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Clinical Trial Results:
A Long-Term Multicenter, Randomized, Double-Blind, Controlled, Parallel-Group Study of the Safety and Efficacy of Lemborexant in Subjects With Insomnia Disorder

Summary
EudraCT number	2015-001463-39
Trial protocol	DE FI PL ES
Global end of trial date	08 Jan 2019

Results information
Results version number	v1(current)
This version publication date	26 Jan 2020
First version publication date	26 Jan 2020
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-G000-303

ISRCTN number

US NCT number

NCT02952820

WHO universal trial number (UTN)

Sponsor organisation name

Eisai Inc.

Sponsor organisation address

100 Tice Boulevard, Woodcliff Lake,New Jersey, United States, 07677

Public contact

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

Scientific contact

Medical Information, Eisai, Inc., +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

08 Jan 2019

Is this the analysis of the primary completion data?

Global end of trial reached?

Yes

Global end of trial date

08 Jan 2019

Was the trial ended prematurely?

Main objective of the trial

Determine the efficacy of lemborexant 5 mg (LEM5) and 10 mg (LEM10) compared to placebo (PBO) on subjective sleep onset latency (sSOL) after 6 months of treatment in subjects 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

15 Nov 2016

Long term follow-up planned

Independent data monitoring committee (IDMC) involvement?

Number of subjects enrolled per country

Country: Number of subjects enrolled

Poland: 61

Country: Number of subjects enrolled

Spain: 21

Country: Number of subjects enrolled

Germany: 124

Country: Number of subjects enrolled

Japan: 161

Country: Number of subjects enrolled

Korea, Democratic People's Republic of: 3

Country: Number of subjects enrolled

Italy: 7

Country: Number of subjects enrolled

New Zealand: 15

Country: Number of subjects enrolled

Romania: 52

Country: Number of subjects enrolled

Canada: 10

Country: Number of subjects enrolled

Mexico: 1

Country: Number of subjects enrolled

United States: 310

Country: Number of subjects enrolled

Finland: 206

Worldwide total number of subjects

971

EEA total number of subjects

471

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)

709

From 65 to 84 years

259

85 years and over

Subject disposition

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Recruitment details

Subjects took part in the study at 119 investigative sites in Japan, Korea, Finland, Germany, Italy, New Zealand, Poland, Romania, Spain, Canada, Mexico, and the United States from 15 November 2016 to 08 January 2019.

Screening details

A total of 2059 subjects were screened, of which 1088 were screen failures and 971 subjects were randomized to receive study treatment.

Period 1 title

Placebo -Controlled Treatment (6 Months)

Is this the baseline period?

Yes

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Placebo

Arm description

Subjects received lemborexant-matched placebo, tablet, orally, once daily for up to Month 6 in the placebo-controlled treatment period. Then they were re-randomized to lemborexant 5 milligram (mg) or lemborexant 10 mg up to Month 12 .

Arm type

Placebo

Investigational medicinal product name

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 for up to Month 6 in the placebo-controlled treatment period.

Lemborexant 5 mg

Arm description

Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Arm type

Experimental

Investigational medicinal product name

Lemborexant

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 6-12 (in Period 2).

Lemborexant 10 mg

Arm description

Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Arm type

Experimental

Investigational medicinal product name

Lemborexant

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 6-12 (in Period 2).

Number of subjects in period 1	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Started	325	323	323
Treated	321	319	319
Safety Analysis Set	319	314	314
Completed	261	254	235
Not completed	64	69	88
Adverse event, non-fatal	8	9	16
Other than specified	-	14	13
Withdrawal of consent	13	11	21
Lost to follow-up	7	7	6
Inadequate therapeutic effect	17	12	11
Subject choice	15	12	17
Not treated	4	4	4

Period 2 title

Active Treatment Period (6 Months)

Is this the baseline period?

Allocation method

Randomised - controlled

Blinding used

Double blind

Roles blinded

Subject, Investigator

Are arms mutually exclusive

Yes

Lemborexant 5 mg

Arm description

Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Arm type

Experimental

Investigational medicinal product name

Lemborexant

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 12.

Lemborexant 10 mg

Arm description

Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Arm type

Experimental

Investigational medicinal product name

Lemborexant

Investigational medicinal product code

Other name

Pharmaceutical forms

Tablet

Routes of administration

Oral use

Dosage and administration details

Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 12.

Number of subjects in period 2 ^[1]	Lemborexant 5 mg	Lemborexant 10 mg
Started	384	352
Completed	346	321
Not completed	38	31
Adverse event, non-fatal	6	5
Other than specified	6	2
Withdrawal of consent	6	8
Lost to follow-up	4	6
Inadequate therapeutic effect	6	2
Subject choice	10	7
Not treated	-	1

Notes
[1] - The number of subjects starting the period is not consistent with the number completing the preceding period. It is expected the number of subjects starting the subsequent period will be the same as the number completing the preceding period.
Justification: Subjects from Placebo were re-randomized to Lemborexant 5 mg and Lemborexant 10 mg.

Baseline characteristics

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Reporting group title

Placebo

Reporting group description

Reporting group title

Lemborexant 5 mg

Reporting group description

Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Reporting group title

Lemborexant 10 mg

Reporting group description

Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Reporting group values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg	Total
Number of subjects	325	323	323	971
Age categorical
Units: Subjects
In utero				0
Preterm newborn infants (gestational age < 37 wks)				0
Newborns (0-27 days)				0
Infants and toddlers (28 days-23 months)				0
Children (2-11 years)				0
Adolescents (12-17 years)				0
Adults (18-64 years)				0
From 65-84 years				0
85 years and over				0
Age continuous
Units: years
arithmetic mean (standard deviation)	54.262 ( 14.017 )	54.087 ( 13.656 )	54.715 ( 13.59 )	-
Gender categorical
Units: Subjects
Female	220	213	225	658
Male	105	110	98	313

End points

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Reporting group title

Placebo

Reporting group description

Reporting group title

Lemborexant 5 mg

Reporting group description

Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Reporting group title

Lemborexant 10 mg

Reporting group description

Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Reporting group title

Lemborexant 5 mg

Reporting group description

Subjects received lemborexant 5 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Reporting group title

Lemborexant 10 mg

Reporting group description

Subjects received lemborexant 10 mg, tablets, orally, once daily through Month 1-6 (in Period 1) and Month 7-12 (in Period 2).

Subject analysis set title

Lemborexant 5 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received lemborexant 5 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 5 mg, tablets, orally, once daily through Month 7-12 (in Period 2)

Subject analysis set title

Lemborexant 10 mg

Subject analysis set type

Sub-group analysis

Subject analysis set description

Subjects received lemborexant 10 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 10 mg, tablets, orally, once daily through Month 7-12 (in Period 2).

Primary: Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6

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End point title

Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6

End point description

sSOL was defined as estimated minutes from the time that the subject attempted to sleep until sleep onset. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Primary

End point timeframe

Baseline and Month 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: minutes
arithmetic mean (standard deviation)
Baseline (n=316, 314, 312)	64.03 ( 45.209 )	62.19 ( 45.674 )	64.97 ( 44.020 )
Change at Month 6 (249, 245, 229)	-16.57 ( 35.313 )	-29.39 ( 33.261 )	-32.49 ( 35.962 )

Statistical Analysis 1

Statistical analysis description

Analysis was based on mixed effect model repeated measurement analysis (MMRM) model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be missing not at random (missing not at random/complete case missing value [MNAR/CCMV]).

