<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/NCT03831113</url>
  </required_header>
  <id_info>
    <org_study_id>PRO18070495/STUDY19100128</org_study_id>
    <secondary_id>R01HD096796</secondary_id>
    <nct_id>NCT03831113</nct_id>
  </id_info>
  <brief_title>Pharmacologically-based Strategies for Opioid Substitution Therapy During Pregnancy</brief_title>
  <official_title>Pharmacologically-based Strategies for Opioid Substitution Therapy During Pregnancy</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Steve N. Caritis, MD</agency>
      <agency_class>Other</agency_class>
    </lead_sponsor>
    <collaborator>
      <agency>Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)</agency>
      <agency_class>NIH</agency_class>
    </collaborator>
  </sponsors>
  <source>University of Pittsburgh</source>
  <oversight_info>
    <has_dmc>No</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
    <is_us_export>No</is_us_export>
  </oversight_info>
  <brief_summary>
    <textblock>
      This study will evaluate maternal tolerance to several BUP dose reduction strategies.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Opioid use has reached a staggering level and the associated deaths, neonatal consequences&#xD;
      and economic impact are devastating. Pregnancy provides a window of opportunity for women&#xD;
      with an opioid use disorder (OUD) to seek assistance by participating in a program that&#xD;
      offers medication-assisted treatment (MAT), most commonly with buprenorphine (BUP) or&#xD;
      methadone. BUP offers advantages over methadone including ease of administration and less&#xD;
      severe neonatal abstinence syndrome (NAS) but has a higher discontinuation rate, especially&#xD;
      during induction. The high discontinuation rate may be due to an inadequate dosing as the&#xD;
      current dosing strategies are not informed by pharmacokinetic (PK) or pharmacodynamic (PD)&#xD;
      data in pregnancy. The lack of BUP PD data hampers development of an effective dosing&#xD;
      strategy and challenges the validity of the primary tools used to gauge maternal and infant&#xD;
      withdrawal. Neither the Clinical Opioid Withdrawal Scale (COWS) nor the Finnegan score for&#xD;
      the diagnosis of NAS considers the pharmacology of BUP and therefore may not provide a valid&#xD;
      representation of opioid withdrawal. BUP PD data are critically necessary to address these&#xD;
      issues and are also necessary to develop detoxification regimens. Creation of safe and&#xD;
      effective detoxification regimens requires a pharmacological basis and must be developed in&#xD;
      the context that the brain requires time to adjust to opioid induced changes. In this&#xD;
      proposal, investigators hypothesize that determination of BUP pharmacodynamics will improve&#xD;
      care for the pregnant opioid dependent mother and her baby and will fill the critical&#xD;
      knowledge gaps needed for safe and effective management of women with an OUD.&#xD;
&#xD;
      For opioid using women, the diagnosis of NAS is viewed as one of the key outcomes to be&#xD;
      identified since those infants will need treatment for their perceived withdrawal. Neonatal&#xD;
      withdrawal, however, is likely a surrogate for fetal exposure to opioids and not an optimal&#xD;
      means of identifying the long-term effects of opioid exposure. The focus on the diagnosis of&#xD;
      NAS ignores the importance and risks of opioid exposure on the brain of the infant without&#xD;
      NAS. Neuroimaging of the fetal and neonatal brain and neurodevelopmental studies of all&#xD;
      infants exposed to opioids, whether or not they are diagnosed as having NAS, will provide&#xD;
      tangible long-term measures of the effect of opioids. The relationship between fetal in utero&#xD;
      exposure and neonatal outcomes will be explored using maternal and baby hair, placenta, cord&#xD;
      and meconium as indicators of chronic maternal and fetal exposure as these are unaffected by&#xD;
      maternal truthfulness or acute dosing at the time of delivery. We will relate these&#xD;
      indicators of opioid exposure to NAS, as well as to the neuroanatomic and neurodevelopmental&#xD;
      outcomes of opioid exposed infants.&#xD;
&#xD;
      As part of the dose reduction clinical trial, investigators will compare dose reduction&#xD;
      strategies for BUP in pregnancy that are based on the pharmacodynamic and pharmacokinetic&#xD;
      characteristics of BUP. The dose reduction strategies that will be evaluated in this clinical&#xD;
