<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/NCT03781752</url>
  </required_header>
  <id_info>
    <org_study_id>GCO 17-0281</org_study_id>
    <secondary_id>1R01HD093612-01A1</secondary_id>
    <nct_id>NCT03781752</nct_id>
  </id_info>
  <brief_title>Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD</brief_title>
  <official_title>Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD</official_title>
  <sponsors>
    <lead_sponsor>
      <agency>Icahn School of Medicine at Mount Sinai</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>
    <collaborator>
      <agency>University of Florida</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Children's Hospital Medical Center, Cincinnati</agency>
      <agency_class>Other</agency_class>
    </collaborator>
    <collaborator>
      <agency>Seattle Children's Hospital</agency>
      <agency_class>Other</agency_class>
    </collaborator>
  </sponsors>
  <source>Icahn School of Medicine at Mount Sinai</source>
  <oversight_info>
    <has_dmc>Yes</has_dmc>
    <is_fda_regulated_drug>Yes</is_fda_regulated_drug>
    <is_fda_regulated_device>No</is_fda_regulated_device>
  </oversight_info>
  <brief_summary>
    <textblock>
      The study team will determine the association between d,l-methylphenidate (MPH) therapeutic&#xD;
      outcomes in ADHD patients and genetic variants of CES1 and reveal key associations between&#xD;
      CES1 genotypes and the PK and PD of MPH.&#xD;
    </textblock>
  </brief_summary>
  <detailed_description>
    <textblock>
      Psychostimulants are the first-line pharmacotherapy for Attention deficit-hyperactivity&#xD;
      disorder (ADHD), and MPH accounts for approximately 50% of all stimulant usage. There has&#xD;
      been an ~10-fold increase in MPH prescribing since 1990, with 18 million prescriptions&#xD;
      dispensed in 2010, including 1.9 million new starts on MPH, making it the 5th most commonly&#xD;
      prescribed medication to children ages 2 -11 and the single most frequently prescribed&#xD;
      medication of any type in those aged 12-17 years. The annual exposure of pediatric patients&#xD;
      to MPH is extremely high and MPH is among the most commonly prescribed chronic use oral&#xD;
      medications for US children. Despite nearly 60 years of accrued clinical experience with MPH,&#xD;
      the significant inter-individual variability in MPH pharmacokinetics (PK), pharmacodynamics&#xD;
      (PD) and adverse effects is inadequately explained and unpredictable. Up to 35% of ADHD&#xD;
      patients do not respond satisfactorily to MPH therapy, and an even larger percentage&#xD;
      discontinues treatment despite persistent ADHD. During clinical trials of MPH in&#xD;
      treatment-naïve patients, a significant number suffer from adverse effects that are severe&#xD;
      and persistent enough to require dose decreases or even study withdrawal. Moreover, some&#xD;
      severe adverse drug reactions (ADRs) - including sudden cardiac death - have been associated&#xD;
      with MPH, although the precise reasons for these associations remain elusive and&#xD;
      controversial. Research efforts have been made to identify genetic biomarkers associated with&#xD;
      MPH therapeutic outcomes, almost exclusively focusing on genes related to MPH PD (e.g.,&#xD;
      dopamine transporter gene [DAT1, SLC6A3]). Unfortunately, findings from these studies have&#xD;
      been somewhat inconsistent, equivocal or even contradictory, and they do not explain the&#xD;
      variability in the PK of MPH. Pharmacogenomic studies in MPH-treated children have not&#xD;
      assessed the influence of genes associated with individual variability in PK in relation to&#xD;
      clinical response. Carboxylesterase-1 (CES1), an abundant hepatic enzyme encoded by the&#xD;
      polymorphic CES1 gene, is the sole hepatic enzyme catalyzing the metabolism (i.e., hydrolytic&#xD;
      deactivation) of MPH. CES1 expression and activity are known to vary substantially among&#xD;
      individuals. The first clinically significant CES1 variant G143E (rs71647871), discovered in&#xD;
      the study team's lab during the course of a healthy volunteer MPH PK study, led to gross&#xD;
