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Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT03781752
Recruitment Status : Active, not recruiting
First Posted : December 20, 2018
Last Update Posted : April 17, 2020
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Florida
Children's Hospital Medical Center, Cincinnati
Seattle Children's Hospital
Information provided by (Responsible Party):
Jeffrey Newcorn, Icahn School of Medicine at Mount Sinai

Brief Summary:
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.

Condition or disease Intervention/treatment Phase
ADHD Attention Deficit Hyperactivity Disorder Drug: Methylphenidate Phase 4

Detailed Description:

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.

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Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 500 participants
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.
Masking: None (Open Label)
Primary Purpose: Basic Science
Official Title: Carboxylesterase 1 Genetic Variation and Methylphenidate in ADHD
Actual Study Start Date : March 4, 2018
Estimated Primary Completion Date : July 31, 2023
Estimated Study Completion Date : July 31, 2023

Resource links provided by the National Library of Medicine

Arm Intervention/treatment
Experimental: Methylphenidate
Youth with ADHD
Drug: Methylphenidate
study to determine dose
Other Names:
  • d,l-methylphenidate
  • MPH

Primary Outcome Measures :
  1. Maximum methylphenidate plasma concentration (Cmax), [ Time Frame: up to 8 Hours ]
    The maximum plasma concentration achieved after dosing.

Secondary Outcome Measures :
  1. Time to maximum concentration (Tmax) [ Time Frame: up 8 hours ]
    The time after administration of a drug when the maximum plasma concentration is reached; when the rate of absorption equals the rate of elimination.

  2. Area under the plasma concentration curve (AUClast) [ Time Frame: up to 8 hours ]
    Area under the plasma concentration-time curve from time zero to the last measurable concentration.

  3. Area under the plasma concentration curve (AUCinf) [ Time Frame: up to 8 hours ]
    Area under the plasma concentration-time curve from time zero to infinity.

Information from the National Library of Medicine

Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the contacts provided below. For general information, Learn About Clinical Studies.

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Ages Eligible for Study:   6 Years to 17 Years   (Child)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • Youth ages 6-17 years with ADHD as a primary diagnosis
  • Participants that are healthy, nonsmokers and are not pregnant
  • Participants are receiving or about to receive methylphenidate for treatment of ADHD from their care providers
  • Newly enrolled youth who have the targeted CES1 variants
  • Youth with banked samples who have the targeted CES1 variants and had agreed to be re-contacted for future studies
  • Age/sex matched controls with ADHD but without the targeted variants will be eligible for inclusion in the 8 hour PK study

Exclusion Criteria:

  • Participants that do not have ADHD as a primary diagnosis
  • Participants that do not want, require, or are not healthy enough for medication treatment with MPH for ADHD per the clinical judgment of the treating and study clinicians
  • Participants that are smokers or, are pregnant

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT03781752

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United States, Florida
University of Florida
Gainesville, Florida, United States, 32610
United States, New York
Icahn School of Medicine at Mount Sinai
New York, New York, United States, 10029
United States, Ohio
Cincinnati Children's Hospital Medical Center
Cincinnati, Ohio, United States, 45229
United States, Washington
Seattle Children's Hospital
Seattle, Washington, United States, 98105
Sponsors and Collaborators
Icahn School of Medicine at Mount Sinai
Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD)
University of Florida
Children's Hospital Medical Center, Cincinnati
Seattle Children's Hospital
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Principal Investigator: Jeffrey Newcorn, MD Icahn School of Medicine at Mount Sinai
Principal Investigator: Mark Stein, PhD University of Washington
Principal Investigator: Tanya Froehlich, MD Children's Hospital Medical Center, Cincinnati
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Responsible Party: Jeffrey Newcorn, Professor, Icahn School of Medicine at Mount Sinai Identifier: NCT03781752    
Other Study ID Numbers: GCO 17-0281
1R01HD093612-01A1 ( U.S. NIH Grant/Contract )
First Posted: December 20, 2018    Key Record Dates
Last Update Posted: April 17, 2020
Last Verified: April 2020
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No

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Studies a U.S. FDA-regulated Drug Product: Yes
Studies a U.S. FDA-regulated Device Product: No
Keywords provided by Jeffrey Newcorn, Icahn School of Medicine at Mount Sinai:
PK Study
PD Study
Additional relevant MeSH terms:
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Attention Deficit Disorder with Hyperactivity
Attention Deficit and Disruptive Behavior Disorders
Neurodevelopmental Disorders
Mental Disorders
Central Nervous System Stimulants
Physiological Effects of Drugs
Dopamine Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Dopamine Agents
Neurotransmitter Agents