<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/NCT02978534</url>
  </required_header>
  <id_info>
    <org_study_id>00201540</org_study_id>
    <nct_id>NCT02978534</nct_id>
  </id_info>
  <brief_title>Pharmacokinetics of Quetiapine Across Pregnancy and Postpartum</brief_title>
  <acronym>Quetiapine</acronym>
  <official_title>Pharmacokinetics of Quetiapine Across Pregnancy and Postpartum</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Northwestern University</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
  </sponsors>
  <source>Northwestern University</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
  </oversight_info>
  <brief_summary>
    <textblock>
      The widespread and common use of quetiapine in childbearing and pregnant women demands more&#xD;
      data to inform dosing and toxicity in pregnancy. The new FDA Pregnancy and Lactation Labeling&#xD;
      Final Rule (PLLR) will go into effect on June 30th, 2015 and will replace the prior A, B, C,&#xD;
      D, and X categories. Additionally, the PLLR will require information to aid prescribing&#xD;
      decisions in three categories 1) Pregnancy (including labor and delivery), 2) Lactation, and&#xD;
      3) Females and Males of Reproductive Potential. The pregnancy category will include a&#xD;
      subsection that will describe pharmacokinetic and pharmacodynamic characteristics of the&#xD;
      medication in pregnancy, fetal risk, and data quality. The data collected in this study will&#xD;
      update the FDA pregnancy pharmacokinetic section for quetiapine and inform physicians that&#xD;
      prescribe to childbearing women.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Bipolar Disorder (BD) and Schizophrenia (SCHZ) in pregnancy are associated with pregnancy&#xD;
      complications and increased maternal mortality due to physiological and psychosocial changes&#xD;
      independent of second-generation antipsychotic (SGA) use. Untreated BD and SCHZ have been&#xD;
      associated with an increased risk of placental abnormalities, antepartum hemorrhage, preterm&#xD;
      birth, pre-eclampsia, low birth-weight, intrauterine growth retardation, small for&#xD;
      gestational age, fetal distress, neonatal hypoglycemia, stillbirth and congenital defects,&#xD;
      and the potential for adverse neurodevelopmental outcomes. Severe maternal stress in&#xD;
      pregnancy increases the risk for offspring mental disorders, and eye, ear, respiratory,&#xD;
      digestive, skin, musculoskeletal, and genitourinary diseases and congenital malformations&#xD;
      (i.e., cleft palate, cleft lip). Also, BD and SCHZ illness symptoms are linked to&#xD;
      psychosocial consequences that result in poor perinatal outcomes including impulsivity that&#xD;
      leads to reckless behavior such as increased indiscriminate sex and exposure to sexually&#xD;
      transmitted infections, smoking, increased alcohol and drug use, less prenatal care, and poor&#xD;
      nutrition. Furthermore, women with recurrence of mental illness in the perinatal period have&#xD;
      increased risk for suicide, a leading cause of maternal death.&#xD;
&#xD;
      The only published case of quetiapine plasma concentrations in a pregnant woman included&#xD;
      cross-sectional levels of a woman on 300 mg of quetiapine across pregnancy and postpartum.&#xD;
      Compared to six months postpartum, the area under the curve decreased by 27%, 42%, and 18% in&#xD;
      the first, second, and third trimester, respectively. Given the complexity of the metabolism&#xD;
      of quetiapine to a very active metabolite, it is important to understand the altered&#xD;
      metabolism of quetiapine and its active metabolite in pregnancy and the implication for&#xD;
      dosing adjustments.&#xD;
&#xD;
      This study will investigate the longitudinal pharmacokinetics of quetiapine in pregnancy,&#xD;
      delivery, and postpartum. The long-term goal of this line of research is to establish&#xD;
      psychotropic medication dosing algorithms informed by longitudinal pharmacokinetic data to&#xD;
      improve mental health and pregnancy outcomes for mothers with serious mental illness.&#xD;
&#xD;
      The primary aims are: 1) Determine the elimination clearance of quetiapine and its major&#xD;
      active metabolite, 7-N-desalkyquetiapine, across pregnancy and postpartum; 2) Determine the&#xD;
      effect of pharmacokinetic changes on symptoms and toxicity during pregnancy and postpartum,&#xD;
      and; 3) Examine the maternal-to-cord plasma concentrations ratios of quetiapine and its major&#xD;
      active metabolite, 7-N-desalkylquetiapine.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Completed</overall_status>
  <start_date>March 2016</start_date>
  <completion_date type="Actual">December 2020</completion_date>
  <primary_completion_date type="Actual">August 2020</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>Change in plasma concentration/elimination</measure>
    <time_frame>2 timepoints during pregnancy (second and third trimesters), and at four and twelve weeks postpartum</time_frame>
