14 CLINICAL STUDIES

14.1 Controlled Clinical Studies

The efficacy of QUVIVIQ was evaluated in two multicenter, randomized, double-blind, placebo-controlled, parallel-group studies, Study 1 (NCT03545191) and Study 2 (NCT03575104).

A total of 1854 patients with Diagnostic and Statistical Manual of Mental Disorders, 5th edition (DSM-5®) insomnia were randomized to receive QUVIVIQ or placebo once daily, in the evening, for 3 months. Study 1 randomized 930 subjects to QUVIVIQ 50 mg (N = 310), 25 mg (N = 310) or placebo (N = 310). Study 2 randomized 924 subjects to QUVIVIQ 25 mg (N = 309), 10 mg (N = 307), or placebo (N = 308). The 10 mg dose is not an approved dose.

At the end of the 3-month treatment period, both studies included a 7-day placebo run-out period, after which patients could enter a 9-month, double-blind, placebo-controlled extension study (Study 3, NCT03679884).

In Study 1, patients had a mean age of 55.4 years (range 18 to 88 years), with 39.1% of subjects ≥ 65 years of age, including 5.8% ≥ 75 years of age. Patients were identified as female or male and by US census-based racial and ethnic categories. The percentages of patients in the respective categories were: female sex (67.1%), White (90%), Black or African American (8%), Asian (1.0%), or Other race (< 1%).

In Study 2, patients had a mean age of 56.7 years (range 19 to 85 years), with 39.3% of subjects ≥ 65 years of age, including 6.1% ≥ 75 years of age. Patients were identified as female or male and by US census-based racial and ethnic categories. The percentages of patients in the respective categories were: female sex (69.0%), White (88%), Black or African American (8%), Asian (4%), or Other race (< 1%).

Primary efficacy endpoints for both studies were the change from baseline to Month 1 and Month 3 in Latency to Persistent Sleep (LPS) and Wake After Sleep Onset (WASO), measured objectively by polysomnography in a sleep laboratory. LPS is a measure of sleep induction and WASO is a measure of sleep maintenance.

Secondary endpoint included in the statistical testing hierarchy with Type 1 error control was patient-reported Total Sleep Time (sTST), evaluated every morning at home using a validated Sleep Diary Questionnaire (SDQ).

In Study 1, doses of 25 and 50 mg QUVIVIQ showed a statistically significant improvement vs placebo on polysomnography (LPS, WASO) and self-reported total sleep (sTST), at Month 1 and Month 3 (Table 4).

In Study 2, QUVIVIQ 25 mg showed a statistically significant improvement vs placebo on WASO and sTST at Month 1 and Month 3 (Table 5). QUVIVIQ 10 mg did not show a statistically significant improvement on LPS, WASO, or sTST at Month 1 or Month 3.

The efficacy of QUVIVIQ was similar across subgroups based on age, sex, race, and region.

Table 4 Primary and Secondary Efficacy Results for Change from Baseline in Sleep Onset, Sleep Maintenance, and Subjective Total Sleep Time at Month 1 and Month 3 in Patients with Insomnia (Study 1)
Treatment group/dose (N)	Baseline	Month 1			Month 3
Treatment group/dose (N)			Change from baseline	Difference to placebo		Change from baseline	Difference to placebo
	mean (SD)	mean (SD)	LSM (95%CL)	LSM (95%CL)	mean (SD)	LSM (95%CL)	LSM (95%CL)
CL = confidence limit; LPS = latency to persistent sleep; LSM = least squares mean; PSG = polysomnography; SD = standard deviation; sTST = subjective total sleep time; WASO = wake after sleep onset.
* doses that were statistically significantly superior (p < 0.05) to placebo after controlling for multiple comparisons.
WASO (wake after sleep onset, min): sleep maintenance, assessed by PSG
50 mg (310)	95 (38)	65 (35)	-29 [-33, -25]	-23* [-28, -18]	65 (39)	-29 [-33, -25]	-18* [-24, -13]
25 mg (310)	98 (39)	77 (42)	-18 [-22, -15]	-12* [-17, -7]	73 (40)	-23 [-27, -19]	-12* [-17, -6]
placebo (310)	103 (41)	92 (42)	-6 [-10, -2]		87 (43)	-11 [-15, -7]
LPS (latency to persistent sleep, min): sleep onset, assessed by PSG
50 mg (310)	64 (37)	34 (27)	-31 [-35, -28]	-11* [-16, -7]	30 (23)	-35 [-38, -31]	-12* [-16, -7]
25 mg (310)	67 (39)	38 (32)	-28 [-32, -25]	-8* [-13, -4]	36 (34)	-31 [-34, -27]	-8* [-12, -3]
placebo (310)	67 (40)	46 (36)	-20 [-23, -17]		43 (34)	-23 [-26, -20]
sTST (subjective total sleep time, min): patient-reported
50 mg (310)	313 (58)	358 (74)	44 [38, 49]	22* [14, 30]	372 (79)	58 [51, 64]	20* [11, 29]
25 mg (310)	310 (60)	345 (66)	34 [29, 40]	13* [5, 20]	358 (72)	48 [41, 54]	10* [1, 19]
placebo (310)	316 (53)	338 (65)	22 [16, 27]		354 (73)	38 [31, 44]

