
      effectively reduce the biochemical effects of procedural pain, what intervention or groups of&#xD;
      intervention will decrease both behavioral markers of procedural pain and reduce ATP&#xD;
      utilization and oxidative stress in premature neonates? For this RO1 renewal, the&#xD;
      investigators propose to test the individual and additive effects of two commonly used&#xD;
      interventions for procedural pain. These interventions are (a) administration of 30% oral&#xD;
      glucose and non-nutritive sucking (NNS) (b) facilitated tucking and NNS c) administration of&#xD;
      30% oral glucose, facilitated tucking and NNS. Administration of 30% oral glucose was&#xD;
      documented to decreased procedural pain scores[6-9] without the potential adverse effects of&#xD;
      fructose, a key ingredient of sucrose[10-11]. Facilitated tucking is the gentle positioning&#xD;
      of preterm infants with arms and legs in a flexed, midline position close to the body, while&#xD;
      either in a side-lying or prone position[12]. Because tachycardia often accompanies pain, a&#xD;
      documented benefit of facilitated tucking is stabilization of heart rate and reduction of&#xD;
      motor activity (flailing)[12-13]. Non-nutritive sucking refers to the provision of a&#xD;
      weight-appropriate pacifier[14]. The painful procedure will be a clinically required heel&#xD;
      lance, which refers to the puncture of a newborn's heel for blood glucose using a specially&#xD;
      designed lancet. Our general hypothesis is that commonly used clinical interventions known to&#xD;
      reduce procedural pain alter biochemical markers of ATP degradation, oxidative stress and&#xD;
      cell injury.&#xD;
&#xD;
      Specific Aim 1 will determine whether (a) 30% oral glucose and NNS or (b) facilitated tucking&#xD;
      and NNS or (c) 30% oral glucose with facilitated tucking and NNS will decrease procedural&#xD;
      pain.&#xD;
&#xD;
      • Pain will be quantified using a validated pain scoring tool, the Premature Infant Pain&#xD;
      Profile (PIPP). Individual and additive effect of interventions will be determined.&#xD;
&#xD;
      Specific Aim 2 will determine whether (a) 30% oral glucose and NNS or (b) facilitated tucking&#xD;
      and NNS or (c) 30% oral glucose with facilitated tucking and NNS will decrease biochemical&#xD;
      markers of ATP degradation, oxidative stress and oxidative cell injury.&#xD;
&#xD;
        -  Products of ATP breakdown in plasma-hypoxanthine (Hx), xanthine (Xa), and uric acid&#xD;
           (UA)-will be measured using high performance liquid chromatography.&#xD;
&#xD;
        -  Oxidative stress will be quantified by measuring plasma levels of allantoin using mass&#xD;
           spectrometry.&#xD;
&#xD;
        -  Cell injury will be quantified by measuring plasma levels of F2 isoprostane using&#xD;
           liquid-chromatography/mass spectrometry.&#xD;
    </textblock>
  </brief_summary>
  <overall_status>Completed</overall_status>
  <start_date type="Actual">August 2014</start_date>
  <completion_date type="Actual">December 2019</completion_date>
  <primary_completion_date type="Actual">December 2019</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>Single Group Assignment</intervention_model>
    <primary_purpose>Supportive Care</primary_purpose>
    <masking>Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Decreased pain score using the Premature Infant Pain Profile pain scoring tool</measure>
    <time_frame>at time of heelstick</time_frame>
    <description>A decrease in pain score will be quantified using the validated tool Premature Infant Pain Profile, which will be scored by a neonatologist blinded to group assignment.</description>
  </primary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Actual">203</enrollment>
  <condition>Prevention of Procedural Pain</condition>
  <condition>Reduction of Procedural Pain</condition>
  <condition>Biochemical Effects of Oral Dextrose</condition>
  <arm_group>
    <arm_group_label>Oral glucose and NNS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Oral glucose and NNS</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Oral glucose and facilitated tucking and NNS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Oral glucose, facilitated tucking and NNS</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Facilitated Tucking and NNS</arm_group_label>
    <arm_group_type>Active Comparator</arm_group_type>
    <description>Facilitated tucking and NNS</description>
  </arm_group>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Oral glucose, facilitated tucking, NNS</intervention_name>
    <arm_group_label>Oral glucose and facilitated tucking and NNS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Oral glucose and NNS</intervention_name>
    <arm_group_label>Oral glucose and NNS</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Other</intervention_type>
    <intervention_name>Facilitated tucking and NNS</intervention_name>
    <arm_group_label>Facilitated Tucking and NNS</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Potential subjects are premature infants between 28-36 weeks gestation, have an&#xD;
             arterial or central catheter in place and have a clinically required heel lance.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Requirement for surgery&#xD;
&#xD;
          -  Intraventricular hemorrhage (IVH) ≥ grade 3&#xD;
&#xD;
          -  Neonates on medications such as morphine, fentanyl, versed, muscle relaxants,&#xD;
             phenobarbital, or dilantin&#xD;
&#xD;
          -  Renal injury (plasma creatinine &gt; 1 mg/dl)&#xD;
&#xD;
          -  Severe cyanotic heart disease or severe respiratory distress&#xD;
&#xD;
          -  Chromosomal anomaly&#xD;
&#xD;
          -  Facial anomaly&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>N/A</minimum_age>
    <maximum_age>1 Month</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <location>
    <facility>
      <name>Loma Linda University Children's Hospital</name>
      <address>
        <city>Loma Linda</city>
        <state>California</state>
        <zip>92354</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>March 2020</verification_date>
  <study_first_submitted>August 7, 2014</study_first_submitted>
  <study_first_submitted_qc>August 8, 2014</study_first_submitted_qc>
  <study_first_posted type="Estimate">August 12, 2014</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 13, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Loma Linda University</investigator_affiliation>
    <investigator_full_name>Danilyn Angeles, PhD</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Premature Birth</mesh_term>
    <mesh_term>Pain, Procedural</mesh_term>
  </condition_browse>
  <!-- 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/NCT02214589
org study id: IRB5140027
nct id: NCT02214589
lead sponsor: 
has dmc: Yes
A. Specific Aims Premature infants admitted to the neonatal intensive care unit (NICU)
      require up to several hundred procedures during their hospitalization. Many of these are
      tissue-damaging procedures (TDPs) known to cause pain [1]. Through funding from NINR, the
      investigators found that TDPs not only caused pain but also increased markers of ATP
      degradation and oxidative stress[2[. The TDP was tape removal, a commonly performed procedure
      in the NICU2.