      impairments in MPH metabolism. This variant has been unequivocally shown in vitro and in&#xD;
      clinical studies to lead to significantly impaired metabolism of MPH and other known CES1&#xD;
      substrates. The study team has established the minor allele frequency (MAF) of the G143E&#xD;
      variant as 3-4% in the general population. Accordingly, with ~1.9 million new starts of MPH&#xD;
      annually, an estimated 133,000 pediatric patients (i.e. G143E carrier's frequency 6-8%) with&#xD;
      a genetically impaired ability to metabolize/deactivate the drug will receive it - exposing&#xD;
      them to high systemic concentrations of MPH and any attendant risks or toxicities. In&#xD;
      addition, the study team's in vitro studies have revealed that another common CES1 variant&#xD;
      D203E (rs2307227) exhibited significantly impaired activity on MPH metabolism, although the&#xD;
      effects on D203E on clinical response are in need of further elucidation. Furthermore,&#xD;
      despite recent intensive research on CES1 pharmacogenetics, the functions of a large number&#xD;
      of additional CES1 variants remain undetermined.&#xD;
&#xD;
      The study team's hypothesis is that the CES1 variants, such as the G143E and D203E, can&#xD;
      significantly alter the expression and/or activity of CES1, thereby influencing the&#xD;
      metabolism and disposition of MPH. These influences will be directly investigated in relation&#xD;
      to MPH therapeutic response and tolerability in ADHD patients.&#xD;
    </textblock>
  </detailed_description>
  <overall_status>Enrolling by invitation</overall_status>
  <start_date type="Actual">March 4, 2018</start_date>
  <completion_date type="Anticipated">September 2024</completion_date>
  <primary_completion_date type="Anticipated">September 2024</primary_completion_date>
  <phase>Phase 4</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>
    <intervention_model_description>Youth will NOT be randomized to drug for this PD study, but will receive MPH from their treatment providers in clinical care either before or after being invited to participate in the PK procedure. Their treatment data will be collected from their providers to augment the study team's analyses. The study team is performing a pharmacokinetic (PK) study using a single dose of methylphenidate (MPH) among youth identified as having specific variants of the CES1 gene. Youth will be identified by cheek swabs for CES1 variants. They will be provided . MPH for the PK procedure.</intervention_model_description>
    <primary_purpose>Basic Science</primary_purpose>
    <masking>None (Open Label)</masking>
  </study_design_info>
  <primary_outcome>
    <measure>Maximum methylphenidate plasma concentration (Cmax),</measure>
    <time_frame>up to 8 Hours</time_frame>
    <description>The maximum plasma concentration achieved after dosing.</description>
  </primary_outcome>
  <secondary_outcome>
    <measure>Time to maximum concentration (Tmax)</measure>
    <time_frame>up 8 hours</time_frame>
    <description>The time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration curve (AUClast)</measure>
    <time_frame>up to 8 hours</time_frame>
    <description>Area under the plasma concentration-time curve from time zero to the last measurable concentration.</description>
  </secondary_outcome>
  <secondary_outcome>
    <measure>Area under the plasma concentration curve (AUCinf)</measure>
    <time_frame>up to 8 hours</time_frame>
    <description>Area under the plasma concentration-time curve from time zero to infinity.</description>
  </secondary_outcome>
  <number_of_arms>1</number_of_arms>
  <enrollment type="Anticipated">500</enrollment>
  <condition>ADHD</condition>
  <condition>Attention Deficit Hyperactivity Disorder</condition>
  <arm_group>
    <arm_group_label>Methylphenidate</arm_group_label>
    <arm_group_type>Experimental</arm_group_type>
    <description>Youth with ADHD</description>
  </arm_group>
  <intervention>
    <intervention_type>Drug</intervention_type>
    <intervention_name>Methylphenidate</intervention_name>
    <description>study to determine dose</description>
    <arm_group_label>Methylphenidate</arm_group_label>
    <other_name>d,l-methylphenidate</other_name>
    <other_name>MPH</other_name>
  </intervention>
  <eligibility>
    <criteria>
      <textblock>
        Inclusion Criteria:&#xD;
&#xD;
          -  Youth ages 6-26 years with ADHD as a primary diagnosis&#xD;
&#xD;
          -  For former participants of MPH trials to be invited back for PK procedures.&#xD;
&#xD;
        Exclusion Criteria:&#xD;
&#xD;
          -  Participants that do not have ADHD as a primary diagnosis&#xD;
&#xD;
          -  Participants that do not want, require, or are not healthy enough for medication&#xD;
             treatment with MPH for ADHD per the clinical judgment of the treating and study&#xD;
             clinicians&#xD;
&#xD;
          -  Participants that are smokers or, are pregnant&#xD;
      </textblock>
    </criteria>
    <gender>All</gender>
    <minimum_age>6 Years</minimum_age>
    <maximum_age>26 Years</maximum_age>
    <healthy_volunteers>No</healthy_volunteers>
  </eligibility>
  <overall_official>
    <last_name>Jeffrey Newcorn, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Icahn School of Medicine at Mount Sinai</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Mark Stein, PhD</last_name>
    <role>Principal Investigator</role>
    <affiliation>University of Washington</affiliation>
  </overall_official>
  <overall_official>
    <last_name>Tanya Froehlich, MD</last_name>
    <role>Principal Investigator</role>
    <affiliation>Children's Hospital Medical Center, Cincinnati</affiliation>
  </overall_official>
  <location>
    <facility>
      <name>University of Florida</name>
      <address>
        <city>Gainesville</city>
        <state>Florida</state>
        <zip>32610</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Icahn School of Medicine at Mount Sinai</name>
      <address>
        <city>New York</city>
        <state>New York</state>
        <zip>10029</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Cincinnati Children's Hospital Medical Center</name>
      <address>
        <city>Cincinnati</city>
        <state>Ohio</state>
        <zip>45229</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location>
    <facility>
      <name>Seattle Children's Hospital</name>
      <address>
        <city>Seattle</city>
        <state>Washington</state>
        <zip>98105</zip>
        <country>United States</country>
      </address>
    </facility>
  </location>
  <location_countries>
    <country>United States</country>
  </location_countries>
  <verification_date>April 2023</verification_date>
  <study_first_submitted>December 18, 2018</study_first_submitted>
  <study_first_submitted_qc>December 18, 2018</study_first_submitted_qc>
  <study_first_posted type="Actual">December 20, 2018</study_first_posted>
  <last_update_submitted>April 14, 2023</last_update_submitted>
  <last_update_submitted_qc>April 14, 2023</last_update_submitted_qc>
  <last_update_posted type="Actual">April 18, 2023</last_update_posted>
  <responsible_party>
    <responsible_party_type>Principal Investigator</responsible_party_type>
    <investigator_affiliation>Icahn School of Medicine at Mount Sinai</investigator_affiliation>
    <investigator_full_name>Jeffrey Newcorn</investigator_full_name>
    <investigator_title>Professor</investigator_title>
  </responsible_party>
  <keyword>PK Study</keyword>
  <keyword>PD Study</keyword>
  <keyword>Pharmacokinetics</keyword>
  <keyword>Pharmacodynamics</keyword>
  <keyword>Methylphenidate</keyword>
  <keyword>MPH</keyword>
  <condition_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Attention Deficit Disorder with Hyperactivity</mesh_term>
  </condition_browse>
  <intervention_browse>
    <!-- CAUTION:  The following MeSH terms are assigned with an imperfect algorithm            -->
    <mesh_term>Methylphenidate</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/NCT03781752
org study id: GCO 17-0281
secondary id: 1R01HD093612-01A1
nct id: NCT03781752
lead sponsor: 
collaborator: 
collaborator: 
collaborator: 
collaborator: 
has dmc: Yes
is fda regulated drug: Yes
is fda regulated device: No
The study team will determine the association between d,l-methylphenidate (MPH) therapeutic
      outcomes in ADHD patients and genetic variants of CES1 and reveal key associations between
      CES1 genotypes and the PK and PD of MPH.
