Treatment of ADHD in children with tics

Subjects.

Subjects were aged 7–14 years, in school, and of any race or ethnic background. Each subject met Diagnostic and Statistical Manual of Mental Disorders, 4th ed. (DSM-IV) criteria for ADHD of any subtype22 as determined by the structured psychiatric interview, the Diagnostic Interview Schedule for Children (DISC).23 A designated teacher in daily direct contact with the subject had to 1) indicate the presence of a sufficient number of ADHD symptoms (rated as “pretty much” or “very much”) in the classroom setting using the Disruptive Behavior Disorders Rating Scale24 (updated to DSM-IV) to meet DSM-IV criteria, and 2) rate the severity of ADHD symptoms above specified cutoff scores (boys: grade 2–3 = 10, grade 4 and above = 9; girls: grade 2–3 = 7, grade 4 and above = 6) on the Iowa Conners teacher rating scale.25 The investigator’s rating of global functioning on the Child-Global Assessment Scale (C-GAS)26 had to be ≤70 (indicating difficulty in at least one area, such as school). Each subject also met DSM-IV criteria for Tourette disorder, chronic motor tic disorder or chronic vocal tic disorder.22

Subjects were excluded if there was evidence of a secondary tic disorder (e.g., tardive tics, neuroacanthocytosis, Huntington disease), major depression, pervasive developmental disorder, autism, psychosis, mental retardation, anorexia nervosa, bulimia, a serious cardiovascular (e.g., significant hypotension, congenital heart disease) or other medical disorder that would preclude the safe use of MPH or CLON, impaired renal function (a routine urinalysis was performed), or pregnancy (a urine pregnancy test was performed for all adolescent girls. The following cardiac features were considered exclusions for enrollment: prolonged Q-Tc interval (>440 milliseconds), high-grade ventricular ectopy, AV block beyond first degree, bundle branch block, intraventricular conduction block (>100 milliseconds), pacemaker rhythm or heart rate less than 60 on the electrocardiogram (ECG), cardiomyopathy, complex heart disease, aortic or pulmonary stenosis, family history of long QT syndrome, cardiomyopathy or premature (age ≤45 years) sudden death, history of syncope, and blood pressure less than 2 standard deviations from the age- and gender-adjusted mean.

Subjects could not receive any other medications for the treatment of ADHD, tics, or other associated behavioral symptoms. Any such treatment had to be discontinued at least 6 weeks (2 weeks for MPH) before enrollment. Nonpharmacologic (e.g., behavioral) interventions were allowed, but remained unchanged throughout the course of the study. Prior use of MPH or CLON, whether judged to be beneficial or not, was permitted. Subjects who reported a worsening of tics during prior treatment with a stimulant were not excluded.

Procedures.

The protocol was approved by the institutional review board (IRB) at each site: University of Rochester, University of Alabama, University of Cincinnati, Colorado Neurologic Institute, Emory University, Johns Hopkins University, McLean Hospital, University of Minnesota, North Shore Hospital, Rush-Presbyterian/St. Luke’s Medical Center, University of South Carolina, Washington University. A placebo group was included because there is no medication established to be effective or well-tolerated for the treatment of ADHD when comorbid with tics. A placebo was required to permit the assessment of the efficacy and the influence on tics of our study medications. Although prior use of MPH or CLON was allowed, in no case was one of the medications discontinued solely for participation in this study. In some instances, subjects enrolled after routine summer “holidays” from their medications. At the screening visit, informed consent/assent was obtained, all entry criteria were confirmed, the subject’s level of physical sexual development was rated (Tanner Sexual Maturity Rating Scale27), the parent self-report rating scales were explained, and the procedures of the study were reviewed. The study coordinator visited each subject’s school to obtain agreement from the designated teacher (for older children with multiple teachers, one teacher in the major courses of Math, English, Science, and Social Studies was selected at random) and principal to explain teacher self-report rating scales and to review the procedures of the study, including the activities of our classroom observers (see below).

After successful screening, a baseline (0 week) evaluation visit occurred within 2 weeks. At this time the following ratings were performed (tests to determine ratings are listed in parentheses): ADHD (Conners Abbreviated Symptom Questionnaire for Teachers [ASQ-Teacher],28 Iowa Conners Teacher Rating Scale,25 Conners Abbreviated Symptom Questionnaire for Parents [ASQ-Parent],28 the Conners Continuous Performance Task (CPT),29 systematic classroom observations of the subject’s behavior [e.g., on-task, disruptive] by a trained, independent observer)30,31⇓; tic severity (Yale Global Tic Severity Scale [YGTSS]32 performed by the site investigator, Tic Symptom Self Report Scale [TSSR]33 completed by the parent/subject and teacher, Global Tic Rating Scale [GTRS]34 completed by the parent/subject and teacher); obsessive–compulsive symptoms (Child-Yale Brown Obsessive Compulsive Scale [C-YBOCS]35 completed by the site investigator); and global functioning (Children’s Global Assessment Scale [C-GAS]26 completed by the site investigator). Vital signs were assessed and an ECG was performed.

At the baseline visit, subjects were randomly assigned by a central coordinating center to receive MPH alone, CLON alone, combined MPH and CLON, or placebo. The computer-generated randomization plan included stratification by center (investigator) and sexual maturity status (prepubertal: Tanner stages I-II; pubertal: Tanner stages III-V). Blocking was used to ensure approximate balance among the treatment groups within each stratum. Only the programmer in the Biostatistics Center who generated the plan and the pharmacist in the Pharmacy Center who packaged and labeled the drug were aware of the treatment assignments. Treatment assignments were not revealed to the subjects or investigators until the entire study was completed and data were analyzed. Each site was supplied with sealed envelopes that contained their subjects’ treatment assignments in the event that such information was needed for emergent medical care, but in no instance did unblinding on this basis occur.

