Clinical trial NCT05597020
Conditions: Insomnia Disorder Nocturia
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2023-02-16; Completion date: 2024-04-18
Enrollment: 60 participants; Allocation: RANDOMIZED; Intervention model: CROSSOVER

Brief summary:
A study to find out if daridorexant is safe and efficacious in patients with insomnia and comorbid nocturia

Detailed description:

Arms: arm 1: Daridorexant will be taken orally, once daily in the evening within approximately 30 min before going to bed. arm 2: Matching placebo will be taken orally, once daily in the evening within approximately 30 min before going to bed.
Interventions: intervention 1: Daridorexant intervention 2: Placebo
Intervention descriptions: intervention 1: Daridorexant is available as oral film-coated tablets at a strength of 50 mg. intervention 2: Placebo matching daridorexant is provided as identical-looking oral tablets, formulated with the same inactive ingredients (excipients) as the active tablets.

Protocol documents:
Prot_000.pdf: 
 
 
 
TPL-100807_v01 
 
 
 
Daridorexant (ACT-541468) 
Insomnia and comorbid nocturia 
Global Protocol ID-078A401 
 
A multi-center, double-blind, randomized, placebo-controlled, 2-way cross-over post 
approval study to investigate the efficacy of daridorexant in subjects with insomnia 
and comorbid nocturia 
 
 
 
Study Phase: 
4 
EU CT Number: 
2022-501246-30-00 
Status and version: 
Final Version 3 
Date: 
4 September 2023 
Document type: 
Global Protocol  
Idorsia document number  
(Doc No.): 
D-23.307 
 
 
 
 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Idorsia Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, and your staff and an independent ethics committee(s) 
or institutional review board(s). It is understood that this information will not be disclosed to others without 
written authorization from Idorsia Pharmaceuticals Ltd, except to the extent necessary to obtain informed 
consent from those persons to whom the study treatment(s) may be administered. 
 
 


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SPONSOR CONTACT DETAILS 
Sponsor 
Idorsia Pharmaceuticals Ltd 
Hegenheimermattweg 91 
CH-4123 Allschwil 
Switzerland 
 
+41 58 844 00 00 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
Toll Telephone Number  
Site-specific toll telephone numbers and toll-free 
telephone numbers for the Medical Emergency 
Hotline can be found in the Investigator Site File 
 
CONTRACT RESEARCH ORGANIZATION INFORMATION 
Some key study activities are delegated to Contract Research Organizations. A list of 
site-specific contact details can be found in the Investigator Site File. 
 
 
 


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SIGNATURE PAGE FOR IDORSIA PHARMACEUTICALS LTD 
Hereinafter called Idorsia 
Compound name / number 
Daridorexant (ACT-541468) 
Indication 
Insomnia and comorbid nocturia 
Protocol number, study title 
ID-078A401 
A multi-center, double-blind, randomized, placebo-controlled, 2-way cross-over post 
approval study to investigate the efficacy of daridorexant in subjects with insomnia and 
comorbid nocturia 
 
 
 
 
Name (Title) 
Date 
 
Signature 
 
 
MSc  
 
 
 
 
 MD, PhD 
 
 
 
 
 
 MSc 
 
 
 
 
 
PPD
PPD
PPD
PPD
PPD
PPD
PPD
PPD


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INVESTIGATOR SIGNATURE PAGE 
Compound name / number 
Daridorexant (ACT-541468) 
Indication 
Insomnia and comorbid nocturia 
Protocol number, study title 
ID-078A401 
A multi-center, double-blind, randomized, placebo-controlled, 2-way cross-over post 
approval study to investigate the efficacy of daridorexant in subjects with insomnia and 
comorbid nocturia 
 
I agree to the terms and conditions relating to this study as defined in this protocol and any 
other protocol-related documents. I fully understand that any changes instituted by the 
investigator(s) without previous agreement with the sponsor would constitute a protocol 
deviation, including any ancillary studies or procedures performed on subjects (other than 
those procedures necessary for the well-being of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, ICH 
GCP guidelines, and applicable regulations and laws. 
 
 
Principal Investigator 
Location 
(Site number) 
Date 
 Signature 
 
 
 
 
 
 
  
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................11 
SUBSTANTIAL GLOBAL AMENDMENT 2 .................................................................14 
1 
PROTOCOL SUMMARY ..........................................................................................16 
1.1 
Protocol synopsis ID-078A401 ....................................................................16 
1.2 
Schema ..........................................................................................................27 
1.3 
Schedule of activities ....................................................................................27 
2 
INTRODUCTION .......................................................................................................31 
2.1 
Insomnia and comorbid nocturia ..................................................................31 
2.1.1 
Definition ..........................................................................................31 
2.1.2 
Current treatment strategies ..............................................................31 
2.2 
Daridorexant .................................................................................................32 
2.3 
Study rationale ..............................................................................................33 
2.4 
Benefit/risk assessment .................................................................................34 
2.4.1 
Clinical trial ......................................................................................34 
2.4.2 
Daridorexant .....................................................................................34 
2.4.3 
Safety and risk-minimization included in this study ........................34 
3 
STUDY OBJECTIVES AND ENDPOINTS ..............................................................35 
3.1 
Objectives .....................................................................................................35 
3.2 
Efficacy assessments and time points ...........................................................36 
3.2.1 
SDQ [Appendix 2] ............................................................................36 
3.2.2 
IDSIQ [Appendix 3] .........................................................................37 
3.2.3 
ISI© [Appendix 4] .............................................................................37 
3.2.4 
PGA-S (daytime symptoms) [Appendix 5] ......................................37 
3.2.5 
PGI-C (daytime symptoms) [Appendix 5] ........................................38 
3.2.6 
PGI-C (nighttime symptoms) [Appendix 5] .....................................38 
3.2.7 
PGA-S (daily life) [Appendix 5] ......................................................38 
3.2.8 
PGI-C (daily life) [Appendix 5] ........................................................38 
3.2.9 
Minze Diary Pod ...............................................................................38 
3.2.10 
EQ-5D-3L [Appendix 6] ...................................................................39 
3.2.11 
ICIQ-NQoL [Appendix 7] ................................................................39 
3.2.12 
ICIQ-MLUTS [Appendix 8] .............................................................39 
3.2.13 
ICIQ-FLUTS [Appendix 9] ..............................................................40 
3.2.14 
Treatment satisfaction [Appendix 12] ..............................................40 
3.2.15 
Treatment period preference [Appendix 13] ....................................40 


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3.2.16 
Narrative [Appendix 14] ...................................................................40 
3.3 
Safety assessments ........................................................................................40 
3.3.1 
Vital signs .........................................................................................41 
3.3.2 
VAS [Appendix 2] ............................................................................41 
3.3.3 
Clinical laboratory assessments ........................................................41 
3.3.4 
C-SSRS© [Appendix 10] ...................................................................41 
3.4 
Endpoints ......................................................................................................42 
3.5 
Appropriateness of endpoints .......................................................................45 
4 
STUDY DESIGN AND PLAN ...................................................................................46 
4.1 
Study design .................................................................................................46 
4.1.1 
Study periods for an individual subject ............................................46 
4.2 
Study duration and global end-of-study definition .......................................47 
4.3 
Study design rationale ..................................................................................47 
4.4 
Study committee(s) .......................................................................................48 
5 
STUDY POPULATION .............................................................................................48 
5.1 
Subject population description .....................................................................48 
5.2 
Inclusion criteria ...........................................................................................48 
5.3 
Exclusion criteria ..........................................................................................49 
5.4 
Rationale for the selection of the study population ......................................51 
5.5 
Contraception requirements for women of childbearing potential ...............52 
5.6 
Contraception for male subjects with a partner who is of childbearing 
potential ........................................................................................................52 
5.7 
Dietary aspects and physical activity restrictions .........................................52 
5.8 
Screen failures and re-screening ...................................................................52 
5.9 
Criteria for withdrawal and retention of subjects .........................................52 
5.9.1 
Study treatment interruption and premature discontinuation of 
study treatment ..................................................................................53 
5.9.1.1 
Pregnancy / pregnancy plans .................................................. 54 
5.9.1.2 
C-SSRS© ................................................................................. 54 
5.9.1.3 
Concomitant use of forbidden medications ............................ 54 
5.9.1.4 
Occurrence of complex sleep behaviors while on study 
treatment ................................................................................. 54 
5.9.2 
Withdrawal from the study ...............................................................54 
5.9.3 
Lost to follow-up ..............................................................................55 
5.9.4 
Retention of subjects .........................................................................55 
6 
TREATMENTS ..........................................................................................................56 
6.1 
Study treatment .............................................................................................56 


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6.1.1 
IMP and matching placebo description ............................................56 
6.1.2 
Study treatment dosing and administration ......................................56 
6.1.2.1 
Study treatment dose adjustments .......................................... 56 
6.1.3 
Justification for dose .........................................................................56 
6.1.4 
Treatment assignment .......................................................................57 
6.1.5 
Blinding ............................................................................................57 
6.1.5.1 
Double-blind treatment period ............................................... 57 
6.1.6 
Unblinding ........................................................................................57 
6.1.6.1 
Unblinding for final analyses ................................................. 57 
6.1.6.2 
Unblinding for IDMC ............................................................. 57 
6.1.6.3 
Unblinding for interim analyses ............................................. 58 
6.1.6.4 
Unblinding for SUSARs ......................................................... 58 
6.1.6.5 
Emergency procedure for unblinding ..................................... 58 
6.1.7 
Study treatment handling/preparation/storage/accountability ..........58 
6.1.7.1 
Study treatment packaging and labeling ................................ 59 
6.1.7.2 
Study treatment distribution and storage at the site ............... 59 
6.1.7.3 
Study treatment dispensing .................................................... 59 
6.1.7.4 
Study treatment accountability ............................................... 59 
6.1.7.5 
Study treatment return and destruction .................................. 60 
6.1.8 
Study treatment compliance ..............................................................60 
6.2 
Previous and concomitant medications / non-pharmacological therapy ......61 
6.2.1 
Allowed concomitant therapy ...........................................................61 
6.2.2 
Forbidden concomitant therapy ........................................................61 
6.3 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................61 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS AND PROCEDURES ...........62 
7.1 
General information ......................................................................................62 
7.1.1 
Screening ..........................................................................................62 
7.1.2 
Unscheduled visits ............................................................................62 
7.1.3 
Study completion ..............................................................................62 
7.2 
Study assessments and procedures ...............................................................63 
7.2.1 
Demographics / baseline characteristics ...........................................63 
7.2.2 
Reporting of previous/concomitant medications / 
non-pharmacological therapy / auxiliary medicinal products 
and methods of birth control in the eCRF .........................................64 
8 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................64 
8.1 
Safety definitions ..........................................................................................64 
8.1.1 
Definition of adverse events of special interest ................................65 


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8.1.2 
Definition of serious adverse events .................................................65 
8.1.3 
Intensity of adverse events ................................................................66 
8.1.4 
Relationship to study treatment ........................................................66 
8.1.5 
Relationship to study design or protocol-mandated procedure ........67 
8.1.6 
Definition of study treatment overdose, misuse, and abuse .............67 
8.2 
Reporting procedures ....................................................................................67 
8.2.1 
Reporting adverse events ..................................................................67 
8.2.2 
Reporting serious adverse events ......................................................68 
8.2.3 
Reporting procedure for SUSARs ....................................................68 
8.3 
Pregnancy .....................................................................................................69 
8.3.1 
Reporting of pregnancy ....................................................................69 
8.3.2 
Follow-up of pregnancy ....................................................................69 
9 
STATISTICAL METHODS .......................................................................................69 
9.1 
Analysis sets .................................................................................................70 
9.1.1 
Screened analysis set ........................................................................70 
9.1.2 
Randomized analysis set ...................................................................70 
9.1.3 
Full analysis set .................................................................................70 
9.1.4 
Per-protocol set .................................................................................70 
9.1.5 
Safety set ...........................................................................................70 
9.1.6 
Other analysis sets ............................................................................70 
9.1.7 
Usage of the analysis sets .................................................................70 
9.2 
Description of statistical analyses .................................................................71 
9.2.1 
Overall testing strategy .....................................................................71 
9.2.2 
Analysis of the primary efficacy endpoint ........................................71 
9.2.2.1 
Estimands ............................................................................... 71 
9.2.2.2 
Variable definition (sTST) ..................................................... 72 
9.2.2.3 
Analysis of primary estimand (primary efficacy analysis) .... 73 
9.2.2.4 
Handling of missing data and intercurrent events .................. 73 
9.2.2.5 
Sensitivity analyses ................................................................ 73 
9.2.2.6 
Supportive analyses ................................................................ 74 
9.2.2.7 
Subgroup analyses .................................................................. 74 
9.2.3 
Analysis of the secondary efficacy endpoints ...................................74 
9.2.4 
Analysis of other efficacy endpoints ................................................74 
9.2.5 
Analysis of safety outcomes .............................................................74 
9.2.5.1 
Adverse events ....................................................................... 74 
9.2.5.2 
Vital signs ............................................................................... 75 
9.2.6 
Analyses of other outcomes ..............................................................75 
9.3 
Interim analyses ............................................................................................75 
9.4 
Sample size ...................................................................................................75 


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9.4.1 
Power considerations for the endpoint change from baseline to 
Week 4 in number of nocturnal voids assessed using a voiding 
diary ..................................................................................................76 
10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ..................................................................................................76 
10.1 
Regulatory and ethical considerations ..........................................................76 
10.2 
Informed consent process .............................................................................77 
10.3 
Data protection and privacy ..........................................................................78 
10.4 
Indemnification, compensation, and refund of expenses to subjects 
and investigators ...........................................................................................78 
10.5 
Essential documents and retention of documents .........................................78 
10.5.1 
Investigator Site File .........................................................................79 
10.5.2 
Source documents .............................................................................79 
10.6 
Data handling ................................................................................................80 
10.6.1 
Data collection, data transfer procedure, and data access .................80 
10.6.2 
Database management and quality control .......................................81 
10.7 
Protocol deviations .......................................................................................81 
10.8 
Clinical monitoring .......................................................................................82 
10.9 
Study safety oversight ..................................................................................83 
10.10 
Early termination or suspension of the study ...............................................83 
10.11 
Audit .............................................................................................................83 
10.12 
Inspections ....................................................................................................84 
10.13 
Reporting of study results and publication ...................................................84 
11 REFERENCES ............................................................................................................86 
12 APPENDICES .............................................................................................................90 
 
 
LIST OF TABLES 
 
Table 1 
Schedule of activities ................................................................................ 28 
Table 2 
Recommended schedule for completion of Minze Diary Pod during 
the Screening Period .................................................................................. 30 
Table 3 
Endpoints and objectives ........................................................................... 43 
Table 4 
Estimand for the primary objective ........................................................... 72 
 
 


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LIST OF FIGURES 
 
Figure 1 
Study design .............................................................................................. 27 
 
 
LIST OF APPENDICES 
 
Appendix 1 
Assessments in the context of a pandemic or epidemic disease: 
Recommendations and instructions ........................................................... 90 
Appendix 2 
Sleep Diary ................................................................................................ 92 
Appendix 3 
Insomnia Daytime Symptoms and Impacts Questionnaire ....................... 94 
Appendix 4 
Insomnia Severity Index®.......................................................................... 98 
Appendix 5 
Global Scales ............................................................................................. 99 
Appendix 6 
EQ-5D-3L ................................................................................................ 102 
Appendix 7 
ICIQ-NQoL ............................................................................................. 104 
Appendix 8 
ICIQ-MLUTS .......................................................................................... 107 
Appendix 9 
ICIQ-FLUTS ........................................................................................... 112 
Appendix 10 Columbia Suicide Severity Rating Scale© (C-SSRS©) ........................... 116 
Appendix 11 Forbidden medications ............................................................................ 118 
Appendix 12 Treatment satisfaction questionnaire ....................................................... 121 
Appendix 13 Treatment period preference questionnaire ............................................. 121 
Appendix 14 Narrative .................................................................................................. 122 
 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AE  
Adverse event 
AESI  
Adverse event of special interest 
BFLUTS-SF  
Bristol Female Lower Urinary Tract Symptoms Short Form 
CBT(-I)  
Cognitive behavioral therapy (for insomnia) 
CNS  
Central nervous system 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
C-SSRS©  
Columbia Suicide Severity Rating Scale© 
CYP  
Cytochrome P450 
DBP  
Diastolic blood pressure 
DDI  
Drug-drug interaction 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, 5th Edition 
eCRF  
Electronic case report form 
eDiary  
Electronic diary 
EMA  
European Medicines Agency 
EOS  
End-of-Study 
EOTP  
End-of-Treatment Period 
EQ-5D-3L  
European Quality of Life 5 Dimensions 3 Level Version 
EU  
European Union 
F  
Forbidden 
FAS  
Full analysis set 
FDA  
Food and Drug Administration (US) 
GCP  
Good Clinical Practice 
IB  
Investigator’s Brochure 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
ICIQ  
International Consultation on Incontinence Questionnaire 
ICIQ-FLUTS  
ICIQ female lower urinary tract symptoms 
ICIQ-MLUTS  
ICIQ male lower urinary tract symptoms 
ICIQ-NQoL  
ICIQ Nocturia Quality of Life 


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ICSmaleSF  
International Continence Society male Short Form 
IDMC  
Independent Data Monitoring Committee 
IDSIQ  
Insomnia Daytime Symptoms and Impacts Questionnaire 
IEC  
Independent ethics committee 
IMP  
Investigational Medicinal Product 
IRB  
Institutional review board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
ISI©  
Insomnia Severity Index© 
LS Mean  
Least squares mean 
LUTS  
Lower urinary tract symptoms 
MedDRA  
Medical Dictionary for Regulatory Activities 
MMRM  
Mixed model for repeated measures 
NRS  
Numeric Rating Scale 
OX1  
Orexin-1 
OX2  
Orexin-2 
PEOT  
Premature End-of-Treatment 
PGA-S  
Patient Global Assessment of Disease Severity 
PGI-C  
Patient Global Impression of Change 
PPS  
Per-protocol set 
PRO  
Patient-reported outcome 
R  
Restricted 
REM  
Rapid eye movement 
RND  
Randomized analysis set 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SBP  
Systolic blood pressure 
SCR  
Screened analysis set 
SD  
Standard deviation 
SDQ  
Sleep Diary Questionnaire 
SmPC  
Summary of Product Characteristics 


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SOC  
System Organ Class 
sTST  
Subjective total sleep time 
SUSAR  
Suspected unexpected serious adverse reaction 
TEAE  
Treatment-emergent adverse event 
UNS  
Unscheduled visit 
US  
United States 
VAS  
Visual analog scale 
 
 
 
 


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SUBSTANTIAL GLOBAL AMENDMENT 2 
Amendment rationale 
This amendment applies to global protocol ID-078A401 Version 2, dated 5 April 2023. 
The resulting amended global protocol is Version 3 dated, 4 September 2023. 
The main reason for this global amendment is to provide clear instructions to the 
investigator for the immediate discontinuation of study treatment upon the occurrence of 
complex sleep behaviors. This protocol amendment is based on post-marketing reports 
from the US and EU of patients treated with daridorexant who experienced complex sleep 
behaviors. The amendment aims at minimizing the risk for subjects in this study.  
In addition, Appendices 12 to 14 related to the treatment satisfaction and treatment period 
preference questionnaires, and the narrative text about the impact of insomnia and nocturia 
on daily life according to the patient have been included. These have been incorporated 
solely for completeness and do not represent new assessments within this study. 
Furthermore, minor editorial changes have also been made and typographical errors 
corrected. 
Amended protocol sections 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document showing deletions and insertions in comparison to the previous 
protocol version. 
The main sections of the protocol affected by this global amendment are listed below. 
Where applicable, the same changes have also been made to the corresponding sections of 
the protocol synopsis [Section 1.1]: 
5.9.1 
Study treatment interruption and premature discontinuation of study 
treatment 
Appendix 12 Treatment satisfaction questionnaire 
Appendix 13 Treatment period preference questionnaire 
Appendix 14 Narrative 
 


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Summary of previous amendments 
Amendment 
Date 
Main reason(s) 
EU.A 
31 Jan 2023 
Clarification on eligibility and study 
interruption/discontinuation criteria 
USA.A 
22 Feb 2023 
Clarification on eligibility criteria and introduction of 
AESIs  
1 
5 Apr 2023 
Summarizing local protocols into global protocol 
 


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1 
PROTOCOL SUMMARY 
1.1 Protocol synopsis ID-078A401 
TITLE 
A multi-center, double-blind, randomized, placebo-
controlled, 2-way cross-over post approval study to 
investigate the efficacy of daridorexant in subjects with 
insomnia and comorbid nocturia 
OBJECTIVES 
Efficacy objectives 
The primary objective of this study is to assess the efficacy 
of daridorexant on insomnia in subjects with insomnia and 
comorbid nocturia. The following variables will be 
evaluated: 
a) Quantitative measure of subjective total sleep time 
(sTST) by the Sleep Diary Questionnaire (SDQ).  
b) Overall rating of the insomnia severity by the Insomnia 
Severity Index© (ISI©). 
c) Other SDQ-derived variables: (i) quality of sleep visual 
analog scale (VAS), (ii) depth of sleep VAS, (iii) 
daytime alertness VAS, (iv) daily ability to function 
VAS, and (v) number of awakenings. 
The secondary objective is to assess the efficacy of 
daridorexant on nocturia. There is no data for daridorexant 
in subjects with insomnia and comorbid nocturia. The 
following variables will be evaluated: 
a) Voiding diary-derived assessments: (i) time to the first 
nocturnal void, (ii) each voiding volume (nighttime and 
daytime) including total volume, (iii) number of 
nocturnal voids. 
b) Lower urinary tract symptoms (LUTS) sub-score using 
the 
International 
Consultation 
on 
Incontinence 
Questionnaire (ICIQ) -MLUTS and -FLUTS for male 
and female subjects, respectively. 
c) Quality of life relative to nocturia, assessed by ICIQ 
Nocturia Quality of Life (ICIQ-NQoL). 


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Other objectives will focus on subject’s overall assessment 
ratings of their condition and symptoms including: 
a) Patient Global Assessment of Disease Severity and 
Patient Global Impression of Change for insomnia and 
for nocturia. 
b) Quality of life using the European Quality of Life 5 
Dimensions 3 Level Version (EQ-5D-3L). 
c) Overall assessment of subjective treatment satisfaction 
by numeric rating scale. 
d) Subject preference for treatment. 
In addition to efficacy and safety, the following exploratory 
efficacy endpoints will be studied: 
a) The sensitivity of the Insomnia Daytime Symptoms and 
Impacts Questionnaire to detect clinical changes in this 
study population,  
b) The use of narratives to report subject’s perception of 
treatment effect.  
Safety objectives 
The safety objectives will be to assess the safety and 
tolerability of daridorexant based on: 
a) Adverse event (AE) reporting 
b) Occurrence of suicidal ideation, suicidal behavior, 
and/or self-injurious behavior with/without suicidal 
intent based on the Columbia Suicide Severity Rating 
Scale© (C-SSRS©) 
c) Morning sleepiness as determined by morning 
sleepiness VAS. 
DESIGN 
Multi-center, 
double-blind, 
randomized, 
placebo-
controlled, 2-way cross-over, post-approval study. 
The study consists of 2 treatment periods (I and II) of 
29 days each, separated by a 14–21 day washout period. 
ENDPOINTS 
Primary efficacy endpoint 
• Change from baseline to Week 4 in sTST in each 
treatment period 


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Baseline is the mean value based on the screening sleep 
diary for sTST, which must be performed on each of the 
7 days preceding Randomization. 
Week 4 is the mean value based on the sleep diary entries 
for sTST performed on study days 23–29 of each period. 
Other efficacy endpoints 
Other endpoints are listed in the main body of the protocol. 
Safety endpoints 
Safety monitoring will include:  
• Occurrence of treatment-emergent AEs up to 5 days 
after End-of-Treatment Period I (EOTP I) and/or 
End-of-Treatment Period II (EOTP II). 
• Occurrence of treatment-emergent AESIs up to 5 days 
after EOTP I and/or EOTP II. 
• Occurrence of treatment-emergent serious AEs up to 
5 days after EOTP I and/or EOTP II. 
• Occurrence of treatment-emergent AEs leading to 
premature discontinuation of the study and/or treatment. 
• Change from baseline to EOTP I and EOTP II in vital 
signs (systolic blood pressure, diastolic blood pressure, 
and pulse rate). 
• Change from baseline to EOTP I and EOTP II in 
morning sleepiness as determined by the scores on the 
VAS in the morning. 
• Occurrence of suicidal ideation, suicidal behavior, 
and/or self-injurious behavior with / without suicidal 
intent based on the C-SSRS© at Visit 1, Visit 4, Visit 5, 
Visit 8, and Visit 9. 
PERIODS 
Screening period: Starts with the full signature of the 
informed consent form (ICF) at Visit 1 and lasts 14–21 days. 
All baseline assessments as well as eligibility checks will be 
done during this period. 
Treatment period (Periods I and II): Randomization will 
take place on Day 1 (Visit 2) after confirmation that all 
eligibility criteria have been met, prior to the first study drug 


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administration of Treatment Period I. The double-blind 
cross-over phase will consist of 2 treatment periods of 
29 days ± 2 days each that are separated by a washout period 
of  
14–21 days. EOTP I and EOTP II is reached on the morning 
after the last treatment intake in the evening of the respective 
treatment period. Each subject will be randomized in a 
1:1 ratio to one of the two treatment sequences defined as: 
• Treatment A: 50 mg daridorexant followed by 
treatment B: Placebo  
• Treatment B: Placebo followed by treatment A: 50 mg 
daridorexant 
Follow-up and washout period: 
The follow-up period to detect any safety events related to 
the cessation of study treatment starts after completion of 
the EOTP I and EOTP II visit of each treatment period (I 
and II) and lasts for 5–10 days. For Period I the washout 
period and follow-up period overlap for 5–10 days, followed 
by an additional 9–16 days of washout, before entering 
Treatment Period II. The End-of-Study (EOS) visit will be 
completed by phone.  
PLANNED DURATION 
The global end-of-study is defined as completion of the last 
subject’s EOS phone call. The study is expected to last 
approximately 15 months. 
SITES / COUNTRIES 
The study will be conducted at approximately 20 sites in 
3 countries. 
SUBJECTS / GROUPS 
Approximately 50 subjects aged ≥ 55 years will be 
randomized (i.e., enrolled) in a 1:1 ratio to either sequence. 
No stratification will be applied. 
INCLUSION CRITERIA 1. Signed and dated ICF prior to any study-mandated 
procedure. 
2. Male or female subjects ≥ 55 years old at the time of 
signing the ICF. 
3. Insomnia complaints for at least 3 months prior to 
Visit 1 


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4. ISI© score ≥ 13 at Visit 1.  
Note: An ISI© score of ≥ 13 is considered appropriate as 
it represents a score suggesting subthreshold to 
moderate insomnia. The wide range of ISI© scores 
between the different insomnia categories indicates that 
the scores are to be considered as a guidance only. In 
this study, a score of at least 13 is adequate to detect 
clinically relevant insomnia.  
5. Diagnosis of nocturia as per International Continence 
Society:  
• 
Waking to pass urine during the main sleep period. 
• 
The first nocturia episode must be preceded by 
sleep. Subsequent nocturia episodes must be 
followed by the intention of getting back to sleep. 
6. Nocturia severity: on average ≥ 3 nocturnal voidings per 
night reported by the subjects for at least 1 month prior 
to Visit 1. 
Note: ≥ 2 voidings per night have been reported to be 
clinically relevant. The threshold set in this study is to 
capture a more severe population that is bothered by 
their frequent nocturia episodes. 
7. Average ≥ 2.6 nocturia episodes reported on the bladder 
diary per night over a period of 3 consecutive nights 
following Visit 1. None of the 3 nights can have less than 
2 voidings. 
Note: Given the night-to-night variability that can be 
observed in the number of nocturia episodes, this 
threshold allows to include a population that suffers 
from clinically relevant nocturia episodes.  
8. Ability to communicate well with the investigator, to 
understand the study requirements, and judged by the 
investigator to be alert and oriented to person, place, 
time, and situation. 


