Study to Assess the Efficacy and Safety of ACT-541468 (Daridorexant) in Adult and Elderly Subjects Suffering From Difficulties to Sleep

• Sponsor: Idorsia Pharmaceuticals Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03575104
• Collaborator: (none)
• Enrollment: 924
• Locations: 86
• Arms: 3
• Actual Duration (Months): 23.5
• Patients Per Site: 10.7
• Patients Per Site Per Month: 0.5

Study Details

Study Description

Brief Summary

The main purpose of this study is to assess efficacy and safety of ACT-541468 (daridorexant) in adult and elderly subjects with insomnia disorder. Efficacy will be evaluated on objective and subjective sleep parameters.

Condition or Disease	Intervention/Treatment	Phase
Insomnia Disorder	Drug: Daridorexant; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 924 participants
• Allocation: Randomized
• Intervention Model: Parallel Assignment
• Masking: Quadruple (Participant, Care Provider, Investigator, Outcomes Assessor)
• Primary Purpose: Treatment
• Official Title: Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Polysomnography Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects With Insomnia Disorder
• Actual Study Start Date: May 29, 2018
• Actual Primary Completion Date: Apr 9, 2020
• Actual Study Completion Date: May 14, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daridorexant 10 mg	Drug: Daridorexant; Daridorexant will be administered as tablets, orally, once daily in the evening.
Experimental: Daridorexant 25 mg	Drug: Daridorexant; Daridorexant will be administered as tablets, orally, once daily in the evening.
Placebo Comparator: Placebo	Other: Placebo; Matching placebo will be administered as tablets, orally, once daily in the evening.

Outcome Measures

Primary Outcome Measures

1. Change From Baseline to Month 1 in Wake After Sleep Onset (WASO) (Sleep Maintenance) [From baseline to Month 1 (i.e. for up to 1 month)]

   "Wake After Sleep Onset" is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography.

2. Change From Baseline to Month 3 in Wake After Sleep Onset (WASO) [From baseline to Month 3 (i.e. for up to 3 months)]

   "Wake After Sleep Onset" is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography.

3. Change From Baseline to Month 1 in Latency to Persistent Sleep (LPS) (Sleep Onset) [From baseline to Month 1 (i.e. for up to 1 month)]

   "Latency to Persistent Sleep" is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography.

4. Change From Baseline to Month 3 in Latency to Persistent Sleep (LPS) [From baseline to Month 3 (i.e. for up to 3 months)]

   "Latency to Persistent Sleep" is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography.

Secondary Outcome Measures

1. Change From Baseline to Month 1 in the Subjective Total Sleep Time (sTST) [From baseline to Month 1 (i.e. for up to 1 month)]

   "Subjective Total Sleep Time" is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time.

2. Change From Baseline to Month 3 in the Subjective Total Sleep Time (sTST) [From baseline to Month 3 (i.e. for up to 3 months)]

   Subjective Total Sleep Time is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time.

3. Change From Baseline to Month 1 in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score [From baseline to Month 1 (i.e. for up to 1 month)]

   The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.

4. Change From Baseline to Month 3 in IDSIQ Sleepiness Domain Score [From baseline to Month 3 (i.e. for up to 3 months)]

   The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.

Eligibility Criteria

Criteria

• Ages Eligible for Study: 18 Years and Older
• Sexes Eligible for Study: All
• Accepts Healthy Volunteers: No

Inclusion Criteria:

• Signed informed consent prior to any study-mandated procedure;

• Male or female aged ≥ 18 years;

• Insomnia disorder according to DSM-5 criteria;

• Insomnia Severity Index score ≥ 15;

• Insufficient sleep quantity as collected subjectively in the sleep diary and validated objectively by polysomnography;

• Women of childbearing potential must have a negative and urine pregnancy test and use the contraception scheme up to at least 30 days after last study treatment intake.

Exclusion Criteria:

• Body mass index below 18.5 or above 40.0 kg/m2;

• Any lifetime history of of related breathing disorder, periodic limb movement disorder, restless legs syndrome, circadian rhythm disorder, rapid eye movement (REM) behavior disorder, narcolepsy, or apnea/hypopnea;

• Cognitive behavioral therapy (CBT) only allowed if, the treatment started at least 1 month prior to Visit 3 and the subject agrees to continue this CBT throughout the study;

• Self-reported usual daytime napping ≥ 1 hour per day and ≥ 3 days per week;

• Acute or unstable psychiatric conditions diagnosed by the Mini International Neuropsychiatric Interview;

• Mini Mental State Examination (MMSE) score < 25 in subjects ≥ 50 years;

• For female subjects: pregnant, lactating or planning to become pregnant during projected duration of the study;

• History or clinical evidence of any disease or medical condition or treatment, which may put the subject at risk of participation in the study or may interfere with the study assessments.