There was an initial 4-week dosage titration period for CLON (0.1 mg scored tablets or matching placebo tablets). Subjects continued to receive CLON (or matching placebo) on entering the subsequent 4-week dosage titration period for MPH (Ritalin [Novartis, Summit, NJ] or matching placebo powder packaged in gelatin capsules equivalent to 5 mg strength). For both medications, an individualized, flexible dose titration procedure was utilized, which was designed to reproduce standard clinical practice and to allow the determination of an optimal (or highest tolerated) dosage for each subject. “Optimal” dosage was defined as the one that allowed the subject to reach a level of school functioning considered good, with no further room for improvement, with an acceptable level of side effects and representing a meaningful clinical change from baseline. As guides to medication dose titration, approximately every 3 days the teacher telephoned or faxed to the site a completed ASQ-Teacher rating scale and a side effects rating scale (modified from Pelham36 to include possible adverse effects of CLON). Regular telephone contact between the parent and site occurred to review scoring of the ASQ-Parent scale and possible adverse events. To achieve a general level of consistency across sites, an ASQ-Teacher score of 5 (the normal childhood population mean28) was considered an approximation to help the investigator determine when there was “no further room for improvement.” Each drug was administered once daily on initiation of therapy and the dosage was increased to 2 to 3 times per day within a few days. The maximum allowable daily drug dosages were 60 mg for MPH and 0.6 mg for CLON.

An 8-week maintenance dosage period followed the dosage titration phases, during which subjects received MPH (or matching placebo) and CLON (or matching placebo) at the dosages found to be optimal (or highest tolerated) in the dosage titration phases. The site investigator was allowed to adjust the dosage of either drug, to minimize side effects (e.g., any perceived worsening of tics), or to optimize efficacy. However, dosage changes to optimize efficacy were not permitted during the final 2 weeks of the dosage maintenance period so that the final evaluation would be an accurate assessment of a treatment regimen that had been in place for at least 14 days.

The same clinical evaluations performed at the baseline (0 week) visit (with the exception of classroom observations) were repeated after the CLON dosage titration period (+4 weeks), after the MPH dosage titration period (+8 weeks), at the halfway point of the maintenance dosage period (+12 weeks), and at the end of the study (+16 weeks). Classroom observations were repeated only at the time of the final evaluation visit (+16 weeks). Post-baseline assessments also included the following: a rating of clinical change (NIMH Clinical Global Impression Scale [CGI]37) separately for ADHD and tics and completed independently by the parent, teacher, and site investigator; a systematic review of adverse events, which were recorded in log format; and a pill count to monitor compliance. Each subject received a small gift, each parent received $75, and each teacher received $100 when the protocol was completed and all necessary rating forms were received. When the final evaluation was completed, subjects received instructions on how to discontinue study medications, including a gradual tapering schedule over 7 days for CLON to avoid possible withdrawal effects. After completion of the study, routine clinical care was provided at the participating site by an individual with expertise in treating tics and ADHD.

An independent safety monitoring committee, consisting of a child psychiatrist, pediatric cardiologist, pediatrician, and statistician, reviewed data regarding adverse events throughout the study. A NIH Performance and Safety Monitoring Review Board similarly reviewed safety data in overseeing the trial.

Statistical methods.

Members of the Tourette’s Syndrome Study Group.

Principal investigator: Roger Kurlan, MD. Co-principal investigator: Christopher G. Goetz, MD. Chief biostatistician: Michael P. McDermott, PhD. Project manager: Sandra Plumb, BS. Site investigators: Harvey Singer, MD, Leon Dure, MD, Peter Como, PhD, Floyd R. Sallee, MD, Cathy Budman, MD, Barbara Coffey, MD, Jorge Juncos, MD, Jonathan Mink, MD, PhD, Glenn Stebbins, PhD, Paul Tuite, MD, Lauren Seeberger, MD. Consultants: William E. Pelham, PhD, Donna Palumbo, PhD. Study coordinators—Joseph Giuliano, Madeline Krieger (Johns Hopkins); Jane Lane, RN, BSN (University of Alabama); Nancy Pearson, RN (University of Rochester); Lauren Sine (University of South Carolina); Kathy Parsons, Sara Peters (University of Cincinnati); Denise Thorne-Petrizzi, RN (North Shore); Ken Parks, Grace Kim, Kathleen Craddock (McLean); Colleen Wood, RN (Emory University); Jennifer Randle (Washington University); Kim Janko (Rush Presbyterian-St. Luke’s); Deborah Lasher, RN (University of Minnesota); Terri Johnston, RN (Colorado Neurologic Institute). Chief pharmacist—Stephen Bean, RPh (University of Rochester). Medical director—Mark Riddle, MD (Johns Hopkins). Scientific advisory committee—James F. Leckman, MD (Yale University); David Oakes, PhD (University of Rochester). Medical monitors—Irene Richard, MD, Neeru Sehgal, MD, Penelope Hogarth, MD, David Marcus, MD (University of Rochester). Clinical trials coordination center director—Karl Kieburtz, MD (University of Rochester). Safety monitoring committee—Peter Harris, MD, Stephen Sulkes, MD, Christopher Cox, PhD (University of Rochester). Administrative secretary—Donna LaDonna (University of Rochester). Computer programmer—Christine Brower, MPH (University of Rochester). Classroom observation trainer—Andrew Greiner.