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Effects of Midodrine and Droxidopa on Splanchnic Capacitance in Autonomic Failure

Primary Purpose

Autonomic Failure, Pure Autonomic Failure, Multiple System Atrophy

Status
Recruiting
Phase
Phase 1
Locations
United States
Study Type
Interventional
Intervention
Droxidopa
Midodrine
Placebo
Sponsored by
Vanderbilt University Medical Center
About
Eligibility
Locations
Arms
Outcomes
Full info

About this trial

This is an interventional basic science trial for Autonomic Failure focused on measuring midodrine, droxidopa, splanchnic circulation

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, Pure Autonomic Failure, or Parkinson disease, 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.
  • Subjects able and willing to provide informed consent.

Exclusion Criteria:

  • Supine hypertension, defined as systolic blood pressure of ≥ 160 mmHg measured on two separate occasions.
  • 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 aneurisms, 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 intraabdominal 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

  • Autonomic Dysfunction Center/ Vanderbilt University Medical CenterRecruiting

Arms of the Study

Arm 1

Arm 2

Arm Type

Experimental

Experimental

Arm Label

Droxidopa and Placebo

Midodrine and Placebo

Arm Description

Patients will be studied on two separate days, two days apart: one day with the active drug and one day with placebo. The order of the study days will be randomized. On each study day, patients will receive a single oral dose of either droxidopa 300 mg or placebo after the first tilt table test, followed two hours later by a single oral dose of placebo.

Patients will be studied on two separate days, two days apart: one day with the active drug and one day with placebo. The order of the study days will be randomized. On each study day, patients will receive a single oral dose of placebo after the first tilt table test, followed two hours later by a single oral dose of either midodrine 10 mg or placebo.

Outcomes

Primary Outcome Measures

Stroke volume
The primary outcome will be the percent change from supine in stroke volume during HUT

Secondary Outcome Measures

Full Information

First Posted
September 7, 2016
Last Updated
August 7, 2023
Sponsor
Vanderbilt University Medical Center
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1. Study Identification

Unique Protocol Identification Number
NCT02897063
Brief Title
Effects of Midodrine and Droxidopa on Splanchnic Capacitance in Autonomic Failure
Official Title
The Effects of Midodrine and Droxidopa on Splanchnic Capacitance in Autonomic Failure Aim 2 of RDCRN (Rare Diseases Clinical Research Network) Project 2
Study Type
Interventional

2. Study Status

Record Verification Date
August 2023
Overall Recruitment Status
Recruiting
Study Start Date
September 2016 (undefined)
Primary Completion Date
March 2024 (Anticipated)
Study Completion Date
August 2024 (Anticipated)

3. Sponsor/Collaborators

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

4. Oversight

Data Monitoring Committee
No

5. Study Description

Brief Summary
The purpose of this study is to learn more about the effects of midodrine and droxidopa, two medications used for the treatment of orthostatic hypotension (low blood pressure on standing), on the veins of the abdomen of patients with autonomic failure. The study will be conducted at Vanderbilt University Medical Center, and consists of 2 parts: a screening and 2 testing days. The total length of the study will be about 5 days. About 34 participants will be screened for the study.
Detailed Description
Patients with multiple system atrophy, pure autonomic failure or Parkinson disease, and orthostatic hypotension will be studied in a randomized, double-blind, 2-arm parallel design to compare the effects of droxidopa and midodrine on stoke volume during head up tilt. A total of 34 participants will be enrolled in the study (17 patients in each arm). Screening Procedures: Potential participants will be screened in the Vanderbilt Autonomic Dysfunction Center (ADC). Medications affecting blood pressure, blood volume and the autonomic nervous system such as pressor medications, fludrocortisone and carbidopa will be withdrawn for at least 5 half-lives before studies. Patients will undergo a complete history and physical examination, ECG, routine clinical laboratory analyses and a blood pregnancy test for women with childbearing potential. Autonomic testing including a tilt table testing and a posture study with plasma catecholamines is then performed to determine if they meet the inclusion/exclusion criteria. Eligible participants will then be randomized to the droxidopa or the midodrine treatment group. All patients will be studied on two separate days, two days apart: one day with the active drug (droxidopa 300mg PO or midodrine 10mg PO) and one day with placebo. On each study day, two tilt table tests will be performed. Patients will be instrumented to measure blood pressure and heart rate (continuously and intermittently), segmental impedance, cardiac output (inert gas rebreathing technique and/or impedance cardiography), and venous capacitance. Baseline measurements will then be taken in the supine position for about 30 minutes, and during head-up tilt for ≤10 minutes at 60 degrees. Supine baseline measurements will include the estimation of splanchnic venous capacitance. At the end of the head up tilt (HUT), patients will be asked to rate severity of their orthostatic symptoms. Patients will then be placed in the seated position (time 0) and will receive a single oral dose of either droxidopa 300 mg or placebo, followed two hours later by a single oral dose of placebo or midodrine 10 mg. On the placebo day, both groups will receive a placebo pill at time 0 and at 2 hours. After ~3 hours of first drug administration, a second tilt table test will be performed, and outcome measurements will be repeated while supine and during HUT. The investigators may apply abdominal compression of 40 mmHg with an inflatable binder at the end of the second HUT. Outcome measurements will be repeated during 5 minutes of compression.

