Official Title: “Evaluation and Treatment of Autonomic Failure.”

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.

Study Type: Interventional

Study Design: Treatment, Randomized, Single Blind (Subject), Placebo Control, Crossover Assignment, Efficacy Study

Study Primary Completion Date: April 2010

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 and plasma renin activity is drawn while the patient is supine, seated 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 and sodium will be collected to analyze for catecholamine excretion (hormones produces by the autonomic nervous system) and to assess if the patients are in sodium balance.

5. 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 determine the effect of the medication on catecholamines.

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 5 teaspoons. The total blood drawn for all the medication trials would not exceed 30 teaspoons.

Intervention(s) in this Clinical Trial

• Drug: Atomoxetine
  • 10-50 mg, PO. Single dose. Alone or in combination with Yohimbine.
• Drug: Acarbose
  • 25-100 mg, PO. Single dose.
• Drug: Pyridostigmine Bromide
  • 30 mg-180 mg PO. Single dose. Alone or in combination with Yohimbine
• Drug: Yohimbine
  • 2.7, 5.4 or 10.8 mg PO. Single dose. Alone or in combination with Atomoxetine or Pyridostigmine.
• Drug: Midodrine HCl
  • 2.5, 5.0, 7.5, 10 mg PO. Single dose
• Drug: placebo
  • PO.Single dose.
• Drug: Modafinil
  • 50-400 mg PO. Single dose
• Drug: Octreotide
  • 5-50 µg, S.C. Single dose.
• 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
• Drug: Ranitidine HCL
  • 150-300 mg PO. Single dose. Alone or in combination with Diphenhydramine.
• Drug: Tranylcypromine
  • 5 - 40 mg PO. Single dose
• Drug: Ergotamine/ Caffeine
  • Ergotamine: 1.0 mg PO. Single dose. Caffeine 100 mg PO.Single dose
• Drug: Celecoxib
  • 50-200 mg PO. Single dose
• Drug: Pseudoephedrine
  • 15, 30 or 60 mg, PO. Single dose.
• Drug: Methylphenidate
  • 5 or 10 mg PO. Single dose.
• Drug: Indomethacin
  • 25, 50 or 75 mg, PO. Singe dose.
• Drug: Ibuprofen
  • 300, 600 or 900 mg, PO. Single dose.
• Drug: Oxymetazoline 0.05% nasal solution
  • 1-2 sprays/ nostril. Single dose.
• Dietary Supplement: Bovril
  • 6-10 g, PO. Single dose.

Arms, Groups and Cohorts in this Clinical Trial

• Experimental: 1
• Placebo Comparator: 2

Primary Measures

• Increase in seated systolic blood pressure 1-hr post drug compared to baseline.
  • Time Frame: 1.5-4 hours
    Safety Issue?: No

Secondary Measures

• Increase in standing time 1-hr post drug compared to baseline
  • Time Frame: 1.5-4 hours
    Safety Issue?: No

Inclusion Criteria:

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

Exclusion Criteria:

• Pregnancy

Gender Eligibility for this Clinical Trial: Both

Minimum Age for this Clinical Trial: 18 Years

Maximum Age for this Clinical Trial: 85 Years

Are Healthy Volunteers Accepted for this Clinical Trial?: No

Lead Sponsor: Vanderbilt University

Overall Clinical Trial Officials and Contacts

Italo Biaggioni, MD Principal Investigator Vanderbilt University  

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

Information obtained from ClinicalTrials.gov on September 04, 2008

Link to the current ClinicalTrials.gov record. http://clinicaltrials.gov/show/NCT00223691

Study ID Number: 000814

ClinicalTrials.gov Identifier: NCT00223691

Health Authority: United States: Institutional Review Board

Autonomic Dysfunction Center Website