Effects of Midodrine and Droxidopa on Splanchnic Capacitance in Autonomic Failure

Patients with multiple system atrophy, pure autonomic failure or Parkinson disease, and
orthostatic hypotension will be studied in a randomized, double-blind, 2-arm parallel design
to compare the effects of droxidopa and midodrine on stoke volume during head up tilt. A
total of 34 participants will be enrolled in the study (17 patients in each arm).

Screening Procedures: Potential participants will be screened in the Vanderbilt Autonomic
Dysfunction Center (ADC). Medications affecting blood pressure, blood volume and the
autonomic nervous system such as pressor medications, fludrocortisone and carbidopa will be
withdrawn for at least 5 half-lives before studies. Patients will undergo a complete history
and physical examination, ECG, routine clinical laboratory analyses and a blood pregnancy
test for women with childbearing potential. Autonomic testing including a tilt table testing
and a posture study with plasma catecholamines is then performed to determine if they meet
the inclusion/exclusion criteria.

Eligible participants will then be randomized to the droxidopa or the midodrine treatment
group. All patients will be studied on two separate days, two days apart: one day with the
active drug (droxidopa 300mg PO or midodrine 10mg PO) and one day with placebo.

On each study day, two tilt table tests will be performed. Patients will be instrumented to
measure blood pressure and heart rate (continuously and intermittently), segmental impedance,
cardiac output (inert gas rebreathing technique and/or impedance cardiography), and venous
capacitance. Baseline measurements will then be taken in the supine position for about 30
minutes, and during head-up tilt for ≤10 minutes at 60 degrees. Supine baseline measurements
will include the estimation of splanchnic venous capacitance. At the end of the head up tilt
(HUT), patients will be asked to rate severity of their orthostatic symptoms.

Patients will then be placed in the seated position (time 0) and will receive a single oral
dose of either droxidopa 300 mg or placebo, followed two hours later by a single oral dose of
placebo or midodrine 10 mg. On the placebo day, both groups will receive a placebo pill at
time 0 and at 2 hours. After ~3 hours of first drug administration, a second tilt table test
will be performed, and outcome measurements will be repeated while supine and during HUT. The
investigators may apply abdominal compression of 40 mmHg with an inflatable binder at the end
of the second HUT. Outcome measurements will be repeated during 5 minutes of compression.

Inclusion Criteria:

- Male and female subjects, age 40-80 years with possible or probable Multiple System
Atrophy, Pure Autonomic Failure, or Parkinson disease, as defined by Consensus
Criteria.

- Neurogenic orthostatic hypotension defined as a ≥30-mmHg decrease in systolic blood
pressure within 3 minutes of standing associated with impaired autonomic reflexes
determined by autonomic testing in the absence of other identifiable causes.

- Subjects able and willing to provide informed consent.

Exclusion Criteria:

- Supine hypertension, defined as systolic blood pressure of ≥ 160 mmHg measured on two
separate occasions.

- Pregnancy.

- Systemic illnesses known to produce autonomic neuropathy, including but not limited to
diabetes mellitus, amyloidosis, monoclonal gammopathies, and autoimmune neuropathies.

- History of known aortic aneurisms, thoracic, abdominal or pelvic surgery in the past 6
months.

- Symptomatic abdominal or inguinal hernias.

- Severe gastroesophageal reflux.

- Recent fractures or fissures of ribs, thoracic or lumbar spine.

- Medical devices implanted on the abdominal wall or abdomen that would interfere with
the abdominal compression.

- Intolerance to any increase in intraabdominal pressure.

- Clinically unstable coronary artery disease or major cardiovascular or neurological
event in the past 6 months, and other factors which in the investigator's opinion
would prevent the subject from completing the protocol including clinically
significant abnormalities in clinical, mental or laboratory testing.