Children and adolescents (aged 6–17 years) with a diagnosis of predominantly hyperactive- or combined-subtype ADHD, on the basis of the Diagnostic and Statistical Manual of Mental Disorders, Fourth Edition
, Text Revision criteria,1
who had a stable regimen of stimulant treatment (ie, methylphenidate or amphetamine) during the previous 4 weeks were included. ADHD was evaluated by using the Kiddie-Sads-Present and Lifetime Version questionnaire 1.0 completed by a trained investigator. Continuous ratings of symptomatology were obtained using the ADHD Rating Scale IV (ADHD-RS-IV) questionnaire.21
To be included in the study, children were required to have inadequate stimulant medication response, defined as a total score ≥ 26 on the ADHD-RS-IV questionnaire after a minimum of 4 weeks on a stable stimulant regimen (ie, ≤10% variation in dose). Additional inclusion criteria were intelligence quotient estimated to be ≥80 by the investigator and a BMI in the ≥5th percentile for the patient's gender and age.
Patients were excluded from participation in the study if they had (1) a current diagnosis or history of a psychiatric disorder that required psychotropic medication or severe comorbid Axis I or Axis II disorder that could interfere with assessment of clonidine efficacy and safety, (2) a history of conduct disorder, (3) a history of syncopal episodes or seizures (except for febrile seizures), (4) current or past drug abuse, (5) a history of clonidine intolerance, or (6) used any investigational drug within 30 days of the study initiation or had a positive drug test (except for ADHD medication). Patients were also excluded if they had a clinically significant illness or abnormality that would increase the safety risk of clonidine or if they had clinically significant electrocardiogram readings. Females of childbearing age who were pregnant or lactating or who refused to use birth control were not allowed to participate. Concomitant use of antihypertensive medications, psychotropic drugs, oral corticosteroids, sedating antihistamines, antidiabetic medications, diet aids, and bronchodilators >3 days per week was not allowed.
The study protocol, amendments, and informed consent form were approved by central and local institutional review boards before study initiation. The study was conducted in accordance with the Declaration of Helsinki and Good Clinical Practice requirements. Written informed consent was obtained from all patients and legal guardians before enrollment.
This 8-week, parallel-group, randomized, double-blind, placebo-controlled study was conducted at 22 centers in the United States between March 2008 and February 2009. A screening period of up to 14 days before initiation of dosing was required, during which eligibility was ascertained and baseline efficacy and safety assessments were performed. After baseline assessment, all patients underwent a 1- to 2-week washout period, during which any ADHD medications except methylphenidate- or amphetamine-based products were discontinued. The treatment period consisted of 8 weeks of flexible dose escalation or dose tapering on the basis of patients' response to treatment. Before week 5, physicians were allowed to adjust the dose of CLON-XR by not escalating the dose to the maximal amount for the study (ie, 0.4 mg per day) or by tapering the dose by 0.1 mg per week if safety concerns arose. After week 5, the dose of CLON-XR was tapered by 0.1 mg per week until reaching the lowest possible dose (ie, 0.1 mg per day) on week 8. Investigators were also allowed to adjust the dose of stimulant medication on the basis of the efficacy and safety profile of the patient; however, the category of stimulant could not be altered. Efficacy and safety were assessed during weekly visits.
Patients who completed screening and washout periods were randomly assigned, via block design, to receive total daily doses of CLON-XR of 0.1 to 0.4 mg per day or placebo in addition to the patient's normal regimen of stimulant. Medication (ie, placebo or CLON-XR) was dispensed weekly by the investigator, who was blinded to treatment. At week 1, patients were instructed to take 1 tablet of CLON-XR 0.1 mg or placebo at night in addition to their normal stimulant regimen. Beginning at week 2, the dose of CLON-XR could be increased by increments of 0.1 mg per week to reach the maximal dose. Additional doses of CLON-XR were added to the morning (if > 0.1 mg was administered) or night dosing regimen (eg, patients who received CLON-XR 0.3 mg per day took 1 tablet in the morning and 2 tablets in the evening). Concomitant stimulant medication was prescribed by the patient's regular physician and was obtained from the patient's usual pharmacy. Caregivers recorded the specific amount of CLON-XR and stimulant medication the patient received each week in a medication diary provided by the site personnel. Compliance was assessed by the investigator at each visit via comparison of the number of tablets dispensed for the previous week and the recorded amount of study medication taken.
The primary efficacy measure was improvement from baseline to week 5 in ADHD-RS-IV total score versus placebo using a last observation carried forward (LOCF) method. The ADHD-RS-IV was completed by the investigator at screening, baseline, and all weekly visits. Additional assessments included improvement in scores from baseline to week 5 compared with placebo on ADHD-RS-IV hyperactivity/impulsivity and inattention subscales, Clinical Global Impression of Severity (CGI-S) and Clinical Global Impression of Improvement (CGI-I) scales, the Conners' Parent Rating Scale, Revised, Long Form (CPRS) hyperactivity and oppositional subscales, and the Parent Global Assessment (PGA) scale using a LOCF method. The ADHD-RS-IV, CGI-S, and CGI-I were completed by the investigator, whereas the CPRS and PGA were evaluated by parents/guardians. Treatment-emergent adverse events (TEAEs), vital signs (eg, blood pressure, heart rate, body temperature), and electrocardiograms were measured throughout the study period.
All predefined primary statistical efficacy analyses were conducted in the intent-to-treat (ITT) population, defined as all patients who were randomly assigned to treatment, took ≥1 dose of study medication, and provided at least 1 efficacy assessment. Sample size calculation using a t test and assuming an effect size of 0.47 (ie, difference of 7 ± 15 [mean ± SD] points on the ADHD-RS-IV total score between groups), at least 90% power, and a 2-sided α level of 0.05 indicated that 100 patients per treatment group were necessary to achieve statistical significance.
Improvement from baseline in ADHD-RS-IV total score to week 5 was evaluated by using analysis of covariance with terms for baseline ADHD-RS-IV score, study site, and treatment group. A LOCF method was used to account for patients who discontinued from the study earlier than week 5. In addition, analysis of covariance with terms for class of concomitant ADHD medication (ie, methylphenidate or amphetamine) was performed on subgroups. P values were derived from 2-sided tests, which were compared with the α level of 0.05 for statistical significance without adjusting for multiple group comparisons. Analyses of secondary end points were similar to those of the primary efficacy variables. Responders were defined posthoc as patients with a ≥30% reduction in ADHD-RS-IV total score from baseline who were considered to be “very much improved” or “much improved” on the investigator-completed CGI-I. Effect size was calculated on the basis of the observed mean differences between the groups and the observed SDs using the unbiased version of Hedges' g. Safety data (ie, TEAEs, vital signs, electrocardiograms) were collected from the defined safety population (ie, all patients who received ≥1 dose of study medication) and were presented as descriptive statistics.