Table 5 Primary and Secondary Efficacy Results for Change from Baseline in Sleep Onset, Sleep Maintenance, and Subjective Total Sleep Time at Month 1 and Month 3 in Patients with Insomnia (Study 2)
Treatment group/dose (N)	Baseline	Month 1			Month 3
Treatment group/dose (N)			Change from baseline	Difference to placebo		Change from baseline	Difference to placebo
	mean (SD)	mean (SD)	LSM (95%CL)	LSM (95%CL)	mean (SD)	LSM (95%CL)	LSM (95%CL)
CL = confidence limit; LPS = latency to persistent sleep; LSM = least squares mean; PSG = polysomnography; SD = standard deviation; sTST = subjective total sleep time; WASO = wake after sleep onset.
* doses that were statistically significantly superior (p < 0.05) to placebo after controlling for multiple comparisons.
WASO (wake after sleep onset, min): sleep maintenance, assessed by PSG
25 mg (309)	106 (49)	80 (44)	-24 [-28, -20]	-12* [-18, -6]	80 (49)	-24 [-29, -19]	-10* [-17, -4]
placebo (308)	108 (49)	93 (50)	-13 [-17, -8]		91 (47)	-14 [-19, -9]
LPS (latency to persistent sleep, min): sleep onset, assessed by PSG
25 mg (309)	69 (41)	42 (39)	-26 [-31, -22]	-6 [-12, -1]	39 (37)	-29 [-33, -24]	-9 [-15, -3]
placebo (308)	72 (46)	50 (40)	-20 [-24, -16]		49 (46)	-20 [-24, -15]
sTST (subjective total sleep time, min): patient-reported
25 mg (309)	308 (53)	353 (67)	44 [38, 49]	16* [8, 24]	365 (70)	56 [50, 63]	19* [10, 28]
placebo (308)	308 (52)	336 (63)	28 [22, 33]		347 (65)	37 [31, 43]

The effects of QUVIVIQ on LPS, WASO, and sTST were observed at Month 1 and were maintained through Month 3. The change from baseline of sTST by week in Study 1 is presented in Figure 4.

Figure 4 Change from Baseline of sTST by Week (Study 1)

14.2 Special Safety Studies

Effects on Driving

A randomized, double-blind, placebo- and active-controlled, four-period crossover study evaluated the effects of nighttime administration of QUVIVIQ on next-morning driving performance, using a driving simulator, 9 hours after dosing in 30 healthy elderly subjects (65–79 years, median age 70 years; 15 men, 15 women) and 30 healthy adult subjects (50–64 years, median age 58 years; 15 men, 15 women). The primary driving performance outcome measure was change in Standard Deviation of Lateral Position (SDLP). Testing was conducted after one night (initial dosing) and after four consecutive nights of treatment with QUVIVIQ 50 mg and 100 mg (two times the maximum recommended daily dose). Zopiclone 7.5 mg was used as an active comparator. For both doses, QUVIVIQ caused a statistically significant impairment in next-morning driving performance in adult or elderly subjects (compared with placebo) after the first dose. Although the mean effect on driving performance was not statistically significant (compared to placebo) after 4 consecutive nights of treatment with either dose of QUVIVIQ, driving ability was impaired in some subjects taking QUVIVIQ.

Patients should be cautioned about the potential for next-morning driving impairment because there is individual variation in sensitivity to QUVIVIQ.

Withdrawal of Therapy

Withdrawal Symptoms

In controlled efficacy and safety studies, withdrawal effects were assessed by the Tyrer Benzodiazepine Withdrawal Symptom Questionnaire following discontinuation of QUVIVIQ, and by adverse event reporting during a single-blind placebo run-out period. No evidence of withdrawal symptoms was observed upon treatment discontinuation.

Loss of Treatment Effect After Discontinuation

The loss of effect from stopping treatment with QUVIVIQ was assessed during the placebo run-out period after 3 months of treatment with QUVIVIQ in Study 1 and Study 2.

After treatment discontinuation, in Study 1, patients previously treated with QUVIVIQ 50 mg experienced mean increases of 25 minutes in WASO, 16 minutes in LPS during the next night of sleep, and a mean decrease in sTST of 14 minutes per night over the next week, as compared to the last assessment on treatment. Following QUVIVIQ 25 mg discontinuation, a similar pattern was observed with mean increases in WASO of 19 minutes, 15 minutes in LPS, and a mean decrease in sTST of 7 minutes. Similar changes were observed with the 25 mg dose in Study 2. In both studies, patients who were on placebo and continued on placebo in the run-out period experienced minimal changes in WASO, LPS, or sTST.

Middle of the Night Safety

The effect of QUVIVIQ on middle of the night safety was evaluated in a randomized, placebo-controlled three-period crossover study in 18 healthy adult (< 65 years) and 18 healthy elderly (≥ 65 years) subjects. The ability to awaken in response to a sound stimulus, postural stability, and memory were assessed following a scheduled awakening 4 hours after administration of 25 or 50 mg QUVIVIQ, or placebo.

The ability to awaken to sound in the middle of the night was assessed using an audiometer that delivered 1000 Hz tones starting at 35 dB and increasing to 100 dB to determine the Auditory Awakening Threshold (AAT). There was no significant difference between QUVIVIQ (25 mg or 50 mg) and placebo in AAT.

Postural stability was measured by assessing body sway using a body sway meter approximately 5 minutes after awakening. Evening dosing of QUVIVIQ 25 mg and 50 mg resulted in respective increases in mean (95% confidence limit) cumulative body sway over 2 minutes of 37 mm [2 mm, 71 mm] and 66 mm [31 mm, 100 mm] at 4 hours post-dose compared to placebo.

A visual verbal learning test (VVLT) of immediate and delayed recall was administered to assess memory after middle of the night awakening (4 hours post-dose) in subjects receiving QUVIVIQ 25 mg or 50 mg. QUVIVIQ was associated with worse performance on the VVLT compared to placebo.