Phase I, double-blind, randomized, placebo-controlled, dose-escalation study of the effects on blood pressure of abrupt cessation versus taper down of guanfacine extended-release tablets in adults aged 19 to 24 years

Background: Guanfacine hydrochloride is an alpha(2a)-adrenoreceptor agonist found to be effective in the treatment of attention-deficit/hyperactivity disorder (ADHD). Because the available immediate-release formulation requires multiple daily dosing and has been associated with rebound hypertension on abrupt cessation, an extended-release (ER) formulation has been developed for study of efficacy and tolerability parameters in patients with ADHD. Objective: This trial was primarily undertaken to determine the effect on blood pressure (BP) of abrupt cessation versus taper-down of guanfacine ER. Methods: This Phase 1, randomized, double-blind, placebo-controlled, dose-escalation trial was conducted at MDS Pharma Services, Lincoln, Nebraska. Male and female healthy young-adult (aged 19-24 years) volunteers were included. Subjects were randomly assigned to receive guanfacine ER as follows. Abrupt-cessation and taper-down groups both received guanfacine ER, at forced titration: 1. ing on days 1 to 4, 2 mg on days 5 to 8, 3 ing on days 9 to 12, and 4 mg on days 13 to 16. The abrupt-cessation group then received placebo daily on days 17 to 32. The taper-down group began the following taper-down schedule: 3 mg on days 17 to 20, 2 mg on days 21 to 24, 1 mg on days 25 to 30, and placebo on days 31 to 32. Placebo was administered daily to the subjects in the placebo group (days 1-32). All doses were given in the morning. Tolerability was assessed before (at the 8-hour baseline visit), during (approximately every 4 days and during 48-hour confinements at days 17/18 and 31/32), and 7 days after the study and included assessment of BP and pulse, 12-lead electrocardiography (ECG), and laboratory assays. Adverse events (AEs) were also tracked every 4 days beginning on day 5 and 7, 14, and 30 days poststudy by recording responses and follow-up to a nonleading question about how the patient was feeling that day. Results: Forty-five subjects were enrolled in the study (15 in each group), and 35 subjects completed it. The mean age of study participants was 22 years, 87% were white, and the ratio of women to men was 2:1. There were no marked differences between groups regarding age, sex, or race. Compared with the taperdown group, the abrupt-cessation group did not exhibit a clinically significant elevation of systolic BP (SBP) or diastolic BP (DBP) or other tolerability parameters, including AEs. Significant differences in BP were observed on days 17/18 (first day of abrupt cessation) and 31/32, but the overall means were not statistically different. The SBP decreases were -7.55% (-8.84 mm Hg) in the abrupt-cessation group and -8.33% (-9.69 mm Hg) in the taper-down group. The DBP decreases were -9.14% (-6.17 mm Hg) in the abrupt-cessation group and -9.94% (-6.59 mm Hg) in the taper-down group. There were no statistically significant or clinically important differences in change or percentage change in pulse from baseline to day 31/32 between the taper-down and placebo groups (least squares mean difference, 2.26 bpm). None of the subjects experienced bradycardia. No clinically important treatment-related trends were noted in the clinical laboratory, ECG, or physical examination findings, including vital signs. No serious treatment-emergent AEs were reported in this study. Overall, 124 treatment-emergent AEs were reported in 29 (64%) subjects. Treatmentemergent AEs were reported in 14 (93.3%) of 15 subjects in the abrupt-cessation group, 8 (53.3%) of 15 subjects in the taper-down group, and 7 (46.7%) of 15 subjects in the placebo group. Headache was the most common AE reported in the abrupt-cessation (46.7%) and placebo (13.3%) groups. For the taperdown group, it was dry mouth (26.7%). All AEs were classified as mild or moderate. Conclusion: In this small study group of healthy, young-adult volunteers, guanfacine ER at doses up to 4 mg/d was abruptly discontinued without significant increases in SBP or DBP or other tolerability parameters, including AEs, compared with taper.