This is a pilot clinical trial of carbidopa to treat the disabling attacks of nausea and vomiting suffered by patients with FD (also known as Riley Day syndrome or hereditary sensory and autonomic neuropathy type III). Familial dysautonomia is a rare autosomal recessive disease in which the growth and development of selective neuronal populations is impaired. Patients with FD suffer recurrent uncontrollable nausea and vomiting accompanied by skin flushing, tachycardia and arterial hypertension. Current treatments of nausea and vomiting are ineffective or have intolerable side sides. 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. They indicate that this strongly suggests 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 does not cross the blood brain barrier. Carbidopa 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 reason that carbidopa could have a similar antiemetic effect in patients with FD. The investigators will conduct a pilot trial to assess the safety, tolerability and efficacy of carbidopa for the treatment of nausea and vomiting in patients with FD. Twenty-five patients with FD who complain of severe nausea that affects their quality of life will participate in this trial. 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. Their long-term goal is to treat nausea effectively and without side effects, a therapeutic intervention that will markedly improve the quality of life of patients with FD.
This clinical trial will determine the safety and efficacy of a new treatment for the disabling and life-threatening recurrent nausea and vomiting suffered by patients with familial dysautonomia, a rare genetic disorder. There are currently no effective treatments for this problem. If successful, this would be a major breakthrough for patients with familial dysautonomia that will dramatically improve the quality of their lives.
| Mendoza-Santiesteban, Carlos E; Palma, Jose-Alberto; Norcliffe-Kaufmann, Lucy et al. (2017) Familial dysautonomia: a disease with hidden tears. J Neurol 264:1290-1291 |
| Gutiérrez, Joel V; Norcliffe-Kaufmann, Lucy; Kaufmann, Horacio (2015) Brainstem reflexes in patients with familial dysautonomia. Clin Neurophysiol 126:626-33 |
| Kaufmann, Horacio; Freeman, Roy; Biaggioni, Italo et al. (2014) Droxidopa for neurogenic orthostatic hypotension: a randomized, placebo-controlled, phase 3 trial. Neurology 83:328-35 |
| Norcliffe-Kaufmann, L; Axelrod, F B; Kaufmann, H (2013) Developmental abnormalities, blood pressure variability and renal disease in Riley Day syndrome. J Hum Hypertens 27:51-5 |
| Norcliffe-Kaufmann, Lucy; Martinez, Jose; Axelrod, Felicia et al. (2013) Hyperdopaminergic crises in familial dysautonomia: a randomized trial of carbidopa. Neurology 80:1611-7 |
| Norcliffe-Kaufmann, Lucy J; Axelrod, Felicia B; Kaufmann, Horacio (2013) Cyclic vomiting associated with excessive dopamine in Riley-day syndrome. J Clin Gastroenterol 47:136-8 |
| Axelrod, Felicia B; Rolnitzky, Linda; Gold von Simson, Gabrielle et al. (2012) A rating scale for the functional assessment of patients with familial dysautonomia (Riley Day syndrome). J Pediatr 161:1160-5 |
| Mendoza-Santiesteban, Carlos E; Hedges 3rd, Thomas R; Norcliffe-Kaufmann, Lucy et al. (2012) Clinical neuro-ophthalmic findings in familial dysautonomia. J Neuroophthalmol 32:23-6 |
| Axelrod, Felicia B; Liebes, Leonard; Gold-Von Simson, Gabrielle et al. (2011) Kinetin improves IKBKAP mRNA splicing in patients with familial dysautonomia. Pediatr Res 70:480-3 |
| Macefield, Vaughan G; Norcliffe-Kaufmann, Lucy; Gutierrez, Joel et al. (2011) Can loss of muscle spindle afferents explain the ataxic gait in Riley-Day syndrome? Brain 134:3198-208 |
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