Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)

Study Results

Results available

Outcome measurements, participant flow, baseline characteristics, and adverse events have been published for this study.

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Basic Information

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Recruitment Status

COMPLETED

Clinical Phase

PHASE2

Total Enrollment

48 participants

Study Classification

INTERVENTIONAL

Study Start Date

2016-08-29

Study Completion Date

2023-06-30

Brief Summary

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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.

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Detailed Description

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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.

Conditions

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Neurogenic Orthostatic Hypotension

Study Design

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Allocation Method

RANDOMIZED

Intervention Model

CROSSOVER

Primary Study Purpose

TREATMENT

Blinding Strategy

QUADRUPLE

Participants Caregivers Investigators Outcome Assessors

Study Groups

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placebo

placebo capsules

Group Type PLACEBO_COMPARATOR

Atomoxetine

Intervention Type DRUG

norepinephrine transporter inhibitor

atomoxetine

atomoxetine capsules 10 mg or 18 mg

Group Type ACTIVE_COMPARATOR

Placebo

Intervention Type DRUG

placebo

Interventions

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Atomoxetine

norepinephrine transporter inhibitor

Intervention Type DRUG

Placebo

placebo

Intervention Type DRUG

Other Intervention Names

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strattera non active medication

Eligibility Criteria

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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

Minimum Eligible Age

40 Years

Maximum Eligible Age

80 Years

Eligible Sex

ALL

Accepts Healthy Volunteers

No