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Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Active Comparator, Parallel-Group Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older with Insomnia Disorder

Summary
EudraCT number	2015-004347-39
Trial protocol	GB DE ES IT
Global end of trial date	30 Jan 2018

Results information
Results version number	v1(current)
This version publication date	15 Feb 2019
First version publication date	15 Feb 2019
Other versions

Trial Information
Subject Disposition
Baseline Characteristics
End Points
Adverse Events
More Information

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Trial information

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Sponsor protocol code

E2006-G000-304

ISRCTN number

US NCT number

NCT02783729

WHO universal trial number (UTN)

Sponsor organisation name

Eisai Inc.

Sponsor organisation address

Woodcliff Lake, New jersey, United States, 07677

Public contact

Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com

Scientific contact

Medical Information, Eisai Ltd., +1 888-274-2378, esi_medinfo@eisai.com

Is trial part of an agreed paediatric investigation plan (PIP)

Does article 45 of REGULATION (EC) No 1901/2006 apply to this trial?

Does article 46 of REGULATION (EC) No 1901/2006 apply to this trial?

Analysis stage

Final

Date of interim/final analysis

29 Nov 2018

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

30 Jan 2018

Was the trial ended prematurely?

Main objective of the trial

To demonstrate using polysomnography (PSG) that lemborexant (lemborexant 10 milligram [mg] [LEM 10] and lemborexant 5 mg [LEM 5]) is superior to placebo (PBO) on objective sleep onset as assessed by latency to persisted sleep (LPS) after the last 2 nights of 1 month of treatment in subjects 55 years and older with insomnia disorder.

Protection of trial subjects

This study was conducted in accordance with standard operating procedures (SOPs) of the sponsor (or designee), which are designed to ensure adherence to Good Clinical Practice (GCP) guidelines as required by the following: - Principles of the World Medical Association Declaration of Helsinki (World Medical Association, 2008) - International Council on Harmonisation (ICH) E6 Guideline for GCP (CPMP/ICH/135/95) of the European Agency for the Evaluation of Medicinal Products, Committee for Proprietary Medicinal Products, International Council for Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use - Title 21 of the United States (US) Code of Federal Regulations (US 21 CFR) regarding clinical studies, including Part 50 and Part 56 concerning informed subject consent and Institutional Review Board (IRB) regulations and applicable sections of US 21 CFR Part 312 - European Good Clinical Practice Directive 2005/28/EC and Clinical Trial Directive 2001/20/EC for studies conducted within any European Union (EU) country. All suspected unexpected serious adverse reactions were reported, as required, to the Competent Authorities of all involved EU member states. - Article 14, Paragraph 3, and Article 80-2 of the Pharmaceutical Affairs Law (Law No. 145, 1960) for studies conducted in Japan, in addition to Japan’s GCP Subject Information and Informed Consent.

Background therapy

Evidence for comparator

Actual start date of recruitment

31 May 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Canada: 20

Country: Number of subjects enrolled

Germany: 68

Country: Number of subjects enrolled

Spain: 71

Country: Number of subjects enrolled

United Kingdom: 2

Country: Number of subjects enrolled

Italy: 2

Country: Number of subjects enrolled

United States: 843

Worldwide total number of subjects

1006

EEA total number of subjects

143

Number of subjects enrolled per age group

In utero

Preterm newborn - gestational age < 37 wk

Newborns (0-27 days)

Infants and toddlers (28 days-23 months)

Children (2-11 years)

Adolescents (12-17 years)

Adults (18-64 years)

553

From 65 to 84 years

449

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 67 investigative sites in the United States, Spain, Germany, Canada, United Kingdom, and Italy from 31 May 2016 to 30 January 2018.

Screening details

A total of 3537 subjects were screened, of which 1006 subjects were randomized to the treatment period. All subjects who were subsequently randomized completed a Run-in Period before randomization to treatment period.

Period 1 title

Overall study (overall period)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator, Monitor, Data analyst, Carer, Assessor

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Arm type

Placebo

Investigational medicinal product name

Zolpidem-matched Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Investigational medicinal product name

Lemborexant-matched Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Zolpidem Tartrate Extended Release 6.25 mg

Arm description

Subjects received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period.

Arm type

Active comparator

Investigational medicinal product name

Lemborexant-matched Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant-matched placebo, tablet, orally, once daily from Day 1 up to Day 30 in the Treatment period.

Investigational medicinal product name

Zolpidem Tartrate Extended Release

Investigational medicinal product code

Other name

Ambien CR

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received zolpidem tartrate extended release 6.25 mg, tablet, orally, once daily from Day 1 up to Day 30 in the Treatment period.

Lemborexant 5 mg

Arm description

Subjects received Lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Arm type

Experimental

Investigational medicinal product name

Zolpidem-matched Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received zolpidem-matched placebo, tablet, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Investigational medicinal product name

Lemborexant 5 mg

Investigational medicinal product code

E2006

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant 5 mg, tablet, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Lemborexant 10 mg

Arm description

Subjects received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Arm type

Experimental

Investigational medicinal product name

Zolpidem-matched Placebo

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received zolpidem-matched placebo, tablet, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Investigational medicinal product name

Lemborexant 10 mg

Investigational medicinal product code

E2006

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant 10 mg, tablet, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Number of subjects in period 1	Placebo	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Started	208	263	266	269
Completed	198	246	258	260
Not completed	10	17	8	9
Consent withdrawn by subject	2	3	1	2
Adverse event, non-fatal	2	6	2	3
Unspecified	1	6	2	3
Lost to follow-up	2	1	1	-
Subject choice	2	1	2	1
Lack of efficacy	1	-	-	-

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Subjects received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Reporting group title

Zolpidem Tartrate Extended Release 6.25 mg

Reporting group description

Subjects received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period.

Reporting group title

Lemborexant 5 mg

Reporting group description

Subjects received Lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Reporting group title

Lemborexant 10 mg

Reporting group description

Subjects received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Reporting group values	Placebo	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg	Total
Number of subjects	208	263	266	269	1006
Age categorical
Units: Subjects
Age continuous
Units: years
arithmetic mean (standard deviation)	63.4 ( 6.36 )	64.3 ( 7.12 )	63.7 ( 6.78 )	64.2 ( 6.88 )	-
Gender categorical
Units: Subjects
Female	184	226	229	230	869
Male	24	37	37	39	137
Ethnicity
Units: Subjects
Hispanic or Latino	35	32	51	47	165
Not Hispanic or Latino	173	231	215	222	841
Race
Units: Subjects
White	153	173	199	202	727
Black or African American	51	80	63	62	256
Japanese	1	1	0	0	2
Chinese	1	0	0	1	2
Other Asian	0	4	2	4	10
American Indian or Alaska Native	0	0	0	0	0
Native Hawaiian or Other Pacific Islander	0	2	0	0	2
Other	2	3	2	0	7
LPS
The baseline values for LPS were analysed in the full analysis set (FAS) defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 208, 262, 266, and 269.
Units: minutes
arithmetic mean (standard deviation)	43.89 ( 33.596 )	44.52 ( 38.349 )	44.86 ( 36.528 )	44.61 ( 32.986 )	-
Sleep Efficiency (SE)
The baseline values for SE were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 208, 262, 266, and 269.
Units: minutes
arithmetic mean (standard deviation)	68.89 ( 9.639 )	68.13 ( 11.419 )	68.36 ( 11.268 )	67.85 ( 10.849 )	-
Wake After Sleep Onset (WASO)
The baseline values for WASO were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 208, 262, 266, and 269.
Units: minutes
arithmetic mean (standard deviation)	111.75 ( 37.179 )	114.31 ( 39.992 )	113.44 ( 38.953 )	114.83 ( 39.997 )	-
Wake After Sleep Onset in Second Half of Night (WASO2H)
The baseline values for WASO2H were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 208, 262, 266, and 269.
Units: minutes
arithmetic mean (standard deviation)	74.44 ( 30.109 )	78.04 ( 33.849 )	76.60 ( 32.903 )	76.88 ( 32.126 )	-
Body Sway
The baseline values for body sway were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 199, 239, 245, and 243.
Units: one-third degree of angle of arc
arithmetic mean (standard deviation)	23.08 ( 17.506 )	26.96 ( 26.502 )	26.40 ( 20.781 )	36.29 ( 197.282 )	-
Total Sleep Time (TST)
The baseline values for TST were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 208, 262, 266, and 269.
Units: minutes
arithmetic mean (standard deviation)	330.67 ( 46.268 )	326.99 ( 54.852 )	328.00 ( 54.224 )	325.07 ( 52.819 )	-
Subjective Sleep Onset Latency (sSOL)
The baseline values for sSol were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 206, 258, 263, and 269.
Units: minutes
arithmetic mean (standard deviation)	55.90 ( 37.389 )	60.54 ( 36.350 )	65.79 ( 43.530 )	60.88 ( 42.514 )	-
Subjective Wake After Sleep Onset (sWASO)
The baseline values for sWASO were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 206, 259, 264, and 266.
Units: minutes
arithmetic mean (standard deviation)	170.89 ( 80.676 )	173.06 ( 77.212 )	166.76 ( 82.047 )	175.35 ( 83.453 )	-
Subjective Sleep Efficiency (sSE)
The baseline values for sSE were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 201, 247, 253, and 258.
Units: minutes
arithmetic mean (standard deviation)	56.08 ( 17.343 )	55.49 ( 15.802 )	56.05 ( 17.094 )	54.31 ( 18.318 )	-
Subjective Total Sleep Time (sTST)
The baseline values for sTST were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 201, 247, 253, and 258.
Units: minutes
arithmetic mean (standard deviation)	276.23 ( 87.649 )	273.07 ( 81.207 )	275.74 ( 83.650 )	266.10 ( 92.164 )	-
Insomnia Severity Index (ISI)
The baseline values for ISI were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 208, 263, 266, and 269.
Units: score in scale
arithmetic mean (standard deviation)	11.21 ( 2.436 )	11.06 ( 2.508 )	10.91 ( 2.419 )	10.84 ( 2.334 )	-
Fatigue Severity Scale (FSS)
The baseline values for FSS were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 208, 263, 266, and 269.
Units: score on scale
arithmetic mean (standard deviation)	37.48 ( 13.602 )	37.15 ( 13.788 )	37.47 ( 13.518 )	37.42 ( 13.111 )	-
Power of Attention (POA)
The baseline values for POA were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 195, 239, 249, and 246.
Units: millisecond
arithmetic mean (standard deviation)	1421.0 ( 210.27 )	1418.7 ( 195.95 )	1452.9 ( 263.04 )	1399.2 ( 192.47 )	-
Speed of Memory Retrieval (SOMT)
The baseline values for SOMT were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 195, 238, 246, and 246.
Units: milliseconds
arithmetic mean (standard deviation)	4507.7 ( 1098.73 )	4513.8 ( 1097.65 )	4674.3 ( 1174.74 )	4619.8 ( 1065.00 )	-
Quality of Memory (QOM)
The baseline values for QOM were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 195, 239, 248, and 246.
Units: units on scale
arithmetic mean (standard deviation)	342.2 ( 66.03 )	350.0 ( 65.30 )	345.7 ( 67.60 )	340.7 ( 72.75 )	-
Continuity of Attention (COA)
The baseline values for COA were analysed in the FAS defined as the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The baseline characteristic was assessed for the following “n” population: 195, 239, 249, and 246.
Units: units on scale
arithmetic mean (standard deviation)	90.7 ( 4.77 )	90.6 ( 6.0 )	91.0 ( 5.15 )	91.3 ( 4.15 )	-

