<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/NCT03035578</url>
  </required_header>
  <id_info>
    <org_study_id>1000053067</org_study_id>
    <nct_id>NCT03035578</nct_id>
  </id_info>
  <brief_title>Development of a Morphine Pharmacokinetic and Pharmacodynamic Model for the Neonatal Population</brief_title>
  <official_title>Development of a Morphine Pharmacokinetic and Pharmacodynamic Model for the Neonatal Population</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>The Hospital for Sick Children</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>The Hospital for Sick Children</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>
      This research aims to study what the baby's body does with morphine and how morphine works in&#xD;
      the baby's body. One hundred newborn babies will be enrolled in this study. With a better&#xD;
      understanding of the drug doctors and nurses will have more information and better administer&#xD;
      the drug in case of pain, stress or discomfort.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Critically ill immature preterm infants experience multiple noxious stimuli while receiving&#xD;
      care in the Neonatal Intensive Care Unit (NICU). These noxious stimuli include, but are not&#xD;
      limited to: venipuncture; insertion of intravenous and arterial catheters; suctioning of the&#xD;
      nose, mouth and oropharynx; endotracheal intubation for mechanical ventilation; insertion of&#xD;
      chest drains; repositioning and other types of patient manipulation. The delivery of optimal&#xD;
      doses of analgesics for these noxious stimuli is a major challenge due to the lack of&#xD;
      knowledge about drug disposition and its effects in this patient population.&#xD;
&#xD;
      Morphine is the commonest analgesic used in the NICU. The Premature Infant Pain Profile&#xD;
      (PIPP) is used to quantify pain in the NICU1. This objective score, which combines&#xD;
      physiological and behavioural variables defining levels of discomfort, is used as a guide for&#xD;
      the use of morphine in newborn infants. Multidimensional pain assessment tools, such as PIPP,&#xD;
      can easily identify behaviour in healthy infants undergoing painful events, however, its&#xD;
      efficiency is questionable when applicable to critically ill premature infants with&#xD;
      neurological impairment, where the pain processing and modulation may be altered.&#xD;
      Pharmacokinetics/Pharmacodynamics (PKPD) models can be used to quantitatively describe and&#xD;
      predict drug disposition in the blood and the target organ (e.g., brain) in relation to doses&#xD;
      and patient characteristics. Although there has been a global effort to describe morphine&#xD;
      plasma levels in this population using a pharmacokinetic modelling approach2-5, PKPD model&#xD;
      development has not been reported. The study of morphine pharmacokinetics to determine the&#xD;
      optimal dose for balancing analgesia/sedation together with the design of pharmacodynamic&#xD;
      model for morphine may provide a better understanding of nociception/pain profile based on&#xD;
      the physiological variables of immature infants. Moreover, the PKPD model may be used to&#xD;
      achieve optimal therapeutic effects through individualised model-based dose selection.&#xD;
      Objective: This study is composed by four main objectives:&#xD;
&#xD;
        1. First: Define target morphine plasma and brain concentrations. To this end, we will&#xD;
           develop a morphine PKPD model based on population PK characteristics and morphine&#xD;
           effects captured by functional readout of central nervous system function;&#xD;
&#xD;
        2. Second: Develop an opportunistic sampling method for fragile populations based on saliva&#xD;
           sampling;&#xD;
&#xD;
        3. Third: Compare pharmacokinetic parameters calculated from saliva with plasma sample;&#xD;
&#xD;
        4. Fourth: Application of the morphine PKPD model for prediction of optimal morphine dosing&#xD;
           in individual patients using the Bayesian framework of model refinement.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Withdrawn</overall_status>
  <why_stopped>
    research project has been abandoned primarily because of the excessive delays associated with&#xD;
    past challenges in obtaining approval from Health Canada&#xD;
  </why_stopped>
  <start_date type="Anticipated">December 1, 2017</start_date>
  <completion_date type="Anticipated">June 1, 2019</completion_date>
  <primary_completion_date type="Anticipated">June 1, 2018</primary_completion_date>
  <phase>Phase 1/Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>N/A</allocation>
    <intervention_model>Single Group Assignment</intervention_model>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Target Morphine Plasma Concentration</measure>
    <time_frame>12 months (blood sampling and modeling)</time_frame>
    <description>Sparse sampling coupled with population (mixed effects) method will be used to design the morphine pharmacokinetics phase. This method captures pharmacokinetics data from many subjects (learning about population), which are based on a relatively few number of samples per patient (learning about individual characteristics considering the large number of samples).Population pharmacokinetic parameters will be estimated using a non-linear mixed effects modelling with NONMEM software.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Brain Morphine Concentrations</measure>
    <time_frame>12 months (a-eeg collection and modeling)</time_frame>
