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Norepinephrine Transporter Blockade, Autonomic Failure (NETAF) (NETAF)

The safety and scientific validity of this study is the responsibility of the study sponsor and investigators. Listing a study does not mean it has been evaluated by the U.S. Federal Government. Read our disclaimer for details. Identifier: NCT02784535
Recruitment Status : Active, not recruiting
First Posted : May 27, 2016
Last Update Posted : April 14, 2022
NYU Langone Health
Information provided by (Responsible Party):
Cyndya Shibao, MD, Vanderbilt University Medical Center

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
Neurogenic Orthostatic Hypotension Drug: Atomoxetine Drug: Placebo 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.

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Study Type : Interventional  (Clinical Trial)
Actual Enrollment : 48 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
Primary Purpose: Treatment
Official Title: Phase 2 Norepinephrine Transporter Blockade, Autonomic Failure IND117394 12/28/12
Actual Study Start Date : August 29, 2016
Actual Primary Completion Date : May 2021
Estimated Study Completion Date : April 2023

Arm Intervention/treatment
Placebo Comparator: placebo
placebo capsules
Drug: Atomoxetine
norepinephrine transporter inhibitor
Other Name: strattera

Active Comparator: atomoxetine
atomoxetine capsules 10 mg or 18 mg
Drug: Placebo
Other Name: non active medication

Primary Outcome Measures :
  1. Orthostatic Hypotension Questionnaire [ Time Frame: 2 weeks ]
    Questionnaire that assess pre-syncopal symptoms

Secondary Outcome Measures :
  1. Blood pressure [ Time Frame: 2 weeks ]
    blood pressure assessment

Information from the National Library of Medicine

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Ages Eligible for Study:   40 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No

Inclusion Criteria:

  • 40 years old or older
  • 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:

  • Pregnancy or breastfeeding
  • Hypersensitivity to atomoxetine (severe allergic reaction, rash, urticaria, anaphylaxis)
  • Use of other norepinephrine transporter inhibitors such as Wellbutrin (Bupropion), Cymbalta (Duloxetine), Effexor (venlafaxine), Pristiq (desvenlafaxine), Savella (milnacipran)
  • Previous history (within 14 days prior to enrollment) and current use of monoamine oxidase inhibitors
  • Concomitant use of strong CYP2D6 inhibitors such as delavirdine, paroxetine, fluoxetine, quinidine
  • Pre-existing sustained severe hypertension (BP ≥ 140/80 mmhg in the sitting position)
  • Impaired hepatic function (aspartate amino transaminase [AST] and/or alanine amino transaminase [ALT] >2 x upper limit of normal range)
  • Impaired renal function (serum creatinine equal or more than 1.6 mg/dl)
  • Myocardial infarction within 6 months prior to enrollment
  • Congestive heart failure (LV hypertrophy acceptable)
  • History of serious neurologic disease such as cerebral hemorrhage, or stroke
  • 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
  • Narrow-angle glaucoma

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its identifier (NCT number): NCT02784535

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United States, New York
Dysautonomic Center at NYU Langone Medical Center
New York, New York, United States, 10016
United States, Tennessee
Vanderbilt University Medical Center
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University Medical Center
NYU Langone Health
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Principal Investigator: Cyndya A Shibao, MD Vanderbilt University Medical Center
Principal Investigator: Horacio Kaufmann, MD NYU Langone Medical Center
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Responsible Party: Cyndya Shibao, MD, Associate Professor of Medicine, Vanderbilt University Medical Center Identifier: NCT02784535    
Obsolete Identifiers: NCT02796209
Other Study ID Numbers: 160415
First Posted: May 27, 2016    Key Record Dates
Last Update Posted: April 14, 2022
Last Verified: April 2022
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD: No
Keywords provided by Cyndya Shibao, MD, Vanderbilt University Medical Center:
norepinephrine transporter inhibitors
Additional relevant MeSH terms:
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Hypotension, Orthostatic
Pure Autonomic Failure
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Atomoxetine Hydrochloride
Adrenergic Uptake Inhibitors
Neurotransmitter Uptake Inhibitors
Membrane Transport Modulators
Molecular Mechanisms of Pharmacological Action
Adrenergic Agents
Neurotransmitter Agents
Physiological Effects of Drugs