      trial are part of a larger project including an observational study.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Recruiting</overall_status>
  <start_date type="Actual">April 13, 2019</start_date>
  <completion_date type="Anticipated">May 31, 2024</completion_date>
  <primary_completion_date type="Anticipated">May 31, 2024</primary_completion_date>
  <phase>Phase 2</phase>
  <study_type>Interventional</study_type>
  <has_expanded_access>No</has_expanded_access>
  <study_design_info>
    <allocation>Non-Randomized</allocation>
    <intervention_model>Sequential Assignment</intervention_model>
    <intervention_model_description>dose alternates between 1 or 2 mg reductions or 1 or 2 week decrements</intervention_model_description>
    <primary_purpose>Treatment</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Plasma levels of buprenorphine + metabolites, neurotransmitters (serotonin, dopamine and nor-adrenaline), and cotinine</measure>
    <time_frame>4.5 years</time_frame>
    <description>Investigators will monitor plasma levels (ng/ml) of buprenorphine+metabolites (BUP+M), neurotransmitters, and cotinine levels during weekly clinic visits. The subject's weekly plasma concentrations will be compared to the VAS scores to determine the change in mu receptor sensitivity.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Visual Analog Scale (VAS) Scores</measure>
    <time_frame>4.5 years</time_frame>
    <description>The VAS questionnaire consists of 4 questions related to cravings, withdrawal, sleep quality and sleep duration. Subjects will complete this questionnaire daily and at the weekly clinic visits. Subjects will grade each category on a scale of 0-100 in increments of 10. The VAS scores will be used within and across groups to evaluate the tolerance of the dose reductions (magnitude and frequency).</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Clinical Opioid Withdrawal Scale (COWS) scores</measure>
    <time_frame>4.5 years</time_frame>
    <description>The COWS questionnaire consists of 11 questions and will be completed at the weekly clinic visits. Responses to each question are graded on a scale of 0-4 and the total of all responses correlates to a particular withdrawal severity: mild (5-12), moderate (13-24), moderately severe (25-36), severe (&gt;36). COWS scores will be used to assess the subject's tolerance to the dose reductions by measuring withdrawal and satiety.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Subjective Opioid Withdrawal Scale (SOWS) scores</measure>
    <time_frame>4.5 years</time_frame>
    <description>The SOWS questionnaire consists of 16 questions and will be completed at the weekly clinic visits. Responses to each question are graded on a scale of 0-4 and the total of all responses correlates to a particular withdrawal severity: mild (1-10), moderate (11-20), severe (21-30). SOWS scores will be used to assess the current subjective symptoms of withdrawal and satiety.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Weekly Follow-up Form</measure>
    <time_frame>4.5 years</time_frame>
    <description>The weekly follow-up form consists of 17 questions and will be completed at the weekly clinic visits. Subjects are asked to grade their cravings, withdrawal symptoms, and sleep quality on a scale of 1-10. The form also includes questions regarding which days were the best and worst for cravings, withdrawal and sleep and what the subject did to manage her symptoms.</description>
  </primary_outcome>
  <primary_outcome>
    <measure>Weekly Smoking and Alcohol Use Form</measure>
    <time_frame>4.5 years</time_frame>
    <description>The weekly smoking and alcohol form consists of 4 questions concerning tobacco, alcohol, vaping, and marijuana use in the last week. If the subject answers &quot;yes&quot; to any questions, they are asked to quantify the amount used and indicate whether this habit has changed since starting the dose reduction.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Urine toxicology screen</measure>
    <time_frame>4.5 years</time_frame>
    <description>Urine toxicology screens will be performed during the weekly clinic visits to confirm that the subject is compliant with the study requirements.</description>
  </secondary_outcome>
  <number_of_arms>3</number_of_arms>
  <enrollment type="Anticipated">30</enrollment>
  <condition>Opiate Addiction</condition>
  <condition>Pregnancy</condition>
  <arm_group>
