Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.

Abstract

OBJECTIVE:

To determine whether droxidopa, an oral norepinephrine precursor, improves symptomatic neurogenic orthostatic hypotension (nOH).

METHODS:

Patients with symptomatic nOH due to Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa dose optimization (100-600 mg 3 times daily), followed, in responders, by 7-day washout and then a 7-day double-blind trial of droxidopa vs placebo. Outcome measures included patient self-ratings on the Orthostatic Hypotension Questionnaire (OHQ), a validated, nOH-specific tool that assesses symptom severity and symptom impact on daily activities.

RESULTS:

From randomization to endpoint (n = 162), improvement in mean OHQ composite score favored droxidopa over placebo by 0.90 units (p = 0.003). Improvement in OHQ symptom subscore favored droxidopa by 0.73 units (p = 0.010), with maximum change in "dizziness/lightheadedness." Improvement in symptom-impact subscore favored droxidopa by 1.06 units (p = 0.003), with maximum change for "standing a long time." Mean standing systolic blood pressure (BP) increased by 11.2 vs 3.9 mm Hg (p < 0.001), and mean supine systolic BP by 7.6 vs 0.8 mm Hg (p < 0.001). At endpoint, supine systolic BP >180 mm Hg was observed in 4.9% of droxidopa and 2.5% of placebo recipients. Adverse events reported in ≥ 3% of double-blind droxidopa recipients were headache (7.4%) and dizziness (3.7%). No patients discontinued double-blind treatment because of adverse events.

CONCLUSIONS:

In patients with symptomatic nOH, droxidopa improved symptoms and symptom impact on daily activities, with an associated increase in standing systolic BP, and was generally well tolerated.

CLASSIFICATION OF EVIDENCE:

This study provides Class I evidence that in patients with symptomatic nOH who respond to open-label droxidopa, droxidopa improves subjective and objective manifestation of nOH at 7 days.

• Authors: Horacio Kaufmann, Roy Freeman, Italo Biaggioni, Phillip Low, Simon Pedder, L Arthur Hewitt, Joe Mauney, Michael Feirtag, Christopher J Mathias, NOH301 Investigators
• Journal: Neurology (Neurology) Vol. 83 Issue 4 Pg. 328-35 (Jul 22 2014) ISSN: 1526-632X [Electronic] United States
• PMID: 24944260 (Publication Type: Clinical Trial, Phase III, Journal Article, Multicenter Study, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, P.H.S.)
• Copyright: © 2014 American Academy of Neurology.

Chemical References

• Autonomic Agents
• Droxidopa

Topics

• Aged
• Autonomic Agents (administration & dosage, adverse effects, therapeutic use)
• Autonomic Nervous System Diseases (complications, drug therapy)
• Blood Pressure (drug effects)
• Dizziness (drug therapy)
• Double-Blind Method
• Droxidopa (administration & dosage, adverse effects, therapeutic use)
• Female
• Humans
• Hypotension, Orthostatic (drug therapy, etiology)
• Male
• Middle Aged
• Multiple System Atrophy (complications, drug therapy)
• Nervous System Diseases (complications, drug therapy)
• Parkinson Disease (complications, drug therapy)
• Posture
• Pure Autonomic Failure (complications, drug therapy)
• Time Factors
• Treatment Outcome