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Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic

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ClinicalTrials.gov Identifier: NCT02726711
Recruitment Status : Recruiting
First Posted : April 4, 2016
Last Update Posted : February 4, 2019
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University

Tracking Information
First Submitted Date  ICMJE January 28, 2016
First Posted Date  ICMJE April 4, 2016
Last Update Posted Date February 4, 2019
Study Start Date  ICMJE April 2016
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Current Primary Outcome Measures  ICMJE
 (submitted: March 29, 2016)
The percentage of increase of the y intercept of the P-V relationship [ Time Frame: 5 years ]
To determine whether autonomic blockade with trimethaphan increases splanchnic capacitance (parallel upward shift in the P-V relationship) compared to placebo.
Original Primary Outcome Measures  ICMJE Same as current
Change History Complete list of historical versions of study NCT02726711 on ClinicalTrials.gov Archive Site
Current Secondary Outcome Measures  ICMJE Not Provided
Original Secondary Outcome Measures  ICMJE Not Provided
Current Other Pre-specified Outcome Measures Not Provided
Original Other Pre-specified Outcome Measures Not Provided
 
Descriptive Information
Brief Title  ICMJE Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic
Official Title  ICMJE Reduction in Splanchnic Capacitance Contributes to Sympathetically Dependent Hypertension in Autonomic Aim 1 of Rare Diseases Clinical Research Network (RDCRN) Project 2
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.

Study Type  ICMJE Interventional
Study Phase  ICMJE Phase 1
Study Design  ICMJE Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Single (Participant)
Primary Purpose: Basic Science
Condition  ICMJE
  • Multiple System Atrophy
  • Orthostatic Hypotension
  • Supine Hypertension
Intervention  ICMJE
  • Drug: Trimethaphan
    Trimethaphan will be infused (0.5 - 4.0 mg IV)
    Other Name: Trimethaphan Camsylate
  • Drug: Placebo
    0.5 - 4.0 mg IV to be infused
    Other Name: saline
Study Arms  ICMJE
  • Experimental: Trimethaphan

    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.

    Intervention: Drug: Trimethaphan
  • Placebo Comparator: Placebo

    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: Drug: Placebo
Publications * Not Provided

*   Includes publications given by the data provider as well as publications identified by ClinicalTrials.gov Identifier (NCT Number) in Medline.
 
Recruitment Information
Recruitment Status  ICMJE Recruiting
Estimated Enrollment  ICMJE
 (submitted: March 29, 2016)
32
Original Estimated Enrollment  ICMJE Same as current
Estimated Study Completion Date  ICMJE March 2021
Estimated Primary Completion Date March 2021   (Final data collection date for primary outcome measure)
Eligibility Criteria  ICMJE

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.
Sex/Gender  ICMJE
Sexes Eligible for Study: All
Ages  ICMJE 40 Years to 80 Years   (Adult, Older Adult)
Accepts Healthy Volunteers  ICMJE No
Contacts  ICMJE
Contact: Emily C Smith, RN 615.875.1516 autonomics@vumc.org
Contact: Bonnie K Black, RN 615-343-6862 autonomics@vumc.org
Listed Location Countries  ICMJE United States
Removed Location Countries  
 
Administrative Information
NCT Number  ICMJE NCT02726711
Other Study ID Numbers  ICMJE 151947
Has Data Monitoring Committee No
U.S. FDA-regulated Product Not Provided
IPD Sharing Statement  ICMJE
Plan to Share IPD: No
Responsible Party Italo Biaggioni, Vanderbilt University
Study Sponsor  ICMJE Vanderbilt University
Collaborators  ICMJE Not Provided
Investigators  ICMJE
Principal Investigator: Italo Biaggioni, M.D. Vanderbilt University
PRS Account Vanderbilt University Medical Center
Verification Date February 2019

ICMJE     Data element required by the International Committee of Medical Journal Editors and the World Health Organization ICTRP