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

Abstract Background: Guanfacine hydrochloride is an α 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 I, 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 mg on days 1 to 4, 2 mg on days 5 to 8, 3 mg 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. Treatment-emergent 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 taper down 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.