Acetylcholinesterase Inhibition and Orthostatic Hypotension in SCI

July 18, 2017 updated by: Jill M. Wecht, Ed.D., James J. Peters Veterans Affairs Medical Center

Acetylcholinesterase Inhibition: A Novel Approach in the Treatment of Orthostatic Hypotension in Spinal Cord Injury

Due to de-centralized cardiovascular control, persons with spinal cord injury (SCI) experience blood pressure (BP) dysregulation which manifests in chronic hypotension with exacerbation during orthostatic positioning. Although many individuals with SCI remain asymptomatic to hypotension and orthostatic hypotension (OH), we recently reported reduced memory and marginally reduced attention and processing speed in hypotensive individuals with SCI compared to a normotensive cohort. Thus, we believe that treatment of overtly asymptomatic hypotension and OH in the SCI population is clinically warranted. Currently the FDA has approved only midodrine hydrochloride for the treatment of dizziness associated with OH and proof of efficacy is limited. Acetylcholinesterase inhibition for treatment of OH is a novel concept and has gained recent recognition in models of neurogenic OH (multiple system atrophy; pure autonomic failure, diabetic neuropathy). The physiological rationale of this concept is unique: acetylcholine (AcH) is the pre-ganglionic neurotransmitter of the sympathetic nervous system. Inhibition of acetylcholinesterase will limit the breakdown of AcH thereby facilitating vascular adrenergic tone and peripheral vasoconstriction. Acetylcholinesterase inhibition has been reported to be efficacious in models of both pre-ganglionic (multiple system atrophy) and post-ganglionic (pure autonomic failure, diabetic neuropathy) origin and persons with SCI reflect a model of a preganglionic disorder. In theory, if an individual has a complete autonomic lesion, acetylcholinesterase inhibition would not be expected to improve orthostatic BP because little/no neural traffic would be transmitted to the pre-synapse. However, individuals with an incomplete autonomic lesion may benefit from this class of agent. Researchers are currently investigating the orthostatic BP effects of acetylcholinesterase inhibition with pyridostigmine bromide (60 mg) in 10 individuals with SCI.

Study Overview

Status

Status

Indicates the current recruitment status or the expanded access status.
Completed

Conditions

Conditions

The disease, disorder, syndrome, illness, or injury that is being studied. On ClinicalTrials.gov, conditions may also include other health-related issues, such as lifespan, quality of life, and health risks.

Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.

Detailed Description

Due to de-centralized cardiovascular control, persons with spinal cord injury (SCI) experience blood pressure (BP) dysregulation which manifests in chronic hypotension with exacerbation during orthostatic positioning. Although many individuals with SCI remain asymptomatic to hypotension and orthostatic hypotension (OH), we recently reported reduced memory and marginally reduced attention and processing speed in hypotensive individuals with SCI compared to a normotensive cohort. Thus, we believe that treatment of overtly asymptomatic hypotension and OH in the SCI population is clinically warranted. Currently the FDA has approved only midodrine hydrochloride for the treatment of dizziness associated with OH and proof of efficacy is limited. Acetylcholinesterase inhibition for treatment of OH is a novel concept and has gained recent recognition in models of neurogenic OH (multiple system atrophy; pure autonomic failure, diabetic neuropathy). The physiological rationale of this concept is unique: acetylcholine (AcH) is the pre-ganglionic neurotransmitter of the sympathetic nervous system. Inhibition of acetylcholinesterase will limit the breakdown of AcH thereby facilitating vascular adrenergic tone and peripheral vasoconstriction. Acetylcholinesterase inhibition has been reported to be efficacious in models of both pre-ganglionic (multiple system atrophy) and post-ganglionic (pure autonomic failure, diabetic neuropathy) origin and persons with SCI reflect a model of a preganglionic disorder. In theory, if an individual has a complete autonomic lesion, acetylcholinesterase inhibition would not be expected to improve orthostatic BP because little/no neural traffic would be transmitted to the pre-synapse. However, individuals with an incomplete autonomic lesion may benefit from this class of agent. Researchers are currently investigating the orthostatic BP effects of acetylcholinesterase inhibition with pyridostigmine bromide (60 mg) in 10 individuals with SCI. The primary objectives of this study are to compare the BP response to head-up tile (HUT: 45°) between no-drug and drug (pyridostigmine 60 mg) in individuals with SCI with documented OH; and to compare the orthostatic BP responses following drug in individuals with SCI.

Subjects will be tested on two separate days. On day 1 of testing, subjects will be transferred onto a tilt table and will remain in the supine position for the entirety of the test. During the first 60 minutes the subject will remain at the resting supine position.

