An open label, dose escalation study with a double blind randomised placebo controlled withdrawal to examine the effects of the histamine H3 antagonist GSK189254 in patients with narcolepsy.

Phase 1

Conditions: arcolepsy
MedDRA version: 8.1Level: LLTClassification code 10028713Term: Narcolepsy

Registration Number: EUCTR2006-002088-18-NL

Lead Sponsor: GlaxoSmithKline Research & Development Ltd

Brief Summary: Not available

Detailed Description: Not available

Recruitment & Eligibility

Status: ot Recruiting

Sex: All

Target Recruitment: 0

Inclusion Criteria

A subject will be eligible for inclusion in this study only if all of the following criteria apply:
1. Male or female patients aged 18 to 65 years with a body mass index (BMI) between 18 and 32 kg/m2.
2. Has documentary evidence of having been diagnosed for narcolepsy, conforming to the International Classification of Sleep Disorder (ICSD-2) criteria for either narcolepsy with cataplexy or narcolepsy without cataplexy to include:
• The patient has a complaint of excessive daytime sleepiness occurring almost daily for at least three months.
• The mean sleep latency of the screening MSLT is less than or equal to eight minutes and two or more SOREMPs are observed following sufficient nocturnal sleep on the previous night (as documented by the PSG prior to the MSLT).
3. A female patient is eligible to enter and participate in the study if she is of:
a. Non-childbearing potential (i.e. physiologically incapable of becoming pregnant, including any female who is post-menopausal) including any female who:
• Has had a documented hysterectomy, or,
• Has had a documented bilateral oophorectomy (ovariectomy), or,
• Is post-menopausal (a demonstration of total cessation of menses for one year).
Or
b. Child bearing potential, has a negative pregnancy test (serum) at screening and agrees to complete abstinence from intercourse from two weeks prior to administration of the study drug and throughout the study until the first menstruation after 5 half-lives have elapsed from the last dose of study medication.
Or
c. Child bearing potential (e.g. age), has a negative pregnancy test (serum) at screening and has undergone, or confirms regular use of one of the following:
• Female sterilisation (i.e. documented bilateral tubal ligation), or,
• Sterilisation of male partner (i.e. vasectomy); or,
• Practising a clinically accepted method of contraception (with a failure rate of <1% a year) during the study and for at least one month prior to baseline and one month following completion of the study. Acceptable methods are use of a barrier method (condom, diaphragm) or intrauterine device (IUD) in combination with hormonal methods (oral, implanted or transdermal). Individually hormonal, barrier or IUD methods alone are not acceptable.
4. For male patients,
a. A willingness to abstain from sexual intercourse (including with pregnant or lactating women) from the time of the first dose of study medication until 84 days after the administration of the last dose of study medication.
Or
b. A willingness to use a condom/spermicide in addition to having their female partner use another form of contraception such as an intra-uterine device (IUD), barrier methods (e.g. condom or occlusive cap (diaphragm or cervical vault/caps)), oral contraceptives, injectable progesterone, subdermal implants or a bilateral tubal ligation if the woman could become pregnant from the time of the first dose of study medication until the post-study follow-up visit is complete and for 84 days after the administration of the last dose of study medication.
5. Agreement from the patient to refrain from driving or operating heavy machinery for the duration of the study at the discretion of the investigator.
6. Negative drug of abuse and alcohol test at screening (with the exception of prescribed stimulant medications).
7. The patient is able to understand and comply with the protocol requirements, and has given written informed consent to voluntarily participate in the study.

Are the trial

Exclusion Criteria

A subject will not be eligible for inclusion in this study if any of the following criteria apply:
1. As a result of the medical interview, and other screening procedures the investigator considers the patient unfit to participate in the study (based on medical history, review of 12 Lead ECG, EEG, laboratory parameters, vital signs, physical examination).
2. The subject has a positive pre-study Hepatitis B surface antigen and/or positive Hepatitis C antibody result.
3. History or presence of major psychiatric disorder, such as schizophrenia, major depressive disorder, bipolar affective disorder or any other condition that could account for their narcolepsy symptoms.
4. Presence of depression as defined by Hospital Anxiety and Depression Scale (HADS) depression score >= 8, or presence of anxiety disorder as defined by HADS anxiety score >= 8.
5. A definite or suspected family history (in first degree relatives) of clinically significant psychiatric disorders including anxiety, depression, self-harm, bipolar disorder and schizophrenia.
6. History of significant head trauma in previous 12 months.
7. The patient has any abnormality on diagnostic EEG (with the exception of signs of sleepiness), or history or presence of seizures or risk factors for seizure.
8. The patient is unable to abstain from the use of non-selective MAOIs or MAO-A inhibitors (e.g. phenelzine) and potent PGP inhibitors (e.g., itraconazole and ketoconazole) for 2 weeks before the first dose of study medication.
9. The patient is unable to withdraw from any medication primarily prescribed as a treatment of daytime hypersomnolence (e.g., methylphenidate, permoline or dexamphetamine, modafinil). Patients are required to stop taking these treatments for at least 48 hours before the first dose of study medication.
10. Patients should not be living on their own (i.e. should be living with a carer) during the out-patient parts of the study. The person living with the patient will need to be aware of the patient’s participation in the study and must be willing to contact the investigator for the patient if required.
11. The patient has participated in another clinical trial with an investigational drug within the previous 3 months of study start.
12. The patient has a significant and recent (within 1 year) history of drug or alcohol abuse.
13. Patient who is pregnant or breast feeding.
14. The patient has had a history or presence of drug or other significant allergy that, in the opinion of the responsible physician, contra-indicated their participation.
15. The patient has any other medical condition that in the opinion of the investigator and GSK medical monitor would compromise the safety of the subject or the subjects’ suitability to complete the study, examples include but are not limited to:
• The patient meets the essential diagnostic criteria for Restless Leg Syndrome (RLS), as assessed by the RLS questionnaire (International Restless Legs Syndrome Study Group (IRLSSG)).
• An apnea-hypopnea index (AHI) larger than 10 during any PSG night up to and including the baseline night (Day -2).
• A periodic limb movement arousal index (PLMAI) larger than 15 during any PSG night up to and including the baseline night (Day -2).

Study & Design

Study Type: Interventional clinical trial of medicinal product

Study Design: Not specified

Primary Outcome Measures

Name	Time	Method
Main Objective: To assess the efficacy of GSK189254 to improve daytime hypersomnolence in patients with narcolepsy.;Secondary Objective: To assess the safety, tolerability and pharmacokinetics of GSK189254 in patients with narcolepsy.<br><br>To investigate any relationship between efficacy and systemic exposure to GSK189254.<br>;Primary end point(s): Sleep latency (in minutes), as measured by the Maintenance of Wakefulness Test (MWT), at the end of the double-blind phase.

Secondary Outcome Measures

Name	Time	Method

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