Clinical trial NCT04366609: The Relationship Between CES1 Genotype and Methylphenidate Response in Children With ADHD - INDICES Work Package 6
Official title: The Relationship Between CES1 Genotype and Methylphenidate Response in Children With ADHD - INDICES Work Package 6
Study type: OBSERVATIONAL
Overall status: COMPLETED
Conditions: ADHD
Lead sponsor: Mental Health Services in the Capital Region, Denmark
Sponsor class: OTHER
Collaborators: name: Copenhagen University Hospital, Denmark
First posted: 2020-04-29
Enrollment: 207
Sex: ALL
Minimum age (years): 7
Maximum age (years): 12
Standard ages: CHILD
Accepts healthy volunteers: no
Observational model: COHORT
Time perspective: PROSPECTIVE
Sampling method: PROBABILITY_SAMPLE
Study population: 207 MPH naïve boys and girls aged 7-12 years with a recent ICD-10 diagnosis of hyperkinetic disorder (F90.0-90.9) or attention deficit disorder without hyperactivity (F98.8) and clinical indication for treatment with IR-MPH.

Patients referred to the Child and Adolescent Mental Health Centre, Mental Health Services (Capital Region of Denmark) in the period from 1st of May 2012 to 1st August 2014, and who were suspected of having ADHD were consecutively screened for study eligibility.

Brief summary: 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.

Detailed description: The study has three aims:

1. Examine the effect of carboxylesterase 1 (CES1) genotype in children with ADHD on the effectiveness and adverse reactions of treatment with MPH.
2. Study predictors for the short- and long-term outcome in childhood ADHD
3. 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

Eligibility criteria: 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

Primary outcomes:
measure: Investigator rated ADHD-RS score
timeFrame: Week 0 to 12
Secondary outcomes:
measure: Clinical Global Impression Severity scale (CGI-S)
timeFrame: Week 0 and 12
measure: Clinical Global Impression Improvement (CGI-I)
timeFrame: Week 4-8-12
measure: Test of Variables of Attention (TOVA)
timeFrame: Week 0 and 12
measure: Parent rated ADHD-RS
timeFrame: Week 0-4-8-12, year 3
measure: Teacher rated ADHD-RS
timeFrame: Week 0-4-8-12
Other outcomes:
measure: Weiss Functional Impairment Rating Scale - Parent version (WFIRS-P).
timeFrame: Week 0 and 12, year 3
measure: Barkley's Stimulant Side Effect Rating Scale (BSSERS-C)
timeFrame: Week 0 to 12
measure: Child Behaviour Check List (CBCL)
timeFrame: Week 0
measure: Teacher Report Form (TRF)
timeFrame: Week 0
measure: MPH dose required for "Borderline normalisation" on ADHD-RS
timeFrame: Week 0 to 12
measure: MPH dose required for normalisation on ADHD-RS
timeFrame: Week 0 to 12
measure: Genetic analyses
timeFrame: Week 0
measure: Body weight
timeFrame: Week 0-4-8-12
measure: Height
timeFrame: Week 0-4-8-12
measure: Heart rate
timeFrame: Week 0-4-8-12
measure: Blood pressure
timeFrame: Week 0-4-8-12
measure: Reduced appetite: single item, [range 0-9].
timeFrame: Week 0-4-8-12
Locations:
Study officials:
affiliation: Mental Health Services in the Capital Region, Denmark
name: Pia Jeppesen, PhD, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: Mental Health Services in the Capital Region, Denmark
name: Tine B Houmann, MD
role: STUDY_DIRECTOR
References:
citation: Kaalund-Brok K, Houmann TB, Hebsgaard MB, Lauritsen MG, Lundstrom LH, Gronning H, Darling L, Reinert-Petersen S, Petersen MA, Jepsen JRM, Pagsberg AK, Plessen KJ, Rasmussen HB, Jeppesen P; INDICES. Outcomes of a 12-week ecologically valid observational study of first treatment with methylphenidate in a representative clinical sample of drug naive children with ADHD. PLoS One. 2021 Oct 21;16(10):e0253727. doi: 10.1371/journal.pone.0253727. eCollection 2021.