Following the 60 minute resting position, a progressive head-up tilt will be utilized in which the table will be adjusted to 15°, 25°, 35° for 5 minutes at each angle and then maintained at 45° for 45 minutes or until the subjects experiences symptoms of compromised cerebral blood flow, which include, but are not limited to, light headedness, blurry vision, dizziness and nausea.

On day 2 of testing, the protocol will be duplicated with the exception of drug administration. 60 mg of the study drug, pyridostigmine will be administered at the 30 minute mark of the resting supine position. Data for heart rate and blood pressure will be monitored continuously during the progressive HUT maneuver and will be recorded at 10 minute intervals during the 45° HUT.

Study Type

Study Type

Describes the nature of a clinical study. Study types include interventional studies (also called clinical trials), observational studies (including patient registries), and expanded access.
Interventional

Enrollment (Actual)

Enrollment

The number of participants in a clinical study. The "anticipated" enrollment is the target number of participants that the researchers need for the study.
10

Phase

Phase

The stage of a clinical trial studying a drug or biological product, based on definitions developed by the U.S. Food and Drug Administration (FDA). The phase is based on the study's objective, the number of participants, and other characteristics. There are five phases: Early Phase 1 (formerly listed as Phase 0), Phase 1, Phase 2, Phase 3, and Phase 4. Not Applicable is used to describe trials without FDA-defined phases, including trials of devices or behavioral interventions.
  • Phase 2

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • United States
    • New Jersey
      • West Orange, New Jersey, United States, 07052
        • Kessler Institute for Rehabilitation

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Eligibility Criteria

The key requirements that people who want to participate in a clinical study must meet or the characteristics they must have. Eligibility criteria consist of both inclusion criteria (which are required for a person to participate in the study) and exclusion criteria (which prevent a person from participating). Types of eligibility criteria include whether a study accepts healthy volunteers, has age or age group requirements, or is limited by sex.

Ages Eligible for Study

18 years to 65 years (Adult, Older Adult)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Age 18-65 years old
  • Spinal cord injury with American Spinal Injury Association Impairment Scale (AIS) level of Grade A, B, C or D 9non-ambulatory)
  • Neurological level of injury C3-T2
  • Duration of injury greater than 1 year

Exclusion Criteria:

  • Currently taking medications with known blood pressure raising or lowering effects.
  • Taking over-the-counter medications for allergies or cold symptoms 24-hours prior to testing.
  • I have a C3 level of injury and I am ventilator dependent.
  • History of cardiovascular arrhythmias (especially slow heart rate, less than 45 bpm), block in the electrical signal within the heart, cardiac arrest.
  • History of convulsions or seizures.
  • Currently taking medication to treat active asthma.
  • Thyroid problems.
  • Current smoker.
  • Known coronary heart and/or artery disease.
  • High blood pressure
  • Diabetes
  • Current illness or infection
  • Major surgery in the last 30 days
  • Hypersensitivity to pyridostigmine, bromides, or any component of the formulation; (as determined by review of known drug allergies reported in the medical history intake form and confirmed by the study physician)
  • Pregnancy

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: Treatment
  • Allocation: N/A
  • Interventional Model: Single Group Assignment
  • Masking: None (Open Label)

Arms and Interventions

Participant Group / Arm

Participant Group / Arm

A group or subgroup of participants in a clinical trial that receives a specific intervention/treatment, or no intervention, according to the trial's protocol.
Intervention / Treatment

Intervention / Treatment

A process or action that is the focus of a clinical study. Interventions include drugs, medical devices, procedures, vaccines, and other products that are either investigational or already available. Interventions can also include noninvasive approaches, such as education or modifying diet and exercise.
Experimental: Spinal Cord Injury
After being transferred onto a tilt table, subject with complete SCI will lie in a rested, supine position in which the study drug, pyridostigmine bromide (60 mg) will be administered at the 30 minute time point. Following the administration of the study drug, the subject will remain in the supine position for an additional 30 minutes until the tilting protocol commences.
Drug: Pyridostigmine Bromide
After being transferred onto a tilt table, subject will lie in a rested, supine position in which the study drug, pyridostigmine bromide will be administered at the 30 minute time point. Following the administration of the study drug, the subject will remain in the supine position for an additional 30 minutes until the tilting protocol commences.
Other Names:
  • Brand Name: Mestinon
Device: Tilt table test
After 60 minutes in supine resting position, a progressive head-up tilt will be utilized in which the table will be adjusted to 15°, 25°, 35° for 5 minutes at each angle and then maintained at 45° for 45 minutes or until the subjects experiences symptoms of compromised cerebral blood flow, which include, but are not limited to, light headedness, blurry vision, dizziness and nausea.
Other Names:
  • Upright tilt testing

What is the study measuring?

