Safety and efficacy of ABT-089 in pediatric attention-deficit/hyperactivity disorder: results from two randomized placebo-controlled clinical trials.

OBJECTIVE: To assess the safety and efficacy of ABT-089, a novel α(4)ß(2) neuronal nicotinic receptor partial agonist, vs. placebo in children with attention-deficit/hyperactivity disorder (ADHD). METHOD: Two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of children 6 through 12 years of age were conducted. Study 1 (n = 274) assessed six treatment groups over 8 weeks: 4 once-daily (QD) ABT-089 doses (0.085-0.700 mg/kg), QD atomoxetine, and placebo. Study 2 (n = 119) assessed three treatment groups over 6 weeks: 2 QD ABT-089 doses (0.7 mg/kg, 1.4 mg/kg) and placebo. The primary efficacy variable was the investigator-administered Attention-Deficit/Hyperactivity Disorder Rating Scale-IV: Home Version (ADHD-RS-IV [HV]) Total Score. Safety was assessed by adverse event (AE) monitoring, laboratory tests, vital signs, physical examinations, and electrocardiogram measures. RESULTS: There was no statistically significant difference between ABT-089 and placebo in mean change from baseline to final evaluation of ADHD-RS-IV (HV) Total Score or other outcome measures at any dose in either study. In Study 1, atomoxetine showed statistically significant improvement for the primary and most secondary endpoints. ABT-089 was generally safe and well tolerated, with no statistically significant difference between any ABT-089 dose and placebo in the overall incidence of any specific AE, and no clinically significant changes in other safety measures. CONCLUSIONS: ABT-089 did not show efficacy on the primary efficacy variable, the ADHD-RS-IV (HV) Total Score, or other measures of ADHD symptomatology in children with ADHD, and had a safety profile similar to placebo. These results contrast with published reports of efficacy of nicotinic modulators in adults with ADHD.

Safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches: results of an open-label extension trial in adolescents.

OBJECTIVE: To evaluate the long-term safety and tolerability of divalproex sodium extended-release in the prophylaxis of migraine headaches in adolescents. BACKGROUND: Divalproex sodium has been approved for migraine prophylaxis in adults. A previous double-blind, placebo-controlled study of the efficacy and safety of divalproex sodium extended-release for prevention of migraine in adolescents was followed by the present long-term extension trial, which was designed to collect additional safety and tolerability data. METHODS: This was a 12-month, Phase 3, open-label extension of a 3-month, double-blind, placebo-controlled, multicenter study of adolescents aged 12 to 17 years with migraine headaches who had either completed the previous study or had discontinued because of lack of efficacy. Subjects from the previous trial who had experienced serious adverse events possibly or probably related to study drug were excluded. Divalproex sodium extended-release 500 mg daily was administered for 15 days then increased to 1000 mg. Study visits were conducted at days 1 and 15 and months 1, 2, 3, 6, 9, and 12. Safety assessments included adverse event collection, laboratory testing, physical and neurological examinations, vital signs, and electrocardiograms, as well as reproductive endocrine analyses for postmenarchal female subjects. Efficacy was evaluated by sequential 4-week migraine headache rates calculated from subjects' headache diaries. RESULTS: A total of 112 subjects enrolled in the trial. The most common adverse events were weight gain (15%), nausea (14%), somnolence (12%), upper respiratory tract infection (11%), increased ammonia (8%), and sinusitis (8%). Five (4%) subjects experienced serious adverse events, and 15 (13%) subjects prematurely discontinued because of an adverse event. Increased ammonia levels were noted in some individuals, and the mean ammonia level for all subjects increased 19.2 microm from baseline. No other clinically significant changes were observed in laboratory values, vital signs, or electrocardiograms. Improvement in mean and median 4-week migraine headache rates occurred by the fourth month and lasted for the duration of the trial. CONCLUSIONS: In this long-term open-label extension study, the safety profile of divalproex sodium extended-release in adolescents with migraine was consistent with that observed in the preceding 3-month, double-blind trial and in previous adult studies. Overall, divalproex sodium extended-release was well-tolerated in adolescents aged 12 to 17 years.

Divalproex extended-release in adolescent migraine prophylaxis: results of a randomized, double-blind, placebo-controlled study.

OBJECTIVE: To evaluate the efficacy, tolerability, and safety of 3 different doses of divalproex sodium extended-release vs placebo in the prophylaxis of migraine headaches in adolescents. BACKGROUND: Divalproex sodium has been approved for migraine prophylaxis in adults, and previous uncontrolled data suggest divalproex sodium may be effective in preventing migraine in children and adolescents with acceptable tolerability. METHODS: This was a 12-week, phase 3, randomized, placebo-controlled, double-blind, parallel-group, multicenter study in approximately 300 adolescents aged 12 to 17 years with migraine headaches. At the end of the baseline phase, subjects still meeting study criteria were randomized in a 1:1:1:1 ratio to receive divalproex sodium extended-release 250 mg, 500 mg, or 1000 mg once daily, or placebo. The primary efficacy variable was reduction from baseline in 4-week migraine headache rate for each active treatment group vs placebo. Standard safety assessments were conducted and testosterone and sex hormone-binding globulin levels were collected for postmenarchal females. RESULTS: There was no statistically significant treatment difference between any divalproex sodium extended-release dose group and placebo for the primary efficacy variable, reduction from baseline in 4-week migraine headache rate. There were no statistically significant differences in adverse events between any active treatment group and placebo. A notable dose-related decrease in platelets was observed, and individuals in all 4 treatment groups had increases in ammonia levels; treatment differences in other laboratory variables were generally small. Among postmenarchal female subjects who were not taking hormonal contraceptives or other steroids, there was no statistically significant change in testosterone levels, but a statistically significant dose-related increase in sex hormone-binding globulin was observed. CONCLUSIONS: In the current study, divalproex sodium extended-release did not differentiate from placebo in the prophylactic treatment of migraine headaches but was generally well-tolerated in adolescents aged 12 to 17 years.

A novel approach to assess inter-rater reliability in the use of the Overt Aggression Scale-Modified.

The ability of raters to apply measures of efficacy accurately and reproducibly in clinical trials of psychotropic medications is vital to the validity of study data. In a large, multi-center trial using the Overt Aggression Scale-Modified (OAS-M), inter-rater reliability was evaluated using standardized patients (SP) in a live 'mock' interview. Thirty raters experienced in the OAS-M each interviewed two actors trained to portray patients with intermittent explosive disorder, borderline and antisocial personality disorder, and/or post-traumatic stress disorder. Inter-rater reliability of OAS-M scores was evaluated using the intra-class correlation coefficient (ICC). The joint reliability of the raters in the study with an expert rater was also assessed by an ICC. The ICC was 0.96 between the raters, and 0.98 between the raters and expert rater. Results suggest that SP can be utilized in rater assessment and that raters administering the OAS-M in this model of rater reliability assessment demonstrate a high level of consistency and reliability. The method described here may be useful in future assessments of inter-rater reliability.