Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)
Study Details
Study Description
Brief Summary
Drug therapy for patients suffering from autonomic failure and neurogenic orthostatic hypotension are scarce and not effective. If left untreated, these patients have the highest risk of syncope, falls and fall-related injuries. The proposed study will determine the clinical benefit of a commercially available drug, atomoxetine, to reduce symptoms associated with neurogenic orthostatic hypotension in patients with autonomic failure.
Condition or Disease | Intervention/Treatment | Phase |
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Phase 2 |
Detailed Description
Autonomic failure is a group of rare neurodegenerative disorders that primarily affect the autonomic nervous system. These patients develop neurogenic orthostatic hypotension (OH) because of impaired autonomic reflexes that control cardiovascular and neuro-humoral adaptation to upright posture. The treatment of neurogenic OH is challenging; the therapeutic options are scarce, and some patients are refractory to treatment.
Atomoxetine is a selective norepinephrine transporter inhibitor that increases the availability of norepinephrine in the synapse by blocking its reuptake. Our preliminary data in sixty-five patients with primary autonomic failure and neurogenic OH showed that atomoxetine was more effective than midodrine, standard of care, in improving standing SBP (+7.5 mm Hg). Notably, only atomoxetine and not midodrine induced a significant reduction in OH-related symptoms (lightheadedness and dizziness) compared with placebo. In this proposal, we will test the hypothesis that prolonged administration of the norepinephrine transporter blocker, atomoxetine, improves OH-related symptoms and OH-impact on daily activities compared with placebo in autonomic failure patients. We propose a randomized, double-blind, placebo-controlled, 2x2 crossover study.
Study Design
Arms and Interventions
Arm | Intervention/Treatment |
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Placebo Comparator: placebo placebo capsules |
Drug: Atomoxetine
norepinephrine transporter inhibitor
Other Names:
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Active Comparator: atomoxetine atomoxetine capsules 10 mg or 18 mg |
Drug: Placebo
placebo
Other Names:
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Outcome Measures
Primary Outcome Measures
- Orthostatic Hypotension Questionnaire [2 weeks]
Questionnaire that assess pre-syncopal symptoms
Secondary Outcome Measures
- Blood pressure [2 weeks]
blood pressure assessment
Eligibility Criteria
Criteria
Inclusion Criteria:
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40 years old or older
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Neurogenic Orthostatic Hypotension (defined by a reduction of ≥20 mmHg drop in SBP within 3 minutes of standing, associated with impaired autonomic reflexes as assessed by autonomic function tests.
Exclusion Criteria:
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Pregnancy or breastfeeding
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Hypersensitivity to atomoxetine (severe allergic reaction, rash, urticaria, anaphylaxis)
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Use of other norepinephrine transporter inhibitors such as Wellbutrin (Bupropion), Cymbalta (Duloxetine), Effexor (venlafaxine), Pristiq (desvenlafaxine), Savella (milnacipran)
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Previous history (within 14 days prior to enrollment) and current use of monoamine oxidase inhibitors
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Concomitant use of strong CYP2D6 inhibitors such as delavirdine, paroxetine, fluoxetine, quinidine
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Pre-existing sustained severe hypertension (BP ≥ 140/80 mmhg in the sitting position)
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Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >2 x upper limit of normal range)
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Impaired renal function (serum creatinine equal or more than 1.6 mg/dl)
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Myocardial infarction within 6 months prior to enrollment
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Congestive heart failure (LV hypertrophy acceptable)
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History of serious neurologic disease such as cerebral hemorrhage, or stroke
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Inability to comply with the protocol, e.g., uncooperative attitude, inability to return for follow-up visits, unlikelihood of completing the study, and mental conditions rendering the subject unable to understand the nature, scope, and possible consequences of the study
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Narrow-angle glaucoma
Contacts and Locations
Locations
Site | City | State | Country | Postal Code | |
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1 | Dysautonomic Center at NYU Langone Medical Center | New York | New York | United States | 10016 |
2 | Vanderbilt University Medical Center | Nashville | Tennessee | United States | 37232 |
Sponsors and Collaborators
- Vanderbilt University Medical Center
- NYU Langone Health
Investigators
- Principal Investigator: Cyndya A Shibao, MD, Vanderbilt University Medical Center
- Principal Investigator: Horacio Kaufmann, MD, NYU Langone Medical Center
Study Documents (Full-Text)
None provided.More Information
Publications
- Ramirez CE, Okamoto LE, Arnold AC, Gamboa A, Diedrich A, Choi L, Raj SR, Robertson D, Biaggioni I, Shibao CA. Efficacy of atomoxetine versus midodrine for the treatment of orthostatic hypotension in autonomic failure. Hypertension. 2014 Dec;64(6):1235-40. doi: 10.1161/HYPERTENSIONAHA.114.04225. Epub 2014 Sep 2.
- Shibao C, Raj SR, Gamboa A, Diedrich A, Choi L, Black BK, Robertson D, Biaggioni I. Norepinephrine transporter blockade with atomoxetine induces hypertension in patients with impaired autonomic function. Hypertension. 2007 Jul;50(1):47-53. Epub 2007 May 21.
- 160415
- NCT02796209