A twenty-six weeks, open-label extension trial to evaluate safety and efficacy of Org 50081 in outpatients with chronic primary insomnia who completed clinical trial protocol 21106

Org 50081 is the maleate salt of the S-enantiomer (Org 4420) of the racemic
mixture mirtazapine. Several preclinical and clinical studies have demonstrated
sleep-promoting effects of mirtazapine. Increases in sleep efficiency,
increases in total sleep time and slow wave sleep, and shorter sleep latency
have been observed in patients with major depressive disorder, primary insomnia
and in healthy subjects. A dosoe-finding trial with Org 50081 has been
performed in 60 patients with primary insomnia to demonstrate superiority of
treatment with Org 50081 compared to placebo on Total Sleep Time as measured by
polysomnography. Secondary objectives were to investigate dose-response, safety
and tolerabilityy and hangover effects after two days of treatment with Org
50081. The fact that sleep promoting effects of Org 50081 may be primarily
related to deep stages of sleep and are exerted through a different
pharmacological action than that of benzodiazepines makes these effects
interesting from both a pharmacological and clinical point of view. Worldwide,
most sleep promoting medicines used in clinical practice act at the
benzodiazepine receptor site. Adverse drug reactions related to
benzodiazepines, such as tolerance, dependence, addiction, withdrawal and
rebound phenomena, have led to a steady decline in the prescription of
benzodiazepine hypnotics over the last decade. Consequently, pharmacotherapy
has shifted gradually from classical benzodiapzepines to new benzodiazepine
agonists such as zolpidem or zaleplon. Since the newer hypnotics also exert
their mode of action via the GABA system, they are still associated with abuse
potential and have been shown to promote the risk of addiction. Unlike other
hypnotics currently available, Org 50081 does not exert its action through the
GABA receptors. Org 50081 is not expected to have abuse potential. Over the
past 10 years, there has been an increasing use of sedating antidepressants for
the symptomatic treatment of insomnia, despite the paucity of data on the
efficacy of these drugs in treating insomnia. Tricyclic antidepressants,
trazodone, nefazodone and mirtazapine are considered to be pharmacotherapeutic
candidates for treating insomnia though they are not approved for this
indication.

To investigate safety and tolerability and to collect exploratory efficacy data
of long-term treatment with Org 50081 in adult patients with chronic primary
insomnia.

This trial is a 26-week, open-label extension trial to investigate safety and
explore efficacy of Org 50081 in subjects who have completed tral 21106.
Subjects who have completed trial 21106 and are willing to continue treatment
with Org 50081, can participate in trial 176003 after the informed consent is
signed.
The trial consists of a 26 week period of open-label treatment with 4.5 mg Org
50081 and a follow-up period. Subjects will be asked at the Week 22 visit of
trial 21106 to consider participating in the extension trial. The start of
trial 176003 coincides with visit 10 (Week 27) of trial 21106 when first 176003
trial medication is dispensed. At this time point informed consent should be
signed. Subjects who participate in trial 176003 will not participate in the 7
day follow-up visit and the 30-day follow-up contact in trial 21106.
If the subject fulfills all selection criteria at Day 1, the subject will have
open-label medication assigned. In the evening of Day 1, the first trial
medication should be taken. This open-label treatment period lasts 26 weeks
during which the subject returns to the clinic for a visit after 2 weeks and
next every 4 weeks (+/- 3 days).

The treatment period will be followed by a follow-up period, during which no
trial medication will be administered. A follow-up visit will take place 7 days
after discontinuation of trial medication for assessment of any (S)AEs. In
addition, a telephone call should be scheduled 30 days after the week 26 visit
or 30 days after premature discontinuation to follow up on any SAEs related to
the trial or occuring after the last intake of active medication.

Subjects participating in this extension trial will be treated during 26 weeks
with 4.5 mg Org 50081. The discomfort consists mainly out of 9 visits to the
clinic (30 days after the 9th visit the subject will be contacted by telephone
to follow up on any SAEs occuring after the follow up visit), rlectronic diary,
questionnaires, urine and bloodsamples, physical examination and ECGs. The
subjects will get extensively check ups, a lot of information and a
compensation for costs for time, eventual discomforts and traveling.