Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia - Full Text View

Purpose

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.

Condition	Intervention	Phase
Familial Dysautonomia	Drug: Carbidopa Drug: Placebo	Phase 3


Study Type:	Interventional
Study Design:	Allocation: Randomized Endpoint Classification: Safety/Efficacy Study Intervention Model: Parallel Assignment Masking: Double Blind (Subject, Investigator) Primary Purpose: Treatment
Official Title:	Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia

Resource links provided by NLM:

Genetics Home Reference related topics: familial dysautonomia hereditary sensory and autonomic neuropathy type IE hereditary sensory neuropathy type 1

MedlinePlus related topics: Autonomic Nervous System Disorders Nausea and Vomiting

Drug Information available for: Carbidopa

Genetic and Rare Diseases Information Center resources: Familial Dysautonomia

U.S. FDA Resources

Further study details as provided by New York University School of Medicine:

Primary Outcome Measures:

Number of Adverse Events [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]

Secondary Outcome Measures:

Nausea Scores and Dopamine Levels [ Time Frame: 4 months ] [ Designated as safety issue: Yes ]


Enrollment:	9
Study Start Date:	December 2009
Study Completion Date:	October 2012
Primary Completion Date:	February 2012 (Final data collection date for primary outcome measure)

Arms	Assigned Interventions
Placebo Comparator: placebo Placebo	Drug: Placebo The trial will be divided into two consecutive, but independent parts. Phase 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. Phase 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.
Active Comparator: Carbidopa carbidopa	Drug: Carbidopa The trial will be divided into two consecutive, but independent parts. Phase 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. Phase 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. Other Name: Lodosyn

Arms

Assigned Interventions

Placebo Comparator: placebo

Placebo

Drug: Placebo

The trial will be divided into two consecutive, but independent parts. Phase 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. Phase 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.

Active Comparator: Carbidopa

carbidopa

Drug: Carbidopa

The trial will be divided into two consecutive, but independent parts. Phase 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. Phase 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.

Other Name: Lodosyn

Detailed Description:

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.

Eligibility


Ages Eligible for Study:	12 Years and older
Genders Eligible for Study:	Both
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Male of female patients aged 12 and older
2. Confirmed diagnosis of familial dysautonomia by genetic testing.
3. Symptoms of severe nausea
4. Written informed consent or ascent to participate in the pilot trial and understanding that they can withdraw consent at anytime without affecting their future care.
5. Ability to comply with the requirements of the study procedures, including taking blood pressure measurements at home.

Exclusion Criteria:

1. Patients taking metroclopromide, domperidone, risperidone or other dopamine blockers
2. Patients taking MAO-inhibitors
3. Patients taking tricyclic antidepressants
4. Patients taking neuroleptic drugs (haloperidol and chlorpromazine)
5. Patients with a known hypersensitivity to any component of this drug.
6. Patients with atrial fibrillation, angina or an electrocardiogram documenting significant abnormality that may jeopardize the patient's health.
7. Patients with significant pulmonary, liver, renal (creatinine >2.0 mg/ml) or cardiac illness
8. Patients who are unable to clearly identify and rate their symptoms of nausea.
9. Women who are pregnant or lactating
10. Patients who have a significant abnormality on clinical examination that may, in

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: NCT01212484

Sponsors and Collaborators

New York University School of Medicine

Investigators


Principal Investigator:	Horacio C Kaufmann, M.D.	New York University School of Medicine

More Information

No publications provided


Responsible Party:	Horacio Kaufmann, Professor of neurology, New York University School of Medicine
ClinicalTrials.gov Identifier:	NCT01212484 History of Changes
Other Study ID Numbers:	09-0011
Study First Received:	September 13, 2010
Last Updated:	April 5, 2013
Health Authority:	United States: Food and Drug Administration

Additional relevant MeSH terms:


Autonomic Nervous System Diseases Dysautonomia, Familial Primary Dysautonomias Autoimmune Diseases Autoimmune Diseases of the Nervous System Congenital Abnormalities Demyelinating Diseases Genetic Diseases, Inborn Hereditary Sensory and Autonomic Neuropathies Heredodegenerative Disorders, Nervous System Immune System Diseases Nervous System Diseases Nervous System Malformations Neurodegenerative Diseases Neuromuscular Diseases	Peripheral Nervous System Diseases Polyneuropathies Polyradiculoneuropathy Carbidopa Anti-Dyskinesia Agents Antiparkinson Agents Central Nervous System Agents Dopamine Agents Enzyme Inhibitors Molecular Mechanisms of Pharmacological Action Neurotransmitter Agents Pharmacologic Actions Physiological Effects of Drugs Therapeutic Uses

Autonomic Nervous System Diseases
Dysautonomia, Familial
Primary Dysautonomias
Autoimmune Diseases
Autoimmune Diseases of the Nervous System
Congenital Abnormalities
Demyelinating Diseases
Genetic Diseases, Inborn
Hereditary Sensory and Autonomic Neuropathies
Heredodegenerative Disorders, Nervous System
Immune System Diseases
Nervous System Diseases
Nervous System Malformations
Neurodegenerative Diseases
Neuromuscular Diseases

Peripheral Nervous System Diseases
Polyneuropathies
Polyradiculoneuropathy
Carbidopa
Anti-Dyskinesia Agents
Antiparkinson Agents
Central Nervous System Agents
Dopamine Agents
Enzyme Inhibitors
Molecular Mechanisms of Pharmacological Action
Neurotransmitter Agents
Pharmacologic Actions
Physiological Effects of Drugs
Therapeutic Uses

ClinicalTrials.gov processed this record on March 01, 2015