Treatment of Excessive Daytime Sleepiness in Narcolepsy Clinical Trial
Official title:
Randomized, Double-blind, Placebo and Comparator-controlled, Parallel-group, Multi-center Trial Assessing the Effects of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy
3. RATIONALE FOR BF2.649 IN NARCOLEPSY Narcolepsy is a disabling syndrome affecting the
generation and organizations of sleep and wakefulness, first described by Westphal and
Gelineau in 19th century. Excessive Daytime Sleepiness (EDS) and cataplexy are two main
symptoms of narcolepsy. Other symptoms referred to as auxiliary symptoms are hypnagogic and
hypnopompic hallucinations, sleep paralysis, dyssomnia and automatic behaviour. The
prevalence of narcolepsy is estimated around 25 per 100 000 in Causasian population. It is
often extremely incapacitating, interfering with every aspect of life, in work and social
settings.
Several breakthroughs in the understanding of physiopathology of narcolepsy have recently
shown that most narcoleptic patients display a strongly decreased CSF level of orexins, a
group of hypothalamic peptides with wake-promoting activity. It was also found that sporadic
narcolepsy in dogs, mice and humans may also be related to a deficiency in the production of
orexin ligands. Narcolepsy may be a neurodegenerative or autoimmune disorder resulting in a
loss of hypothalamic neurons containing the orexin [Baumann CR & Bassetti CL Lancet Neurol.
2005 ; Dauvilliers Y et al, Clin Neurophysiol. 2003 ].
In accordance with guidelines published by the European task force [Billiard M et al, Eur J
Neurol. 2006] , management of narcolepsy with or without cataplexy relies on several classes
of drugs, namely stimulants for EDS, antidepressants for cataplexy and hypnosedative drugs
for disturbed nocturnal sleep. The first line pharmacological treatment of EDS and
irresistible episodes of sleep rely on Modafinil, 100-400 mg/day, given in two doses, one in
the morning and one early in the afternoon, the need for amphetamines and amphetamine-like
stimulants (e.g. methylphenidate) has been decreased. Sodium oxybate and antidepressants are
main drug therapies of cataplexy.
BF2.649, an H3R inverse agonist promotes significantly vigilance in mice knock out for the
orexin gene, a reliable model of narcolepsy, whereas the animals remain calm, a difference
with treatment by amphetamine-like drugs which induce psychomotor excitation. In addition,
BF2.649 shows a significant inhibitory effect on the occurrence of narcolepsy episodes
during the dark period. These narcolepsy episodes are to be compared to cataplexy episodes
in human [Chemelli et al., Cell 1999] 11. In agreement, Modafinil, in humans, does not show
any effects on cataplexy, even if it improves wakefulness by an ill-defined mechanism. Thus
anticataplectic drugs, such as antidepressants, are given in addition to Modafinil to
narcoleptic patients.
Taken together, the preclinical and clinical results provide a compelling rationale for this
study to verify and confirm, under randomized double-blind and placebo-controlled
conditions, the safety and efficacy of escalating dose of BF2.649 in the treatment of EDS
and cataplexy in narcolepsy.
It is on the basis of preclinical studies, and on the observation of the first included
patients, that the doses to be administered were determined.
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