A 6-month, double-blind, randomized, placebo-controlled, parallel group outpatient trial, investigating the efficacy and safety of Org 50081 in adult patients with chronic primary insomnia.

Org 50081 is the maleate salt of the S-enantiomer (Org 4420) of the racemic
mixture mirtazapine. Several preclinical and clinicial 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 dose-finding trial with Org 50081
has beeen 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 tolerability 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 form both a pharmacological and clincal 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 benzodiazepines to new benzodiazepine
agonists such as zolpidem or zaleplon. Since the newer hypnotics als 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.

Primary: To demonstrate the long-term efficacy of treatment with Org 50081, as
compared to placebo, on sleep maintenance in patients with chronic primary
insomnia as measured by the subjective Total Sleep Time. Primary efficacy
endpoint is the average of subjective Total Sleep Time (TST) during month 4 to
month 6, as recorded daily in the sleep diary.

This trial is a 6-month, double bllind, placebo-controlled, randomized,
multi-center, international, parallel group investigation of the efficacy and
safety of 4.5 mg Org 50081 with single-blind placebo run-in and a double-blind
7 day discontinuation period after 6 months of treatment in patients with
chronic primary insomnia.
Subjects will be selected on the basis of a screening process (7-20 days),
during which the trial selection criteria should be fulfilled. During this
screening period the subjects receive single-blind placebo. When eligible,
subjects will be randomized in a double-blind manner to 4.5 mg of Org 50081 or
placebo at a ratio of 3:1 on Day 1.
At the end of the 6-month double-blind treatment period, Org 50081 treated
subjects will be re-randomized to receive double-blind treatment of either Org
50081 or placebo at a 1:2 ratio, respectively for additional 7 days. The
placebo treated subjects, will continue to receive double-blind placebo for
these additional 7 days.

Subjects who have completed Trial 21106 and are willing, will be asked to
participate in the long-term open label extension trial 176003. These subjects,
provided they meet the entry criteria, will continue with trial 176003
immediately after the 7-day discontinuation period of trial 21106 is complete.

For subjects not participating in the open label extension study 176003, 7 days
after the double-blind discontinuation assessment period or after discontinuing
prematurely, a follow up visit will be conducted to assesss AEs that had
occured after treatment discontinuation. This visit will be followed by a
telephone contact 30 days after the discontinuation period to follow-up on any
SAEs occruing after the 7 day follow up visit.

Subjects will be treated during 6 months with 4.5 mg Org 50081 or placebo. The
discomfort consists mainly out of 11 visits to the clinical (30 days after the
11th visit the subject will be contacted by telephone to follow up on any SAEs
occuring after the follow up visit (11th). Electronic diary, questionnaires,
urine and bloodsamples, physical examiniation and ECGs. The subjects will get
extensively check ups, a lot of information and a compensation for costs for
time, eventual discomforts and traveling.