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

least squares geometric mean (LSGM)ratio

Point estimate

0.732

Confidence interval

level

95%

sides

2-sided

lower limit

0.636

upper limit

0.843

Statistical Analysis 2

Statistical analysis description

Analysis was based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSGM ratio

Point estimate

0.701

Confidence interval

level

95%

sides

2-sided

lower limit

0.607

upper limit

0.81

Secondary: Change From Baseline in sSOL at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1 and 3

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End point title

Change From Baseline in sSOL at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1 and 3

End point description

sSOL was defined as estimated minutes from time attempted to sleep to sleep onset. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Secondary

End point timeframe

Baseline, (mean of 7 nights [approximately Week 1]), Months 1 and 3

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: minutes
arithmetic mean (standard deviation)
Baseline (n=316, 314, 312)	64.03 ( 45.209 )	62.19 ( 45.674 )	64.97 ( 44.020 )
Change at 1st 7 nights (n= 314, 310, 310)	-4.11 ( 27.671 )	-16.86 ( 27.784 )	-18.89 ( 31.003 )
Change at Month 1 (n=299, 298, 297)	-11.48 ( 32.726 )	-19.41 ( 32.221 )	-24.06 ( 35.234 )
Change at Month 3 (n=279, 268, 264)	-13.84 ( 35.277 )	-25.08 ( 34.081 )	-27.94 ( 39.192 )

First 7 nights (Statistical Analysis 1)

Statistical analysis description

Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSGM ratio

Point estimate

0.781

Confidence interval

level

95%

sides

2-sided

lower limit

0.725

upper limit

0.842

First 7 nights (Statistical Analysis 2)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSGM ratio

Point estimate

0.752

Confidence interval

level

95%

sides

2-sided

lower limit

0.698

upper limit

0.811

Month 1 (Statistical analysis 3)

Statistical analysis description

Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSGM ratio

Point estimate

0.81

Confidence interval

level

95%

sides

2-sided

lower limit

0.735

upper limit

0.893

Month 1 (Statistical analysis 4)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSGM ratio

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.698

upper limit

0.848

Month 3 (Statistical Analysis 5)

Statistical analysis description

Based on MMRM model with log transformation of sSOL and factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and the study baseline sSOL as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSGM ratio

Point estimate

0.778

Confidence interval

level

95%

sides

2-sided

lower limit

0.69

upper limit

0.878

Month 3 (Statistical Analysis 6)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSGM ratio

Point estimate

0.77

Confidence interval

level

95%

sides

2-sided

lower limit

0.681

upper limit

0.869

Secondary: Change From Baseline in Subjective Sleep Efficiency (sSE) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

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End point title

Change From Baseline in Subjective Sleep Efficiency (sSE) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

End point description

sSE was defined as percentage of subjective total sleep time (sTST) divided by subjective time spent in bed, calculated as the interval from the time the subject reported attempting to sleep until the time subject stopped trying to sleep for the night (operationalized as the time the subject got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Secondary

End point timeframe

Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: percentage of sTST
arithmetic mean (standard deviation)
Baseline (n=307, 302, 299)	61.34 ( 17.836 )	63.14 ( 18.231 )	62.03 ( 17.248 )
Change at 1st 7 nights (n=303, 295, 296)	2.68 ( 10.765 )	6.61 ( 10.386 )	8.27 ( 10.566 )
Change at Month 1 (n= 291, 284, 282)	6.11 ( 12.876 )	7.87 ( 12.263 )	9.92 ( 12.922 )
Change at Month 3 (n= 269, 256, 251)	9.16 ( 13.644 )	13.03 ( 13.522 )	13.61 ( 14.035 )
Change at Month 6 (n= 242, 235, 220)	10.36 ( 13.799 )	15.34 ( 14.613 )	15.55 ( 15.617 )

First 7 nights (Statistical Analysis 1)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

4.299

Confidence interval

level

95%

sides

2-sided

lower limit

2.638

upper limit

5.961

Variability estimate

Standard error of the mean

Dispersion value

0.848

First 7 nights (Statistical Analysis 2)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

5.793

Confidence interval

level

95%

sides

2-sided

lower limit

4.133

upper limit

7.452

Variability estimate

Standard error of the mean

Dispersion value

0.846

Month 1 (Statistical Analysis 3)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.023

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

2.227

Confidence interval

level

95%

sides

2-sided

lower limit

0.307

upper limit

4.146

Variability estimate

Standard error of the mean

Dispersion value

0.979

Month 1 (Statistical Analysis 4)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

3.615

Confidence interval

level

95%

sides

2-sided

lower limit

1.635

upper limit

5.595

Variability estimate

Standard error of the mean

Dispersion value

1.01

Month 3 (Statistical Analysis 5)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Confidence interval

level

95%

sides

2-sided

lower limit

2.068

upper limit

6.377

Variability estimate

Standard error of the mean

Dispersion value

1.099

Month 3 (Statistical Analysis 6)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

4.361

Confidence interval

level

95%

sides

2-sided

lower limit

2.22

upper limit

6.501

Variability estimate

Standard error of the mean

Dispersion value

1.092

Month 6 (Statistical Analysis 7)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sSE as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

4.549

Confidence interval

level

95%

sides

2-sided

lower limit

2.236

upper limit

6.861

Variability estimate

Standard error of the mean

Dispersion value

1.179

Month 6 (Statistical Analysis 8)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

4.667

Confidence interval

level

95%

sides

2-sided

lower limit

2.373

upper limit

6.96

Variability estimate

Standard error of the mean

Dispersion value

1.17

Secondary: Change From Baseline in Subjective Wake After Sleep Onset (sWASO) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

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End point title

Change From Baseline in Subjective Wake After Sleep Onset (sWASO) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

End point description

sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the subject stopped trying to sleep for the night, operationalized as the time the subject got out of bed for the day. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Secondary

End point timeframe

Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: minutes
arithmetic mean (standard deviation)
Baseline (n=314, 313, 311)	132.49 ( 80.198 )	132.77 ( 82.518 )	136.83 ( 87.391 )
Change at first 7 nights (n= 312, 308, 309)	-6.12 ( 45.893 )	-20.21 ( 46.015 )	-23.30 ( 47.700 )
Change at Month 1 (n=297, 297, 293)	-19.01 ( 50.279 )	-23.42 ( 56.251 )	-26.82 ( 56.989 )
Change at Month 3 (n=278, 267, 262)	-27.08 ( 54.408 )	-42.98 ( 60.064 )	-39.42 ( 62.783 )
Change at Month 6 (n=248, 244, 227)	-32.14 ( 55.279 )	-51.45 ( 67.295 )	-48.12 ( 68.550 )

First 7 nights (Statistical Analysis 1)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-14.328

Confidence interval

level

95%

sides

2-sided

lower limit

-21.411

upper limit

-7.245

Variability estimate

Standard error of the mean

Dispersion value

3.614

First 7 nights (Statistical Analysis 2)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-16.72

Confidence interval

level

95%

sides

2-sided

lower limit

-23.813

upper limit

-9.626

Variability estimate

Standard error of the mean

Dispersion value

3.619

Month 1 (Statistical Analysis 3)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.1796

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-5.514

Confidence interval

level

95%

sides

2-sided

lower limit

-13.568

upper limit

2.54

Variability estimate

Standard error of the mean

Dispersion value

4.109

Month 1 (Statistical Analysis 4)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0898

