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

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.

Inclusion Criteria:

1. Males and females of any ethnic origin, 18 years old and over.
2. Both new and previously diagnosed patients with narcolepsy with or without cataplexy could be included. All patients should meet the International Classification of Sleep Disorders (ICSD-2) criteria.
3. Patients should be free of drugs or discontinue any psychostimulant medications for at least 14 days at the start of baseline period. Patients with severe cataplexy are permitted to remain on their anticataplectic medication at stable dose except tricyclic antidepressants. The authorized anticataplectic treatment should have been administrated for at least 1 month prior to the trial and these doses should not be changed throughout the trial (from V1 to V8).
4. Epworth Sleepiness Scale (ESS) score should be ≥ 14 during the baseline period.
5. Patients have expressed a willingness to participate in and complete the study, and signed and dated informed consent prior to beginning protocol required procedures.
6. Females must be surgically sterile or 2 years postmenopausal. Females of child-bearing potential must use a medically accepted effective method of birth control (i.e. oral contraceptives of normal average dosage ≥ 0.05 mg ethinyl-oestradiol, intra-uterine device, with a barrier method such as spermicides…), agree to continue this method for the duration of the study and be negative to serum pregnancy test performed at the screening visit. Females should not be breast-feeding patient.
7. In the opinion of the investigator, the patient must have adequate support to comply with the entire study requirements as described in the protocol (e.g., transportation to and from trial site, self rating scales and diaries completion, drug compliance, scheduled visits, tests).
8. If indicated by investigator, the patient must be willing to not operate a car or heavy machinery for the duration of the trial or as long as the investigator deems clinically indicated. In addition, the patient should be willing to maintain during the study their usual behaviour which could affect their diurnal sleepiness (e.g. circadian rhythm, caffeine consumption, nocturnal sleep duration).
9. Patient should be assured by appropriate healthy insurance system (only applicable where mandatory e.g. in France).

Exclusion Criteria:

1. The use of BF2.649 or any previous investigational drugs within 30-day period prior to initial screening visit (V1) for this trial.
2. In narcoleptic patients without cataplexy, they should not have any other conditions that can be considered the primary causes of EDS: such as sleep related breathing disorders as defined by a sleep Apnea Index ≥ 10 per hour or and an Apnea/Hypopnea Index ≥ 15 per hour, periodic limbs movement (PLM) disorders as defined by a PLM arousal index (PLMAI) ≥ 10 per hour, shift work, chronic sleep deprivation, circadian sleep wake rhythm disorder or any other medical or neurological causes that could account for narcolepsy symptoms associated with EDS.
3. Patients who are unable or unwilling to temporarily discontinue any no-authorized drugs or substances (see Section Non-authorized treatments).
4. Current or recent (within one year) history of a substance abuse or dependence disorder including alcohol abuse as defined in Diagnostic and Statistical Manual of Mental Disorders (DSM-IV).
5. Any significant serious abnormality of the cardiovascular system e.g. recent myocardial infarction, angina, hypertension or dysrhythmia (within the prior 6 months), Electrocardiogram Bazett's corrected QT interval (QT x square root[HR/60]) higher than 450 ms, history of left ventricular hypertrophy or mitral valve prolapse.
6. Patients with severe depression (BDI13 ≥ 16) or with a suicidal risk (item G BDI13 > 0)
7. Patients with Severe hepatic Impairment (e.g. prothrombin ratio, < 50% or factor V < 50% if the patient receiving anti-vitamin K) or with Severe Renal Impairment (e.g. serum creatine greater than 2.0 mg/dL), or with any other significant abnormality in the physical examination or clinical laboratory results.
8. Psychiatric and neurological disorders, such as moderate or severe psychosis or dementia, bipolar illness, severe anxiety, clinical depression, history of seizure disorder or other problem that in the investigator's opinion would preclude the patient's participation and completion of this trial or comprise reliable representation of subjective symptoms.
9. Prior severe adverse reactions to CNS stimulants.
10. Known hypersensitivity to the tested treatment including active substance and excipients.
11. The inability to continue daily activities safely, without the use of treatment against EDS.
12. Other active clinically significant illness, including unstable cardiovascular, endocrine, neoplastic, gastrointestinal, hematologic, hepatic, immunologic, metabolic, neurological (other than narcolepsy/cataplexy), pulmonary, and/or renal disease which could interfere with the study conduct or counter-indicate the study treatments or place the patient at risk during the trial or compromise the study objectives.
13. Any patients presenting congenital galactosemia, glucose-galactose malabsorption or lactase deficiency due to the presence of lactose in investigational treatments
14. Patients participating in another study or being in a follow-up period for another study