The Effects of Normalizing Blood Pressure on Cerebral Blood Flow in Hypotensive Individuals With Spinal Cord Injury

Sponsor

James J. Peters Veterans Affairs Medical Center (U.S. Fed)

Overall Status

Unknown status

CT.gov ID

NCT02893553

Collaborator

Kessler Foundation (Other)

Enrollment

Locations

Arms

Duration (Months)

Patients Per Site

0.4

Patients Per Site Per Month

Study Details

Study Description

Brief Summary

Dysregulation of blood pressure (BP), secondary to decentralized autonomic nervous system (ANS) control of the cardiovascular system, often results in chronic hypotension and orthostatic hypotension (OH) in persons with spinal cord injury (SCI), particularly in those with high cord lesions (i.e., above T6). While most hypotensive individuals with chronic SCI remain asymptomatic and do not complain of symptoms associated with cerebral hypoperfusion, evidence of reduced resting cerebral blood flow (CBF) has been reported in association with low systemic BP in the SCI and non-SCI populations. Reduced CBF in hypotensive individuals may lead to cognitive dysfunction, and we reported significantly impaired memory and marginally impaired attention processing in hypotensive individuals with SCI compared to a normotensive SCI cohort. Furthermore, we found that CBF was not increased during cognitive testing in individuals with SCI, which may contribute to impaired cognitive function compared to non-SCI controls. Although asymptomatic hypotension may have an adverse impact on cognitive function and quality of quality of life (QOL) clinical management of this condition is extremely low. In fact, we reported that while nearly 40% of Veterans with SCI were hypotensive, less than 1% carried the diagnosis of hypotension or were prescribed an anti-hypotensive medication. The discrepancy between incidence and treatment of asymptomatic hypotension in the SCI population may relate to a paucity of treatment options which are supported by rigorous clinical trials documenting safe and effective use of anti-hypotensive therapy on BP, CBF and cognitive function. We hypothesize these study medications may increase systolic blood pressure to the normal range and improve cerebral blood flow velocity. Results and conclusions will not be removed from the record.

Condition or Disease	Intervention/Treatment	Phase
Spinal Cord Injury Autonomic Dysreflexia Baroreceptor Integrity Sympathetic Integrity Vagal Integrity Autonomic Integrity Hypotensive Cognitive Function Cerebral Blood Flow Blood Pressure	Drug: Midodrine Hydrochloride Drug: Pyridostigmine Bromide Drug: Mirabegron Other: Placebo	Phase 2

Detailed Description

Study 1: Subjects will visit the laboratory between 3 and 9 times for 4 hours to determine the BP response to each dose of the 3 study medications (midodrine, pyridostigmine, and mirabegron). Upon arrival to the laboratory subjects will be randomized to receive midodrine, pyridostigmine, or mirabegron. Subjects will remain seated in their wheelchair for the duration of testing. Instrumentation will be applied by study personnel while subject is seated quietly, this can take up to 20 minutes. Instrumentation includes placement of 3 ECG electrodes for continuous HR monitoring and finger and brachial BP cuffs. BP, BR and HR will be recorded for 5-minutes before medication administration (baseline). After baseline, a small pill will be given with a glass of water. BP, BR and HR will be monitored for 5-minutes every 30 minutes for 4 hours after drug administration.

Study 2: Twenty will visit the laboratory on 4 occasions to determine the effects of three anti-hypotensive agents, compared to placebo, on BP, CBFv, and cognitive performance on selected neuropsychological tests. Upon arrival to the laboratory for every visit subjects will be randomized to receive midodrine, pyridostigmine, mirabegron, or matching placebo. Neither the study subject nor the investigator will know which is being administered. Subjects will remain seated in their wheelchair throughout the duration of the study session and will be closely monitored by study personnel. Instrumentation will include placement of 3 ECG electrodes for continuous heart rate (HR) monitoring, finger and brachial BP cuffs, and a Doppler ultrasound probe positioned at the left MCA for continuous CBFv monitoring. Subjects will remain quietly seated in their wheelchair for 30-minutes after instrumentation for a 5-minute recording of continuous HR, BP, and CBFv (baseline). Prior to the baseline data collection period, the first battery of cognitive tests will be administered. The study medication will be administered to the subject along with a glass of water approximately 30-minutes after arrival to the laboratory. There will be a 2 hour break period until the second cognitive battery begins.

Study Design

Study Type:

Interventional

Anticipated Enrollment :

50 participants

Allocation:

Randomized

Intervention Model:

Parallel Assignment

Masking:

Double (Participant, Investigator)

Primary Purpose:

Treatment

Official Title:

The Effects of Normalizing Blood Pressure on Cerebral Blood Flow in Hypotensive Individuals With Spinal Cord Injury

Study Start Date :

Dec 1, 2016

Anticipated Primary Completion Date :

Dec 1, 2021

Anticipated Study Completion Date :

Dec 1, 2021

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Study 1 Study 1: is a dose escalation to determine the individualized dose of each of 3 medications (midodrine, pyridostigmine, mirabegron) that increases SBP into the normal range (111-139 mmHg). The investigator will be using midodrine hydrochloride, pyridostigmine bromide and mirabegron.	Drug: Midodrine Hydrochloride study 1 will be single blind. study 2 will be blinded randomized-control trial. Other Names: midodrine Drug: Pyridostigmine Bromide study 1 will be single blind. study 2 will be blinded randomized-control trial. Other Names: pyridostigmine Drug: Mirabegron study 1 will be single blind. study 2 will be blinded randomized-control trial.
Experimental: Study 2 Study2: is a randomized placebo-controlled double-blinded investigation to determine the effect of the normalization of SBP on cerebral blood flow, cognitive function (memory and attention processing) and quality of life. The investigator will be using midodrine hydrochloride, pyridostigmine bromide, mirabegron and placebo.	Drug: Midodrine Hydrochloride study 1 will be single blind. study 2 will be blinded randomized-control trial. Other Names: midodrine Drug: Pyridostigmine Bromide study 1 will be single blind. study 2 will be blinded randomized-control trial. Other Names: pyridostigmine Drug: Mirabegron study 1 will be single blind. study 2 will be blinded randomized-control trial. Other: Placebo placebo will only be used for study arm 2, the randomized blinded phase.

Arm

Intervention/Treatment

Experimental: Study 1

Study 1: is a dose escalation to determine the individualized dose of each of 3 medications (midodrine, pyridostigmine, mirabegron) that increases SBP into the normal range (111-139 mmHg). The investigator will be using midodrine hydrochloride, pyridostigmine bromide and mirabegron.

Drug: Midodrine Hydrochloride