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Droxidopa in Patients with Neurogenic Orthostatic Hypotension Associated with Parkinson's Disease (NOH306A)

Article type: Research Article

Authors: Hauser, Robert A. | Hewitt, L. Arthur | Isaacson, Stuart

Affiliations: University of South Florida, Tampa, FL, USA | Chelsea Therapeutics, Inc., Charlotte, NC, USA | Parkinson's Disease and Movement Disorders Center of Boca Raton, Boca Raton, FL, USA

Note: [] Correspondence to: Robert A. Hauser, MD, MBA, University of South Florida, Parkinson's Disease and Movement Disorders Center, National Parkinson Foundation Center of Excellence, 4001 E. Fletcher Ave, 6th Floor, Tampa, FL 33613, USA. Tel.: +1 813 396 0765; Fax: +1 813 905 9829; E-mail: rhauser@health.usf.edu

Keywords: Hypotension, orthostatic, Parkinson's disease, droxidopa, falls, treatment

DOI: 10.3233/JPD-130259

Journal: Journal of Parkinson's Disease, vol. 4, no. 1, pp. 57-65, 2014

Published: 2014
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Abstract

Background: Neurogenic orthostatic hypotension (nOH) is common in Parkinson's disease (PD), and represents a failure to generate norepinephrine responses appropriate for postural change. Droxidopa (L-threo-3,4-dihydroxyphenylserine) is an oral norepinephrine prodrug. Objective: Interim analyses of the initial patients enrolled in a multicenter, randomized, double-blind, placebo-controlled phase 3 trial of droxidopa for nOH in PD (ClinicalTrials.gov Identifier: NCT01176240). Methods: PD patients with documented nOH underwent ≤2 weeks of double-blind droxidopa or placebo dosage optimization followed by 8 weeks of maintenance treatment (100–600 mg t.i.d.). The primary efficacy measure was change in Orthostatic Hypotension Questionnaire (OHQ) composite score from baseline to Week 8. Key secondary variables included dizziness/lightheadedness score (OHQ item 1) and patient-reported falls. Results: Among 24 droxidopa and 27 placebo recipients, mean OHQ composite-score change at Week 8 was −2.2 versus −2.1 (p = 0.98); in response to this pre-planned futility analysis, the study was temporarily stopped and all data from these patients were considered exploratory. At Week 1, mean dizziness/lightheadedness score change favored droxidopa by 1.5 units (p = 0.24), with subsequent numerical differences favoring droxidopa throughout the observation period, and at Week 1, mean standing systolic blood-pressure change favored droxidopa by 12.5 mmHg (p = 0.04). Compared with placebo, the droxidopa group exhibited an approximately 50% lower rate of reported falls (p = 0.16) and fall-related injuries (post-hoc analysis). Conclusions: This exploratory analysis of a small dataset failed to show benefit of droxidopa, as compared with placebo by the primary endpoint. Nonetheless, there were signals of potential benefit for nOH, including improvement in dizziness/lightheadedness and reduction in falls, meriting evaluation in further trials.

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