|- candidate number||10436|
|- NTR Number||NTR3103|
|- ISRCTN||ISRCTN wordt niet meer aangevraagd.|
|- Date ISRCTN created|
|- date ISRCTN requested|
|- Date Registered NTR||13-okt-2011|
|- Secondary IDs||NL34509.000.10 CCMO|
|- Public Title||Effects of methylphenidate on the developing brain.|
|- Scientific Title||Effect modification by age of methylphenidate on the development of the dopaminergic system in the brain.|
|- ACRONYM||ePOD - MPH|
|- hypothesis||Administration of MPH during brain development, but not in adulthood, results in an altered outgrowth of the dopaminergic system. This long-lasting disturbance of the dopaminergic system may result in behavioral abnormalities, such as anxiety and depression.|
|- Healt Condition(s) or Problem(s) studied||ADHD, Methylphenidat, Dopaminergic system|
|- Inclusion criteria||Male outpatients (ages 10-12 and 23-40) newly diagnosed with ADHD as defined in the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition (DSM-IV, American Psychiatric Association 1994) and as determined by a structured interview: Diagnostic Interview Schedule for Children fourth edition (DISC-IV; Ferdinand et al., 1998) in parents or Diagnostic Interview voor ADHD bij volwassenen (DIVA; Kooij andFrancken, 2010) in adults.|
|- Exclusion criteria||1. Co-morbid Axis I psychiatric disorders requiring treatment with medication at study entry;|
2. Major medical illness, such as a history of epilepsy and traumatic brain injury;
3. IQ < 80;
4. Current or previous (including prenatal) dependency of drugs or medications that influence the dopamine system before age 23
5. Any contraindications to methylfenidate treatment or MRI proceedings.
|- mec approval received||yes|
|- multicenter trial||yes|
|- Type||2 or more arms, randomized|
|- planned startdate ||1-mei-2011|
|- planned closingdate||31-dec-2012|
|- Target number of participants||100|
|- Interventions||1. Random assignment to a flexible dose of methylphenidate or placebo drug treatment for 16 weeks, followed by a medication-free wash-out period of one week;|
2. 3.0 Tesla MR imaging including diffusion tensor imaging (DTI), task-related functional MRI (fMRI) and pharmacological MRI (phMRI) following dopaminergic challenge with oral methylphenidate (0.5 mg/kg);
3. Assessment of a neuropsychological test battery and short questionnaires;
4. Assessment of sleep with actigraphy.
|- Primary outcome||1. phMRI: % change in ASL signal from baseline in response to acute oral MPH challenge before and after 16 weeks of MPH treatment;|
2. DTI: % change in FA and MD values from baseline after 16 weeks of MPH treatment;
3. Resting state fMRI (rs-fMRI): % change in functional connectivity (FC) within specific (DA) neuronal networks;
4. % change of above mentioned outcome parameters during treatment vs. baseline and post-treatment.
|- Secondary outcome||1. fMRI: % change in task related BOLD signal from baseline;|
2. Neuropsychological functioning: change in outcome of several well-validated neuropsychological (computer) tasks addressing emotional processing and impulsivity/behavioral inhibition compared to baseline measurements;
3. Sleep log and actigraphy: % change from baseline.
|- Timepoints||1. Screening;|
2. Baseline: Week 0;
3. Midtreatment: Week 8;
4. Washout: Week 16;
5. Post-treatment: Week 17.
|- Trial web site||www.epod-study.nl|
|- status||stopped: trial finished|
|- CONTACT FOR PUBLIC QUERIES||MD, PhD Liesbeth Reneman|
|- CONTACT for SCIENTIFIC QUERIES||MD, PhD Liesbeth Reneman|
|- Sponsor/Initiator ||Academic Medical Center (AMC), Amsterdam|
(Source(s) of Monetary or Material Support)
|Ministry of Education, Culture and Science|
|- Brief summary||Background of the study:|
50-90% of prescribed pediatric drugs have never been tested or licensed in children, only in adults. Approximately 100 million children in the European Union are prescribed off-label or unauthorized drugs and in doing so risk adverse reactions or do not respond to treatment at all. In fact, medication doses used in children are no more than ‘guestimates’. Clearly, there are potential dangers in assuming that children will have the same response to therapy as adults. Methylphenidate (MPH) is primarily used as treatment for attention deficit hyperactivity disorder (ADHD), effectively reducing symptoms of inattention, hyperactivity, and impulsivity in up to 70% of children. It is assumed MPH does this by blocking the DA transporter (DAT) thus increasing extracellular DA in the brain. Its efficacy and safety has been documented in many studies. However, there is still a gap of knowledge concerning the influence of MPH on brain development and its effect on brain structure and function. Studies in animals raise serious concerns and call for further investigation of possible effects on brain structure and function.
Primary objective of the study:
To report on the effectmodification by age of MPH treatment on the outgrowth of the DA system using state-of-the-art Magnetic Resonance Imaging (MRI) techniques.
1. To report on the effectmodification by age of MPH on the outgrowth of the DA system using several functional outcome measures (functional MRI (fMRI), neuropsychological test battery);
2. To report on the effects of MPH on restless legs syndrome (RLS) symptoms and insomnia.
A pharmacological MRI (phMRI) study for assessment of dopaminergic function and connectivity in an 18-week multicenter randomized, double-blind, placebo-controlled trial with methylphenidate in 100 children-, and adult male ADHD patients in which the effect of age is investigated before and after treatment. Patients will be stratified into two age groups: adolescents (10-12 years of age) and adults (23-40 years of age) and randomly assigned to receive a flexible dose of either MPH or placebo, resulting in four groups consisting of 25 subjects each.
50 adolescent (10-12 years of age) and 50 adult (23-40 years of age) male outpatients diagnosed with combined type ADHD (combined type) as defined in the DSM-IV, and in need of pharmacotherapy according to existing guidelines.
1. Random assignment to a flexible dose of methylphenidate or placebo drug treatment for a period of 16 weeks with a 1 week washout period;
2. 3.0 Tesla MRI scan. Total duration 2 x 30 minutes (with a 90 minute break in between scans) including a pharmacological phMRI (phMRI), diffusion tensor imaging (DTI), functional connectivity (rs-fMRI) and task-related fMRI scans before and after a DA challenge with oral MPH (0.5 mg/kg). Before, during and after trial end. The MRI scan during the trial will last 30 minutes, without a DA challenge;
3. Assessment of a neuropsychological (NPO) test battery and questionnaires (duration approximately 1 hour), Before, during and after trial end. The NPO during the trial will last 30 minutes;
4. Assessment of sleep architecture using a questionnaire, actigraph and a sleep log during 3 x 5 days: Before, during and after trial end.
|- Main changes (audit trail)||Nieuwe einddatum: 1-7-2014
Leeftijd inclusie aangepast: nu 40 jaar, was 30 jaar: 26-3-2014 11-aug-2015: per 15-jun-2015: onderzoek afgerond-EB|
|- RECORD||13-okt-2011 - 11-aug-2015|