    <description>The drug effect will be design using the sigmoid modelling. The effect of drugs modeled by relating drug effect to the drug concentration (obtain in the primary outcome). The pain scores and amplitude-integrated electroencephalography (aEEG) will be used as markers of drug effect on the central nervous system for the development of the pharmacodynamic model. The effect-site concentration will be validated by comparing the predicted time of peak effect with the time of peak effect of aEEG effect. Heart rate, respiratory rate, blood oxygen saturation, and blood pressure will be captured continuously through neonatal computational platform with the intent to investigate, other pharmacodynamic relationship using the sigmoid modelling.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Actual">0</enrollment>
  <condition>Pain</condition>
  <condition>Drug Effect</condition>
  <arm_group>
    <arm_group_label>Morphine Blood and Saliva sampling</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>The infants will receive a 50 mcg/kg loading dose of morphine followed by a constant infusion.Morphine Injection: 10mg/mL, 1mL ampoules.Two strengths of stock syringes:&#xD;
a)patients &lt;1.5kg, morphine 0.5mg/25mL; b)patients 1.5kg to &lt;5kg, morphine 1mg/25mL.&#xD;
Time blood samples will be collected for measurement of whole blood concentration of morphine in 24h. Total morphine, morphine-3-glucuronide and morphine-6-glucuronide concentrations; volume of blood required is 0.25 ml. Sparse sampling strategy will be used for those neonates &lt; 1250; total volume of blood required is 0.50 ml. Frequent sampling strategy will be used for those neonates ≥ 1250 gm; total volume of blood required is 0.50 ml.Saliva samples will be collected at 10 and 30 minutes and at 6, 12 and 24h after morphine infusion started.100 uL of saliva, captured using a collection swab.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Morphine</intervention_name>
    <description>Sampling blood for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population</description>
    <arm_group_label>Morphine Blood and Saliva sampling</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Morphine</intervention_name>
    <description>Sampling saliva for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population</description>
    <arm_group_label>Morphine Blood and Saliva sampling</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Gestational age &gt; 24 completed weeks.&#xD;
&#xD;
          -  Clinically prescribed to commence a continuous morphine infusion.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Gestational age &lt; 24 completed weeks.&#xD;
&#xD;
          -  Critically ill infant unlikely to survive for more than 72 hours.&#xD;
&#xD;
          -  Prolonged fetal exposure to morphine, any other narcotic, or methadone, as a&#xD;
             consequence of maternal use of the drug.&#xD;
&#xD;
          -  Any postnatal exposure to morphine during the 72 hours prior to the commencement of&#xD;
             the second morphine infusion.&#xD;
&#xD;
          -  Neonates with impaired cardiac, hepatic or renal functioning as defined by clinical&#xD;
             signs of impaired perfusion, abnormal liver function tests, or an elevated serum&#xD;
             creatinine.&#xD;
&#xD;
          -  Neonates with seizures.&#xD;
&#xD;
          -  The attending neonatologist considers that participation in the study is&#xD;
             contraindicated.&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>24 Weeks</minimum_age>
    <maximum_age>42 Weeks</maximum_age>
    <healthy_volunteers>Accepts Healthy Volunteers</healthy_volunteers>
  </eligibility>
  <verification_date>February 2020</verification_date>
  <study_first_submitted>January 24, 2017</study_first_submitted>
  <study_first_submitted_qc>January 27, 2017</study_first_submitted_qc>
  <study_first_posted type="Estimate">January 30, 2017</study_first_posted>
  <last_update_submitted>February 21, 2020</last_update_submitted>
  <last_update_submitted_qc>February 21, 2020</last_update_submitted_qc>
  <last_update_posted type="Actual">February 25, 2020</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>The Hospital for Sick Children</investigator_affiliation>
    <investigator_full_name>Andrew James</investigator_full_name>
    <investigator_title>Interim Head, Division of Neonatology</investigator_title>
  </responsible_party>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Pharmacodynamics</keyword>
  <keyword>Morphine</keyword>
  <keyword>Neonatal</keyword>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Morphine</mesh_term>
  </intervention_browse>
  <patient_data>
    <sharing_ipd>No</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/NCT03035578
org study id: 1000053067
nct id: NCT03035578
lead sponsor: 
has dmc: No
is fda regulated drug: No
is fda regulated device: No
This research aims to study what the baby's body does with morphine and how morphine works in
      the baby's body. One hundred newborn babies will be enrolled in this study. With a better
      understanding of the drug doctors and nurses will have more information and better administer
      the drug in case of pain, stress or discomfort.
Critically ill immature preterm infants experience multiple noxious stimuli while receiving
      care in the Neonatal Intensive Care Unit (NICU). These noxious stimuli include, but are not
      limited to: venipuncture; insertion of intravenous and arterial catheters; suctioning of the
      nose, mouth and oropharynx; endotracheal intubation for mechanical ventilation; insertion of
      chest drains; repositioning and other types of patient manipulation. The delivery of optimal
      doses of analgesics for these noxious stimuli is a major challenge due to the lack of
      knowledge about drug disposition and its effects in this patient population.

