Brain Perfusion & Oxygenation in Parkinson's Disease With NOH

Evaluation of Brain Perfusion and Oxygenation in PD Patients With Neurogenic Orthostatic Hypotension: 4 Week Comparison of Droxidopa Versus Placebo

This is a double blind placebo controlled trial in Parkinson's disease (PD) patients with neurogenic orthostatic hypotension (NOH). Investigators hypothesize that the study drug (droxidopa) may improve cerebral perfusion more robustly than systemic BP, possibly by direct action within the CNS vasculature. This study is designed to determine if droxidopa improves cerebral perfusion measures in PD patients with NOH, in addition to peripheral BP measures and subjective responses.

Study Overview

• Status: Completed
• Conditions: Parkinson Disease; Neurogenic Orthostatic Hypotension
• Intervention / Treatment: Drug: Placebo; Drug: Droxidopa

Detailed Description

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.

• Study Type: Interventional
• Enrollment (Actual): 17
• Phase: Phase 4

Contacts and Locations

Study Locations

• United States
  • Texas
    • Houston, Texas, United States, 77030
      • Houston Methodist Hospital

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years to 85 years (Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

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

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: Double

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Intervention phase; Droxidopa unforced titration dose (starting at 100mg by mouth TID) or matching placebo and titrated over 2 weeks up to maximum of 600 TID. Efficacy evaluation of given dose at week 4	Drug: Placebo; Placebo (sugar pill); Other Names: Sugar pill; Drug: Droxidopa; Droxidopa initial dose 100mg TID, titrated in increments of 100mg every 24-48 hours to symptomatic response.; Other Names: Northera
Other: Open label extension phase; All subjects allowed into a 4 week open label extension. Similar titration will start at 100mg Droxidopa three times a day (TID), but can be titrated up daily using the same dose escalation scale.	Drug: Droxidopa; Droxidopa initial dose 100mg TID, titrated in increments of 100mg every 24-48 hours to symptomatic response.; Other Names: Northera

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Cerebral perfusion	Cerebral perfusion measured by trans-cranial ultrasound of middle cerebral artery "supine and standing" delta.	8 weeks
Brain oxygenation	Brain oxygenation as measured by cerebral pulse oximetry device, delta between supine and standing	8 weeks

Secondary Outcome Measures

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

Other Outcome Measures

Outcome Measure	Measure Description	Time Frame
Assessment of depressive symptoms	Beck Depression Inventory	8 weeks
Assessment of sleepiness	Epworth sleepiness scale (ESS)	8 weeks
Assessment of cognitive changes	Montreal cognitive assessment (MOCA)	8 weeks
Assessment of fatigue	Fatigue severity scale (FSS)	8 weeks
Participant impression of light-headedness	Subjective assessment of "light-headedness"	8 weeks

Collaborators and Investigators

• Sponsor: William Ondo, MD
• Collaborators: Lundbeck LLC
• Investigators: Principal Investigator: William Ondo, MD, The Methodist Hospital Research Institute

Study record dates

Study Major Dates

• Study Start (Actual): August 23, 2018
• Primary Completion (Actual): February 2, 2022
• Study Completion (Actual): February 2, 2022

Study Registration Dates

• First Submitted: April 21, 2017
• First Submitted That Met QC Criteria: July 21, 2017
• First Posted (Actual): July 25, 2017

Study Record Updates

• Last Update Posted (Actual): September 6, 2022
• Last Update Submitted That Met QC Criteria: September 1, 2022
• Last Verified: September 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cardiovascular Diseases; Vascular Diseases; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Parkinsonian Disorders; Basal Ganglia Diseases; Movement Disorders; Synucleinopathies; Neurodegenerative Diseases; Autonomic Nervous System Diseases; Primary Dysautonomias; Orthostatic Intolerance; Parkinson Disease; Hypotension; Hypotension, Orthostatic; Antiparkinson Agents; Anti-Dyskinesia Agents; Droxidopa
• Other Study ID Numbers: PRO00013931

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: No

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: Yes
• Studies a U.S. FDA-regulated device product: No
• product manufactured in and exported from the U.S.: Yes