    <arm_group_label>Buprenorphine Magnitude Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive alternating reductions of 1 mg and then 2 mg weekly. Subjects on thrice daily (TID) or four times daily (QID) dosing, as prescribed by their MAT provider, will be assigned to either the Magnitude or Frequency group (n=10).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Buprenorphine Frequency Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive dose reductions of 2 mg on alternating intervals of 1 and 2 weeks. Subjects on TID or QID dosing, as prescribed by their MAT provider, will be assigned to either the Magnitude or Frequency group (n=10).</description>
  </arm_group>
  <arm_group>
    <arm_group_label>Buprenorphine Dosing Group</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Subjects will receive dose reductions identical to either the Magnitude (alternating 1 and 2 mg reductions) or Frequency (2 mg reductions on alternating 1 and 2 week intervals) groups. Subjects on BID dosing, as prescribed by their MAT provider, will be assigned to the Dosing group (n=10).</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Buprenorphine: Magnitude Group</intervention_name>
    <description>Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.</description>
    <arm_group_label>Buprenorphine Frequency Group</arm_group_label>
    <arm_group_label>Buprenorphine Magnitude Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Buprenorphine: Frequency Group</intervention_name>
    <description>Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.</description>
    <arm_group_label>Buprenorphine Frequency Group</arm_group_label>
    <arm_group_label>Buprenorphine Magnitude Group</arm_group_label>
  </intervention>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Buprenorphine: Dosing Group</intervention_name>
    <description>Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.</description>
    <arm_group_label>Buprenorphine Dosing Group</arm_group_label>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Specific Aim 1:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. Singleton gestation between 14-35 weeks&#xD;
&#xD;
          2. On a stable BUP dose (for at least 2 weeks) through a MAT program or just starting BUP&#xD;
             therapy through a MAT program.&#xD;
&#xD;
          3. Willingness to consent to the study and for those on a stable BUP dose, willingness to&#xD;
             experience mild, temporary withdrawal symptoms&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Multifetal gestation, major fetal malformation&#xD;
&#xD;
          2. Urine drug screen results positive for benzodiazepines, cocaine, heroin, barbiturates,&#xD;
             phencyclidine (PCP), or opioids other than BUP&#xD;
&#xD;
               1. Subjects already enrolled in a MAT program must have negative urine drug screens&#xD;
                  at the Pre-Study Screening and again on the day of the PD study.&#xD;
&#xD;
               2. Subjects initiating BUP therapy will have a comprehensive drug screen performed&#xD;
                  on the day of the PD study. Results that are positive for the presence of&#xD;
                  cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP) or opioids&#xD;
                  other than BUP will be documented, but will not be used to determine eligibility&#xD;
                  for the study.&#xD;
&#xD;
          3. Currently taking more than one mental health medication&#xD;
&#xD;
          4. Active moderately severe depression (PHQ-9 score ≥15 or suicidal ideation)&#xD;
&#xD;
          5. Clinical signs of intoxication or mental disorientation at time of study&#xD;
&#xD;
          6. Uncontrolled hypertension&#xD;
&#xD;
          7. HIV or AIDS&#xD;
&#xD;
          8. Diagnosis of schizoaffective disorder or psychosis&#xD;
&#xD;
        Specific Aim 2:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. Singleton gestation greater than 37 0/7 weeks&#xD;
&#xD;
          2. Mother on BUP for at least 8 weeks prior to delivery.&#xD;
&#xD;
          3. Mother in a MAT program.&#xD;
&#xD;
          4. Infant with 5 minute Apgar scores &gt;/= 6.&#xD;
&#xD;
          5. No maternal cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or&#xD;
             opioids other than BUP in last 8 weeks of pregnancy, based on the urine drug screen&#xD;
             results from the MAT clinic.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Major fetal/neonatal malformation.&#xD;
&#xD;
          2. Delivery at non-study hospital.&#xD;
&#xD;
          3. Fetal growth restriction - BW &lt; 10th percentile&#xD;
&#xD;
          4. Known fetal renal or hepatic disease that affects drug metabolism or elimination&#xD;
