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Water and Sudafed in Autonomic Failure

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ClinicalTrials.gov Identifier: NCT02149901
Recruitment Status : Active, not recruiting
First Posted : May 29, 2014
Last Update Posted : March 27, 2018
Sponsor:
Collaborators:
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Advancing Translational Science (NCATS)
Information provided by (Responsible Party):
Emily M. Garland, Vanderbilt University

Brief Summary:
The specific aim of this study is to determine whether water ingestion potentiates the pressor response to pseudoephedrine in patients with primary disorders of autonomic failure. The study design will enable us to also evaluate the pressor response to water alone and to pseudoephedrine alone. In a secondary analysis, we will compare the results in patients with two autonomic disorders, pure autonomic failure (PAF) and multiple system atrophy (MSA). We hypothesize that drinking water following a dose of pseudoephedrine will lead to a greater increase in blood pressure than pseudoephedrine alone.

Condition or disease Intervention/treatment Phase
Shy-Drager Syndrome Multiple System Atrophy Drug: Pseudoephedrine + 480 ml water Drug: Pseudoephedrine + 50 ml water Other: Placebo + 480 ml water (optional) Other: Placebo + 50 ml water (optional) Early Phase 1

Detailed Description:

The maximal pressor response to water is reached when other pressor agents are only beginning to act. In addition to the therapeutic value of water ingestion alone, the blood pressure-raising effects of agents that increase sympathetic nervous system tone, such as phenylpropanolamine, are potentiated by water drinking. These drug interaction effects can be exploited in the treatment of orthostatic hypotension with the combination of water and a sympathomimetic potentially able to increase blood pressure to a greater extent and for a longer period of time than either water or the medication alone. However, the interaction can also lead to potentially dangerous blood pressure surges.

This protocol requires an initial screening history and physical of study participants, including safety labs and EKGs, and evaluation of their autonomic nervous system status following the consent process. If the patient meets study criteria and is willing to undergo study testing, the 4-way crossover protocol will follow.

Study Testing days 1 and 2 Arm 1: Pseudoephedrine 30 mg PO + 50 ml water Arm 2: Pseudoephedrine 30 mg PO + 480 ml water

  • Testing will be performed at the same time of day for all studies, at least 2 hours after a meal to avoid any confounding effects from postprandial hypotension.
  • A saline lock will be inserted for blood sampling at least 30 minutes before baseline data collection.
  • Participants will be asked to empty their bladders before beginning the test to avoid any effect of a full urinary bladder on peripheral sympathetic activity.
  • Participants will be seated comfortably in a chair. They will be asked to remain in the seated position for the duration of the study.
  • The Dinamap electrocardiographic and blood pressure (brachial cuff) recorder will be attached to the patient and set up for measurements every 5 minutes throughout the study with digital download into the ADC (Autonomic Dysfunction Center) BP database.
  • Participants will also be instrumented with EKG, finger cuff and sensor for continuous monitoring of blood pressure, heart rate, respiration, SpO2, stroke volume, systemic vascular resistance, and cardiac output, using a Nexfin system and Ivy Biomedical Vital-Guard monitor.
  • After a 30 minute baseline monitoring period (time -30 min to 0 min), 4 ½ teaspoons of blood will be collected for osmolality measurement and assays of hormones that regulate blood pressure.
  • The subject will then be given 30 mg of pseudoephedrine PO (time 0 min). Monitoring will be continued for 45 minutes.
  • At 45 minutes, the participant will be asked to drink 50 ml (Arm 1) or 480 ml (Arm 2) of water.
  • Additional blood samples (4 ½ teaspoons) for osmolality and BP-regulating hormones will be collected 30 and 60 minutes after water (+75 and +105 minutes of study).
  • Monitoring will be continued until + 135 min.
  • At 135 minutes, the study will end for the day. The timing of pseudoephedrine administration relative to water ingestion and the duration of the monitoring period are based on previous results3 and pharmacokinetic data7 reporting a Tmax for pseudoephedrine between 1 and 2 hours. Testing on study day 2 will be identical with the participant consuming the alternate water volume.

Study Testing days 3 and 4 are optional Arm 3: Placebo PO + 50 ml water Arm 4: Placebo PO + 480 ml water Testing will be performed according to the same schedule as for Arms 1 and 2. Instrumentation will be limited to the Dinamap electrocardiographic and blood pressure (brachial cuff) recorder set up for measurements every 5 minutes throughout the study for Arms 3 and 4.


