Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial
Horacio Kaufmann, Ross Vickery, Whedy Wang, Jitendra Kanodia, Cyndya A Shibao, Lucy Norcliffe-Kaufmann, Brett Haumann, Italo Biaggioni, Horacio Kaufmann, Ross Vickery, Whedy Wang, Jitendra Kanodia, Cyndya A Shibao, Lucy Norcliffe-Kaufmann, Brett Haumann, Italo Biaggioni
Abstract
Purpose: In neurogenic orthostatic hypotension, blood pressure falls when upright owing to impaired release of norepinephrine, leading to dizziness. Ampreloxetine, a selective norepinephrine reuptake inhibitor, increases circulating norepinephrine levels. This study explored the safety of ampreloxetine and its effect on blood pressure and symptoms in patients with neurogenic orthostatic hypotension.
Methods: A multicenter ascending-dose trial (range 1-20 mg, Part A) was followed by a 1 day, double-blind, randomized, placebo-controlled study (median dose 15 mg, Part B). Eligible patients then enrolled in a 20-week, open-label, steady-state extension phase (median dose 10 mg, Part C) followed by a 4-week withdrawal. Assessments included the Orthostatic Hypotension Symptom Assessment Scale (item 1), supine/seated/standing blood pressure, and safety.
Results: Thirty-four patients (age 66 ± 8 years, 22 men) were enrolled. Part A: The proportion of participants with a positive response (i.e., increase from baseline in seated systolic blood pressure of ≥ 10 mmHg) was greater with the 5 and 10 mg ampreloxetine doses than with placebo or other active ampreloxetine doses. Part B: Seated blood pressure increased 15.7 mmHg 4 h after ampreloxetine and decreased 14.2 mmHg after placebo [least squares mean difference (95% CI) 29.9 mmHg (7.6-52.3); P = 0.0112]. Part C: Symptoms of dizziness/lightheadedness improved 3.1 ± 3.0 points from baseline and standing systolic blood pressure increased 11 ± 12 mmHg. After 4 weeks of withdrawal, symptoms returned to pretreatment levels. The effect of ampreloxetine on supine blood pressure was minimal throughout treatment duration.
Conclusion: Ampreloxetine was well tolerated and improved orthostatic symptoms and seated/standing blood pressure with little change in supine blood pressure.
Trial registration: NCT02705755 (first posted March 10, 2016).
Keywords: Ampreloxetine; Neurogenic orthostatic hypotension (nOH); Norepinephrine reuptake inhibitor (NRI); Synucleinopathies.
Conflict of interest statement
HK was a consultant to and has received research support from Theravance Biopharma US, Inc. RV is an employee of Theravance Biopharma Ireland Limited and stockholder of Theravance Biopharma, Inc. WW is a former employee of Theravance Biopharma US, Inc. JK is an employee of Theravance Biopharma US, Inc. and a stockholder of Theravance Biopharma, Inc. CS has received research support from Theravance Biopharma and is a member of the Advisory Board of Lundbeck US. LNK is an employee of Theravance Biopharma US, Inc. BH is a former employee of Theravance Biopharma UK Limited and a stockholder of Theravance Biopharma, Inc. IB is a consultant for and has received research support from Theravance Biopharma and is a patent holder of an automated abdominal binder for the treatment of orthostatic hypotension.
© 2021. The Author(s).
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