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-7.005

Confidence interval

level

95%

sides

2-sided

lower limit

-15.098

upper limit

1.088

Variability estimate

Standard error of the mean

Dispersion value

4.129

Month 3 (Statistical Analysis 5)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0028

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-13.424

Confidence interval

level

95%

sides

2-sided

lower limit

-22.218

upper limit

-4.631

Variability estimate

Standard error of the mean

Dispersion value

4.486

Month 3 (Statistical Analysis 6)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0277

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-10.079

Confidence interval

level

95%

sides

2-sided

lower limit

-19.053

upper limit

-1.104

Variability estimate

Standard error of the mean

Dispersion value

4.578

Month 6 (Statistical Analysis 7)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sWASO as a covariate. Missing values are imputed using multiple imputation and assumed to be MNAR/CCMV.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0005

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-17.474

Confidence interval

level

95%

sides

2-sided

lower limit

-27.306

upper limit

-7.643

Variability estimate

Standard error of the mean

Dispersion value

5.014

Month 6 (Statistical Analysis 8)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0105

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-12.671

Confidence interval

level

95%

sides

2-sided

lower limit

-22.378

upper limit

-2.964

Variability estimate

Standard error of the mean

Dispersion value

4.951

Secondary: Change From Baseline in sTST at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

Top of page

End point title

Change From Baseline in sTST at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

End point description

sTST was defined as minutes of sleep from sleep onset to time stopped trying to sleep for the night. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Secondary

End point timeframe

Baseline, (mean of 7 nights [approximately Week 1]), Months 1, 3 and 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: minutes
arithmetic mean (standard deviation)
Baseline (n=307, 302, 299)	304.25 ( 91.459 )	315.52 ( 93.498 )	306.89 ( 88.031 )
Change at first 7 nights (n=303, 295, 296)	14.78 ( 54.995 )	34.29 ( 54.142 )	46.01 ( 55.110 )
Change at Month 1 (n=291, 284, 282)	30.74 ( 70.687 )	39.32 ( 63.548 )	53.22 ( 67.910 )
Change at Month 3 (n= 269, 256, 251)	48.16 ( 75.859 )	65.82 ( 71.331 )	70.95 ( 70.913 )
Change at Month 6 (n=242, 235, 220)	53.53 ( 74.539 )	76.21 ( 77.714 )	78.32 ( 80.741 )

First 7 Nights (Statistical Analysis 1)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be missing at random (MAR).

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

22.034

Confidence interval

level

95%

sides

2-sided

lower limit

13.488

upper limit

30.579

Variability estimate

Standard error of the mean

Dispersion value

4.354

First 7 nights (Statistical Analysis 2)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

31.796

Confidence interval

level

95%

sides

2-sided

lower limit

23.258

upper limit

40.334

Variability estimate

Standard error of the mean

Dispersion value

4.35

Month 1 (Statistical analysis 3)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0259

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

11.76

Confidence interval

level

95%

sides

2-sided

lower limit

1.418

upper limit

22.102

Variability estimate

Standard error of the mean

Dispersion value

5.269

Month 1 (Statistical Analysis 4)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

22.131

Confidence interval

level

95%

sides

2-sided

lower limit

11.757

upper limit

32.505

Variability estimate

Standard error of the mean

Dispersion value

5.286

Month 3 (Statistical Analysis 5)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0034

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

17.374

Confidence interval

level

95%

sides

2-sided

lower limit

5.781

upper limit

28.968

Variability estimate

Standard error of the mean

Dispersion value

5.906

Month 3 (Statistical Analysis 6)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0003

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

21.686

Confidence interval

level

95%

sides

2-sided

lower limit

10.014

upper limit

33.359

Variability estimate

Standard error of the mean

Dispersion value

5.946

Month 6 (Statistical Analysis 7)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline sTST as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0034

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

18.555

Confidence interval

level

95%

sides

2-sided

lower limit

6.14

upper limit

30.969

Variability estimate

Standard error of the mean

Dispersion value

6.324

Month 6 (Statistical Analysis 8)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

22.686

Confidence interval

level

95%

sides

2-sided

lower limit

10.137

upper limit

35.234

Variability estimate

Standard error of the mean

Dispersion value

6.392

Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6

Top of page

End point title

Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6

End point description

Sleep onset responder was defined as follows: sSOL at study Baseline was greater than or equal to (>=) 30 minutes and mean sSOL at 6 months was less than or equal to (<=) 20 minutes. Sleep maintenance responder was defined as follows: sWASO at study Baseline was >=60 minutes and mean sWASO at 6 months was <=60 minutes and showed a reduction of greater than (>)10 minutes compared to Study Baseline. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to number of subjects evaluable for specified category.

End point type

Secondary

End point timeframe

Month 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: percentage of responders
number (not applicable)
Sleep Onset Responders (n= 254, 250, 249)	17.7	31.2	30.1
Sleep Maintenance Responders (n=250, 263, 257)	20.4	35.0	30.0

Sleep Onset Responders: Statistical Analysis 1

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0004

Method

Cochran-Mantel-Haenszel

Parameter type

Difference of percentage

Point estimate

13.67

Confidence interval

level

95%

sides

2-sided

lower limit

6.24

upper limit

21.1

Sleep Onset Responders: Statistical Analysis 2

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0009

Method

Cochran-Mantel-Haenszel

Parameter type

Difference of percentage

Point estimate

12.53

Confidence interval

level

95%

sides

2-sided

lower limit

5.2

upper limit

19.86

Sleep Maintenance Responders

Statistical analysis description

Statistical Analysis 3

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0002

Method

Cochran-Mantel-Haenszel

Parameter type

Difference of percentage

Point estimate

14.65

Confidence interval

level

95%

sides

2-sided

lower limit

6.97

upper limit

22.33

Sleep Maintenance Responders

Statistical analysis description

Statistical Analysis 4

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.011

Method

Cochran-Mantel-Haenszel

Parameter type

Difference of percentage

Point estimate

9.82

Confidence interval

level

95%

sides

2-sided

lower limit

2.29

upper limit

17.35

Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12

Top of page

End point title

Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12

End point description

Sleep onset responder was defined as follows: sSOL at study Baseline was >=30 minutes and mean sSOL at 6 months was <=20 minutes. Sleep maintenance responder was defined as follows: sWASO at study Baseline was >=60 minutes and mean sWASO at 6 months was <=60 minutes and showed a reduction of > 10 minutes compared to study Baseline. On-treatment FAS was the group of subjects who received at least 1 dose of lemborexant and had at least 1 post dose primary efficacy measurement. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Month 12

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: percentage of subjects
number (not applicable)
Sleep Onset Responders (n= 310, 285)	34.2	37.2
Sleep Maintainance Responders (n= 317, 280)	35.0	39.6

No statistical analyses for this end point

Secondary: Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6

Top of page

End point title

Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6

End point description

The ISI is a 4-7 item, self-report questionnaire assessing the nature, severity, and impact of insomnia. The dimensions evaluated were: 1. severity of sleep onset; 2. sleep maintenance; 3. early morning awakening problems; 4. sleep dissatisfaction; 5. interference of sleep difficulties with daytime functioning; 6. noticeability of the sleep problems by others; and 7. 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). Daytime functioning score (sum of items 4 to 7) were analyzed. Higher score indicated severe insomnia problem. The total score range for sum of items is 0-16. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Secondary