• Any circumstances or conditions, which, in the opinion of the investigator, may affect the subject's full participation in the study or compliance with the protocol.

Contacts and Locations

Locations

	Site	City	State	Country	Postal Code
1	Pulmonary Associates, Pa	Glendale	Arizona	United States	85306
2	Noble Clinical Research	Tucson	Arizona	United States	85704
3	Baptist Health Center for Clinical Research	Little Rock	Arkansas	United States	72205
4	Woodland International Research Group	Little Rock	Arkansas	United States	72211
5	Core Healthcare Group	Cerritos	California	United States	90703
6	Artemis Institute For Clinical Research - Riverside	Riverside	California	United States	92503
7	Pacific Research Network	San Diego	California	United States	92103
8	Artemis Institute for Clinical Research	San Marcos	California	United States	92078
9	Santa Monica Clinical Trials	Santa Monica	California	United States	90404
10	Empire Clinical Research	Upland	California	United States	91786
11	Innovative Clinical Research	Lafayette	Colorado	United States	80026
12	Clinical Research of South Florida	Coral Gables	Florida	United States	33134
13	Fleming Island Center for Clinical Research	Fleming Island	Florida	United States	32003
14	Clinical Trials Research	Lincoln	Florida	United States	95648
15	Clinical Research Group of St. Petersburgh	Saint Petersburg	Florida	United States	33707
16	Neurotrials Research Incorporated	Atlanta	Georgia	United States	30342
17	Sleep Practitioners, LLC	Macon	Georgia	United States	31210
18	Hawaii Pacific Neurosciences	Honolulu	Hawaii	United States	96817
19	Saltzer Clinical Research	Nampa	Idaho	United States	83686
20	Rowe Neurology Institute	Lenexa	Kansas	United States	66214
21	Sleep Disorders Center of the Mid-Atlantic	Glen Burnie	Maryland	United States	21061
22	Neurocare Inc.	Newton	Massachusetts	United States	02459
23	Precise Research Centers	Flowood	Mississippi	United States	39232
24	Garden City Asthma and Sleep Center	Garden City	New York	United States	11530
25	Research Carolina of Hickory	Hickory	North Carolina	United States	28601
26	Wake Research Associates	Raleigh	North Carolina	United States	27612
27	Clinical Trials of America - NC, LLC	Winston-Salem	North Carolina	United States	27103
28	CTI Clinical Research II	Cincinnati	Ohio	United States	45212
29	Ohio Sleep Medicine Institue	Dublin	Ohio	United States	43017
30	Cleveland Sleep Research Center	Middleburg Heights	Ohio	United States	44130
31	Robert V. Sibilia, MD, Inc.	Wooster	Ohio	United States	44691
32	Brian Abaluck LLC	Paoli	Pennsylvania	United States	19301
33	Wesley Neurology Clinic Pc (Multiple Sclerosis)	Cordova	Tennessee	United States	38018
34	FutureSearch Trials of Neurology, LP	Austin	Texas	United States	78731
35	InSite Clinical Research	DeSoto	Texas	United States	75115
36	Jacksonville Center for Clinical Research	Jacksonville	Texas	United States	32216
37	Dm Clinical Research / Martin Diagnostic Clinic	Tomball	Texas	United States	77375
38	HOSPITAL AZ SINT-JAN_Neurology department	Brugge		Belgium	8000
39	Hospital Universitair Zieknhuis Brussel, Pneumology and Sleep Laboratory	Brussels		Belgium	1090
40	University Hospital Gent, Department of General Internal Medicine and Center of neurophysiological Monitoring	Gent		Belgium	9000
41	Hospital UZ Leuven_ Pneumology Department	Leuven		Belgium	3000
42	Acibadem City Clinic Tokuda Hospital EAD	Sofia		Bulgaria	1407
43	Canadian Phase Onward Inc.	Toronto	Ontario	Canada	M3J 2C5