    <description>For patients taking the immediate release formulation, plasma levels will be obtained beginning at time 0 and at hours, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16. For patients on the extended release formulation, plasma levels will be obtained at time 0 and at hours 0.5, 1, 1.5, 2, 2,5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, and 24.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Arterial and Venous Umbilical Cord Concentration of Quetiapine and 7-N-desalylquetiapine</measure>
    <time_frame>30 minutes</time_frame>
    <description>Arterial and venous cord blood samples will be obtained immediately post-delivery and banked for later analysis</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Cerebrospinal Fluid (CSF) Quetiapine and 7-N-desalkyquetiapine Concentrations</measure>
    <time_frame>CSF to be obtained within 10 minutes of the epidural placement during labor</time_frame>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Scores on Depression assessment, Inventory of Depression Symptomatology- Self Report (IDS-SR)</measure>
    <time_frame>Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum</time_frame>
    <description>To determine if there is a pattern of increasing scores on self-report depression assessment (IDS-SR) and declining plasma levels. Increasing scores indicate worsening symptoms or depression episode recurrence.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Scores on anxiety scale, Generalized Anxiety Disorder (GAD-7)</measure>
    <time_frame>Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum</time_frame>
    <description>To determine if there is a pattern of increasing scores on GAD-7 and declining plasma levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Scores on mania assessment, Young Mania Reporting Scale (YMRS)</measure>
    <time_frame>Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.</time_frame>
    <description>To determine if there is a pattern of increasing scores on clinician administered mania assessment (YMRS) and declining plasma levels</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Scores on Brief Psychosis Rating Scale (BPRS)</measure>
    <time_frame>Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.</time_frame>
    <description>assessment to evaluate psychotic symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Positive responses on SAFTEE</measure>
    <time_frame>Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.</time_frame>
    <description>surveys general and specific side effects including somatic, behavioral, and affective symptoms</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Delivery outcomes as determined by the Peripartum Events Scale (PES)</measure>
    <time_frame>4 and 12 weeks postpartum</time_frame>
    <description>assessment to quantify stressful events related to delivery.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Scores on the separate domains of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health</measure>
    <time_frame>Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.</time_frame>
    <description>Assesses patient perceptions in 5 domains:physical function, pain, emotional distress, social function, and fatigue.</description>
  </secondary_outcome>
  <number_of_groups>1</number_of_groups>
  <enrollment type="Actual">4</enrollment>
  <condition>Bipolar Disorder</condition>
  <arm_group>
    <arm_group_label>Quetiapine</arm_group_label>
    <description>Patients taking quetiapine during pregnancy are eligible to participate in the study. Their dose and plasma concentration levels of quetiapine will be monitored throughout pregnancy and up to three months postpartum.</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Quetiapine</intervention_name>
    <description>Quetiapine concentrations will be observed in women who have already (under the guidance of a physician) decided to continue taking Quetiapine for the treatment of Bipolar Disorder (any subtype) or Schizophrenia during pregnancy.</description>
    <arm_group_label>Quetiapine</arm_group_label>
    <other_name>Seroquel</other_name>
  </intervention>
  <biospec_retention>Samples Without DNA</biospec_retention>
  <biospec_descr>
    <textblock>
      Blood serum specimen will be obtained to measure quetiapine and estradiol levels. Standard of&#xD;
      care labs will be obtained on every participant that is eligible and signs informed consent.&#xD;
      Participants will not have more than 50 ml of blood drawn every 8 weeks. Participants will&#xD;
      also have the option to have blood drawn for DNA banking.&#xD;
&#xD;
      Participants in the study that elect to receive analgesia for pain related to labor and have&#xD;
      a spinal-epidural at Northwestern University will have CSF stored and banked for future&#xD;
      analysis.&#xD;
    </textblock>
  </biospec_descr>
  <eligibility>
    <study_pop>
      <textblock>
        Pregnant women taking quetiapine for the purpose of mood stabilizing will be recruited&#xD;
        broadly from Northwestern clinical services, including Internal Medicine, OB/GYN, Family&#xD;
        Medicine, and Psychiatry, registries, and from the local Chicagoland community. Patients&#xD;
        that sign consent, complete the evaluation and meet criteria will be enrolled into the&#xD;
        study.&#xD;
      </textblock>
    </study_pop>
    <sampling_method>Non-Probability Sample</sampling_method>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Age 18-45 years&#xD;
&#xD;
          -  Pregnant, second trimester&#xD;
