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Clinical Trial
. 2010 Jul;18(3):229-37.
doi: 10.1016/j.yebeh.2010.02.022. Epub 2010 May 21.

Adaptive phase I study of OROS methylphenidate treatment of attention deficit hyperactivity disorder with epilepsy

Joseph Gonzalez-Heydrich  1 , Jane Whitney, Deborah Waber, Peter Forbes, Olivia Hsin, Stephen V Faraone, Alice Dodds, Sneha Rao, Christine Mrakotsky, Carlene Macmillan, David R Demaso, Carl de Moor, Alcy Torres, Blaise Bourgeois, Joseph Biederman
Affiliations
Clinical Trial

Adaptive phase I study of OROS methylphenidate treatment of attention deficit hyperactivity disorder with epilepsy

Joseph Gonzalez-Heydrich et al. Epilepsy Behav. 2010 Jul.

Abstract

Objective: The goal of this study was to pilot a randomized controlled trial of OROS methylphenidate (OROS-MPH) to treat attention deficit hyperactivity disorder (ADHD) plus epilepsy.

Methods: Thirty-three patients, 6-18years of age, taking antiepileptic drugs and with a last seizure 1-60months prior were assigned to a maximum daily dose of 18, 36, or 54mg of OROS-MPH in a double-blind placebo-controlled crossover trial.

Results: There were no serious adverse events and no carryover effects in the crossover trial. OROS-MPH reduced ADHD symptoms more than did placebo treatment. There were too few seizures during the active (5) and placebo arms (3) to confidently assess seizure risk; however, considering exposure time, we observed an increased daily risk of seizures with increasing dose of OROS-MPH, suggesting that potential safety concerns require further study.

Conclusion: A larger study to assess the effect of OROS-MPH on seizure risk is needed. A crossover design including subjects with frequent seizures could maximize power and address high patient heterogeneity and recruitment difficulties.

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Figures

Figure 1
Figure 1. Adaptive Phase I Design
A randomized double-blind placebo-controlled crossover trial. Each patient remained at the maximum dose for up to 1 week before endpoint measures for that arm were taken and the patient was crossed-over to the other arm of the study or was referred to clinical care outside the study. If 1 child had a significant worsening of epilepsy on active OROS-MPH at least 3 more patients would be tested at that dose level. If at any dose level 2 patients had significant worsening of epilepsy during the active arm, the dose level just below would be fixed as the maximum dose for the rest of the study. As patients enrolled they were assigned to the highest dose group recruiting at the time such that the daily dose of OROS-MPH did not exceed 2mg/kg/day. Thus more than 3 patients could be assigned to each group even if no patient experienced a significant worsening of epilepsy.
Figure 2
Figure 2
Percentage of Patients Responding to Treatment for Active OROS-MPH and Placebo at Each Dose Level
Figure 3
Figure 3. Clinician Rated ADHD Rating Scale IV Total Score by Dose*
* Boxes show the 25th, 50th, the 75th percentiles. Whiskers extend to the 10th and 90th percentiles. Dots indicate mean level. Oros-mph means are lower than placebo means for doses 18, 36, and 54 mg (each p<.002).
See this image and copyright information in PMC

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