44	Queensway Sleep Lab Sleep Clinic (MedSleep)- 5359 Dundas Street West, Suite 202, Etobicoke, ON M9B 1B1	Etobicoke		Canada	M9C 5N2
45	The Medical Arts Health Research Group	Kelowna		Canada	V1Y 3G8
46	Somni Research Inc.	Markham		Canada	L3R 1A3
47	Somni Research, Calgary	Toronto		Canada	M3H 3W1
48	CANADIAN PHASE ONWARD INC. (Toronto)	Toronto		Canada	M3J 0K2
49	Narodni Ustav Dusevniho Zdravi (National Institute of Mental Health)	Klecany		Czechia
50	Fakultní nemocnice Ostrava, Spánková laboratoř	Ostrava-Poruba		Czechia	70852
51	Nemocnice České Budějovice, Centrum pro poruchy spánku a spánkovou medicínu	České Budějovice		Czechia	37087
52	Vitalmed Uniklinikka	Helsinki		Finland	380
53	Oivauni Oy - Kuopio	Kuopio		Finland	70100
54	Oivauni Oy - Tampere	Tampere		Finland
55	Unitutkimusyksikkö, Turun Yliopisto	Turku		Finland
56	CHRU De Lille - Hospital Salengro - Neurophysiologie Clinique	Lille		France	59037
57	Clinique beau soleil - Department Sleep and Neurology	Montpellier		France
58	CHU NIMES - Unité de Sommeil	Nîmes		France	30029
59	Advanced Sleep Research GmbH	Berlin		Germany	10117
60	Klinische Forschung Berlin-Mitte GmbH	Berlin		Germany	10117
61	Charité - Universitätsmedizin Berlin - Campus Benjamin Franklin Kompetenzzentrum Schlafmedizin	Berlin		Germany	12200
62	Synexus Clinical Research GmbH	Bochum		Germany	44787
63	Klinische Forschung Dresden GmbH	Dresden		Germany	1069
64	Synexus Clinical Research GmbH	Frankfurt		Germany	60313
65	Klinische Forschung Hannover Mitte GmbH	Hannover		Germany	30159
66	Interdisziplinäre Schlafmedizin, Pfalzklinikum	Klingenmünster		Germany	76889
67	Zentrum für Integrative Psychiatrie (ZiP) Universität zu Lübeck	Lübeck		Germany	23538
68	Central Insitute of Mental Health Sleep laboratory Medical Faculty Mannheim/Heidelberg University	Mannheim		Germany	68159
69	Klinik und Poliklinik für Psychiatrie, Psychosomatik und Psychotherapie der Universität am Bezirksklinikum Regensburg	Regensburg		Germany	93053
70	SOMNIBENE Institut für Medizinische Forschung und Schlafmedizin Schwerin GmbH	Schwerin		Germany	19053
71	Magyar Honvédség Egészségügyi Központ, Neurológiai Osztály	Budapest		Hungary	1134
72	Somnius Kft. SomnoCenter Szeged	Szeged		Hungary	6725
73	Dong-A University Hospital	Busan		Korea, Republic of	49201
74	4F Neuroimaging analysis laboratory, 56 Dalseong-ro, Jung-gu	Daegu		Korea, Republic of	41931
75	Chungnam National University Hospital	Daejeon		Korea, Republic of	35015
76	3F, 2nd Building, Psychiatry Outpatient, Family Counseling Room, 42 Jebong-ro, Donggu	Gwangju		Korea, Republic of	61469
77	8F Sleep Lab, 1st Building,82, Gumi-ro 173 Beon-gil, Bundang-gu	Seongnam		Korea, Republic of	13620
78	3F Sleep Medicine Center, 101 Daehak-Ro Jongno-Gu	Seoul		Korea, Republic of	3080
79	1st CRC room, 2F, Jejoong building, 50-1 Yonsei-ro,, Seodaemun-gu	Seoul		Korea, Republic of	3722
80	B2F, Clinical Trial Center, Konkuk University Medical Center 120-1, Neungdong-ro, Gwangjin-gu	Seoul		Korea, Republic of	5030
81	B1F Neurological examination room, 892 Dongnam-ro, Gangdong-gu	Seoul		Korea, Republic of	5278
82	2F Psychiatry Outpatient, 93, Jungbu-daero, Paldal-gu	Suwon		Korea, Republic of	16247
83	Göteborgs Universitet, Centrum för sömn och vakenhetsstörningar	Göteborg		Sweden	41390
84	SOPHIAHEMMET (Stockholm)	Stockholm		Sweden	11486
85	Sömnutredningsmottagningen, smärtcentrum Akademiska sjukhuset	Uppsala		Sweden	75185
86	Universitetssjukhuset Örebro Neurokliniken, Sömnenheten	Örebro		Sweden	70185

Sponsors and Collaborators

• Idorsia Pharmaceuticals Ltd.