&#xD;
          -  English-speaking&#xD;
&#xD;
          -  DSM-V diagnosis of Bipolar Disorder or Schizophrenia, any subtype&#xD;
&#xD;
          -  Medically healthy&#xD;
&#xD;
          -  Singleton gestation&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Chronic use of drugs for medical disorders, except thyroid replacement for stable&#xD;
             hypothyroidism&#xD;
&#xD;
          -  No psychiatrist or obstetrician&#xD;
&#xD;
          -  QIDS-SR 16 positive answer 3 on item 12, &quot;I have made specific plans for suicide or&#xD;
             have actually tried to take my life&quot; within the past week&#xD;
&#xD;
          -  DSM-V diagnosis of substance abuse or dependence in last 6 months, with the exception&#xD;
             of cannabis; positive urine drug screen&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Crystal T Clak, MD, MSc</last_name>
    <role>Principal Investigator</role>
    <affiliation>Northwestern University</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>Northwestern Memorial Hospital</name>
      <address>
        <city>Chicago</city>
        <state>Illinois</state>
        <zip>60611</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>September 2022</verification_date>
  <study_first_submitted>November 22, 2016</study_first_submitted>
  <study_first_submitted_qc>November 28, 2016</study_first_submitted_qc>
  <study_first_posted type="Estimate">December 1, 2016</study_first_posted>
  <last_update_submitted>September 26, 2022</last_update_submitted>
  <last_update_submitted_qc>September 26, 2022</last_update_submitted_qc>
  <last_update_posted type="Actual">September 27, 2022</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Northwestern University</investigator_affiliation>
    <investigator_full_name>Crystal Clark</investigator_full_name>
    <investigator_title>Assistant Professor</investigator_title>
  </responsible_party>
  <keyword>pregnant</keyword>
  <keyword>quetiapine</keyword>
  <keyword>bipolar</keyword>
  <keyword>women</keyword>
  <keyword>female</keyword>
  <keyword>postpartum</keyword>
  <keyword>seroquel</keyword>
  <keyword>perinatal</keyword>
  <keyword>manic-depressive</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Bipolar Disorder</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Quetiapine Fumarate</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/NCT02978534
org study id: 00201540
nct id: NCT02978534
lead sponsor: 
has dmc: No
The widespread and common use of quetiapine in childbearing and pregnant women demands more
      data to inform dosing and toxicity in pregnancy. The new FDA Pregnancy and Lactation Labeling
      Final Rule (PLLR) will go into effect on June 30th, 2015 and will replace the prior A, B, C,
      D, and X categories. Additionally, the PLLR will require information to aid prescribing
      decisions in three categories 1) Pregnancy (including labor and delivery), 2) Lactation, and
      3) Females and Males of Reproductive Potential. The pregnancy category will include a
      subsection that will describe pharmacokinetic and pharmacodynamic characteristics of the
      medication in pregnancy, fetal risk, and data quality. The data collected in this study will
      update the FDA pregnancy pharmacokinetic section for quetiapine and inform physicians that
      prescribe to childbearing women.
Bipolar Disorder (BD) and Schizophrenia (SCHZ) in pregnancy are associated with pregnancy
      complications and increased maternal mortality due to physiological and psychosocial changes
      independent of second-generation antipsychotic (SGA) use. Untreated BD and SCHZ have been
      associated with an increased risk of placental abnormalities, antepartum hemorrhage, preterm
      birth, pre-eclampsia, low birth-weight, intrauterine growth retardation, small for
      gestational age, fetal distress, neonatal hypoglycemia, stillbirth and congenital defects,
      and the potential for adverse neurodevelopmental outcomes. Severe maternal stress in
      pregnancy increases the risk for offspring mental disorders, and eye, ear, respiratory,
      digestive, skin, musculoskeletal, and genitourinary diseases and congenital malformations
      (i.e., cleft palate, cleft lip). Also, BD and SCHZ illness symptoms are linked to
      psychosocial consequences that result in poor perinatal outcomes including impulsivity that
      leads to reckless behavior such as increased indiscriminate sex and exposure to sexually
      transmitted infections, smoking, increased alcohol and drug use, less prenatal care, and poor
      nutrition. Furthermore, women with recurrence of mental illness in the perinatal period have
      increased risk for suicide, a leading cause of maternal death.

      The only published case of quetiapine plasma concentrations in a pregnant woman included
      cross-sectional levels of a woman on 300 mg of quetiapine across pregnancy and postpartum.
      Compared to six months postpartum, the area under the curve decreased by 27%, 42%, and 18% in
      the first, second, and third trimester, respectively. Given the complexity of the metabolism
      of quetiapine to a very active metabolite, it is important to understand the altered
      metabolism of quetiapine and its active metabolite in pregnancy and the implication for
      dosing adjustments.