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EXCLUSION 
CRITERIA 
1. Woman of childbearing potential, pregnant, or planning 
to become pregnant. 
Note: A woman is considered of childbearing potential, 
i.e., fertile, following menarches and until becoming 
post-menopausal unless permanently sterile. 
2. Planned travel across ≥ 3 time zones during study. 
Note: It is expected that by changing time zones 
subject’s sleep will be impaired. 
3. Any of the following conditions related to suicidality: 
• Any suicidal ideation with intent, with or without a 
plan, at Screening, i.e., answering “Yes” to 
questions 4 or 5 on the suicidal ideation section of 
the lifetime (screening visit) version of the 
C-SSRS©. 
• History of suicide attempt on the suicidal behavioral 
section of the lifetime version of the C-SSRS© 
(screening visit). 
Note: As with many hypnotics, suicidal thoughts and 
actions may occur especially in those with a history of 
them. For that purpose, these subjects will be excluded 
from the study 
4. Regular caffeine consumption after 4 pm. 
Note: Caffeine consumption may interfere with sleep 
and nocturia assessments. 
5. Unable to refrain from smoking during the night. 
Note: Heavy smoking may interfere with sleep and 
nocturia assessments. 
6. Known and documented diagnosis of narcolepsy, 
periodic limb movement disorder, moderate to severe 
obstructive sleep apnea, restless legs syndrome, 
circadian rhythm sleep-wake disorder, or rapid eye 
movement (REM) sleep behavior disorder. 
Note: Daridorexant is contraindicated in narcoleptic 
subjects. The occurrence of other sleep disorders may 
interfere with the efficacy and safety assessments. 
7. Known and documented diagnosis of Type 1 diabetes 
mellitus, uncontrolled Type 2 diabetes mellitus, central 


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or 
nephrogenic 
diabetes 
insipidus, 
and 
primary/secondary polydipsia within the last 6 months 
prior to Visit 1. 
Note: Conditions that manifest with the symptoms of 
large intake of fluids may suggest the presence of other 
underlying diseases that need appropriate medical 
attention. The investigator must certify the absence of 
these conditions. 
8. Known and documented nocturia linked to urinary tract 
infection, neoplasms of bladder, prostate or urethral 
cancer, bladder or urethral calculi, or neurogenic 
voiding dysfunction within the last 6 months prior to 
Visit 1. 
Note: These conditions are known to cause nocturia for 
a limited time period and/or are not expected to remain 
stable during the duration of the study and may interfere 
with the efficacy and safety assessments. The 
investigator must certify the absence of these conditions. 
9. Any signs or symptoms of active, ongoing infection 
judged to be clinically relevant by the investigator.  
Note: Investigators should not screen subjects if an 
ongoing infectious disease is suspected. 
10. Known 
and 
documented 
diagnosis 
of 
severe 
compromised 
respiratory 
function (e.g., 
chronic 
obstructive pulmonary disease). 
Note: See the Summary of Product Characteristics 
(SmPC) or the Investigator’s Brochure (IB). 
11. Known and documented moderate to severe hepatic 
impairment. 
Note: Daridorexant is not recommended in subjects with 
severe hepatic impairment, while subjects with 
moderate hepatic impairment require a dose adjustment 
which is not allowed in this study. In accordance with 
the EU SmPC or IB, the investigator must certify the 
absence of these conditions and may refer to local 
laboratory testing. 
12. Known hypersensitivity to the investigational treatment, 
any of its excipients or drugs of the same class. 


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13. Treatment with forbidden medications including 
moderate or strong Cytochrome P450 (CYP) 3A4 
inhibitors and inducers within 2 weeks or 5 half-lives 
(whichever is longer) prior to Visit 2. 
Note: As per daridorexant label, 50 mg daridorexant 
must not be taken if co-administered with moderate to 
strong CYP3A4 inducers or inhibitors. This includes 
other medication that could interfere with the efficacy or 
safety assessment. See the SmPC or IB. Background 
treatment of nocturia is allowed if started prior to 
entering the study, is considered to remain stable during 
the study and does not meet the criteria for forbidden 
medication.  
14. Treatment with another investigational treatment or 
participation in another clinical trial up to 3 months prior 
to Visit 2. 
15. Any known factor or disease that might interfere with 
treatment compliance, study conduct, or interpretation 
of the results, such as drug or alcohol dependence or 
psychiatric disease. 
16. Known concomitant life-threatening disease with a life 
expectancy < 12 months. 
Note: The cross-over study design is only applicable for 
chronic and stable diseases that are expected to be 
comparable during the different study periods.  
17. Ongoing cognitive behavioral therapy for insomnia at 
Visit 1 or planned start during the study. 
STUDY TREATMENTS 
Investigational treatment and matching placebo 
description 
Daridorexant is available as oral film-coated tablets at a 
strength of 50 mg.  
Daridorexant-matching placebo is provided as identically 
looking oral tablets, formulated with the same inactive 
ingredients (excipients) as the active tablets. 


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After randomization, daridorexant or matching placebo will 
be taken orally, once daily in the evening within 
approximately 30 min before going to bed.  
Missed doses must not be replaced and the subject must 
continue with the regular treatment on the next evening 
STATISTICAL 
METHODOLOGY 
Analysis sets  
Randomized analysis set (RND)  
The RND includes all subjects who have been assigned to 
double-blind study treatment. 
Full analysis set (FAS)  
The FAS includes all subjects from the RND who received 
at least one dose of double-blind study treatment.  
To adhere to the intention-to-treat principle:  
• Subjects will be evaluated according to their assigned 
study treatment, which may differ from the treatment 
they have received.  
• Unless otherwise stated, all available data will be 
included in analyses.  
The FAS will be used for analyses of the primary endpoint 
and all exploratory efficacy endpoints. 
Per-protocol set (PPS)  
The PPS includes all subjects from the FAS without 
important protocol deviations, occurring prior to Week 4, 
which could affect the analysis of the primary endpoint 
variable. 
The precise reasons for excluding subjects from the PPS will 
be fully defined and documented in the statistical analysis 
plan before breaking the randomization blind.  
Safety set  
The Safety set will include all subjects who received at least 
one dose of double-blind study treatment. Subjects will be 
analyzed based on the treatment received (in each period). 
The Safety set will be used for the analysis of safety 


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endpoints 
(including 
previous 
and 
concomitant 
medications, and study treatment exposure). 
Description of statistical analyses  
All available data for each subject will be used in all 
statistical analyses, unless otherwise specified. 
Analysis of the primary estimand based on the primary 
efficacy endpoint 
The primary efficacy endpoint of this study is defined as the 
change from Baseline to Week 4 in sTST. The primary 
estimand follows a ‘treatment policy’ strategy for 
intercurrent events. 
Baseline is the mean value based on the screening sleep 
diary for sTST, performed on the 7 days preceding 
Randomization. 
Week 4 is the mean value based on the sleep diary entries 
for sTST performed on study days 23–29 for each period. 
Data after the EOTP I/II visits will not be included in the 
analysis, as subjects are expected to be on double-blind 
treatment up to that point. 
Changes from baseline to post-baseline visits in sTST will 
be analyzed using a mixed model for repeated measures 
(MMRM) with change from baseline in sTST as response, 
treatment group (daridorexant 50 mg; placebo), period 
(Period I; Period II), and week within period (Week 1, Week 
2, Week 3, Week 4) as factors, baseline sTST assessment as 
covariate, and the interaction of treatment group × week. 
Each weekly average for Weeks 1–3 will be included in the 
MMRM and computed following the same approach as for 
Week 4. 
To evaluate the efficacy hypotheses, the difference in least 
squares mean change from baseline between daridorexant 
50 mg and placebo at Week 4 will be estimated from the 
MMRM. An unstructured covariance matrix will be used to 
account for the correlation between repeated measurements 
from the same subject. 


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Hypotheses for the primary endpoint are defined as follows: 
• H0: Mean of the within-subject changes in sTST from 
baseline to Week 4 between daridorexant 50 mg and 
placebo = 0 
• H1: Mean of the within-subject changes in sTST from 
baseline to Week 4 between daridorexant 50 mg and 
placebo ≠ 0 
Sample size estimation 
The assumptions for the sample size calculations were 
determined using data from studies ID-078A202 and 
ID-078A301 for the treatment groups daridorexant 50 mg 
and placebo.  
Data of sTST changes from baseline and the corresponding 
standard deviations (SDs) were derived based on 
simulations using sTST data at Baseline and at Month 1 
from the ID-078A301 study for the age group ≥ 55 years. 
Subsets of 50 subjects were randomly selected from both the 
daridorexant 50 mg and placebo groups and compared via 
t-tests for independent samples, with means and SDs 
averaged across 1000 iterations. The simulations resulted in 
a mean difference of the change from baseline to Month 1 
in sTST of 26 min for daridorexant 50 mg and placebo, with 
SDs of 42.5 min for placebo and 50.5 min for daridorexant 
50 mg.  
Correlations between daridorexant 50 mg and placebo for 
sTST data were derived based on the cross-over study 
ID-078A202 (based on subjects aged ≥ 65 years). The 
Pearson correlation coefficient was estimated at 0.58. 
Combining all the information above resulted in an SD of 
the difference in the change of sTST from baseline to Month 
1 of 44 min (based on the variance/covariance formula). 
Based on a two-sided type I error of 0.05, an estimated 
within-subject mean difference of the change from baseline 
to Month 1 in sTST between daridorexant 50 mg and 
placebo of 26 min and an associated SD of 44 min, a total 
sample size of 50 subjects, in this cross-over setting, 
provides at least 90% power, based on a two-sided paired 


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t-test. A smaller within-subject mean difference between 
daridorexant 50 mg and placebo of 20 min would still result 
in a power of at least 80%. 
 
1.2 Schema 
The overall study design is depicted in Figure 1. 
Figure 1 
Study design 
  
D = Day; EOS = End-of-Study; EOTP = End-of-Treatment Period; V = Visit.  
 
1.3 Schedule of activities 
The visit schedule and protocol-mandated activities are performed according to the 
schedule of activities Table 1 and are described in Section 7 and Sections 3.2 and 3.3. 
 


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Table 1 
Schedule of activities  
PERIODS 
Name 
SCREENING 
PERIOD 
TREATMENT PERIOD I 
Washout 
TREATMENT PERIOD II 
 
FOLLOW-UP 
 
Duration 
14–21 days  
29 ± 2 days 
14–21 days 
29 ± 2 days 
 
5–10 days 
VISITS 
Number 
1 
2 
3 
4*/ EOTP I 
5 
- 
6 
7 
8*/ EOTP II 
PEOT** 
9/EOS 
 
Name 
Screening 
Visit 
 
Randomization 
Phone call 
End of treatment 
Period I 
Safety 
Follow-up 
Phone call 
 
 
Phone call 
End of 
treatment 
Period II 
Premature 
End-of-
Treatment 
Phone call 
 
Time window 
Day −14 to 
Day −1 
Day 1  
Day 14 
± 2 days 
 
Day 29 ± 2 days  5 - 10 days 
after EOTP 
visit  
 
Day 1 Day 14 ± 2 days 
 
Day 29 ± 2 days  1 - 5 days 
after last 
study 
treatment 
intake 
5 - 10 days after 
EOTP visit 
 
Informed consent 
X 
  
 
 
 
 
 
 
 
 
 
Contact IRT 
X 
X 
 
X 
 
 
X 
 
X 
X3 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X2 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Previous/concomitant therapy 
X 
X2 
X4 
X 
X4 
 
X 
X4 
X 
X3 
X4 
Vital signs (BP, PR) 
X 
 
 
X 
 
 
 
 
X 
X3 
 
C-SSRS© 
X 
 
 
X 
X4 
 
 
 
X 
X3 
X4 
Sleep diary including VAS6 
 
 
 
 
 
 
 
 
 
 
 
ISI© 
X 
 
X4 
X 
 
 
 
X4 
X 
 
 
IDSIQ8 
 
 
 
 
 
 
 
 
 
 
 
Voiding Diary7 
X 
X 
 
X 
 
 
X 
 
X 
 
 
PGA-S5 
X 
 
 
 
 
 
 
 
 
 
 
PGI-C daytime symptoms 5 
 
 
 
 
 
 
 
 
 
 
 
PGI-C nighttime symptoms5 
 
 
 
 
 
 
 
 
 
 
 
PGA-S (daily life) 
X 
 
 
X 
 
 
 
 
X 
 
 


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PERIODS 
Name 
SCREENING 
PERIOD 
TREATMENT PERIOD I 
Washout 
TREATMENT PERIOD II 
 
FOLLOW-UP 
 
Duration 
14–21 days  
29 ± 2 days 
14–21 days 
29 ± 2 days 
 
5–10 days 
VISITS 
Number 
1 
2 
3 
4*/ EOTP I 
5 
- 
6 
7 
8*/ EOTP II 
PEOT** 
9/EOS 
 
Name 
Screening 
Visit 
 
Randomization 
Phone call 
End of treatment 
Period I 
Safety 
Follow-up 
Phone call 
 
 
Phone call 
End of 
treatment 
Period II 
Premature 
End-of-
Treatment 
Phone call 
 
Time window 
Day −14 to 
Day −1 
Day 1  
Day 14 
± 2 days 
 
Day 29 ± 2 days  5 - 10 days 
after EOTP 
visit  
 
Day 1 Day 14 ± 2 days 
 
Day 29 ± 2 days  1 - 5 days 
after last 
study 
treatment 
intake 
5 - 10 days after 
EOTP visit 
 
PGI-C (daily life) 
 
 
 
X 
 
 
 
 
X 
 
 
Nocturia Quality of Life 
(ICIQ-NQoL) 
X 
 
 
X 
 
 
 
 
X 
 
 
ICIQ-MLUTS/FLUTS9 
X 
 
 
X 
 
 
 
 
X 
 
 
EQ-5D-3L 
X 
 
X 
X 
 
 
 
X 
X 
 
 
Treatment satisfaction 
 
 
 
X 
 
 
 
 
X 
X3 
 
Treatment period preference 
 
 
 
 
 
 
 
 
X 
X3 
 
Narrative 
X 
 
 
X 
 
 
 
 
X 
X3 
 
Study treatment dispensing/return 
 
X 
 
X 
 
 
X 
 
X 
X3 
 
Study drug intake 
 
 
 
 
 
 
 
 
 
 
 
Treatment accountability 
 
 
 
X 
 
 
 
 
X 
X3 
 
SAEs/AEs1 
 
 
 
 
 
 
 
 
 
 
 
1 All AEs and SAEs that occur after signing the ICF and up to 5–10 days after study treatment discontinuation must be reported [see also Section 8.1 and 8.2]. 
2 Must be done before randomizing the subject. 
3 Only applicable for subjects who prematurely discontinued study treatment. All subjects withdrawn from study treatment will be encouraged to follow planned study procedures (e.g., visits, diary and 
questionnaire completion until planned EOS visit) provided that the subject’s consent for this limited participation in the study has not been withdrawn. 
4Will be completed by phone call. 
5PGA-S and PGI-C (daytime symptoms and nighttime symptoms questionnaires) will be completed at home once a week between Visit 2 and Visit 8. The patient global scales are completed on the same 
days. 
6The hand-held device is handed out to the subject and completed at home daily from Visit 1 to Visit 8.  


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7The voiding diary must be completed by the subjects for 3 consecutive days and nights after the Visit 1, Visit 2 and Visit 6 as well as for 3 consecutive days and nights immediately preceding Visit 4 and 
Visit 8, respectively [see Table 2]. The investigator should plan the completion of the diary according to the visit schedule.  
8The IDSIQ will be administered from Visit 1 to Visit 8 and completed daily. 
9The ICIQ-MLUTS will only be given to male subjects, while females will receive the ICIQ-FLUTS.  
*The site will contact the subject to remind him/her to complete the voiding diary for 3 consecutive days preceding the EOTP visit. 
** The subject will be asked to return for a PEOT visit within 5 days of last intake of study treatment and thereafter to attend the following visits up to the respective EOTP visit. 
 
AE = adverse event; BP = blood pressure; C-SSRS© = Columbia Suicide Severity Rating Scale©; EOS = End-of-Study; EOTP = End-of-Treatment Period; EQ-5D-3L = European Quality of Life 5 
Dimensions 3 Level Version; ICF = informed consent form; ICIQ-MLUTS/FLUTS = International Consultation on Incontinence Questionnaire (male/female) lower urinary tract symptoms; 
IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; IRT = Interactive Response Technology; ISI© = Insomnia Severity Index©; PEOT = Premature End-of-Treatment; PGA-S = Patient 
Global Assessment of Disease Severity; PGI-C = Patient Global Impression of Change; PR = pulse rate; SAE = serious adverse event; VAS = visual analog scale. 
 
Table 2 
Recommended schedule for completion of Minze Diary Pod during the Screening Period 
Visit 1  
Screening Visit  
Day −14 
Day −13 
Day −12 
D -11 
Day −10 
Day −9 
Day −8 
Day −7 
Day −6 
Day −5 
Day −4 
Day −3 
Day −2 
Day −1 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
Schedule for completion of Minze Diary Pod for Visits 2, 4, 6 and 8 
 
Visit 2 / 
Visit 6 
Day 1 
Day 
2 
Day 
3 
Day 
4 
Day 
5 
Day 
6 
Day 
7 
Day 
8 
Day 
9 
Day 
10 
Day 
11 
Day 
12 
Day 
13 
Visit 3 / 
Visit 7 
Day 14 
Day 
15 
Day 
16 
Day 
17 
Day 
18 
Day 
19 
Day 
20 
Day 
21 
Day 
22 
Day 
23 
Day 
24 
Day 
25 
Day 
26 
Day 
27 
Day 
28 
Visit 4 / 
Visit 8 
Day 29 
 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
 
 


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2 
INTRODUCTION 
2.1 Insomnia and comorbid nocturia 
2.1.1 Definition 
Insomnia and nocturia show an increased prevalence with age, and both conditions show 
similar impairments of daytime functioning (excessive daytime sleepiness, fatigue, 
concentration deficits) and an increased risk of falls and injuries.  
Insomnia is often assessed using the ISI©, which uses a 5-point Likert scale to assess the 
severity of sleep onset, sleep maintenance and early morning awakening problems, sleep 
dissatisfaction, as well as the interference with daytime functioning and quality of life. 
Using the ISI© total score, insomnia can be grouped into 4 categories: 0–7, 8–14, 15–21, 
and 22–28 for no clinically significant insomnia, subthreshold insomnia, moderate 
insomnia, and severe insomnia, respectively.  
Nocturia is defined by the International Continence Society as waking at least once nightly 
to void, where the first void must be preceded by sleep and all subsequent voidings must 
be followed by the intention of getting back to sleep [Van Kerrebroeck 2002]. 
Patients suffering from nocturia are confronted with nocturnal awakenings that may result 
in severe sleep disruption including difficulties maintaining sleep, as well as difficulties 
falling back asleep after getting up for voiding. This condition not only affects sleep at 
night but continues to negatively impact the daytime functioning of affected patients by 
causing excessive daytime sleepiness and reducing productivity [Ohayon 2008, 
Miller 2016]. In fact, nocturia has been identified as an independent predictor of insomnia 
where increasing number of voiding episodes have been associated with worsened sleep 
disruptions and reduced quality of life [Asplund 1992, Yu 2006, Bliwise 2009].  
2.1.2 Current treatment strategies 
Despite the high prevalence of sleep disruptions in patients suffering from nocturia, only a 
limited number of studies have investigated the effect of sleeping agents and these studies 
are limited by low sample sizes and lack of placebo arms. Nevertheless, these studies 
suggest that treatment of the sleep disorder in patients with nocturia may improve both 
conditions. The combination of tamsulosin and zolpidem reduced nocturia episodes better 
than tamsulosin alone, and at the same time improved sleep disturbances [Miwa 2011]. 
Nocturia may be improved by lifestyle and behavioral modification such as reducing 
caffeine intake, reducing fluid intake before bedtime, and restriction of alcohol intake. If 
behavioral modifications do not adequately improve the condition, pharmacological 
treatments of underlying causes focus on improving nocturnal bladder storage capacity and 
increasing the volume at which bladder activity is elicited and/or aim at decreasing urine 
production at night. It should not be forgotten that the multifactorial nature of nocturia 


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usually requires the tailored treatment of the underlying cause. Therefore, a variety of 
pharmacological therapies are used in clinical practice, including; muscarinic receptor 
antagonists, β3-adrenoceptor antagonists (mirabegron), α1-adrenoreceptor antagonists, 
5α-reductase inhibitors, phosphodiesterase type 5 inhibitors, and various natural products. 
In nocturia associated with nocturnal polyuria (increased urine production), treatment with 
an antidiuretic, such as desmopressin acetate is warranted to counteract the insufficient 
secretion of arginine vasopressin during the night, therefore inducing antidiuresis. 
Diuretics, alone or in combination with desmopressin, can also be used in the treatment of 
nocturia with the rationale of reducing salt and water load in the body prior to bedtime 
(e.g., given 6 h before sleep) [Reynard 1998, Fu 2011, Oelke 2017, Weiss 2019].  
Non-pharmacological CBT-I is generally the recommended first-line treatment for 
insomnia [Schutte-Rodin 2008]. However, this may not be the ideal treatment for all 
patients. Many patients with insomnia are not interested in CBT, and when they are, access 
to CBT may be limited by the lack of therapists with adequate training and experience, and 
the fact that CBT is time-consuming, costly, and its reimbursement challenging 
[Pigeon 2007, Schutte-Rodin 2008]. Furthermore, pharmacological treatments that address 
sleep onset problems alone do not provide relief to people with sleep maintenance 
difficulties, and treatments indicated for those with sleep maintenance problems may be 
associated with risks of cognitive impairment, postural instability, or next-day residual 
sedation that may impair driving [Neubauer 2014]. Moreover, the use of benzodiazepines 
and benzodiazepine receptor agonists is associated with an increased risk of falling 
[McCall 2004] leading to hip and femur fractures, increased disability, and use of 
healthcare resources. This suggests that current pharmacological interventions have a 
significant potential to impair motor and cognitive functions and are of specific safety 
concern to the nocturia population experiencing multiple awakenings during the night. 
Additionally, current treatment options for insomnia have failed to show an improvement 
on daytime functioning, despite the importance of daytime symptoms to patients with 
insomnia. This is especially relevant to nocturia as these patients often report daytime 
sleepiness [Shao 2016]. Daridorexant may close this gap by offering a safe and effective 
solution to patients with frequent nighttime awakenings.  
Therefore, there is a need for a pharmacological treatment with favorable benefit/risk 
profile supported by an adequate, controlled clinical study in subjects with insomnia with 
associated nocturia and different underlying medical conditions. 
2.2 Daridorexant 
Daridorexant is a potent and selective orexin receptor antagonist that blocks the actions of 
the orexin neuropeptides at both OX1 and OX2 receptors. The orexin system is involved in 
the regulation of sleep and arousal and is targeted in the development of new therapies for 
sleep disorders in adult and elderly subjects. Daridorexant has been approved in the US, 


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EU, United Kingdom, Iceland, Norway, Switzerland, and Liechtenstein for the treatment 
of adult patients with insomnia.  
The human clinical experience with daridorexant to date consists of: 
• Twenty completed Phase 1 studies [Daridorexant IB]. 
• Two completed Phase 2 studies in subjects with insomnia disorder in 360 adults and 
58 elderly subjects, respectively [Dauvilliers 2020, Zammit 2020].  
• Three completed Phase 3 studies in adult and elderly subjects with insomnia disorder. 
ID-078A301 and ID-078A302 were conducted in 930 and 924 subjects, respectively 
[Mignot 2022]. ID-078A303 consisted of a common extension to both pivotal studies 
in which 804 subjects were included. 
For additional information please refer to the IB [Daridorexant IB] or the EU SmPC 
[QUVIVIQ™ SmPC.  
2.3 Study rationale 
Daridorexant at a dose of 50 mg has been proven safe and efficacious in the treatment of 
adult and elderly subjects with insomnia disorder [Daridorexant IB, showing benefits in 
improving sleep onset and sleep maintenance, as well as daytime functioning, with the 
latter two being the most frequent complaints observed in patients suffering from insomnia 
and having associated nocturia. In addition, daridorexant was shown to be devoid of 
morning or even daytime somnolence effects, as compared to placebo. This leads to the 
assumption that daridorexant may be ideal in targeting some of the key symptoms observed 
in subjects with insomnia and comorbid nocturia. 
The potential effect of daridorexant on nocturia will be assessed for the first time in this 
study. A few studies in older adults reported that behavioral treatments and 
gamma-aminobutyric acid receptor agonists for sleep disruptions resulted in better clinical 
outcomes in these patients, by improving both their sleep and nocturia symptomatology 
and their quality of life [Miwa 2011, Tyagi 2014]. The hypothesis is that nocturia may be 
partly a consequence of sleep disruption; the urge to urinate may become evident in these 
patients due to prolonged awakening during the night; thus, an effective treatment for 
insomnia could also improve nocturia. In the same vein, some literature suggests that sleep 
disorders play an important role in the severity of nocturia [Konishi 2021]. However, 
nocturia may also be the cause of poor sleep [Bliwise 2009]. 
                                                 
1 QUVIVIQ is a trademark of Idorsia Pharmaceuticals Ltd which is registered in a number of countries. 


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2.4 Benefit/risk assessment 
2.4.1 Clinical trial 
With the participation in this clinical trial subjects will receive an approved treatment that 
has been proven safe and efficacious for the treatment of insomnia, thus potentially 
providing a benefit for both their sleep problems and the impairment of their daytime 
activities. Furthermore, subjects enrolled in this study will contribute to the research into 
and understanding of the link between insomnia and frequent nocturia. Importantly, with 
the implemented cross-over design, all subjects will be exposed to an active treatment (i.e., 
50 mg daridorexant) at one point in the study, which will translate into a potential benefit 
for all participants. On the other hand, in the cross-over design, it is critically important 
that subjects are willing to remain in the study for its entire duration to limit the amount of 
missing data and ensure a fair comparison between the new treatment and placebo through 
objective and subjective endpoints. As with every clinical study, the clinical efficacy and 
safety in this specific population, despite the well-established profile of daridorexant in 
insomnia, remain unknown. It is therefore the responsibility of the investigator to ensure 
that the subjects are informed about the benefits and risks of participating in this study 
during the informed consent process, as well as the importance of their commitment to 
remain in the study until their EOS visit.  
2.4.2 Daridorexant 
Based on the mechanism of action of daridorexant, nonclinical data, and results from the 
Phase 1, 2, and 3 studies in adults and elderly subjects, an increased total sleep time, a 
decrease in wakening after sleep onset, a shortened latency to sleep onset as well as 
improved daytime functioning are anticipated without rebound effects / withdrawal 
symptoms upon treatment cessation. 
Daridorexant metabolism is mainly dependent on CYP3A4, therefore, co-administration 
of moderate and strong CYP3A4 inducers or inhibitors must be avoided. 
Additional information can be found in the IB [Daridorexant IB] or in the EU SmPC 
[QUVIVIQ™ SmPC. 
2.4.3 Safety and risk-minimization included in this study 
The most frequent TEAEs for daridorexant (reported in at least 2% of subjects treated with 
daridorexant with a ≥ 1% difference to subjects receiving placebo during the adult Phase 3 
program) were headache, somnolence, fatigue, dizziness, and nausea. 
Risk of suicidality will be assessed at Visit 1, Visit 4, Visit 5, Visit 8, Visit 9 and PEOT 
using the C-SSRS©. At Screening (Visit 1), the C-SSRS© will inquire about the subject’s 
lifetime state, and all other visits will refer to the time elapsed since the previous visit. 
Participants who demonstrate any suicidal ideation, suicidal behavior, and/or self-injurious 


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behavior without suicidal intent at any time during the study must be referred to the 
investigator for follow-up evaluation. 
The risk of falls is known to be increased in elderly subjects compared to younger adults, 
regardless of treatment. Falls may happen when subjects wake up and go to the bathroom. 
However, in the Phase 3 clinical trials, daridorexant was not associated with an increase of 
falls compared to placebo, including at a dose of 50 mg daridorexant in the elderly 
population. Subjects will be informed of the potential risk of fall, and this risk will be 
carefully monitored by the investigator and by the sponsor.  
It is the investigator / authorized delegate’s responsibility to monitor the benefit/risk ratio 
of study treatment administration, as well as the degree of distress caused by study 
procedures on an individual subject level, and to discontinue study treatment or the study 
if, on balance, he/she believes that continuation would be detrimental to the subject’s 
well-being. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
3.1 Objectives 
The overall objective of this study is to explore the clinical efficacy of daridorexant and to 
further evaluate its safety and tolerability in subjects with insomnia and comorbid nocturia.  
Based on the mode of action of daridorexant and the knowledge acquired during its 
development, it is reasonable to identify the following objectives to be explored in this 
study: 
Efficacy objectives 
The primary objective of this study is to assess the efficacy of daridorexant on insomnia in 
subjects with insomnia and comorbid nocturia. The following variables will be evaluated: 
a) Quantitative measure of sTST by the SDQ.  
b) Overall rating of the insomnia severity by the ISI© with a recall period of 2 weeks. 
c) Other SDQ-derived variables: (i) quality of sleep VAS, (ii) depth of sleep VAS, (iii) 
daytime alertness VAS, (iv) daily ability to function VAS, and (v) number of 
awakenings.  
The secondary objective is to assess the efficacy of daridorexant on nocturia. There is no 
data for daridorexant in subjects with insomnia and comorbid nocturia. The following 
variables will be evaluated: 
a) Voiding diary derived assessments: (i) time to the first nocturnal void, (ii) each voiding 
volume (nighttime and daytime) including total volume, (iii) number of nocturnal 
voids. 


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b) Lower urinary tract symptoms sub-score using the ICIQ-MLUTS and -FLUTS for male 
and female subjects, respectively. 
c) Quality of life relative to nocturia assessed by ICIQ-NQoL. 
Other objectives will focus on patient’s overall assessment ratings of their condition and 
symptoms including: 
a) PGA-S and PGI-C for insomnia and for nocturia. 
b) Quality of life using the EQ-5D-3L. 
c) Overall assessment of subjective treatment satisfaction by NRS. 
d) Subject preference for treatment.  
In addition to efficacy and safety this study the following exploratory efficacy endpoints 
will be studied a) the sensitivity of the IDSIQ to detect clinical changes in this study 
population, and b) the use of narratives to report subject’s perception of treatment effect.  
Safety objectives 
The safety objectives will be to assess the safety and tolerability of daridorexant based on: 
a) AE reporting. 
b) Occurrence of suicidal ideation, suicidal behavior and/or self-injurious behavior 
with/without suicidal intent based on the C-SSRS©. 
c) Morning sleepiness as determined by morning sleepiness VAS. 
3.2 Efficacy assessments and time points 
3.2.1 SDQ [Appendix 2] 
The sleep diary includes a morning and evening questionnaire and four VASs related to 
the efficacy assessments (and a fifth VAS to collect morning sleepiness, described below 
in the safety assessment Section 3.3.2). The morning and evening questionnaires collect 
information on self-reported sleep characteristics (e.g., sTST and other sleep quantitative 
characteristics), napping, bedtime, and timing of study treatment intake. The VAS collects 
information on quality of sleep, depth of sleep, daytime alertness, and daytime ability to 
function by asking the subjects to report their feelings by placing a mark on a VAS. 
Self-reported quality of sleep and depth of sleep are assessed in the morning whereas 
self-reported daytime alertness and daytime ability to function are assessed in the evening.  
The sleep diary will be uploaded into an electronic hand-held device and given to the 
subjects at Visit 1. Sleep diaries will be available in the subject’s language and must be 
completed daily from Visit 1 until Visit 8 and at PEOT.  


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For further information about the set-up and the use of the sleep diary on the hand-held 
device, refer to the investigator site electronic Clinical Outcome Assessment study 
information guide. 
For assessments that derive from the SDQ, baseline is defined as the average of the 7 days 
immediately preceding Visit 2. The endpoints will be assessed at Week 1, Week 2, Week 3, 
and Week 4 using averages of 7 days. 
3.2.2 IDSIQ [Appendix 3] 
The IDSIQ is programmed on the electronic hand-held device and must be completed every 
day in the evening before the evening sleep diary by the subject from Visit 1 until Visit 8 
and at PEOT. It will be completed by the subjects on the hand-held device. 
The IDSIQ is structured in 3 domains (i.e., alertness/cognition; negative mood; 
tiredness/sleepiness) and contains overall 14 items, each based on an 11-point NRS, with 
a recall period of “today”. The psychometric validation of the IDSIQ instrument was 
performed in study ID-078A203 [Hudgens 2021]. 
Baseline is defined as the average of the 7 days immediately preceding Visit 2. The 
endpoints will be assessed at Week 1, Week 2, Week 3, and Week 4 using averages of 
7 days. 
3.2.3 ISI© [Appendix 4] 
The ISI© assesses the severity of a subject’s insomnia by scoring the severity of sleep onset 
and sleep maintenance difficulties and any insomnia-related interference with daytime 
functioning. The assessment is on a 5-point scale (0–4), where the composite score is 
obtained by summing the 7 rated dimensions measuring the subject’s perception of his or 
her insomnia. A score of 15–21 indicates a moderate level of insomnia and a score of  
22–28 indicates severe insomnia. An ISI© total score < 10 indicates that the subject’s 
subjectively rated insomnia symptoms, daytime impairment, and quality of life have 
improved to the minimal-to-none range [Morin 1993, Scharf 2007]. The ISI© will be 
completed by the subject on the electronic device at Visit 1, Visit 3, Visit 4, Visit 7, and 
Visit 8. The ISI© questionnaire used in this study uses a recall period of 2 weeks.  
Baseline is defined as the ISI© score at Visit 1. The ISI© score will be assessed based on 
the entries on Visit 3 and Visit 7 (Week 2) as well as Visit 4 and Visit 8 (Week 4).  
3.2.4 PGA-S (daytime symptoms) [Appendix 5] 
The PGA-S (daytime symptoms) is a question concerning the overall severity of daytime 
symptoms (e.g., sleepiness) and impacts (e.g., effort to perform daily activities) that the 
subject may have experienced due to their insomnia over the 7 days preceding the PGA-S. 


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It will be completed by the subjects on the electronic device at Visit 1 and weekly during 
both treatment periods. 
3.2.5 PGI-C (daytime symptoms) [Appendix 5] 
The PGI-C (daytime symptoms) is a question concerning the change in overall severity of 
daytime symptoms (e.g., sleepiness) and impacts (e.g., effort to perform daily activities) 
that the subject may have experienced due to their insomnia over the 7 days preceding the 
PGI-C daytime symptoms compared to the week before he/she started treatment. It will be 
completed weekly by the subjects on the electronic device during both treatment periods. 
3.2.6 PGI-C (nighttime symptoms) [Appendix 5] 
The PGI-C (nighttime symptoms) is a question concerning the change in the subject’s 
insomnia symptoms at night (e.g., trouble falling asleep, total time asleep, time to fall back 
asleep or number of times they wake up) over the past week (7 nights) preceding the PGI-C 
nighttime symptoms compared to the week before the subject started treatment. It will be 
completed weekly by the subjects on the electronic device during both treatment periods. 
3.2.7 PGA-S (daily life) [Appendix 5] 
The PGA-S (daytime symptoms) is a question concerning the overall impacts on the daily 
life (e.g., effort to perform daily activities) that the subject may have experienced due to 
their insomnia and their nocturia over the 4 weeks preceding the PGA-S. It will be 
completed by the subjects on the electronic device at Visit 1, Visit 4, and Visit 8. 
3.2.8 PGI-C (daily life) [Appendix 5] 
The PGI-C is a question concerning the change in overall severity of the daily life 
symptoms that the subject may have experienced due to their insomnia and their nocturia 
over a period of 4 weeks. It will be completed by the subjects on the electronic device at 
Visit 4 and Visit 8. 
3.2.9 Minze Diary Pod 
The Minze Diary Pod consists of a voiding pod and a voiding diary and uses a derivation 
from the ICIQ bladder diary which is a 3-day diary that allows subjects to record urinary 
frequency, volume voided, urgency and fluid intake (amount and type) [Bright 2014]. The 
voiding pod will automatically transfer the voiding information (i.e., volume and 
timepoints) to the voiding diary and the subjects must provide additional information. The 
Minze Diary Pod must be completed during the day, and it must preferably be started in 
the morning meaning that the completion starts only in the morning after Visit 1 to assess 
eligibility. Furthermore, the Minze Diary Pod must be completed the morning after Visit 2 
and Visit 6 and lasts 3 days; the Minze Diary Pod must also be completed for 3 full days 
immediately preceding Visit 4 and Visit 8. 


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For assessments derived from the voiding diary, baseline is defined as the average of the 
3 consecutive nights following Visit 1. The endpoints are collected on 3 consecutive days 
and nights immediately following Visit 2 and Visit 6 (defined as Week 1), and 3 days 
immediately preceding the end of each treatment at Visit 4 and Visit 8 (defined as Week 4), 
respectively.  
3.2.10 EQ-5D-3L [Appendix 6] 
The EQ-5D-3L is an instrument that assesses quality of life, irrespective of the disease. 
The 5 Dimensions include: mobility, self-care, usual activities, pain/discomfort, 
anxiety/depression. “None, some, extreme” are the 3 modalities for each dimension. 
Depending on the box checked by the subject a number is assigned to each dimension 
resulting into a 5-digit number combination (e.g., a completely healthy subject would have 
a score of 11111).  
Additionally, the EQ VAS records the subject’s self-rated health ranging from “best 
imaginable health state” to “worst imaginable health state”. 
The EQ-5D has no recall period, instead it represents a snapshot of how the subject feels 
on the day it is completed. It will be completed by the subjects on an electronic device at 
Visit 1, Visit 3, Visit 4, Visit 7, and Visit 8. 
Baseline is defined as the EQ-5D-3L score at Visit 1. The EQ-5D-3L score will be assessed 
based on the entries on Visit 3 and Visit 7 (Week 2) as well as Visit 4 and Visit 8 (Week 4).  
3.2.11 ICIQ-NQoL [Appendix 7] 
The ICIQ-NQoL is an adaptation of the NQoL [Abraham 2004] for use within the ICIQ 
structure. It is a subject-completed questionnaire covering daytime and nighttime impact 
of nocturia in men and women and consists of 13 items. The recall period is 4 weeks. The 
overall score is calculated by summing the first 12 items (ranging from 0 to 4), resulting in 
an overall score that ranges from 0–48 where greater scores indicate a decrease in quality 
of life. It will be completed by the subjects on the electronic device at Visit 1, Visit 4, and 
Visit 8. 
Baseline is defined as the ICIQ-NQoL score at Visit 1. Week 4 is defined as the 
ICIQ-NQoL score assessed at the end of each treatment period at Visit 4 and Visit 8, 
respectively. 
3.2.12 ICIQ-MLUTS [Appendix 8] 
The ICIQ-MLUTS is a questionnaire that evaluates lower urinary tract symptoms in males. 
It is a patient-completed questionnaire that includes 13 items and is derived from the 
ICSmaleSF questionnaire [Donovan 2000]. The questionnaire is split into two subscales 
ranging from 0–20 for voiding symptoms and 0–24 for incontinence symptoms, where 


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higher numbers indicate a higher burden. It will be completed by the subjects on the 
electronic device at Visit 1, Visit 4, and Visit 8. 
Baseline is defined as the ICIQ-MLUTS sub-scores at Visit 1. Week 4 is defined as the 
lower urinary tract symptoms sub-scores assessed at the end of each treatment period at 
Visit 4 and Visit 8, respectively. 
3.2.13 ICIQ-FLUTS [Appendix 9] 
The ICIQ-FLUTS is a questionnaire that evaluates lower urinary tract symptoms in 
females. It is a patient completed questionnaire that includes 12 items and is derived from 
the BFLUTS-SF questionnaire [Brookes 2004]. The questionnaire is split into three 
subscales ranging from 0–16 for filling symptoms, 0–12 for voiding symptoms, and 0–20 
for incontinence symptoms, where higher numbers indicate a higher burden. It will be 
completed by the subjects on the electronic device at Visit 1, Visit 4, and Visit 8. 
Baseline is defined as the ICIQ-FLUTS sub-scores at Visit 1. Week 4 is defined as the 
lower urinary tract symptoms sub-scores assessed at the end of each treatment period at 
Visit 4 and Visit 8, respectively. 
3.2.14 Treatment satisfaction [Appendix 12] 
The NRS collects information on the treatment satisfaction during the clinical trial by 
asking the subjects to mark the number that best describes the overall satisfaction. 
Self-reported treatment satisfaction is assessed in the morning of Visit 4,Visit 8 and PEOT 
on the electronic device.  
3.2.15 Treatment period preference [Appendix 13] 
The subjects will be asked at Visit 8 and PEOT to select which treatment period (Period I 
or II) was preferred and complete it on the electronic device.  
3.2.16 Narrative [Appendix 14] 
The subjects will complete a free text question on the electronic device at Visit 1, Visit 4, 
Visit 8 and PEOT. They will also be asked to write a short text about their overall feeling.  
At Visit 1 the narrative question will refer to the time before being on treatment, while at 
Visits 4, 8 and PEOT the narrative will refer to the time while on treatment. 
3.3 Safety assessments 
Unless otherwise specified, the date of each assessment will be collected in the eCRF. 
The definitions, reporting and follow-up of AEs, SAEs, and pregnancies are described in 
Section 8. 


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3.3.1 Vital signs 
SBP, DBP and pulse rate will be measured and recorded in the eCRF. The date and actual 
time of vital sign measurements will be entered in the eCRF. 
Blood pressure and pulse measurements will be assessed with the subject in a supine or 
sitting position using an automated device. Manual techniques will be used only if an 
automated device is not available. 
The subject should be allowed to rest for at least 5 min in a quiet setting without distractions 
(e.g., television, cell phones), and to use the same position (supine or sitting) and same arm 
throughout the study for an individual subject. 
Vital signs will be collected at Visit 1, Visit 4, Visit 8 and PEOT. 
3.3.2 VAS [Appendix 2] 
The VAS collects information on morning sleepiness by asking the subjects to report their 
feelings by placing a mark on a VAS and is part of the SDQ. It is collected every morning 
on the electronic device from Visit 1 to Visit 8 and at PEOT.  
3.3.3 Clinical laboratory assessments 
Exceptional circumstances that may require recording of local laboratory results include 
the possible need for clarification of certain exclusion criteria or hospitalization of the 
subject due to a medical emergency. Local laboratory results must be reported in the eCRF. 
The following documents will be collected from the local laboratory: normal ranges, 
laboratory certification, and curriculum vitae of laboratory director. 
3.3.4 C-SSRS© [Appendix 10] 
The C-SSRS© is an instrument that reports the presence and severity of both suicidal 
ideation and behaviors [Posner 2007]. Suicidal ideation is classified on a 5-item scale:  
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 
The C-SSRS© also captures information about the intensity of ideation, specifically the 
frequency, duration, controllability, deterrents, and reasons for the most severe types of 
ideation. In addition, the C-SSRS© captures information using yes/no question and answers 
on suicidal behaviors, specifically actual, interrupted, and aborted attempts; preparatory 
acts or behaviors; and if suicidal behaviors were present during the assessment period. 


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More than one classification can be selected provided they represent separate episodes. For 
actual attempts only, the actual or potential lethality is classified for the initial, most lethal, 
and most recent attempts.  
At Visit 1 (Screening) the C-SSRS© will be completed for the subject lifetime history of 
suicidal ideation and behaviors. At all other visits (Visit 4, Visit 5, Visit 8, Visit 9 and 
PEOT), the C-SSRS© will be completed for suicidal ideation and behaviors since the 
previous visit. 
The investigator, a delegated physician, or a nurse trained according to local requirements 
and local clinical practice will complete this questionnaire with the subject on an electronic 
device and assess the findings. 
Participants who answer “yes” to items 1, 2, 3, 4, or 5 on the C-SSRS© assessment at any 
post-randomization visit must undergo further evaluation by the investigator to assess the 
risk. Study treatment will be interrupted in such participants until after the investigator 
confirms suitability of the participant to remain under treatment. This evaluation and 
decision should also be clearly recorded in the source documents. 
3.4 Endpoints 
It is anticipated that the collection of the voiding volume will interfere with sleep-related 
endpoints, therefore a staggered approach for the endpoint assessments is pursued. The 
details are described below and apply for each treatment period. 
Information on the endpoints and their relation to the objectives is shown in Table 3.  
Further details on the endpoints are described in the SAP. 


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Table 3 
Endpoints and objectives 
Objectives 
Endpoints in period I and period II 
To assess the efficacy of daridorexant on 
insomnia in subjects with insomnia and 
comorbid nocturia 
Primary endpoint: 
• 
Change from baseline to Week 4 in sTST 
Other insomnia related endpoints: 
• 
Changes from baseline to Week 1, Week 2, and Week 3 in sTST  
• 
Changes from baseline to Week 2 and Week 4 in ISI© total score 
• 
Changes from baseline to Week 1, Week 2, Week 3, and Week 4 in quality and depth of sleep as determined by scores on the 
VAS (mm) in the morning 
• 
Changes from baseline to Week 1, Week 2, Week 3, and Week 4 in the daytime alertness and daily ability to function as 
determined by scores on the VAS (mm) in the evening  
• 
Changes from baseline to Week 1, Week 2, Week 3, and Week 4 in mean number of self-reported awakenings based on the 
sleep diary  
To assess the efficacy of daridorexant on 
nocturia  
Nocturia related:  
• 
Changes from baseline to Week 1 and Week 4 in number of nocturnal voids assessed using a voiding diary  
• 
Changes from baseline to Week 1 and Week 4 in the time to the first nocturnal void assessed using the voiding diary  
• 
Changes from baseline to Week 1 and Week 4 in the volume of the first nocturnal void assessed using the voiding diary  
• 
Changes from baseline to Week 1 and Week 4 in the total nighttime voiding volume assessed using the voiding diary  
• 
Change from baseline to Week 1 and Week 4 in number of daytime voids assessed using a voiding diary  
• 
Changes from baseline to Week 1 and Week 4 in the total daytime voiding volume assessed using the voiding diary  
• 
Change from baseline to Week 4 in ICIQ-NQoL 
• 
Change from baseline to Week 4 in lower urinary tract symptoms sub-score using the ICIQ-MLUTS and FLUTS for male and 
female subjects, respectively 
To assess the overall patient’s ratings of their 
condition and symptoms 
• 
Changes from baseline to Week 1, Week 2, Week 3, and Week 4 in Patient Global Assessment of Disease Severity (daytime 
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Objectives 
Endpoints in period I and period II 
• 
Changes from baseline to Week 1, Week 2, Week 3, and Week 4 in Patient Global Impression of Change (daytime and 
nighttime symptoms)  
• 
Change from baseline to Week 4 in Patient Global Assessment of Disease Severity (daily life)  
• 
Change from baseline to Week 4 in Patient Global Impression of Change (daily life)  
• 
Change from baseline to Week 2 and Week 4 in EQ-5D-3L score 
• 
Treatment satisfaction at Week 4 assessed via NRS 
• 
Treatment period preference at Visit 8 (EOTP II) 
To explore a) the sensitivity of the IDSIQ to 
detect clinical changes in this study population 
and b) the use of narratives to report subject’s 
perception of treatment effect 
• 
The change from baseline to Week 1, Week 2, Week 3, and Week 4 in all IDSIQ domains 
• 
The subjects will be asked to complete a narrative at the end of each treatment period. More details on the analysis will be 
provided in the SAP. 
To assess the safety and tolerability of 
daridorexant 
Safety endpoints 
Safety monitoring will include:  
• 
Occurrence of TEAEs up to 5 days after EOTP I and/or EOTP II. 
• 
Occurrence of treatment emergent AESIs up to 5 days after EOTP I and/or EOTP II. 
• 
Occurrence of treatment-emergent serious adverse events up to 5 days after EOTP I and/or EOTP II. 
• 
Occurrence of TEAEs leading to premature discontinuation of the study and/or treatment. 
• 
Change from baseline to EOTP I and EOTP II in vital signs (systolic blood pressure, diastolic blood pressure, and pulse rate). 
• 
Change from baseline to EOTP I and EOTP II in morning sleepiness as determined by the scores on the VAS in the morning. 
• 
Occurrence of suicidal ideation, suicidal behavior, and/or self-injurious behavior with / without suicidal intent based on the 
C-SSRS© at Visit 1, Visit 4, Visit 5, Visit 8, and Visit 9. 
AE = adverse event; AESI = adverse event of special interest; C-SSRS© = Columbia Suicide Severity Rating Scale©; EOTP = End-of-Treatment Period; EQ-5D-3L = European Quality of Life 5 
Dimensions 3 Level Version; ICIQ-(M/F)LUTS = International Consultation on Incontinence Questionnaire – (male/female) lower urinary tract symptoms; ICIQ-NQoL = International Consultation 
on Incontinence Questionnaire – Nocturia Quality of Life; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; ISI© = Insomnia Severity Index©; NRS = Numeric Rating Scale; 
SAP = statistical analysis plan; (s)TST = (subjective) total sleep time; TEAE = treatment-emergent adverse event(s); VAS = visual analog scale.  


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3.5 Appropriateness of endpoints 
This study is a post-approval study and aims to investigate the effect of daridorexant on 
managing insomnia as well as frequent nocturnal voids (nocturia). The chosen endpoints 
in this study have not been adequately statistically powered except for sTST, however it is 
anticipated that the study is large enough to detect efficacy and safety signals of 
daridorexant on nocturia and sleep variables.  
This study will assess sleep-related endpoints such as sTST, which has been selected as a 
primary endpoint as it is a clinically meaningful subjective endpoint that has already 
showed good response during the first weeks of treatment in both pivotal Phase 3 studies 
of daridorexant, although in a different subject population (insomniacs diagnosed through 
DSM-5 criteria, without nocturia). By measuring an improvement in sTST, the study will 
capture the effect of daridorexant on both wake periods at the beginning and end of the 
night. Nocturia by definition causes disruption of sleep continuity, and the need to void 
occurs throughout the entire night; in fact, the number of voidings has been significantly 
associated with the number of hours of sleep per night [Coyne 2003]. Moreover, these 
subjects have been diagnosed with insomnia and will likely experience sleep problems 
throughout the full night. Therefore, sTST is the variable that correlates best with both 
conditions.  
Furthermore, to assess the potential effects of daridorexant on nocturia, this study will also 
measure nocturia-related variables such as the number and volume of voidings, as well as 
the nocturia quality of life questionnaire. As even ≥ 2 voidings during the night are 
considered clinically meaningful [Kim 2016], it is expected that a reduction in the number 
of voidings will directly result in a clinical benefit in these subjects. Additionally, with the 
nocturia quality of life questionnaire, the change in nocturia symptoms can be quantified 
into an impact on the subject’s life. 
Finally, this study will also assess the sensitivity to change of the IDSIQ, thus providing 
further information on the applicability of this instrument in the population in this study.  
Accounting for the safety data that were collected in the entire daridorexant clinical 
program, the proposed safety endpoints are considered adequate as they capture all relevant 
safety aspects related to the use of an orexin receptor antagonist. In the Phase 3 studies the 
occurrence of narcolepsy-like events was low and there was no pattern to the occurrence 
of falls. Therefore, the proposed safety endpoints allow for an adequate characterization of 
safety following administration with daridorexant in subjects with insomnia and comorbid 
nocturia.  


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4 
STUDY DESIGN AND PLAN 
4.1 Study design 
This is a multi-center, double-blind, randomized, placebo-controlled, 2-way cross-over 
post-approval study. 
Approximately 50 subjects aged ≥ 55 years will be randomized (i.e., enrolled) in a 1:1 ratio 
to either sequence for 1 month. No stratification will be applied. The study will be 
conducted at approximately 20 sites in 3 countries. 
4.1.1 Study periods for an individual subject 
Screening period: Starts with the full signature of the ICF at Visit 1 and lasts 14–21 days. 
All baseline assessments and eligibility checks will be done during this period. 
Treatment period (Periods I and II): Randomization will take place on Day 1 (Visit 2) 
after confirmation that all eligibility criteria have been met, prior to the first study drug 
administration of Treatment Period I. The double-blind cross-over phase will consist of 
2 treatment periods of 29 days ± 2 days each that are separated by a washout period of  
14–21 days. EOTP I and EOTP II is reached on the morning after last treatment intake in 
the evening of the respective treatment period. Each subject will be randomized in a 
1:1 ratio to one of the treatment sequences defined as: 
• Treatment A: 50 mg daridorexant, followed by Treatment B: placebo 
• Treatment B: Placebo, followed by Treatment A: 50 mg daridorexant 
Follow-up and Washout period: 
The follow-up period, to detect any safety events related to the cessation of study treatment, 
starts after completion of the EOTP I and EOTP II visit of each treatment period (I and II) 
and lasts for 5–10 days.  
For period I, the first 5–10 days of the washout period overlap with the follow-up period 
and are followed by an additional 9–16 days of washout, for a total of 14–21 days washout 
period before entering treatment period II. 
A subject’s participation in the study ends with the completion of the EOS phone call  
5–10 days after EOTP II (Visit 9) of Period II [Table 1]. 
The visit schedule and protocol-mandated procedures are performed according to the 
schedule of activities [Table 1] and are described in Section 3.2, 3.3, and 7.2. 
The overall study design is depicted in Figure 1. 


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4.2 Study duration and global end-of-study definition 
The study starts with the recruitment of the first subject. A subject is considered recruited 
when the subject’s ICF has been fully signed.  
The study primary completion date is the date of the last subject’s Visit 8 morning visit, 
when the last assessment for the primary efficacy endpoint is collected. 
The duration of individual subject’s participation in the study will be approximately 
3.5 months. 
The global end-of-study is defined as completion of the last subject’s EOS phone call. The 
study is expected to last approximately 15 months.  
Study results will be submitted within 1 year of the primary completion date of the study. 
4.3 Study design rationale 
The randomized, placebo-controlled, 2-way cross-over study setting is considered 
adequate to prevent and account for bias in the endpoints that are assessed, as every subject 
will act as their own control, resulting in reduced variability and, therefore, also in a smaller 
sample size. Furthermore, a cross-over design is adequate to assess chronic conditions like 
insomnia and nocturia as it is not expected that the disease status changes over the duration 
of study. To avoid the risk of carry-over, a washout period of 14–21 days is implemented 
between the two treatment periods to allow variables to return to baseline conditions. This 
is considered adequate given the half-life of 8 h of daridorexant.  
This study is a post-approval investigation to study efficacy and safety in subjects with 
insomnia and comorbid nocturia. In line with the EMA guideline on medicinal products 
for the treatment of insomnia [EMA 2011], the FDA guideline for the clinical evaluation 
of hypnotic drugs [FDA 1977] as well as the entire clinical developmental program of 
daridorexant, this study includes a placebo group to allow proper characterization of the 
efficacy and safety results of daridorexant. The use of a placebo group for a period of 
1 month in this population is considered medically acceptable. 
Data from the Phase 2 and Phase 3 studies support the duration of the treatment period of 
29 days ± 2 days to assess subjective changes in day- and nighttime variables in subjects 
with insomnia. No placebo run-out is included in the trial, as the Phase 3 studies did not 
indicate any withdrawal symptoms and/or rebound effect, which is anticipated to be similar 
in this population. Potential AEs related to the cessation of the study drug will be assessed 
during the 5–10 day follow-up period.  


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4.4 Study committee(s) 
No Independent Safety Board or IDMC will be appointed for this study, given the 
established safety profile of daridorexant, the small size, the anticipated recruitment time 
and the short duration of the study. 
5 
STUDY POPULATION 
5.1 Subject population description 
This study will enroll male and female subjects aged ≥ 55 years with insomnia and 
comorbid nocturia. 
5.2 Inclusion criteria 
Subjects must meet all the following inclusion criteria: 
1. Signed and dated ICF prior to any study-mandated procedure. 
2. Male or female subjects ≥ 55 years old at the time of signing the ICF. 
3. Insomnia complaints for at least 3 months prior to Visit 1. 
4. ISI© score ≥ 13 at Visit 1.  
Note: An ISI© score of ≥ 13 is considered appropriate as it represents a score 
suggesting subthreshold to moderate insomnia. The wide range of ISI© scores between 
the different insomnia categories indicate that the scores are to be considered as a 
guidance only. In this study, a score of at least 13 is adequate to detect clinically 
relevant insomnia [Morin 2011].  
5. Diagnosis of nocturia as per International Continence Society:  
• 
Waking to pass urine during the main sleep period. 
• 
The first nocturia episode must be preceded by sleep. Subsequent nocturia 
episodes must be followed by the intention of getting back to sleep. 
6. Nocturia severity: on average ≥ 3 nocturnal voidings per night reported by the subjects 
for at least 1 month prior to Visit 1. 
Note: ≥ 2 voidings per night have been reported to be clinically relevant. The threshold 
set in this study is to capture a more severe population that is bothered by their frequent 
nocturia episodes. 
7. Average ≥ 2.6 nocturia episodes reported on the bladder diary per night over a period 
of 3 consecutive nights following Visit 1. None of the 3 nights can have less than 
2 voidings. 
Note: Given the night-to-night variability that can be observed in the number of 
nocturia episodes, this threshold enables inclusion of a population that suffers from 
clinically relevant nocturia episodes. 