End points

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Reporting group title

Placebo

Reporting group description

Subjects received lemborexant-matched placebo and zolpidem matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Reporting group title

Zolpidem Tartrate Extended Release 6.25 mg

Reporting group description

Subjects received zolpidem tartrate extended release (ZOL ER) 6.25 mg and lemborexant-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment period.

Reporting group title

Lemborexant 5 mg

Reporting group description

Subjects received Lemborexant 5 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Reporting group title

Lemborexant 10 mg

Reporting group description

Subjects received lemborexant 10 mg and zolpidem-matched placebo, tablets, orally, once daily from Day 1 up to Day 30 in the Treatment Period.

Primary: Change From Baseline in Mean LPS of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

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End point title

Change From Baseline in Mean LPS of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 ^[1]

End point description

LPS is defined as the time in minutes from lights off to the first epoch of 20 consecutive epochs of non-wakefulness as measured by PSG. Change from baseline to average LPS on Day 29 and 30 was reported. FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.

End point type

Primary

End point timeframe

Baseline, Days 29/30

Notes
[1] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Placebo, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	200	260	260
Units: minutes
arithmetic mean (standard deviation)	-7.93 ( 31.946 )	-19.53 ( 33.054 )	-21.46 ( 32.436 )

Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003 ^[2]

Method

MMRM

Parameter type

Least Squares Geometric Mean(LSGM) Ratio

Point estimate

0.773

Confidence interval

level

95%

sides

2-sided

lower limit

0.672

upper limit

0.889

Notes
[2] - Based on mixed effect model repeated measurement (MMRM) model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[3]

Method

MMRM

Parameter type

LSGM Ratio

Point estimate

0.723

Confidence interval

level

95%

sides

2-sided

lower limit

0.628

upper limit

0.832

Notes
[3] - Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

Secondary: Change From Baseline in Mean SE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

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End point title

Change From Baseline in Mean SE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 ^[4]

End point description

SE is defined as percentage of time spent asleep per time in bed (TIB), calculated as total sleep time (TST) divided by interval from lights off until lights on as measured by PSG. Change from baseline to average SE on Day 29 and 30 was reported. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.

End point type

Secondary

End point timeframe

Baseline, Days 29/30

Notes
[4] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Placebo, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	200	260	260
Units: minutes
arithmetic mean (standard deviation)	5.35 ( 9.897 )	12.93 ( 9.741 )	14.09 ( 10.514 )

Placebo, Lemborexant 5 mg

Comparison groups

Lemborexant 5 mg v Placebo

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[5]

Method

MMRM

Parameter type

Least Squares Mean (LSM) Difference

Point estimate

7.07

Confidence interval

level

95%

sides

2-sided

lower limit

5.61

upper limit

8.54

Variability estimate

Standard error of the mean

Dispersion value

0.746

Notes
[5] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline SE as a covariate.

Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[6]

Method

MMRM

Parameter type

LSM Difference

Point estimate

8.03

Confidence interval

level

95%

sides

2-sided

lower limit

6.57

upper limit

9.49

Variability estimate

Standard error of the mean

Dispersion value

0.746

Notes
[6] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline SE as a covariate.

Secondary: Change From Baseline in Mean WASO of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

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End point title

Change From Baseline in Mean WASO of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 ^[7]

End point description

WASO is defined as minutes of wake from the onset of persistent sleep until lights on as measured by PSG. Change from baseline to average WASO on Days 29 and 30 was reported. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.

End point type

Secondary

End point timeframe

Baseline, Days 29/30

Notes
[7] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Placebo, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	200	260	260
Units: minutes
arithmetic mean (standard deviation)	-18.58 ( 41.931 )	-43.89 ( 39.264 )	-46.43 ( 39.595 )

Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[8]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-23.96

Confidence interval

level

95%

sides

2-sided

lower limit

-29.98

upper limit

-17.95

Variability estimate

Standard error of the mean

Dispersion value

3.068

Notes
[8] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO as a covariate.

Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[9]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-25.35

Confidence interval

level

95%

sides

2-sided

lower limit

-31.36

upper limit

-19.34

Variability estimate

Standard error of the mean

Dispersion value

3.067

Notes
[9] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO as a covariate.

Secondary: Change From Baseline in WASO in the Second Half of the Night WASO2H of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 29/30

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End point title

Change From Baseline in WASO in the Second Half of the Night WASO2H of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 29/30 ^[10]

End point description

WASO2H is defined as time in minutes of wake during the interval from 240 minutes after lights off until lights on as measured by PSG. Change from baseline to average WASO2H on Days 29 and 30 was reported. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.

End point type

Secondary

End point timeframe

Baseline, Days 29/30

Notes
[10] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Zolpidem ER 6.25 mg, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	250	260	260
Units: minutes
arithmetic mean (standard deviation)	-21.42 ( 36.257 )	-27.19 ( 33.047 )	-28.84 ( 33.138 )

Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

510

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0038 ^[11]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-6.65

Confidence interval

level

95%

sides

2-sided

lower limit

-11.15

upper limit

-2.15

Variability estimate

Standard error of the mean

Dispersion value

2.298

Notes
[11] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.

Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

510

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0005 ^[12]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-8

Confidence interval

level

95%

sides

2-sided

lower limit

-12.53

upper limit

-3.47

Variability estimate

Standard error of the mean

Dispersion value

2.309

Notes
[12] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.

Other pre-specified: Change from Baseline in Mean Body Sway upon Awakening in the Morning for Lemborexant 5 mg and Lemborexant 10 mg Compared to Zolpidem ER on Days 2/3

Top of page

End point title

Change from Baseline in Mean Body Sway upon Awakening in the Morning for Lemborexant 5 mg and Lemborexant 10 mg Compared to Zolpidem ER on Days 2/3 ^[13]

End point description

Body sway is detected through a cable around the subject's waist by the ataxia meter. Body sway is measured in units of 1/3° of the angle of arc. For ease in reporting, these are called arbitrary units, with a higher number indicating more body sway (less postural stability). Change from baseline in mean body sway on Days 2 and 3 was reported. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.

End point type

Other pre-specified

End point timeframe

Baseline, Days 2/3

Notes
[13] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Zolpidem ER 6.25 mg, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	234	237	234
Units: one-third degree of angle of arc
arithmetic mean (standard deviation)	8.47 ( 69.894 )	-0.82 ( 20.383 )	-8.97 ( 146.679 )

Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

471

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0171 ^[14]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-9.63

Confidence interval

level

95%

sides

2-sided

lower limit

-17.53

upper limit

-1.72

Variability estimate

Standard error of the mean

Dispersion value

4.029

Notes
[14] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline posture stability of body sway as a covariate.

Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

468

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.008 ^[15]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-10.74

Confidence interval

level

95%

sides

2-sided

lower limit

-18.67

upper limit

-2.81

Variability estimate

Standard error of the mean

Dispersion value

4.04

Notes
[15] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline posture stability of body sway as a covariate.

Other pre-specified: Change from Baseline in Mean LPS, WASO, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 1/2 and Days 29/30

Top of page

End point title

Change from Baseline in Mean LPS, WASO, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 1/2 and Days 29/30 ^[16]

End point description

LPS is defined as the time in minutes from lights off to the first epoch of 20 consecutive epochs of non-wakefulness as measured by the PSG. WASO is defined as minutes of wake from the onset of persistent sleep until lights on as measured by PSG. TST is defined as the amount of sleep in minutes from LPS until terminal awakening as measured by PSG. Change from baseline to average LPS, WASO, and TST on Days 1 and 2, and Days 29 and 30 were reported. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. Here “n” were subjects who were evaluable for the outcome measure at given time points.

End point type

Other pre-specified

End point timeframe

Baseline, Days 1/2, and Days 29/30

Notes
[16] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Zolpidem ER 6.25 mg, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	263	266	269
Units: minutes
arithmetic mean (standard deviation)
LPS: Days 1/2 (n=262, 266, 269)	-12.56 ( 32.506 )	-16.59 ( 28.742 )	-19.48 ( 31.809 )
LPS: Days 29/30 (n=250, 260, 260)	-7.51 ( 35.065 )	-19.53 ( 33.047 )	-21.46 ( 32.436 )
WASO: Days 1/2 (n =262, 266, 269)	-44.36 ( 38.074 )	-49.96 ( 39.578 )	-59.59 ( 37.749 )
WASO: Days 29/30 (n=250, 260, 260)	-36.50 ( 43.406 )	-43.89 ( 39.264 )	-46.43 ( 39.595 )
TST: Days 1/2 (n=262, 266, 269)	55.31 ( 48.138 )	65.22 ( 46.695 )	79.58 ( 47.350 )
TST: Days 29/30 (n=250, 260, 260)	43.34 ( 54.012 )	61.99 ( 46.817 )	67.86 ( 52.117 )

LPS, Days 1/2: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0218 ^[17]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.874

Confidence interval

level

95%

sides

2-sided

lower limit

0.78

upper limit

0.981

Notes
[17] - Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

LPS, Days 1/2: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006 ^[18]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.818

Confidence interval

level

95%

sides

2-sided

lower limit

0.729

upper limit

0.917

Notes
[18] - Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

LPS, Days 29/30: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[19]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.634

Confidence interval

level

95%

sides

2-sided

lower limit

0.556

upper limit

0.724

Notes
[19] - Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

LPS, Days 29/30: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[20]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.594

Confidence interval

level

95%

sides

2-sided

lower limit

0.521

upper limit

0.677

Notes
[20] - Based on MMRM model with log transformation of LPS and factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

WASO, Days 1/2: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0154 ^[21]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-6.16

Confidence interval

level

95%

sides

2-sided

lower limit

-11.15

upper limit

-1.17

Variability estimate

Standard error of the mean

Dispersion value

2.544

Notes
[21] - Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline WASO as a covariate.

WASO, Days 1/2: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[22]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-15.03

Confidence interval

level

95%

sides

2-sided

lower limit

-20.01

upper limit

-10.05

Variability estimate

Standard error of the mean

Dispersion value

2.542

Notes
[22] - Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline WASO as a covariate.

WASO, Days 29/30: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0073 ^[23]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-7.72

Confidence interval

level

95%

sides

2-sided

lower limit

-13.36

upper limit

-2.08

Variability estimate

Standard error of the mean

Dispersion value

2.876

Notes
[23] - Based on MMRM model with factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline WASO as a covariate.

WASO, Days 29/30: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016 ^[24]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-9.1

Confidence interval

level

95%

sides

2-sided

lower limit

-14.75

upper limit

-3.45

Variability estimate

Standard error of the mean

Dispersion value

2.883

Notes
[24] - Based on MMRM model with factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline WASO as a covariate.

TST, Days 1/2: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.001 ^[25]

Method

MMRM

Parameter type

LSM Difference

Point estimate

10.25

Confidence interval

level

95%

sides

2-sided

lower limit

4.18

upper limit

16.32

Variability estimate

Standard error of the mean

Dispersion value

3.094

Notes
[25] - Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.

TST, Days 1/2: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[26]

Method

MMRM

Parameter type

LSM Difference

Point estimate

23.1

Confidence interval

level

95%

sides

2-sided

lower limit

17.04

upper limit

29.15

Variability estimate

Standard error of the mean

Dispersion value

3.085

Notes
[26] - Based on MMRM model with factors for age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.

TST, Days 29/30: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[27]

Method

MMRM

Parameter type

LSM Difference

Point estimate

19.41

Confidence interval

level

95%

sides

2-sided

lower limit

12.63

upper limit

26.2

Variability estimate

Standard error of the mean

Dispersion value

3.457

Notes
[27] - Based on MMRM model with factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.

TST, Days 29/30: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[28]

Method

MMRM

Parameter type

LSM Difference

Point estimate

24.1

Confidence interval

level

95%

sides

2-sided

lower limit

17.32

upper limit

30.88

Variability estimate

Standard error of the mean

Dispersion value

3.456

Notes
[28] - Based on MMRM model with factors for age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effects, and the baseline TST as a covariate.

Other pre-specified: Change From Baseline in sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER

Top of page

End point title

Change From Baseline in sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER ^[29]

End point description

sSOL: estimated minutes from time attempted to sleep to sleep onset. sWASO: estimated minutes of wake at night after initial sleep onset to time stopped trying to sleep for the night. sSE: percentage of sTST per subjective time spent in bed (time attempted to sleep to time stopped trying to sleep for the night, and time spent asleep derived from subjective time spent in bed minus sWASO). sTST: minutes of sleep from sleep onset to time stopped trying to sleep for the night. sSOL, sSE, sWASO, sTST were analyzed with diary handling rules (DHR) on an electronic sleep diary. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals. FAS: group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. “n”: subjects who were evaluable for outcome measure at given time points.

End point type

Other pre-specified

End point timeframe

First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)

Notes
[29] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Zolpidem ER 6.25 mg, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	263	266	269
Units: minutes
arithmetic mean (standard deviation)
sSOL: 1st 7 nights: With DHR(n=251, 259, 266)	-16.23 ( 29.531 )	-22.54 ( 32.812 )	-21.88 ( 29.269 )
sSOL: last 7 nights: With DHR(n=246, 252, 258)	-17.04 ( 30.683 )	-25.20 ( 34.854 )	-24.79 ( 34.068 )
sWASO: 1st 7 nights: With DHR(n=253, 261, 262)	-48.91 ( 51.761 )	-39.33 ( 55.022 )	-55.06 ( 66.696 )
sWASO: last 7 nights: With DHR(n=247, 253, 253)	-63.52 ( 64.161 )	-44.51 ( 58.090 )	-57.96 ( 72.791 )
sSE: 1st 7 nights: With DHR(n=240, 251, 254)	11.96 ( 12.526 )	10.56 ( 12.296 )	13.97 ( 14.188 )
sSE: last 7 nights: With DHR(n=235, 245, 244)	14.83 ( 15.011 )	12.92 ( 13.884 )	16.12 ( 16.300 )
sTST: 1st 7 nights: With DHR(n=240, 251, 254)	56.99 ( 62.880 )	50.30 ( 60.065 )	67.80 ( 71.134 )
sTST: last 7 nights: With DHR(n=235, 245, 244)	71.01 ( 76.574 )	62.41 ( 68.555 )	79.95 ( 81.211 )

sSOL,First 7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0122 ^[30]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.898

Confidence interval

level

95%

sides

2-sided

lower limit

0.825

upper limit

0.977

Notes
[30] - Based on MMRM model model with log transformation of sSOL and factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.

sSOL,First7 nights: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[31]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.83

Confidence interval

level

95%

sides

2-sided

lower limit

0.763

upper limit

0.902

Notes
[31] - Based on MMRM model model with log transformation of sSOL and factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effect, and the baseline sSOL as a covariate.

sSOL,Last 7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0176 ^[32]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.882

Confidence interval

level

95%

sides

2-sided

lower limit

0.796

upper limit

0.978

Notes
[32] - Based on MMRM model model with log transformation of sSOL and factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.

sSOL,Last 7 nights: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[33]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.811

Confidence interval

level

95%

sides

2-sided

lower limit

0.732

upper limit

0.899

Notes
[33] - Based on MMRM model model with log transformation of sSOL and with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.

sWASO,First7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0706 ^[34]