End point timeframe

Baseline, Months 1, 3, and 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n=318, 316, 315)	11.0 ( 2.10 )	11.4 ( 2.02 )	11.0 ( 2.15 )
Change at Month 1 (n= 296, 300, 286)	-3.1 ( 3.41 )	-4.1 ( 3.66 )	-4.2 ( 4.01 )
Change at Month 3 (n=283, 274, 259)	-3.7 ( 3.55 )	-5.2 ( 3.88 )	-5.2 ( 4.05 )
Change at Month 6 (n= 257, 258, 234)	-4.3 ( 3.66 )	-6.0 ( 3.76 )	-5.7 ( 4.00 )

Month 1 (Statistical Analysis 1)

Statistical analysis description

Based on MMRM model with factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0137

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.71

Confidence interval

level

95%

sides

2-sided

lower limit

-1.27

upper limit

-0.15

Variability estimate

Standard error of the mean

Dispersion value

0.287

Month 1 (Statistical Analysis 2)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0011

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-0.94

Confidence interval

level

95%

sides

2-sided

lower limit

-1.51

upper limit

-0.38

Variability estimate

Standard error of the mean

Dispersion value

0.289

Month 3 (Statistical Analysis 3)

Statistical analysis description

Based on MMRM model with factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-1.16

Confidence interval

level

95%

sides

2-sided

lower limit

-1.75

upper limit

-0.57

Variability estimate

Standard error of the mean

Dispersion value

0.302

Month 3 (Statistical Analysis 4)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Confidence interval

level

95%

sides

2-sided

lower limit

-1.96

upper limit

-0.76

Variability estimate

Standard error of the mean

Dispersion value

0.305

Month 6 (Statistical Analysis 5)

Statistical analysis description

Based on MMRM model with factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and study baseline ISI score as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-1.3

Confidence interval

level

95%

sides

2-sided

lower limit

-1.9

upper limit

-0.71

Variability estimate

Standard error of the mean

Dispersion value

0.302

Month 6 (Statistical Analysis 8)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

< 0.0001

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-1.32

Confidence interval

level

95%

sides

2-sided

lower limit

-1.92

upper limit

-0.71

Variability estimate

Standard error of the mean

Dispersion value

0.307

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and

Top of page

End point title

Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and

End point description

The FSS is a self-reported scale on which subjects were instructed to choose a number from 1 to 7 that indicated their degree of agreement with 9 statements about their fatigue where “1” indicates strongly disagree and “7”, strongly agree. The FSS total score was the sum of all responses to the 9 questions. Higher total scores and average item scores indicated greater fatigue. Total score range is 9 to 63. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Secondary

End point timeframe

Baseline, Months 1, 3 and 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n=318, 316, 315)	35.2 ( 13.55 )	37.4 ( 12.74 )	36.0 ( 13.01 )
Change at Month 1 (n= 296, 300, 286)	-3.9 ( 11.62 )	-6.6 ( 11.83 )	-6.4 ( 13.68 )
Change at Month 3 (n= 283, 274, 259)	-4.3 ( 11.37 )	-7.7 ( 12.97 )	-7.9 ( 13.56 )
Change at Month 6 (n= 257, 258, 234)	-6.3 ( 12.07 )	-10.1 ( 13.56 )	-8.9 ( 14.91 )

Month 1 (Statistical Analysis 1)

Statistical analysis description

Based on MMRM model with factors for age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.067

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-1.66

Confidence interval

level

95%

sides

2-sided

lower limit

-3.44

upper limit

0.12

Variability estimate

Standard error of the mean

Dispersion value

0.905

Month 1 (Statistical Analysis 2)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0257

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-2.04

Confidence interval

level

95%

sides

2-sided

lower limit

-3.83

upper limit

-0.25

Variability estimate

Standard error of the mean

Dispersion value

0.913

Month 3 (Statistical Analysis 3)

Statistical analysis description

Based on MMRM model with factors for age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0206

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-2.18

Confidence interval

level

95%

sides

2-sided

lower limit

-4.02

upper limit

-0.34

Variability estimate

Standard error of the mean

Dispersion value

0.939

Month 3 (Statistical Analysis 4)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0014

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-3.04

Confidence interval

level

95%

sides

2-sided

lower limit

-4.91

upper limit

-1.18

Variability estimate

Standard error of the mean

Dispersion value

0.95

Month 6 (Statistical Analysis 5)

Statistical analysis description

Based on MMRM model with factors for age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effects, and study baseline FSS score as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0134

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-2.5

Confidence interval

level

95%

sides

2-sided

lower limit

-4.48

upper limit

-0.52

Variability estimate

Standard error of the mean

Dispersion value

0.112

Month 6 (Statistical Analysis 6)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0128

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

-2.56

Confidence interval

level

95%

sides

2-sided

lower limit

-4.57

upper limit

-0.54

Variability estimate

Standard error of the mean

Dispersion value

1.026

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), Month 1, 3 and 6

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End point title

Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), Month 1, 3 and 6

End point description

The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: “How sleepy/alert do you feel this morning?” subjects rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. The FAS was the group of randomized subjects who received at least one dose of randomized study drug and had at least one postdose primary efficacy measurement. Number analyzed refers to subjects evaluable for this outcome measure at specified time point.

End point type

Secondary

End point timeframe

Baseline, (mean of 7 nights [approximately Week 1]) in placebo-controlled period, Month 1, 3, 6

End point values	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	318	316	315
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n=316, 314, 312)	3.94 ( 1.558 )	3.93 ( 1.349 )	3.93 ( 1.324 )
Change at First 7 nights (n= 314, 310, 310)	0.15 ( 0.991 )	0.36 ( 0.964 )	0.33 ( 1.018 )
Change at Month 1 (n= 300, 298, 297)	0.44 ( 1.233 )	0.53 ( 1.172 )	0.55 ( 1.298 )
Change at Month 3 (n= 280, 268, 264)	0.62 ( 1.366 )	0.74 ( 1.325 )	0.90 ( 1.452 )
Change at Month 6 (n=249, 245, 229)	0.79 ( 1.392 )	0.98 ( 1.463 )	1.05 ( 1.524 )

First 7 nights (Statistical Analysis 1)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (First 7 nights), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0067

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.205

Confidence interval

level

95%

sides

2-sided

lower limit

0.057

upper limit

0.353

Variability estimate

Standard error of the mean

Dispersion value

0.076

First 7 nights (Statistical Analysis 2)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0237

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.171

Confidence interval

level

95%

sides

2-sided

lower limit

0.023

upper limit

0.32

Variability estimate

Standard error of the mean

Dispersion value

0.076

Month 1 (Statistical analysis 3)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 1), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.412

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.077

Confidence interval

level

95%

sides

2-sided

lower limit

-0.107

upper limit

0.261

Variability estimate

Standard error of the mean

Dispersion value

0.094

Month 1 (Statistical Analysis 4)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4347

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.073

Confidence interval

level

95%

sides

2-sided

lower limit

-0.111

upper limit

0.258

Variability estimate

Standard error of the mean

Dispersion value

0.094

Month 3 (Statistical Analysis 5)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 3), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.4992

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.074

Confidence interval

level

95%

sides

2-sided

lower limit

-0.141

upper limit

0.289

Variability estimate

Standard error of the mean

Dispersion value

0.109

Month 3 (Statistical Analysis 6)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0208

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.255

Confidence interval

level

95%

sides

2-sided

lower limit

0.039

upper limit

0.471

Variability estimate

Standard error of the mean

Dispersion value

0.11

Month 6 (Statistical Analysis 7)

Statistical analysis description

Based on MMRM model with factors of age group, region, treatment, visit (Month 6), and treatment-by-visit interaction as fixed effect, and the study baseline Mean Rating on Morning Sleepiness as a covariate. Missing values are not imputed and assumed to be MAR.

