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

• ClinicalTrials.gov Identifier: NCT02784535
• Recruitment Status: Active, not recruiting
• First Posted: May 27, 2016
• Last Update Posted: April 14, 2022
• Sponsor: Vanderbilt University Medical Center
• Collaborator: NYU Langone Health
• Information provided by (Responsible Party): Cyndya Shibao, MD, Vanderbilt University Medical Center

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
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.

Study Design

• 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

Arms and Interventions

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; placebo; Other Name: non active medication

Outcome Measures

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

Eligibility Criteria

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

Criteria

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

Contacts and Locations

Locations

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

Investigators

• Principal Investigator: Cyndya A Shibao, MD; Vanderbilt University Medical Center
• Principal Investigator: Horacio Kaufmann, MD; NYU Langone Medical Center

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.

• Responsible Party: Cyndya Shibao, MD, Associate Professor of Medicine, Vanderbilt University Medical Center
• ClinicalTrials.gov Identifier: NCT02784535
• Obsolete Identifiers: NCT02796209
• Other Study ID Numbers: 160415
• First Posted: May 27, 2016
• 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:

Hypotension, Orthostatic; Pure Autonomic Failure; Hypotension; 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