Method

MMRM

Parameter type

LSM Difference

Point estimate

8.12

Confidence interval

level

95%

sides

2-sided

lower limit

-0.68

upper limit

16.91

Variability estimate

Standard error of the mean

Dispersion value

4.484

Notes
[34] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sWASO,First7 nights: Zolpidem ER,Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1949 ^[35]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-5.81

Confidence interval

level

95%

sides

2-sided

lower limit

-14.61

upper limit

2.98

Variability estimate

Standard error of the mean

Dispersion value

4.481

Notes
[35] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sWASO,Last 7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0059 ^[36]

Method

MMRM

Parameter type

LSM Difference

Point estimate

14.45

Confidence interval

level

95%

sides

2-sided

lower limit

4.16

upper limit

24.73

Variability estimate

Standard error of the mean

Dispersion value

5.241

Notes
[36] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sWASO,Last 7 nights:Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3064 ^[37]

Method

MMRM

Parameter type

LSM Difference

Point estimate

5.36

Confidence interval

level

95%

sides

2-sided

lower limit

-4.92

upper limit

15.65

Variability estimate

Standard error of the mean

Dispersion value

5.241

Notes
[37] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sSE,First 7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1963 ^[38]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-1.37

Confidence interval

level

95%

sides

2-sided

lower limit

-3.46

upper limit

0.71

Variability estimate

Standard error of the mean

Dispersion value

1.063

Notes
[38] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.

sSE,First 7 nights: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1093 ^[39]

Method

MMRM

Parameter type

LSM Difference

Point estimate

1.7

Confidence interval

level

95%

sides

2-sided

lower limit

-0.38

upper limit

3.78

Variability estimate

Standard error of the mean

Dispersion value

1.06

Notes
[39] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.

sSE,Last 7 nights:Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2196 ^[40]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-1.53

Confidence interval

level

95%

sides

2-sided

lower limit

-3.98

upper limit

0.92

Variability estimate

Standard error of the mean

Dispersion value

1.247

Notes
[40] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.

sSE,Last 7 nights:Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4013 ^[41]

Method

MMRM

Parameter type

LSM Difference

Point estimate

1.05

Confidence interval

level

95%

sides

2-sided

lower limit

-1.4

upper limit

3.49

Variability estimate

Standard error of the mean

Dispersion value

1.246

Notes
[41] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.

sTST,First 7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2174 ^[42]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-6.57

Confidence interval

level

95%

sides

2-sided

lower limit

-17.02

upper limit

3.88

Variability estimate

Standard error of the mean

Dispersion value

5.325

Notes
[42] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baselines sTST as a covariate.

sTST,First7 nights: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0949 ^[43]

Method

MMRM

Parameter type

LSM Difference

Point estimate

8.88

Confidence interval

level

95%

sides

2-sided

lower limit

-1.55

upper limit

19.31

Variability estimate

Standard error of the mean

Dispersion value

5.313

Notes
[43] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.

sTST,Last 7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2718 ^[44]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-6.82

Confidence interval

level

95%

sides

2-sided

lower limit

-19.01

upper limit

5.36

Variability estimate

Standard error of the mean

Dispersion value

6.207

Notes
[44] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.

sTST,Last 7 nights: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2317 ^[45]

Method

MMRM

Parameter type

LSM Difference

Point estimate

7.43

Confidence interval

level

95%

sides

2-sided

lower limit

-4.75

upper limit

19.61

Variability estimate

Standard error of the mean

Dispersion value

6.206

Notes
[45] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.

Other pre-specified: Change From Baseline in Mean LPS, SE, WASO, WASO2H, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2

Top of page

End point title

Change From Baseline in Mean LPS, SE, WASO, WASO2H, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2 ^[46]

End point description

LPS: amount of time in minutes from lights off to first epoch of 20 consecutive epochs of non-wakefulness. SE: percentage of time spent asleep per time in bed (TIB), calculated as TST divided by interval from lights off until lights on. WASO: amount of time in minutes of wake from the onset of persistent sleep until lights. WASO2H: amount of time in minutes of wake during the interval from 240 minutes after lights off until lights on. TST: amount of time in minutes of sleep from sleep onset until terminal awakening. LPS, SE, WASO, WASO2H, and TST were measured by PSG. Change from baseline to average LPS, SE, WASO, WASO2H, and TST on Day 1 and 2 were reported. FAS: group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement.

End point type

Other pre-specified

End point timeframe

Baseline, Days 1/2

Notes
[46] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Placebo, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	208	266	269
Units: minutes
arithmetic mean (standard deviation)
LPS: Days 1/2	-6.45 ( 32.618 )	-16.59 ( 28.742 )	-19.48 ( 31.809 )
SE: Days 1/2	4.22 ( 9.033 )	13.60 ( 9.725 )	16.48 ( 9.623 )
WASO: Days 1/2	-15.07 ( 36.938 )	-49.96 ( 39.578 )	-59.59 ( 37.749 )
WASO2H: Days 1/2	-7.06 ( 31.097 )	-30.28 ( 32.056 )	-37.10 ( 30.815 )
TST: Days 1/2	19.44 ( 43.348 )	65.22 ( 46.695 )	79.58 ( 47.350 )

LPS: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0092 ^[47]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.85

Confidence interval

level

95%

sides

2-sided

lower limit

0.752

upper limit

0.961

Notes
[47] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

LPS: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[48]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.795

Confidence interval

level

95%

sides

2-sided

lower limit

0.704

upper limit

0.899

Notes
[48] - Based on MMRM model with factors of age group, region, treatment, visit (Days1/2), and treatment-by-visit interaction as fixed effects, and the baseline LPS as a covariate.

SE: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[49]

Method

MMRM

Parameter type

LSM Difference

Point estimate

9.01

Confidence interval

level

95%

sides

2-sided

lower limit

7.7

upper limit

10.31

Variability estimate

Standard error of the mean

Dispersion value

0.666

Notes
[49] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline SE as a covariate.

SE: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[50]

Method

MMRM

Parameter type

LSM Difference

Point estimate

11.6

Confidence interval

level

95%

sides

2-sided

lower limit

10.3

upper limit

12.9

Variability estimate

Standard error of the mean

Dispersion value

0.664

Notes
[50] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline SE as a covariate.

WASO: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[51]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-33.4

Confidence interval

level

95%

sides

2-sided

lower limit

-38.71

upper limit

-28.09

Variability estimate

Standard error of the mean

Dispersion value

2.711

Notes
[51] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline WASO as a covariate.

WASO: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[52]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-42.27

Confidence interval

level

95%

sides

2-sided

lower limit

-47.57

upper limit

-36.97

Variability estimate

Standard error of the mean

Dispersion value

2.705

Notes
[52] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline WASO as a covariate.

WASO2H: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[53]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-21.66

Confidence interval

level

95%

sides

2-sided

lower limit

-26.01

upper limit

-17.3

Variability estimate

Standard error of the mean

Dispersion value

2.221

Notes
[53] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.

WASO2H: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[54]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-28.33

Confidence interval

level

95%

sides

2-sided

lower limit

-32.68

upper limit

-23.98

Variability estimate

Standard error of the mean

Dispersion value

2.219

Notes
[54] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.

TST: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[55]

Method

MMRM

Parameter type

LSM Difference

Point estimate

44.05

Confidence interval

level

95%

sides

2-sided

lower limit

37.59

upper limit

50.51

Variability estimate

Standard error of the mean

Dispersion value

3.291

Notes
[55] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.

TST: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[56]

Method

MMRM

Parameter type

LSM Difference

Point estimate

56.9

Confidence interval

level

95%

sides

2-sided

lower limit

50.46

upper limit

63.34

Variability estimate

Standard error of the mean

Dispersion value

3.284

Notes
[56] - Based on MMRM model with factors of age group, region, treatment, visit (Days 1/2), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.

Other pre-specified: Change From Baseline in Mean WASO2H and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Top of page

End point title

Change From Baseline in Mean WASO2H and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30 ^[57]

End point description

WASO2H is defined as the time in minutes of wake during the interval from 240 minutes after lights off until lights on. TST is defined as the amount of sleep in minutes from sleep onset until terminal awakening. WASO and TST were measured by PSG. Change from baseline to average WASO and TST on Day 29 and 30 were reported. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.

End point type

Other pre-specified

End point timeframe

Baseline, Days 29/30

Notes
[57] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Placebo, Lemborexant 5 mg, and lemborexant 10 mg.

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	200	260	260
Units: minutes
arithmetic mean (standard deviation)
WASO2H: Days 29 /30	-8.92 ( 31.909 )	-27.19 ( 33.047 )	-28.84 ( 33.138 )
TST: Days 29/30	25.65 ( 47.587 )	61.99 ( 46.817 )	67.86 ( 52.117 )

WASO2H: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[58]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-16.41

Confidence interval

level

95%

sides

2-sided

lower limit

-21.23

upper limit

-11.6

Variability estimate

Standard error of the mean

Dispersion value

2.457

Notes
[58] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.

