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

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).

Figures

Fig. 1

Overall trial design. Part A: Day 1, placebo was administered single blind and on subsequent days, participants received ascending doses of ampreloxetine (1–10 mg or 2.5–20 mg from day 2 to day 5). Stopping criteria included safety concerns/adverse events or seated BP > 180/110 mmHg. Responders were defined as those with a seated systolic pressor response ≥ 10 mmHg relative to placebo and underwent a washout. Part B: Participants were randomized (1:1) to ampreloxetine or placebo for 1 day. Part A and Part B were inpatient studies and the primary endpoint in both was the change in seated BP 6–8 h post-ampreloxetine. Part C: Predose assessments were taken as baseline. Participants received open-label ampreloxetine for 20 weeks as outpatients (median dose 10 mg/day). The primary endpoint in Part C was a change from baseline in OHSA #1 scores at week 4. At the end of the 20 weeks, ampreloxetine was withdrawn to determine whether symptoms diminished to baseline levels. Key: Blue pills = ampreloxetine. Gray pills = placebo. Red = primary endpoints for Parts A, B, and C. Green asterisk = main protocol amendments (i) to start the dose escalation at 2.5 mg and (ii) to eliminate Part B in order for patients to directly enter Part C. BP blood pressure, h hours, mg milligrams, min minutes, mmHg millimeters of mercury, OHSA #1 dizziness/lightheadedness score on Orthostatic Hypotension Symptom Assessment (question 1), R randomization, SBP systolic blood pressure

Fig. 2

Consort diagram describing the flow of participants through the study. *Participants who completed Part A and entered Part B before amendment. **Number of participants who entered Part C after completion of Part B (before amendment) and those who directly entered Part C from Part A (after amendment). mg milligrams, n number

Fig. 3

Pressor response to ampreloxetine. a Mean ± SE placebo time-matched change in seated SBP (primary endpoint) throughout dose escalation in the overall cohort (light blue) and responders (dark blue). Owing to an early trial amendment, not all participants received the 1 mg dose on day 1. Responders were not escalated to a higher dose. b Mean ± SE change in seated SBP 4 h after ampreloxetine (15 mg, n = 4, 10 mg, n = 1) vs. placebo (n = 5) in the 1 day double-blind, placebo-controlled randomized study. c Timeline of change in seated BP over 12 h after ampreloxetine and placebo. d Change in standing SBP 4 h after ampreloxetine and placebo. e Timeline of changes in standing SBP when assigned to ampreloxetine vs. placebo. Red dotted line denotes cutoff for a pressor responder, determined by a change in seated SBP ≥ 10 mmHg compared to baseline. In panels C through E, data shown as least squares mean ± SE; blue represents ampreloxetine, gray represents placebo. Red star indicates significance. BP blood pressure, mmHg millimeters of mercury, SBP systolic blood pressure, SE standard error

Fig. 4

Symptoms and BP response over 20 weeks of open-label extension. a Mean change from baseline in dizziness/lightheadedness scores (OHQ symptom assessment item 1) in the subset of symptomatic participants (OHSA#1 > 4 points). A decrease in scores indicates clinical improvement. The primary endpoint was the change observed at week 4. Values below dotted red line indicate improvement above the MCID. The observed effect was sustained throughout the 20 weeks. After withdrawal of ampreloxetine, symptoms diminished to baseline levels. b Similar pattern of changes observed with the composite scores of symptom severity (OHSA) and impact of symptoms on activities of daily living (OHDAS). c Change from baseline in systolic BP at 1 min standing over the 20-week trial. Note, after withdrawal of ampreloxetine, most patients (N = 7) resumed taking other pressor agents. An increase in BP was observed off-treatment without corresponding improvement in symptoms. Data are mean ± standard error. BP blood pressure, MCID minimal clinically important difference, OHDAS Orthostatic Hypotension Daily Activities Scale, OHQ Orthostatic Hypotension Questionnaire, OHSA Orthostatic Hypotension symptom assessment, OHSA #1  dizziness/lightheadedness score on Orthostatic Hypotension Symptom Assessment (question 1)

Fig. 5

Responses in autonomic failure. a Change in SBP supine vs. change in 3-min standing SBP at week 4. Data are mean ± SD. A 5-mmHg increase in supine SBP was accompanied by an approximately 10-mmHg increase in standing SBP. b The durability of the pressor effect supine vs. standing was demonstrated to a greater degree on 3-min standing SBP at week 20. The increase in standing SBP exceeded the increase in supine SBP in participants receiving ampreloxetine. Red indicates before breakfast; blue indicates before lunch. Data from Part C; open-label extension. mmHg millimeters of mercury, pg picogram, SBP systolic blood pressure, SD standard deviation