14 CLINICAL STUDIES

14.1 Controlled Clinical Studies

BELSOMRA was evaluated in three clinical trials in patients with insomnia characterized by difficulties with sleep onset and sleep maintenance.

Two similarly designed, 3-month, randomized, double-blind, placebo-controlled, parallel-group studies were conducted (Study 1 and Study 2). In both studies, non-elderly (age 18-64) and elderly (age ≥ 65) patients were randomized separately. For the studies together, non-elderly adults (mean age 46 years; 465 females, 275 males) were treated with BELSOMRA 20 mg (n=291) or placebo (n=449). Elderly patients (mean age 71 years, 346 females, 174 males) were treated with BELSOMRA 15 mg (n=202) or placebo (n=318).

In Study 1 and Study 2, BELSOMRA 15 mg or 20 mg was superior to placebo for sleep latency as assessed both objectively by polysomnography (Table 3) and subjectively by patient-estimated sleep latency (Table 4). BELSOMRA 15 mg or 20 mg was also superior to placebo for sleep maintenance, as assessed both objectively by polysomnography (Table 5) and subjectively by patient-estimated total sleep time (Table 6). The effects of BELSOMRA at night 1 (objective) and week 1 (subjective) were generally consistent with later time points. The efficacy of BELSOMRA was similar between women and men and, based on limited data, between Caucasians and non-Caucasians. Twenty seven percent of patients treated with BELSOMRA 15 mg or 20 mg in Study 1 and Study 2 were non-Caucasians. The majority (69%) of the non-Caucasian patients was Asian.

Table 3: Polysomnographic Assessment of Time to Sleep Onset in Studies 1 and 2
	Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
† Change from baseline and treatment differences based upon estimated means.
‡ 15 mg in elderly and 20 mg in non-elderly patients
* p<0.05; p<0.01; *p<0.001
Study 1
	Placebo (n=290)	BELSOMRA 15-20 mg‡ (n=193)
Baseline	66	69
Change from Baseline
Month 1	- 23	- 34	- 10***
Month 3	- 27	- 35	- 8**
Study 2
	Placebo (n=286)	BELSOMRA 15-20 mg‡ (n=145)
Baseline	69	65
Change from Baseline
Month 1	- 25	- 33	- 8*
Month 3	- 29	- 29	0

Table 4: Patient-Estimated Time to Sleep Onset in Studies 1 and 2
	Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
† Change from baseline and treatment differences based upon estimated means.
‡ 15 mg in elderly and 20 mg in non-elderly patients
* p<0.05; p<0.01; *p<0.001
Study 1
	Placebo (n=382)	BELSOMRA 15-20 mg‡ (n=251)
Baseline	67	64
Change from Baseline
Month 1	- 12	- 17	- 5
Month 3	- 17	- 23	- 5*
Study 2
	Placebo (n=369)	BELSOMRA 15-20 mg‡ (n=231)
Baseline	83	86
Change from Baseline
Month 1	- 14	- 21	- 7*
Month 3	- 21	- 28	- 8*

Table 5: Polysomnographic Assessment of Sleep Maintenance (Wake After Sleep Onset) in Studies 1 and 2
	Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
† Change from baseline and treatment differences based upon estimated means.
‡ 15 mg in elderly and 20 mg in non-elderly patients
* p<0.05; p<0.01; *p<0.001
Study 1
	Placebo (n=290)	BELSOMRA 15-20 mg‡ (n=193)
Baseline	115	120
Change from Baseline
Month 1	- 19	- 45	- 26***
Month 3	- 25	- 42	- 17***
Study 2
	Placebo (n=286)	BELSOMRA 15-20 mg‡ (n=145)
Baseline	118	119
Change from Baseline
Month 1	- 23	- 47	- 24***
Month 3	- 25	- 56	- 31***

Table 6: Patient-Estimated Total Sleep Time in Studies 1 and 2
	Mean Baseline and Change from Baseline† After 1 and 3 Months (minutes)		Difference† Between BELSOMRA and Placebo (minutes)
† Change from baseline and treatment differences based upon estimated means.
‡ 15 mg in elderly and 20 mg in non-elderly patients
* p<0.05; p<0.01; *p<0.001
Study 1
	Placebo (n=382)	BELSOMRA 15-20 mg‡ (n=251)
Baseline	315	322
Change from Baseline
Month 1	23	39	16***
Month 3	41	51	11*
Study 2
	Placebo (n=369)	BELSOMRA 15-20 mg‡ (n=231)
Baseline	307	299
Change from Baseline
Month 1	22	43	21***
Month 3	38	60	22***

In the 1-month crossover study (Study 3), non-elderly adults (age 18-64 years, mean age 44 years) were treated with placebo (n=249) and BELSOMRA at a dose of 10 mg (n=62), 20 mg (n=61), or up to 80 mg. BELSOMRA 10 mg and 20 mg were superior to placebo for sleep latency and sleep maintenance, as assessed objectively by polysomnography.