Psychostimulants are the first-line pharmacotherapy for Attention deficit-hyperactivity
      disorder (ADHD), and MPH accounts for approximately 50% of all stimulant usage. There has
      been an ~10-fold increase in MPH prescribing since 1990, with 18 million prescriptions
      dispensed in 2010, including 1.9 million new starts on MPH, making it the 5th most commonly
      prescribed medication to children ages 2 -11 and the single most frequently prescribed
      medication of any type in those aged 12-17 years. The annual exposure of pediatric patients
      to MPH is extremely high and MPH is among the most commonly prescribed chronic use oral
      medications for US children. Despite nearly 60 years of accrued clinical experience with MPH,
      the significant inter-individual variability in MPH pharmacokinetics (PK), pharmacodynamics
      (PD) and adverse effects is inadequately explained and unpredictable. Up to 35% of ADHD
      patients do not respond satisfactorily to MPH therapy, and an even larger percentage
      discontinues treatment despite persistent ADHD. During clinical trials of MPH in
      treatment-naïve patients, a significant number suffer from adverse effects that are severe
      and persistent enough to require dose decreases or even study withdrawal. Moreover, some
      severe adverse drug reactions (ADRs) - including sudden cardiac death - have been associated
      with MPH, although the precise reasons for these associations remain elusive and
      controversial. Research efforts have been made to identify genetic biomarkers associated with
      MPH therapeutic outcomes, almost exclusively focusing on genes related to MPH PD (e.g.,
      dopamine transporter gene [DAT1, SLC6A3]). Unfortunately, findings from these studies have
      been somewhat inconsistent, equivocal or even contradictory, and they do not explain the
      variability in the PK of MPH. Pharmacogenomic studies in MPH-treated children have not
      assessed the influence of genes associated with individual variability in PK in relation to
      clinical response. Carboxylesterase-1 (CES1), an abundant hepatic enzyme encoded by the
      polymorphic CES1 gene, is the sole hepatic enzyme catalyzing the metabolism (i.e., hydrolytic
      deactivation) of MPH. CES1 expression and activity are known to vary substantially among
      individuals. The first clinically significant CES1 variant G143E (rs71647871), discovered in
      the study team's lab during the course of a healthy volunteer MPH PK study, led to gross
      impairments in MPH metabolism. This variant has been unequivocally shown in vitro and in
      clinical studies to lead to significantly impaired metabolism of MPH and other known CES1
      substrates. The study team has established the minor allele frequency (MAF) of the G143E
      variant as 3-4% in the general population. Accordingly, with ~1.9 million new starts of MPH
      annually, an estimated 133,000 pediatric patients (i.e. G143E carrier's frequency 6-8%) with
      a genetically impaired ability to metabolize/deactivate the drug will receive it - exposing
      them to high systemic concentrations of MPH and any attendant risks or toxicities. In
      addition, the study team's in vitro studies have revealed that another common CES1 variant
      D203E (rs2307227) exhibited significantly impaired activity on MPH metabolism, although the
      effects on D203E on clinical response are in need of further elucidation. Furthermore,
      despite recent intensive research on CES1 pharmacogenetics, the functions of a large number
      of additional CES1 variants remain undetermined.

      The study team's hypothesis is that the CES1 variants, such as the G143E and D203E, can
      significantly alter the expression and/or activity of CES1, thereby influencing the
      metabolism and disposition of MPH. These influences will be directly investigated in relation
      to MPH therapeutic response and tolerability in ADHD patients.
allocation: N/A
intervention model: Single Group Assignment
intervention model description: Youth will NOT be randomized to drug for this PD study, but will receive MPH from their treatment providers in clinical care either before or after being invited to participate in the PK procedure. Their treatment data will be collected from their providers to augment the study team's analyses. The study team is performing a pharmacokinetic (PK) study using a single dose of methylphenidate (MPH) among youth identified as having specific variants of the CES1 gene. Youth will be identified by cheek swabs for CES1 variants. They will be provided . MPH for the PK procedure.
primary purpose: Basic Science
masking: None (Open Label)
measure: Maximum methylphenidate plasma concentration (Cmax),
time frame: up to 8 Hours
description: The maximum plasma concentration achieved after dosing.
measure: Time to maximum concentration (Tmax)
time frame: up 8 hours
description: The time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.
measure: Area under the plasma concentration curve (AUClast)
time frame: up to 8 hours
description: Area under the plasma concentration-time curve from time zero to the last measurable concentration.
measure: Area under the plasma concentration curve (AUCinf)
time frame: up to 8 hours
description: Area under the plasma concentration-time curve from time zero to infinity.
arm group label: Methylphenidate
arm group type: Experimental
description: Youth with ADHD
intervention type: Drug
intervention name: Methylphenidate
description: study to determine dose
arm group label: Methylphenidate
other name: d,l-methylphenidate
other name: MPH
criteria: 
gender: All
minimum age: 6 Years
maximum age: 26 Years
healthy volunteers: No
last name: Jeffrey Newcorn, MD
role: Principal Investigator
affiliation: Icahn School of Medicine at Mount Sinai
last name: Mark Stein, PhD
role: Principal Investigator
affiliation: University of Washington
last name: Tanya Froehlich, MD
role: Principal Investigator
affiliation: Children's Hospital Medical Center, Cincinnati
facility: 
facility: 
facility: 
facility: 
country: United States
responsible party type: Principal Investigator
investigator affiliation: Icahn School of Medicine at Mount Sinai
investigator full name: Jeffrey Newcorn
investigator title: Professor
mesh term: Attention Deficit Disorder with Hyperactivity
mesh term: Methylphenidate
sharing ipd: No