      Based on this finding, the investigators sought to determine if interventions that relieve
      pain also reduce biochemical markers of ATP degradation and oxidative stress. The
      investigators first examined the effect of oral sucrose, a commonly used intervention, when
      given before a heel lance. The investigators chose heel lance because it is the most
      predominant painful procedure in the NICU, as shown in 29 different clinical trials[3]. The
      investigators hypothesized that since oral sucrose is documented to significantly reduce pain
      scores, then administration of this analgesic will also decrease markers of ATP degradation
      and oxidative stress. However,the investigators observed the opposite effect. Although a
      single dose of oral sucrose reduced behavioral markers of pain, it significantly increased
      biochemical markers of ATP degradation (hypoxanthine, uric acid) and oxidative stress
      (allantoin) over time[4]. More importantly, the effect of oral sucrose on breakdown markers
      of ATP were enhanced and were significantly higher in neonates that were intubated or were
      receiving more than 30% FiO25. These findings lead to the question: If oral sucrose does not
      effectively reduce the biochemical effects of procedural pain, what intervention or groups of
      intervention will decrease both behavioral markers of procedural pain and reduce ATP
      utilization and oxidative stress in premature neonates? For this RO1 renewal, the
      investigators propose to test the individual and additive effects of two commonly used
      interventions for procedural pain. These interventions are (a) administration of 30% oral
      glucose and non-nutritive sucking (NNS) (b) facilitated tucking and NNS c) administration of
      30% oral glucose, facilitated tucking and NNS. Administration of 30% oral glucose was
      documented to decreased procedural pain scores[6-9] without the potential adverse effects of
      fructose, a key ingredient of sucrose[10-11]. Facilitated tucking is the gentle positioning
      of preterm infants with arms and legs in a flexed, midline position close to the body, while
      either in a side-lying or prone position[12]. Because tachycardia often accompanies pain, a
      documented benefit of facilitated tucking is stabilization of heart rate and reduction of
      motor activity (flailing)[12-13]. Non-nutritive sucking refers to the provision of a
      weight-appropriate pacifier[14]. The painful procedure will be a clinically required heel
      lance, which refers to the puncture of a newborn's heel for blood glucose using a specially
      designed lancet. Our general hypothesis is that commonly used clinical interventions known to
      reduce procedural pain alter biochemical markers of ATP degradation, oxidative stress and
      cell injury.

      Specific Aim 1 will determine whether (a) 30% oral glucose and NNS or (b) facilitated tucking
      and NNS or (c) 30% oral glucose with facilitated tucking and NNS will decrease procedural
      pain.

      • Pain will be quantified using a validated pain scoring tool, the Premature Infant Pain
      Profile (PIPP). Individual and additive effect of interventions will be determined.

      Specific Aim 2 will determine whether (a) 30% oral glucose and NNS or (b) facilitated tucking
      and NNS or (c) 30% oral glucose with facilitated tucking and NNS will decrease biochemical
      markers of ATP degradation, oxidative stress and oxidative cell injury.

        -  Products of ATP breakdown in plasma-hypoxanthine (Hx), xanthine (Xa), and uric acid
           (UA)-will be measured using high performance liquid chromatography.

        -  Oxidative stress will be quantified by measuring plasma levels of allantoin using mass
           spectrometry.

        -  Cell injury will be quantified by measuring plasma levels of F2 isoprostane using
           liquid-chromatography/mass spectrometry.
allocation: Randomized
intervention model: Single Group Assignment
primary purpose: Supportive Care
masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
measure: Decreased pain score using the Premature Infant Pain Profile pain scoring tool
time frame: at time of heelstick
description: A decrease in pain score will be quantified using the validated tool Premature Infant Pain Profile, which will be scored by a neonatologist blinded to group assignment.
arm group label: Oral glucose and NNS
arm group type: Active Comparator
description: Oral glucose and NNS
arm group label: Oral glucose and facilitated tucking and NNS
arm group type: Active Comparator
description: Oral glucose, facilitated tucking and NNS
arm group label: Facilitated Tucking and NNS
arm group type: Active Comparator
description: Facilitated tucking and NNS
intervention type: Other
intervention name: Oral glucose, facilitated tucking, NNS
arm group label: Oral glucose and facilitated tucking and NNS
intervention type: Other
intervention name: Oral glucose and NNS
arm group label: Oral glucose and NNS
intervention type: Other
intervention name: Facilitated tucking and NNS
arm group label: Facilitated Tucking and NNS
criteria: 
gender: All
minimum age: N/A
maximum age: 1 Month
healthy volunteers: No
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Loma Linda University
investigator full name: Danilyn Angeles, PhD
investigator title: Professor
mesh term: Premature Birth
mesh term: Pain, Procedural