BELSOMRA was also evaluated at doses of 30 mg and 40 mg in the 3-month placebo-controlled trials (Study 1 and Study 2). The higher doses were found to have similar efficacy to lower doses, but significantly more adverse reactions were reported at the higher doses.

Insomnia Study in Patients with Mild to Moderate Alzheimer's Disease

A randomized, double-blind, placebo-controlled, parallel-group, multi-site 4-week trial of BELSOMRA was conducted in patients with mild to moderate Alzheimer's disease (n=285) for the treatment of insomnia. Male and female subjects aged 50-90 years (inclusive) were treated with BELSOMRA (n=142) or placebo (n=143). Patients treated with BELSOMRA received 10 mg for approximately 14 days, of whom 77% were increased to 20 mg for approximately 14 additional days.

In this study, patients treated with BELSOMRA exhibited a statistically significant improvement for both Total Sleep Time (TST) and Wake After Sleep Onset (WASO) measures, compared to those treated with placebo, as assessed by polysomnography at Week 4.

14.2 Special Safety Studies

Effects on Driving

Two randomized, double-blind, placebo- and active-controlled, four-period crossover studies evaluated the effects of nighttime administration of BELSOMRA on next-morning driving performance 9 hours after dosing in 24 healthy elderly subjects (≥65 years old, mean age 69 years; 14 men, 10 women) who received 15 mg and 30 mg BELSOMRA, and 28 non-elderly subjects (mean age 46 years; 13 men, 15 women) who received 20 mg and 40 mg BELSOMRA. Testing was conducted after one night and after 8 consecutive nights of treatment with BELSOMRA at these doses.

The primary outcome measure was change in Standard Deviation of Lane Position (SDLP), a measure of driving performance, assessed using a symmetry analysis. The analysis showed clinically meaningful impaired driving performance in some subjects. After one night of dosing, this effect was observed in non-elderly subjects after either a 20 mg or 40 mg dose of BELSOMRA. A statistically significant effect was not observed in elderly subjects after a 15 mg or 30 mg dose of BELSOMRA. Across these two studies, five subjects (4 non-elderly women on BELSOMRA; 1 elderly woman on placebo) prematurely stopped their driving tests due to somnolence. Patients using the 20 mg dose of BELSOMRA should be cautioned against next-day driving and other activities requiring full mental alertness. Patients taking lower doses of BELSOMRA should also be cautioned about the potential for driving impairment because there is individual variation in sensitivity to BELSOMRA [see Warnings and Precautions (5.1)].

Effects on Next-Day Memory and Balance in Elderly and Non-Elderly

Four placebo-controlled trials evaluated the effects of nighttime administration of BELSOMRA on next-day memory and balance using word learning tests and body sway tests, respectively. Three trials showed no significant effects on memory or balance compared to placebo. In a fourth trial in healthy non-elderly subjects, there was a significant decrease in word recall after the words were presented to subjects in the morning following a single dose of 40 mg BELSOMRA, and there was a significant increase on body sway area in the morning following a single dose of 20 mg or 40 mg BELSOMRA.

Middle of the Night Safety in Elderly Subjects

A double-blind, randomized, placebo-controlled trial evaluated the effect of a single dose of BELSOMRA on balance, memory and psychomotor performance in healthy elderly subjects (n=12) after being awakened during the night. Nighttime dosing of BELSOMRA 30 mg resulted in impairment of balance (measured by body sway area) at 90 minutes as compared to placebo. Memory was not impaired, as assessed by an immediate and delayed word recall test at 4 hours post-dose.

Rebound Effects

In 3-month controlled safety and efficacy trials (Study 1, Study 2), rebound insomnia was assessed following discontinuation of BELSOMRA relative to placebo and baseline in non-elderly adult patients receiving BELSOMRA 40 mg or 20 mg and in elderly patients receiving BELSOMRA 30 mg or 15 mg. No clear effects were observed on measures of sleep onset or maintenance.

Withdrawal Effects

In 3-month controlled safety and efficacy trials (Study 1, Study 2), withdrawal effects were assessed following discontinuation in non-elderly adult patients who received BELSOMRA 40 mg or 20 mg and elderly patients who received BELSOMRA 30 mg or 15 mg. The analysis showed no clear evidence of withdrawal in the overall study population based on assessment of patient responses to the Tyrer Withdrawal Symptom Questionnaire or assessment of withdrawal-related adverse events following the discontinuation of BELSOMRA.

Respiratory Safety

Use in Healthy Subjects with Normal Respiratory Function

A randomized, placebo-controlled, double-blind, crossover trial in healthy non-elderly subjects (n=12) evaluated the respiratory depressant effect of BELSOMRA (40 mg and 150 mg) after one night of treatment. At the doses studied, BELSOMRA had no respiratory depressant effect as measured by oxygen saturation [see Warnings and Precautions (5.5) and Use in Specific Populations (8.6)].