      This study will investigate the longitudinal pharmacokinetics of quetiapine in pregnancy,
      delivery, and postpartum. The long-term goal of this line of research is to establish
      psychotropic medication dosing algorithms informed by longitudinal pharmacokinetic data to
      improve mental health and pregnancy outcomes for mothers with serious mental illness.

      The primary aims are: 1) Determine the elimination clearance of quetiapine and its major
      active metabolite, 7-N-desalkyquetiapine, across pregnancy and postpartum; 2) Determine the
      effect of pharmacokinetic changes on symptoms and toxicity during pregnancy and postpartum,
      and; 3) Examine the maternal-to-cord plasma concentrations ratios of quetiapine and its major
      active metabolite, 7-N-desalkylquetiapine.
observational model: Cohort
time perspective: Prospective
measure: Change in plasma concentration/elimination
time frame: 2 timepoints during pregnancy (second and third trimesters), and at four and twelve weeks postpartum
description: For patients taking the immediate release formulation, plasma levels will be obtained beginning at time 0 and at hours, 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16. For patients on the extended release formulation, plasma levels will be obtained at time 0 and at hours 0.5, 1, 1.5, 2, 2,5, 3, 4, 5, 6, 7, 8, 9, 10, 12, 14, 16, 18, 20, 22, and 24.
measure: Arterial and Venous Umbilical Cord Concentration of Quetiapine and 7-N-desalylquetiapine
time frame: 30 minutes
description: Arterial and venous cord blood samples will be obtained immediately post-delivery and banked for later analysis
measure: Cerebrospinal Fluid (CSF) Quetiapine and 7-N-desalkyquetiapine Concentrations
time frame: CSF to be obtained within 10 minutes of the epidural placement during labor
measure: Scores on Depression assessment, Inventory of Depression Symptomatology- Self Report (IDS-SR)
time frame: Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum
description: To determine if there is a pattern of increasing scores on self-report depression assessment (IDS-SR) and declining plasma levels. Increasing scores indicate worsening symptoms or depression episode recurrence.
measure: Scores on anxiety scale, Generalized Anxiety Disorder (GAD-7)
time frame: Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum
description: To determine if there is a pattern of increasing scores on GAD-7 and declining plasma levels
measure: Scores on mania assessment, Young Mania Reporting Scale (YMRS)
time frame: Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
description: To determine if there is a pattern of increasing scores on clinician administered mania assessment (YMRS) and declining plasma levels
measure: Scores on Brief Psychosis Rating Scale (BPRS)
time frame: Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
description: assessment to evaluate psychotic symptoms
measure: Positive responses on SAFTEE
time frame: Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
description: surveys general and specific side effects including somatic, behavioral, and affective symptoms
measure: Delivery outcomes as determined by the Peripartum Events Scale (PES)
time frame: 4 and 12 weeks postpartum
description: assessment to quantify stressful events related to delivery.
measure: Scores on the separate domains of the Patient Reported Outcomes Measurement Information System (PROMIS) Global Health
time frame: Participants will complete these assessments an average of every 10 weeks from the time they enter the study, up to 12 weeks postpartum.
description: Assesses patient perceptions in 5 domains:physical function, pain, emotional distress, social function, and fatigue.
arm group label: Quetiapine
description: Patients taking quetiapine during pregnancy are eligible to participate in the study. Their dose and plasma concentration levels of quetiapine will be monitored throughout pregnancy and up to three months postpartum.
intervention type: Drug
intervention name: Quetiapine
description: Quetiapine concentrations will be observed in women who have already (under the guidance of a physician) decided to continue taking Quetiapine for the treatment of Bipolar Disorder (any subtype) or Schizophrenia during pregnancy.
arm group label: Quetiapine
other name: Seroquel
Blood serum specimen will be obtained to measure quetiapine and estradiol levels. Standard of
      care labs will be obtained on every participant that is eligible and signs informed consent.
      Participants will not have more than 50 ml of blood drawn every 8 weeks. Participants will
      also have the option to have blood drawn for DNA banking.

      Participants in the study that elect to receive analgesia for pain related to labor and have
      a spinal-epidural at Northwestern University will have CSF stored and banked for future
      analysis.
study pop: 
sampling method: Non-Probability Sample
criteria: 
gender: Female
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: No
last name: Crystal T Clak, MD, MSc
role: Principal Investigator
affiliation: Northwestern University
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Northwestern University
investigator full name: Crystal Clark
investigator title: Assistant Professor
mesh term: Bipolar Disorder
mesh term: Quetiapine Fumarate
sharing ipd: No