&#xD;
          5. Infant on ventilator support&#xD;
&#xD;
          6. HIV or AIDS&#xD;
&#xD;
        Specific Aim 3:&#xD;
&#xD;
        Part 1:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. Singleton gestation greater than 37 0/7 weeks&#xD;
&#xD;
          2. Mother on BUP for at least 12 weeks prior to delivery and compliant with clinic&#xD;
             policies&#xD;
&#xD;
          3. Willingness to consent to the collection of biological samples; at a minimum, she must&#xD;
             consent to a maternal hair sample, as well as a neonate hair sample and/or meconium.&#xD;
&#xD;
          4. Availability of prenatal records from Ob care provider and BUP dosing records&#xD;
&#xD;
          5. Infant with 5 minute Apgar scores ≥ 6&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Multifetal gestation&#xD;
&#xD;
          2. Major fetal malformation&#xD;
&#xD;
          3. HIV or AIDS&#xD;
&#xD;
          4. Planned delivery at another institution&#xD;
&#xD;
          5. Medical or obstetrical complications in current pregnancy including: preeclampsia,&#xD;
             poorly controlled diabetes or hypertension, or fetal growth restriction&#xD;
&#xD;
          6. Use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or opioids&#xD;
             other than BUP in the last 12 weeks of pregnancy, based on urine drug screen results&#xD;
             from the MAT clinic&#xD;
&#xD;
          7. Currently taking more than one mental health medication&#xD;
&#xD;
          8. Active moderately severe depression (PHQ-9 score ≥15 or suicidal ideation)&#xD;
&#xD;
          9. Alcohol abuse anytime during the current pregnancy&#xD;
&#xD;
        Specific Aim 3:&#xD;
&#xD;
        Part 2:&#xD;
&#xD;
        Inclusion Criteria&#xD;
&#xD;
          1. Single gestation between 35 0/7 and 38 0/7 weeks at the time of fetal imaging&#xD;
&#xD;
          2. Mother on BUP or methadone for at least 12 weeks prior to delivery and compliant with&#xD;
             clinic policies&#xD;
&#xD;
          3. Willingness to consent to study requirements; at a minimum, she must consent to a&#xD;
             fetal and neonatal MRI, maternal hair sample, as well as a neonate hair sample and/or&#xD;
             meconium.&#xD;
&#xD;
          4. Availability of prenatal records from Ob care provider and BUP or methadone dosing&#xD;
             records&#xD;
&#xD;
        Exclusion Criteria&#xD;
&#xD;
          1. Multifetal gestation&#xD;
&#xD;
          2. Major fetal malformation&#xD;
&#xD;
          3. HIV or AIDS&#xD;
&#xD;
          4. Medical or obstetrical complications in current pregnancy including: preeclampsia,&#xD;
             poorly controlled diabetes or hypertension, or fetal growth restriction&#xD;
&#xD;
          5. Current use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or&#xD;
             opioids other than BUP or methadone based on the comprehensive urine drug screen&#xD;
             performed within 1-2 weeks prior to the fetal MRI exam.&#xD;
&#xD;
             Use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or opioids&#xD;
             other than BUP or methadone in last 12 weeks prior to the fetal MRI exam, based on&#xD;
             urine drug screen results from the MAT clinic&#xD;
&#xD;
          6. Currently taking more than one mental health medication&#xD;
&#xD;
          7. Active moderately severe depression (PHQ-9 score ≥15 or suicidal ideation)&#xD;
&#xD;
          8. Alcohol abuse anytime during the current pregnancy&#xD;
&#xD;
          9. Any contraindication to MRI such as a pacemaker, claustrophobia, or any metallic&#xD;
             implant&#xD;
&#xD;
         10. Current or recent (last 2 years) history of incarceration&#xD;
&#xD;
        Specific Aim 4:&#xD;
&#xD;
        Inclusion Criteria:&#xD;
&#xD;
          1. On a stable BID, TID or QID dosing regimen of BUP for at least 2 weeks as part of an&#xD;
             established medication- assisted treatment (MAT) program.&#xD;
&#xD;
          2. Willingness to undergo supervised dose reduction&#xD;
&#xD;
          3. Subjects on BID, TID or QID dosing, willingness to be assigned to either the&#xD;
             Magnitude, Interval/Frequency, or Dosing group, depending on their current dosing.&#xD;
&#xD;
          4. Single gestation between 14-30 weeks at the initiation of the dose reduction&#xD;
&#xD;
          5. On a BUP dose between 6- 24 mg daily (lower doses will not provide sufficient data&#xD;
             points)&#xD;
&#xD;
          6. Willingness to have urine samples tested for drugs of abuse and blood samples tested&#xD;
