Effects of BF2.649 in the Treatment of Excessive Daytime Sleepiness in Narcolepsy.

Summary

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.

Conditions

• Treatment of Excessive Daytime Sleepiness in Narcolepsy

Interventions

DRUG

BF2.649

BF2.649 is provided in capsules. One-quarter or one-half of BF2.649 tablet at 20 mg (corresponding to 5-, and 10 mg, respectively). Patients should take 2 capsules per day with a glass of water. They will be instructed to take 1 capsule in the morning (after waking up, before breakfast around 8.00 a.m.) and 1 capsule at noon.

DRUG

Vigil

Modafinil is provided in capsules. The capsules are identical in appearance to ensure that neither the patient nor the investigator nor members of the clinical staff knows the identity of the study medication. Modafinil tablet at 100 mg are enclosed in gelatine capsules. Patients should take 2 capsules per day with a glass of water. They will be instructed to take 1 capsule in the morning (after waking up, before breakfast around 8.00 a.m.) and 1 capsule at noon.

DRUG

palcebo

placebo is provided in capsules. The capsules are identical in appearance to ensure that neither the patient nor the investigator nor members of the clinical staff knows the identity of the study medication. placebo consist of identical capsules containing lactose only. Patients should take 2 capsules per day with a glass of water. They will be instructed to take 1 capsule in the morning (after waking up, before breakfast around 8.00 a.m.) and 1 capsule at noon.

Sponsors & Collaborators

• Bioprojet

  lead OTHER

Principal Investigators

• DAUVILLIERS Yves · Hôpital Gui de Chauliac - 80, avenue A. Fliche , 34295 Montpellier cedex 5 - FRANCE

Study Design

Allocation

RANDOMIZED

Purpose

TREATMENT

Masking

DOUBLE

Model

PARALLEL

Eligibility

Min Age

18 Years

Sex

ALL

Healthy Volunteers

No

Timeline & Regulatory

Start

2010-11-30

Primary Completion

2012-04-30

Completion

2012-07-31

Countries

• France

Study Locations