Primary Outcome Measures

Primary Outcome Measures

In a clinical study's protocol, the planned outcome measure that is the most important for evaluating the effect of an intervention/treatment. Most clinical studies have one primary outcome measure, but some have more than one.
Outcome Measure
Time Frame
Systolic Blood Pressure
Time Frame: Average systolic blood pressure of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees after pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.
Average systolic blood pressure of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees after pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.
Diastolic Blood Pressure
Time Frame: Average diastolic blood pressure of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees after pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.
Average diastolic blood pressure of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees after pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.
Heart Rate
Time Frame: Average heart rate of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees following pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.
Average heart rate of 10 minutes supine rest before pyridostigmine and after 45 minutes at 45 degrees following pyridostigmine administration compared to 10 minutes supine rest before tilt and at 45 degrees during no-drug head-up tilt maneuver.

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Sponsor

The organization or person who initiates the study and who has authority and control over the study.
James J. Peters Veterans Affairs Medical Center

Investigators

Investigators

A researcher involved in a clinical study. Related terms include site principal investigator, site sub-investigator, study chair, study director, and study principal investigator.
  • Principal Investigator: Jill M. Wecht, EdD, James J. Peters VAMC

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start

Study Start

The actual date on which the first participant was enrolled in a clinical study. The "anticipated" study start date is the date that the researchers think will be the study start date.
January 1, 2011

Primary Completion (Actual)

Primary Completion

The date on which the last participant in a clinical study was examined or received an intervention to collect final data for the primary outcome measure. Whether the clinical study ended according to the protocol or was terminated does not affect this date. For clinical studies with more than one primary outcome measure with different completion dates, this term refers to the date on which data collection is completed for all the primary outcome measures. The "anticipated" primary completion date is the date that the researchers think will be the primary completion date for the study.
March 1, 2015

Study Completion (Actual)

Study Completion

The date on which the last participant in a clinical study was examined or received an intervention/treatment to collect final data for the primary outcome measures, secondary outcome measures, and adverse events (that is, the last participant's last visit). The "anticipated" study completion date is the date that the researchers think will be the study completion date.
March 1, 2015

Study Registration Dates

First Submitted

First Submitted

The date on which the study sponsor or investigator first submitted a study record to ClinicalTrials.gov. There is typically a delay of a few days between the first submitted date and the record's availability on ClinicalTrials.gov (the first posted date).
May 21, 2014

First Submitted That Met QC Criteria

First Submitted That Met QC Criteria

The date on which the study sponsor or investigator first submits a study record that is consistent with National Library of Medicine (NLM) quality control (QC) review criteria. The sponsor or investigator may need to revise and submit a study record one or more times before NLM's QC review criteria are met. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
December 1, 2014

First Posted (Estimate)

First Posted

The date on which the study record was first available on ClinicalTrials.gov after National Library of Medicine (NLM) quality control (QC) review has concluded. There is typically a delay of a few days between the date the study sponsor or investigator submitted the study record and the first posted date.
December 4, 2014

Study Record Updates

Last Update Posted (Actual)

Last Update Posted

The most recent date on which changes to a study record were made available on ClinicalTrials.gov. There may be a delay between when the changes were submitted to ClinicalTrials.gov by the study's sponsor or investigator (the last update submitted date) and the last update posted date.
July 21, 2017

Last Update Submitted That Met QC Criteria

Last Update Submitted That Met QC Criteria

The most recent date on which the study sponsor or investigator submitted changes to a study record that are consistent with National Library of Medicine (NLM) quality control (QC) review criteria. It is the responsibility of the sponsor or investigator to ensure that the study record is consistent with the NLM QC review criteria.
July 18, 2017

Last Verified

Last Verified

The most recent date on which the study sponsor or investigator confirmed the information about a clinical study on ClinicalTrials.gov as accurate and current. If a study with a recruitment status of recruiting; not yet recruiting; or active, not recruiting has not been confirmed within the past 2 years, the study's recruitment status is shown as unknown.
July 1, 2017

More Information

Terms related to this study

Keywords

Additional Relevant MeSH Terms

Other Study ID Numbers

Other Study ID Numbers

Identifiers or ID numbers other than the NCT number that are assigned to a clinical study by the study's sponsor, funders, or others. These numbers may include unique identifiers from other trial registries and National Institutes of Health grant numbers.
  • WEC-11-04

Plan for Individual participant data (IPD)

Plan to Share Individual Participant Data (IPD)?

Undecided

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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