Plasma Exchange for Autoimmune Autonomic Failure
Information source: National Institutes of Health Clinical Center (CC)
ClinicalTrials.gov processed this data on August 20, 2015 Link to the current ClinicalTrials.gov record.
Condition(s) targeted: Plasma Exchange; Autonomic Failure
Phase: N/A
Status: Completed
Sponsored by: National Institute of Neurological Disorders and Stroke (NINDS)
Summary
This study will explore whether an antibody is influencing the autonomic nervous system, and
if its removal will eliminate signs and symptoms of failure in that system. The autonomic
nervous system is responsible for many automatic changes involved in everyday activities,
such as standing up, digesting food, and exercising in the heat. Antibodies fight germs but
sometimes cause health problems. Removal of the antibody is done through a procedure called
a plasma exchange.
Patients with primary chronic autonomic failure and a circulating antibody to what is called
the neuronal nicotinic receptor may be eligible for this study. To be eligible, patients
will have participated in an earlier study, protocol number 03-N-0004. Patients will undergo
tests and procedures that include an electrocardiogram, and blood collection for hepatitis,
HIV, and pregnancy. Blood will be tested for a complete blood count, clotting factors, and
chemistries. There will also be tests for liver function, kidney function, cortisol, and
thyroid. Participants will be tested for signs and symptoms of autonomic failure, and will
be asked to complete questionnaires about various symptoms before the plasma exchange, 1 or
2 weeks afterward, and then monthly or bimonthly for up to 1 year. Patients will undergo a
series of other tests. In one test, a patient is upright and blows against a resistance
(Valsalva maneuver). The quantitative sudomotor axon reflex test (QSART) uses iontophoresis,
involving application of acetylcholine, a chemical messenger, and a small amount of
electricity. QSART examines the regulation of sweating, a particular aspect of the autonomic
nervous system. There will be a test using edrophonium, given intravenously (IV), to
evaluate that drug's effects on the heart, skin, glands, gastrointestinal activity, bladder
tone, and salivation. A glucagon test, also by IV, will show patients' ability to release
the hormone adrenaline.
The plasma exchange will be performed by use of an automated cell separator. Patients' blood
will be removed continuously through a needle in the arm. Blood cells will be separated from
the plasma by a spinning process and continuously returned to circulation through a needle
in the patients' opposite arm. Blood cells that are returned will be mixed with albumin, a
sterile replacement solution. A blood thinner, citrate, will be given, to prevent clotting
of blood. This whole procedure will take about 2 hours. Patients will typically undergo five
exchange procedures in about 10 days while they are inpatients at the NIH Clinical Center.
The amount of plasma removed in a single session and the number of sessions will be set by
the NIH Blood Bank. It is expected that patients' autonomic failure will improve after
several days of starting the plasma exchange. Testing for symptoms of autonomic failure and
autonomic function testing will occur about 1 month after the plasma exchange and monthly or
bimonthly for up to 1 year. For each visit of testing, patients will be inpatients for about
2 days. If autonomic failure recurs, patients may have a second plasma exchange, with the
same follow-up tests, for about 1 year.
Clinical Details
Official title: Plasma Exchange for Autoimmune Autonomic Failure
Study design: N/A
Detailed description:
Background: Until recently, it was thought that primary chronic autonomic failure occurring
without central neurodegeneration (pure autonomic failure, PAF) reflected diffuse loss of
catecholamine-producing cells (sympathetic noradrenergic nerves and adrenomedullary
chromaffin cells) outside the brain. Rarely, however, PAF patients have clinical laboratory
findings suggesting decreased post-ganglionic nerve traffic in intact autonomic nerves,
rather than denervation. To date, all of four such patients have also had a high titer of a
circulating antibody to the nicotinic receptor mediating ganglionic neurotransmission. In
one case, studied by another group, plasma exchange reversed signs and symptoms of autonomic
failure, consistent with the antibody being pathogenic.
Purpose: In this Protocol, we will carry out plasma exchange in patients we identify as
having PAF, intact cardiac noradrenergic innervation, and a circulating antibody to the
neuronal nicotinic receptor, to determine whether antibody pathogenicity is a consistent
finding in this condition. We will assess the extent of relationship between symptoms,
signs, and clinical laboratory indices of autonomic function with the titer of the antibody
and obtain abundant plasma for antibody characterization and target protein identification.