Comparison groups

Placebo v Lemborexant 5 mg

Number of subjects included in analysis

634

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.2248

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.144

Confidence interval

level

95%

sides

2-sided

lower limit

-0.089

upper limit

0.378

Variability estimate

Standard error of the mean

Dispersion value

0.119

Month 6 (Statistical Analysis 8)

Statistical analysis description

Comparison groups

Placebo v Lemborexant 10 mg

Number of subjects included in analysis

633

Analysis specification

Pre-specified

Analysis type

superiority

P-value

= 0.0298

Method

Mixed models analysis

Parameter type

LSM Difference

Point estimate

0.261

Confidence interval

level

95%

sides

2-sided

lower limit

0.026

upper limit

0.497

Variability estimate

Standard error of the mean

Dispersion value

0.12

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Active Treatment Period)

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End point title

Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Active Treatment Period)

End point description

Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, First 7 nights (approximately Week 1) in active treatment period

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: score on scale
arithmetic mean (standard deviation)
Baseline (n=442, 434)	4.15 ( 1.526 )	4.16 ( 1.428 )
Change at First 7 nights (n=310, 310)	0.36 ( 0.964 )	0.33 ( 1.018 )

No statistical analyses for this end point

Secondary: Change From Screening in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the First and Second 7 Mornings of the Follow-up Period

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End point title

Change From Screening in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the First and Second 7 Mornings of the Follow-up Period

End point description

The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: “How sleepy/alert do you feel this morning?” Subjects rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. On-treatment FAS was the group of subjects who received at least 1 dose of lemborexant and had at least 1 post dose primary efficacy measurement. Overall subjects analyzed here is based on the number in the "On-Treatment FAS". Hence these numbers include the lemborexant data from the subjects re-randomized from placebo in Period 1.

End point type

Secondary

End point timeframe

Screening, First and second 7 mornings in follow-up period (Week 52 to 54)

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: score on a scale
arithmetic mean (standard deviation)
Screening (n=440, 436)	3.63 ( 1.393 )	3.54 ( 1.197 )
Change at First 7 mornings (n=335, 328)	1.03 ( 1.615 )	1.32 ( 1.611 )
Change at Second 7 mornings (n=327, 313)	0.98 ( 1.699 )	1.22 ( 1.635 )

No statistical analyses for this end point

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12

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End point title

Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12

End point description

The Sleep Diary was used to assess subjective ratings of morning sleepiness with the following question: “How sleepy/alert do you feel this morning?” Subjects rated their sleepiness/alertness level on a scale from 1 to 9, with 1 being extremely poor (sleepy) and 9 being extremely good (alert). Higher score indicated better outcome. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 1, 3, 6, 9 and 12

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: score on a scale
arithmetic mean (standard deviation)
Baseline (n=442, 434)	4.15 ( 1.516 )	4.16 ( 1.428 )
Change at Month 1 of exposure (n=415, 412)	0.46 ( 1.082 )	0.42 ( 1.223 )
Change at Month 3 of exposure (n=386, 375)	0.60 ( 1.264 )	0.70 ( 1.356 )
Change at Month 6 of exposure (n=352, 331)	0.78 ( 1.424 )	0.86 ( 1.461 )
Change at Month 9 of exposure (n=233, 213)	1.00 ( 1.512 )	1.08 ( 1.489 )
Change at Month 12 of exposure (216, 204)	1.11 ( 1.499 )	1.31 ( 1.604 )

No statistical analyses for this end point

Secondary: Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

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End point title

Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

End point description

Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sSOL was defined as estimated minutes from the time that the subject attempted to sleep until sleep onset. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: minutes
arithmetic mean (standard deviation)
Mean of first 3 nights (n=287, 284)	40.35 ( 48.661 )	41.73 ( 55.694 )
Mean sSOL of the first 7 nights (n=337, 328)	41.35 ( 38.967 )	41.90 ( 47.826 )
Mean sSOL of the second 7 nights (329, 312)	44.10 ( 38.030 )	41.30 ( 47.471 )

No statistical analyses for this end point

Secondary: Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

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End point title

Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

End point description

Rebound Insomnia: Rebound insomnia was defined as insomnia that occurred following discontinuation of a sedative substance taken to relieve primary insomnia. sWASO was defined as sum of estimated minutes of wake during the night after initial sleep onset until the time the subject stopped trying to sleep for the night, operationalized as the time the subject got out of bed for the day. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: minutes
arithmetic mean (standard deviation)
Mean of first 3 nights (n=282, 282)	86.66 ( 80.038 )	97.88 ( 83.302 )
Mean of the first 7 nights (337, 326)	91.56 ( 81.738 )	95.79 ( 79.784 )
Mean of the Last 7 nights (329, 312)	92.62 ( 82.672 )	98.19 ( 80.668 )

No statistical analyses for this end point

Secondary: Rebound Insomnia: Percentage of Subjects Whose sSOL Was Longer Than at Screening for First 3 Nights of the Follow-up Period, or Whom Mean sSOL Was Longer Than at Screening for First 7 Nights or Last 7 Nights of the Follow-up Period

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End point title

Rebound Insomnia: Percentage of Subjects Whose sSOL Was Longer Than at Screening for First 3 Nights of the Follow-up Period, or Whom Mean sSOL Was Longer Than at Screening for First 7 Nights or Last 7 Nights of the Follow-up Period

End point description

End point type

Secondary

End point timeframe

First 3 nights, first and last 7 nights of the follow up period (Week 52 to 54)

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: percentage of subjects
number (not applicable)
Average of first 3 nights (285, 284)	9.46	9.38
Average of first 7 nights (n=335, 328)	11.94	10.53
Average of second 7 nights (327, 312)	11.71	9.38

No statistical analyses for this end point

Secondary: Rebound Insomnia: Percentage of Subjects Whose sWASO is Higher Than at Screening for First 3 Nights of the Follow-up Period, or Whose Mean sWASO is Higher Than at Screening for the First 7 Nights or Last 7 Nights of the Follow-up Period

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End point title

Rebound Insomnia: Percentage of Subjects Whose sWASO is Higher Than at Screening for First 3 Nights of the Follow-up Period, or Whose Mean sWASO is Higher Than at Screening for the First 7 Nights or Last 7 Nights of the Follow-up Period

End point description

End point type

Secondary

End point timeframe

First 3 nights, First and Last 7 nights of the follow up period (Week 52 to 54)

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: percentage of subjects
number (not applicable)
Average of first 3 nights (n=280, 282)	11.26	12.59
Average of first 7 nights (n= 335, 325)	12.39	14.19
Average of second 7 nights (n= 327, 311)	13.51	11.90

No statistical analyses for this end point

Secondary: Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1

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End point title

Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1

End point description

At each month beyond Month 1, the change from Baseline was compared to either the lower bound of the 95% CI (for sTST) or the upper bound of the 95% CI (for sSOL and sWASO) at Month 1. Persistence of efficacy was defined as present if the mean change from Baseline at Month 6 was above the lower bound of the 95% CI at Month 1 for sTST and below the upper bound of the 95% CI at Month 1 for sSOL and sWASO. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 1, 3, 6, 9, 12