WASO2H: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[59]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-17.76

Confidence interval

level

95%

sides

2-sided

lower limit

-22.57

upper limit

-12.96

Variability estimate

Standard error of the mean

Dispersion value

2.451

Notes
[59] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline WASO2H as a covariate.

TST: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[60]

Method

MMRM

Parameter type

LSM Difference

Point estimate

34.16

Confidence interval

level

95%

sides

2-sided

lower limit

26.95

upper limit

41.36

Variability estimate

Standard error of the mean

Dispersion value

3.673

Notes
[60] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.

TST: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

460

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[61]

Method

MMRM

Parameter type

LSM Difference

Point estimate

38.85

Confidence interval

level

95%

sides

2-sided

lower limit

31.64

upper limit

46.05

Variability estimate

Standard error of the mean

Dispersion value

3.672

Notes
[61] - Based on MMRM model with factors of age group, region, treatment, visit (Days 29/30), and treatment-by-visit interaction as fixed effect, and the baseline TST as a covariate.

Other pre-specified: Change From Baseline in Mean sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo

Top of page

End point title

Change From Baseline in Mean sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo ^[62]

End point description

End point type

Other pre-specified

End point timeframe

First 7 nights (approximately Week 1) and Last 7 nights (approximately Week 4)

Notes
[62] - The end point is not reporting statistics for all the arms in the baseline period. It is expected all the baseline period arms will be reported on when providing values for an end point on the baseline period.
Justification: The endpoint was only planned to be analyse for the following reporting groups: Placebo, Lemborexant 5 mg, and Lemborexant 10 mg.

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	208	266	269
Units: minutes
arithmetic mean (standard deviation)
sSOL: 1st 7 nights :With DHR(n=202, 259, 266)	-6.83 ( 23.040 )	-22.54 ( 32.812 )	-21.88 ( 29.269 )
sSOL: last 7 nights: With DHR(n=196, 252, 258)	-8.10 ( 27.447 )	-25.20 ( 34.854 )	-24.79 ( 34.068 )
sWASO: 1st 7 nights: With DHR(n=202, 261, 262)	-27.92 ( 45.201 )	-39.33 ( 55.022 )	-55.06 ( 66.696 )
sWASO: last 7 nights: With DHR(n=196, 253, 253)	-36.01 ( 57.584 )	-44.51 ( 58.090 )	-57.96 ( 72.791 )
sSE: 1st 7 nights: With DHR(n=197, 251, 254)	6.73 ( 10.930 )	10.56 ( 12.296 )	13.97 ( 14.188 )
sSE: last 7 nights: With DHR(n=190, 245, 244)	8.35 ( 13.273 )	12.92 ( 13.884 )	16.12 ( 16.300 )
sTST: 1st 7 nights: With DHR(n=197, 251, 254)	30.86 ( 57.437 )	50.30 ( 60.065 )	67.80 ( 71.134 )
sTST: last 7 nights: With DHR(n=190, 245, 244)	38.98 ( 66.174 )	62.41 ( 68.555 )	79.95 ( 81.211 )

sSOL,First 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[63]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.815

Confidence interval

level

95%

sides

2-sided

lower limit

0.745

upper limit

0.891

Notes
[63] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.

sSOL,First 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[64]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.753

Confidence interval

level

95%

sides

2-sided

lower limit

0.689

upper limit

0.823

Notes
[64] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.

sSOL,Last 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[65]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.75

Confidence interval

level

95%

sides

2-sided

lower limit

0.671

upper limit

0.837

Notes
[65] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.

sSOL,Last 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[66]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.689

Confidence interval

level

95%

sides

2-sided

lower limit

0.618

upper limit

0.769

Notes
[66] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSOL as a covariate.

sWASO,First 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0093 ^[67]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-12.41

Confidence interval

level

95%

sides

2-sided

lower limit

-21.76

upper limit

-3.06

Variability estimate

Standard error of the mean

Dispersion value

4.764

Notes
[67] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sWASO,First 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[68]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-26.34

Confidence interval

level

95%

sides

2-sided

lower limit

-35.68

upper limit

-16.99

Variability estimate

Standard error of the mean

Dispersion value

4.762

Notes
[68] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sWASO,Last 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0396 ^[69]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-11.49

Confidence interval

level

95%

sides

2-sided

lower limit

-22.42

upper limit

-0.55

Variability estimate

Standard error of the mean

Dispersion value

5.573

Notes
[69] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sWASO,Last 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[70]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-20.57

Confidence interval

level

95%

sides

2-sided

lower limit

-31.51

upper limit

-9.63

Variability estimate

Standard error of the mean

Dispersion value

5.574

Notes
[70] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sWASO as a covariate.

sSE,First 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008 ^[71]

Method

MMRM

Parameter type

LSM Difference

Point estimate

3.76

Confidence interval

level

95%

sides

2-sided

lower limit

1.56

upper limit

5.97

Variability estimate

Standard error of the mean

Dispersion value

1.122

Notes
[71] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.

sSE,First 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[72]

Method

MMRM

Parameter type

LSM Difference

Point estimate

6.84

Confidence interval

level

95%

sides

2-sided

lower limit

4.64

upper limit

9.04

Variability estimate

Standard error of the mean

Dispersion value

1.12

Notes
[72] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.

sSE,Last 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0005 ^[73]

Method

MMRM

Parameter type

LSM Difference

Point estimate

4.61

Confidence interval

level

95%

sides

2-sided

lower limit

2.02

upper limit

7.19

Variability estimate

Standard error of the mean

Dispersion value

1.319

Notes
[73] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effect, and the baseline sSE as a covariate.

sSE,Last 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[74]

Method

MMRM

Parameter type

LSM Difference

Point estimate

7.18

Confidence interval

level

95%

sides

2-sided

lower limit

4.6

upper limit

9.77

Variability estimate

Standard error of the mean

Dispersion value

1.319

Notes
[74] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sSE as a covariate.

sTST,First 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007 ^[75]

Method

MMRM

Parameter type

LSM Difference

Point estimate

19.05

Confidence interval

level

95%

sides

2-sided

lower limit

8.03

upper limit

30.08

Variability estimate

Standard error of the mean

Dispersion value

5.619

Notes
[75] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baselines sTST as a covariate.

sTST,First 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[76]

Method

MMRM

Parameter type

LSM Difference

Point estimate

34.51

Confidence interval

level

95%

sides

2-sided

lower limit

23.5

upper limit

45.52

Variability estimate

Standard error of the mean

Dispersion value

5.609

Notes
[76] - Based on MMRM model with factors of age group, region, treatment, visit (First 7 Nights), and treatment-by-visit interaction as fixed effects, and the baselines sTST as a covariate.

sTST,Last 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003 ^[77]

Method

MMRM

Parameter type

LSM Difference

Point estimate

23.57

Confidence interval

level

95%

sides

2-sided

lower limit

10.68

upper limit

36.45

Variability estimate

Standard error of the mean

Dispersion value

6.565

Notes
[77] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.

sTST,Last 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[78]

Method

MMRM

Parameter type

LSM Difference

Point estimate

37.82

Confidence interval

level

95%

sides

2-sided

lower limit

24.94

upper limit

50.71

Variability estimate

Standard error of the mean

Dispersion value

6.565

Notes
[78] - Based on MMRM model with factors of age group, region, treatment, visit (Last 7 Nights), and treatment-by-visit interaction as fixed effects, and the baseline sTST as a covariate.

Other pre-specified: Percentage of Responders With Objective and Subjective Sleep Onset Response, and Objective and Subjective Sleep Maintenance Response

Top of page

End point title

Percentage of Responders With Objective and Subjective Sleep Onset Response, and Objective and Subjective Sleep Maintenance Response

End point description

Objective sleep onset response: LPS less than or equal to (<=) 20 minutes (mins) provided baseline LPS was greater than(>) 30 mins. Subjective sleep onset response: sSOL <=20 mins provided mean baseline sSOL was >30 mins. Objective sleep maintenance response: WASO <=60 minutes provided baseline WASO was > 60 mins and was reduced by >10 mins compared to baseline. Subjective sleep maintenance response: sWASO <=60 mins provided mean WASO was >60 mins and was reduced by >10 mins compared to baseline. Subjective measures were derived from sleep diaries entries, collected daily and analyzed at appropriate intervals. Average data for first and last 7 nights of treatment period was reported. FAS: group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. “n”: subjects who were evaluable for the outcome measure at given time points.

End point type

Other pre-specified

End point timeframe

Days 1/2, Days 29/30, first 7 night (approximately Week 1), and Last seven nights (approximately Week 4)

End point values	Placebo	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	208	263	266	269
Units: percentage of subjects
number (not applicable)
LPS: Days 1/2	15.4	10.3	15.8	17.8
LPS: Days 29/30	15.9	11.4	20.3	22.3
sSOL: First 7 nights (with DHR)	2.9	7.6	9.8	10.4
sSOL: Last 7 nights (with DHR)	7.2	8.7	16.9	14.5
WASO: Days 1/2	16.8	46.0	51.1	64.3
WASO: Days 29/30	22.1	34.6	44.4	46.1
sWASO: First 7 nights (with DHR)	9.6	16.7	16.9	20.4
sWASO: Last 7 nights (with DHR)	15.4	23.2	23.3	23.0

LPS, Days 1/2: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9028 ^[79]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

0.41

Confidence interval

level

95%

sides

2-sided

lower limit

-6.22

upper limit

7.04

Notes
[79] - Based on Cochran-Mantel-Haenszel test stratified by age group.