      Morphine is the commonest analgesic used in the NICU. The Premature Infant Pain Profile
      (PIPP) is used to quantify pain in the NICU1. This objective score, which combines
      physiological and behavioural variables defining levels of discomfort, is used as a guide for
      the use of morphine in newborn infants. Multidimensional pain assessment tools, such as PIPP,
      can easily identify behaviour in healthy infants undergoing painful events, however, its
      efficiency is questionable when applicable to critically ill premature infants with
      neurological impairment, where the pain processing and modulation may be altered.
      Pharmacokinetics/Pharmacodynamics (PKPD) models can be used to quantitatively describe and
      predict drug disposition in the blood and the target organ (e.g., brain) in relation to doses
      and patient characteristics. Although there has been a global effort to describe morphine
      plasma levels in this population using a pharmacokinetic modelling approach2-5, PKPD model
      development has not been reported. The study of morphine pharmacokinetics to determine the
      optimal dose for balancing analgesia/sedation together with the design of pharmacodynamic
      model for morphine may provide a better understanding of nociception/pain profile based on
      the physiological variables of immature infants. Moreover, the PKPD model may be used to
      achieve optimal therapeutic effects through individualised model-based dose selection.
      Objective: This study is composed by four main objectives:

        1. First: Define target morphine plasma and brain concentrations. To this end, we will
           develop a morphine PKPD model based on population PK characteristics and morphine
           effects captured by functional readout of central nervous system function;

        2. Second: Develop an opportunistic sampling method for fragile populations based on saliva
           sampling;

        3. Third: Compare pharmacokinetic parameters calculated from saliva with plasma sample;

        4. Fourth: Application of the morphine PKPD model for prediction of optimal morphine dosing
           in individual patients using the Bayesian framework of model refinement.
allocation: N/A
intervention model: Single Group Assignment
primary purpose: Basic Science
masking: None (Open Label)
measure: Target Morphine Plasma Concentration
time frame: 12 months (blood sampling and modeling)
description: Sparse sampling coupled with population (mixed effects) method will be used to design the morphine pharmacokinetics phase. This method captures pharmacokinetics data from many subjects (learning about population), which are based on a relatively few number of samples per patient (learning about individual characteristics considering the large number of samples).Population pharmacokinetic parameters will be estimated using a non-linear mixed effects modelling with NONMEM software.
measure: Brain Morphine Concentrations
time frame: 12 months (a-eeg collection and modeling)
description: The drug effect will be design using the sigmoid modelling. The effect of drugs modeled by relating drug effect to the drug concentration (obtain in the primary outcome). The pain scores and amplitude-integrated electroencephalography (aEEG) will be used as markers of drug effect on the central nervous system for the development of the pharmacodynamic model. The effect-site concentration will be validated by comparing the predicted time of peak effect with the time of peak effect of aEEG effect. Heart rate, respiratory rate, blood oxygen saturation, and blood pressure will be captured continuously through neonatal computational platform with the intent to investigate, other pharmacodynamic relationship using the sigmoid modelling.
arm group label: Morphine Blood and Saliva sampling
arm group type: Experimental
description: The infants will receive a 50 mcg/kg loading dose of morphine followed by a constant infusion.Morphine Injection: 10mg/mL, 1mL ampoules.Two strengths of stock syringes:
a)patients <1.5kg, morphine 0.5mg/25mL; b)patients 1.5kg to <5kg, morphine 1mg/25mL.
Time blood samples will be collected for measurement of whole blood concentration of morphine in 24h. Total morphine, morphine-3-glucuronide and morphine-6-glucuronide concentrations; volume of blood required is 0.25 ml. Sparse sampling strategy will be used for those neonates < 1250; total volume of blood required is 0.50 ml. Frequent sampling strategy will be used for those neonates ≥ 1250 gm; total volume of blood required is 0.50 ml.Saliva samples will be collected at 10 and 30 minutes and at 6, 12 and 24h after morphine infusion started.100 uL of saliva, captured using a collection swab.
intervention type: Drug
intervention name: Morphine
description: Sampling blood for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population
arm group label: Morphine Blood and Saliva sampling
intervention type: Drug
intervention name: Morphine
description: Sampling saliva for development of Morphine Pharmacokinetic/Pharmacodynamic Model for Neonatal Population
arm group label: Morphine Blood and Saliva sampling
criteria: 
gender: All
minimum age: 24 Weeks
maximum age: 42 Weeks
healthy volunteers: Accepts Healthy Volunteers
responsible party type: Principal Investigator
investigator affiliation: The Hospital for Sick Children
investigator full name: Andrew James
investigator title: Interim Head, Division of Neonatology
mesh term: Morphine
sharing ipd: No