Investigators

• Study Director: Clinical Trials, Idorsia Pharmaceuticals Ltd.

Study Documents (Full-Text)

• Study Protocol - Nov 8, 2018
• Statistical Analysis Plan - Jun 12, 2020

More Information

Publications

• Hudgens S, Phillips-Beyer A, Newton L, Seboek Kinter D, Benes H. Development and Validation of the Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ). Patient. 2021 Mar;14(2):249-268. doi: 10.1007/s40271-020-00474-z. Epub 2020 Nov 1.

• Responsible Party: Idorsia Pharmaceuticals Ltd.
• ClinicalTrials.gov Identifier: NCT03575104
• Other Study ID Numbers: ID-078A302
• First Posted: Jul 2, 2018
• Last Update Posted: Mar 25, 2022
• Last Verified: Mar 1, 2022

• Individual Participant Data (IPD) Sharing Statement: No
• Plan to Share IPD: No
• Studies a U.S. FDA-regulated Drug Product: Yes
• Studies a U.S. FDA-regulated Device Product: No
• Additional relevant MeSH terms: Sleep Initiation and Maintenance Disorders

Study Results

Participant Flow

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Period Title: Overall Study
STARTED	307	309	308
COMPLETED	283	280	286
NOT COMPLETED	24	29	22

Baseline Characteristics

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo	Total
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.	Total of all reporting groups
Overall Participants	307	309	308	924
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	186 60.6%	188 60.8%	187 60.7%	561 60.7%
>=65 years	121 39.4%	121 39.2%	121 39.3%	363 39.3%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	57.1 (14.0)	56.3 (14.4)	56.7 (14.1)	56.7 (14.2)
Sex: Female, Male (Count of Participants)
Female	215 70%	218 70.6%	205 66.6%	638 69%
Male	92 30%	91 29.4%	103 33.4%	286 31%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	17 5.5%	14 4.5%	16 5.2%	47 5.1%
Not Hispanic or Latino	288 93.8%	295 95.5%	290 94.2%	873 94.5%
Unknown	1 0.3%	0 0%	1 0.3%	2 0.2%
Not permitted as per legislation/regulation	1 0.3%	0 0%	1 0.3%	2 0.2%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	16 5.2%	26 8.4%	29 9.4%	71 7.7%
American Indian or Alaska Native	2 0.7%	0 0%	0 0%	2 0.2%
Native Hawaiian or other Pacific Islander	0 0%	1 0.3%	1 0.3%	2 0.2%
Asian	14 4.6%	11 3.6%	10 3.2%	35 3.8%
White	273 88.9%	271 87.7%	267 86.7%	811 87.8%
Not permitted as per legislation/regulation	1 0.3%	0 0%	1 0.3%	2 0.2%
Other	1 0.3%	0 0%	0 0%	1 0.1%

Outcome Measures

1. Primary Outcome

Title	Change From Baseline to Month 1 in Wake After Sleep Onset (WASO) (Sleep Maintenance)
Description	"Wake After Sleep Onset" is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography.
Time Frame	From baseline to Month 1 (i.e. for up to 1 month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [minutes]	-15.31	-24.19	-12.57

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in WASO (min) to Month 1 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.0001
	Comments	Mixed effects model for repeated measures: change from baseline in WASO = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.025; statistically significant = YES
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-11.62
	Confidence Interval	(2-Sided) 95%; -17.604 to -5.633
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in WASO (min) to Month 1 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.3669
	Comments	Mixed effects model for repeated measures: change from baseline in WASO = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.00977; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-2.74
	Confidence Interval	(2-Sided) 95%; -8.693 to 3.215
	Parameter Dispersion	Type: Value:
	Estimation Comments

2. Primary Outcome

Title	Change From Baseline to Month 3 in Wake After Sleep Onset (WASO)
Description	"Wake After Sleep Onset" is the time spent awake after onset of persistent sleep until lights on, as determined by polysomnography.
Time Frame	From baseline to Month 3 (i.e. for up to 3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [minutes]	-15.95	-24.25	-14.00