LPS,Days 1/2: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4699 ^[80]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

2.49

Confidence interval

level

95%

sides

2-sided

lower limit

-4.2

upper limit

9.18

Notes
[80] - Based on Cochran-Mantel-Haenszel test stratified by age group.

LPS, Days 1/2: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0566 ^[81]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

5.58

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

11.31

Notes
[81] - Based on Cochran-Mantel-Haenszel test stratified by age group.

LPS, Days 1/2: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0122 ^[82]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

7.57

Confidence interval

level

95%

sides

2-sided

lower limit

1.71

upper limit

13.44

Notes
[82] - Based on Cochran-Mantel-Haenszel test stratified by age group.

LPS, Days 29/30: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2176 ^[83]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

4.42

Confidence interval

level

95%

sides

2-sided

lower limit

-2.5

upper limit

11.34

Notes
[83] - Based on Cochran-Mantel-Haenszel test stratified by age group.

LPS, Days 29/30: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0773 ^[84]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

6.47

Confidence interval

level

95%

sides

2-sided

lower limit

-0.55

upper limit

13.49

Notes
[84] - Based on Cochran-Mantel-Haenszel test stratified by age group.

LPS, Days 29/30: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0054 ^[85]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

8.85

Confidence interval

level

95%

sides

2-sided

lower limit

2.68

upper limit

15.02

Notes
[85] - Based on Cochran-Mantel-Haenszel test stratified by age group.

LPS, Days 29/30: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0008 ^[86]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

10.89

Confidence interval

level

95%

sides

2-sided

lower limit

4.61

upper limit

17.17

Notes
[86] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, First 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.003 ^[87]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

6.9

Confidence interval

level

95%

sides

2-sided

lower limit

2.66

upper limit

11.14

Notes
[87] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, First 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016 ^[88]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

7.5

Confidence interval

level

95%

sides

2-sided

lower limit

3.19

upper limit

11.81

Notes
[88] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, First 7 nights: Zolpidem, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3643 ^[89]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

2.22

Confidence interval

level

95%

sides

2-sided

lower limit

-2.56

upper limit

7.01

Notes
[89] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, First 7 nights: Zolpidem, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2553 ^[90]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

2.82

Confidence interval

level

95%

sides

2-sided

lower limit

-2.02

upper limit

7.66

Notes
[90] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, Last 7 nights: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016 ^[91]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

9.69

Confidence interval

level

95%

sides

2-sided

lower limit

3.98

upper limit

15.4

Notes
[91] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, Last 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0128 ^[92]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

7.29

Confidence interval

level

95%

sides

2-sided

lower limit

1.8

upper limit

12.79

Notes
[92] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, Last 7 nights: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg v Lemborexant 5 mg

Number of subjects included in analysis

798

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0051 ^[93]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

8.16

Confidence interval

level

95%

sides

2-sided

lower limit

2.51

upper limit

13.81

Notes
[93] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sSOL, Last 7nights: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0389 ^[94]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

5.76

Confidence interval

level

95%

sides

2-sided

lower limit

0.34

upper limit

11.18

Notes
[94] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO, Days 1/2: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[95]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

34.26

Confidence interval

level

95%

sides

2-sided

lower limit

26.46

upper limit

42.06

Notes
[95] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO, Days 1/2: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[96]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

47.57

Confidence interval

level

95%

sides

2-sided

lower limit

40.02

upper limit

55.13

Notes
[96] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO, Days 1/2: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2534 ^[97]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

4.89

Confidence interval

level

95%

sides

2-sided

lower limit

-3.49

upper limit

13.28

Notes
[97] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO: Days 1/2: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[98]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

18.25

Confidence interval

level

95%

sides

2-sided

lower limit

10.1

upper limit

26.4

Notes
[98] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO, Days 29/30: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[99]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

22.2

Confidence interval

level

95%

sides

2-sided

lower limit

14.06

upper limit

30.35

Notes
[99] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO, Days 29/30: Placebo, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001 ^[100]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

24.13

Confidence interval

level

95%

sides

2-sided

lower limit

16.16

upper limit

32.1

Notes
[100] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO, Days 29/30: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023 ^[101]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

9.59

Confidence interval

level

95%

sides

2-sided

lower limit

1.36

upper limit

17.81

Notes
[101] - Based on Cochran-Mantel-Haenszel test stratified by age group.

WASO, Days 29/30: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0058 ^[102]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

11.43

Confidence interval

level

95%

sides

2-sided

lower limit

3.38

upper limit

19.48

Notes
[102] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO,First7 nights: Placebo,Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0222 ^[103]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

7.3

Confidence interval

level

95%

sides

2-sided

lower limit

1.27

upper limit

13.33

Notes
[103] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO, First 7 nights: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0013 ^[104]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

10.84

Confidence interval

level

95%

sides

2-sided

lower limit

4.57

upper limit

17.11

Notes
[104] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO,First7 nights:Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9495 ^[105]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

0.21

Confidence interval

level

95%

sides

2-sided

lower limit

-6.17

upper limit

6.58

Notes
[105] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO: First7 nights:Zolpidem ER, Lemborexant 10mg

Comparison groups

Lemborexant 10 mg v Zolpidem Tartrate Extended Release 6.25 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2708 ^[106]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

3.72

Confidence interval

level

95%

sides

2-sided

lower limit

-2.88

upper limit

10.32

Notes
[106] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO, Last7nights: Placebo,Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0322 ^[107]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

7.91

Confidence interval

level

95%

sides

2-sided

lower limit

0.86

upper limit

14.96

Notes
[107] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO,Last7 nights:Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0363 ^[108]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

7.69

Confidence interval

level

95%

sides

2-sided

lower limit

0.68

upper limit

14.71

Notes
[108] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO, Last7 nights:Zolpidem ER,Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9885 ^[109]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

0.05

Confidence interval

level

95%

sides

2-sided

lower limit

-7.14

upper limit

7.24

Notes
[109] - Based on Cochran-Mantel-Haenszel test stratified by age group.

sWASO, Last7 nights:Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9651 ^[110]

Method

Cochran-Mantel-Haenszel

Parameter type

LSM Difference

Point estimate

-0.16

Confidence interval

level

95%

sides

2-sided

lower limit

-7.31

upper limit

6.99

Notes
[110] - Based on Cochran-Mantel-Haenszel test stratified by age group.

Other pre-specified: Change From Baseline in Score From Items 4 to 7 on the ISI of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

Top of page

End point title

Change From Baseline in Score From Items 4 to 7 on the ISI of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

End point description

The ISI is a 7-item self-report questionnaire assessing the nature, severity, and impact of insomnia. The dimensions evaluated were: severity of sleep onset; sleep maintenance; early morning awakening problems; sleep dissatisfaction; interference of sleep difficulties with daytime functioning; noticeability of the sleep problems by others; and distress caused by the sleep difficulties. A 5-point Likert scale was used to rate each item (from 0 = no problem to 4 = very severe problem) yielding a total score from 0 to 28. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement at given time points.

End point type

Other pre-specified

End point timeframe

Baseline and Day 31

End point values	Placebo	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	198	244	257	253
Units: score in scale
arithmetic mean (standard deviation)	-3.88 ( 3.559 )	-5.24 ( 3.764 )	-4.83 ( 3.593 )	-4.77 ( 3.735 )

Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0006 ^[111]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-1.1

Confidence interval

level

95%

sides

2-sided

lower limit

-1.73

upper limit

-0.47

Variability estimate

Standard error of the mean

Dispersion value

0.319

Notes
[111] - Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.

Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

451

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0007 ^[112]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-1.08

Confidence interval

level

95%

sides

2-sided

lower limit

-1.71

upper limit

-0.46

Variability estimate

Standard error of the mean

Dispersion value

0.32

Notes
[112] - Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.

Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

501

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2951 ^[113]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

0.32

Confidence interval

level

95%

sides

2-sided

lower limit

-0.28

upper limit

0.91

Variability estimate

Standard error of the mean

Dispersion value

0.301

Notes
[113] - Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.

Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

497

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2744 ^[114]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

0.33

Confidence interval

level

95%

sides

2-sided

lower limit

-0.26

upper limit

0.92

Variability estimate

Standard error of the mean

Dispersion value

0.303

Notes
[114] - Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.

Other pre-specified: Change From Baseline in FSS Score of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

Top of page

End point title

Change From Baseline in FSS Score of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

End point description

The FSS is a self-report scale on which subjects are instructed to choose a number from 1 to 7 that indicates their degree of agreement with each of 9 statements about their fatigue where “1” indicates strongly disagree, and “7” indicates strongly agree. The FSS total score was the sum of all responses to the 9 questions. The FSS average item score was the average of the score for each item. Higher total scores and higher average item scores indicated greater fatigue. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. The FAS was the group of subjects where data was available at given time points.

