Familial Dysautonomia Clinical Trial
Official title:
Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia
This is a pilot clinical trial of carbidopa to treat disabling attacks of nausea and
vomiting in patients with familial dysautonomia (FD, also known as Riley Day syndrome or
hereditary sensory and autonomic neuropathy type III). FD is a rare autosomal recessive
disease in which the growth and development of selective nerves is impaired. Patients with
FD suffer recurrent uncontrollable nausea and vomiting crises accompanied by skin flushing,
tachycardia and arterial hypertension. Current treatments of nausea are ineffective or have
intolerable side sides. Our long-term goal is to treat nausea effectively and without side
effects, a therapeutic intervention that would markedly improve the quality of life of
patients with FD.
The investigators have recently found that resting plasma dopamine levels are high in
patients with FD and increase up to 40-fold during nausea and vomiting attacks. This led us
to postulate that stimulation of dopamine receptors in the chemoreceptor trigger zone of the
brainstem is the likely mechanism of vomiting.
Carbidopa is a reversible competitive inhibitor of aromatic L-amino acid decarboxylase (also
known as dopa-decarboxylase) that cannot cross the blood brain barrier. It has been used
successfully for many years to block the extracerebral synthesis of dopamine and avoid
nausea and vomiting in patients with Parkinson's disease taking levodopa. The investigators
reasoned that carbidopa could have a similar antiemetic effect in patients with FD.
The investigators propose to conduct a pilot trial to assess the safety, tolerability and
efficacy of carbidopa for the treatment of nausea in patients with FD. The pilot trial will
recruit 25 patients with FD who complain of severe nausea that affects their quality of
life. The trial will be divided into two consecutive, but independent parts. Part 1, will
address the safety and tolerability of carbidopa in patients with FD using an open-label
dose titration phase followed by 4-weeks of open-label treatment. Part 2, will address the
efficacy of carbidopa for the treatment of nausea in patients with FD using a randomized,
placebo controlled, double blind, 4-week cross over design.
The investigators hope to demonstrate that carbidopa is a safe, well-tolerated drug that
blocks the peripheral formation of dopamine and thus prevents dopamine-induced nausea and
vomiting attacks in patients with FD.
Patients with familial dysautonomia (FD), also called Riley Day syndrome or hereditary
sensory and autonomic neuropathy type III, suffer recurrent attacks of uncontrollable nausea
and vomiting that can last several hours or days and are severely disabling. Hypertension,
tachycardia and skin blotching frequently accompany these attacks. Our long-term objective
is to develop an effective treatment for nausea and vomiting in patients with FD.
In preliminary studies we found that plasma levels of dopamine were very high during
attacks. Stimulation of dopamine receptors in the chemoreceptor trigger zone in the
brainstem is a well-known cause of nausea and vomiting. The investigators postulate that
acute increases in circulating dopamine levels are the cause of paroxysmal nausea and
vomiting in FD.
Dopamine is synthesized by decarboxylation of the aminoacid L-dihydroxyphenylserine (L-DOPA)
by the enzyme aromatic L-aminoacid decarboxylase, also known as DOPA decarboxylase. Patients
with Parkinson's disease suffer nausea and vomiting when they receive treatment with L-DOPA.
However, when L-DOPA is administered together with carbidopa, a reversible competitive
inhibitor of DOPA decarboxylase that does not cross the blood brain barrier, nausea and
vomiting are prevented. The investigators hypothesize that by blocking the conversion of
DOPA to dopamine and thus preventing its increase in plasma, treatment with carbidopa will
decrease nausea and vomiting in patients with FD.
Although carbidopa has been used for many years in patients with Parkinson's disease, it has
never been used in patients with FD. The first specific aim of this proposal is to assess
the safety and tolerability of carbidopa in patients with FD.
The second specific aim of this proposal is to determine whether blocking the peripheral
synthesis of dopamine with carbidopa will improve recurrent nausea in patients with FD.
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Allocation: Randomized, Endpoint Classification: Safety/Efficacy Study, Intervention Model: Parallel Assignment, Masking: Double Blind (Subject, Investigator), Primary Purpose: Treatment
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