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8. Ability to communicate well with the investigator, to understand the study 
requirements, and judged by the investigator to be alert and oriented to person, place, 
time, and situation. 
5.3 Exclusion criteria 
Subjects must not meet any of the following exclusion criteria:  
1. Woman of childbearing potential, pregnant or planning to become pregnant. 
Note: A woman is considered of childbearing potential, i.e., fertile, following 
menarches and until becoming post-menopausal unless permanently sterile. 
2. Planned travel across ≥ 3 time zones during study. 
Note: It is expected that by changing time zones subject’s sleep will be impaired. 
3. Any of the following conditions related to suicidality: 
• 
Any suicidal ideation with intent, with or without a plan, at Screening, i.e., 
answering “Yes” to questions 4 or 5 on the suicidal ideation section of the lifetime 
(screening visit) version of the C-SSRS©. 
• 
History of suicide attempt on the suicidal behavioral section of the lifetime version 
of the C-SSRS© (screening visit). 
Note: As with many hypnotics, suicidal thoughts and actions may occur especially 
in those with a history of them. For that purpose, these subjects will be excluded 
from the study. 
4. Regular caffeine consumption after 4 pm. 
Note: Caffeine consumption may interfere with sleep and nocturia assessments. 
5. Unable to refrain from smoking during the night. 
Note: Heavy smoking may interfere with sleep and nocturia assessments. 
6. Known and documented diagnosis of narcolepsy, periodic limb movement disorder, 
moderate to severe obstructive sleep apnea, restless legs syndrome, circadian rhythm 
sleep-wake disorder, or REM sleep behavior disorder. 
Note: Daridorexant is contraindicated in narcoleptic subjects. The occurrence of other 
sleep disorders may interfere with the efficacy and safety assessments. 
7. Known and documented diagnosis of Type 1 diabetes mellitus, uncontrolled Type 2 
diabetes mellitus, central or nephrogenic diabetes insipidus, and primary/secondary 
polydipsia within the last 6 months prior to Visit 1. 
Note: Conditions that manifest with the symptoms of large intake of fluids may suggest 
the presence of other underlying diseases that need appropriate medical attention. The 
investigator must certify the absence of these conditions. 


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8. Known and documented nocturia linked to urinary tract infection, neoplasms of 
bladder, prostate or urethral cancer, bladder or urethral calculi, or neurogenic voiding 
dysfunction within the last 6 months prior to Visit 1. 
Note: These conditions are known to cause nocturia for a limited time period and/or 
are not expected to remain stable during the duration of the study and may interfere 
with the efficacy and safety assessments. The investigator must certify the absence of 
these conditions. 
9. Any signs or symptoms of active, ongoing infection judged to be clinically relevant by 
the investigator.  
Note: Investigators should not screen subjects if an ongoing infectious disease is 
suspected. 
10. Known and documented diagnosis of severe compromised respiratory function (e.g., 
chronic obstructive pulmonary disease).  
Note: See the SmPC or the IB.  
11. Known and documented moderate to severe hepatic impairment. 
Note: Daridorexant is not recommended in subjects with severe hepatic impairment, 
while subjects with moderate hepatic impairment require a dose adjustment which is 
not allowed in this study. In accordance with the EU SmPC or IB, the investigator must 
certify the absence of these conditions and may refer to local laboratory testing. 
12. Known hypersensitivity to the investigational treatment, any of its excipients or drugs 
of the same class. 
13. Treatment with forbidden medications including moderate or strong CYP3A4 
inhibitors and inducers within 2 weeks or 5 half-lives (whichever is longer) prior to 
Visit 2.  
Note: As per daridorexant label, 50 mg daridorexant must not be taken if 
co-administered with moderate to strong CYP3A4 inducers or inhibitors. This includes 
other medication that could interfere with the efficacy or safety assessments. See the 
SmPC or IB. Background treatment of nocturia is allowed if started at least 1 month 
prior to entering the study, is considered to remain stable during the study and does 
not meet the criteria for forbidden medication. 
14. Treatment with another investigational treatment or participation in another clinical 
trial up to 3 months prior to Visit 2. 
15. Any known factor or disease that might interfere with treatment compliance, study 
conduct, or interpretation of the results, such as drug or alcohol dependence or 
psychiatric disease. 
16. Known concomitant life-threatening disease with a life expectancy < 12 months.  


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Note: The cross-over study design is only applicable for chronic and stable diseases 
that are expected to be comparable during the different study periods.  
17. Ongoing CBT-I at Visit 1 or planned start during the study. 
5.4 Rationale for the selection of the study population 
Sleep disruptions in adults with frequent nocturia complaints are very common. One survey 
identified that going to the bathroom was the most frequent cause for waking up at night 
in adults and it increased with age [Ohayon 2008]. The severity of the nocturia defined by 
the number of awakenings for voiding has been shown to correlate with the severity of 
sleep disruption as well as with impaired quality of life in patients [Drake 2005]. While 
nocturia is a multifactorial condition that can have several origins, it is usually split into 
three categories:  
1. Nocturnal polyuria: 
These patients have a large production of urine during sleep, usually related to alterations 
in biological master clock regulations, large liquid intake before bedtime, diurnal 
perturbations of antidiuretic hormone, and increased atrial natriuretic peptide release with 
increasing age [Van Kerrebroeck 2002].  
2. Bladder storage problems:  
These symptoms are of neurogenic or myogenic origins. The storage problems can have 
several causes, e.g., by detrusor overactivity caused by secondary conditions such as 
benign prostatic hyperplasia, bladder hypersensitivity, or urogenital aging.  
3. Nocturia due to global polyuria: 
This population will not be included in this study, as these subjects usually have other 
severe underlying conditions that would make participation in this trial unfeasible. For 
example, subjects with severe global polyuria require large fluid intake, including at night, 
which would directly influence the defined study outcomes. However, subjects on stable 
treatment for type 2 diabetes mellitus for at least 3 months will be allowed to participate if 
study criteria are met. 
While pharmacological interventions exist to relieve nocturia complaints, the comorbid 
sleep disruption is usually left untreated even though its treatment has been associated with 
improvement in the overall clinical outcome for these subjects. This indicates that sleep 
disruptions may not necessarily be a consequence of nocturia, but also the cause for the 
nocturnal voidings. There is a high unmet medical need to identify effective and safe 
treatments that target the frequent sleep complaints in this population.  


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5.5 Contraception requirements for women of childbearing potential 
No contraceptive methods are needed for female subjects participating in this clinical study 
as women of childbearing potential will not be included.  
5.6 Contraception for male subjects with a partner who is of childbearing 
potential 
No contraceptive methods are needed for male subjects participating in this clinical study. 
5.7 Dietary aspects and physical activity restrictions 
During the study, subjects will be instructed about the following restrictions: 
• No alcohol consumption within 3 hours before going to bed. 
• Avoiding intake of large quantities of fluid before going to bed that will likely result in 
the need to void. 
• No caffeine consumption after 4 pm (this includes also different types of tea such as 
black or green tea, coffee, caffeinated gums, caffeine tablets). 
• No heavy tobacco use leading to inability to refrain from smoking during the night. 
• No driving or engaging in activities that require operating vehicles or dangerous 
machinery within 7 hours following study treatment intake. 
• No travelling across ≥ 3 times zones or planned travel across ≥ 3 times zones at any 
time during the study. 
• No daytime naps during the study. 
5.8 Screen failures and re-screening 
Screen failures are defined as subjects recruited in the clinical study (i.e., ICF fully signed) 
who are not subsequently randomized in the study. Minimum information includes 
demography (i.e., age, sex, race, and ethnicity) screen failure details (e.g., eligibility criteria 
not met, withdrawal of consent), medical history, any SAEs, as well as concomitant 
medications related to the treatment or occurrence of the SAEs. 
It is not permitted to re-screen subjects in this study, however procedures or assessments 
conducted as part of the subject’s routine clinical management (e.g., laboratory sample) 
and obtained before signing the ICF may be used for screening or baseline purposes 
[Section 7.1.1]. This includes repeating assessments in the event of exceptional 
circumstances (e.g., technical issues). 
5.9 Criteria for withdrawal and retention of subjects 
A subject has the right to prematurely discontinue study treatment at any time, by 
withdrawal from study treatment only or by withdrawal from study treatment and any 


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further participation in the study (i.e., premature withdrawal from the study). It is 
recommended that the investigator / authorized delegate makes a reasonable effort to 
maintain subjects on treatment, as medically appropriate, and follow the schedule of visits, 
as data robustness depends on such compliance. Should a subject stop treatment or 
withdraw from the study, the investigator / authorized delegate should ascertain the 
reason(s), while fully respecting the subject’s rights. 
Subjects who prematurely discontinue study treatment / the study for any reason will not 
be replaced, given the low discontinuation rate observed in the clinical program of 
daridorexant. 
5.9.1 Study treatment interruption and premature discontinuation of study 
treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator / authorized delegate, or the sponsor personnel.  
The investigator / authorized delegate has the option of temporarily interrupting or 
prematurely discontinuing study treatment for a given subject in response to an AE, a 
diagnostic or therapeutic procedure, a laboratory abnormality, or for administrative 
reasons. If study treatment is interrupted by the subject for any reason, he/she must inform 
the investigator / authorized delegate as soon as possible. All study treatment interruptions 
must be recorded in the eCRF. 
The investigator / authorized delegate must permanently discontinue study treatment for a 
given subject if, on balance, he/she believes that continued administration would be 
contrary to the best interests of the subject. 
Study-specific criteria for temporary interruption and permanent discontinuation of study 
treatment are described in Sections 5.9.1.1, 5.9.1.2, 5.9.1.3 and 5.9.1.4. 
The main reason for permanent discontinuation of study treatment (e.g., due to 
pre-specified study treatment discontinuation criteria, an AE, lack of efficacy, study 
termination) must be documented in the eCRF.  
A subject who prematurely discontinues study treatment is NOT considered withdrawn 
from the study. The subject will be asked to return for a PEOT visit within 5 days of last 
intake of study treatment and thereafter to attend the following visits up to the respective 
EOTP visit as defined in the schedule of activities [Table 1] and in Section 7.2. After the 
EOTP visit has been completed, the subject will perform the Safety Follow-up Phone call 
5 to 10 days later which will be considered an EOS visit. All subjects withdrawn from 
study treatment will be encouraged to follow planned study procedures (e.g., visits, diary, 
and questionnaire completion [Table 1]) until planned EOS provided that the subject’s 


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consent for this limited participation in the study has not been withdrawn. This will reduce 
the amount of missing data which is important from a study integrity perspective. 
5.9.1.1 Pregnancy / pregnancy plans  
If a subject becomes pregnant while on study treatment, study treatment must be 
permanently discontinued. The investigator / authorized delegate must counsel the subject 
and discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
For reporting of pregnancies, refer to Section 8.3.1. 
5.9.1.2 C-SSRS© 
Subjects who answer “yes” to items 1, 2, 3, 4, or 5 on the C-SSRS© assessment at any 
post-randomization visit must undergo further evaluation by the investigator to assess the 
risk. If a positive answer is provided during the first treatment period, the investigator must 
interrupt study treatment and confirm the suitability of the subject to remain under 
treatment. This evaluation and decision must be clearly recorded in the source documents. 
5.9.1.3 Concomitant use of forbidden medications 
Subjects must not take forbidden medications during the study. However, if the subject is 
treated with a forbidden medication [Appendix 11], study treatment must be discontinued. 
See Section 5.9.1 for the handling of subjects that have prematurely discontinued study 
treatment. 
5.9.1.4 Occurrence of complex sleep behaviors while on study treatment 
Complex sleep behaviors include sleepwalking, sleep driving, sleep-talking or engaging in 
other activities while not fully awake (e.g., preparing and eating food, making phone calls, 
having sex). Subjects who experience a complex sleep behavior event during the study 
must discontinue study treatment immediately.  
5.9.2 Withdrawal from the study  
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost to 
follow-up [see Section 5.9.3. If a subject withdraws consent for further study participation, 
no further data will be collected in the eCRF from the date of withdrawal onward. The 
investigator / authorized delegate may withdraw a subject from the study (without regard 
to the subject’s consent) if, on balance, he/she believes that continued participation in the 
study would be contrary to the best interests of the subject. Withdrawal from the study may 
also result from a decision by the sponsor for any reason, including early termination or 
suspension of the study [see Section 10.10]. Enrolled subjects who prematurely discontinue 
from the study for any reason will not be replaced. 


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If, for whatever reason (except death or loss-to-follow-up), a subject is withdrawn from the 
study, the investigator / authorized delegate should make best efforts to schedule a last 
appointment / phone call to assess the safety and well-being of the subject, collect unused 
study treatment and discuss follow-up medical care. Data obtained during this last 
appointment / phone call will be recorded in the subject’s medical records, but it will not 
be collected in the eCRF.  
The main reason for premature withdrawal from the study must be documented in the 
eCRF.  
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care, as described 
in Section 6.3. 
5.9.3 Lost to follow-up 
A subject will be considered as lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and the site is unable to contact him/her. 
The site must take preventive measures to avoid a subject being lost to follow-up (e.g., 
document different ways of contact such as phone number, home address, email address, 
person to be contacted if the subject cannot be reached).  
The following actions must be taken if a subject fails to return to the site for a scheduled 
study visit: 
• The site staff must attempt to contact the subject and reschedule the missed visit as 
soon as possible and counsel the subject on the importance of maintaining the assigned 
visit schedule and ascertain if the subject wishes to and/or should continue in the study. 
• If the subject cannot be reached, the site must make a reasonable effort to contact the 
subject and document all attempts in the subject’s medical chart. Reasonable efforts 
include where possible 3 phone calls to the last available phone number and 
1 registered/certified letter to the subject’s last known mailing address or local 
equivalent methods. 
• If the subject is still unreachable after all contact attempts listed above, he/she will be 
considered to be lost to follow-up. 
The date of last contact with the subject will be collected in the eCRF. 
5.9.4 Retention of subjects 
To avoid missing data caused by subjects dropping out of the study, the investigator / 
authorized delegate must inform subjects on the study duration and train subjects on 
upcoming procedures upfront, as part of the information to subjects prior to signing 


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consent. It is not advisable to consider subjects for screening if there is any suspicion that 
the subject may not be inclined to remain in the study for its entire duration, although 
subjects remain free to withdraw anytime as per text in Section 5.9.2. The benefit/ risk 
assessment as provided in Section 2.4 must be discussed and the doctor-patient relationship 
should be strengthened to reduce drop-out rates. If the study participant’s usual physician 
is not the investigator, if the subject consents the investigator should make sure that the 
subject’s usual physician, for example the general practitioner, is aware of the subject’s 
participation in the study. It is important to note that the retention measures should be in 
line with ICH GCP, meaning that the subject’s safety and wellbeing prevail over interests 
of science and society. 
6 
TREATMENTS 
6.1 Study treatment 
6.1.1 IMP and matching placebo description  
Daridorexant is available as oral film-coated tablets at a strength of 50 mg.  
Placebo matching daridorexant is provided as identical-looking oral tablets, formulated 
with the same inactive ingredients (excipients) as the active tablets. 
6.1.2 Study treatment dosing and administration 
At Visit 1, after the ICF has been signed, the investigator / authorized delegate will contact 
the IRT system to get a subject number allocated to the subject.  
At Visit 2, the investigator / authorized delegate contacts the IRT system to assign the 
treatment wallet number. 
After randomization, daridorexant or matching placebo will be taken orally, once daily in 
the evening within approximately 30 min before going to bed.  
Missed doses must not be replaced and the subject must continue with the regular treatment 
the next evening.  
6.1.2.1 Study treatment dose adjustments  
Study treatment dose adjustments are not permitted. 
6.1.3 Justification for dose 
The 50 mg dose is the dose with the best risk-benefit ratio as assessed during the entire 
clinical developmental program and represents the dose that also showed a significant 
improvement in the daytime functioning in subjects with insomnia disorder in the pivotal 
Phase 3 program. Daytime functioning is also documented to be impaired in subjects 
suffering from frequent nighttime voidings.  


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6.1.4 Treatment assignment 
Approximately 50 subjects aged ≥ 55 years will be randomized (i.e., enrolled) in a 1:1 ratio 
to either sequence. No stratification will be applied. 
After verifying that the subject meets all inclusion criteria and that none of the exclusion 
criteria are violated, the investigator / authorized delegate contacts the IRT system at 
Visit 2 to randomize the subject. The IRT system assigns the treatment kit number to the 
subject, which matches the treatment arm assigned by the randomization list to the 
randomization number.  
The IRT system is handled by an external independent vendor who will generate the 
randomization list. 
6.1.5 Blinding 
6.1.5.1 Double-blind treatment period 
This study will be performed in a double-blind fashion. The investigator, site study 
personnel, subjects, sponsor personnel, CRAs, and vendor/CRO personnel responsible for 
the conduct of the study will remain blinded to the study treatment allocation until study 
database lock.  
To ensure adequate supply of study treatment, the IRT vendor personnel responsible for 
clinical study distribution and the sponsor individuals contributing to clinical supply 
distribution will need to be unblinded at subject level and depot level, respectively. These 
persons will be clearly identified, their unblinding status will be documented in the trial 
master file and controlled as per sponsor/CRO procedures. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to authorized persons, e.g., Quality Assurance, dedicated 
members of the Pharmaceutical Development department who are not involved in the 
conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment kits will be packaged in the same way. 
6.1.6 Unblinding 
6.1.6.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
lock, in accordance with the sponsor and/or the CRO’s Quality System documents. 
6.1.6.2 Unblinding for IDMC 
Not applicable. 


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6.1.6.3 Unblinding for interim analyses 
Not applicable. 
6.1.6.4 Unblinding for SUSARs 
If a SUSAR see definition in Section 8.2.3 occurs for a subject, the sponsor’s Global 
Drug Safety department will perform unblinding of the treatment assignment for that 
subject in order to meet regulatory requirements.  
Unblinded information will only be accessible to sponsor personnel who need to be 
involved in the safety reporting to the regulatory authorities and/or IECs/IRBs, and to the 
sponsor’s Global Drug Safety personnel performing ongoing safety evaluations during the 
clinical study.  
6.1.6.5 Emergency procedure for unblinding 
The identity of the study treatment may be revealed only if the subject experiences a 
medical event, the management of which would require knowledge of the blinded treatment 
assignment. In this case, the investigator / authorized delegate can receive the unblinded 
treatment assignment through the IRT.  
In these situations, the decision to unblind resides solely with the investigator and must be 
clearly justified and explained. Whenever possible, and if it does not interfere with (or does 
not delay) any decision in the best interest of the subject, the investigator is invited to 
discuss the intended unblinding with the sponsor personnel. In all cases, the sponsor 
personnel must be informed as soon as possible before or after the unblinding. 
Once unblinding has occurred, the knowledge of the blinded treatment assignment must 
stay restricted at the site level except if an SAE has occurred and must be reported to Global 
Drug Safety, then the treatment assignment must be provided on the SAE Form.  
A subject may stay on study treatment after unblinding if considered appropriate by the 
medical judgment of the investigator. 
The circumstances leading to unblinding must be documented in the hospital charts, the 
ISF, and in the IRT system. 
6.1.7 Study treatment handling/preparation/storage/accountability 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 


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6.1.7.1 Study treatment packaging and labeling 
Study treatment is provided as film-coated tablets and supplied in blister packs. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
6.1.7.2 Study treatment distribution and storage at the site 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the IMP label and according to local requirements.  
6.1.7.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used, partially used, and unused study 
treatment blister packs at each visit. Should the treatment blister packs dispensed at a 
scheduled visit be lost or damaged, a replacement kit can be requested via the IRT system.  
The protocol-mandated study treatment dispensing procedures may not be altered without 
prior written approval from the sponsor. In exceptional circumstances (e.g., if the subject 
is unable to return to the site due to a medical emergency / hospitalization at another 
hospital / long distance to travel / pandemic restriction), unscheduled dispensing and 
delivery of study treatment may occur outside of a scheduled visit. If the study treatment 
needs to be shipped to the subject, the site staff must first contact the sponsor representative 
to check whether the dispensing and delivery process is in accordance with the sponsor / 
CRO’s Quality System documents as well as any local or national regulatory requirements.  
An accurate record of the date and amount of study treatment dispensed to each subject 
must be available for inspection at any time. 
6.1.7.4 Study treatment accountability 
The inventory of study treatment dispensed to and returned by the subject (i.e., study 
treatment accountability) must be performed by site personnel on the day of the visit and 
before dispensing further study treatment. The inventory is to be recorded by site personnel 
in the site documentation and in the eCRF. The study treatment accountability log in the 
eCRF will include at least the following information for each study treatment unit (i.e., 
blister) dispensed to the subject: 
• Dispensed blisters 
• Date dispensed and number of tablets dispensed 
• Date returned and number of tablets returned 
All study treatment supplies, including partially used or empty blisters must be retained at 
the site. 


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If the subject forgets to bring the remaining study treatment to a study visit, he/she must be 
instructed to not take any tablets from the remaining study treatment blister and to return 
it at the next visit in person or by shipping it to the site, if allowed by local regulations. 
6.1.7.5 Study treatment return and destruction 
On an ongoing basis and/or when the study ends, the CRA will collect used and unused 
treatment kits, which will be sent to the warehouse, where the sponsor / depot personnel or 
a deputy will check treatment reconciliation.  
In certain circumstances (e.g., local hospital procedures), used and unused study treatment 
containers may be destroyed at the site. In general, this can only be done once study 
treatment accountability is finalized and has been checked by the sponsor personnel 
representative, and written permission for destruction has been obtained from the sponsor. 
Exceptions might occur if a local process requests immediate destruction of the study 
treatment. Such local study treatment destruction processes must be provided and approved 
by the sponsor. 
6.1.8 Study treatment compliance 
Study treatment compliance with the prescribed study treatment dose regimen is based on 
study treatment accountability. Study treatment compliance will be calculated by site 
personnel at Visit 4 and Visit 8 using the formula below: 
Compliance =  [(number of tablets dispensed − number of tablets returned) / Total 
number of tablets that should have been taken during the period*]  100 
*The period is defined as the number of days during which study treatment should have 
been taken according to the actual visit dates. 
A compliance of between 80–100% is expected during the treatment period. Any values 
deviating from this range will be considered protocol deviations and will be reported by 
the CRA in the Clinical Trial Management System. 
The investigator / authorized delegate must discuss the non-compliance with the subject to 
clarify the reasons and to take appropriate actions to avoid re-occurrence. This discussion 
and its outcome must be documented in the source documents. 
Subjects also report their daily study treatment intake in the eDiary every morning, 
however these entries will not be considered to assess compliance. 


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6.2 Previous and concomitant medications / non-pharmacological therapy 
6.2.1 Allowed concomitant therapy 
Therapies necessary for the subject’s well-being and not categorized as prohibited 
medications can be used in this study.  
Use of non-sedating antihistamines is allowed no more than twice per week. Use of inhaled 
corticosteroids is allowed. Use of narcotics or muscle relaxants to treat pain is allowed if 
the use of alternative medications, such as non-steroidal anti-inflammatory drugs is not 
sufficient to manage the pain. Use of nocturia-related treatments is allowed if they are 
treating the underlying condition, considered to remain stable during the study and are not 
listed as forbidden [Appendix 11]. 
Subjects can receive vaccinations with any available vaccine as per local guidelines, 
provided the vaccination conditions set forth by the respective manufacturer (consistent 
with the respective prescribing information/package insert) are observed. Prior to any 
vaccination the investigator must be informed by the study participant of such a plan. 
Receipt of the vaccine, and details thereof, should be recorded in the subject’s medical 
charts and in the eCRF under concomitant medications.  
General reporting of AEs should continue to be implemented as described in Section 8.2 
and reports of AEs for approved vaccines should be submitted as appropriate. 
6.2.2 Forbidden concomitant therapy 
Concomitant therapies must not be discontinued, instead subjects must be considered 
ineligible both due to their condition and the need for these therapies.  
The following concomitant therapies are forbidden: 
• Treatment with another investigational product within 3 months prior to Visit 2 until 
EOS. 
• CNS-active medications including over-the-counter medications, herbal medicines or 
other sleep medications within 2 weeks or 5 half-lives (whichever is longer) prior to 
Visit 2 until 24 hours after study treatment discontinuation.  
• Treatment with moderate or strong CYP3A4 inhibitors/inducers within 2 weeks or 
5 half-lives (whichever is longer) prior to Visit 2 until 24 hours after study treatment 
discontinuation. 
A non-exclusive list of forbidden medications is available in Appendix 11. 
6.3 Medical care of subjects after study completion / withdrawal from study  
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator / authorized delegate will explain to subjects what treatment / 


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medical care is necessary and available according to local medical practice and applicable 
guidelines.  
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS AND PROCEDURES  
7.1 General information 
The study visits and their respective time windows are listed in the schedule of activities 
[Table 1]. All assessments pertaining to a visit must be performed on the same day.  
7.1.1 Screening  
The subjects who agree to be part of the study and the investigator / authorized delegate 
must both sign the ICF prior to participation in the study. The ICF must be fully signed 
see Section 10.2 for informed consent procedure on the day of Screening.  
If the first study-specific procedures or assessments are performed on the day that the ICF 
is signed, it must be clear from the source documents that informed consent was obtained 
prior to any study-specific procedures being performed (i.e., time of signature must be 
available).  
Procedures or assessments conducted as part of the subject’s routine clinical management 
(e.g., laboratory sample) and obtained before signing the ICF may be used for screening or 
baseline purposes, provided the procedures met the protocol-specified criteria and were 
performed within the time frame defined in the schedule of activities [Table 1]. 
After the ICF has been fully signed, the investigator / authorized delegate contacts the IRT 
system to get a subject identification number allocated to the subject. 
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study and will be recorded in 
the eCRF. Depending on the reason for the unscheduled visit (e.g., AE), appropriate 
assessments will be performed based on the judgment of the investigator and the results 
will be recorded in the eCRF. After an unscheduled visit, the regular scheduled study visits 
must continue according to the schedule of activities [Table 1]. 
7.1.3 Study completion  
A subject who completes both treatment periods and the safety follow-up period is 
considered to have completed the study. A subject who prematurely discontinues the study 
due to pre-defined criteria see Section 5.9.1 or is withdrawn from the study because of 
study closure or early termination or suspension of the study [see Section 10.10 is 
considered as an early discontinuation. In the event of a pandemic or epidemic disease, the 
process for this study is described in Appendix 1. 


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7.2 Study assessments and procedures 
All study assessments performed during study visits (scheduled or unscheduled) are done 
by the investigator / authorized delegate and are recorded in the eCRF, unless otherwise 
specified. Under exceptional circumstances (e.g., technical issues) an assessment can be 
repeated.  
All PROs collected daily (e.g., evening/morning diary) or during a site visit will be 
recorded on the handheld device or on the site tablet.  
• Assessments during the visit include:  
– Vital signs (Visit 1, Visit 4,Visit 8 and PEOT) 
– Recording of concomitant medications (All visits) 
– AEs and SAEs (All visits) 
– C-SSRS© (Visit 1, Visit 4, Visit 5, Visit 8, Visit 9 and PEOT) 
– ISI© (Visit 1, Visit 3, Visit 4, Visit 7, and Visit 8) 
– EQ-5D-3L (Visit 1, Visit 3, Visit 4, Visit 7, and Visit 8) 
– ICIQ-NQoL (Visit 1, Visit 4, and Visit 8) 
– ICIQ-MLUTS or ICIQ-FLUTS (Visit 1, Visit 4, and Visit 8) 
– Treatment satisfaction (Visit 4,Visit 8 and PEOT)  
– Treatment period preference (Visit 8 and PEOT) 
– Narrative (Visit 1, Visit 4, Visit 8 and PEOT) 
If the investigator/institution retains the services of any individual or party to perform 
trial-related duties and functions, the investigator/institution must ensure this individual or 
party is qualified to perform those trial-related duties and functions and must implement 
procedures to ensure the integrity of the trial-related duties and functions performed and 
any data generated. The investigator / authorized delegate must inform the sponsor before 
using these services. The supervision of any external facilities remains the responsibility 
of the investigator. 
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available prior to the recruitment of 
the first subject. Calibration certificates / evidence of equipment maintenance of other 
equipment must be available as per local requirements: 
• Temperature measurement devices for study treatment storage area.  
7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristic data to be collected in the eCRF for all subjects 
include: age, sex, race, and ethnicity (if allowed in the country). Relevant medical history 


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and/or current medical conditions based on the investigator / authorized delegate’s 
judgment (e.g., chronic and ongoing acute conditions, serious past conditions) present 
before and/or at the time of signing informed consent will be recorded in the eCRF. Where 
possible, diagnoses and not symptoms will be recorded. 
Insomnia severity will be assessed with the ISI©. Subjects will need to have a score of at 
least 13 at Visit 1.  
The number of voidings per night will be captured using a voiding diary and will be applied 
in the first 3 days following Visit 1. Subjects will have to report on average ≥ 2.6 voidings 
during the night to be eligible.  
The reason for not being of childbearing potential will be recorded in the eCRF.  
7.2.2 Reporting of previous/concomitant medications / non-pharmacological 
therapy / auxiliary medicinal products and methods of birth control in the 
eCRF  
A concomitant medication / non-pharmacological therapy is any treatment that is either 
ongoing at the start of study treatment or is initiated during the treatment period.  
A previous medication / non-pharmacological therapy is any treatment for which the end 
date is prior to the start of study treatment. 
The use of all concomitant medications / non-pharmacological therapies (including 
traditional and alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will 
be recorded in the eCRF. Previous medications / non‑pharmacological therapies must be 
recorded in the eCRF if discontinued within 30 days prior to signing of the informed 
consent.  
Subjects will be asked to list any sleep medications that have been taken up to 1 year prior 
to the study. 
8 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
8.1 Safety definitions 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the study, whether or not considered by the investigator / authorized delegate as 
related to study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease if considered medically relevant.  


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• Exacerbation of a pre-existing disease except for efficacy endpoints and associated 
symptoms. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the study, even though it 
may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen after the 
start of the study. 
• Abnormal change on physical examination or ECG findings, if they represent a 
clinically significant finding that was not known at study start or worsened during the 
study as per investigator medical assessment. 
• Laboratory test abnormalities if they represent a clinically significant finding 
(symptomatic or not) which was not known at study start or worsened during the study 
as per investigator judgment, led to dose reduction, interruption or permanent 
discontinuation of study treatment. 
8.1.1 Definition of adverse events of special interest 
AESIs are defined as: 
• Events of falls 
If the subject reports an event of fall at any time during the study, the investigator will be 
asked to complete the form in the eCRF that collects further information (e.g., time of 
event, external causes). 
• Events of incontinence episodes 
Worsening or new onset of urinary incontinence will be documented by the study sites 
including patient’s demographic information, medical history, current medications, 
voiding diary information, and time of occurrence of the incontinence episode if available.  
8.1.2 Definition of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least 1 of the following 
criteria: 
• Fatal. 
• Life-threatening: Refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe. 
• Requiring in-patient hospitalization (i.e., the AE required admission to hospital) or 
prolongation of existing hospitalization. 


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• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: Refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs based upon appropriate medical judgment, as they may jeopardize the subject, 
and/or may require medical or surgical intervention to prevent 1 of the outcomes listed 
in the definitions above. 
The following reasons for hospitalization are not considered as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing the ICF) surgery or 
standard monitoring of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for coronary angiography in a subject with stable angina pectoris. 
8.1.3 Intensity of adverse events 
The intensity of AEs is graded on a three-point scale — mild, moderate, severe — as 
follows: 
• Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
• Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
• Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 8.1.2]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
8.1.4 Relationship to study treatment  
Each AE/SAE must be assessed by the investigator / authorized delegate as to whether or 
not there is a reasonable possibility of causal relationship to the study treatment and 
reported as either related or unrelated.  


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8.1.5 Relationship to study design or protocol-mandated procedure  
An AE/SAE is defined as related to the study design or protocol-mandated procedure if it 
appears to have a reasonable possibility of a causal relationship to either the study design 
or to a protocol-mandated procedure. 
The determination of the likelihood that a protocol-mandated procedure caused the 
AE/SAE will be provided by the investigator / authorized delegate. 
8.1.6 Definition of study treatment overdose, misuse, and abuse 
An overdose is defined as the administration of a study treatment dose (per intake or 
cumulatively) which is above the instructions provided in the protocol. When applying this 
definition, clinical judgement should always be applied (e.g., just because a subject 
returned less tablets than anticipated number is not an overdose as per definition). 
The sponsor does not recommend specific treatment for an overdose. The subject should 
be monitored to detect any potential AE linked to the overdose 
Study treatment misuse is defined as any intentional and inappropriate use of the study 
treatment which is different from the instruction provided in the protocol. 
Study treatment abuse is defined as any intentional and excessive use of the study 
treatment, with harmful physical or psychological effects. 
In the event of a study treatment overdose, abuse or misuse, the investigator / authorized 
delegate must contact the sponsor and closely monitor the subject for any AEs/SAEs as 
well as complete an additional form in the eCRF.  
8.2 Reporting procedures 
8.2.1 Reporting adverse events 
The occurrence of an AE may come to the attention of study personnel during study visits, 
phone calls, narrative texts or interviews with subjects presenting for medical care.  
At each study visit (scheduled or unscheduled), the investigator / authorized delegate will 
inquire about the occurrence of AEs since the last visit. 
All AEs with an onset date after signing the ICF and up to 5 days after study treatment 
discontinuation must be recorded in the eCRF.  
The AE should be reported as a final diagnosis (if possible) rather than a list of symptoms. 
Information to be collected on an AE form in the eCRF includes date of onset, action taken 
with the study treatment, outcome of AE, date of resolution (if applicable), and 


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investigator / authorized delegate’s assessment of intensity as well as relationship to study 
treatment, study design or protocol-mandated procedures.  
Information on worsening of intensity will be collected on a new AE form. If the AE 
lessens in intensity, no change in the severity is required to be reported. 
AEs still ongoing after study treatment discontinuation must be followed up until 
resolution, until they are no longer considered clinically relevant, or until stabilization.  
8.2.2 Reporting serious adverse events 
All SAEs must be reported by the investigator / authorized delegate to the sponsor’s Global 
Drug Safety department within 24 hours of site staff first becoming aware of the event. 
All SAEs occurring after signing the ICF up to 5 days after study treatment discontinuation 
must be recorded on an SAE form, regardless of the investigator-/delegate-attributed causal 
relationship with study treatment or study-mandated procedures. 
The SAE forms must be sent to the sponsor’s Global Drug Safety department (see contact 
details on the SAE form). The investigator / authorized delegate must complete the SAE 
form in English and must assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
Follow-up information about a previously reported SAE must be promptly reported. The 
sponsor’s Global Drug Safety personnel may contact the investigator / authorized delegate 
to obtain further information. 
If the subject is hospitalized in a hospital other than that of the study site, it is the 
investigator / authorized delegate’s responsibility to obtain all SAE-relevant information 
and documentation. 
New SAEs occurring after the follow-up period must be reported to the sponsor’s Global 
Drug Safety department within 24 hours of site staff first awareness/knowledge of the 
event, only if considered by the investigator / authorized delegate to be causally related to 
previous exposure to the study treatment. 
SAEs still ongoing after study treatment discontinuation must be followed up until 
resolution, stabilization, or until the event outcome is provided. 
8.2.3 Reporting procedure for SUSARs 
For patients included in the trial in the US, the expectedness of an SAE is determined by 
the sponsor according to the reference safety information section provided in the IB. For 
patients included in the trial in Europe, the expectedness of an SAE is determined by the 


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sponsor according to the list of adverse reactions detailed in section 4.8 of the EU SmPC. 
Any SAE that is assessed as related and unexpected against the reference safety 
information is considered a SUSAR. 
Any SUSAR must be reported by the sponsor/CRO to relevant health authorities, and 
investigators. Submission to central/local IECs/IRBs will be done as per their requirements. 
8.3 Pregnancy 
Although women of childbearing potential are excluded from this study, a pregnancy could 
still occur. If a woman becomes pregnant while on study treatment, study treatment must 
be discontinued. The investigator / authorized delegate must counsel the subject and 
discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
8.3.1 Reporting of pregnancy 
Any pregnancy occurring in a female subject after signing the ICF, the start of study 
treatment administration and up to 30 days after study treatment discontinuation must be 
reported to the sponsor’s Global Drug Safety department within 24 hours of site staff first 
becoming aware of the event. 
All pregnancies must be reported on the sponsor Pregnancy form, which is sent to the 
sponsor’s Global Drug Safety department (see contact details provided on the Pregnancy 
form) and the eCRF. 
The investigator / authorized delegate must complete the Pregnancy form in English. 
8.3.2 Follow-up of pregnancy 
Any pregnancies must be followed up to their conclusion and the outcome must be reported 
to the sponsor’s Global Drug Safety department.  
Any AE associated with the pregnancy of a female subject occurring during the AE 
reporting time must be reported on separate AE forms in the eCRF as described in 
Section 8.2.1.  
Any SAE occurring during the pregnancy must be reported on an SAE form as described 
in Section 8.2.2. 
9 
STATISTICAL METHODS 
All statistical analyses will be conducted by the sponsor or a CRO designated by the 
sponsor. 
A SAP will provide full details of the analyses, data displays, and algorithms to be used 
for data derivations. 


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9.1 Analysis sets 
9.1.1 Screened analysis set 
The SCR includes all subjects for whom informed consent to participate in the study was 
obtained [see Section 10.2] and have a subject identification number. 
9.1.2 Randomized analysis set 
The RND includes all subjects who have been assigned to double-blind study treatment. 
9.1.3 Full analysis set 
The FAS includes all subjects from the RND who received at least one dose of double-blind 
study treatment.  
To adhere to the intention-to-treat principle:  
• Subjects will be evaluated according to their assigned study treatment, which may 
differ from the treatment they have received.  
• Unless otherwise stated, all available data will be included in analyses. 
9.1.4 Per-protocol set 
The PPS includes all subjects from the FAS without important protocol deviations, 
occurring prior to Week 4, which could affect the analysis of the primary endpoint variable.  
The precise reasons for excluding subjects from the PPS will be fully defined and 
documented in the SAP before breaking the randomization blind.  
9.1.5 Safety set 
The Safety set will include all subjects who received at least one dose of double-blind study 
treatment. Subjects will be analyzed based on the treatment received (in each period). 
9.1.6 Other analysis sets 
Other analysis datasets might be defined in the SAP, e.g., sub-study sets or subgroups of 
interest. 
9.1.7 Usage of the analysis sets 
The analyses of the primary endpoint and all exploratory efficacy endpoints will be 
performed using the FAS. Baseline and disease characteristics will be analyzed on the FAS 
as well. 
The analyses of the primary endpoint will be repeated based on the PPS. 
The Safety set will be used for the analysis of safety endpoints (including previous and 
concomitant medications, and study treatment exposure).  


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Subject data will be listed using the SCR, unless otherwise specified. 
9.2 Description of statistical analyses 
All available data for each subject, regardless of intercurrent events, will be used in all 
statistical analyses, unless otherwise specified. 
All efficacy analyses will be based on the FAS, unless otherwise specified. 
9.2.1 Overall testing strategy 
The primary efficacy endpoint of this study is defined as the change from Baseline to 
Week 4 in sTST. 
Hypotheses are defined as follows: 
• H0: Mean of the within-subject changes in sTST from baseline to Week 4 between 
daridorexant 50 mg and placebo = 0 
• H1: Mean of the within-subject changes in sTST from baseline to Week 4 between 
daridorexant 50 mg and placebo ≠ 0 
The null hypothesis will be tested at a two-sided alpha of 0.05. 
9.2.2 Analysis of the primary efficacy endpoint 
The primary endpoint will be analyzed based on an MMRM. Some sensitivity analyses 
will also be performed for the primary endpoint. These analyses will not form part of the 
testing strategy. 
No secondary endpoints are defined for this study. 
9.2.2.1 Estimands 
Estimands are defined by five attributes: treatment condition of interest, target population, 
endpoint, strategy for addressing intercurrent events (i.e., premature discontinuation of 
treatment or use of other, forbidden, medication), and population‑level summary. 
The primary estimand is based on the primary endpoint. For the primary estimand the 
treatment condition is daridorexant 50 mg once daily for up to 4 weeks, whereas the 
alternative condition is placebo once daily for the same period. The other four attributes 
are given in Table 4. 
The secondary estimand is based on the primary endpoint as well. Intercurrent events 
considered are premature treatment discontinuations. Details are provided in Table 4. 


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Table 4 
Estimand for the primary objective 
Estimand 
Target Population 
Endpoint 
Strategy for 
addressing 
intercurrent 
events 
Population-level 
summary 
Primary 
Estimand 
Study subjects with 
insomnia and nocturia 
Change 
from 
Baseline 
to Week 
4 in sTST 
Treatment policy, 
i.e., endpoint data 
after intercurrent 
events are used. 
Treatment effect 
expressed as 
difference of LS 
Mean changes from 
Baseline to Week 4 
(daridorexant minus 
placebo; from 
MMRM) 
Secondary 
Estimand 
Study subjects with 
insomnia and nocturia 
Change 
from 
Baseline 
to Week 
4 in sTST 
Hypothetical, i.e., 
endpoint data 
collected after 
intercurrent events 
are not used. 
Treatment effect 
expressed as 
difference of LS 
Mean changes from 
Baseline to Week 4 
(daridorexant minus 
placebo; from 
MMRM) 
LS Mean = least squares mean; MMRM = mixed model for repeated measures; sTST = subjective total sleep time. 
 
9.2.2.2 Variable definition (sTST) 
The change from Baselinea to Week 4b in sTST is calculated as follows: 
Change from Baseline = Averaged value at Week 4 – Averaged value at Baseline. 
a Baseline is the mean value based on the screening sleep diary for sTST, performed on the 
7 days preceding Randomization. 
b ‘Week 4’ is the mean value based on the sleep diary entries for sTST performed on study 
days 23–29 for each period. Data after the EOTP I/II visits will not be included in the 
analysis, as subjects are expected to be on double-blind treatment up to that point. 
As sTST for Weeks 1–3 will also be included in the MMRM, definitions for the changes 
from baseline will be identical. For Week 1, sTST is averaged across days 2–8, for Week 2 
across days 9–15, and for Week 3 across days 16–22. 
Subjects must have at least 2 days of data during each week to calculate a weekly mean. 
Otherwise, the mean value will be considered missing for that week.  


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9.2.2.3 Analysis of primary estimand (primary efficacy analysis) 
Changes from baseline to post-baseline visits in sTST will be analyzed using an MMRM 
with change from baseline in sTST as response, treatment group (daridorexant 50 mg; 
placebo), period (Period I; Period II), and week within period (Week 1; Week 2; Week 3; 
Week 4) as factors, baseline sTST assessment as covariate, and the interaction of treatment 
group × week. 
To evaluate the efficacy hypotheses, the difference in LS mean change from baseline 
between daridorexant 50 mg and placebo at Week 4 will be estimated from the MMRM. 
An unstructured covariance matrix will be used to account for the correlation between 
repeated measurements from the same subject. In the event of convergence issues of the 
MMRM, the primary estimand will be estimated as described in the SAP. This approach 
relies on the Missing at Random assumption. 
9.2.2.4 Handling of missing data and intercurrent events 
Section 9.2.2.1 explains how the primary efficacy endpoint is derived in the event of 
partially missing data. 
The analyses of the primary endpoint will only include subjects with a valid baseline and 
at least one of the four weekly assessments for sTST, following the same approach as in 
the Phase 3 program. The approach is justified, as very limited dropouts are expected 
(< 3%) due to the short duration of the treatment period (4 weeks). Every effort will be 
made to keep all subjects in the study, even in the event of premature treatment 
discontinuations, to collect all the relevant data for the analysis of the primary endpoint. 
Data collected after premature discontinuation of treatment will be included in the analysis 
(following the treatment policy strategy for the primary estimand). 
The analysis of the primary endpoint will also be performed excluding data collected after 
premature discontinuation of treatment (following the hypothetical strategy for the 
secondary estimand). 
9.2.2.5 Sensitivity analyses  
As the collection of urine during pre-defined study nights might have an impact on the 
primary outcome sTST, a sensitivity analysis will be performed removing those days from 
the weekly averages. 
For this analysis, ‘Baseline’ is defined as the mean value based on the screening sleep diary 
for sTST, recorded on the 7 days preceding Randomization, except for the nights where 
urine was collected. ‘Week 4’ is defined as the mean value based on the sleep diary entries 
for sTST recorded on study days 23–29 for each period, except for the nights where urine 
was collected. As sTST for Weeks 1–3 will also be included in the MMRM, definitions for 
the changes from baseline will be identical. Subjects must have at least 2 days of data 


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during each week to calculate a weekly mean. Otherwise, the mean value will be considered 
missing for that week. 
9.2.2.6 Supportive analyses 
The analyses of the primary endpoint will be repeated on the PPS (based on the same 
MMRM). 
No supplementary analyses are currently foreseen in the protocol. Additional analyses may 
be added to the SAP at a later time point. 
9.2.2.7 Subgroup analyses 
No subgroup analyses are planned for this study because of the small study size. Some 
potential subgroup analyses might be added at a later stage and will be defined in the SAP. 
9.2.3 Analysis of the secondary efficacy endpoints 
No secondary efficacy endpoints are defined in this study. 
9.2.4 Analysis of other efficacy endpoints 
The analyses of all other exploratory efficacy outcomes will be described in detail in the 
SAP. Exploratory variables may also be analyzed by subgroup. Exploratory efficacy 
endpoints will be analyzed at each relevant time point listed in the schedule of activities 
Table 1 along with any data from unscheduled visits as appropriate.  
9.2.5 Analysis of safety outcomes 
The Safety set will be used to perform all safety analyses. Safety analyses will be conducted 
by period. 
If not otherwise stated, only treatment-emergent safety data will be considered in tables 
and figures. All safety data will be included in listings, with flags for safety data not 
considered to be treatment emergent.  
9.2.5.1 Adverse events 
9.2.5.1.1 Treatment-emergent AEs and SAEs 
TEAEs and SAEs will be tabulated by study treatment, SOC, and preferred terms within 
each SOC: the number and percentage of subjects who experienced at least 1 (S)AE, at 
least 1 (S)AE within each SOC, and at least 1 (S)AE within each preferred term will be 
displayed. (S)AEs will also be summarized by decreasing frequency of preferred term. 
(S)AEs will also be tabulated by maximum intensity and by relationship to study treatment. 
AEs and SAEs are considered treatment-emergent AEs and SAEs if they occur up to 5 days 
after DB study treatment discontinuation. 


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9.2.5.1.2 AEs leading to premature discontinuation of study treatment 
AEs leading to premature discontinuation of study treatment will be summarized in a 
similar manner as those described in Section 9.2.5.1.1. 
9.2.5.2 Vital signs 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and absolute changes from baseline in pulse rate, systolic and 
diastolic blood pressure.  
9.2.6 Analyses of other outcomes 
A full description of all other safety analyses will be provided in the SAP.  
9.3 Interim analyses 
No interim analysis is planned for this study.  
9.4 Sample size 
The assumptions for the sample size calculations were determined using data from studies 
ID-078A202 and ID-078A301 for the treatment groups daridorexant 50 mg and placebo.  
Data of sTST changes from baseline and the corresponding SDs were derived based on 
simulations using sTST data at Baseline and at Month 1 from the ID-078A301 study for 
the age group ≥ 55 years. Subsets of 50 subjects were randomly selected from both the 
daridorexant 50 mg and placebo groups and compared via t-tests for independent samples, 
with means and SDs averaged across 1000 iterations. The simulations resulted in a mean 
difference of the change from baseline to Month 1 in sTST of 26 min for daridorexant 
50 mg and placebo, with SDs of 42.5 min for placebo and 50.5 min for daridorexant 50 mg.  
Correlations between daridorexant 50 mg and placebo for sTST data were derived based 
on the cross-over study ID-078A202 (for subjects aged ≥ 65 years). The Pearson 
correlation coefficient was estimated at 0.58. Combining all the information above resulted 
in an SD of the difference in the change of sTST from baseline to Month 1 of 44 min (based 
on the variance/covariance formula). 
Based on a two-sided type I error of 0.05, an estimated within subject mean difference of 
the change from baseline to Month 1 in sTST between daridorexant 50 mg and placebo of 
26 min and an associated SD of 44 min, a total sample size of 50 subjects, in this cross-over 
setting, provides at least 90% power, based on a two-sided paired t-test. A smaller within 
subject mean difference between daridorexant 50 mg and placebo of 20 min still results in 
power of at least 80%. 


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9.4.1 Power considerations for the endpoint change from baseline to Week 4 in 
number of nocturnal voids assessed using a voiding diary 
Sample size calculations/considerations for the endpoint change from baseline to Week 4 
in number of nocturnal voids assessed using a voiding diary were performed based on 
two-sided paired t-tests for different scenarios: 
1. Assuming a within-subject mean difference between daridorexant 50 mg and placebo 
in the number of nocturnal voids of 0.30 (averaged across 3 consecutive nights) after 
4 weeks of treatment, and assuming an SD of the within-subject difference of 0.7, leads 
to approximately 80% power, based on 50 subjects and a type I error of 0.05, using a 
two-sided paired t-test. 
2. Increasing the SD of the within-subject difference between daridorexant 50 mg and 
placebo to 1.0, would require a within-subject mean difference in the number of 
nocturnal voids of 0.45 to reach 80% power for the same number of subjects. 
3. Increasing the SD of the within-subject difference between daridorexant 50 mg and 
placebo to 1.2, would require a within-subject mean difference in the number of 
nocturnal voids of 0.55 to reach 80% power for the same number of subjects. 
Assumptions for the sample size calculations were derived based on Key Opinion Leader 
feedback and based on data from previous nocturia studies with a study duration of up to 
4 weeks [Ferring 2015, Ferring 2012, Miwa 2011]. 
10 REGULATORY, 
ETHICAL, 
AND 
STUDY 
OVERSIGHT 
CONSIDERATIONS 
10.1 Regulatory and ethical considerations 
The sponsor personnel and the investigator(s) will ensure that the study is conducted in full 
compliance with ICH GCP guidelines, the principles of the Declaration of Helsinki, the 
protocol and with the laws and regulations of the country in which the study is conducted. 
The investigator and/or sponsor/CRO will submit this protocol and any related 
document(s) provided to the subject (such as the ICF) to an IEC/IRB and to the health 
authority (as applicable). Approval from both the IEC/IRB and the health authority must 
be obtained before starting the study and must be documented in a dated letter to the 
investigator and/or sponsor/CRO, clearly identifying the study, the documents reviewed, 
and the date of approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator / authorized delegate and/or sponsor/CRO to 
the IEC/IRB and to the health authority in accordance with local procedures and 
regulations. 


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10.2 Informed consent process 
It is the responsibility of the investigator / authorized delegate to obtain informed consent 
according to ICH GCP and Declaration of Helsinki guidelines and local regulations from 
each individual participating in this study. The investigator / authorized delegate must 
explain to subjects that they are completely free to refuse to enter the study, or to 
voluntarily withdraw from the study at any time for any reason without having to provide 
any justification. Special attention must be paid to the information needs of specific subject 
populations and of individual subjects, as well as to the methods used to deliver the 
information. Adequate time must be given for the subject to consider his or her decision to 
participate in the study and it must be verified that the subject has understood the 
information (e.g., by asking the subject to explain what is going to happen).  
If a revised version of the ICF is approved by health authorities (if applicable) and 
IRBs/IECs:  
• Newly recruited subjects must provide consent using the most current version of the 
ICF(s). 
• Subjects who are already participating in the study (e.g., already recruited) must be 
re-consented using the most current version of the ICF(s) if necessary (e.g., additional 
study procedure, new safety information) and/or requested (e.g., as per IRB/IEC 
requirements). 
A copy of the signed and dated ICF is given to the subject; the original is filed in the site 
documentation. The informed consent process must be fully documented in the subject’s 
medical records. This must include at a minimum the study reference, the subject 
identification number, the date and, if applicable, time when the subject was first 
introduced to the study, the language in which the study has been explained, the date and, 
if applicable, time of consent, who participated in the consent discussion, who consented 
the subject, and any additional persons present during the consent process (e.g., subject’s 
family member[s]), and the information that a copy of the signed ICF was given to the 
subject. 
If the site intends to recruit subjects who are considered vulnerable (e.g., subject cannot 
read or write, does not speak or understand the ICF language), additional measures must 
be implemented to ensure the subject’s rights are respected and the consent obtained is 
legally valid. The sponsor, the regulatory authorities (if applicable), and the IEC/IRB must 
be informed prior to the recruitment. The consent process (e.g., involvement of an impartial 
witness) must be fully described, submitted to, and approved by the IEC/IRB, according to 
procedures and before subjects are recruited. 