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in WASO (min) to Month 3 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.0028
	Comments	Mixed effects model for repeated measures: change from baseline in WASO = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.01563; statistically significant = YES
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-10.25
	Confidence Interval	(2-Sided) 95%; -16.95 to -3.548
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in WASO (min) to Month 3 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.5686
	Comments	Mixed effects model for repeated measures: change from baseline in WASO = baseline WASO + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0; statistically significant = NO
Method of Estimation	Estimation Parameter	LS Mean difference to placebo
	Estimated Value	-1.95
	Confidence Interval	(2-Sided) 95%; -8.666 to 4.764
	Parameter Dispersion	Type: Value:
	Estimation Comments

3. Primary Outcome

Title	Change From Baseline to Month 1 in Latency to Persistent Sleep (LPS) (Sleep Onset)
Description	"Latency to Persistent Sleep" is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography.
Time Frame	From baseline to Month 1 (i.e. for up to 1 month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [minutes]	-22.62	-26.46	-20.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in LPS (min) to Month 1 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.0303
	Comments	Mixed effects model for repeated measures: change from baseline in LPS = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.025; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-6.45
	Confidence Interval	(2-Sided) 95%; -12.282 to -0.614
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in LPS (min) to Month 1 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.3782
	Comments	Mixed effects model for repeated measures: change from baseline in LPS = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.00195; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-2.61
	Confidence Interval	(2-Sided) 95%; -8.41 to 3.197
	Parameter Dispersion	Type: Value:
	Estimation Comments

4. Primary Outcome

Title	Change From Baseline to Month 3 in Latency to Persistent Sleep (LPS)
Description	"Latency to Persistent Sleep" is the time from start of recording to the beginning of the first continuous 20 epochs (i.e., 10 minutes) scored as non-awake, i.e., epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep) or REM, as determined by polysomnography.
Time Frame	From baseline to Month 3 (i.e. for up to 3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [minutes]	-23.09	-28.91	-19.89

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in LPS (min) to Month 3 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.0053
	Comments	Mixed effects model for repeated measures: change from baseline in LPS = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.00313; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-9.01
	Confidence Interval	(2-Sided) 95%; -15.339 to -2.684
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in LPS (min) to Month 3 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	0.3233
	Comments	Mixed effects model for repeated measures: change from baseline in LPS = baseline LPS + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-3.19
	Confidence Interval	(2-Sided) 95%; -9.528 to 3.146
	Parameter Dispersion	Type: Value:
	Estimation Comments

5. Secondary Outcome

Title	Change From Baseline to Month 1 in the Subjective Total Sleep Time (sTST)
Description	"Subjective Total Sleep Time" is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time.
Time Frame	From baseline to Month 1 (i.e. for up to 1 month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [minutes]	41.01	43.77	27.64

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in sTST (min) to Month 1 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Hypothesis testing result: threshold for significance p = 0.0125; statistically significant = YES
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	16.13
	Confidence Interval	(2-Sided) 95%; 8.224 to 24.035
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in sTST (min) to Month 1 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	= 0.0009
	Comments	Mixed effects model for repeated measures: change from baseline in sTST = baseline sTST + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	13.37
	Confidence Interval	(2-Sided) 95%; 5.507 to 21.226
	Parameter Dispersion	Type: Value:
	Estimation Comments

6. Secondary Outcome

Title	Change From Baseline to Month 3 in the Subjective Total Sleep Time (sTST)
Description	Subjective Total Sleep Time is the total sleep time reported by the participant in the sleep diary questionnaire. A positive change from baseline indicates an increase in the subjective Total Sleep Time. A negative change from baseline indicates a decrease in subjective Total Sleep Time.
Time Frame	From baseline to Month 3 (i.e. for up to 3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [minutes]	50.70	56.18	37.12

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in sTST (min) to Month 3 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	<.0001
	Comments	Mixed effects model for repeated measures: change from baseline in sTST = baseline sTST + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.00781; statistically significant = YES
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	19.06
	Confidence Interval	(2-Sided) 95%; 10.125 to 27.994
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in sTST (min) to Month 3 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	= 0.0028
	Comments	Mixed effects model for repeated measures: change from baseline in sTST = baseline sTST + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	13.58
	Confidence Interval	(2-Sided) 95%; 4.691 to 22.475
	Parameter Dispersion	Type: Value:
	Estimation Comments

