Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia

• Sponsor: NYU Langone Health (Other)
• Overall Status: Completed
• CT.gov ID: NCT01212484
• Collaborator: (none)
• Enrollment: 12
• Arms: 2
• Duration (Months): 34

Study Details

Study Description

Brief Summary

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 or Disease	Intervention/Treatment	Phase
Familial Dysautonomia	Drug: Carbidopa; Drug: Placebo	Phase 3

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.

Study Design

• Study Type: Interventional
• Actual Enrollment: 12 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Double (Participant, Investigator)
• Primary Purpose: Treatment
• Official Title: Carbidopa for the Treatment of Nausea and Vomiting in Familial Dysautonomia
• Study Start Date: Dec 1, 2009
• Actual Primary Completion Date: Feb 1, 2012
• Actual Study Completion Date: Oct 1, 2012

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Placebo (first), Carbidopa (second) Crossover design Placebo first followed by 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 Names: Lodosyn ; 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.
Experimental: Carbidopa (first), Placebo (second) Crossover design carbidopa first followed by placebo	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 Names: Lodosyn ; 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.

Outcome Measures

Primary Outcome Measures

1. Composite Daily Score [4 weeks]

   Daily scores were reported on a modified version of the Rhodes Index of Nausea, Vomiting and Retching, which included all 5 items relating to nausea and retching. Items addressing vomiting/throwing up were omitted, as all participants had antireflux surgery that prevented vomiting (Nissen fundoplication). Retching distress, nausea distress, number of nausea episodes per day, number of retching episodes per day, and the amount of time spent feeling nauseous were graded on a 5-point scale. Scores range from 0 (no nausea/distress) to 20 (most nausea/distress).

2. 24 Hour Dopamine Levels [4 weeks]

   Assay of 24 hour dopamine level excretion in urine

Secondary Outcome Measures

1. Number of Episodes of Daily Nausea [4 weeks]

Eligibility Criteria

Criteria

• Ages Eligible for Study: 12 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Male of female patients aged 12 and older

• Confirmed diagnosis of familial dysautonomia by genetic testing.

• Symptoms of severe nausea

• 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.

• Ability to comply with the requirements of the study procedures, including taking blood pressure measurements at home.

Exclusion Criteria:

• Patients taking metroclopromide, domperidone, risperidone or other dopamine blockers

• Patients taking MAO-inhibitors

• Patients taking tricyclic antidepressants

• Patients taking neuroleptic drugs (haloperidol and chlorpromazine)

• Patients with a known hypersensitivity to any component of this drug.

• Patients with atrial fibrillation, angina or an electrocardiogram documenting significant abnormality that may jeopardize the patient's health.

• Patients with significant pulmonary, liver, renal (creatinine >2.0 mg/ml) or cardiac illness

• Patients who are unable to clearly identify and rate their symptoms of nausea.

• Women who are pregnant or lactating

• Patients who have a significant abnormality on clinical examination that may, in

Contacts and Locations

Locations

No locations specified.

Sponsors and Collaborators

• NYU Langone Health

Investigators

• Principal Investigator: Horacio C Kaufmann, M.D., NYU Langone Health

Study Documents (Full-Text)

None provided.

More Information

Publications

None provided.

• Responsible Party: NYU Langone Health
• ClinicalTrials.gov Identifier: NCT01212484
• Other Study ID Numbers: 09-0011
• First Posted: Sep 30, 2010
• Last Update Posted: Mar 28, 2016
• Last Verified: Mar 1, 2016

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Additional relevant MeSH terms: Primary Dysautonomias; Autonomic Nervous System Diseases; Dysautonomia, Familial; Vomiting; Carbidopa

Study Results

Participant Flow

Recruitment Details	All patients were recruited at the NYU medical center's Dysautonomia Center.
Pre-assignment Detail	Patients with FD that complain of severe nausea will be screened.

Arm/Group Title	Placebo (First), Carbidopa (Second)	Carbidopa (First), Placebo (Second)
Arm/Group Description	Subjects will be given placebo first (4 weeks), followed by carbidopa (4 weeks).	Subjects will be given Carbidopa for a 4 week period followed by placebo for a 4 week period.
Period Title: Carbidopa Titration Period (4 Weeks)
STARTED	6	6
COMPLETED	5	6
NOT COMPLETED	1	0
Period Title: Carbidopa Titration Period (4 Weeks)
STARTED	5	6
COMPLETED	5	4
NOT COMPLETED	0	2
Period Title: Carbidopa Titration Period (4 Weeks)
STARTED	5	4
COMPLETED	5	3
NOT COMPLETED	0	1

Baseline Characteristics

Arm/Group Title	All Study Subjects
Arm/Group Description
Overall Participants	12
Age (Count of Participants)
<=18 years	8 66.7%
Between 18 and 65 years	4 33.3%
>=65 years	0 0%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	18.5 (6.45)
Sex: Female, Male (Count of Participants)
Female	4 33.3%
Male	8 66.7%

Outcome Measures

1. Primary Outcome

Title	Composite Daily Score
Description	Daily scores were reported on a modified version of the Rhodes Index of Nausea, Vomiting and Retching, which included all 5 items relating to nausea and retching. Items addressing vomiting/throwing up were omitted, as all participants had antireflux surgery that prevented vomiting (Nissen fundoplication). Retching distress, nausea distress, number of nausea episodes per day, number of retching episodes per day, and the amount of time spent feeling nauseous were graded on a 5-point scale. Scores range from 0 (no nausea/distress) to 20 (most nausea/distress).
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carbidopa	Placebo
Arm/Group Description
Measure Participants	8	8
Mean (Standard Deviation) [units on a scale]	6.9 (2.2)	9.7 (2.5)

2. Secondary Outcome

Title	Number of Episodes of Daily Nausea
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carbidopa	Placebo
Arm/Group Description
Measure Participants	8	8
Mean (Standard Deviation) [episodes of nausea]	1.2 (0.8)	2.0 (1.0)

3. Primary Outcome

Title	24 Hour Dopamine Levels
Description	Assay of 24 hour dopamine level excretion in urine
Time Frame	4 weeks

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Carbidopa	Placebo
Arm/Group Description
Measure Participants	8	8
Mean (Standard Deviation) [ug/gCR]	127 (29)	222 (41)

Adverse Events

Arm/Group Title	Carbidopa		Placebo
Arm/Group Description	carbidopa 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.		Placebo 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.
All Cause Mortality
	Carbidopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	/ (NaN)		/ (NaN)
Serious Adverse Events
	Carbidopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/12 (8.3%)		0/12 (0%)
Nervous system disorders
lightheadedness / faint	1/12 (8.3%)	1	0/12 (0%)	0
Other (Not Including Serious) Adverse Events
	Carbidopa		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/12 (0%)		0/12 (0%)

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

There is NOT an agreement between Principal Investigators and the Sponsor (or its agents) that restricts the PI's rights to discuss or publish trial results after the trial is completed.