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Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa.
Hypertension. 2015 Jan; 65(1):101-7.H

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.

CLINICAL TRIAL REGISTRATION URL

http://www.clinicaltrials.gov. Unique identifier: NCT00633880.

Authors+Show Affiliations

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.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.).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.).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.).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.).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.).No affiliation info available

Pub Type(s)

Clinical Trial, Phase III
Journal Article
Multicenter Study
Randomized Controlled Trial
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

25350981

Citation

Biaggioni, Italo, et al. "Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa." Hypertension (Dallas, Tex. : 1979), vol. 65, no. 1, 2015, pp. 101-7.
Biaggioni I, Freeman R, Mathias CJ, et al. Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension. 2015;65(1):101-7.
Biaggioni, I., Freeman, R., Mathias, C. J., Low, P., Hewitt, L. A., & Kaufmann, H. (2015). Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. Hypertension (Dallas, Tex. : 1979), 65(1), 101-7. https://doi.org/10.1161/HYPERTENSIONAHA.114.04035
Biaggioni I, et al. Randomized Withdrawal Study of Patients With Symptomatic Neurogenic Orthostatic Hypotension Responsive to Droxidopa. Hypertension. 2015;65(1):101-7. PubMed PMID: 25350981.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Randomized withdrawal study of patients with symptomatic neurogenic orthostatic hypotension responsive to droxidopa. AU - Biaggioni,Italo, AU - Freeman,Roy, AU - Mathias,Christopher J, AU - Low,Phillip, AU - Hewitt,L Arthur, AU - Kaufmann,Horacio, AU - ,, Y1 - 2014/10/27/ PY - 2014/10/29/entrez PY - 2014/10/29/pubmed PY - 2015/2/26/medline KW - Parkinson disease KW - autonomic nervous system KW - droxidopa KW - multiple system atrophy KW - norepinephrine SP - 101 EP - 7 JF - Hypertension (Dallas, Tex. : 1979) JO - Hypertension VL - 65 IS - 1 N2 - UNLABELLED: 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. CLINICAL TRIAL REGISTRATION URL: http://www.clinicaltrials.gov. Unique identifier: NCT00633880. SN - 1524-4563 UR - https://www.unboundmedicine.com/medline/citation/25350981/Randomized_withdrawal_study_of_patients_with_symptomatic_neurogenic_orthostatic_hypotension_responsive_to_droxidopa_ L2 - https://www.ahajournals.org/doi/10.1161/HYPERTENSIONAHA.114.04035?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -