Study to Assess the Efficacy and Safety of ACT-541468 (Daridorexant) in Adult and Elderly Subjects With Insomnia Disorder

• Sponsor: Idorsia Pharmaceuticals Ltd. (Industry)
• Overall Status: Completed
• CT.gov ID: NCT03545191
• Collaborator: (none)
• Enrollment: 930
• Locations: 81
• Arms: 3
• Actual Duration (Months): 20.7
• Patients Per Site: 11.5
• Patients Per Site Per Month: 0.6

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 25 mg; Drug: Daridorexant 50 mg; Other: Placebo	Phase 3

Study Design

• Study Type: Interventional
• Actual Enrollment: 930 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: Jun 4, 2018
• Actual Primary Completion Date: Jan 25, 2020
• Actual Study Completion Date: Feb 25, 2020

Arms and Interventions

Arm	Intervention/Treatment
Experimental: Daridorexant 25 mg	Drug: Daridorexant 25 mg; Daridorexant will be administered as tablets, orally, once daily in the evening.
Experimental: Daridorexant 50 mg	Drug: Daridorexant 50 mg; 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;

• 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	Pinnacle Research Group, LLC	Anniston	Alabama	United States	36207
2	Pulmonary Associates of the Southeast/WCR	Birmingham	Alabama	United States	35243
3	Preferred Research Partners, Inc	Little Rock	Arkansas	United States	72211
4	Woodland Research Northwest	Rogers	Arkansas	United States	72758
5	Marvel Clinical Research	Huntington Beach	California	United States	92647
6	Long Beach Clinical Trials	Long Beach	California	United States	90806
7	Artemis Institute for Clinical Research	San Diego	California	United States	92103
8	PAB Clinical Research	Brandon	Florida	United States	33511
9	St. Francis Sleep Allergy and Lung Institute	Clearwater	Florida	United States	33765
10	Innovative Clinical Research, Inc.	Hialeah	Florida	United States	33012
11	Research Centers of America	Hollywood	Florida	United States	33024
12	Canvas Clinical Research, LLC	Lake Worth	Florida	United States	33467
13	BioMed Research Institute	Miami	Florida	United States	33126
14	Clinical Site Partners, LLC	Winter Park	Florida	United States	32789
15	LaPorte County Institute for Clinical Research	Michigan City	Indiana	United States	46360
16	Kentucky Research Group	Louisville	Kentucky	United States	40218
17	Helene Emsellem, MD	Chevy Chase	Maryland	United States	20815
18	Infinity Medical Research, Inc.	North Dartmouth	Massachusetts	United States	02747
19	Barrett Clinic	La Vista	Nebraska	United States	68128
20	Clinical Research Center of Nevada	Las Vegas	Nevada	United States	89104
21	Clinilabs NYC	New York	New York	United States	10019
22	Research Carolina of Huntersville	Huntersville	North Carolina	United States	28078
23	Coastal Carolina Healthcare	New Bern	North Carolina	United States	28562
24	CTI Clinical Research Center	Cincinnati	Ohio	United States	45212
25	Oregon Center for Clinical Investigations,Inc	Salem	Oregon	United States	97301
26	BTC of Lincoln	Lincoln	Rhode Island	United States	02865
27	Omega Medical Research	Warwick	Rhode Island	United States	02886
28	Bogan Sleep Consulting, LLC	Columbia	South Carolina	United States	29201
29	Coastal Carolina Research Center	Mount Pleasant	South Carolina	United States	29464
30	Tri-State Mountain Neurology	Johnson City	Tennessee	United States	37604
31	Inquest Clinical Research	Baytown	Texas	United States	77521
32	Sleep Therapy & Research Center	San Antonio	Texas	United States	78229
33	Aspen Clinical Research	Orem	Utah	United States	84058
34	Pulmonary Associates of Richmond	Richmond	Virginia	United States	23225
35	Sleep Disorders Centers of the Mid-Atlantic	Vienna	Virginia	United States	22182
36	Swedish Medical Center	Seattle	Washington	United States	98122
37	Respiratory Clinical Trials	Adelaide		Australia	5065
38	Genesis Sleep Care Queensland	Auchenflower		Australia	4066
39	Melbourne Sleep Disorders Centre	East Melbourne		Australia	3002
40	The Woolcock Institute of Medical Research	Glebe		Australia	2037
41	Royal Melbourne Hospital, Department of Respiratory Medicine	Parkville		Australia	3052
42	Gold Coast University Hospital, Respiratory Medicine and Sleep Services	Southport		Australia	4215
43	Westmead Hospital, Department of Respiratory and Sleep Medicine	Westmead		Australia	2145
44	Tri-Hospital Sleep Laboratory West	Mississauga		Canada	L5B 4M4
45	CRIUSMQ- CIUSSSCN, CETS (clinique du sommeil)	Quebec		Canada	G1J 2G2
46	MedSleep	Toronto		Canada	M4P 1P2
47	Jodha Tishon Inc.	Toronto		Canada	M5G1N8
48	Scan Sleep Specialists	København		Denmark	1053
49	St Hedwig-Krankenhaus, Klinik für Schlaf- und Chronomedizin	Berlin		Germany	10115
50	emovis GmbH	Berlin		Germany	10629
51	Synexus Berlin Research Centre	Berlin		Germany	12627
52	Clinical Trial Center North GmbH & Co. KG	Hamburg		Germany	20251
53	Klinische Forschung Hamburg GmbH	Hamburg		Germany	20253
54	Klinische Forschung Karlsruhe GmbH	Karlsruhe		Germany	76137
55	Studienzentrum Wilhelmshöhe GmbH	Kassel		Germany	34131
56	Synexus Leipzig Research Centre	Leipzig		Germany	4103
57	Klinikum Rechts der lsar TU München Dept. of Psychiatry and Psychotherapy	München		Germany	81675
58	Kinische Forschung Schwerin GmbH	Schwerin		Germany	19055
59	ZMS Zentrum für medizinische Studien GmbH	Warendorf		Germany	48231
60	Ospedale San Raffaele - Centro per i Disturbi del Sonno San Raffaele - Ville-Turro - Pallazzina E	Milano		Italy	20127
61	IRCCS FONDAZIONE Istituto Neurologico Nazionale "Casimiro Mondino" - Centro di Ricerca Interdipartimentale per la SSclerosi Multipla (CRISM) -	Pavia		Italy	27100
62	Azienda Ospedaliero Universitaria Pisana - Ospedale S. Chiara - Centro di Medicina del Sonno - Clinica Neuroligica - Dipartimento de Neuroscienze	Pisa		Italy	56126
63	AOU Citta della Salute e della Scienza - Molinette - SSD Medicina del Sonno	Torino		Italy	10146
64	PI-House - Centrum Badań Klinicznych	Gdańsk		Poland	80-546
65	Ośrodek Medycyny Study Nurseu Instytutu Psychiatrii i Neurologii (Sleep Disorders Center)	Warsaw		Poland	02-957
66	EMC Instytut Medyczny SA, Przychodnia przy Łowieckiej	Wroclaw		Poland	50220
67	General Hospital Bel Medic, Center for Sleep disorders	Belgrade		Serbia	11000
68	Medigroup - Health Center Dr Ristic (MediGroup Dom zdravlja "Dr Ristic") - Neurology Department	Novi Beograd		Serbia	11070
69	Centro Médico Teknon - Medicina del Sueño	Barcelona		Spain	8017
70	Hospital de La Santa Creu I Sant Pau	Barcelona		Spain	8025
71	Hospital Universitari Vall d'Hebron - Neurophisiology Deparment - Sleep Unit	Barcelona		Spain	8035
72	Hospital General de Castellon	Castelló de la Plana		Spain	12004
73	Instituto de Investigaciones del Sueno	Madrid		Spain	28036
74	San Carlos University Hospital - Servicio de Neurofisiología Clínica	Madrid		Spain	28040
75	Hospital Universitario Araba - Unidad Funcional de Trastornos del Sueño	Vitoria-Gasteiz		Spain	1004
76	Hospital MAZ - Neurophisiology and Sleep Department	Zaragoza		Spain	50015
77	KSM Bad Zurzach, Klinik für Schlafmedizin	Bad Zurzach		Switzerland	5330
78	Universitäre Psychiatrische Kliniken Basel (Upk)	Basel		Switzerland	4002
79	Universitätsklinik für Neurologie, Inselspital Bern, Schlaf-Wach-Epilepsie-Zentrum	Bern		Switzerland	3010
80	Zentrum für Schlafmedizin Zürcher Oberland, Zürcher RehaZentrum Wald	Wald		Switzerland	8636
81	Zentrum für Schlafmedizin GZO AG Spital Wetzikon	Wetzikon		Switzerland	8620

Sponsors and Collaborators

• Idorsia Pharmaceuticals Ltd.

Investigators

• Study Director: Clinical Trials, Idorsia Pharmaceuticals Ltd.

Study Documents (Full-Text)

• Study Protocol - Jul 30, 2018
• Statistical Analysis Plan - Mar 25, 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: NCT03545191
• Other Study ID Numbers: ID-078A301
• First Posted: Jun 4, 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 25 mg	Daridorexant 50 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	310	310	310
COMPLETED	288	285	280
NOT COMPLETED	22	25	30

Baseline Characteristics

Arm/Group Title	Daridorexant 25 mg	Daridorexant 50 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	310	310	310	930
Age (Count of Participants)
<=18 years	0 0%	0 0%	0 0%	0 0%
Between 18 and 65 years	189 61%	189 61%	188 60.6%	566 60.9%
>=65 years	121 39%	121 39%	122 39.4%	364 39.1%
Age (years) [Mean (Standard Deviation) ]
Mean (Standard Deviation) [years]	55.8 (15.3)	55.5 (15.3)	55.1 (15.4)	55.4 (15.3)
Sex: Female, Male (Count of Participants)
Female	215 69.4%	199 64.2%	210 67.7%	624 67.1%
Male	95 30.6%	111 35.8%	100 32.3%	306 32.9%
Race/Ethnicity, Customized (Count of Participants)
Hispanic or Latino	51 16.5%	44 14.2%	51 16.5%	146 15.7%
Not Hispanic or Latino	259 83.5%	265 85.5%	259 83.5%	783 84.2%
Unknown	0 0%	1 0.3%	0 0%	1 0.1%
Race/Ethnicity, Customized (Count of Participants)
Black or African American	19 6.1%	30 9.7%	28 9%	77 8.3%
American Indian or Alaska Native	0 0%	1 0.3%	0 0%	1 0.1%
Native Hawaiian or other Pacific Islander	1 0.3%	1 0.3%	0 0%	2 0.2%
Asian	3 1%	4 1.3%	2 0.6%	9 1%
White	287 92.6%	274 88.4%	278 89.7%	839 90.2%
Other	0 0%	0 0%	2 0.6%	2 0.2%

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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [minutes]	-18.40	-28.98	-6.20

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
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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-12.20
	Confidence Interval	(2-Sided) 95%; -17.435 to -6.961
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in WASO (min) to Month 1 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-22.78
	Confidence Interval	(2-Sided) 95%; -27.996 to -17.567
	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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [minutes]	-22.97	-29.41	-11.11

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
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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-11.86
	Confidence Interval	(2-Sided) 95%; -17.494 to -6.23
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in WASO (min) to Month 3 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-18.3
	Confidence Interval	(2-Sided) 95%; -23.945 to -12.661
	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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [minutes]	-28.17	-31.20	-19.85

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
Statistical Test of Hypothesis	p-Value	0.0005
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-8.32
	Confidence Interval	(2-Sided) 95%; -13.014 to -3.629
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in LPS (min) to Month 1 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-11.35
	Confidence Interval	(2-Sided) 95%; -16.022 to -6.687
	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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [minutes]	-30.73	-34.80	-23.13

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
Statistical Test of Hypothesis	p-Value	0.0015
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-7.59
	Confidence Interval	(2-Sided) 95%; -12.265 to -2.923
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in LPS (min) to Month 3 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-11.67
	Confidence Interval	(2-Sided) 95%; -16.348 to -6.994
	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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [minutes]	34.18	43.62	21.56

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
Statistical Test of Hypothesis	p-Value	= 0.0013
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	12.62
	Confidence Interval	(2-Sided) 95%; 4.953 to 20.288
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 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
Statistical Test of Hypothesis	p-Value	< 0.0001
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	22.06
	Confidence Interval	(2-Sided) 95%; 14.405 to 29.708
	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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [minutes]	47.83	57.67	37.90

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
Statistical Test of Hypothesis	p-Value	= 0.0334
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	9.93
	Confidence Interval	(2-Sided) 95%; 0.782 to 19.082
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in sTST (min) to Month 3 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	< .00001
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	19.77
	Confidence Interval	(2-Sided) 95%; 10.623 to 28.918
	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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-2.77	-3.77	-2.02

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
Statistical Test of Hypothesis	p-Value	= 0.0547
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-0.75
	Confidence Interval	(2-Sided) 95%; -1.515 to 0.015
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 1 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	< .00001
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-1.75
	Confidence Interval	(2-Sided) 95%; -2.508 to -0.983
	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 25 mg	Daridorexant 50 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	310	310	310
Least Squares Mean (95% Confidence Interval) [Scores on a scale]	-4.78	-5.70	-3.79

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
Statistical Test of Hypothesis	p-Value	0.0534
	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
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-0.99
	Confidence Interval	(2-Sided) 95%; -1.990 to 0.014
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in IDSIQ sleepiness domain score to Month 3 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	= 0.0002
	Comments
	Method	Mixed Models Analysis
	Comments
Method of Estimation	Estimation Parameter	LS mean difference to placebo
	Estimated Value	-1.90
	Confidence Interval	(2-Sided) 95%; -2.905 to -0.905
	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 25 mg	Daridorexant 50 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	310	310	310
Geometric Least Squares Mean (95% Confidence Interval) [minutes]	0.49	0.45	0.62

Statistical Analysis 1

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	0.0003
	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	LSGM ratio to placebo
	Estimated Value	0.79
	Confidence Interval	(2-Sided) 95%; 0.70 to 0.90
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 1 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	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	LSGM ratio to placebo
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.65 to 0.82
	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 25 mg	Daridorexant 50 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	310	310	310
Geometric Least Squares Mean (95% Confidence Interval) [minutes]	0.43	0.41	0.56

Statistical Analysis 1

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 3 (Daridorexant 25 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	0.0002
	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	LSGM ratio to placebo
	Estimated Value	0.78
	Confidence Interval	(2-Sided) 95%; 0.68 to 0.89
	Parameter Dispersion	Type: Value:
	Estimation Comments

Statistical Analysis 2

Statistical Analysis Overview	Comparison Group Selection	Daridorexant 50 mg, Placebo
	Comments	Between-treatment analysis for change from baseline in log transformed LPS (min) to Month 3 (Daridorexant 50 mg vs placebo).
	Type of Statistical Test	Other
	Comments
Statistical Test of Hypothesis	p-Value	<0.0001
	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	LSGM ratio to placebo
	Estimated Value	0.73
	Confidence Interval	(2-Sided) 95%; 0.64 to 0.83
	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 25 mg		Daridorexant 50 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 25 mg		Daridorexant 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	1/310 (0.3%)		0/308 (0%)		0/309 (0%)
Serious Adverse Events
	Daridorexant 25 mg		Daridorexant 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	2/310 (0.6%)		3/308 (1%)		7/309 (2.3%)
Cardiac disorders
Cardiac arrest	1/310 (0.3%)	1	0/308 (0%)	0	0/309 (0%)	0
General disorders
Influenza like illness	1/310 (0.3%)	1	0/308 (0%)	0	0/309 (0%)	0
Infections and infestations
Anal abscess	0/310 (0%)	0	0/308 (0%)	0	1/309 (0.3%)	1
Herpes zoster	0/310 (0%)	0	0/308 (0%)	0	1/309 (0.3%)	1
Injury, poisoning and procedural complications
Post procedural haemorrhage	0/310 (0%)	0	1/308 (0.3%)	1	0/309 (0%)	0
Ankle fracture	0/310 (0%)	0	0/308 (0%)	0	1/309 (0.3%)	1
Investigations
Haemoglobin decreased	0/310 (0%)	0	1/308 (0.3%)	1	0/309 (0%)	0
Neoplasms benign, malignant and unspecified (incl cysts and polyps)
Adenocarcinoma of colon	0/310 (0%)	0	1/308 (0.3%)	1	0/309 (0%)	0
Nervous system disorders
Syncope	0/310 (0%)	0	1/308 (0.3%)	1	2/309 (0.6%)	2
Psychiatric disorders
Depression	0/310 (0%)	0	0/308 (0%)	0	2/309 (0.6%)	2
Panic attack	0/310 (0%)	0	0/308 (0%)	0	1/309 (0.3%)	1
Renal and urinary disorders
Renal colic	0/310 (0%)	0	1/308 (0.3%)	1	0/309 (0%)	0
Other (Not Including Serious) Adverse Events
	Daridorexant 25 mg		Daridorexant 50 mg		Placebo
	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events	Affected / at Risk (%)	# Events
Total	44/310 (14.2%)		41/308 (13.3%)		35/309 (11.3%)
Infections and infestations
Nasopharyngitis	28/310 (9%)	28	24/308 (7.8%)	26	24/309 (7.8%)	29
Nervous system disorders
Headache	17/310 (5.5%)	24	20/308 (6.5%)	27	12/309 (3.9%)	18

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.