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10.3 Data protection and privacy 
Subject data confidentiality and privacy are strictly held in trust by the investigators, their 
staff and the sponsor or delegate.  
The investigator / authorized delegate must ensure that data confidentiality is maintained. 
On eCRFs or other documents (e.g., documents attached to SAE forms / Pregnancy forms) 
submitted to the sponsor and any vendors or CROs, subjects must be identified only by 
number and never by their name or initials, hospital numbers, or any other personal 
identifier. The investigator / authorized delegate must keep a subject identification code 
list at the site. Documents identifying the subjects (e.g., signed ICFs) must not be sent to 
the sponsor or any vendors or CROs, and must be kept in strict confidence by the 
investigator / authorized delegate.  
In the electronic device, there will be no possibility to enter any personal identifier and the 
subject will only be identified by the study site and subject identification number. Each 
time the subject makes an entry in the electronic device, he/she will be required to enter 
his/her own confidential password.  
The subjects must be informed that their personal study-related data will be used by the 
sponsor in accordance with the applicable data protection law.  
The subjects must be informed that their medical records may be inspected by the sponsor 
or sponsor’s delegate, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
10.4 Indemnification, compensation, and refund of expenses to subjects and 
investigators 
The sponsor provides insurance to indemnify (with both legal and financial coverage) the 
investigator/site against claims arising from the study, except for claims that arise from 
malpractice and/or negligence. 
The indemnification of the subjects in the event of study-related injuries will comply with 
applicable regulations. 
Subjects will be reimbursed for study-related expenses (e.g., travel costs, meals, 
accommodation), and may be offered financial compensation for their participation in the 
study only to the extent permitted by applicable local law. 
10.5 Essential documents and retention of documents 
The investigator / authorized delegate must maintain adequate records necessary for the 
reconstruction and evaluation of the study. Several attributes are considered of universal 
importance to source data and the records that hold those data. These include that the data 


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and records are accurate, legible, contemporaneous, original (or a certified copy), 
attributable, complete, consistent, enduring, and available when needed. 
These records are to be classified into 2 different categories of document: ISF and subjects’ 
source documents. 
These records must be kept by the investigator/site for as long as is necessary to comply 
with the sponsor’s requirements (i.e., as specified in the clinical study agreement), ICH 
GCP and national and/or international regulations, whichever is the longest period. If the 
investigator/site cannot guarantee this archiving requirement at the site for any or all of the 
documents, special arrangements, respecting the data confidentiality, must be made 
between the investigator/site and the sponsor to store these documents off site, so that they 
can be retrieved in the event of a regulatory inspection. Study documents must not be 
destroyed without prior written approval from the sponsor. If the site needs to transfer the 
study records to another location and/or if the site facility can no longer store the study 
records, the investigator/site must immediately inform the sponsor.  
10.5.1 Investigator Site File 
Each site will maintain an ISF. It will contain all the essential documents that are required 
to be up-to-date and filed at the site as per ICH GCP section 8. 
The ISF must be stored in a secure and access-restricted area during and after the study.  
10.5.2 Source documents 
All source documents should be completed in a neat and legible manner to ensure accurate 
interpretation and traceability of the data. Data reported in the eCRF derived from source 
documents must be consistent with the source documents. 
If the site is using electronic/computerized system(s) to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per 21 CFR Part 11 or 
equivalent standard) and if the CRA has been provided personal access to subjects’ medical 
records in order to verify consistency between electronic source data and the eCRF during 
monitoring visits. 
If the site is using electronic/computerized system(s) to store subject medical records but 
it could not be confirmed that the system(s) is/are validated or if the CRA could not be 
provided access to the system(s), the site is requested to print the complete set of source 
data needed for verification by the CRA. The printouts must be numbered, stapled together 
with a cover sheet, signed, and dated by the investigator / authorized delegate to confirm 
that these certified copies are exact copies containing the same information as the original 
source data. The printouts will be considered as the official clinical study records. Once 
printed and certified, the document must not be edited/changed (e.g., manual notes added, 
clinical value changed) in order not to impact the validity of the certification. If the data 


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needed to be changed (e.g., correction of a mistake) the change(s) must be done in the 
electronic/computerized system and a new copy must be printed and certified. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA periodically requests that a site representative logs into the electronic/computerized 
system so the CRA could verify the entries in the system against the printouts. The CRA 
does not need to perform these activities for all subjects but at least for some of them and 
for key data (e.g., eligibility criteria, primary and key secondary endpoints) as per the 
sponsor/CRO instructions. 
All records on the electronic device will be date and time stamped.  
Entries recorded by the subject in the electronic device (i.e., sleep diary including VAS, 
ISI©, IDSIQ, EQ-5D-3L, PGA-S daytime symptoms, PGI-C daytime and nighttime 
symptoms, PGA-S daily life, PGI-C daily life, ICIQ-NQoL, ICIQ-MLUTS or 
ICIQ-FLUTS, treatment satisfaction NRS, treatment preference, and narrative) as well as 
the physician‑reported global assessment (i.e., C-SSRS©) on an electronic device are 
considered source data.  
Entries recorded on paper such as the physician-reported global assessment (i.e., the 
C-SSRS© in the event the table is not accessible) are considered source data.  
10.6 Data handling 
10.6.1 Data collection, data transfer procedure, and data access 
The investigator / authorized delegate is responsible for ensuring the accuracy, 
completeness, and timely reporting of subject’s data.  
Electronic data capture will be used to collect eCRF data. The investigator and site 
personnel will be trained to enter and edit the data via a secure network, with secure access 
features (username, password, and identification — an electronic password system). A 
complete electronic audit trail will be maintained. The investigator / authorized delegate 
will approve the data (i.e., confirm the accuracy and completeness of the data recorded) 
using an electronic signature (as per US 21 CFR Part 11). 
Subject recruitment and enrollment data will be completed for all subjects (i.e., eligible 
and non-eligible) through the IRT system and eCRF. 
For each subject recruited, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator / authorized delegate. This also applies to those 
subjects who fail to complete the study.  
Site personnel will review and ensure completeness and readability of the subjects’ entries. 
Site personnel can correct electronic subject data in the electronic device. To request any 


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data changes, a data correction form will be completed by the site personnel and processed 
according to the CRO procedures.  
10.6.2 Database management and quality control 
The eCRF must be completed in a timely manner as per eCRF completion guidelines. 
While entering the data, the investigator / authorized delegate will be instantly alerted to 
data queries by validated programmed checks. Additional data review will be performed 
by the sponsor personnel or delegate on an ongoing basis to look for unexpected patterns 
in data and for study monitoring. Should discrepant data be detected, a manual query 
specifying the matter and requesting clarification will be issued and visible to the 
investigator / authorized delegate via the eCRF. All electronic queries visible in the system 
either require a data correction (when applicable) and a response from the investigator / 
authorized delegate to clarify the queried data directly in the eCRF, or simply a data 
correction in the eCRF. The investigator / authorized delegate must, on request, supply the 
sponsor with any required background data from the study documentation or clinical 
records. This is particularly important when errors in data transcription are suspected. In 
the event of health authority queries, it is also necessary to have access to the complete 
study records, provided that subject data confidentiality is protected. 
This process will continue until database lock. 
Electronic questionnaires will be processed through a central vendor and the results of the 
enrolled subjects will be electronically sent to the sponsor at pre-specified intervals with a 
final transfer prior to database lock. During the study, the site staff and sponsor 
representatives can access the data in view-only mode on the central server of the respective 
vendor see also Section 10.6.1. 
AEs and medical history will be coded with MedDRA. Medications will be coded with the 
World Health Organization Drug Dictionary. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made as described in the 
appropriate sponsor Quality System documents. The sponsor is responsible for ensuring 
that the investigator / authorized delegate will have permanent access (either “write” access 
or “read-only” access) to the site eCRF subject data, until receipt of an electronic copy of 
the site eCRFs (including the audit trail). 
10.7 Protocol deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. 


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Prospective approvals of protocol deviations, also known as protocol waivers or 
exemptions, are not permitted.  
The investigator must conduct the study in compliance with the IEC/IRB-approved and/or 
the regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the subject. 
Protocol deviations must be reported to the IEC/IRB and regulatory authorities according 
to local requirements. 
10.8 Clinical monitoring 
Prior to study start at a site, all required approvals must be obtained. A site initiation visit 
will be performed after the required essential study documents are approved by the sponsor. 
The study treatment will be shipped to the site upon approval of the required essential 
documents. 
The investigator must ensure that all key site personnel involved in the study are 
present/available during the site initiation visit and will dedicate sufficient time to it. 
The site initiation visit must be completed before the site can start recruiting subjects. 
Following the site initiation visit, a copy of the completed initiation visit report and 
follow-up letter will be provided to the investigator and filed in the ISF. 
During the study, the CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the eCRFs and other protocol-related documents. Monitoring activities will be 
performed according to the study-specific monitoring guidelines. The methodology and the 
frequency of the monitoring visits will be mainly based on subject recruitment rate and 
critical data-collection times. 
The investigator / authorized delegate must ensure that the eCRF is completed as per the 
eCRF completion guidelines and that all requested subject files (e.g., ICFs, medical 
notes/charts, other documentation verifying the activities conducted for the study) are 
available for review by the CRA. The required site personnel must be available during 
monitoring visits and allow adequate time to meet with the CRA to discuss study-related 
issues. 
The investigator agrees to cooperate with the CRA to ensure that any issues detected in the 
course of these monitoring visits are resolved. 


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A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. If a site does not screen any subjects, 
the close-out visit may be performed prior to study closure at the discretion of the sponsor. 
10.9 Study safety oversight 
Study safety information (AEs, SAEs, vital signs, and study-specific examinations, as 
required) is monitored and reviewed on a continuous basis by the sponsor.  
The sponsor may request additional data pertaining to the diagnostic work-up of an AE or 
SAE (e.g., medical imaging, local laboratory values) for the purpose of monitoring safety. 
Such additional data may be shared with external experts. 
10.10 Early termination or suspension of the study 
The sponsor reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If the study is suspended or early terminated, the sponsor will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons 
for the suspension or termination. 
If the study is suspended or early terminated for any reason, the investigator — in 
agreement with the sponsor — must promptly inform all recruited subjects and ensure their 
appropriate treatment and follow-up, as described in Section 6.3. The sponsor may inform 
the investigator of additional procedures to be followed to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates the study without prior agreement 
from the sponsor, the investigator must promptly inform the sponsor personnel and the 
IEC/IRB and provide both with a detailed written explanation of the termination or 
suspension.  
10.11 Audit 
The sponsor representatives may audit the investigator site during the study or after its 
completion. The purpose of this visit will be to determine the investigator’s adherence to 
ICH GCP, the protocol, and applicable regulations. Adherence to the sponsor requirements 
(e.g., SOPs) will also be verified. Prior to initiating this audit, the investigator will be 
contacted by the sponsor to arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 


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10.12 Inspections 
Health authorities and/or the IEC/IRB may also conduct an inspection of this study at the 
site (during the study or after its completion). 
Should an inspection be announced by a health authority and/or the IEC/IRB, the 
investigator must immediately inform the sponsor (usually via the CRA and copying the 
following mailbox: gcp@idorsia.com) that such a request has been made. 
The investigator and site personnel must cooperate with the sponsor to handle the 
inspection related to sponsor studies. The investigator and site personnel must also 
cooperate with the inspector(s) to ensure proper performance of the inspection and allow 
access to all study documentation (e.g., subject records) and study facilities. 
10.13 Reporting of study results and publication 
The sponsor will register the clinical study in publicly accessible registers (e.g., 
clinicaltrials.gov) and disclose the results as required by law. 
Study results will be documented in a clinical study report that will be signed by the 
sponsor’s representatives and the coordinating investigator. 
The sponsor will provide a short summary of this clinical study in lay language to the sites, 
who are then encouraged to share it with the participants, 12 months following completion 
of the study. 
In accordance with the Good Publication Practices and ethical practice as outlined in 
internationally recognized guidance documents (e.g., European Medical Writers 
Association, American Medical Writers Association, International Society for Medical 
Publication Professionals), the results of the study will be submitted for publication in a 
peer-reviewed journal. Study results can be submitted for presentation at a congress before 
submission to a peer-reviewed journal. 
The coordinating investigator will have the opportunity to review the analysis of the data 
and to discuss the interpretation of the study results with the sponsor personnel prior to 
submission to a peer-reviewed journal or presentation at a congress. 
Authorship will be determined in accordance with the International Committee of Medical 
Journal Editors criteria, and be based on: 
• substantial contributions to the conception or design of the study, or the acquisition, 
analysis, or interpretation of data; and 
• drafting of the publication or critical review for important intellectual content; and 
• providing final approval of the version to be published; and 


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• agreement to be accountable for all aspects of the work in ensuring that questions 
related to the accuracy or integrity of any part of the work are appropriately investigated 
and resolved. 
The list of authors of any publication of study results may include representatives of the 
sponsor and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
the sponsor for review at least 60 days prior to submission for publication or presentation 
at a congress. Upon review, the sponsor 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 is permitted to write a 
publication during such a review period. 
 
 


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11 REFERENCES 
[Daridorexant IB] Investigator’s Brochure for daridorexant, version 10. Idorsia 
Pharmaceuticals Ltd; January 2023. 
[Abraham 2004] Abraham L, Hareendran A, Mills IW, Martin ML, Abrams P, Drake MJ, 
et al. Development and validation of a quality-of-life measure for men with nocturia. 
Urology. 2004 Mar; 63(3):481-6. 
[Asplund 1992] Asplund R, Aberg H. Health of the elderly with regard to sleep and 
nocturnal micturition. Scand J Prim Health Care. 1992 Jun; 10(2):98-104. 
[Bliwise 2009] Bliwise DL, Foley DJ, Vitiello MV, Ansari FP, Ancoli-Israel S, Walsh JK. 
Nocturia and disturbed sleep in the elderly. Sleep Med. 2009 May; 10(5):540-8. 
[Brookes 2004] Brookes ST, Donovan JL, Wright M, Jackson S, Abrams P. A scored form 
of the Bristol Female Lower Urinary Tract Symptoms questionnaire: data from a 
randomized controlled trial of surgery for women with stress incontinence. Am J 
Obstet Gynecol. 2004 Jul;191(1):73-82. 
[Bright 2014] Bright E, Cotterill N, Drake M, Abrams P. Developing and validating the 
International Consultation on Incontinence Questionnaire bladder diary. Eur Urol. 
2014 Aug;66(2):294-300. 
[Coyne 2003] Coyne KS, Zhou Z, Bhattacharyya SK, Thompson CL, Dhawan R, Versi E. 
The prevalence of nocturia and its effect on health-related quality of life and sleep in 
a community sample in the USA. BJU Int. 2003 Dec; 92(9):948-54. 
[Dauvilliers 2020] Dauvilliers Y, Zammit G, Fietze I, Mayleben D, Kinter DS, Pain S, et 
al. Daridorexant, a new dual orexin receptor antagonist to treat insomnia disorder. 
Ann Neurol. 2020 Mar;87(3):347-56. 
[Donovan 2000] Donovan JL, Peters TJ, Abrams P, Brookes ST, de aa Rosette JJ, Schäfer 
W. Scoring the short form ICSmaleSF questionnaire. International Continence 
Society. J Urol. 2000 Dec;164(6):1948-55. 
[Drake 2005] Drake NL, Flynn MK, Romero AA, Weidner AC, Amundsen CL. Nocturnal 
polyuria in women with overactive bladder symptoms and nocturia. Am J Obstet 
Gynecol. 2005 May; 192(5):1682-6. 
[EMA 2011] European Medicines Agency. Guideline on medicinal products for the 
treatment of insomnia. EMA/CHMP/16274/2009 Rev. 1. 17 February 2011 
[accessed on 6 April 2022]. Available from:  
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
1/02/WC500102351.pdf 


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[FDA 1977] Food and Drug Administration (US): Guideline for the clinical evaluation of 
hypnotic 
drugs. 
September 
1977; 
Available 
from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM071711.pdf 
[Ferring 2012] Ferring Pharmaceuticals. Comparative Trial to Investigate the Dose-
Response of 4 Different Dose Levels of Minirin Melt and Placebo (NOC). 
ClinicalTrials.gov Study Record, Identifier: NCT01184859. Last update posted: 
25 May 2012. Accessed on 12 April 2022. Available from: 
 
https://clinicaltrials.gov/ct2/show/NCT01184859 
[Ferring 2015] Ferring Pharmaceuticals. Efficacy and Safety of Desmopressin Melt for the 
Treatment of Nocturia. ClinicalTrials.gov Study Record, Identifier: NCT00477490. 
Last update posted: 1 November 2015. Accessed on 12 April 2022. Available from:  
https://clinicaltrials.gov/ct2/show/NCT00477490 
[Fu 2011] Fu F-G, Lavery HJ, Wu D-L. Reducing nocturia in the elderly: A randomized 
placebo-controlled trial of staggered furosemide and desmopressin. Neurourol 
Urodyn. 2011;30(3):312-16. 
[Hudgens 2021] 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;14(2):249-68. 
[Kim 2016] Kim JW, Moon YT, Kim KD. Nocturia: The circadian voiding disorder. 
Investig Clin Urol. 2016 May;57(3):165-73.  
[Konishi 2021] Konishi S, Hatakeyama S, Imai A, Kumagai M, Okamoto T, Okita K, et 
al. A longitudinal study of bidirectional relationships between sleep disorder and 
frequency of nocturia: Results from the Iwaki Health Promotion Project. Urol Int. 
2021; 105(3-4):232-9. 
[McCall 2004] McCall WV. Sleep in the elderly: Burden, diagnosis, and treatment. Prim 
Care Companion J Clin Psychiatry. 2004;6(1):9–20. 
[Mignot 2022] Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CLA, et al. 
Safety and efficacy of daridorexant in patients with insomnia disorder: results from 
two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet 
Neurol. 2022 Feb;21(2):125-39. Erratum in: Lancet Neurol. 2022 Apr 5. 
[Miller 2016] Miller PS, Hill H, Andersson FL. Nocturia work productivity and activity 
impairment compared with other common chronic diseases. Pharmacoeconomics. 
2016 Dec; 34(12):1277-97. 


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[Miwa 2011] Miwa K, Nishino Y, Kikuchi M, Masue T, Moriyama Y, Deguchi T. Efficacy 
of combination therapy with tamsulosin and zolpidem on nocturia in patients with 
benign prostatic hyperplasia. Cent European J Urol. 2011; 64(4):232-5. 
[Morin 1993] Morin CM, Kowatch RA, Barry T, Walton E. Cognitive-behavior therapy 
for late-life insomnia. J Consult Clin Psychol. 1993;61(1):137-46. 
[Morin 2011] Morin CM, Belleville G, Bélanger L, Ivers H. The Insomnia Severity Index: 
psychometric indicators to detect insomnia cases and evaluate treatment response. 
Sleep. 2011 May 1;34(5):601-8. 
[Neubauer 2014] Neubauer DN. New and emerging pharmacotherapeutic approaches for 
insomnia. Int Rev Psychiatry. 2014;26(2):214-24. 
[Oelke 2017] Oelke M, De Wachter S, Drake MJ, Giannantoni A, Kirby M, Orme S, et al. 
A practical approach to the management of nocturia. Int J Clin Pract. 2017 Nov; 
71(11). 
[Ohayon 2008] Ohayon MM. Nocturnal awakenings and comorbid disorders in the 
American general population. J Psychiatr Res. 2008 Nov; 43(1):48-54. 
[Pigeon 2007] Pigeon WR, Crabtree VM, Scherer MR. The future of behavioral sleep 
medicine. J Clin Sleep Med. 2007;3(1):73-9. 
[Posner 2007] Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia 
Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal 
events in the FDA’s pediatric suicidal risk analysis of antidepressants. Am J 
Psychiatry. 2007 Jul;164(7):1035-43. 
[QUVIVIQ™ SmPC] QUVIVIQ™ (daridorexant) 25 mg and 50 mg film-coated tablets. 
Summary of Product Characteristics. [accessed on 12 July 2022] Available from: 
https://www.ema.europa.eu/en/documents/product-information/quviviq-epar-
product-information_en.pdf  
[Reynard 1998] Reynard JM, Cannon A, Yang Q, Abrams P. A novel therapy for nocturnal 
polyuria: a double-blind randomized trial of frusemide against placebo. Br J Urol. 
1998 Feb; 81(2):215-8. 
[Scharf 2007] Scharf MB, Black J, Hull S, Landin R, Farber R. Long-term nightly 
treatment with indiplon in adults with primary insomnia: results of a double-blind, 
placebo-controlled, 3-month study. Sleep. 2007;30(6):743-52 
[Schutte-Rodin 2008] Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical 
guideline for the evaluation and management of chronic insomnia in adults. J Clin 
Sleep Med. 2008;4:487–504. 


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[Shao 2016] Shao IH, Wu CC, Hsu HS, Chang SC, Wang HH, Chuang HC, et al. The effect 
of nocturia on sleep quality and daytime function in patients with lower urinary tract 
symptoms: a cross-sectional study. Clin Interv Aging. 2016;11:879-85. 
[Tyagi 2014] Tyagi S, Resnick NM, Perera S, Monk TH, Hall MH, Buysse DJ. Behavioral 
treatment of insomnia: also effective for nocturia. J Am Geriatr Soc. 2014 Jan; 
62(1):54-60. 
[Van Kerrebroeck 2002] Van Kerrebroeck P, Abrams P, Chaikin D, Donovan J, Fonda D, 
Jackson S, et al. The standardization of terminology in nocturia: report from the 
standardization subcommittee of the International Continence Society. BJU Int. 2002 
Dec; 90 Suppl 3:11-5. 
[Weiss 2019] Weiss JP, Everaert K. Management of nocturia and nocturnal polyuria. 
Urology. 2019 Nov; 133S:24-33. 
[Yu 2006] Yu HJ, Chen FY, Huang PC, Chen TH, Chie WC, Liu CY. Impact of nocturia 
on symptom-specific quality of life among community-dwelling adults aged 40 years 
and older. Urology. 2006 Apr; 67(4):713-8. 
[Zammit 2020] Zammit G, Dauvilliers Y, Pain S, Kinter DS, Mansour Y, Kunz D. 
Daridorexant, a new dual orexin receptor antagonist, in elderly subjects with 
insomnia disorder. Neurology. 2020 May 26;94(21):e2222-e2232 
 
 


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12 APPENDICES 
Appendix 1 
Assessments in the context of a pandemic or epidemic disease: 
Recommendations and instructions 
Visit 1, Visit 2, Visit 4, Visit 6, and Visit 8 must be performed on site. Should any travel 
restrictions or quarantine be in place, the EOTP I or EOTP II visit of Period I or II, 
respectively, can be performed via a phone call or a video call. 
The window between two visits can be adapted to accommodate potential restrictions. Any 
adaptations must be documented in the subject’s medical charts. 
Flexibility regarding site visits for subjects who can go to sites 
If the subject can travel to the investigator’s site: 
• The investigator should ensure the subject’s safety on their way to the site by following 
local/country regulations (e.g., not using public transportation). Alternatively, taxis or 
private cars can be used, the cost of which will be reimbursed by the sponsor as per 
local guidelines. 
• The on-site visit assessments should be performed according to the protocol. 
• Visit windows can be extended, as long as the subject has enough study treatment. The 
reason for the delayed scheduled visit must be documented in the subject’s medical 
charts.  
Conduct of remote visits for subjects who cannot, are not allowed to, or are not willing 
to travel to the investigator’s site  
If the subject cannot, is not allowed to, or is not willing to travel to the investigator’s site, 
the EOTP I or EOTP II visit of Period I or II, respectively, can be replaced by a phone call 
or video call to keep close contact with subjects. The investigator should notify the 
IEC/IRB in advance of remote visits if this is a local requirement.  
Before the telephone call or video call visit:  
The investigator / authorized delegate should ensure the following:  
• The date and time that consent was obtained is documented in the subject’s medical 
records.  
• Provide details regarding how to return the study material and the remaining study 
treatment blister kits. 


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During the telephone call or video call visit:  
All efforts should be made to collect the same information as collected during an on-site 
visit. Efficacy data will be collected, questionnaires and other assessments should be 
performed, even remotely, if possible. To ensure subjects’ safety, the investigator / 
authorized delegate will conduct an interview to detect any potential AE as described 
below. 
The investigator will interview the subject for:  
• Occurrence of any new AEs or worsening of existing ones. 
• When asking about the occurrence of AEs, the same process as for a site visit should 
be followed, i.e., use an open-ended question, such as: “Have you had any significant 
medical problems since the last study visit?”. 
• Completion of the C-SSRS© questionnaire, on-site by the investigator. 
• Changes in any ongoing medication or start of new medication(s).  
• Check compliance with study medication and potential overdose or other medication 
error(s). 
Note: If closer monitoring of any of the above detected findings is required but not possible, 
depending on the severity of the symptoms observed and the investigator’s assessment of 
the benefit-risk for the study participants in the trial, the investigator may consider 
discontinuing treatment while trying to maintain the subject in the study.  
The phone or video contact must be entered in the eCRF under the EOTP I or EOTP II 
visit, respectively, and documented in detail (day, time and conversation) in the subject’s 
medical charts. All assessments not performed must be entered as “Not done”. 
Should any additional phone calls be performed to ensure the subject’s safety that are not 
part of the regular visit plan, the call must be entered as an unscheduled visit (‘UNS’) in 
the eCRF and documented in detail (day and reason for the ‘UNS’) in the subject’s medical 
charts. 
 
 


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Appendix 2 
Sleep Diary 
 
 
 
 
 
 
 
 
 
 


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Appendix 3 
Insomnia Daytime Symptoms and Impacts Questionnaire 
 
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CCI


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CCI


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CCI


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Appendix 4 
Insomnia Severity Index® 
  
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Appendix 5 
Global Scales 
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CCI


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CCI


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Appendix 6 
EQ-5D-3L 
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CCI


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Appendix 7 
ICIQ-NQoL 
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CCI


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Appendix 8 
ICIQ-MLUTS 
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CCI


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CCI


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CCI


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Appendix 9 
ICIQ-FLUTS 
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CCI


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CCI


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Appendix 10 Columbia Suicide Severity Rating Scale© (C-SSRS©) 
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Appendix 11 Forbidden medications 
Forbidden (F) or restricted (R) concomitant medications due to CNS side effects and DDI 
interactions.  
To be eligible, subjects must not be treated with CNS-active drugs for 5 half-lives of the 
respective drug or 2 weeks prior to Visit 2 (whichever is longer) until 24 hours after study 
treatment discontinuation. 
Drug Class  
Examples  
Forbidden 
/ 
Restricted  
Comment  
Anticholinergics  
e.g., oxybutynin, solifenacin 
R 
The use of anticholinergics 
are allowed if initiated at 
least 1 month prior to Visit 1 
and planned to remain stable 
during the study. 
Antihistamines  
Sedating: e.g., carbinoxamine, 
triprolidine HCl, azatadine, 
chlorpheniramine, doxylamine, 
hydroxyzine, ketotifen, 
promethazine & timeprazine, 
diphenhydramine HCl, 
dimenhydrinate 
F  
 
Psychotropics  
Stimulants: e.g., amphetamine 
derivatives, ephedrine 
derivatives, modafinil, 
armodafinil, methylphenidate, 
aripiprazole, pramipexole, 
levodopa, guanfacine, 
atomoxetine 
F  
 
 
Antidepressants: e.g., bupropion, 
citalopram, doxepin, duloxetine, 
escitalopram, fluoxetine, 
fluvoxamine, nefazodone, 
paroxetine, sertraline, trazodone, 
amitriptyline, clomipramine, 
desipramine, imipramine, 
mirtazapine, nortriptyline, 
trimipramine, venlafaxine, 
moclobemide, selegiline 
F  
 
 
Antipsychotics, including depot 
neuroleptics: e.g., quetiapine, 
olanzapine, haloperidol, 
loxapine, molindone, 
thiothixene, fluphenazine, 
mesoridazine 
F  
 


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Drug Class  
Examples  
Forbidden 
/ 
Restricted  
Comment  
 
Anxiolytics: e.g., alprazolam, 
buspirone, clorazepate, 
diazepam, flurazepam, 
lorazepam, midazolam, 
quazepam, temazepam, triazolam 
F  
 
 
Hypnotics: e.g., ramelteon, 
suvorexant, lemborexant, 
zolpidem  
F  
 
 
Cholinesterase inhibitors: e.g., 
donepezil, galantamine 
  
 
 
Mood stabilizers, e.g., 
carbamazepine, gabapentin, 
lithium, oxcarbazepine, 
pregabalin, valproic acid, 
tiagabine 
F  
 
 
Opioids/Narcotics: e.g., codeine, 
oxycodone, heroin, marijuana 
R  
Use of narcotics for pain 
relief must be avoided if 
there are effective alternative 
medications (such as 
NSAIDs)  
 
Centrally acting muscle 
relaxants with psychotropic 
effects: e.g., methocarbamol, 
tetrazepam 
R  
Use of centrally acting 
muscle relaxants must be 
avoided if there are effective 
alternative medications (such 
as NSAIDs)  
 
Herbal preparations with 
possible psychotropic effects: 
e.g., St John’s Wort  
F  
 
 
Others: e.g., tryptophan, 
melatonin, clonidine, 
dextromethorphan 
F  
 
Anticonvulsants  
Barbiturates, benzodiazepines, 
GABA analogs, hydantoins 
phenyltriazines (e.g., 
lamotrigine)  
succinimides (e.g., 
ethosuximide) 
F  
 
Alpha Blockers: 
Silodosin, tamsulosin 
R 
Allowed if initiated at least 
1 month prior to Visit 1 and 
planned to remain stable 
during the study 
5-Alpha-Reductase-Inhibitors e.g., finasteride, dutasteride 
R 
5-alpha-reductase-inhibitors 
are allowed if initiated at 
least 6 months prior to Visit 1 


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Drug Class  
Examples  
Forbidden 
/ 
Restricted  
Comment  
and planned to remain stable 
during the study 
Other  
Desmopressin  
R  
Desmopressin is allowed at 
therapeutic doses of  
25–50 mg, only if initiated at 
least 6 months prior to Visit 1 
and planned to remain stable 
during the study  
 
Systemic glucocorticoids: e.g., 
dexamethasone, 
methylprednisone, prednisone 
F  
Inhaled/topical 
corticosteroids are permitted  
 
Diet pills (prescription and OTC) 
F  
 
 
Pseudoephedrine  
R 
Use as nasal decongestant is 
allowed  
GABA = gamma-aminobutyric acid; NSAID = non-steroidal anti-inflammatory drug; OTC = over-the-counter. 
 
Non-exhaustive list of forbidden concomitant medications and diets due to potential drug 
interactions with CYP3A4 (moderate and strong inhibitors, inducers). 
Those medications must be discontinued no later than 2 weeks or 5 half-lives (whichever 
is longer) prior to Visit 2 and are forbidden until 24 hours after study treatment 
discontinuation. 
Inhibitors of CYP3A4 
Inducers of CYP3A4 
HIV antivirals: atazanavir, boceprevir, cobicistat, 
darunavir, delaviridine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, 
telaprevir 
HIV antivirals: efavirenz, etravirine 
Antibiotics: ciprofloxacin, clarithromycin, 
erythromycin, norfloxacin, quinupristin, 
telithromycin, troleandomycin 
Antibiotics: nafcillin, rifabutin, rifampin 
Antifungal: fluconazole, itraconazole, 
ketoconazole, posaconazole, voriconazole 
 
CNS-active: fluvoxamine, nefazodone 
CNS-active: carbamazepine, fenobarbital, 
modafinil, phenytoin, St. John’s Wort 
Cardiovascular: amiodarone, diltiazem, 
dronedarone, verapamil 
Cardiovascular: bosentan 
Aprepitant, conivaptan, cimetidine, imatinib 
 
CNS = central nervous system; CYP = cytochrome P450; HIV = human immunodeficiency virus. 
 


