2. Academic Validation
  3. Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

Safety and efficacy of ampreloxetine in symptomatic neurogenic orthostatic hypotension: a phase 2 trial

  • Clin Auton Res. 2021 Dec;31(6):699-711. doi: 10.1007/s10286-021-00827-0.
Horacio Kaufmann 1,  Ross Vickery 2,  Whedy Wang 3,  Jitendra Kanodia 4,  Cyndya A Shibao 5,  Lucy Norcliffe-Kaufmann 4,  Brett Haumann 6,  Italo Biaggioni 5
Affiliations

Affiliations

  • 1 Department of Neurology, Dysautonomia Center, NYU Langone Health, New York University School of Medicine, 530 First Avenue, Suite 9Q, New York, NY, 10016, USA. Horacio.Kaufmann@nyulangone.org.
  • 2 Theravance Biopharma Ireland Limited, Dublin, Ireland.
  • 3 Formerly of Theravance Biopharma US, Inc., South San Francisco, CA, USA.
  • 4 Theravance Biopharma US, Inc., South San Francisco, CA, USA.
  • 5 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 6 Formerly of Theravance Biopharma UK Limited, London, UK.
PMID: 34657222 DOI: 10.1007/s10286-021-00827-0
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.

Figures
Products