Brain Perfusion & Oxygenation in Parkinson's Disease With NOH

1. This is a double blind placebo controlled trial in PD patients with NOH. The controlled portion consists of two visits (baseline and week 4) and a phone call (week 2). An open label extension will include a phone call (week 6) and a final visit (week 8). Subjects will undergo a baseline assessment including continuous tilt table (10 minutes supine / 30 minutes at 70o / 10 minute supine) measurements of arteriole BP. Assessment will be done in the "on" state 1-3 hours after last dose and 1-3 hours after last meal. During both supine and standing positions, subjects will undergo a quantified transcranial cerebral ultrasound of the middle cerebral artery. A secondary analysis of the posterior circulation (basilar artery) will also be done when technically possible. An experienced technician will use a Spencer ST-3 Transcranial Doppler and MHz frequency probes (Spencer Technologies, Redmond WA), with ability to display all data in real time with M-mode and spectral waveform, depth of sample volume, size of sample volume, peak systolic and end diastolic velocities, pulsatility index and frequency of transducer. Cerebral oxygenation will be assessed throughout the tilt table with an FORE-SIGHT ELITE Oximetry System (CASMED) with FORE-SIGHT ELITE large advanced sensor. Mean/Max/Min vales will be analyzed. The tilt table BP and HR monitor with autonomic function will be recorded with a Task Force monitor from CNsystem. Subjective assessments will be done prior to the tilt table and will include demographics, general medical history, UPDRS, and the orthostatic hypotension questionnaire, and some gait analysis. We will also query their subjective "light headedness" throughout the tilt table test to determine for objective correlates.
2. Subjects will be titrated with droxidopa or matching placebo over two weeks using current guidelines. The dose will be held constant for the final two weeks and taken on the day of the week 4 visit. After a safety and dose determination call at two weeks, subjects will return at 4 weeks for an identical evaluation, along with clinical global impressions of change.
3. All subjects will be allowed into a 4 week open label extension. They will start titration at 100 mg droxidopa TID but can titrate up daily if preferred. After a safety call (week 6) they will return for a final tilt table/ultrasound perfusion study/oximetry study and subjective questionnaires. The patients will be provided two additional weeks medication to ensure a safe transition to purchased droxidopa if desired.

• Droxidopa (Drug), also known as Northera: Droxidopa initial dose 100mg TID, titrated in increments of 100mg every 24-48 hours to symptomatic response.
• Placebo (Drug), also known as Sugar pill: Placebo (sugar pill)

Primary outcomes

• Cerebral perfusion [8 weeks]: Cerebral perfusion measured by trans-cranial ultrasound of middle cerebral artery "supine and standing" delta.
• Brain oxygenation [8 weeks]: Brain oxygenation as measured by cerebral pulse oximetry device, delta between supine and standing

Secondary outcomes

• Arteriole Blood Pressure [8 weeks]: Change in arteriole BP (supine/standing) via tilt table
• R-R variability [8 weeks]: changes in autonomic influence on heart rate placebo vs drug
• Orthostatic hypotension [8 weeks]: Orthostatic hypotension scale
• Assessment of Parkinson's disease symptoms [8 weeks]: Movement disorder society- Unified parkinson disease rating scale (MDS-UPDRS)
• Assessment of gait and falls [8 weeks]: Timed Up and Go test

Other outcomes

• Assessment of depressive symptoms [8 weeks]: Beck Depression Inventory
• Assessment of sleepiness [8 weeks]: Epworth sleepiness scale (ESS)
• Assessment of cognitive changes [8 weeks]: Montreal cognitive assessment (MOCA)
• Assessment of fatigue [8 weeks]: Fatigue severity scale (FSS)
• Participant impression of light-headedness [8 weeks]: Subjective assessment of "light-headedness"

Sex: All, ages: 18 Years to 85 Years

Inclusion Criteria:

* Idiopathic Parkinson's disease patients with orthostatic hypotension (Systolic Blood Pressure drop of > 20 mm hg or Diastolic Blood Pressure drop of >10 mm hg measured at some point) within a month of inclusion.

Exclusion Criteria:

* Age >85
* Concurrent use of Midodrine
* Medical conditions that in the opinion of the investigator, might not allow for same completion of the study i.e. unstable angina, neoplasm, etc

• William Ondo, MD, Principal investigator, The Methodist Hospital Research Institute