6. Conditions and Keywords

Primary Disease or Condition Being Studied in the Trial, or the Focus of the Study
Autonomic Failure, Pure Autonomic Failure, Multiple System Atrophy, Parkinson Disease, Orthostatic Hypotension
Keywords
midodrine, droxidopa, splanchnic circulation

7. Study Design

Primary Purpose
Basic Science
Study Phase
Phase 1
Interventional Study Model
Parallel Assignment
Masking
ParticipantInvestigator
Allocation
Randomized
Enrollment
34 (Anticipated)

8. Arms, Groups, and Interventions

Arm Title
Droxidopa and Placebo
Arm Type
Experimental
Arm Description
Patients will be studied on two separate days, two days apart: one day with the active drug and one day with placebo. The order of the study days will be randomized. On each study day, patients will receive a single oral dose of either droxidopa 300 mg or placebo after the first tilt table test, followed two hours later by a single oral dose of placebo.
Arm Title
Midodrine and Placebo
Arm Type
Experimental
Arm Description
Patients will be studied on two separate days, two days apart: one day with the active drug and one day with placebo. The order of the study days will be randomized. On each study day, patients will receive a single oral dose of placebo after the first tilt table test, followed two hours later by a single oral dose of either midodrine 10 mg or placebo.
Intervention Type
Drug
Intervention Name(s)
Droxidopa
Other Intervention Name(s)
Northera
Intervention Description
Single oral dose 300 mg
Intervention Type
Drug
Intervention Name(s)
Midodrine
Intervention Description
Single oral dose 10 mg
Intervention Type
Drug
Intervention Name(s)
Placebo
Intervention Description
sugar pill
Primary Outcome Measure Information:
Title
Stroke volume
Description
The primary outcome will be the percent change from supine in stroke volume during HUT
Time Frame
Up to 10 min of head up tilt

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, Pure Autonomic Failure, or Parkinson disease, 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. Subjects able and willing to provide informed consent. Exclusion Criteria: Supine hypertension, defined as systolic blood pressure of ≥ 160 mmHg measured on two separate occasions. 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 aneurisms, 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 intraabdominal 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.
Central Contact Person:
First Name & Middle Initial & Last Name or Official Title & Degree
Bonnie K Black, RN
Phone
615-343-6862
Email
autonomics@vumc.org
First Name & Middle Initial & Last Name or Official Title & Degree
Luis E Okamoto, MD
Phone
615-936-6119
Email
autonomics@vumc.org
Overall Study Officials:
First Name & Middle Initial & Last Name & Degree
Italo Biaggioni, MD
Organizational Affiliation
Vanderbilt University Medical Center
Official's Role
Principal Investigator
Facility Information:
Facility Name
Autonomic Dysfunction Center/ Vanderbilt University Medical Center
City
Nashville
State/Province
Tennessee
ZIP/Postal Code
37232
Country
United States
Individual Site Status
Recruiting
Facility Contact:
First Name & Middle Initial & Last Name & Degree
Emily C Smith, RN
Phone
615-875-1516
Email
autonomics@vumc.org
First Name & Middle Initial & Last Name & Degree
Bonnie K Black, RN
Phone
615-322-3304
Email
autonomics@vumc.org
First Name & Middle Initial & Last Name & Degree
Bonnie K Black, RN
First Name & Middle Initial & Last Name & Degree
Luis E Okamoto, MD
First Name & Middle Initial & Last Name & Degree
Italo Biaggioni, MD
First Name & Middle Initial & Last Name & Degree
Alfredo Gamboa, MD
First Name & Middle Initial & Last Name & Degree
Cyndya A Shibao, MD
First Name & Middle Initial & Last Name & Degree
Andre Diedrich, MD, PhD

12. IPD Sharing Statement

Plan to Share IPD
No

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Effects of Midodrine and Droxidopa on Splanchnic Capacitance in Autonomic Failure

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