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: minutes
least squares mean (confidence interval 95%)
sSOL: Change at Month 1 of exposure (n=415, 412)	-17.17 (-19.76 to -14.58)	-18.64 (-21.26 to -16.02)
sSOL: Change at Month 3 of exposure (n=386, 375)	-21.47 (-24.46 to -18.48)	-21.58 (-24.61 to -18.54)
sSOL: Change at Month 6 of exposure (n=352, 331)	-24.13 (-27.22 to -21.04)	-22.99 (-26.14 to -19.83)
sSOL: Change at Month 9 of exposure (n=233, 213)	-26.00 (-29.25 to -22.75)	-27.36 (-30.70 to -24.01)
sSOL: Change at Month 12 of exposure (n=216, 214)	-25.83 (-29.44 to -22.22)	-26.32 (-30.03 to -22.61)
sWASO: Change at Month 1 of exposure (n=414, 408)	-17.26 (-22.54 to -11.97)	-18.69 (-24.05 to -13.33)
sWASO: Change at Month 3 of exposure (n=385, 373)	-31.34 (-37.12 to -25.57)	-28.97 (-34.86 to -23.09)
sWASO: Change at Month 6 of exposure (n=351, 329)	-36.10 (-42.57 to -29.63)	-31.54 (-38.16 to -24.91)
sWASO: Change at Month 9 of exposure (n=232, 212)	-39.28 (-46.74 to -31.83)	-40.39 (-48.08 to -32.71)
sWASO: Change at Month 12 of exposure (n=215, 203)	-42.87 (-50.13 to -35.61)	-43.76 (-51.21 to -36.31)
sTST: Change at Month 1 of exposure (n=400, 396)	31.98 (25.54 to 38.42)	38.04 (31.51 to 44.57)
sTST: Change at Month 3 of exposure (n=373, 361)	49.27 (42.33 to 56.22)	53.51 (46.42 to 60.61)
sTST: Change at Month 6 of exposure (n=342, 321)	54.99 (47.18 to 62.80)	56.36 (48.35 to 64.36)
sTST: Change at Month 9 of exposure (n=222, 205)	55.41 (46.49 to 64.33)	61.13 (51.93 to 70.32)
sTST: Change at Month 12 of exposure (n=207, 196)	58.15 (49.29 to 67.01)	66.50 (57.41 to 75.60)

No statistical analyses for this end point

Secondary: Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1

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End point title

Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1

End point description

sSE was defined as percentage of sTST per subjective time spent in bed, calculated as the interval from the time the subject reports attempting to sleep until the time the subject stopped trying to sleep for the night (operationalized as the time the participant got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. At each month beyond Month 1, the change from Baseline was compared to the lower bound of the 95% CI at Month 1. Persistence of efficacy was defined as present if the mean change from Baseline at Month 6 was above the lower bound of the 95% CI at Month 1 for sSE. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Months 1, 3, 6, 9, and 12

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: percentage of sTST
least squares mean (confidence interval 95%)
Change at Month 1 of exposure (n= 400, 396)	6.35 (5.13 to 7.57)	7.32 (6.09 to 8.56)
Change at Month 3 of exposure (n=373, 361)	10.01 (8.69 to 11.34)	10.25 (8.90 to 11.60)
Change at Month 6 of exposure (n=342, 321)	11.10 (9.61 to 12.58)	11.08 (9.56 to 12.60)
Change at Month 9 of exposure (n=222, 205)	11.85 (10.13 to 13.56)	12.84 (11.08 to 14.61)
Change at Month 12 of exposure (n=207, 196)	12.61 (10.92 to 14.31)	13.66 (11.92 to 15.40)

No statistical analyses for this end point

Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 9 and 12 Compared to Month 7

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End point title

Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 9 and 12 Compared to Month 7

End point description

At each month beyond Month 7, the change from Baseline was compared to either the lower bound of the 95% CI for sTST or the upper bound of the 95% CI (for sSOL and sWASO) at Month 7. Persistence of effect was defined as present if the mean change from Baseline at Month 12 was above the lower bound of the 95% CI at Month 7 for sTST and below the upper bound of the 95% CI at Month 7 for sSOL and sWASO. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 7, 9, 12

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: minutes
least squares mean (confidence interval 95%)
sSOL: Change at Month 7 of exposure (n=355, 334)	-28.55 (-32.39 to -24.70)	-29.46 (-33.42 to -25.50)
sSOL: Change at Month 9 of exposure (n=349, 324)	-32.10 (-35.39 to -28.80)	-30.91 (-34.31 to -27.52)
sSOL: Change at Month 12 of exposure (n=323, 306)	-31.40 (-34.85 to -27.96)	-31.33 (-34.88 to -27.78)
sWASO: Change at Month 7 of exposure (n=355, 304)	-45.62 (-52.53 to -38.70)	-43.09 (-50.20 to -35.99)
sWASO: Change at Month 9 of exposure (n=349, 324)	-47.70 (-54.54 to -40.86)	-48.87 (-55.92 to -41.82)
sWASO: Change at Month 12 of exposure (n=323, 306)	-48.46 (-55.35 to -41.57)	-49.28 (-56.36 to -42.19)
sTST: Change at Month 7 of exposure (n=355, 334)	75.00 (65.30 to 84.71)	76.95 (66.97 to 86.92)
sTST: Change at Month 9 of exposure (n=349, 324)	78.69 (68.99 to 88.39)	81.24 (71.26 to 91.23)
sTST: Change at Month 12 of exposure (n=323, 306)	78.61 (68.61 to 88.61)	83.61 (73.33 to 93.90)

No statistical analyses for this end point

Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7

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End point title

Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7

End point description

sSE: percentage of sTST per subjective time spent in bed, calculated as the interval from the time the subject reports attempting to sleep until the time the subject stopped trying to sleep for the night (operationalized as the time the subject got out of bed for the day), and time spent asleep derived from subjective time spent in bed minus sWASO. At each month beyond Month 7, the change from Baseline was compared to the lower bound of the 95% CI for sSE at Month 7. Persistence of effect was defined as present if the mean change from Baseline at Month 12 was above the lower bound of the 95% CI at Month 7 for sSE. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 7, 9, 12

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: percentage of sTST
least squares mean (confidence interval 95%)
Change at Month 7 of exposure (n=354, 334)	12.88 (9.01 to 16.75)	15.12 (11.13 to 19.10)
Change at Month 9 of exposure (n=349, 324)	16.54 (14.88 to 18.20)	16.49 (14.78 to 18.20)
Change at Month 12 of exposure (n=323, 306)	16.34 (14.70 to 17.98)	16.82 (15.13 to 18.50)

No statistical analyses for this end point

Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 3 and 6 Exposure Compared to Month 1

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End point title

Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 3 and 6 Exposure Compared to Month 1

End point description

At 3 and 6 months of exposure, the change from Baseline was compared to either the lower bound of the 95% CI for sTST or the upper bound of the 95% CI (for sSOL and sWASO) at 1 month of exposure. Persistence of effect was defined as present if the mean change from Baseline at 6 months of exposure was above the lower bound of the 95% CI at 1 month of exposure for sTST and below the upper bound of the 95% CI at 1 month of exposure for sSOL and sWASO. On-treatment FAS was the group of subjects who received at least 1 dose of lemborexant and had at least 1 post dose primary efficacy measurement. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 1, 3, 6

