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Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial.
Neurology. 2014 Jul 22; 83(4):328-35.Neur

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+Show Affiliations

From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK. horacio.kaufmann@nyumc.org.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.From the Department of Neurology (H.K.), NYU Medical Center, New York; Department of Neurology (R.F.), Beth Israel Deaconess Medical Center, Boston, MA; Department of Medicine (I.B.), Vanderbilt University Medical Center, Nashville, TN; Department of Neurology (P.L.), Mayo Clinic, Rochester, MN; Chelsea Therapeutics, Inc. (S.P., L.A.H.), Charlotte, NC; Chiltern (J.M.), Wilmington, NC; The Curry Rockefeller Group, LLC (M.F.), Tarrytown, NY; Autonomic and Neurovascular Medicine Departments (C.J.M.), Imperial College London; and Institute of Neurology (C.J.M.), University College London, UK.No affiliation info available

Pub Type(s)

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.

Language

eng

PubMed ID

24944260

Citation

Kaufmann, Horacio, et al. "Droxidopa for Neurogenic Orthostatic Hypotension: a Randomized, Placebo-controlled, Phase 3 Trial." Neurology, vol. 83, no. 4, 2014, pp. 328-35.
Kaufmann H, Freeman R, Biaggioni I, et al. Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology. 2014;83(4):328-35.
Kaufmann, H., Freeman, R., Biaggioni, I., Low, P., Pedder, S., Hewitt, L. A., Mauney, J., Feirtag, M., & Mathias, C. J. (2014). Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology, 83(4), 328-35. https://doi.org/10.1212/WNL.0000000000000615
Kaufmann H, et al. Droxidopa for Neurogenic Orthostatic Hypotension: a Randomized, Placebo-controlled, Phase 3 Trial. Neurology. 2014 Jul 22;83(4):328-35. PubMed PMID: 24944260.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. AU - Kaufmann,Horacio, AU - Freeman,Roy, AU - Biaggioni,Italo, AU - Low,Phillip, AU - Pedder,Simon, AU - Hewitt,L Arthur, AU - Mauney,Joe, AU - Feirtag,Michael, AU - Mathias,Christopher J, AU - ,, Y1 - 2014/06/18/ PY - 2014/6/20/entrez PY - 2014/6/20/pubmed PY - 2014/9/10/medline SP - 328 EP - 35 JF - Neurology JO - Neurology VL - 83 IS - 4 N2 - 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. SN - 1526-632X UR - https://www.unboundmedicine.com/medline/citation/24944260/Droxidopa_for_neurogenic_orthostatic_hypotension:_a_randomized_placebo_controlled_phase_3_trial_ L2 - http://www.neurology.org/cgi/pmidlookup?view=long&amp;pmid=24944260 DB - PRIME DP - Unbound Medicine ER -