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NCT Number: NCT04366609

The Relationship Between CES1 Genotype and Methylphenidate Response in Children With ADHD - INDICES Work Package 6

This is a prospective observational study of a cohort of children diagnosed with Attention Deficit Hyperactive Disorder (ADHD) and followed with weekly assessments during the first 12 weeks of Methylphenidate (MPH) treatment, and after three years.

The overall aim is to gain knowledge in order to develop guidelines for more individualized treatments with (MPH), obtain a better drug response, and reduce the risk of adverse reactions, in order to improve adherence and long-term outcome.

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Key information

Conditions

ADHD Attention Deficit Disorder with Hyperactivity Attention Deficit and Disruptive Behavior Disorders Mental Disorders Neurodevelopmental Disorders

Age range

7 year–12 year

Sex eligibility

All sexes

Study type

Observational

About this study

The study has three aims:

  • Examine the effect of carboxylesterase 1 (CES1) genotype in children with ADHD on the effectiveness and adverse reactions of treatment with MPH.
  • Study predictors for the short- and long-term outcome in childhood ADHD
  • Examine the long-term outcome with respect to ADHD symptoms, and impairment in daily functioning in the cohort

The specific aims are to:

  • Describe the treatment response during the first 12 weeks after initiation of IR-MPH treatment, based on weekly clinician- rated ADHD core symptoms, the rate of normalisation/ borderline normalisation of ADHD core symptoms, adverse reactions, daily and social functioning, and measures of sustained attention.
  • Describe the three-year outcome, based on parent rated ADHD core- and behavior symptoms, and level of impairment in daily functioning.
  • Provide information about predictors for outcome after 12 weeks: clinical characteristics at entry (sex, age group, global severity of psychiatric disorder, psychiatric comorbidity, subtype of ADHD diagnoses), and predictors for outcome after three years: sex, age group, baseline severity of ADHD- and behavior symptoms, IQ, parental psychiatric disorder, maternal educational level, and time to treatment response.
  • Determine the end-dose of IR-MPH after 12 weeks of treatment.
  • Systematically sequence the CES1 gene and associate the identified genotypes of this gene with treatment responses, including dosage of IR-MPH

Who can participate

Healthy volunteers accepted: No

Only the study team can determine whether someone qualifies for participation.

Inclusion criteria

  • MPH naïve
  • recent ICD-10 diagnosis of hyperkinetic disorder (F90.0-90.9) or attention deficit disorder without hyperactivity (F98.8)
  • clinical indication for treatment with IR-MPH

Exclusion criteria

  • mental retardation (ICD-F70.X or IQ < 70)
  • previous treatment with drugs metabolised by carboxylesterase 1 (CES1)
  • severe comorbid psychiatric or somatic disease that resulted in contraindication for treatment with MPH
  • language barriers
  • lack of informed consent.

Specific additional exclusion criteria for genetic analyses:

  • Non-caucasian
  • Lack of DNA
  • Consanguine patients
  • Variants with a minor allele frequency (MAF) above 0.05 or not in Hardy-Weinberg equilibrium

Treatment and study plan

Methylphenidate

Drug

Treatment with methylphenidate through dose escalation

Other names: Medikinet - N06BA04, Motiron - N06BA04

Primary outcomes

  1. Investigator rated ADHD-RS score

    Time frame: Week 0 to 12

    Psychometric instrument: 18 item clinician rated; Inattention subscale: 9 items, [range 0-27]. Hyperactivity-Impulsivity subscale: 9 items [range 0-27], evaluated on a four-point Likert scale from 0 (none = never or rarely) to 3 (severe = very often). Higher score, worse outcome. Normalisation: T-score<60, Borderline normalisation: T-score 60-70.

Secondary outcomes

  1. Clinical Global Impression Severity scale (CGI-S)

    Time frame: Week 0 and 12

    Psychometric instrument: The clinician-rated CGI-S is a seven-point Likert scale, rated 1 (normal, not ill at all) to 7 (among the most extremely ill patients)A beneficial symptom reduction was defined by a CGI-S score of 1 or 2 (normal, not ill at all or borderline ill).

  2. Clinical Global Impression Improvement (CGI-I)

    Time frame: Week 4-8-12

    Psychometric instrument, clinician-rated CGI-I seven-point Likert scale rated from 1 (very much improved) to 7 (very much worse). A beneficial symptom reduction was defined by a CGI-I score of 1 or 2 (very

  3. Test of Variables of Attention (TOVA)

    Time frame: Week 0 and 12

    Computerized, continuous performance test, number of commission errors (response to non-target), number of omission errors (non-response to target), the response time in microseconds, and the variability of response time in correct responses to target were measured over the 21.6-minute-long test used as total raw scores.