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: minutes
least squares mean (confidence interval 95%)
sSOL: Change at Month 1 of exposure (n=415, 412)	-17.17 (-19.76 to -14.58)	-18.64 (-21.26 to -16.02)
sSOL: Change at Month 3 of exposure (n=386, 375)	-21.47 (-24.46 to -18.48)	-21.58 (-24.61 to -18.54)
sSOL: Change at Month 6 of exposure (n=352, 331)	-24.13 (-27.22 to -21.04)	-22.99 (-26.14 to -19.83)
sWASO: Change at Month 1 of exposure (n=414, 408)	-17.26 (-22.54 to -11.97)	-18.69 (-24.05 to -13.33)
sWASO: Change at Month 3 of exposure (n=385, 373)	-31.34 (-37.12 to 25.57)	-28.97 (-34.86 to -23.09)
sWASO: Change at Month 6 of exposure (n=351, 329)	-36.10 (-42.57 to -29.63)	-31.54 (-38.16 to -24.91)
sTST: Change at Month 1 of exposure (n=400, 396)	31.98 (25.54 to 38.42)	38.04 (31.51 to 44.57)
sTST: Change at Month 3 of exposure (n=373, 361)	49.27 (42.33 to 56.22)	53.51 (46.42 to 60.61)
sTST: Change at Month 6 of exposure (n=342, 321)	54.99 (47.18 to 62.80)	56.36 (48.35 to 64.36)

No statistical analyses for this end point

Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSE at Months 3 and 6 Exposure Compared to Month 1

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End point title

Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSE at Months 3 and 6 Exposure Compared to Month 1

End point description

At 3 and 6 months of exposure, the change from Baseline was compared to the lower bound of the 95% CI for sSE at 1 month of exposure. Persistence of effect was defined as present if the mean change from Baseline at 6 months of exposure was above the lower bound of the 95% CI at 1 month of exposure for sSE. Overall subjects analyzed based on number in “On-Treatment FAS (subjects who received at least 1 dose of lemborexant and had at least 1 postdose primary efficacy measurement)”. Hence, these numbers include lemborexant data from subjects re-randomized from placebo in Period 1. Number analyzed=subjects analyzed at specified timepoint.

End point type

Secondary

End point timeframe

Baseline, Month 1, 3, 6

End point values	Lemborexant 5 mg	Lemborexant 10 mg
Number of subjects analysed	444	437
Units: percentage of sTST
least squares mean (confidence interval 95%)
Change at Month 1 of exposure (n=400, 396)	6.35 (5.13 to 7.57)	7.32 (6.09 to 8.56)
Change at Month 3 of exposure (n=373, 361)	10.01 (8.69 to 11.34)	10.25 (8.90 to 11.60)
Change at Month 6 of exposure (n=342, 321)	11.10 (9.61 to 12.58)	11.08 (9.56 to 12.60)

No statistical analyses for this end point

Adverse events

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Timeframe for reporting adverse events

From start of study drug administration up to Week 54

Adverse event reporting additional description

Placebo arm included AE data for subjects who received placebo in Period 1. Lemborexant 5 mg and 10 mg arms included AE data of subjects who received either lemborexant 5 mg or 10 mg throughout the study (Period 1 and 2 both) and subjects re-randomized from placebo (in Period 1) to either lemborexant 5 mg or lemborexant 10 mg in Period

Assessment type

Systematic

Dictionary name

MedDRA

Dictionary version

21.0

Reporting group title

Placebo

Reporting group description

Reporting group title

Lemborexant 5 mg

Reporting group description

Subjects received lemborexant 5 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 5 mg, tablets, orally, once daily through Month 7-12 (in Period 2)

Reporting group title

Lemborexant 10 mg

Reporting group description

Subjects received lemborexant 10 mg/placebo, tablets, orally, once daily through Month 1-6 (in Period 1) and lemborexant 10 mg, tablets, orally, once daily through Month 7-12 (in Period 2).

Serious adverse events	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Total subjects affected by serious adverse events
subjects affected / exposed	5 / 319 (1.57%)	18 / 447 (4.03%)	16 / 437 (3.66%)
number of deaths (all causes)	0	0	0
number of deaths resulting from adverse events	0	0	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Breast Cancer
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intraductal Proliferative Breast Lesion
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Vascular disorders
Hypertension
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Deep Vein Thrombosis
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
General disorders and administration site conditions
Inflammation
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Chest Pain
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Non-Cardiac Chest Pain
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cyst
subjects affected / exposed	1 / 319 (0.31%)	0 / 447 (0.00%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Reproductive system and breast disorders
Hydrosalpinx
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Respiratory, thoracic and mediastinal disorders
Chronic Obstructive Pulmonary Disease
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Laryngeal Inflammation
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Injury, poisoning and procedural complications
Ankle Fracture
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Fall
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hand Fracture
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Lower Limb Fracture
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Intentional Overdose
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 7	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Rib Fracture
subjects affected / exposed	1 / 319 (0.31%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Meniscus Injury
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pelvic Fracture
subjects affected / exposed	1 / 319 (0.31%)	0 / 447 (0.00%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Tibia fracture
subjects affected / exposed	1 / 319 (0.31%)	0 / 447 (0.00%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cardiac disorders
Acute Myocardial Infarction
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Angina Pectoris
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Atrial Fibrillation
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Extrasystoles
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Nervous system disorders
Cerebrovascular Accident
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Diabetic Neuropathy
subjects affected / exposed	0 / 319 (0.00%)	2 / 447 (0.45%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 2	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Disturbance In Attention
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	1 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Eye disorders
Diabetic Retinopathy
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Floppy Eyelid Syndrome
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal disorders
Alcoholic Pancreatitis
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal Haemorrhage
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Gastrointestinal Inflammation
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hiatus Hernia
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatobiliary disorders
Cholestasis
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Hepatotoxicity
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Skin and subcutaneous tissue disorders
Dermal Cyst
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Renal and urinary disorders
Nephrolithiasis
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Endocrine disorders
Goitre
subjects affected / exposed	1 / 319 (0.31%)	0 / 447 (0.00%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Musculoskeletal and connective tissue disorders
Osteoarthritis
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	3 / 437 (0.69%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 3
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaw Fistula
subjects affected / exposed	1 / 319 (0.31%)	0 / 447 (0.00%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Jaw Cyst
subjects affected / exposed	1 / 319 (0.31%)	0 / 447 (0.00%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 0	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Infections and infestations
Erysipelas
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Cystitis
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Pneumonia
subjects affected / exposed	1 / 319 (0.31%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 1	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Postoperative Wound Infection
subjects affected / exposed	0 / 319 (0.00%)	1 / 447 (0.22%)	0 / 437 (0.00%)
occurrences causally related to treatment / all	0 / 0	0 / 1	0 / 0
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0
Metabolism and nutrition disorders
Type 2 Diabetes Mellitus
subjects affected / exposed	0 / 319 (0.00%)	0 / 447 (0.00%)	1 / 437 (0.23%)
occurrences causally related to treatment / all	0 / 0	0 / 0	0 / 1
deaths causally related to treatment / all	0 / 0	0 / 0	0 / 0

