In both trials, patients taking GXR demonstrated statistically signifcant improvements in ADHD-RS-IV score starting 1 to 2 weeks after they began receiving once-daily GXR:
- In the first trial, the mean reduction in ADHD-RS-IV total score at endpoint was –16.7 for GXR compared with –8.9 for placebo (P < .0001).
- In the second, the reduction was –19.6 for GXR and –12.2 for placebo (P=.004).
Placebo-adjusted least squares mean changes from baseline were statistically significant for all GXR doses in the randomized treatment groups in both studies.
Secondary efficacy outcome measures included the Conners’ Parent Rating Scale-Revised: Short Form (CPRS-R) and the Conners’ Teacher Rating Scale-Revised: Short Form (CTRS-R).
Significant improvements were seen on both scales. On the CPRS-R, parents reported significant improvement across a full day (as measured at 6 PM, 8 PM, and 6 AM the next day). On the CTRS-R—which was used only in the first trial—teachers reported significant improvement throughout the school day (as measured at 10 AM and 2 PM).
Treating oppositional symptoms. In a collateral study,9 GXR was evaluated in complex ADHD patients age 6 to 12 who exhibited oppositional symptoms. The primary efficacy measure was change from baseline to endpoint in the oppositional subscale of the Conners’ Parent Rating Scale-Revised: Long Form (CPRS-R:L) score.
All subjects randomized to GXR started on a dose of 1 mg/d—which could be titrated by 1 mg/week during the 5-week, dose-optimization period to a maximum of 4 mg/d—and were maintained at their optimal doses for 3 additional weeks. Among the 217 subjects enrolled, 138 received GXR and 79, placebo.
Least-squares mean reductions from baseline to endpoint in CPRS-R:L oppositional subscale scores were –10.9 in the GXR group compared with –6.8 in the placebo group (P < .001; effect size 0.590). The GXR-treated group showed a significantly greater reduction in ADHD-RS-IV total score from baseline to endpoint compared with the placebo group (–23.8 vs –11.4, respectively, P < .001; effect size 0.916).
Table 2
Randomized, controlled trials supporting GXR’s effectiveness
for treating ADHD symptoms
| Study | Subjects | GXR dosages | Results |
|---|---|---|---|
| Biederman et al, 20087 ; phase III, forced-dose parallel-design | 345 ADHD patients age 6 to 17 | 2, 3, or 4 mg given once daily for 8 weeks | GXR was associated with significantly lower ADHD-RS-IV score compared with placebo (-16.7 vs -8.9) |
| Sallee et al, 20098 ; phase III, forced-dose parallel-design | 324 ADHD patients age 6 to 17 | 1,* 2, 3, or 4 mg given once daily for 9 weeks | GXR was associated with significantly lower ADHD-RS-IV score compared with placebo (-19.6 vs -12.2) |
| Connor et al, 20099 ; collateral study | 217 complex ADHD patients age 6 to 12 with oppositional symptoms | Starting dose 1 mg/d, titrated to a maximum of 4 mg/d for a total of 8 weeks | GXR was associated with significantly lower scores on CPRS-R:L oppositional subscale (-10.9 vs -6.8) and ADHD-RS-IV (-23.8 vs -11.4) compared with placebo |
| *1-mg dose was given only to subjects weighing <50 kg (<110 lbs) | |||
| ADHD: attention-deficit/hyperactivity disorder; ADHD-RS-IV: Attention-Deficit/Hyperactivity Disorder Rating Scale-IV; CPRS-R:L: Conners’ Parent Rating Scale-Revised: Long Form; GXR: guanfacine extended release | |||
Tolerability
In the phase III trials, the most commonly reported drug-related adverse reactions (occurring in ≥2% of patients) were:
- somnolence (38%)
- headache (24%)
- fatigue (14%)
- upper abdominal pain (10%)
- nausea, lethargy, dizziness, hypotension/decreased blood pressure, irritability (6% for each)
- decreased appetite (5%)
- dry mouth (4%)
- constipation (3%).
Many of these adverse reactions appear to be dose-related, particularly somnolence, sedation, abdominal pain, dizziness, and hypotension/decreased blood pressure.
Overall, GXR was well tolerated; clinicians rated most events as mild to moderate. Twelve percent of GXR patients discontinued the clinical studies because of adverse events, compared with 4% in the placebo groups. The most common adverse reactions leading to discontinuation were somnolence/sedation (6%) and fatigue (2%). Less common adverse reactions leading to discontinuation (occurring in 1% of patients) included hypotension/decreased blood pressure, headache, and dizziness.
Open-label safety trial. Sallee et al10 conducted a longer-term, open-label, flexible-dose safety continuation study of 259 GXR-treated patients (mean exposure 10 months), some of whom also received a psychostimulant. Common adverse reactions (occurring in ≥5% of subjects) included somnolence (45%), headache (26%), fatigue (16%), upper abdominal pain (11%), hypotension/decreased blood pressure (10%), vomiting (9%), dizziness (7%), nausea (7%), weight gain (7%), and irritability (6%).10 In a subset of patients, the onset of sedative events typically occurred within the first 3 weeks of GXR treatment and then declined with maintenance to a frequency of approximately 16%. The rates of somnolence, sedation, or fatigue were lowest among patients who also received a psychostimulant ( Figure ).
Distribution of GXR doses before the end of this study was 37% of patients on 4 mg, 33% on 3 mg, 27% on 2 mg, and 3% on 1 mg, suggesting a preference for maintenance doses of 3 to 4 mg/d. The most frequent adverse reactions leading to discontinuation were somnolence (3%), syncopal events (2%), increased weight (2%), depression (2%), and fatigue (2%). Other adverse reactions leading to discontinuation (occurring in approximately 1% of patients) included hypotension/decreased blood pressure, sedation, headache, and lethargy. Serious adverse reactions in the longer-term study in >1 patient included syncope (2%) and convulsion (0.4%).