Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)

Sponsor

Vanderbilt University Medical Center (Other)

Overall Status

Active, not recruiting

CT.gov ID

NCT02784535

Collaborator

NYU Langone Health (Other)

Enrollment

Locations

Arms

Anticipated Duration (Months)

Patients Per Site

0.3

Patients Per Site Per Month

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
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

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 :

Aug 29, 2016

Actual Primary Completion Date :

May 1, 2021

Anticipated Study Completion Date :

Apr 1, 2023

Arms and Interventions

Arm	Intervention/Treatment
Placebo Comparator: placebo placebo capsules	Drug: Atomoxetine norepinephrine transporter inhibitor Other Names: strattera
Active Comparator: atomoxetine atomoxetine capsules 10 mg or 18 mg	Drug: Placebo placebo Other Names: non active medication

Arm

Intervention/Treatment

Placebo Comparator: placebo

placebo capsules

Drug: Atomoxetine

norepinephrine transporter inhibitor

Other Names:

strattera

Active Comparator: atomoxetine

atomoxetine capsules 10 mg or 18 mg

Drug: Placebo

placebo

Other Names:

non active medication

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

Ages Eligible for Study:

40 Years to 80 Years

Sexes Eligible for Study:

All

Accepts Healthy Volunteers:

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

	Site	City	State	Country	Postal Code
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