             for BUP+M concentrations during the Medical Supervised Withdrawal (MSW) clinic&#xD;
             appointments&#xD;
&#xD;
          7. Willingness to attend weekly or biweekly MSW clinic appointments and to have daily&#xD;
             contact via text messaging and to complete daily logs of sleep quality, withdrawal&#xD;
             symptoms and symptoms of craving.&#xD;
&#xD;
          8. Willingness to attend psychosocial support meetings as needed.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          1. Current use of cocaine, heroin, benzodiazepines, barbiturates, phencyclidine (PCP), or&#xD;
             opioids other than BUP.&#xD;
&#xD;
          2. Currently taking more than two mental health medications&#xD;
&#xD;
          3. Active moderately severe depression (PHQ-9 score ≥15 or suicidal ideation)&#xD;
&#xD;
          4. Current incarceration&#xD;
&#xD;
          5. Lack of a phone or transportation to and from clinic&#xD;
&#xD;
          6. Major fetal malformation&#xD;
&#xD;
          7. Mother with significant vaginal bleeding or serious medical or obstetrical&#xD;
             complication that could adversely affect the study&#xD;
&#xD;
          8. Planned delivery at another institution&#xD;
&#xD;
          9. HIV or AIDS&#xD;
&#xD;
         10. Diagnosis of schizoaffective disorder or psychosis&#xD;
      </textblock>
    </criteria>
    <gender>Female</gender>
    <gender_based>Yes</gender_based>
    <gender_description>Pregnant women who have been prescribed buprenorphine by a Medication Assisted Treatment (MAT) clinic.</gender_description>
    <minimum_age>18 Years</minimum_age>
    <maximum_age>45 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Steve Caritis, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Pittsburgh</affiliation>
  </overall_official>
  <overall_contact>
    <last_name>Donna DeAngelis, BS</last_name>
    <phone>4126414258</phone>
    <email>deangelisd@UPMC.edu</email>
  </overall_contact>
  <overall_contact_backup>
    <last_name>Steve Caritis, MD</last_name>
    <phone>412-641-5403</phone>
    <email>scaritis@upmc.edu</email>
  </overall_contact_backup>
  <location>
    <facility>
      <name>Univerity of Pittsburgh Magee-Womens Hospital</name>
      <address>
        <city>Pittsburgh</city>
        <state>Pennsylvania</state>
        <zip>15213</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Recruiting</status>
    <contact>
      <last_name>Donna DeAngelis, BS</last_name>
      <phone>412-641-4258</phone>
      <email>deangelisd@upmc.edu</email>
    </contact>
    <investigator>
      <last_name>Steve N Caritis, MD</last_name>
      <role>Principal Investigator</role>
    </investigator>
    <investigator>
      <last_name>Raman Venkataramanan, PhD</last_name>
      <role>Sub-Investigator</role>
    </investigator>
  </location>
  <location>
    <facility>
      <name>High Risk Obstetrical Consultants</name>
      <address>
        <city>Knoxville</city>
        <state>Tennessee</state>
        <zip>39720</zip>
        <country>United States</country>
      </address>
    </facility>
    <status>Terminated</status>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>June 2023</verification_date>
  <study_first_submitted>January 22, 2019</study_first_submitted>
  <study_first_submitted_qc>February 4, 2019</study_first_submitted_qc>
  <study_first_posted type="Actual">February 5, 2019</study_first_posted>
  <last_update_submitted>June 2, 2023</last_update_submitted>
  <last_update_submitted_qc>June 2, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">June 6, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Sponsor-Investigator</responsible_party_type>
    <investigator_affiliation>University of Pittsburgh</investigator_affiliation>
    <investigator_full_name>Steve N. Caritis, MD</investigator_full_name>
    <investigator_title>Professor, Department of OB/Gyn/RS</investigator_title>
  </responsible_party>
  <keyword>Buprenorphine</keyword>
  <keyword>medication-assisted treatment (MAT) programs</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Opioid-Related Disorders</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Buprenorphine</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/NCT03831113
org study id: PRO18070495/STUDY19100128
secondary id: R01HD096796
nct id: NCT03831113
lead sponsor: 
collaborator: 
has dmc: No
is fda regulated drug: Yes
is fda regulated device: No
is us export: No
This study will evaluate maternal tolerance to several BUP dose reduction strategies.
