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Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic

Primary Purpose

Multiple System Atrophy, Orthostatic Hypotension, Supine Hypertension

Status
Active
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Trimethaphan
Placebo
Sponsored by
Vanderbilt University
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Multiple System Atrophy

Eligibility Criteria

40 Years - 80 Years (Adult, Older Adult)All SexesDoes not accept healthy volunteers

Inclusion Criteria:

  • Male and female subjects, age 40-80 years, with possible or probable Multiple System Atrophy, 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.
  • Supine hypertension, defined as systolic blood pressure ≥150 mmHg measured on two separate occasions.
  • Subjects able and willing to provide informed consent.

Exclusion Criteria:

  • 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 aneurysms, 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 intra-abdominal 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.

Sites / Locations

  • Vanderbilt University Medical Center

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Placebo Comparator

Arm Label

Trimethaphan

Placebo

Arm Description

The investigator will measure cardiac output by studying the air the participant breathes in and out. The participant will also wear a facemask to apply a low air pressure to the airway. After this, the trimethaphan infusion will begin with a small dose and the investigators increase at 1-2 minute intervals for up to five doses. The measurements will be collected again. Next, a standard blood pressure cuffs will be wrapped around the participant's abdomen. the cuff will inflate to apply pressure for 5 - 15 minutes.

The investigator will measure cardiac output by studying the air the participant breathes in and out. The participant will also wear a facemask to apply a low air pressure to the airway. After this, the placebo (saline) infusion will begin with a small dose and the investigators increase at 1-2 minute intervals for up to five doses. The measurements will be collected again. Next, a standard blood pressure cuffs will be wrapped around the participant's abdomen. the cuff will inflate to apply pressure for 5 - 15 minutes.

Outcomes

Primary Outcome Measures

The percentage of increase of the y intercept of the P-V relationship
To determine whether autonomic blockade with trimethaphan increases splanchnic capacitance (parallel upward shift in the P-V relationship) compared to placebo.

Secondary Outcome Measures

Full Information

First Posted
January 28, 2016
Last Updated
March 17, 2023
Sponsor
Vanderbilt University
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1. Study Identification

Unique Protocol Identification Number
NCT02726711
Brief Title
Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic
Official Title
Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic Aim 1 of Rare Diseases Clinical Research Network (RDCRN) Project 2
Study Type
Interventional

2. Study Status

Record Verification Date
March 2023
Overall Recruitment Status
Active, not recruiting
Study Start Date
April 2016 (undefined)
Primary Completion Date
August 2023 (Anticipated)
Study Completion Date
November 2023 (Anticipated)

3. Sponsor/Collaborators

Responsible Party, by Official Title
Principal Investigator
Name of the Sponsor
Vanderbilt University

