Treatment of Orthostatic Hypotension in Autonomic Failure

This study is currently recruiting participants. (see Contacts and Locations)
Verified May 2014 by Vanderbilt University
Sponsor:
Information provided by (Responsible Party):
Italo Biaggioni, Vanderbilt University
ClinicalTrials.gov Identifier:
NCT00223691
First received: September 14, 2005
Last updated: May 2, 2014
Last verified: May 2014
  Purpose

The autonomic nervous system serves multiple regulatory functions in the body, including the regulation of blood pressure and heart rate, gut motility, sweating and sexual function. There are several diseases characterized by abnormal function of the autonomic nervous system. Medications can also alter autonomic function. Impairment of the autonomic nervous system by diseases or drugs may lead to several symptoms, including blood pressure problems (e.g., high blood pressure lying down and low blood pressure on standing), sweating abnormalities, constipation or diarrhea and sexual dysfunction. Because treatment options for these patients are limited. We propose to study patients autonomic failure and low blood pressure upon standing and determine the cause of their disease by history and examination and their response to autonomic testing which have already been standardized in our laboratory. Based on their possible cause, we will tests different medications that may alleviate their symptoms.


Condition Intervention Phase
Autonomic Failure
Orthostatic Hypotension
Drug: Atomoxetine
Drug: Acarbose
Drug: Pyridostigmine Bromide
Drug: Yohimbine
Drug: Midodrine HCl
Drug: placebo
Drug: Modafinil
Drug: Octreotide
Other: water intake
Drug: Diphenhydramine Hydrochloride
Drug: Ranitidine HCL
Drug: Tranylcypromine
Drug: Ergotamine/ Caffeine
Drug: Celecoxib
Drug: Pseudoephedrine
Drug: Methylphenidate
Drug: Indomethacin
Drug: Ibuprofen
Drug: Oxymetazoline 0.05% nasal solution
Dietary Supplement: Bovril
Drug: Acetazolamide
Drug: Rivastigmine tartrate
Drug: Carbidopa/levodopa
Device: Inflatable abdominal binder
Device: inflatable abdominal binder (sham)
Phase 3

Study Type: Interventional
Study Design: Allocation: Randomized
Endpoint Classification: Efficacy Study
Intervention Model: Crossover Assignment
Masking: Single Blind (Subject)
Primary Purpose: Treatment
Official Title: Evaluation and Treatment of Autonomic Failure.

Resource links provided by NLM:


Further study details as provided by Vanderbilt University:

Primary Outcome Measures:
  • Increase in seated systolic blood pressure 1-hr post drug compared to baseline. [ Time Frame: 1.5-4 hours ] [ Designated as safety issue: No ]

Secondary Outcome Measures:
  • Increase in standing time 1-hr post drug compared to baseline [ Time Frame: 1.5-4 hours ] [ Designated as safety issue: No ]