End point type

Other pre-specified

End point timeframe

Baseline and Day 31

End point values	Placebo	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	198	244	257	253
Units: score on scale
arithmetic mean (standard deviation)	-6.75 ( 11.916 )	-7.80 ( 12.879 )	-8.14 ( 13.411 )	-8.00 ( 14.058 )

Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

455

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2348 ^[115]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-1.26

Confidence interval

level

95%

sides

2-sided

lower limit

-3.35

upper limit

0.82

Variability estimate

Standard error of the mean

Dispersion value

1.063

Notes
[115] - Based on ANCOVA model with factors of age group, region, treatment and the baseline FSS as a covariate.

Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

451

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2745 ^[116]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-1.17

Confidence interval

level

95%

sides

2-sided

lower limit

-3.26

upper limit

0.93

Variability estimate

Standard error of the mean

Dispersion value

1.067

Notes
[116] - Based on ANCOVA model with factors of age group, region, treatment and the baseline FSS as a covariate.

Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

501

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.711 ^[117]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.37

Confidence interval

level

95%

sides

2-sided

lower limit

-2.35

upper limit

1.6

Variability estimate

Standard error of the mean

Dispersion value

1.005

Notes
[117] - Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.

Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

497

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.7854 ^[118]

Method

ANCOVA

Parameter type

LSM Difference

Point estimate

-0.27

Confidence interval

level

95%

sides

2-sided

lower limit

-2.26

upper limit

1.71

Variability estimate

Standard error of the mean

Dispersion value

1.009

Notes
[118] - Based on ANCOVA model with factors of age group, region, treatment and the baseline ISI as a covariate.

Other pre-specified: Change From Baseline in Mean POA and SOMT on Days 2/3

Top of page

End point title

Change From Baseline in Mean POA and SOMT on Days 2/3

End point description

POA reflects the ability to focus attention and process information. POA is calculated from the sum of simple reaction time, choice reaction time and digit vigilance. SOMT reflects time taken to retrieve information from working and episodic memory. SOMT is a composite score created by combining numerical working memory and spatial working memory and word recognition and picture recognition. Cognitive performance assessment was done by a computerized performance assessment battery (PAB) which was administered on a laptop computer. A positive change from baseline reflects impairment and a lower value of decrease from baseline indicates better performance. Change from baseline to average POA and SOMT on Days 2 and 3 was reported. The FAS was the group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose primary efficacy measurement. Here “n” were subjects who were evaluable for the outcome measure at given time points.

End point type

Other pre-specified

End point timeframe

Baseline, Days 2/3

End point values	Placebo	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	208	263	266	269
Units: millisecond
arithmetic mean (standard deviation)
POA (n=186, 233, 240, 236)	-14.2 ( 149.31 )	37.1 ( 107.15 )	8.9 ( 154.33 )	31.1 ( 142.38 )
SOMT (n=186, 232, 237, 235)	-177.9 ( 668.77 )	60.7 ( 749.12 )	-185.1 ( 645.18 )	-152.8 ( 722.49 )

POA: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0141 ^[119]

Method

MMRM

Parameter type

LSM Difference

Point estimate

30.77

Confidence interval

level

95%

sides

2-sided

lower limit

6.23

upper limit

55.31

Variability estimate

Standard error of the mean

Dispersion value

12.505

Notes
[119] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline POA as a covariate.

POA: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016 ^[120]

Method

MMRM

Parameter type

LSM Difference

Point estimate

39.67

Confidence interval

level

95%

sides

2-sided

lower limit

15.05

upper limit

64.29

Variability estimate

Standard error of the mean

Dispersion value

12.542

Notes
[120] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline POA as a covariate.

POA: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1031 ^[121]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-19.22

Confidence interval

level

95%

sides

2-sided

lower limit

-42.34

upper limit

3.9

Variability estimate

Standard error of the mean

Dispersion value

11.779

Notes
[121] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline POA as a covariate.

POA: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3825 ^[122]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-10.32

Confidence interval

level

95%

sides

2-sided

lower limit

-33.5

upper limit

12.86

Variability estimate

Standard error of the mean

Dispersion value

11.813

Notes
[122] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline POA as a covariate.

SOMT: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.6348 ^[123]

Method

MMRM

Parameter type

LSM Difference

Point estimate

28.81

Confidence interval

level

95%

sides

2-sided

lower limit

-90.18

upper limit

147.8

Variability estimate

Standard error of the mean

Dispersion value

60.626

Notes
[123] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline SOMT as a covariate.

SOMT: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4026 ^[124]

Method

MMRM

Parameter type

LSM Difference

Point estimate

50.83

Confidence interval

level

95%

sides

2-sided

lower limit

-68.3

upper limit

169.97

Variability estimate

Standard error of the mean

Dispersion value

60.702

Notes
[124] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline SOMT as a covariate.

SOMT: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004 ^[125]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-203.36

Confidence interval

level

95%

sides

2-sided

lower limit

-315.56

upper limit

-91.15

Variability estimate

Standard error of the mean

Dispersion value

57.171

Notes
[125] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline SOMT as a covariate.

SOMT: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0016 ^[126]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-181.33

Confidence interval

level

95%

sides

2-sided

lower limit

-293.71

upper limit

-68.96

Variability estimate

Standard error of the mean

Dispersion value

57.255

Notes
[126] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline SOMT as a covariate.

Other pre-specified: Change From Baseline in Mean QOM and COA on Days 2/3

Top of page

End point title

Change From Baseline in Mean QOM and COA on Days 2/3

End point description

QOM: ability to store information in memory and subsequently retrieve it. It is a composite score created by combining accuracy measures from 2 sets of working memory and 4 sets of episodic memory. 2 sets of working memory were included: numerical and spatial working memory, and ranges from -2 to 2. 4 sets of episodic memory were included: immediate and delayed word recall, and word and picture recognition, and ranges from -200 to 400. COA is ability to sustain attention. Number of correct responses (out of 50) for choice reaction time was added to total number of targets correctly identified (out of 45) digit vigilance minus number of false alarms (total score of -45 to 95). Higher values were better. Change from baseline to average QOM and COA on Days 2 and 3 was reported. FAS: group of randomized subjects who received at least 1 dose of randomized study drug and had at least 1 postdose efficacy measurement. “n”: subjects who were evaluable for outcome measure at given time points.

End point type

Other pre-specified

End point timeframe

Baseline, Days 2/3

End point values	Placebo	Zolpidem Tartrate Extended Release 6.25 mg	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	208	263	266	269
Units: units on scale
arithmetic mean (standard deviation)
QOM (n=185, 233, 239, 235)	3.5 ( 45.20 )	-12.1 ( 46.94 )	1.4 ( 44.21 )	-2.8 ( 44.11 )
COA (n=186, 233, 240, 236)	0.0 ( 4.16 )	-1.0 ( 4.48 )	0.2 ( 4.95 )	-0.7 ( 3.92 )

QOM: Placebo, Lemborexant 5 mg

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.9936 ^[127]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-0.03

Confidence interval

level

95%

sides

2-sided

lower limit

-8.16

upper limit

8.09

Variability estimate

Standard error of the mean

Dispersion value

4.141

Notes
[127] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline QOM as a covariate.

QOM: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1595 ^[128]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-5.85

Confidence interval

level

95%

sides

2-sided

lower limit

-14

upper limit

2.3

Variability estimate

Standard error of the mean

Dispersion value

4.154

Notes
[128] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline QOM as a covariate.

QOM: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0011 ^[129]

Method

MMRM

Parameter type

LSM Difference

Point estimate

12.73

Confidence interval

level

95%

sides

2-sided

lower limit

5.09

upper limit

20.38

Variability estimate

Standard error of the mean

Dispersion value

3.894

Notes
[129] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline QOM as a covariate.

QOM: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0774 ^[130]

Method

MMRM

Parameter type

LSM Difference

Point estimate

6.92

Confidence interval

level

95%

sides

2-sided

lower limit

-0.76

upper limit

14.6

Variability estimate

Standard error of the mean

Dispersion value

3.913

Notes
[130] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline QOM as a covariate.

COA: Placebo, Lemborexant 5 mg

Comparison groups

Lemborexant 5 mg v Placebo

Number of subjects included in analysis

474

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.3726 ^[131]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.35

Confidence interval

level

95%

sides

2-sided

lower limit

-0.42

upper limit

1.12

Variability estimate

Standard error of the mean

Dispersion value

0.393

Notes
[131] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline COA as a covariate.

COA: Placebo, Lemborexant 10 mg

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

477

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2579 ^[132]

Method

MMRM

Parameter type

LSM Difference

Point estimate

-0.45

Confidence interval

level

95%

sides

2-sided

lower limit

-1.22

upper limit

0.33

Variability estimate

Standard error of the mean

Dispersion value

0.394

Notes
[132] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline COA as a covariate.