Study Type : Interventional  (Clinical Trial)
Estimated Enrollment : 35 participants
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: None (Open Label)
Primary Purpose: Other
Official Title: Effect of Drinking Water on the Pressor Response to Pseudoephedrine in Patients With Autonomic Failure
Study Start Date : October 2014
Estimated Primary Completion Date : December 2019
Estimated Study Completion Date : December 2019


Arm Intervention/treatment
Experimental: Pseudoephedrine + 480 ml water
Pseudoephedrine 30 mg PO 45 minutes before water 480 ml
Drug: Pseudoephedrine + 480 ml water
30 mg pseudoephedrine to be given with a pressor dose (480 ml) of drinking water
Other Names:
  • Sudafed
  • drinking water

Placebo Comparator: Pseudoephedrine + 50 ml water
Pseudoephedrine 30 mg PO 45 minutes before water 50 ml
Drug: Pseudoephedrine + 50 ml water
Pseudoephedrine given with a non-pressor (50 ml) dose of drinking water
Other Names:
  • Sudafed
  • drinking water

Experimental: Placebo + 480 ml water (optional)
Placebo PO 45 minutes before water 480 ml
Other: Placebo + 480 ml water (optional)
placebo PO with a pressor (480 ml) dose of drinking water
Other Name: drinking water

Placebo Comparator: Placebo + 50 ml water (optional)
Placebo PO 45 minutes before water 50 ml
Other: Placebo + 50 ml water (optional)
placebo PO with a non-pressor (50 ml) dose of drinking water
Other Name: drinking water




Primary Outcome Measures :
  1. The primary outcome measure in each Aim will be the peak increase in systolic blood pressure after pseudoephedrine or placebo relative to baseline (delta SBP). [ Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo ]

Secondary Outcome Measures :
  1. Change in diastolic blood pressure relative to baseline [ Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo ]
  2. Change in heart rate relative to baseline [ Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo ]
  3. Absolute systolic blood pressure after treatment [ Time Frame: between 60 and 120 minutes after pseudoephedrine and placebo ]
  4. Absolute diastolic blood pressure after treatment [ Time Frame: between 60 and 120 minutes after pseudoephedrine or placebo ]
  5. area under the curve for systolic blood pressure from baseline to 135 minutes post-treatment [ Time Frame: from baseline to 135 minutes after pseudoephedrine or placebo ]
    Area under the curve can better measure an extension of the duration of response.

  6. Peak plasma norepinephrine concentration after treatment [ Time Frame: between baseline and 135 minutes after pseudoephedrine or placebo ]


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Ages Eligible for Study:   18 Years to 80 Years   (Adult, Older Adult)
Sexes Eligible for Study:   All
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Age 18-80 years, with
  • Neurogenic orthostatic hypotension, ≥30 mmHg drop in SBP within 5 minutes of standing,
  • Associated with impaired autonomic reflexes, as determined by absence of blood pressure overshoot during phase IV of the valsalva maneuver,
  • Absence of other identifiable causes of autonomic neuropathy, and
  • Able and willing to provide informed consent

Exclusion Criteria

  • Pregnancy
  • Current smoking habit
  • Systemic illnesses known to produce autonomic neuropathy, including but not limited to diabetes mellitus, amyloidosis, monoclonal gammopathy of unknown significance, and autoimmune neuropathies.
  • Known intolerance to pseudoephedrine
  • Pre-existing sustained severe hypertension (BP > 180/110 mmHg in the sitting position)
  • Clinically unstable coronary artery disease or major cardiovascular or neurological event in the past 6 months.
  • Any other significant systemic, hepatic, cardiac or renal illness
  • Use of MAO-I (i.e. selegiline; rasagiline - Azilect, linezolid and others) within 14 days
  • Known closed-angle glaucoma
  • Clinically meaningful arrhythmias
  • Other factors which in the investigator's opinion would prevent the participant from completing the protocol, including poor compliance during previous studies or an unpredictable schedule

Information from the National Library of Medicine

To learn more about this study, you or your doctor may contact the study research staff using the contact information provided by the sponsor.

Please refer to this study by its ClinicalTrials.gov identifier (NCT number): NCT02149901


Locations
United States, Tennessee
Vanderbilt University
Nashville, Tennessee, United States, 37232
Sponsors and Collaborators
Vanderbilt University
National Heart, Lung, and Blood Institute (NHLBI)
National Center for Advancing Translational Science (NCATS)
Investigators
Principal Investigator: Emily M Garland, PhD, MSCI Vanderbilt University Medical Center

Publications:

Responsible Party: Emily M. Garland, Research Associate Professor, Vanderbilt University
ClinicalTrials.gov Identifier: NCT02149901     History of Changes
Other Study ID Numbers: 140547
P01HL056693 ( U.S. NIH Grant/Contract )
UL1TR000445 ( U.S. NIH Grant/Contract )
First Posted: May 29, 2014    Key Record Dates
Last Update Posted: March 27, 2018
Last Verified: March 2018

Keywords provided by Emily M. Garland, Vanderbilt University:
Pure Autonomic Failure
Multiple System Atrophy
Pseudoephedrine
Water
Osmopressor

Additional relevant MeSH terms:
Multiple System Atrophy
Shy-Drager Syndrome
Atrophy
Pure Autonomic Failure
Pathological Conditions, Anatomical
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Basal Ganglia Diseases
Brain Diseases
Central Nervous System Diseases
Movement Disorders
Neurodegenerative Diseases
Hypotension
Vascular Diseases
Cardiovascular Diseases
Pseudoephedrine
Ephedrine
Bronchodilator Agents
Autonomic Agents
Peripheral Nervous System Agents
Physiological Effects of Drugs
Anti-Asthmatic Agents
Respiratory System Agents
Nasal Decongestants
Vasoconstrictor Agents
Central Nervous System Stimulants
Sympathomimetics
Adrenergic Agents
Neurotransmitter Agents