Safety and Durability of Effect with Long-Term, Open-Label Droxidopa Treatment in Patients with Symptomatic Neurogenic Orthostatic Hypotension (NOH303)

Abstract

Abstract.Background: Neurogenic orthostatic hypotension (nOH) is associated with insufficient norepinephrine release in response to postural change. Objective: The objective of this study was to evaluate the long-term safety and durability of efficacy of the norepinephrine precursor droxidopa in patients with symptomatic nOH. Methods: This multinational study consisted of 3 sequential phases: a 3-month open-label droxidopa treatment phase followed by a 2-week double-blind, placebo-controlled withdrawal phase, and a 9-month open-label extension phase in which all patients received droxidopa. Patients were adults diagnosed with symptomatic nOH associated with Parkinson's disease, multiple system atrophy, pure autonomic failure, dopamine ␤-hydroxylase deficiency, or nondiabetic autonomic neuropathy. Efficacy was evaluated using patient-and investigator-reported questionnaire responses and the orthostatic standing test. Safety was assessed through adverse event (AE) reports and vital signs. Results: A total of 102 patients received treatment with droxidopa. Initial improvements from baseline in patient-reported nOH symptom severity and impact on daily activities, evaluated using the Orthostatic Hypotension Questionnaire, exceeded 50% and were maintained throughout the 12-month study. Decreased nOH severity was also reflected in clinician and patient ratings on the Clinical Global Impression questionnaire. Standing systolic and diastolic blood pressures were increased from baseline throughout the study with droxidopa treatment. The most frequently reported AEs were falls, urinary tract infection, and headache. There was a low incidence (≤2%) of cardiac AEs (eg, first-degree atrioventricular block, supraventricular extrasystoles).

Integrated analysis of droxidopa trials for neurogenic orthostatic hypotension

“…The efficacy of droxidopa has not been studied in the treatment of OH due to other causes. Also, evidence of efficacy was limited to 1–2 and 8–10 weeks in these studies, although longer-term safety and efficacy data have been reported [21, 22]. Droxidopa received accelerated FDA approval, with commitment from the sponsor to undertake a postmarketing trial to assess the durability of efficacy; such a study is underway [23].…”

Integrated Analysis of Droxidopa for the Treatment of Neurogenic Orthostatic Hypotension in Patients with Parkinson Disease

“…It should be noted that symptomatic nOH is an orphan indication, and the establishment of statistical significance is challenging in this patient population because of the limited number of patients eligible for enrollment into clinical trials. Also, the present efficacy and tolerability analyses examined a limited duration of treatment (1 to ≤ 10 weeks) with the main pooled efficacy outcomes evaluated after one week of treatment; however, longer‐term safety and efficacy outcomes with droxidopa in the broader population of patients with nOH have been reported …”

Impact of the Norepinephrine Prodrug Droxidopa on the QTc Interval in Healthy Individuals

“…High rates of concomitant medication use occur in patients with nOH . In patients receiving polypharmacy, metabolic effects resulting from drug combinations and the potential for drug–drug interaction effects on QT interval and proarrhythmia risk are a concern .…”

“…[4][5][6][7] Similarly, low rates of cardiac AEs were found in 2 long-term openlabel extension studies of droxidopa treatment. 25,26 High rates of concomitant medication use occur in patients with nOH. 25,27 In patients receiving polypharmacy, metabolic effects resulting from drug combinations and the potential for drug-drug interaction effects on QT interval and proarrhythmia risk are a concern.…”