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Appendix 12 Treatment satisfaction questionnaire  
 
 
 
 
 
 
 
 
 
Appendix 13 Treatment period preference questionnaire 
 
 
 


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Appendix 14 Narrative 
 
CCI

SAP_001.pdf: 
 
 
 
TPL-100721_v02 
 
 
 
DARIDOREXANT (ACT-541468) 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
FOR CLINICAL STUDY REPORT  
 
ID-078A401 
 
Version 2 
 
A multi-center, double-blind, randomized, placebo-controlled, 2-way 
cross-over post approval study to investigate the efficacy of 
daridorexant in subjects with insomnia and comorbid nocturia 
 
 
 
 
 
Document Number: D-24.149 
 
 
30 May 2024 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................6 
1 
INTRODUCTION .........................................................................................................8 
2 
STUDY DESIGN AND FLOW ....................................................................................8 
3 
OBJECTIVES .............................................................................................................10 
3.1 
Primary objectives ........................................................................................10 
3.2 
Secondary objectives ....................................................................................10 
3.3 
Safety objectives ...........................................................................................10 
4 
ANALYSIS SETS .......................................................................................................10 
4.1 
Definitions of analysis sets ...........................................................................10 
4.1.1 
Screened analysis set ........................................................................10 
4.1.2 
Randomized analysis set ...................................................................10 
4.1.3 
Full analysis set .................................................................................10 
4.1.4 
Per-protocol set .................................................................................10 
4.1.5 
Safety analysis set .............................................................................11 
4.2 
Analysis ........................................................................................................11 
4.3 
Usage of the analysis sets .............................................................................11 
5 
SUBJECT VARIABLES AND ANALYSES .............................................................12 
5.1 
Subject disposition ........................................................................................12 
5.1.1 
Screen failures ...................................................................................12 
5.1.2 
Study disposition ...............................................................................13 
5.1.3 
Study and study treatment completion/discontinuation ....................13 
5.1.4 
Study enrollment ...............................................................................14 
5.2 
Protocol deviations .......................................................................................14 
5.3 
Subject characteristics ..................................................................................14 
5.3.1 
Demographics ...................................................................................14 
5.3.2 
Baseline disease characteristics ........................................................15 
5.3.3 
Medical history and concomitant diseases at Screening ...................15 
5.3.4 
Previous and concomitant therapy ....................................................15 
5.4 
Study treatment exposure and compliance ...................................................16 
5.4.1 
Exposure ...........................................................................................16 
5.4.2 
Compliance with study treatment .....................................................16 
6 
EFFICACY VARIABLES AND ANALYSES ...........................................................17 
6.1 
Primary endpoint analysis ............................................................................17 


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6.1.1 
Primary efficacy endpoint .................................................................17 
6.1.2 
Overall testing strategy .....................................................................18 
6.1.3 
Statistical model ................................................................................19 
6.1.4 
Handling of missing data ..................................................................20 
6.1.5 
Descriptive statistics .........................................................................20 
6.1.6 
Sensitivity analyses ...........................................................................21 
6.1.6.1 
Per-protocol set .............................................................. 21 
6.1.6.2 
Analysis not considering the days of urine collection ... 21 
6.1.7 
Supplementary analyses ....................................................................21 
6.1.8 
Subgroup analyses ............................................................................21 
6.2 
Secondary endpoint analysis ........................................................................21 
6.3 
Analysis of other efficacy variables .............................................................21 
6.3.1 
Analysis of insomnia-related endpoints (ISI©, VAS, number of 
awakenings) ......................................................................................22 
6.3.1.1 
Insomnia Severity Index© .............................................. 22 
6.3.1.2 
Visual analog scale ........................................................ 23 
6.3.1.3 
Number of awakenings .................................................. 23 
6.3.2 
Analysis of nocturia-related endpoints (time to first nocturnal 
void; voiding volume; number of nocturnal voids) ..........................23 
6.3.2.1 
Time to the first nocturnal void ..................................... 24 
6.3.2.2 
Within-subject comparison of time to the first nocturnal 
void ................................................................................ 25 
6.3.2.3 
Changes from baseline to Week 1 and Week 4 in the 
volume of the first nocturnal void ................................. 26 
6.3.2.4 
Change from baseline in total voiding volume (nighttime 
and daytime) .................................................................. 26 
6.3.2.5 
Change in number of nocturnal and daytime voids ....... 27 
6.3.3 
Quality of life and treatment preference endpoints ..........................28 
6.3.3.1 
ICIQ-MLUTS and ICIQ-FLUTS .................................. 29 
6.3.3.2 
ICIQ-NQoL ................................................................... 29 
6.3.3.3 
EQ-5D-3L ...................................................................... 30 
6.3.3.4 
PGA-S and PGI-C endpoints ......................................... 30 
6.3.3.5 
IDSIQ endpoints ............................................................ 32 
6.3.3.6 
Treatment satisfaction ................................................... 33 
6.3.3.7 
Treatment preference ..................................................... 33 
7 
SAFETY VARIABLES AND ANALYSES ...............................................................34 
7.1 
Overview of safety analyses .........................................................................34 
7.2 
Adverse events ..............................................................................................34 
7.3 
Laboratory tests ............................................................................................35 
7.4 
Vital signs, blood pressure and pulse rate ....................................................35 


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7.5 
Columbia Suicide Severity Rating Scale© ....................................................35 
7.6 
Morning sleepiness (VAS) ...........................................................................36 
7.7 
Analysis of narratives ...................................................................................37 
8 
GENERAL STATISTICAL METHODOLOGY ........................................................37 
8.1 
General rules for data presentations .............................................................37 
8.2 
Handling of missing dates ............................................................................37 
9 
INTERIM ANALYSES ..............................................................................................38 
10 GENERAL DEFINITIONS AND DERIVATIONS ...................................................38 
10.1 
Treatment start and end dates .......................................................................38 
10.2 
Study periods ................................................................................................38 
10.3 
Treatment day and Study day .......................................................................39 
10.4 
Baseline ........................................................................................................39 
10.5 
Change from baseline ...................................................................................39 
11 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................40 
11.1 
Changes to the analyses planned in the study protocol ................................40 
11.2 
Changes in the conduct of the study / data collection ..................................40 
11.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................40 
11.4 
Additional analyses to those planned in the study protocol .........................40 
12 REFERENCES ............................................................................................................42 
13 APPENDICES .............................................................................................................43 
13.1 
Revision history ............................................................................................43 
13.2 
SAS® code for mixed model for repeated measures .....................................43 
13.3 
SAS® code for Kaplan-Meier analyses .........................................................43 
13.4 
Reference data for EQ-5D-3L ......................................................................43 
 
 
 
 


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LIST OF TABLES 
 
Table 1 
Study documents .............................................................................................. 8 
Table 2 
Usage of analysis datasets .............................................................................. 12 
Table 3 
Estimands for the primary objective .............................................................. 19 
Table 4 
Contingency table of preferences ................................................................... 26 
Table 5 
Insomnia Daytime Symptoms and Impacts Questionnaire description ......... 32 
Table 6 
Imputation rules for an incomplete or missing concomitant therapy or 
AE date ........................................................................................................... 38 
Table 7 
EQ-5D-3L Coding.......................................................................................... 44 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design for ID-078A401 .......................................................................... 9 
 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ATC  
Anatomical Therapeutic Chemical 
CI  
Confidence interval 
C-SSRS©  
Columbia Suicide Severity Rating Scale© 
eCRF  
Electronic case report form 
eDiary  
Electronic diary 
EOS  
End-of-study 
EOT  
End-of-treatment 
EOTP  
End-of-treatment period 
EQ-5D-3L  
European Quality of Life 5 Dimensions 3 Level Version 
FAS  
Full analysis set 
ICH  
International Council for Harmonisation 
ICIQ  
International Consultation on Incontinence Questionnaire 
ICIQ-FLUTS  
ICIQ female lower urinary tract symptoms 
ICIQ-MLUTS  
ICIQ male lower urinary tract symptoms 
ICIQ-NQoL  
ICIQ Nocturia Quality of Life 
IDSIQ  
Insomnia Daytime Symptoms and Impacts Questionnaire 
IMP  
Investigational Medicinal Product 
ISI©  
Insomnia Severity Index© 
LS   
Least squares  
MedDRA  
Medical Dictionary for Regulatory Activities 
MMRM  
Mixed model for repeated measures 
PD  
Protocol deviation 
PGA-S  
Patient Global Assessment of Disease Severity 
PGI-C  
Patient Global Impression of Change 
PPS  
Per-protocol set 
PT  
Preferred term 
RND  
Randomized analysis set 
SAE  
Serious adverse event 
SAF  
Safety analysis set 


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SCR  
Screened analysis set 
SOC  
System organ class 
sTST  
Subjective total sleep time 
TEAE  
Treatment-emergent adverse event 
TP I  
Treatment Period I 
TP II  
Treatment Period II 
V  
Visit 
VAS  
Visual analog scale 
WHO  
World Health Organization 


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1 
INTRODUCTION 
This statistical analysis plan describes the analyses and data presentation for the clinical 
study report prepared for study ID-078A401 in detail. The analyses will be conducted once 
all randomized subjects have completed the study and the database has been locked.  
Obvious corrections to address minor formatting errors or spelling mistakes may be 
performed at the time of analysis without amending this and related documentation (e.g., 
mock shells).  
Data will be analyzed by Idorsia and designated contract research organizations supervised 
by Idorsia using SAS® version 9.4 or higher and R version 3.4.3 or higher. 
This statistical analysis plan is based on Version 3 of the protocol of ID-078A401, dated 
4 September 2023 [D-23.307, Table 1]. 
Table 1 
Study documents 
Document 
Date, Version 
Clinical Study Protocol  
4SEP2023, Version 3 
eCRF specifications 
14NOV2023, Version 5 
Protocol deviation list 
14MAY2024, Version 6 
eCRF = electronic case report form. 
 
2 
STUDY DESIGN AND FLOW 
This is a post-approval, multi-center, double-blind, randomized, placebo-controlled, 2-way 
cross-over study assessing daridorexant at a dosing regimen of 50 mg, once daily, vs 
placebo over a 4-week treatment period in adult subjects of 55 years and older with 
insomnia and comorbid nocturia. 
Approximately 50 subjects will be randomized in a 1:1 ratio to one of two treatment 
sequences: daridorexant 50 mg / placebo or placebo / daridorexant 50 mg. 
The study will be conducted at approximately 18 sites in the United States, Spain, and 
Germany. 
The study design is shown in Figure 1. 


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Figure 1 
Study design for ID-078A401 
 
 
D = day; EOS = end-of-study; EOTP = end-of-treatment period; V = visit.  
 
The study comprises the following 5 periods: the screening period, TP I, washout period, 
TP II, and the safety follow-up period.  
The screening period starts with the signing of the informed consent form at Visit 1 and 
ends with Randomization at Visit 2 or with a screening failure. It lasts 14–21 days.  
TP I starts with the administration of the first dose of study treatment and ends on the day 
after the last dose of study treatment (Day 29). The study subjects will be treated for 
4 weeks. 
The washout period starts after completion of the TP I and lasts 14–21 days. During the 
washout period the subjects will not be treated at all and will be followed up for safety  
(5–10 days). 
TP II starts with the administration of the first dose of the ‘other’ study treatment and ends 
on the day after the last dose of study treatment (Day 29). The study subjects will be treated 
for another 4 weeks. 
The safety follow-up period starts on the day after the last dose of study treatment in TP II 
and ends at the EOS visit (5–10 days after EOTP II).  


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3 
OBJECTIVES 
The overall objective of this post-approval study is to evaluate the clinical efficacy, safety, 
and tolerability of daridorexant 50 mg administered once daily, compared to placebo in 
adult subjects with insomnia and comorbid nocturia over a period of 4 weeks. 
3.1 
Primary objectives 
The primary objective of this study is to assess the efficacy of daridorexant on insomnia 
variables in subjects with insomnia and comorbid nocturia. 
3.2 
Secondary objectives 
The secondary objective is to assess the efficacy of daridorexant on nocturia variables. 
3.3 
Safety objectives 
The safety objectives will be to assess the safety and tolerability of daridorexant. 
4 
ANALYSIS SETS 
4.1 
Definitions of analysis sets 
A study subject must have given informed consent before being included in any analysis 
set.  
4.1.1 Screened analysis set 
The SCR includes all study subjects who entered Screening and have a subject number.  
Summaries based on the SCR set will be presented as one group (i.e., all study subjects), 
unless otherwise specified. 
4.1.2 Randomized analysis set 
The RND includes all study subjects from the SCR who were randomized (i.e., assigned to 
a treatment sequence). 
4.1.3 Full analysis set 
The FAS includes all subjects from the RND who received at least one dose of double-blind 
study treatment. 
To adhere to the intent-to-treat principle, 
• Subjects will be evaluated according to their assigned study treatment, which may 
differ from the treatment they have received (in each treatment period). 
• Unless otherwise specified all available data will be included in the analyses. 
4.1.4 Per-protocol set 
The PPS includes all subjects from the FAS without important PDs occurring during the 
screening/baseline assessments or prior to Week 4 (in both treatment periods, i.e., between 


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Visit 2 and Visit 4 in TP I, and between Visit 6 and Visit 8 in TP II), which could affect 
the analysis of the primary endpoint variable. 
The following important PDs will lead to exclusion from the PPS: 
• At least one key inclusion criterion (except #1) was not met (#3, #4, #5, #6, #7; 
PD Code: 01A02); 
• At least one key exclusion criterion was met (#3, #6, #7, #8, #13; PD Code: 01B01); 
• Incorrect blister dispensed to the subject and at least one tablet was taken 
(PD Code: 02A01); 
• Failure to comply with IMP storage/retention requirements impacting the quality of 
the IMP, reported as ‘not to be used’ by the Quality Assurance department, and at 
least one tablet was taken by the subject (PD Code: 02B01); 
• At least one IMP compliance value < 80% (PD Code: 02E01); 
• Non-compliance with blinding procedure/maintenance with consequences of patient 
treatment / study arm revealed or easily identifiable (PD Code: 03D01); 
• Sleep diary not completed at least 2 days during Screening and Week 4 of each 
treatment period (PD Code: 03G02); 
• Treatment with forbidden medication (PD Code: 04A01).  
Study subjects will be evaluated according to the treatment they have been assigned to. If 
only one of the two treatment periods of a subject is affected by one of the above PDs, the 
subject still will be completely excluded from the analysis as the deviation also might have 
an impact on the second treatment period (e.g., forbidden medication with a long half-life 
or similar). 
4.1.5 Safety analysis set 
The SAF will include all subjects who received at least one dose of double-blind study 
treatment. Subjects will be analyzed based on the treatment received (in each period). 
4.2 
Analysis 
The number of study subjects in each analysis set defined above will be tabulated by 
treatment sequence (daridorexant 50 mg / placebo or placebo / daridorexant 50 mg) and 
overall. Any study subject excluded, along with the reason(s) for exclusion from the PPS, 
will be summarized and listed. 
4.3 
Usage of the analysis sets 
The analyses of the primary endpoint and all other efficacy endpoints will be performed 
using the FAS.  
The analyses of the primary endpoint will be repeated based on the PPS. 


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The SAF will be used for the analysis of safety endpoints (including previous and 
concomitant medications, and study treatment exposure).  
The SCR is used to provide the same summaries for the screen failures. 
Subject disposition will be described based on the SCR. 
Study subjects’ data will be listed using the SCR, unless otherwise specified. 
Of note, there are no baseline disease characteristics collected in this study other than 
baseline values of efficacy and safety variables. 
Table 2 
Usage of analysis datasets 
Analysis 
SCR 
RND 
FAS 
PPS 
SAF 
Subject disposition 
X 
 
 
 
 
Demographics / Baseline Characteristics 
 
X* 
X* 
 
 
Previous and concomitant medication 
 
 
 
 
X 
Study drug exposure 
 
 
 
 
X 
Efficacy analysis 
 
 
X 
X 
 
Safety and tolerability analyses 
 
 
 
 
X 
FAS = full analysis set; PPS = per-protocol analysis set; RND = randomized analysis set; SAF = safety analysis set; 
SCR = screened analysis set. 
* Regulatory request for both RND and FAS. 
 
5 
SUBJECT VARIABLES AND ANALYSES 
Due to the cross-over design, each subject will contribute to both treatment columns if the 
summary tables or figures are presented by treatment.  
5.1 
Subject disposition 
5.1.1 Screen failures 
Screen failures will be summarized based on the SCR and will include:  
• Number (%) of study subjects who did not successfully complete the screening period 
(based on ‘Was the subject randomized?’ recorded as ‘No’ on the ‘Randomization’ 
page). 
• Primary reason for screen failure (based on reason entered on the ‘Randomization’ 
page).  
The eligibility criteria not met will be summarized. All reasons for screen failures will be 
listed. 
Of note, no re-screening is allowed in the study. 


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5.1.2 Study disposition  
Study subject disposition will be summarized based on the SCR, presented by treatment 
sequence and overall, and will include:  
• Number of study subjects screened (only for overall column).  
• Number (%) of study subjects randomized (based on non-missing randomization 
number).  
• Number (%) of study subjects who received study treatment during the TP I (based on 
non-missing ‘Treatment start date’ for TP I on the ‘Study Treatment Log’ page). 
Percentage will be based on randomized subjects. 
• Number (%) of study subjects who received study treatment during the TP II (based on 
non-missing ‘Treatment start date’ for TP II on the ‘Study Treatment Log’ page). 
Percentage will be based on randomized subjects. 
• Number (%) of study subjects who completed TP I (based on ‘Reason for treatment 
stop’ entered as ‘Completion as per protocol’ for TP I on the ‘Study Treatment Log’ 
page). Percentage will be based on study subjects who received study treatment (in 
TP I). 
• Number (%) of study subjects who completed the TP II (based on ‘Reason for treatment 
stop’ entered as ‘Completion as per protocol’ for TP II on the ‘Study Treatment Log’ 
page). Percentage will be based on study subjects who received study treatment (in 
TP II). 
• Number (%) of study subjects completing the study (based on ‘Did the subject complete 
the study?’ recorded as ‘Yes’ on the ‘End of Study Status’ page). Percentage will be 
based on randomized subjects. 
• Number (%) of study subjects completing the washout-period, i.e., subjects being 
treated in TP I and TP II. 
5.1.3 Study and study treatment completion/discontinuation 
The following summary will be based on the SAF and presented by treatment and overall:  
• Number (%) of study subjects who prematurely discontinued study treatment (based 
on ‘Reason for treatment stop’ entered as ‘Discontinuation’ on the ‘Study Treatment 
Log’ page).  
• Primary reason for premature study treatment discontinuation (based on 
‘Discontinuation, Reason’ entered on the ‘Study Treatment Log’ page). 
The treatment discontinuation table will also be presented by treatment period and 
treatment based on the SAF. 


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The following summary will be based on the RND and FAS, and presented by treatment 
and overall:  
• Number (%) of study subjects who prematurely discontinued from the study (based on 
non-missing reason for stopping study entered on the ‘End of Study Status’ page).  
• Primary reason for premature discontinuation from the study (based on ‘Study stopped 
due to’ entered on the ‘End of Study Status’ page).  
The study discontinuation table will also be presented by study period and treatment (TP I, 
washout-period, TP II, safety follow-up period). 
All reasons for premature study treatment discontinuation and study discontinuation will 
be listed based on the RND. 
5.1.4 Study enrollment 
The number (%) of screened and randomized study subjects will be displayed by site based 
on the SCR.   
The randomization scheme and codes will be listed for randomized study subjects only 
based on the RND. 
5.2 
Protocol deviations 
The RND will be used for the summary of PDs. All PDs and important PDs will be 
summarized in separate tables as per pre-specified category (i.e., selection criteria, IMP, 
study conduct/procedure, forbidden medication, withdrawal criteria and other).  
A study subject with multiple occurrences of a PD is counted only once per PD category. 
The PD outputs will be summarized by treatment sequence and overall. 
A listing of PDs will be provided using the SCR.  
5.3 
Subject characteristics 
Unless noted otherwise, summaries and listings described in this section will be based on 
the RND.  
Summaries will be provided by treatment sequence and overall. Data will be listed 
individually by study subject. 
5.3.1 Demographics  
Demographic data at Screening, including age, sex, race, and ethnicity, will be summarized 
(by treatment sequence and overall) based on the RND and FAS, and listed.  
The same summary will also be provided for screen failures based on the SCR. 


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5.3.2 Baseline disease characteristics 
The baseline disease characteristics table will contain a summary of sTST, ISI© score, the 
ISI© score in categories (≤ 14, 15–21, ≥ 22) and the summary of the average number of 
nocturnal voidings at baseline, as derived by Minze Health [Bladt 2022]. Baseline disease 
characteristics will be summarized based on the RND and FAS. 
Baseline disease characteristics data will be listed based on the RND. 
5.3.3 Medical history and concomitant diseases at Screening 
Relevant medical history and current medical conditions will be coded using MedDRA.  
Any disease or diagnosis is defined as previous if ‘Ongoing at informed consent’ is 
answered as ‘No’; all other diseases/diagnoses are considered as study concomitant (where 
answer is ‘Yes’).  
Medical history and current (ongoing) medical conditions will be summarized separately 
and listed (based on the RND). Summaries will be presented for each treatment sequence 
and overall, by primary SOC and PT. Medical history will be sorted by SOC and PT within 
each SOC by descending frequency based on all treatment sequences combined.  
The MedDRA version used for reporting will be specified in the footnote of the applicable 
output. 
5.3.4 Previous and concomitant therapy  
Previous and concomitant therapies will be coded using the WHO Drug Global reference 
dictionary that employs the WHO ATC classification system. The WHO Drug Global 
version used for reporting will be specified in the footnote of the applicable output.  
Previous therapies are any treatments for which the end date is prior to the start of study 
treatment. A previous therapy is to be recorded in the ‘Previous/Concomitant Medication’ 
page if discontinued less than 30 days prior to signing of the informed consent form.  
Study treatment-concomitant therapies are any treatments that are either ongoing at the 
start of study treatment or initiated on or after the start of TP I. The use of all 
treatment-concomitant therapies (including contraceptives and traditional and alternative 
medicines, e.g., plant-, animal-, or mineral-based medicines) is to be recorded in the 
‘Previous/Concomitant Medication’ page.  
Number (%) of study subjects having taken at least one previous or concomitant therapy 
will be summarized by ATC classification level 4 (or next highest available level) and 
individual preferred name within each ATC classification based on the SAF. Previous and 
concomitant therapy will be sorted by ATC class and preferred name within each ATC 
class by descending frequency based on all treatment sequences combined.  


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Summary tables will be provided for previous and study treatment-concomitant therapies 
separately (by treatment sequence and overall). All concomitant therapies will be listed 
using the SAF and those related to an AE will be flagged. 
5.4 
Study treatment exposure and compliance 
Summaries and listings described in this section will be based on the SAF.  
5.4.1 Exposure 
The duration of study treatment (including categories: ≤ 1, > 1–2, > 2–3, > 3– 4, > 4 weeks) 
will be summarized based on the SAF, by treatment and overall. 
The duration of treatment (in days) is defined as the difference between the treatment end 
date and the treatment start date plus one day. This calculation ignores periods of treatment 
interruption. 
Due to the cross-over design, the duration of the washout period will also be summarized 
based on the SAF (only for those subjects who were treated in both treatment periods).  The 
washout period is defined as: 
• Washout-period (in days) = Treatment start date of TP II – Treatment end date of TP I 
+ 1 day. 
The duration of treatment along with the reason for treatment discontinuation will be listed 
by treatment sequence and period based on the SAF. The duration of the washout period 
will also be listed based on the SAF. 
5.4.2 Compliance with study treatment 
Study treatment compliance will be assessed through study treatment dispensing and 
accountability.  
The following formula will be used to calculate compliance for the treatment period: 
• Study treatment compliance (%) = [(Number of capsules dispensed – Number of 
capsules returneda) / (Treatment duration – Total duration of treatment interruptions)] 
× 100. 
Treatment duration and total duration of treatment interruptions are calculated using the 
dedicated eCRF page ‘Study Treatment Log’.  
 
a If a study subject did not return his/her bottle (e.g., it is lost), compliance will not be calculated, and compliance will 
be set to missing. 


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Treatment duration is calculated as:  
• Treatment duration (days) = Date of last drug intake of study treatment – Date of first 
drug intake of study treatment + 1 day. 
Total duration of treatment interruption (days) is the sum of all the treatment interruptions’ 
durations, calculated as: 
• Treatment interruption duration = Date restarted study treatment – End date of study 
treatment due to an interruption − 1 day.  
For example, if a study subject stopped his/her treatment on 19MAR2022 and started again 
on 23MAR2022, as the treatment is taken on the start and end dates, the calculation will 
be 23MAR2022 – 19MAR2022 – 1 day = 3 days of interruption. Should the study subject 
interrupt the treatment again for 7 days, the total duration of interruptions will be 10 days.  
Study treatment compliance (including categories 0%, > 0%–< 50%, 50%–< 80%,  
80%–< 100%, 100%, > 100%), treatment interruptions (Yes/No), and duration of treatment 
interruptions will be summarized based on the SAF. The summary table will be repeated 
by treatment period based on the SAF. 
The number (%) of study subjects who have treatment interruptions, and the corresponding 
reasons will be tabulated based on the SAF. 
Study treatment compliance, dispensing and accountability data will be listed based on the 
SAF. 
6 
EFFICACY VARIABLES AND ANALYSES 
The analyses of efficacy endpoints will be performed using the FAS. Efficacy data 
described below will be listed using the FAS. 
As there were no secondary endpoints defined in the protocol, only the primary endpoint 
and other efficacy endpoints will be analyzed. 
6.1 
Primary endpoint analysis 
All available data for each subject, regardless of intercurrent events, will be used in all 
statistical analyses, unless otherwise specified. 
6.1.1 Primary efficacy endpoint 
The primary efficacy endpoint of this study is defined as the change from baseline to 
Week 4 (of both treatment periods) in sTST. 


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In each treatment period, the change from baselinea to Week 4b in sTST is calculated as 
follows: 
• Change from baseline = Mean value at Week 4b – Mean value at baselinea. 
Changes from baseline in sTST for Weeks 1–3 will be included in the MMRM. Definitions 
for the changes from baseline will be identical. For Week 1, sTST is averaged across 
days 2–8, for Week 2 across days 9–15, and for Week 3 across days 16–22. 
Subjects must have at least 2 days of data during each week to calculate a weekly mean. 
Otherwise, the mean value will be considered missing for that week. 
For subjects discontinuing a treatment period prematurely (TP I or TP II), all data up to 
Day 29 will be included to derive the weekly averages (if data is available up to that point). 
In the event that subjects have extended treatment periods > 4 weeks, only data up to 
Day 29 will be included in the derivation of the weekly averages. 
6.1.2 Overall testing strategy 
The primary endpoint will be analyzed based on an MMRM. Some sensitivity analyses 
will also be performed for the primary endpoint. Those analyses are not part of the testing 
strategy. 
Hypotheses are defined as follows: 
• H0: Mean of the within-subject changes in sTST from baseline to Week 4 between 
daridorexant 50 mg and placebo = 0; 
• H1: Mean of the within-subject changes in sTST from baseline to Week 4 between 
daridorexant 50 mg and placebo ≠ 0. 
The null hypothesis will be tested at a 2-sided 0.05 significance level. 
A preview of the main analyses is given in Table 3 using the estimand terminology 
[ICH 2019]. Estimands are defined by five attributes: treatment condition of interest, target 
population, endpoint, strategy for addressing intercurrent events (i.e., premature 
discontinuation of treatment), and population‑level summary. 
The primary estimand is based on the primary endpoint: the difference in means between 
the two treatments in the change from baseline to Week 4 in sTST, regardless of treatment 
discontinuation. For the primary estimand, the treatment condition is daridorexant 50 mg 
once daily for up to 4 weeks whereas the alternative condition is placebo once daily for the 
 
a Baseline is the mean value based on the screening sleep diary for sTST, performed on the 7 days preceding 
Randomization. 
b Week 4 is the mean value based on the sleep diary entries for sTST performed on study days 23–29 for each period. 