Estimated Enrollment: 500
Study Start Date: March 2002
Estimated Study Completion Date: May 2016
Estimated Primary Completion Date: May 2015 (Final data collection date for primary outcome measure)
Arms Assigned Interventions
Experimental: 1: active intervention
atomoxetine, pyridostigmine bromide, yohimbine, midodrine hcl, modafinil, octreotide, water intake, ranitidine hcl, diphenhydramine hydrochloride, tranylcypromine, ergotamine/ caffeine, celecoxib, pseudoephedrine, methylphenidate, indomethacin, ibuprofen, Oxymetazoline 0.05% nasal solution, acarbose, Rivastigmine tartrate, acetazolamide, carbidopa/levodopa, inflatable abdominal binder or bovril
Drug: Atomoxetine
10-50 mg, PO. Single dose. Alone or in combination with Yohimbine or Mestinon.
Other Name: Strattera
Drug: Acarbose
25-100 mg, PO. Single dose.
Other Name: Precose
Drug: Pyridostigmine Bromide
30 mg-180 mg PO. Single dose. Alone or in combination with Yohimbine or atomoxetine.
Other Name: Mestinon
Drug: Yohimbine
2.7, 5.4 or 10.8 mg PO. Single dose. Alone or in combination with Atomoxetine or Pyridostigmine.
Other Name: Yocon
Drug: Midodrine HCl
2.5, 5.0, 7.5, 10 mg PO. Single dose
Other Name: ProAmatine
Drug: Modafinil
50-400 mg PO. Single dose
Other Name: Provigil
Drug: Octreotide
5-50 µg, S.C. Single dose.
Other Name: Sandostatin
Other: water intake
Tap water 2 onz., 8 oz., 16 oz. PO, alone or in combination with any of the above medications. Single dose.
Drug: Diphenhydramine Hydrochloride
12.5 mg-100 mg PO. Single dose. Alone or in combination with Ranitidine
Other Name: Benadryl
Drug: Ranitidine HCL
150-300 mg PO. Single dose. Alone or in combination with Diphenhydramine.
Other Name: zantac
Drug: Tranylcypromine
5 - 40 mg PO. Single dose
Other Name: Parnate
Drug: Ergotamine/ Caffeine
Ergotamine: 1.0 mg PO. Single dose. Caffeine 100 mg PO.Single dose
Other Name: Cafergot
Drug: Celecoxib
50-200 mg PO. Single dose
Other Name: Celebrex
Drug: Pseudoephedrine
15, 30 or 60 mg, PO. Single dose.
Other Name: Sudafed
Drug: Methylphenidate
5 or 10 mg PO. Single dose.
Other Name: Ritalin
Drug: Indomethacin
25, 50 or 75 mg, PO. Singe dose.
Other Name: Indocin
Drug: Ibuprofen
300, 600 or 900 mg, PO. Single dose.
Other Name: Advil, Motrin
Drug: Oxymetazoline 0.05% nasal solution
1-2 sprays/ nostril. Single dose.
Other Name: Afrin
Dietary Supplement: Bovril
6-10 g, PO. Single dose.
Drug: Acetazolamide
125-1000 mg PO. Single dose. Alone or in combination with yohimbine or midodrine
Other Name: Diamox
Drug: Rivastigmine tartrate
1.5-6 mg PO. Single dose.
Other Name: Exelon
Drug: Carbidopa/levodopa
10mg/100mg or 25mg/100mg. 1-2 tab PO. Single dose. Alone or in combination with carbidopa (Lodosyn) 25-175 mg
Other Name: Sinemet, Lodosyn
Device: Inflatable abdominal binder
External abdominal compression (20-40 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).
Other Name: external abdominal compression
Placebo Comparator: 2: Placebo or sham device
placebo pill or inflatable abdominal binder (sham)
Drug: placebo
PO.Single dose.
Device: inflatable abdominal binder (sham)
External abdominal compression (5 mm Hg) with an inflatable abdominal binder applied after a pressor agent (e.g. midodrine, yohimbine).
Other Name: external abdominal compression (sham)

  Hide Detailed Description

Detailed Description:

Subjects will be admitted to the Clinical Research Center at Vanderbilt University for the studies. The average inpatient stay is 7 days. Initially a complete history and physical will be performed and the patient will be placed on a low monamine, no methylxanthine, 150 mEq sodium, 60-80 mEq potassium diet.

The following tests will be performed:

  1. Meal challenge:

    We observed profound effects of diet on blood pressure in many patients with orthostatic hypotension. Some patients dropped their blood pressure by 40-60 mmHg during the postprandial period. Blood pressure will be monitored with an automated device (Dinamap) after feeding the patients with a standardized diet.

  2. Physiologic autonomic tests:

    Patients are studied supine, and blood pressure is monitored with a sphygmomanometer or an automated device (Dinamap, Finapres or tonometer).

    1. Orthostatic test: Blood pressure and heart rate are measured in the supine and standing positions. Orthostatic hypotension without an adequate heart rate increase is indicative of autonomic failure. On the other hand, orthostatic tachycardia in the absence of volume depletion is seen in "hyperadrenergic orthostatic hypotension".
    2. Standing time: The time the patient can stand motionless gives a very good indication of functional capacity.
    3. Deep breathing: Heart rate is monitored with an ECG and the patient is asked to breathe deeply 6 times each minute for two minutes. Heart rate variation due to respiration is an autonomic function. The loss of this respiratory arrhythmia is indicative of autonomic failure.
    4. Valsalva maneuver: The patient is asked to exhale against a 40 mmHg pressure. This produces transient changes in blood pressure and heart rate which are autonomically mediated, and can be monitored with an ECG. Failure to observe heart rate changes is indicative of autonomic failure.
    5. Hyperventilation: The patient is asked to hyperventilate for 30 seconds. The normal response is an increase in heart rate and no significant change in blood pressure. Patients with autonomic failure have profound reductions in blood pressure without compensatory heart rate increases.
    6. Handgrip: The patient is asked to maintain a handgrip for three minutes. Increases in heart rate and blood pressure are seen in normal subjects but not in patients with autonomic failure.
    7. Cold pressor test: The patient is asked to place an hand in ice cold water for one minute. The results are similar to the handgrip test.
    8. Supine hypertension screening: We will measure the blood pressure every two hours during one night to determine if the patient has supine hypertension or high blood pressure while lying down.
  3. Posture Study:

    Blood for catecholamine, bradykinins, plasma renin activity, aldosterone and plasma angiotensin II is drawn while the patient is supine and upright. Blood pressure is measured with a sphygmomanometer or an automated device (Dinamap). Normally, on assuming the upright posture, plasma norepinephrine and renin activity should double. Patients with autonomic failure typically show low supine levels of both norepinephrine and renin activity which failed to increase on assuming the upright posture. In contrast, patients with hyperadrenergic orthostatic hypotension typically have normal or exaggerated responses.

  4. Twelve hour urine collections for catecholamines, urinalysis, protein, glucose, creatinine, osmolality, electrolytes and F2-isoprostanes will be collected to analyze for catecholamine excretion (hormones produces by the autonomic nervous system) oxidative stress markers and to assess the patient's kidney function.
  5. Blood will be collected in the fasted state through and intravenous catheter to analyze for PAI-1, CRP, F2-isoprostanes, proinflammatory cytokines and renal function.
  6. EKG will be recorded while the patient is lying down and while the patient is standing.
  7. Orthostatic vital signs will be measured several times a day. This testing consists of blood pressure and heart rate measured while the patient is lying down and then repeated after standing quietly for 10 minutes. Several readings are measured in sequence using an automated blood pressure monitor (Dinamap).
  8. Tilt table test: This test uses a tilt table, which is a motorized table with a footboard. The participant rests quietly on the table while the monitoring equipment is assembled. EKG electrodes are applied to the chest to monitor heart rate and rhythm. Blood pressure will be measured with a cuff applied to a finger. Blood pressure will also be checked periodically using a traditional blood pressure cuff wrapped around an upper arm. Safety straps are used to secure the patient to the table to prevent falling or unsteadiness when the table is moved to an upright position. Gradual head up tilt will be performed until a systolic blood pressure of 70 mm Hg is reached or the appearance of symptoms related to hypotension. Changes in cardiac output (heart's pumping capacity) will be measured by analyzing the air that is breathed ("rebreathing test", Innocor). This will be done through a mouthpiece connected to a bag full of air and small concentrations of the inactive gases SF6 and N2O. Subjects will breathe normally through a mouthpiece connected to a bag for about 5 minutes at baseline, at 30º and at the maximum head up tilt. Innocor is FDA approved for inert gases cardiac output measurement.

    This test may or may not be performed. Some patients may have already undergone this test or it may not be pertinent to a particular patient. The principal investigator will decide whether this test is performed or not.

  9. Therapeutic Drug Trials:

We will try different medications to determine if blood pressure improves upon standing. For all these tests, blood pressure is monitored with a sphygmomanometer and heart rate with an ECG. The procedures are detailed below.

Patients will be in the fasted state in the seated position throughout the study. They will be connected to an automated blood pressure monitor (Dinamap). Thirty minutes after baseline blood pressure and heart rate measurements, they will be given a dose of the medicine to be tested. Blood pressure will be monitored every 5 to 15 minutes for up to four additional hours. Upright blood pressure, heart rate and the standing time will be measure periodically throughout the study. The patients will be asked to rate their symptoms at various time during the study.

This study has been designed to determine optimal candidate drugs and therapy for the treatment of orthostatic hypotension. Potential pressor agents have been selected for this study because of their different mechanism of action. We propose also to use the combination of different therapeutic agents.

