Guanfacine XR for Pediatric ADHD?
Guanfacine XR for Pediatric ADHD?
Biederman J, Melmed RD, Patel A, et al.
Pediatrics. 2008;121:e73-84.
This randomized, controlled trial examines whether extended-release guanfacine, a selective alpha2-adrenoceptor agonist, is effective for children and adolescents with attention deficit/hyperactivity disorder (ADHD).
Stimulants are the primary class of agents used in ADHD, but in some children, an alpha2-adrenoceptor agonist has been used as a second-line agent, the most familiar being clonidine. Because clonidine is relatively short acting and binds to a number of other receptors besides the alpha2-adrenoceptor (implicated in attention and organization functioning), it is thought that a longer-acting and more selective agent may be a better choice for ADHD treatment.
The study included a fixed-dosage escalation component, meaning that every child in the treatment group started at 1 mg/day and increased every week to their final dose -- 2, 3, or 4 mg/day, resulting in 1 placebo group and 3 treatment groups (of different dosages). The study was preceded by a washout period. By the 6th week of the study, the dosage was tapered back to 2 mg/day (for those in the 3- and 4-mg/day groups). A total of 345 patients were enrolled, and each group started with 86 patients (87 in the 2-mg/day group).
Their primary outcome measure was the ADHD Rating Scale (RS) IV total score, based on the Diagnostic and Statistical Manual of Mental Disorders (DSMR), 4th ed. There was a statistically significant reduction in ADHD RS for all groups, -16.7 vs -8.9 for placebo (P < .0001), with similar effect size between the 2-mg and 3-mg groups and a larger effect size (-10.39 difference between groups) for the 4-mg group.
There were numerous other analyses in this paper using several different outcome variables, including the Conners' Rating Scale-Revised: Short Form for both parents and teachers and Clinical Global Impression of Improvement among others. There were similar differences found between groups.
As mentioned above, this study included 86 to 87 patients in each group, and the study was powered for 70 subjects per treatment group. However, there was at least 33% attrition in each group. For each arm of the study, there were 53, 58, 55, and 49 that completed the study. In the placebo group, 15 of 33 discontinued because of lack of efficacy and 1 because of adverse effects (AE). In the 2-mg, 3-mg, and 4-mg groups, 9 of 29, 13 of 31, and 20 of 37 discontinued because of AE, respectively.
The study medication appears to be better than placebo, and also has a good dose response effect. However, I remain skeptical that the drug was tolerated as well as the authors state in their conclusion. As dose increased, a greater number of subjects dropped out because of adverse events. More than half of the patients in the 3-mg and 4-mg groups reported AE compared with 9% taking placebo. Proper dosage, in terms of milligrams per kilogram, needs to be worked out better. The dropout rate was greatest in the placebo groups, but they presumably dropped out for reasons other than AEs. In addition, a comparison of guanfacine extended release with another long-acting stimulant would provide us with a better idea of where this medication might fit into treatment plans.
Abstract
A Randomized, Double-Blind, Placebo-Controlled Study of Guanfacine Extended Release in Children and Adolescents With Attention-Deficit/Hyperactivity Disorder
Biederman J, Melmed RD, Patel A, et al.
Pediatrics. 2008;121:e73-84.
Summary
This randomized, controlled trial examines whether extended-release guanfacine, a selective alpha2-adrenoceptor agonist, is effective for children and adolescents with attention deficit/hyperactivity disorder (ADHD).
Stimulants are the primary class of agents used in ADHD, but in some children, an alpha2-adrenoceptor agonist has been used as a second-line agent, the most familiar being clonidine. Because clonidine is relatively short acting and binds to a number of other receptors besides the alpha2-adrenoceptor (implicated in attention and organization functioning), it is thought that a longer-acting and more selective agent may be a better choice for ADHD treatment.
The study included a fixed-dosage escalation component, meaning that every child in the treatment group started at 1 mg/day and increased every week to their final dose -- 2, 3, or 4 mg/day, resulting in 1 placebo group and 3 treatment groups (of different dosages). The study was preceded by a washout period. By the 6th week of the study, the dosage was tapered back to 2 mg/day (for those in the 3- and 4-mg/day groups). A total of 345 patients were enrolled, and each group started with 86 patients (87 in the 2-mg/day group).
Their primary outcome measure was the ADHD Rating Scale (RS) IV total score, based on the Diagnostic and Statistical Manual of Mental Disorders (DSMR), 4th ed. There was a statistically significant reduction in ADHD RS for all groups, -16.7 vs -8.9 for placebo (P < .0001), with similar effect size between the 2-mg and 3-mg groups and a larger effect size (-10.39 difference between groups) for the 4-mg group.
There were numerous other analyses in this paper using several different outcome variables, including the Conners' Rating Scale-Revised: Short Form for both parents and teachers and Clinical Global Impression of Improvement among others. There were similar differences found between groups.
As mentioned above, this study included 86 to 87 patients in each group, and the study was powered for 70 subjects per treatment group. However, there was at least 33% attrition in each group. For each arm of the study, there were 53, 58, 55, and 49 that completed the study. In the placebo group, 15 of 33 discontinued because of lack of efficacy and 1 because of adverse effects (AE). In the 2-mg, 3-mg, and 4-mg groups, 9 of 29, 13 of 31, and 20 of 37 discontinued because of AE, respectively.
Viewpoint
The study medication appears to be better than placebo, and also has a good dose response effect. However, I remain skeptical that the drug was tolerated as well as the authors state in their conclusion. As dose increased, a greater number of subjects dropped out because of adverse events. More than half of the patients in the 3-mg and 4-mg groups reported AE compared with 9% taking placebo. Proper dosage, in terms of milligrams per kilogram, needs to be worked out better. The dropout rate was greatest in the placebo groups, but they presumably dropped out for reasons other than AEs. In addition, a comparison of guanfacine extended release with another long-acting stimulant would provide us with a better idea of where this medication might fit into treatment plans.
Abstract
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