7. Secondary Outcome

Title	Change From Baseline to Month 1 in Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) Sleepiness Domain Score
Description	The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.
Time Frame	From baseline to Month 1 (i.e. for up to 1 month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-3.18	-3.51	-2.75

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 1 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	= 0.0733
	Comments	Mixed effects model for repeated measures: change from baseline in IDSIQ sleepiness domain score = baseline IDSIQ sleepiness domain score + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.00625; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) 95%; -1.581 to 0.071
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 1 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	= 0.3048
	Comments	Mixed effects model for repeated measures: change from baseline in IDSIQ sleepiness domain score = baseline IDSIQ sleepiness domain score + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-0.43
	Confidence Interval	(2-Sided) 95%; -1.251 to 0.392
	Parameter Dispersion	Type: Value:
	Estimation Comments

8. Secondary Outcome

Title	Change From Baseline to Month 3 in IDSIQ Sleepiness Domain Score
Description	The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a validated patient reported outcome instrument comprising 14 items (each using a numeric rating scale from 0 to 10) grouped into three domains (i.e., sleepiness, mood, and alert/cognition) reflecting daytime impairment of insomnia. The IDSIQ sleepiness domain has 4 items, and the domain score ranges from 0 to a maximum of 40, where a higher score indicates a greater burden. A negative change from baseline indicates an improvement and a positive change from baseline indicates a worsening.
Time Frame	From baseline to Month 3 (i.e. for up to 3 months)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-4.75	-5.27	-4.01

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 3 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	= 0.0120
	Comments	Mixed effects model for repeated measures: change from baseline in IDSIQ sleepiness domain score = baseline IDSIQ sleepiness domain score + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0.00391; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-1.25
	Confidence Interval	(2-Sided) 95%; -2.230 to -0.276
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 3 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments	The Type I error rate was controlled for the testing of multiple null hypotheses associated with the endpoint assessed at 1 and 3 months of treatment and the two dose levels studied. Each null hypothesis was tested against the alternative hypothesis that daridorexant improved the endpoint at the given dose and time point compared to placebo. The order of testing and the alpha level applied to each null hypothesis was based on the Bonferroni-based gatekeeping procedure (see SAP for details).
Statistical Test of Hypothesis	p-Value	= 0.1393
	Comments	Mixed effects model for repeated measures: change from baseline in IDSIQ sleepiness domain score = baseline IDSIQ sleepiness domain score + age group (< 65; ≥ 65 years) + treatment + visit + treatment × visit + baseline × visit.
	Method	Mixed Models Analysis
	Comments	Hypothesis testing result: threshold for significance p = 0; statistically significant = NO
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-0.73
	Confidence Interval	(2-Sided) 95%; -1.706 to 0.239
	Parameter Dispersion	Type: Value:
	Estimation Comments

9. Post-Hoc Outcome

Title	Change From Baseline to Month 1 in Log-transformed LPS (LSGM Ratio to Baseline)
Description	Post-hoc analyses were performed using log-transformed LPS data, as the LPS values at baseline more closely resembled a log-normal distribution (skewed to the right) than a normal distribution.
Time Frame	From baseline to Month 1 (i.e. for up to 1 month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Geometric Least Squares Mean (95% Confidence Interval) [minutes]	0.59	0.50	0.63

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 1 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.2506
	Comments	Mixed effects model for repeated measures: log(value/baseline) = log(baseline) + age group(< 65; ≥ 65 years) + treatment + visit + treatment x visit + log(baseline) x visit.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	0.93
	Confidence Interval	(2-Sided) 95%; 0.82 to 1.05
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 1 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0004
	Comments	Mixed effects model for repeated measures: log(value/baseline) = log(baseline) + age group(< 65; ≥ 65 years) + treatment + visit + treatment x visit + log(baseline) x visit.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	0.80
	Confidence Interval	(2-Sided) 95%; 0.71 to 0.91
	Parameter Dispersion	Type: Value:
	Estimation Comments

10. Post-Hoc Outcome

Title	Change From Baseline to Month 3 in Log-transformed LPS (LSGM Ratio to Baseline)
Description	Post-hoc analyses were performed using log-transformed LPS data, as the LPS values at baseline more closely resembled a log-normal distribution (skewed to the right) than a normal distribution.
Time Frame	From baseline to Month 3 (i.e. for up to 3 month)

Outcome Measure Data

Analysis Population Description

[Not Specified]

