Clinical trial NCT02784535: Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)
Official title: Phase 2 Norepinephrine Transporter Blockade, Autonomic Failure IND117394 12/28/12
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE2
Conditions: Neurogenic Orthostatic Hypotension
Keywords: norepinephrine transporter inhibitors
Lead sponsor: Vanderbilt University Medical Center
Sponsor class: OTHER
Collaborators: name: NYU Langone Health
First posted: 2016-05-27
Enrollment: 48
Sex: ALL
Minimum age (years): 40
Maximum age (years): 80
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: CROSSOVER
Primary purpose: TREATMENT

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.

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.

Eligibility 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

Primary outcomes:
measure: Change in the OHQ (Orthostatic Hypotension Questionnaire) Composite Score
timeFrame: week 0 to week 4
Secondary outcomes:
measure: Change in Blood Pressure
timeFrame: Baseline to 4 weeks
measure: Change in Heart Rate (HR)
timeFrame: Baseline and at 4 weeks
Other outcomes:
Locations:
city: New York
country: United States
facility: Dysautonomic Center at NYU Langone Medical Center
state: New York
city: Nashville
country: United States
facility: Vanderbilt University Medical Center
state: Tennessee
Study officials:
affiliation: Vanderbilt University Medical Center
name: Cyndya A Shibao, MD
role: PRINCIPAL_INVESTIGATOR
affiliation: NYU Langone Medical Center
name: Horacio Kaufmann, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: 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.
citation: 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. doi: 10.1161/HYPERTENSIONAHA.107.089961. Epub 2007 May 21.