Opioid use has reached a staggering level and the associated deaths, neonatal consequences
      and economic impact are devastating. Pregnancy provides a window of opportunity for women
      with an opioid use disorder (OUD) to seek assistance by participating in a program that
      offers medication-assisted treatment (MAT), most commonly with buprenorphine (BUP) or
      methadone. BUP offers advantages over methadone including ease of administration and less
      severe neonatal abstinence syndrome (NAS) but has a higher discontinuation rate, especially
      during induction. The high discontinuation rate may be due to an inadequate dosing as the
      current dosing strategies are not informed by pharmacokinetic (PK) or pharmacodynamic (PD)
      data in pregnancy. The lack of BUP PD data hampers development of an effective dosing
      strategy and challenges the validity of the primary tools used to gauge maternal and infant
      withdrawal. Neither the Clinical Opioid Withdrawal Scale (COWS) nor the Finnegan score for
      the diagnosis of NAS considers the pharmacology of BUP and therefore may not provide a valid
      representation of opioid withdrawal. BUP PD data are critically necessary to address these
      issues and are also necessary to develop detoxification regimens. Creation of safe and
      effective detoxification regimens requires a pharmacological basis and must be developed in
      the context that the brain requires time to adjust to opioid induced changes. In this
      proposal, investigators hypothesize that determination of BUP pharmacodynamics will improve
      care for the pregnant opioid dependent mother and her baby and will fill the critical
      knowledge gaps needed for safe and effective management of women with an OUD.

      For opioid using women, the diagnosis of NAS is viewed as one of the key outcomes to be
      identified since those infants will need treatment for their perceived withdrawal. Neonatal
      withdrawal, however, is likely a surrogate for fetal exposure to opioids and not an optimal
      means of identifying the long-term effects of opioid exposure. The focus on the diagnosis of
      NAS ignores the importance and risks of opioid exposure on the brain of the infant without
      NAS. Neuroimaging of the fetal and neonatal brain and neurodevelopmental studies of all
      infants exposed to opioids, whether or not they are diagnosed as having NAS, will provide
      tangible long-term measures of the effect of opioids. The relationship between fetal in utero
      exposure and neonatal outcomes will be explored using maternal and baby hair, placenta, cord
      and meconium as indicators of chronic maternal and fetal exposure as these are unaffected by
      maternal truthfulness or acute dosing at the time of delivery. We will relate these
      indicators of opioid exposure to NAS, as well as to the neuroanatomic and neurodevelopmental
      outcomes of opioid exposed infants.

      As part of the dose reduction clinical trial, investigators will compare dose reduction
      strategies for BUP in pregnancy that are based on the pharmacodynamic and pharmacokinetic
      characteristics of BUP. The dose reduction strategies that will be evaluated in this clinical
      trial are part of a larger project including an observational study.
allocation: Non-Randomized
intervention model: Sequential Assignment
intervention model description: dose alternates between 1 or 2 mg reductions or 1 or 2 week decrements
primary purpose: Treatment
masking: None (Open Label)
measure: Plasma levels of buprenorphine + metabolites, neurotransmitters (serotonin, dopamine and nor-adrenaline), and cotinine
time frame: 4.5 years
description: Investigators will monitor plasma levels (ng/ml) of buprenorphine+metabolites (BUP+M), neurotransmitters, and cotinine levels during weekly clinic visits. The subject's weekly plasma concentrations will be compared to the VAS scores to determine the change in mu receptor sensitivity.
measure: Visual Analog Scale (VAS) Scores
time frame: 4.5 years
description: The VAS questionnaire consists of 4 questions related to cravings, withdrawal, sleep quality and sleep duration. Subjects will complete this questionnaire daily and at the weekly clinic visits. Subjects will grade each category on a scale of 0-100 in increments of 10. The VAS scores will be used within and across groups to evaluate the tolerance of the dose reductions (magnitude and frequency).
