Norepinephrine Transporter Blockade, Autonomic Failure (NETAF)

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.

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