Arm/Group Title	Daridorexant 10 mg	Daridorexant 25 mg	Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.	Daridorexant was administered as tablets, orally, once daily in the evening.	Matching placebo was administered as tablets, orally, once daily in the evening.
Measure Participants	307	309	308
Geometric Least Squares Mean (95% Confidence Interval) [minutes]	0.56	0.48	0.58

Statistical Analysis 1

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 10 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 3 (Daridorexant 10 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.5037
	Comments	Mixed effects model for repeated measures: log(value/baseline) = log(baseline) + age group(< 65; ≥ 65 years) + treatment + visit + treatment x visit + log(baseline) x visit.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	0.96
	Confidence Interval	(2-Sided) 95%; 0.84 to 1.09
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 25 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in LPS (min) to Month 3 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0021
	Comments	Mixed effects model for repeated measures: log(value/baseline) = log(baseline) + age group(< 65; ≥ 65 years) + treatment + visit + treatment x visit + log(baseline) x visit.
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	0.81
	Confidence Interval	(2-Sided) 95%; 0.71 to 0.93
	Parameter Dispersion	Type: Value:
	Estimation Comments

Adverse Events

Time Frame	Treatment-emergent AEs were AEs that started or worsened on or after the DB study treatment start date up to the earlier of 30 days after DB study treatment end date or the date of enrollment in the ID-078A303 extension study. The planned duration of DB treatment was 84 days ± 2 days, i.e., 12 weeks ± 2 days.
Adverse Event Reporting Description	The number of subjects affected is the number of subjects with at least one event.
Arm/Group Title	Daridorexant 10 mg		Daridorexant 25 mg		Placebo
Arm/Group Description	Daridorexant was administered as tablets, orally, once daily in the evening.		Daridorexant was administered as tablets, orally, once daily in the evening.		Matching placebo was administered as tablets, orally, once daily in the evening.
All Cause Mortality
	Daridorexant 10 mg		Daridorexant 25 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	0/306 (0%)		0/308 (0%)		0/306 (0%)
Serious Adverse Events
	Daridorexant 10 mg		Daridorexant 25 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	3/306 (1%)		3/308 (1%)		4/306 (1.3%)
Cardiac disorders
Microvascular coronary artery disease	1/306 (0.3%)	1	0/308 (0%)	0	0/306 (0%)	0
Ear and labyrinth disorders
Vertigo	1/306 (0.3%)	1	0/308 (0%)	0	0/306 (0%)	0
Infections and infestations
Appendicitis	1/306 (0.3%)	1	0/308 (0%)	0	0/306 (0%)	0
Injury, poisoning and procedural complications
Joint dislocation	0/306 (0%)	0	0/308 (0%)	0	1/306 (0.3%)	1
Meniscus injury	0/306 (0%)	0	0/308 (0%)	0	1/306 (0.3%)	1
Musculoskeletal and connective tissue disorders
Rotator cuff syndrome	0/306 (0%)	0	0/308 (0%)	0	1/306 (0.3%)	1
Nervous system disorders
Lumbar radiculopathy	0/306 (0%)	0	1/308 (0.3%)	1	0/306 (0%)	0
Psychiatric disorders
Schizophrenia	0/306 (0%)	0	1/308 (0.3%)	1	0/306 (0%)	0
Respiratory, thoracic and mediastinal disorders
Haemoptysis	0/306 (0%)	0	1/308 (0.3%)	1	0/306 (0%)	0
Vascular disorders
Hypertensive crisis	0/306 (0%)	0	0/308 (0%)	0	1/306 (0.3%)	1
Other (Not Including Serious) Adverse Events
	Daridorexant 10 mg		Daridorexant 25 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	49/306 (16%)		28/308 (9.1%)		30/306 (9.8%)
Infections and infestations
Nasopharyngitis	38/306 (12.4%)	41	13/308 (4.2%)	15	20/306 (6.5%)	22
Nervous system disorders
Headache	14/306 (4.6%)	19	16/308 (5.2%)	16	11/306 (3.6%)	12

Limitations/Caveats

[Not Specified]

More Information

Certain Agreements

Principal Investigators are NOT employed by the organization sponsoring the study.

Any study-related publication written independently by investigators must be submitted to Idorsia for review at least 30 days prior to submission for publication or presentation at a congress. Upon review, Idorsia may provide comments, and may also request alterations and/or deletions for the sole purpose of protecting its confidential information and/or patent rights. Neither the institution nor the investigator should permit publication during such a review period.