Methods: Autonomic function testing will be done before plasma exchange, 1-2 weeks after
plasma exchange, and monthly or bi-monthly thereafter for up to one year. Plasma exchange
may be repeated once, when symptoms of autonomic failure return as the antibody level builds
up, to verify in individual patients whether repetition of plasma exchange produces
reproducible amelioration of clinical and laboratory measures of autonomic failure.
Eligibility
Minimum age: 18 Years.
Maximum age: N/A.
Gender(s): Both.
Criteria:
- INCLUSION CRITERIA:
The subjects have primary chronic autonomic failure, intact cardiac sympathetic
innervation, and a circulating antibody to the nicotinic cholinergic receptor mediating
ganglionic neurotransmission. This triad will be identified based on results of
participation in NIH Clinical Protocol 03-N-0004.
EXCLUSION CRITERIA:
Subjects are excluded if they do not meet all three of the above Inclusion Criteria.
Venous Access Candidate subjects are excluded if there is inadequate peripheral venous
access, identified during participation in NIH Clinical Protocol 03-N-0004.
Abnormal Clinical Pathology Test Results Candidate subjects are excluded based on abnormal
Clinical Pathology results identified during participation in NIH Clinical Protocol
03-N-0004 (platelet count less than 100,000 per microliter, HIV-1 or 2 or chronic
hepatitis B or C infection, or pregnancy).
Medical Risk Candidate subjects are excluded for safety reasons if, in the opinion of the
Associate Investigator of the NIH Department of Transfusion Medicine (DTM), therapeutic
plasma exchange would pose an excessive risk of complications (e. g., stroke, hemorrhage,
infection) outweighing the potential scientific and clinical benefit. In female patients
with child-bearing potential, a blood test for pregnancy is done prior to testing on each
visit. The finding of a positive test for pregnancy excludes the patient from further
participation.
Patients with autonomic failure have an increased risk of hypotension in response to
manipulations that decrease venous return to the heart, such as plasma exchanges. Patients
with autonomic failure typically also have high blood pressure when they are lying down.
We expect that at the beginning of plasma exchanges, the blood pressure will be relatively
high, and the plasma exchanges may be started with the patient in a sitting position. The
Principal Investigator or one of the other Associate Investigators of the Clinical
Neurocardiology Section will monitor the blood pressure frequently or continuously during
the plasma exchanges. Patients with autonomic failure often tolerate remarkably low blood
pressure. A systolic blood pressure of 90 mm Hg will be the threshold for intervening. The
first intervention will be to place the patient in a supine position. Second, we would
administer saline and albumin and slow down the rate of or stop the plasma exchange. Drugs
to control blood pressure will also be on hand for immediate emergency use if needed. If
we think that we cannot prevent low blood pressure and fainting during future plasma
exchanges, then we would exclude the patient from further plasma exchanges under this
Protocol. If uncontrollable hypotension occurs in a second patient, then the Protocol will
be terminated.
Patients are tested for hepatitis and for HIV before undergoing plasma exchange. Blood
from people with hepatitis or HIV can contaminate the Blood Bank equipment. If a subject
has hepatitis or HIV, the subject will be excluded from further participation in the
study. The Consent Form includes standard consent language about HIV testing.
Age - The Protocol is restricted to subjects at least 18 years old.
Medications - Medications likely to interfere with the scientific results will be
discontinued on an inpatient basis.
Termination of Participation - A subject may refuse certain tests or procedures, or may
terminate participation early, without loss of benefits to which the subject was
previously entitled. The Investigators may also exclude a subject from further
participation, such as in the event of known or suspect falsification of medical history
information or refusal to undergo planned tests or procedures, without loss of benefits to
which the subject was previously entitled.
Locations and Contacts
National Institutes of Health Clinical Center, 9000 Rockville Pike, Bethesda, Maryland 20892, United States
Additional Information
Related publications: Ziegler MG, Lake CR, Kopin IJ. The sympathetic-nervous-system defect in primary orthostatic hypotension. N Engl J Med. 1977 Feb 10;296(6):293-7. Goldstein DS, Holmes C, Dendi R, Li ST, Brentzel S, Vernino S. Pandysautonomia associated with impaired ganglionic neurotransmission and circulating antibody to the neuronal nicotinic receptor. Clin Auton Res. 2002 Aug;12(4):281-5. Schroeder C, Vernino S, Birkenfeld AL, Tank J, Heusser K, Lipp A, Benter T, Lindschau C, Kettritz R, Luft FC, Jordan J. Plasma exchange for primary autoimmune autonomic failure. N Engl J Med. 2005 Oct 13;353(15):1585-90.
Starting date: July 2006
Last updated: April 17, 2009
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