  4. Parent rated ADHD-RS

    Time frame: Week 0-4-8-12, year 3

    Psychometric instrument: Inattention subscale: 9 items, [range 0-27]. Hyperactivity-Impulsivity subscale: 9 items [range 0-27]. Conduct problems subscale: 8 items, [range 0-24]. Higher score, worse outcome.

  5. Teacher rated ADHD-RS

    Time frame: Week 0-4-8-12

    Psychometric instrument: Inattention subscale: 9 items, [range 0-27]. Hyperactivity-Impulsivity subscale: 9 items [range 0-27]. Conduct problems subscale: 8 items, [range 0-24]. Higher score, worse outcome.

Other outcomes

  1. Weiss Functional Impairment Rating Scale - Parent version (WFIRS-P).

    Time frame: Week 0 and 12, year 3

    Psychometric instrument: WFIRS-P is a parent-rated questionnaire, with 50 questions about a child's daily and social functioning in six different domains of a child's life: family (10 items), learning and school (10 items), activities of daily living (10 items), self-concept (3 items), social activities (7 items), and risky activities (10 items). It is evaluated on a four-point Likert scale from 0 (never or not at all) to 3 (very often or very much). Single item scores = 2-3 signal impairment (> 2 SD). Higher score, worse outcome.

  2. Barkley's Stimulant Side Effect Rating Scale (BSSERS-C)

    Time frame: Week 0 to 12

    Psychometric instrument: 17 effect items rated by the clinician, based on information from patients, parents, and clinical observations: insomnia, nightmares, staring, talks less, disinterested in others, reduced appetite, irritable, stomachaches, headaches, drowsiness, sadness, prone to crying, anxious, nail biting, euphoria, dizziness, and tics/nervous movements. BSSERS-C is a 10-point Likert scale rated from 0 (problem absent) to 9 (problem evokes serious impairment). Severities of ARs were calculated as the sum of problem scores on the 17-item BSSERS-C. Significant changes in single items were also explored (e.g., reduced appetite; 1 item, range 0-9).

  3. Child Behaviour Check List (CBCL)

    Time frame: Week 0

    Psychometric instrument: Parent rated. Externalizing score: 35 items [range 0-70]. Internalizing score: 32 items [range 0-64]. Total problem score: 118 [range 0-236].

  4. Teacher Report Form (TRF)

    Time frame: Week 0

    Psychometric instrument: Teacher rated. Externalizing score, 34 items [range 0-68]. Internalizing score: 34 items [range 0-68]. Total problem score: 118 [range 0-236].

  5. MPH dose required for "Borderline normalisation" on ADHD-RS

    Time frame: Week 0 to 12

    The IR-MPH doses were individually titrated, based on the weekly evaluations of symptom reductions and ARs (and the body weight of a child), which were carried out by the clinical investigator. The dose of IR-MPH (mg/kg/day) at the end of the study was registered. Dose required for T-score of 60-70 on ADHD-DSM-IV-RS.

  6. MPH dose required for normalisation on ADHD-RS

    Time frame: Week 0 to 12

    The IR-MPH doses were individually titrated, based on the weekly evaluations of symptom reductions and ARs (and the body weight of a child), which were carried out by the clinical investigator. The dose of IR-MPH (mg/kg/day) at the end of the study was registered. Dose required for T-score < 60 on ADHD-DSM-IV-RS.

  7. Genetic analyses

    Time frame: Week 0

    The genetic analyses of CES1 were carried out using PCR and sequencing.

  8. Body weight

    Time frame: Week 0-4-8-12

    Body weight in kilograms

  9. Height

    Time frame: Week 0-4-8-12

    Height in centimeters

  10. Heart rate

    Time frame: Week 0-4-8-12

    Heart rate, bp/m

  11. Blood pressure

    Time frame: Week 0-4-8-12

    Both diastolic blood pressure, mmHg, and Systolic blood pressure, mmHg, measured after 10 minutes of rest with a sphygmomanometer (nonelectrical) three times and the average of the last two measures is used

  12. Reduced appetite: single item, [range 0-9].

    Time frame: Week 0-4-8-12

    Single item of psychometric instrument Barkley's Stimulant Side Effect Rating Scale (BSSERS-C), [range 0-9]. Higher value, worse outcome.

Sponsors and collaborators

Lead sponsor

Mental Health Centre Copenhagen, Bispebjerg and Frederiksberg Hospital

Other

Collaborators

  • Copenhagen University Hospital, Denmark

Registry information

Important dates

Study start
2012
Primary completion
2014
Study completion
2017
First posted
Apr 29, 2020
Registry last updated
Apr 29, 2020

OpenTrials presents study information sourced from ClinicalTrials.gov. The official registry record should be consulted for the latest information.

View the official ClinicalTrials.gov record (opens in a new tab)

This listing is for discovery and informational purposes only. It is not medical advice, does not guarantee that a study is recruiting, and does not determine eligibility. Contact the study team and a qualified healthcare professional when considering participation.

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