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

Non-serious adverse events	Placebo	Lemborexant 5 mg	Lemborexant 10 mg
Total subjects affected by non serious adverse events
subjects affected / exposed	75 / 319 (23.51%)	129 / 447 (28.86%)	140 / 437 (32.04%)
Nervous system disorders
Somnolence
subjects affected / exposed	5 / 319 (1.57%)	38 / 447 (8.50%)	60 / 437 (13.73%)
occurrences all number	5	44	64
Headache
subjects affected / exposed	21 / 319 (6.58%)	43 / 447 (9.62%)	32 / 437 (7.32%)
occurrences all number	33	76	41
Infections and infestations
Influenza
subjects affected / exposed	15 / 319 (4.70%)	22 / 447 (4.92%)	26 / 437 (5.95%)
occurrences all number	15	22	29
Nasopharyngitis
subjects affected / exposed	40 / 319 (12.54%)	51 / 447 (11.41%)	48 / 437 (10.98%)
occurrences all number	43	67	56

More information

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Were there any global substantial amendments to the protocol? Yes

29 Sep 2016

The purpose of this amendment is 1. Stated that enrollment of subjects <65 years would be limited if the percentage of enrolled subjects >65 years was below expectations toward the end of the study. 2. Clarified that subjects who discontinued study medication but did not agree to return for study visits underwent an EOS visit. 3. Clarified the term abstinence. 4. Clarified excessive caffeine use. 5. Clarified that subjects who lacked capacity and/or whose cognitive decline indicated disorientation to person/place/time and/or situation are excluded. 6. Specified that the statistical model included region if necessary, that countries with small numbers of subjects would be pooled by region, and that regions were grouped in consideration of the number and homogeneity of subjects from each region. 7. Specified that informed consent was taken by personnel in accordance with national legislation. 8. Clarified the reason why subjects should not eat a meal within 3 hours before taking the study drug. 9. Specified that the neurological examination was conducted by a clinician whose clinical experience ensured that an adequate assessment of domains underlying the exclusion criteria could be performed. 10. Specified that the investigator agreed to allow direct access to source documents and study facilities to sponsor representative(s), monitor(s) and auditor(s), and agree to inspection by regulatory authorities or IRB/IEC representative.

28 Jun 2018

Amendment 4: 1. Added analysis of Treatment Period 1. Because based on the results of pivotal Study 304 and special safety studies, the sponsor decided to include a database lock with interim analysis to assess efficacy in the double-blind placebo-controlled treatment period. All available safety data were assessed. 2. In the event of an interim analysis, Sponsor staff will be unblinded; however, site personnel, investigator, and subjects will remain blinded 3. To align with Regulatory Authority provision ICH-E9 addendum, analysis sets and analysis plan were updated

03 Aug 2018

Amendment 5: Updated interim analysis description (to clarify that no interim analysis was being performed and that when all subjects had completed Period 1, all data were unblinded to the sponsor and that study sites and subjects would remain blinded until the study had been completed.)

13 Aug 2018

Amendment 6: 1. Added results from Study E2006-A001-012 2. Updated list of prohibited concomitant medications to prohibit moderate cytochrome P450 3A (CYP3A) inhibitors 3. Revised other secondary endpoint analyses for FSS.

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 Long-Term Multicenter, Randomized, Double-Blind, Controlled, Parallel-Group Study of the Safety and Efficacy of Lemborexant in Subjects With Insomnia Disorder

Trial information

Trial information

Subject disposition

Subject disposition

Baseline characteristics

Baseline characteristics

End points

End points

Primary: Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6

Primary: Change From Baseline in Subjective Sleep Onset Latency (sSOL) at Month 6

Secondary: Change From Baseline in sSOL at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1 and 3

Secondary: Change From Baseline in sSOL at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1 and 3

Secondary: Change From Baseline in Subjective Sleep Efficiency (sSE) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

Secondary: Change From Baseline in Subjective Sleep Efficiency (sSE) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

Secondary: Change From Baseline in Subjective Wake After Sleep Onset (sWASO) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

Secondary: Change From Baseline in Subjective Wake After Sleep Onset (sWASO) at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

Secondary: Change From Baseline in sTST at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

Secondary: Change From Baseline in sTST at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), and at Months 1, 3 and 6

Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6

Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 6

Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12

Secondary: Percentage of Sleep Onset Responders and Sleep Maintenance Responders at Month 12

Secondary: Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6

Secondary: Change From Baseline in Insomnia Severity Index (ISI) Daytime Functioning Score at Months 1, 3, and 6

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and

Secondary: Change From Baseline in Fatigue Severity Scale (FSS) Total Score at Months 1, 3 and

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), Month 1, 3 and 6

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Placebo-Controlled Period), Month 1, 3 and 6

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Active Treatment Period)

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the Beginning of Treatment (Mean of the 7 Nights After the First Dose in Active Treatment Period)

Secondary: Change From Screening in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the First and Second 7 Mornings of the Follow-up Period

Secondary: Change From Screening in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at the First and Second 7 Mornings of the Follow-up Period

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12

Secondary: Change From Baseline in Mean Rating on the Morning Sleepiness Item of the Sleep Diary at Months 1, 3, 6, 9 and 12

Secondary: Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

Secondary: Rebound Insomnia: Mean sSOL on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

Secondary: Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

Secondary: Rebound Insomnia: Mean sWASO on Each of the First 3 Nights, First 7 Nights, and Last 7 Nights of the Follow-up Period

Secondary: Rebound Insomnia: Percentage of Subjects Whose sSOL Was Longer Than at Screening for First 3 Nights of the Follow-up Period, or Whom Mean sSOL Was Longer Than at Screening for First 7 Nights or Last 7 Nights of the Follow-up Period

Secondary: Rebound Insomnia: Percentage of Subjects Whose sSOL Was Longer Than at Screening for First 3 Nights of the Follow-up Period, or Whom Mean sSOL Was Longer Than at Screening for First 7 Nights or Last 7 Nights of the Follow-up Period

Secondary: Rebound Insomnia: Percentage of Subjects Whose sWASO is Higher Than at Screening for First 3 Nights of the Follow-up Period, or Whose Mean sWASO is Higher Than at Screening for the First 7 Nights or Last 7 Nights of the Follow-up Period

Secondary: Rebound Insomnia: Percentage of Subjects Whose sWASO is Higher Than at Screening for First 3 Nights of the Follow-up Period, or Whose Mean sWASO is Higher Than at Screening for the First 7 Nights or Last 7 Nights of the Follow-up Period

Secondary: Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1

Secondary: Persistence of Effect: Mean Change From Baseline in sSOL, sWASO, and sTST at Months 3, 6, 9, and 12 Compared to Month 1

Secondary: Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1

Secondary: Persistence of Effect: Mean Change From Baseline in sSE at Months 3, 6, 9, and 12 Compared to Month 1

Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 9 and 12 Compared to Month 7

Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 9 and 12 Compared to Month 7

Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7

Secondary: Persistence of Effect: Mean Change From Period 2 Baseline (Month 6) in sSE at Months 9 and 12 Compared to Month 7

Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 3 and 6 Exposure Compared to Month 1

Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSOL, sWASO, and sTST at Months 3 and 6 Exposure Compared to Month 1

Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSE at Months 3 and 6 Exposure Compared to Month 1

Secondary: Persistence of Effect: Mean Change From Study Baseline and Period 2 Baseline (Month 6) in sSE at Months 3 and 6 Exposure Compared to Month 1

Adverse events

Adverse events

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Substantial protocol amendments (globally)

Interruptions (globally)

Limitations and caveats

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Clinical Trial Results:
A Long-Term Multicenter, Randomized, Double-Blind, Controlled, Parallel-Group Study of the Safety and Efficacy of Lemborexant in Subjects With Insomnia Disorder