measure: Clinical Opioid Withdrawal Scale (COWS) scores
time frame: 4.5 years
description: The COWS questionnaire consists of 11 questions and will be completed at the weekly clinic visits. Responses to each question are graded on a scale of 0-4 and the total of all responses correlates to a particular withdrawal severity: mild (5-12), moderate (13-24), moderately severe (25-36), severe (>36). COWS scores will be used to assess the subject's tolerance to the dose reductions by measuring withdrawal and satiety.
measure: Subjective Opioid Withdrawal Scale (SOWS) scores
time frame: 4.5 years
description: The SOWS questionnaire consists of 16 questions and will be completed at the weekly clinic visits. Responses to each question are graded on a scale of 0-4 and the total of all responses correlates to a particular withdrawal severity: mild (1-10), moderate (11-20), severe (21-30). SOWS scores will be used to assess the current subjective symptoms of withdrawal and satiety.
measure: Weekly Follow-up Form
time frame: 4.5 years
description: The weekly follow-up form consists of 17 questions and will be completed at the weekly clinic visits. Subjects are asked to grade their cravings, withdrawal symptoms, and sleep quality on a scale of 1-10. The form also includes questions regarding which days were the best and worst for cravings, withdrawal and sleep and what the subject did to manage her symptoms.
measure: Weekly Smoking and Alcohol Use Form
time frame: 4.5 years
description: The weekly smoking and alcohol form consists of 4 questions concerning tobacco, alcohol, vaping, and marijuana use in the last week. If the subject answers "yes" to any questions, they are asked to quantify the amount used and indicate whether this habit has changed since starting the dose reduction.
measure: Urine toxicology screen
time frame: 4.5 years
description: Urine toxicology screens will be performed during the weekly clinic visits to confirm that the subject is compliant with the study requirements.
arm group label: Buprenorphine Magnitude Group
arm group type: Experimental
description: Subjects will receive alternating reductions of 1 mg and then 2 mg weekly. Subjects on thrice daily (TID) or four times daily (QID) dosing, as prescribed by their MAT provider, will be assigned to either the Magnitude or Frequency group (n=10).
arm group label: Buprenorphine Frequency Group
arm group type: Experimental
description: Subjects will receive dose reductions of 2 mg on alternating intervals of 1 and 2 weeks. Subjects on TID or QID dosing, as prescribed by their MAT provider, will be assigned to either the Magnitude or Frequency group (n=10).
arm group label: Buprenorphine Dosing Group
arm group type: Experimental
description: Subjects will receive dose reductions identical to either the Magnitude (alternating 1 and 2 mg reductions) or Frequency (2 mg reductions on alternating 1 and 2 week intervals) groups. Subjects on BID dosing, as prescribed by their MAT provider, will be assigned to the Dosing group (n=10).
intervention type: Drug
intervention name: Buprenorphine: Magnitude Group
description: Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.
arm group label: Buprenorphine Frequency Group
arm group label: Buprenorphine Magnitude Group
intervention type: Drug
intervention name: Buprenorphine: Frequency Group
description: Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.
arm group label: Buprenorphine Frequency Group
arm group label: Buprenorphine Magnitude Group
intervention type: Drug
intervention name: Buprenorphine: Dosing Group
description: Dose reductions will continue until the subject is no longer taking buprenorphine or is at the lowest tolerable dose.
arm group label: Buprenorphine Dosing Group
criteria: 
gender: Female
gender based: Yes
gender description: Pregnant women who have been prescribed buprenorphine by a Medication Assisted Treatment (MAT) clinic.
minimum age: 18 Years
maximum age: 45 Years
healthy volunteers: No
last name: Steve Caritis, MD
role: Principal Investigator
affiliation: University of Pittsburgh
last name: Donna DeAngelis, BS
phone: 4126414258
email: deangelisd@UPMC.edu
last name: Steve Caritis, MD
phone: 412-641-5403
email: scaritis@upmc.edu
facility: 
status: Recruiting
contact: 
investigator: 
investigator: 
facility: 
status: Terminated
country: United States
responsible party type: Sponsor-Investigator
investigator affiliation: University of Pittsburgh
investigator full name: Steve N. Caritis, MD
investigator title: Professor, Department of OB/Gyn/RS
mesh term: Opioid-Related Disorders
mesh term: Buprenorphine
sharing ipd: No