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

ADHD Clinical Trial

Official title:

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

Clinical Trial Details — Status: Completed

Administrative data

• NCT number: NCT04366609
• Other study ID #: H-B-2009-026
• Status: Completed
• Start date: May 1, 2012
• Est. completion date: November 1, 2017

Study information

• Verified date: January 2012
• Source: Mental Health Services in the Capital Region, Denmark
• Contact: n/a
• Is FDA regulated: No
• Study type: Observational

Clinical Trial 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.

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

Recruitment information / eligibility

• Status: Completed
• Enrollment: 207
• Est. completion date: November 1, 2017
• Est. primary completion date: August 1, 2014
• Accepts healthy volunteers: No
• Gender: All
• Age group: 7 Years to 12 Years

Eligibility

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

Related Conditions & MeSH terms

• ADHD

Intervention

Drug:
• Methylphenidate
Treatment with methylphenidate through dose escalation

Locations

Country	Name	City	State
n/a

Sponsors (2)

Lead Sponsor	Collaborator
Mental Health Services in the Capital Region, Denmark	Copenhagen University Hospital, Denmark

Outcome

Type	Measure	Description	Time frame	Safety issue
Other	Weiss Functional Impairment Rating Scale - Parent version (WFIRS-P).	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.	Week 0 and 12, year 3
Other	Barkley's Stimulant Side Effect Rating Scale (BSSERS-C)	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).	Week 0 to 12
Other	Child Behaviour Check List (CBCL)	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].	Week 0
Other	Teacher Report Form (TRF)	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].	Week 0
Other	MPH dose required for "Borderline normalisation" on ADHD-RS	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.	Week 0 to 12
Other	MPH dose required for normalisation on ADHD-RS	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.	Week 0 to 12
Other	Genetic analyses	The genetic analyses of CES1 were carried out using PCR and sequencing.	Week 0
Other	Body weight	Body weight in kilograms	Week 0-4-8-12
Other	Height	Height in centimeters	Week 0-4-8-12
Other	Heart rate	Heart rate, bp/m	Week 0-4-8-12
Other	Blood pressure	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	Week 0-4-8-12
Other	Reduced appetite: single item, [range 0-9].	Single item of psychometric instrument Barkley's Stimulant Side Effect Rating Scale (BSSERS-C), [range 0-9]. Higher value, worse outcome.	Week 0-4-8-12
Primary	Investigator rated ADHD-RS score	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.	Week 0 to 12
Secondary	Clinical Global Impression Severity scale (CGI-S)	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).	Week 0 and 12
Secondary	Clinical Global Impression Improvement (CGI-I)	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	Week 4-8-12
Secondary	Test of Variables of Attention (TOVA)	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.	Week 0 and 12
Secondary	Parent rated ADHD-RS	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.	Week 0-4-8-12, year 3
Secondary	Teacher rated ADHD-RS	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.	Week 0-4-8-12