Attention Deficit, Hyperactivity disorder (ADHD) is a common mental health disorder of significant morbidity for which approximately 100,000 children yearly are treated with clonidine (CLON) in the US, either as an alternative to psychostimulants, or as combination therapy. Adequate ADHD efficacy and safety data are lacking and CLON is not FDA approved for ADHD. Rationales for combination with methylphenidate (MPH) are that it may be synergistic, may extend the stimulant effect, and/or that CLON may address certain core symptoms not treated by stimulants alone. No data support these rationales, yet the combination is increasingly being prescribed despite reports of serious adverse events linked to combination therapy. CLON has yet to be comprehensively studied in primary ADHD, but an NINDS sponsored evaluation of the safety and efficacy of CLON alone and in combination with MPH is currently being conducted in children with Tourette Syndrome with comorbid ADHD (TACT). TACT subjects however may be predominantly """"""""inattentive"""""""" subtype, in contrast to combined type, most commonly seen in primary ADHD. TACT data also cannot be extrapolated to primary ADHD because treatment with CLON in TACT is dually targeted to the treatment of both tics and ADHD such that dosing interval and potentially safety findings (if adverse events are dose related) may not be readily applied to primary ADHD. Efficacy and safety data from TACT therefore may be inadequate for primary ADHD treatment, for which the majority of CLON is prescribed. The clinical trial machinery and expertise of the TACT team however is uniquely positioned to study CLON in primary ADHD. Advantages would be: 1) reduced cost by using TACT existing infrastructure; 2) an opportunity to pool safety data across studies such that low frequency adverse events may be detected; 3) to compare therapeutic outcomes in primary ADHD to ADHD with comorbid Tourette Syndrome to determine if CLON has differential effects in """"""""inattentive subtype"""""""" versus """"""""hyperactive/impulsive"""""""" or combined subtypes; and 4) to determine if chronic treatment with MPH can contribute to the development of tic disorder. We propose a multicenter, controlled study of CLON, MPH, and CLON plus MPH for children with primary ADHD. The study will A) determine the safety and efficacy of CLON for the treatment of ADHD in children; B) evaluate the safety and efficacy of combined CLON+MPH for treatment of ADHD compared to standard MPH therapy; C) provide a lyr extension for all subjects to follow-up tic development during course of the study.
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