For some of these tests,we will do the following:

  1. we will determine the effect of the medication on catecholamines and/or markers of inflammation and/or oxidative stress. We will draw a blood sample at baseline and after the medication has taken effect. A saline lock or small flexible intravenous catheter will be placed for this purpose. For each medication trial, the amount of blood drawn would be up to 6 teaspoons. The total blood drawn for all the medication trials would not exceed 36 teaspoons.
  2. We will apply external abdominal compression (up to 40mm Hg) to evaluate the ability of this counterpressure method in combination with a pressor agent to improve orthostatic tolerance. For this purpose, we will use an abdominal binder with an inflatable cuff placed underneath, which will be inflated to exert pressure at the level of the umbilicus while patients are standing. Patients may be randomly assigned to 5mm Hg (sham treatment) and/or 20-40mm Hg external abdominal compression with an abdominal binder applied at baseline of some of the therapeutic trials described above. The principal investigator will decide which medication will be used in each trial.
  3. We will measure changes in cardiac output (heart's pumping capacity) by analyzing the air that is breathed ("rebreathing test", Innocor). This will be done through a mouthpiece connected to a bag full of air and small concentrations of the inactive gases SF6 and N2O. Subjects will breathe normally through a mouthpiece connected to a bag for about 5 minutes before and after the medication. Innocor is FDA approved for inert gases cardiac output measurement.
  4. We will measure the cerebral blood flow to determine if it can be improved with the medication. A middle cerebral artery will be continuously insonated by transcranial Doppler ultrasonography. The transducer will be affixed with head straps.
  5. We will apply eleven sticky patches to the front of the body to measure the impedance (electrical resistance). This will allow us to determine fluid shifts between body segments and obtain a continuous measurement of cardiac output and peripheral resistance.
  Eligibility

Ages Eligible for Study:   18 Years to 85 Years
Genders Eligible for Study:   Both
Accepts Healthy Volunteers:   No
Criteria

Inclusion Criteria:

  • Patients referred for evaluation of their autonomic function
  • Ages 18-85

Exclusion Criteria:

  • Pregnancy
  Contacts and Locations
Choosing to participate in a study is an important personal decision. Talk with your doctor and family members or friends about deciding to join a study. To learn more about this study, you or your doctor may contact the study research staff using the Contacts provided below. For general information, see Learn About Clinical Studies.

Please refer to this study by its ClinicalTrials.gov identifier: NCT00223691

Contacts
Contact: Bonnie Black, RN adcresearch@vanderbilt.edu

Locations
United States, Tennessee
Vanderbilt University Recruiting
Nashville, Tennessee, United States, 37232
Contact: Bonnie Black, RN       adcresearch@vanderbilt.edu   
Principal Investigator: Biaggioni Italo, MD         
Sub-Investigator: Cyndya Shibao, MD         
Sub-Investigator: David Robertson, MD         
Sub-Investigator: Andre Diedrich, MD         
Sub-Investigator: Alfredo Gamboa, MD         
Sub-Investigator: Satish Raj, MD         
Sub-Investigator: Luis E Okamoto, MD         
Sub-Investigator: Amy C Arnold, PhD         
Sub-Investigator: Cindy A Dorminy, MEd, LPN         
Sub-Investigator: Emily M Garland, PhD         
Sub-Investigator: Melissa R Kaufman, MD, PhD         
Sub-Investigator: Claudia Ramirez, MD         
Sub-Investigator: Jorge Celedonio, MD         
Sponsors and Collaborators
Vanderbilt University
Investigators
Principal Investigator: Italo Biaggioni, MD Vanderbilt University
  More Information

Additional Information:
Publications:

Responsible Party: Italo Biaggioni, Professor of Medicine and Pharmacology, Vanderbilt University
ClinicalTrials.gov Identifier: NCT00223691     History of Changes
Other Study ID Numbers: 000814, HL46681
Study First Received: September 14, 2005
Last Updated: May 2, 2014
Health Authority: United States: Institutional Review Board

Keywords provided by Vanderbilt University:
orthostatic hypotension
autonomic failure

Additional relevant MeSH terms:
Hypotension
Hypotension, Orthostatic
Pure Autonomic Failure
Vascular Diseases
Cardiovascular Diseases
Orthostatic Intolerance
Primary Dysautonomias
Autonomic Nervous System Diseases
Nervous System Diseases
Ibuprofen
Celecoxib
Indomethacin
Ergotamine
Methylphenidate
Caffeine
Levodopa
Modafinil
Carbidopa
Diphenhydramine
Ephedrine
Rivastigmine
Acetazolamide
Carbidopa, levodopa drug combination
Tranylcypromine
Pyridostigmine Bromide
Pseudoephedrine
Midodrine
Oxymetazoline
Phenylephrine
Yohimbine

ClinicalTrials.gov processed this record on September 18, 2014