title: Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.
abstract: We evaluated whether droxidopa, a prodrug converted to norepinephrine, is beneficial in the treatment of symptomatic neurogenic orthostatic hypotension, which results from failure to generate an appropriate norepinephrine response to postural challenge. Patients with symptomatic neurogenic orthostatic hypotension and Parkinson disease, multiple system atrophy, pure autonomic failure, or nondiabetic autonomic neuropathy underwent open-label droxidopa titration (100-600 mg, 3× daily). Responders then received an additional 7-day open-label treatment at their individualized dose. Patients were subsequently randomized to continue with droxidopa or withdraw to placebo for 14 days. We then assessed patient-reported scores on the Orthostatic Hypotension Questionnaire and blood pressure measurements. Mean worsening of Orthostatic Hypotension Questionnaire dizziness/lightheadedness score from randomization to end of study (the primary outcome; N=101) was 1.9±3.2 with placebo and 1.3±2.8 units with droxidopa (P=0.509). Four of the other 5 Orthostatic Hypotension Questionnaire symptom scores and all 4 symptom-impact scores favored droxidopa, with statistical significance for the patient's self-reported ability to perform activities requiring standing a short time (P=0.033) and standing a long time (P=0.028). Furthermore, a post hoc analysis of a predefined composite score of all symptoms (Orthostatic Hypotension Questionnaire composite) demonstrated a significant benefit for droxidopa (P=0.013). There was no significant difference between groups for standing systolic blood pressure (P=0.680). Droxidopa was well tolerated. In summary, this randomized withdrawal droxidopa study failed to meet its primary efficacy end point. Additional clinical trials are needed to confirm that droxidopa is beneficial in symptomatic neurogenic orthostatic hypotension, as suggested by the positive secondary outcomes of this trial.
  
  
  BACKGROUND
  http://www.clinicaltrials.gov. Unique identifier: NCT00633880.
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN (I.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (R.F.); Autonomic and Neurovascular Medicine Departments, Imperial College London and Institute of Neurology, University College London, London, United Kingdom (C.J.M.); Department of Neurology, Mayo Clinic, Rochester, MN (P.L.); Drug Development, Lundbeck, NA Ltd., Deerfield, IL (L.A.H.); and Department of Neurology, New York University Medical Center (H.K.). italo.biaggioni@vanderbilt.edu.
authors.forename: Italo
authors.initials: I
authors.lastname: Biaggioni
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN (I.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (R.F.); Autonomic and Neurovascular Medicine Departments, Imperial College London and Institute of Neurology, University College London, London, United Kingdom (C.J.M.); Department of Neurology, Mayo Clinic, Rochester, MN (P.L.); Drug Development, Lundbeck, NA Ltd., Deerfield, IL (L.A.H.); and Department of Neurology, New York University Medical Center (H.K.).
authors.forename: Roy
authors.initials: R
authors.lastname: Freeman
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN (I.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (R.F.); Autonomic and Neurovascular Medicine Departments, Imperial College London and Institute of Neurology, University College London, London, United Kingdom (C.J.M.); Department of Neurology, Mayo Clinic, Rochester, MN (P.L.); Drug Development, Lundbeck, NA Ltd., Deerfield, IL (L.A.H.); and Department of Neurology, New York University Medical Center (H.K.).
authors.forename: Christopher J
authors.initials: CJ
authors.lastname: Mathias
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN (I.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (R.F.); Autonomic and Neurovascular Medicine Departments, Imperial College London and Institute of Neurology, University College London, London, United Kingdom (C.J.M.); Department of Neurology, Mayo Clinic, Rochester, MN (P.L.); Drug Development, Lundbeck, NA Ltd., Deerfield, IL (L.A.H.); and Department of Neurology, New York University Medical Center (H.K.).
authors.forename: Phillip
authors.initials: P
authors.lastname: Low
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN (I.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (R.F.); Autonomic and Neurovascular Medicine Departments, Imperial College London and Institute of Neurology, University College London, London, United Kingdom (C.J.M.); Department of Neurology, Mayo Clinic, Rochester, MN (P.L.); Drug Development, Lundbeck, NA Ltd., Deerfield, IL (L.A.H.); and Department of Neurology, New York University Medical Center (H.K.).
authors.forename: L Arthur
authors.initials: LA
authors.lastname: Hewitt
authors.affiliation: From the Division of Clinical Pharmacology, Department of Medicine, Vanderbilt University Medical Center, Vanderbilt University School of Medicine, Nashville, TN (I.B.); Department of Neurology, Beth Israel Deaconess Medical Center, Boston, MA (R.F.); Autonomic and Neurovascular Medicine Departments, Imperial College London and Institute of Neurology, University College London, London, United Kingdom (C.J.M.); Department of Neurology, Mayo Clinic, Rochester, MN (P.L.); Drug Development, Lundbeck, NA Ltd., Deerfield, IL (L.A.H.); and Department of Neurology, New York University Medical Center (H.K.).
authors.forename: Horacio
authors.initials: H
authors.lastname: Kaufmann
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D000978:Antiparkinson Agents / Q000008:administration & dosage; D001794:Blood Pressure / Q000187:drug effects*; D004305:Dose-Response Relationship, Drug; D004311:Double-Blind Method; D015103:Droxidopa / Q000008:administration & dosage*; D004334:Drug Administration Schedule; D005260:Female; D005500:Follow-Up Studies; D006801:Humans; D007024:Hypotension, Orthostatic / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D008875:Middle Aged; D011187:Posture / Q000502:physiology*; D011795:Surveys and Questionnaires; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D000978:Antiparkinson Agents; D015103:Droxidopa
keywords: Parkinson disease; autonomic nervous system; droxidopa; multiple system atrophy; norepinephrine