COA: Zolpidem ER, Lemborexant 5 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 5 mg

Number of subjects included in analysis

529

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002 ^[133]

Method

MMRM

Parameter type

LSM Difference

Point estimate

1.39

Confidence interval

level

95%

sides

2-sided

lower limit

0.66

upper limit

2.11

Variability estimate

Standard error of the mean

Dispersion value

0.37

Notes
[133] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline COA as a covariate.

COA: Zolpidem ER, Lemborexant 10 mg

Comparison groups

Zolpidem Tartrate Extended Release 6.25 mg v Lemborexant 10 mg

Number of subjects included in analysis

532

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.112 ^[134]

Method

MMRM

Parameter type

LSM Difference

Point estimate

0.59

Confidence interval

level

95%

sides

2-sided

lower limit

-0.14

upper limit

1.32

Variability estimate

Standard error of the mean

Dispersion value

0.372

Notes
[134] - Based on MMRM model with factors of age group, region, treatment, visit (Days 2/3), and treatment-by-visit interaction as fixed effect, and the baseline COA as a covariate.

Adverse events

Top of page

Timeframe for reporting adverse events

Run-in Phase (Day -7) up to End of treatment (Day 44)

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

20.1

Reporting group title

Zolpidem tartrate

Reporting group description

Subjects received ZOL ER 6.25 mg and LEM-matched PBO, tablets, orally, once on each night for 30 consecutive nights, immediately before the time the subject intended to try to sleep of treatment period.

Reporting group title

Lemborexant 5 mg

Reporting group description

Subjects received LEM 5 and ZOL ER -matched PBO, tablets, orally, once on each night for 30 consecutive nights, immediately before the time the subject intended to try to sleep of treatment period.

Reporting group title

Placebo

Reporting group description

Subjects received LEM-matched PBO and ZOL ER-matched PBO, tablets, orally once on each night for 30 consecutive nights, immediately before the time the subject intended to try to sleep of treatment period.

Reporting group title

Lemborexant 10 mg

Reporting group description

Subjects received LEM 10 mg (LEM 10) and ZOL ER-matched PBO, tablets, orally, once on each night for 30 consecutive nights, immediately before the time the subject intended to try to sleep of treatment period.

Reporting group title

Run -in Period Placebo

Reporting group description

Subjects received LEM-matched PBO and ZOL ER-matched PBO, tablets, orally, once on each night for 7 consecutive nights up to Baseline (Day 1), immediately before the time the subject intended to try to sleep of run-in period.

Serious adverse events	Zolpidem tartrate	Lemborexant 5 mg	Placebo	Lemborexant 10 mg	Run -in Period Placebo
Total subjects affected by serious adverse events
subjects affected / exposed	4 / 263 (1.52%)	2 / 266 (0.75%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
number of deaths (all causes)	0	0	0	0	0
number of deaths resulting from adverse events	0	0	0	0	0
Vascular disorders
Peripheral vascular disorder
subjects affected / exposed	1 / 263 (0.38%)	0 / 266 (0.00%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Cardiac disorders
Coronary artery disease
subjects affected / exposed	1 / 263 (0.38%)	0 / 266 (0.00%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Chest pain
subjects affected / exposed	1 / 263 (0.38%)	0 / 266 (0.00%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Abdominal hernia
subjects affected / exposed	0 / 263 (0.00%)	1 / 266 (0.38%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Small intestinal obstruction
subjects affected / exposed	1 / 263 (0.38%)	0 / 266 (0.00%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Back pain
subjects affected / exposed	1 / 263 (0.38%)	0 / 266 (0.00%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Infections and infestations
Pneumonia
subjects affected / exposed	1 / 263 (0.38%)	0 / 266 (0.00%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0
Gastroenteritis viral
subjects affected / exposed	0 / 263 (0.00%)	1 / 266 (0.38%)	0 / 209 (0.00%)	0 / 268 (0.00%)	0 / 1006 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0	0 / 0	0 / 0

Frequency threshold for reporting non-serious adverse events: 5%

Non-serious adverse events	Zolpidem tartrate	Lemborexant 5 mg	Placebo	Lemborexant 10 mg	Run -in Period Placebo
Total subjects affected by non serious adverse events
subjects affected / exposed	18 / 263 (6.84%)	27 / 266 (10.15%)	16 / 209 (7.66%)	28 / 268 (10.45%)	34 / 1006 (3.38%)
Nervous system disorders
Headache
subjects affected / exposed	14 / 263 (5.32%)	17 / 266 (6.39%)	13 / 209 (6.22%)	13 / 268 (4.85%)	34 / 1006 (3.38%)
occurrences all number	21	21	13	15	34
Somnolence
subjects affected / exposed	4 / 263 (1.52%)	11 / 266 (4.14%)	4 / 209 (1.91%)	19 / 268 (7.09%)	0 / 1006 (0.00%)
occurrences all number	5	11	4	20	0

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Were there any global substantial amendments to the protocol? Yes

24 Jun 2016

Amendment 01: The protocol was amended to update that exclusion criteria include current diagnosis of obstructive sleep apnea, prohibition of strong CYP3A inhibitors from being used any time during study, even if intermittently, added sleep onset latency as a PSG variable and moved analysis of cognitive PAB tasks from exploratory to secondary analyses.

16 Feb 2017

Amendment 02: The protocol was amended to update screening period from up to -28 days to up to -35 days, inclusion and exclusion criteria, requirement for monitoring of seizures and falls and T-BWSQ assessment description such that scores above 20 will not be considered clinically significant and that the symptoms will no longer be summarized separately from all other AEs.

16 Jun 2017

Amendment 03: The protocol was amended to update WASO1H as a sleep architecture parameter (efficacy) and age groups for analysis.

Were there any global interruptions to the trial? No

Limitations of the trial such as small numbers of subjects analysed or technical problems leading to unreliable data.

None reported

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Clinical trials

Clinical Trial Results: A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Active Comparator, Parallel-Group Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older with Insomnia Disorder

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Mean LPS of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Primary: Change From Baseline in Mean LPS of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Secondary: Change From Baseline in Mean SE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Secondary: Change From Baseline in Mean SE of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Secondary: Change From Baseline in Mean WASO of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Secondary: Change From Baseline in Mean WASO of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Secondary: Change From Baseline in WASO in the Second Half of the Night WASO2H of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 29/30

Secondary: Change From Baseline in WASO in the Second Half of the Night WASO2H of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 29/30

Other pre-specified: Change from Baseline in Mean Body Sway upon Awakening in the Morning for Lemborexant 5 mg and Lemborexant 10 mg Compared to Zolpidem ER on Days 2/3

Other pre-specified: Change from Baseline in Mean Body Sway upon Awakening in the Morning for Lemborexant 5 mg and Lemborexant 10 mg Compared to Zolpidem ER on Days 2/3

Other pre-specified: Change from Baseline in Mean LPS, WASO, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 1/2 and Days 29/30

Other pre-specified: Change from Baseline in Mean LPS, WASO, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER on Days 1/2 and Days 29/30

Other pre-specified: Change From Baseline in sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER

Other pre-specified: Change From Baseline in sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER

Other pre-specified: Change From Baseline in Mean LPS, SE, WASO, WASO2H, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2

Other pre-specified: Change From Baseline in Mean LPS, SE, WASO, WASO2H, and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 1/2

Other pre-specified: Change From Baseline in Mean WASO2H and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Other pre-specified: Change From Baseline in Mean WASO2H and TST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo on Days 29/30

Other pre-specified: Change From Baseline in Mean sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo

Other pre-specified: Change From Baseline in Mean sSOL, sWASO, sSE, and sTST of Lemborexant 10 mg and Lemborexant 5 mg Compared to Placebo

Other pre-specified: Percentage of Responders With Objective and Subjective Sleep Onset Response, and Objective and Subjective Sleep Maintenance Response

Other pre-specified: Percentage of Responders With Objective and Subjective Sleep Onset Response, and Objective and Subjective Sleep Maintenance Response

Other pre-specified: Change From Baseline in Score From Items 4 to 7 on the ISI of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

Other pre-specified: Change From Baseline in Score From Items 4 to 7 on the ISI of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

Other pre-specified: Change From Baseline in FSS Score of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

Other pre-specified: Change From Baseline in FSS Score of Lemborexant 10 mg and Lemborexant 5 mg Compared to Zolpidem ER and Placebo on Day 31

Other pre-specified: Change From Baseline in Mean POA and SOMT on Days 2/3

Other pre-specified: Change From Baseline in Mean POA and SOMT on Days 2/3

Other pre-specified: Change From Baseline in Mean QOM and COA on Days 2/3

Other pre-specified: Change From Baseline in Mean QOM and COA on Days 2/3

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

More information

Clinical Trial Results:
A Multicenter, Randomized, Double-Blind, Placebo-Controlled, Active Comparator, Parallel-Group Study of the Efficacy and Safety of Lemborexant in Subjects 55 Years and Older with Insomnia Disorder