A randomized long-term safety study of Org 50081 in elderly outpatients with chronic primary insomnia examining the effects of 1.5 mg or 3.0 mg of Org 50081

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 dose-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 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 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 decade6. Consequently, pharmacotherapy
has shifted gradually from classical benzodiazepines 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.

Primary • To investigate the safety and tolerability of long-term treatment
with 1.5 mg or 3.0 mg of Org 50081 in elderly outpatients with chronic primary
insomnia.
Secondary • To collect exploratory efficacy data of long-term treatment with
Org 50081 in elderly outpatients with chronic primary insomnia.

This trial is a 52-week, randomized, parallel group investigation of the
dose-related safety and tolerability of Org 50081. Subjects and investigators
will be blinded to the dose of Org 50081.
Subjects will be selected on the basis of a screening process (14 days), during
which the trial selection criteria should be fulfilled. During this screening
period, the subjects will be trained on the LogPad at both Days -14 (Visit 1)
and -7 (Visit 2). In the 2 weeks following the Day -14 visit, subjects will
practice using the LogPad by daily completing a practice sleep diary on the
device. This practice sleep diary, completed daily, is very similar to the
once-weekly version, which is used throughout the trial. To be eligible,
subjects must have demonstrated capacity to independently complete the LogPad
questionnaires in the week preceding Day 1. The practice diary data from the
LogPad may be used at a later stage to compare weekly versus daily assessments
of sleep parameters.
If eligible, subjects will be randomized in a double-blind manner to 1.5 mg or
3.0 mg of Org 50081 at Day 1 (Visit 3). The treatment duration will be 364 days
(52 weeks) and the first dose of trial medication will be administered in the
evening of Day 1. During the first month of the trial, subjects will have
visits at the end of Weeks 1 (Visit 4), 2 (Visit 5), and 4 (Visit 6).
Following the Week 4 visit, the visit frequency will be every 4 weeks. Patients
should adhere to the visit schedule, but deviations of ±1 day are allowed until
Visit 6. From Visit 6 onwards, for the event that it is not possible to
maintain the visit schedule, a deviation of ±5 days is allowed. The sleep diary
will be recorded weekly from Day 1 onwards until Week 52 (Visit 18; see Table
1). The sleep diary will assess subjective sleep parameters, alertness, daytime
functioning, energy level and napping in the past 7 days. The ratings on the
weekly sleep diary, collected at Day 1, will be used as baseline data. A
follow-up visit will take place on Day 372 (Visit 19), 7 days after completion
of the active treatment period, or 7 days after premature discontinuation.
Unresolved (S)AEs will be followed up until resolved. A telephone call should
be scheduled 30 days after the last intake of active treatment (i.e., Day 395
for trial completers) to follow up on any SAE occurring after the follow-up
visit.

Subjects will be treated during 52 weeks with 1.5 mg or 3.0 mg of Org 50081.
The discomfort consists mainly out of 19 visits to the clinic ( 3 weeks after
the 19th visit the subject will be contacted by telephone to follow up on any
SAEs occurring after the follow up visit (19th)). Electronic diary,
questionnaires, urine- and bloodsamples, physical examinations and ECGs. The
subjects will get extensively check ups, a lot of information and a
compensation for costs for time, eventual discomforts and traveling.