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to learn more about the regulation of the veins of the abdomen by the autonomic (involuntary) nervous system, and how this may affect high blood pressure. Normally, the autonomic nervous system controls how much blood flows in the veins. In people with high blood pressure, however, the autonomic nervous system is changed. This change may affect the way blood flows in the veins of the abdomen which may play a role in their high blood pressure. About 32 participants will be screened for the study. The investigators estimate 16 will be eligible to participate in all of the study days.
Detailed Description
The investigators will study male and female subjects, age 40-80 years with possible or probable Multiple System Atrophy, as defined by Consensus Criteria who suffer from supine hypertension defined as SBP≥150, and neurogenic orthostatic hypotension, defined as a ≥30-mmHg decrease in systolic BP within 3 minutes of standing associated with impaired autonomic reflexes determined by autonomic testing in the absence of other identifiable causes. All participants will be able and willing to provide informed consent. Screening Procedures. Potential participants will be studied in the Vanderbilt Autonomic Dysfunction Center (ADC). Medications affecting BP, blood volume and the autonomic nervous system such as antihypertensives, pressor medications and fludrocortisone will be withdrawn for at least 5 half-lives before studies. Screening procedures can be performed in one or more days depending on the patient's and investigator's availability. Patients will undergo a complete history and physical examination, ECG, routine clinical laboratory analysis and a blood pregnancy test for women with childbearing potential. Autonomic testing including sinus arrhythmia, Valsalva maneuver and a posture study with plasma catecholamines is then performed to determine if they meet the inclusion/exclusion criteria. During these tests, blood pressure (BP) and heart rate (HR) will be obtained using an automated oscillometric sphygmomanometer, finger photoplethysmography, and continuous ECG. During the orthostatic test, blood samples will be obtained for hormones that regulate BP, such as catecholamines, while patients are supine and upright. Medical history information and results from any of the screening procedures obtained within the previous 6 months for other studies within this research group may be utilized. Study Procedures: Study Day 1 and 2 Eligible Multiple System Atrophy patients with supine hypertension will be studied twice in a randomized, single blind, crossover design, once with trimethaphan and once with placebo. The order of administration is randomized. The placebo day will have identical interventions, but saline will be infused instead of trimethaphan to provide a time control. Studies will be conducted in a postvoid state and ≥2 hours after meals. Each study day will last 2-3 hours. The following procedures will be conducted: Patients will be instrumented to measure blood pressure continuously with photoplethysmography, and intermittently with an automated oscillometric device. Heart rate will be monitored continuously with ECG. Electrodes will be placed on thorax and abdomen to measure segmental impedance. Skin blood flow will be measured in the forearm with a laser Doppler. Cardiac output will be measured by the inert gas rebreathing technique and/or by impedance cardiography. An IV will be placed in one arm for drug administration. After instrumentation baseline measurements will be recorded, including cardiac output and splanchnic venous capacitance. Venous capacitance will be estimated using an adaptation of the method of Schmitt et al. In this technique, segmental impedance is monitored, while continuous positive airway pressure (CPAP) is applied sequentially at 0, 4, 8, 12 and 16 cm water (H20) for 1-2 minute each. Patients will then receive either placebo (time control) or trimethaphan, to induce complete withdrawal of residual sympathetic tone. Intravenous infusion of trimethaphan camsylate (Cambridge Labs) will be started at 0.5-1 mg/min and increased by 1.0 mg/min in 2-6 minute intervals to one of the following endpoints: presyncopal symptoms, no further decrease in blood pressure with increased infusion rates, or an infusion rate of 4 mg/min. Once a stable decrease in blood pressure is obtained, outcome measurements will be repeated. Abdominal compression will be applied to a sustained 40 mm Hg pressure while supine with an inflatable binder. Outcome measurements will be repeated 5-15 minutes later. The investigator may decide not to perform this procedure (due to a longer than anticipated study day duration / drug infusion). In this case, the study will include only the outcome measurements during the drug infusion. The infusion of trimethaphan is then stopped and patient monitored until blood pressure is restored to baseline values.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Multiple System Atrophy, Orthostatic Hypotension, Supine Hypertension

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Crossover Assignment
Masking
Participant
Allocation
Randomized
Enrollment
2 (Actual)

8. Arms, Groups, and Interventions

Arm Title
Trimethaphan
Arm Type
Experimental
Arm Description
The investigator will measure cardiac output by studying the air the participant breathes in and out. The participant will also wear a facemask to apply a low air pressure to the airway. After this, the trimethaphan infusion will begin with a small dose and the investigators increase at 1-2 minute intervals for up to five doses. The measurements will be collected again. Next, a standard blood pressure cuffs will be wrapped around the participant's abdomen. the cuff will inflate to apply pressure for 5 - 15 minutes.
Arm Title
Placebo
Arm Type
Placebo Comparator
Arm Description
The investigator will measure cardiac output by studying the air the participant breathes in and out. The participant will also wear a facemask to apply a low air pressure to the airway. After this, the placebo (saline) infusion will begin with a small dose and the investigators increase at 1-2 minute intervals for up to five doses. The measurements will be collected again. Next, a standard blood pressure cuffs will be wrapped around the participant's abdomen. the cuff will inflate to apply pressure for 5 - 15 minutes.
Intervention Type
Drug
Intervention Name(s)
Trimethaphan
Other Intervention Name(s)
Trimethaphan Camsylate
Intervention Description
Trimethaphan will be infused (0.5 - 4.0 mg IV)
Intervention Type
Drug
Intervention Name(s)
Placebo
Other Intervention Name(s)
saline
Intervention Description
0.5 - 4.0 mg IV to be infused
Primary Outcome Measure Information:
Title
The percentage of increase of the y intercept of the P-V relationship
Description
To determine whether autonomic blockade with trimethaphan increases splanchnic capacitance (parallel upward shift in the P-V relationship) compared to placebo.
Time Frame
5 years

10. Eligibility

Sex
All
Minimum Age & Unit of Time
40 Years
Maximum Age & Unit of Time
80 Years
Accepts Healthy Volunteers
No
Eligibility Criteria
Inclusion Criteria: Male and female subjects, age 40-80 years, with possible or probable Multiple System Atrophy, 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. Supine hypertension, defined as systolic blood pressure ≥150 mmHg measured on two separate occasions. Subjects able and willing to provide informed consent. Exclusion Criteria: 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 aneurysms, 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 intra-abdominal 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.
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Italo Biaggioni, M.D.
Organizational Affiliation
Vanderbilt University
Official's Role
Principal Investigator
Facility Information:
Facility Name
Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States

12. IPD Sharing Statement

Plan to Share IPD
No

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Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic

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