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same period. The other four attributes are given in the table below. The primary estimand 
follows a ‘treatment policy’ strategy. 
The secondary estimand is also based on the primary endpoint. Intercurrent events are 
defined as premature treatment discontinuations. Details are provided in Table 3. The 
secondary estimand follows a ‘hypothetical’ strategy. 
Table 3 
Estimands for the primary objective 
Estimand 
Target 
population 
Endpoint 
Strategy for addressing 
intercurrent events 
Population-level 
summary 
Primary 
estimand 
Subjects with 
insomnia 
associated to 
nocturia 
Change 
from 
baseline to 
Week 4 in 
sTST 
Treatment policy strategy, 
i.e., endpoint data after 
premature treatment 
discontinuation are used. 
Treatment effect expressed 
as difference of LS Mean 
changes from baseline to 
Week 4 (daridorexant 
minus placebo; from 
MMRM) 
Secondary 
estimand 
Subjects with 
insomnia 
associated to 
nocturia 
Change 
from 
baseline to 
Week 4 in 
sTST 
Hypothetical strategy, i.e., 
endpoint data after 
premature treatment 
discontinuation are not 
used. 
Treatment effect expressed 
as difference of LS Mean 
changes from baseline to 
Week 4 (daridorexant 
minus placebo; from 
MMRM) 
LS Mean = least squares mean; MMRM = mixed model for repeated measures; sTST = subjective total sleep time. 
 
6.1.3 Statistical model 
Changes from baseline to post-baseline visits in sTST will be analyzed using an MMRM 
with treatment (daridorexant 50 mg; placebo), period (TP I; TP II), week within period 
(Week 1; Week 2; Week 3; Week 4), the interaction of treatment and week as factors, and 
baseline sTST assessment as covariate.  
An unstructured covariance matrix will be used to account for the correlation between 
repeated measurements from the same subject. This approach relies on the missing at 
random assumption. A restricted maximum likelihood approach in combination with the 
Newton Raphson Algorithm will be used to derive (unbiased) estimates of variance 
components. The Kenward-Roger approximation will be used to compute the denominator 
degrees of freedom and adjust standard errors [Kenward 1997]. If the analysis fails to 
converge, the following structures will be tested in the subsequent order until 
model-convergence is achieved: heterogeneous Toeplitz, Toeplitz, autoregressive, and 
compound symmetry. 
To evaluate the efficacy hypotheses, appropriate contrasts will be used to test the treatment 
differences of interest (i.e., the difference in LS Mean change from baseline to Week 4 
between daridorexant 50 mg and placebo). 


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The LS Mean for each treatment per time point will be displayed along with its associated 
standard error and 95% CI. For the daridorexant comparison with placebo, the 
placebo-adjusted LS Mean will be displayed along with the associated standard error, 
95% CI and unadjusted 2-sided p-value. The null hypothesis will be rejected if the 95% CI 
for this difference excludes 0. 
6.1.4 Handling of missing data 
Section 6.1.1 explains how the primary efficacy endpoint is derived in the event of partially 
missing data. 
The primary endpoint analysis will only include subjects with a valid baseline and at least 
one of the four weekly assessments for sTST, following the same approach as in the Phase 
3 program [Mignot 2022]. Even though this does not fully follow the intent-to-treat 
principle, the approach seems justified as limited dropouts are expected (< 3%) due to the 
short duration of each treatment period (4 weeks) and the known safety and efficacy profile 
of daridorexant. Every effort will be made to keep all subjects in the study, even in the 
event of premature treatment discontinuation, to collect all the relevant data for analysis of 
the primary endpoint. Data collected after premature treatment discontinuation will be 
included in the primary analysis (following a ‘treatment policy’ strategy). 
6.1.5 Descriptive statistics 
The primary efficacy endpoint (based on data used for the primary estimand) and its 
observed values (i.e., weekly averages of sTST) will be summarized over time by treatment 
using descriptive statistics.  
A plot of the mean change from baseline over time for sTST will be provided by treatment 
(based on data used for the primary estimand). 
The incidence and pattern of missing values will be explored to assess the appropriateness 
of the statistical analysis and the possible impact on the results (for the data used for the 
primary estimand). The incidence of missing data and the observed missing data patterns 
for the primary endpoint at baseline and each timepoint (Weeks 1, 2, 3, and 4) will be 
presented for each treatment. The missing data patterns will be sorted from completely 
missing to completely observed in the order of the first occurrence of missing data. 
In addition, descriptive statistics will be provided by week and treatment, summarizing the 
number of available days that contribute to the weekly averages for sTST (for the data of 
the primary estimand). The analysis will be repeated by treatment period. 
Based on the exploration of the observed missing data patterns, further sensitivity analyses 
in addition to those described below might be performed. 


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6.1.6 Sensitivity analyses 
6.1.6.1 Per-protocol set 
The analyses of the primary endpoint will be repeated on the PPS (based on the same 
MMRM and data used for the primary estimand). 
6.1.6.2 Analysis not considering the days of urine collection 
As the collection of urine during pre-defined study nights might have an impact on the 
primary outcome sTST, a sensitivity analysis will be performed removing the days with 
urine collection from the weekly averages (based on data of the primary estimand). 
For this analysis, ‘Baseline’ is defined as the mean value based on the screening sleep diary 
entries for sTST, completed for the 7 days preceding Randomization, except for the nights 
where urine was collected. ‘Week 4’ is defined as the mean value based on sleep diary 
entries for sTST completed for study days 23–29 for each period, except for the nights 
where urine was collected. As sTST for Weeks 1–3 will also be included in the MMRM, 
definitions for the changes from baseline will be identical. Subjects must have at least 
2 days of data during each week to calculate a weekly mean (including baseline mean). 
Otherwise, the mean value will be considered missing for that week. 
6.1.7 Supplementary analyses 
No supplementary analyses are planned for this study.   
6.1.8 Subgroup analyses 
Subgroup analyses of the primary endpoint will be conducted by sex and country (based 
on the MMRM of the primary estimand and using data of the primary estimand). 
6.2 
Secondary endpoint analysis 
Not applicable. 
6.3 
Analysis of other efficacy variables 
The following other efficacy endpoints will be analyzed for this study: 
Insomnia-related endpoints: 
• Change from baseline up to Week 2 and Week 4 of the insomnia severity by the ISI©; 
• Change from baseline to Week 1, 2, 3, and 4 in quality of sleep VAS, depth of sleep 
VAS, daytime alertness VAS, daily ability to function VAS; 
• Change from baseline to Week 1, 2, 3, and 4 in the mean number of self-reported 
awakenings (based on the sleep diary); 


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Nocturia-related endpoints: 
• Change from baseline to Week 1 and Week 4 in number of nocturnal voids assessed 
using a voiding diary; 
• Change from baseline to Week 1 and Week 4 in the time to the first nocturnal void 
assessed using the voiding diary; 
• Change from baseline to Week 1 and Week 4 in the volume of the first nocturnal void 
assessed using the voiding diary; 
• Change from baseline to Week 1 and Week 4 in the total nighttime voiding volume 
assessed using the voiding diary; 
• Change from baseline to Week 1 and Week 4 in number of daytime voids assessed 
using a voiding diary; 
• Change from baseline to Week 1 and Week 4 in the total daytime voiding volume 
assessed using the voiding diary; 
Quality of life and treatment preference endpoints: 
• Change from baseline to Week 4 in lower urinary tract symptoms sub-score using the 
ICIQ-MLUTS and -FLUTS for male and female subjects, respectively; 
• Change from baseline to Week 4 in quality of life relative to nocturia assessed by 
ICIQ-NQoL; 
• Change from baseline to Week 1, Week 2, Week 3, Week 4 in PGA-S and PGI-C for 
insomnia and for nocturia; 
• Change from baseline to Week 2 and Week 4 in quality of life using the EQ-5D-3L; 
• Assessment of subjective treatment satisfaction at Week 4 by Numeric Rating Scale; 
• Subject preference for treatment; 
• Change from baseline to Week 1, Week 2, Week 3, Week 4 in IDSIQ scores (total; 
alert/cognition; sleepiness; mood). 
Analyses of the other endpoints are described below. 
6.3.1 Analysis of insomnia-related endpoints (ISI©, VAS, number of awakenings) 
All endpoints will be summarized based on the FAS. 
6.3.1.1 Insomnia Severity Index© 
The ISI© assesses the severity of a subject’s insomnia by scoring the severity of sleep onset 
and sleep maintenance difficulties and any insomnia-related interference with daytime 
functioning. The assessment is on a 5-point scale (0–4) where the composite score is 
obtained by summing the 7 rated dimensions measuring the subject’s perception of his or 
her insomnia. The ISI© will be completed by the subject on the eDiary at Visit 1 (baseline), 
Visit 3 (Week 2, Period 1), Visit 4 (Week 4, Period 1), Visit 7 (Week 2, Period 2), and 
Visit 8 (Week 4, Period 2). 


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The change from baseline to Week 2 and Week 4 will be summarized by treatment. 
Observed values will also be summarized. Changes from baseline to Week 2 and Week 4 
will also be analyzed based on an MMRM, as described in Section 6.1.3. 
In addition, the proportion of subjects with an ISI© decrease from baseline of greater than 
or equal to 6 will be summarized, as well as the proportion of subjects with ISI© values of 
7 or less at Week 2 and Week 4, by treatment. 
6.3.1.2 Visual analog scale 
The VAS collects information on quality of sleep, depth of sleep, daytime alertness, and 
daytime ability to function by asking the subjects to report their feelings by placing a mark 
on a VAS. Self-reported quality of sleep and depth of sleep are assessed in the morning 
whereas self-reported daytime alertness and daytime ability to function are assessed in the 
evening. Sleep diaries must be completed daily from Visit 1 to Visit 8. 
6.3.1.2.1 Variables 
Baseline VAS is defined as the mean value based on the sleep diary entries completed for 
the 7 days immediately preceding the randomization visit. 
For Week 1, the VAS scores are averaged across Days 2–8, for Week 2 across Days 9–16, 
for Week 3 across Days 17–22, and for Week 4 across Days 23–29 (in both treatment 
periods). Subjects must have at least 2 days of data during each week to calculate a weekly 
mean. Otherwise, the mean value will be considered missing for that week. 
6.3.1.2.2 Analysis 
The change from baseline to Week 1–Week 4 in VAS scores will be summarized by 
treatment. Observed values will also be summarized by treatment. Changes from baseline 
to Week 1–Week 4 will also be analyzed based on an MMRM, as described in Section 6.1.3. 
6.3.1.3 Number of awakenings 
The number of awakenings is collected daily via a Sleep Diary Questionnaire. 
The change from baseline to Week 1–Week 4 in number of awakenings will be summarized 
by treatment. Observed values will also be summarized by treatment.  
Definitions of the weekly averages are the same as described in Section 6.3.1.2. 
6.3.2 Analysis of nocturia-related endpoints (time to first nocturnal void; voiding 
volume; number of nocturnal voids) 
The Minze Diary Pod [Bladt 2022] consists of a voiding pod and a voiding diary and uses 
a derivation from the ICIQ bladder diary, which is a 3-day diary that allows subjects to 
record urinary frequency, volume voided, urgency and fluid intake (amount and type) 
[Bright 2014]. The voiding pod will automatically transfer the voiding information (i.e., 
volume and timepoints) to the voiding diary, and the subjects must provide additional 


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information (i.e., urgency, and amount and type of fluid intake). The Minze Diary Pod must 
be completed during the day, and it must be started in the morning, i.e., completion only 
starts on the first morning after Visit 1, Visit 2, and Visit 6 and lasts for 3 days; the Minze 
Diary Pod must also be completed for 3 full days immediately preceding Visit 4 and Visit 
8. The Minze Diary Pod collects all data for the endpoints time to the first nocturnal void, 
change in voiding volume (nighttime and daytime) including total voiding volume, and 
change in number of nocturnal voids. 
For all analyses below, ‘pod voids’ as well as ‘manual voids’ will be used. Only data from 
completed cycles will be included in the analysis. Bedtime and waketime were collected 
by Minze Health. Bedtime is defined as the ‘exact time the subject went to sleep’, and 
waketime is defined as the ‘exact time the subject woke in the morning’, according to 
Minze Health specifications. 
6.3.2.1 Time to the first nocturnal void 
6.3.2.1.1 Variable 
The variable derivation follows the approach as used by Minze Health. 
The time to first nocturnal void (hours) is derived for each voiding night (‘Cycle’) 
separately as follows: 
• Time to first nocturnal void (in hours) = Time of first nocturnal void (after bedtime 
and before waketime) – Bedtime. 
Potentially, a date is required for computation of the variable if the bedtime is prior to 
midnight and the first void is after midnight. In the event of missing information on bedtime 
and/or waketime, the variable is set to missing and the data will not be included in the 
analyses defined below. 
After derivation of the time to first nocturnal void per night (in hours), the average time to 
first void will also be computed across the 3 voiding nights (by visit). In the event of 
missing nights or nights without voids, the average will be computed based on the nights 
with available data. 
In the event of no voiding during any of the 3 consecutive nights, the censoring time is 
defined as follows: 
• Censoring time (in hours) = Maximum (Waketime – Bedtime) during voiding cycle 1, 
2 or 3 (by visit). 
6.3.2.1.1.1 Minimum and maximum time to first void 
The minimum and maximum time to first void will be analyzed to establish a range during 
which subjects are having their first void of the night. 


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To assess the minimum time to first void across all 3 voiding nights, variables will be 
derived as follows: 
• Minimum time to first nocturnal void (in hours) = Minimum (Time of first nocturnal 
void – Bedtime) during cycles 1, 2 or 3 (by visit). 
The derivation of the variable will be repeated for the maximum time to first void: 
• Maximum time to first nocturnal void (in hours) = Maximum (Time of first nocturnal 
void – Bedtime) during cycles 1,2 or 3 (by visit). 
The same derivations apply in the event of missing voiding nights, and censoring is also 
defined in the same way [see Section 6.3.2.1.1]. 
6.3.2.1.2 Analysis 
All analyses will be conducted based on the FAS. 
6.3.2.1.2.1 Kaplan-Meier analysis 
Kaplan-Meier summary tables and plots will be constructed separately for Week 1 and 
Week 4 by treatment. The number of subjects with events and censored observations will 
be presented by treatment and visit. 
Kaplan-Meier plots at baseline will be constructed by sequence and overall. 
No inferential statistics will be provided due to the dependence of the observations in this 
cross-over design. 
The average time to first void and the changes from baseline will be summarized via 
descriptive statistics by treatment and visit. 
6.3.2.2 Within-subject comparison of time to the first nocturnal void 
6.3.2.2.1 Variable 
The time to first nocturnal void is derived as described in Section 6.3.2.1.1 (for Week 1 
and Week 4). As each subject receives both treatments, a within-subject comparison of the 
time to first nocturnal void is performed, separately at Week 1 and Week 4, i.e., the 
‘preferences’ (= longer average duration to first nocturnal void across 3 cycles) are 
summarized in a 2 × 2 contingency table, as shown in Table 4. If a subject is missing data 
in one or both treatment periods, this subject’s information is considered as missing and 
will not be included in the analysis. In the event of censored data, i.e., subjects that have 
no single void in 3 cycles, the preference will be assigned to the period where the subject 
was censored. 


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Table 4 
Contingency table of preferences 
Treatment preference 
Treatment group 
TP I 
TP II 
Total 
Daridorexant 50 mg  
x 
y 
x + y 
Placebo  
z 
a 
z + a 
Total 
x + z 
y + a 
x + y + z + a 
TP I/II = treatment period I/II 
 
From this table it can be derived that (x + y) subjects prefer daridorexant 50 mg, whereas 
(z + a) subjects prefer placebo. The differences across periods can be observed in the total 
row (x + z for TP I; y + a for TP II). 
6.3.2.2.2 Analysis 
The contingency table is analyzed separately at Week 1 and Week 4 based on the FAS via 
a 2-sided sign test for matched pairs. A binomial distribution will be used to compute the 
p-values (2-sided), which will be presented in the table. 
6.3.2.3 Changes from baseline to Week 1 and Week 4 in the volume of the first 
nocturnal void  
The first nocturnal voiding volume is defined as the volume of the first nocturnal void 
collected after bedtime and before waketime.   
The first voiding volume per night will be averaged across voiding nights. The mean first 
voiding volume and corresponding change from baseline will be summarized descriptively 
by visit and treatment. 
6.3.2.4 Change from baseline in total voiding volume (nighttime and daytime) 
Three analyses will be conducted for the change from baseline in total nocturnal voiding 
volume: 
1. Nocturnal voiding volume as derived by Minze Health (derived data are provided 
by Minze Health). 
2. Derived nocturnal voiding volume, defined as cumulative voiding volume between 
bedtime and waketime. 
3. Derived nocturnal voiding volume, defined as cumulative voiding volume between 
bedtime and waketime, excluding nights with a total voiding volume of 0. 
The rationale for the conducted analyses is the partially incorrect labelling of day, night 
and morning voids in the Minze Health database and nights without any voids. For nights 


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without any voids, it is unclear whether the data were not collected or if the patient did not 
void at all. 
Analyses for the nocturnal voiding volume plus the morning volume will be conducted as 
well, but only based on data as derived by Minze Health. 
6.3.2.4.1 Variable 
For analysis 2, the total nocturnal voiding volume will be derived as cumulative voiding 
volume between bedtime and waketime. 
For analysis 3, the total nocturnal voiding volume will be derived as cumulative voiding 
volume between bedtime and wake time. Nights with 0 total nocturnal voiding volume will 
be set as missing. 
6.3.2.4.2 Analysis 
The total voiding volume per night will be averaged across voiding nights with available 
data (for baseline, Week 1, and Week 4 assessments). The mean total voiding volume and 
corresponding changes from baseline will be summarized descriptively by visit and 
treatment (based on all 3 approaches as described above). In addition, the total night 
voiding volume plus the morning volume will be summarized descriptively by visit and 
treatment (based on data derived by Minze Health). 
Analyses will be repeated for the morning voiding volume and the total daytime voiding 
volume based on the data provided by Minze Health. 
6.3.2.5 Change in number of nocturnal and daytime voids 
Three analyses will be conducted for the number of nocturnal voids: 
1. Number of nocturnal voids as derived by Minze Health (derived data are provided 
by Minze Health). 
2. Derived number of nocturnal voids, defined as the number of nocturnal voids 
between bedtime and waketime. 
3. Derived number of nocturnal voids, defined as the number of nocturnal voids 
between bedtime and waketime, excluding nights with 0 number of voids. 
The rationale for the analysis is the same as described in Section 6.3.2.4. 
6.3.2.5.1 Variable 
For analysis 2, the number of nocturnal voids will be derived as the number of nocturnal 
voids between bedtime and waketime. 
For analysis 3, the number of nocturnal voids will be derived as the number of nocturnal 
voids between bedtime and waketime. Nights with 0 voids will be set as missing. 


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Changes from baseline in the total number of nocturnal voids will be computed using 
averages across the 3 voiding nights (‘Cycles’) at baseline, Week 1, and Week 4 (based on 
available data in the corresponding treatment period). 
6.3.2.5.2 Analysis 
Changes from baseline to post-baseline visits in the number of nocturnal voids will be 
analyzed using an MMRM with treatment (daridorexant 50 mg; placebo), week within 
period (Week 1; Week 4), and period (TP I; TP II) as factors, baseline number of nocturnal 
voids as covariate, and the interaction of treatment and week. The MMRM will be applied 
to all 3 approaches, as described above. 
An unstructured covariance matrix will be used to account for the correlation between 
repeated measurements from the same subject. A restricted maximum likelihood approach 
in combination with the Newton Raphson Algorithm will be used to derive (unbiased) 
estimates of variance components. The Kenward-Roger approximation will be used to 
compute the denominator degrees of freedom and adjust standard errors [Kenward 1997]. 
If the analysis fails to converge, the following structures will be tested in the subsequent 
order until model-convergence is achieved: heterogeneous Toeplitz, Toeplitz, 
autoregressive, and compound symmetry. 
To evaluate the efficacy hypotheses, appropriate contrasts will be used to test the treatment 
differences of interest (i.e., the difference in LS Mean change from baseline to Week 4 
between daridorexant 50 mg and placebo). 
The LS Mean for each treatment per time point will be displayed with the associated 
standard errors and 95% CIs. For the comparison of daridorexant with placebo, the 
placebo-adjusted LS Mean will be displayed with the associated standard error, 95% CI 
and unadjusted 2-sided p-value. 
The changes from baseline in the total number of nocturnal voids will be plotted over time 
(averaged across the 3 nights) by treatment (based on all 3 approaches). 
The number of nocturnal voids and the change in the number of nocturnal voids will be 
analyzed descriptively, averaged across the 3 voiding nights, by treatment and visit (based 
on all 3 approaches). 
Descriptive analyses will be repeated for the number of daytime voids, based on the data 
provided by Minze Health, by treatment and visit. 
6.3.3 Quality of life and treatment preference endpoints 
All analyses will be conducted based on the FAS. 


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6.3.3.1 ICIQ-MLUTS and ICIQ-FLUTS 
The ICIQ-MLUTS is a questionnaire that evaluates lower urinary tract symptoms in males. 
It is a patient-completed questionnaire that includes 13 items. It is split into two subscales 
ranging from 0–20 for voiding symptoms and 0–24 for incontinence symptoms, where 
higher numbers indicate a higher burden. It will be completed by the subjects on the eDiary 
at Visit 1, Visit 4, and Visit 8. 
The ICIQ-FLUTS is a questionnaire that evaluates lower urinary tract symptoms in 
females. It is a patient-completed questionnaire that includes 12 items. It is split into 
3 subscales ranging from 0–16 for filling symptoms, 0–12 for voiding symptoms, and  
0–20 for incontinence symptoms, where higher numbers indicate a higher burden. It will 
be completed by the subjects on the eDiary at Visit 1, Visit 4, and Visit 8. 
6.3.3.1.1 Variable 
For the ICIQ-MLUTS voiding symptoms score, the items of questions 2a–6a will be 
summed. For the ICIQ-MLUTS incontinence symptoms score, the items of  
questions 7a–12a will be summed. Answers to questions 2b–12b will not be analyzed. 
For the ICIQ-FLUTS filling symptoms score, the items of questions 2a–5a will be summed. 
For the ICIQ-FLUTS voiding symptoms score, the items of questions 6a–8a will be 
summed. For the ICIQ-FLUTS incontinence symptoms score, the items of questions  
9a–13a will be summed. Answers to questions 2b–13b will not be analyzed. 
Changes from baseline (Visit 1) will be calculated for each sub-score, separately for men 
and women. 
6.3.3.1.2 Analysis 
The change from baseline to Week 4 for all sub-scores of ICIQ-MLUTS and ICIQ-FLUTS 
will be summarized by treatment and sex. Observed values will also be summarized. 
6.3.3.2 ICIQ-NQoL 
The ICIQ-NQoL is a subject-completed questionnaire covering daytime and nighttime 
impact of nocturia in men and women, and consists of 13 items. The recall period is 
4 weeks. The overall score is calculated by summing the first 12 items (ranging from 0–4), 
resulting in an overall score that ranges from 0–48, where greater scores indicate a greater 
decrease in quality of life. It will be completed by the subjects on the eDiary at Visit 1, 
Visit 4, and Visit 8. 
6.3.3.2.1 Variable 
All items of questions 3–14 will be summed for one overall score. Changes from baseline 
will be calculated. 


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6.3.3.2.2 Analysis 
The change from baseline to Week 4 for the overall ICIQ-NQoL score will be summarized 
by treatment. Observed values will also be summarized. 
6.3.3.3 EQ-5D-3L 
The EQ-5D-3L is an instrument that assesses quality of life, irrespective of the disease. 
The 5 dimensions include mobility, self-care, usual activities, pain/discomfort, and 
anxiety/depression. ‘None’, ‘some’, and ‘extreme’ are the 3 modalities for each dimension. 
Depending on the box checked by the subject, a number is assigned to each dimension 
resulting into a 5-digit number combination (e.g., a completely healthy subject would have 
a score of 11111). It will be completed by the subjects at Visit 1, Visit 3, Visit 4, Visit 7, 
and Visit 8. 
6.3.3.3.1 Variable 
As the study is mainly conducted in the Unites States, the derivation of the scores for 
EQ-5D-3L follows the publication by Shaw et al. [Shaw 2005] 
Each of the 5-digit number combinations is assigned a score, e.g., for combination 11111 
a score of 1.000 is assigned, while for combination 12332 a score of 0.302 is assigned. The 
assignments of all scores are summarized in Appendix 13.4. 
6.3.3.3.2 Analysis 
The change from baseline to Week 2 and Week 4 for the overall EQ-5D-3L score will be 
summarized by treatment. Observed values will also be summarized. 
6.3.3.4 PGA-S and PGI-C endpoints 
6.3.3.4.1 PGA-S endpoints 
The PGA-S (daytime symptoms) is indicative of the overall severity of daytime symptoms 
(e.g., sleepiness) and impact (e.g., effort to perform daily activities) that the subject may 
have experienced due to their insomnia over the 7 days preceding the PGA-S. The PGA-S 
(daytime symptoms) is a 1-item, 6-point scale that ranges from ‘None’ to ‘Very severe’. It 
will be completed by the subjects on the eDiary at Visit 1 and weekly during both treatment 
periods.  
The PGA-S (daily life) is indicative of the overall impact on daily life (e.g., effort to 
perform daily activities) that the subject may have experienced due to their insomnia and 
nocturia over the 4 weeks preceding the PGA-S. The PGA-S (daily life) is a 1-item, 5-point 
scale that ranges from ‘Not at all’ to ‘Extremely’. It will be completed by the subjects on 
the eDiary at Visit 1, Visit 4, and Visit 8.  


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6.3.3.4.2 Variable 
The PGA-S (daytime symptoms) scales ranges from 1–6, the PGA-S (daily life) ranges 
from 1–5. Changes from baseline will be calculated. 
Time windows will be assigned for both PGA-S assessments due to missing visit labels in 
the eDiary database. Data were supposed to be collected on Day 8 (Week 1), Day 15 
(Week 2), Day 22 (Week 3) and Day 29 (Week 4) after treatment start date for PGA-S 
(daytime symptoms) and on Day 29 (Week 4) after treatment start date for PGA-S (daily 
life) in each treatment period.  
PGA-S (daytime symptoms) data for Week 1–Week 3 were collected based on a 7-day 
schedule in the eDiary. A time window of ± 2 days will be assigned to those weeks to select 
the data (Days 6–10 for Week 1, Days 13–17 for Week 2, and Days 20–24 for Week 3). 
As the Week 4 data was collected during the hospital visit, the variability of the collection 
dates is higher. Therefore, a time window of –4 to +7 days will apply for Week 4  
(Days 25–36; no overlap with Week 3 data). If two data points were collected within the 
same time window, the collection date closest to the pre-defined days will be used (Day 8 
for Week 1, Day 15 for Week 2, Day 22 for Week 3, and Day 29 for Week 4). Data will be 
assigned independent of visit labels. 
For PGA-S (daily life) a time window of ± 7 days will apply for Week 4. If 2 data points 
were collected within the same time window, the collection date closest to the pre-defined 
day will be used (as defined above). 
6.3.3.4.3 Analysis 
The change from baseline to Week 1–Week 4 for PGA-S (daytime symptoms) and the 
change from baseline to Week 4 for PGA-S (daily life) will be summarized by treatment. 
Observed values will also be summarized. 
6.3.3.4.4 PGI-C endpoints 
The PGI-C (daytime symptoms) is indicative of the change in overall severity of daytime 
symptoms (e.g., sleepiness) and impact (e.g., effort to perform daily activities) that the 
subject may have experienced due to their insomnia over the 7 days preceding the PGI-C 
(daytime symptoms) compared to the week before he/she started treatment. The PGI-C 
(daytime symptoms) is a 1-item, 7-point scale that ranges from ‘Very much better’ to ‘Very 
much worse’. It will be completed weekly by the subjects on the eDiary during both 
treatment periods.  
The PGI-C (nighttime symptoms) is indicative of the change in the subject’s insomnia 
symptoms at night (e.g., trouble falling asleep, total time asleep, time to fall back asleep or 
number of times they wake up) over the 7 nights preceding the PGI-C (nighttime 
symptoms) compared to the week before the subject started treatment. The PGI-C 
(nighttime symptoms) is a 1-item, 7-point scale that ranges from ‘Very much better’ to 


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‘Very much worse’. It will be completed weekly by the subjects on the eDiary during both 
treatment periods.  
The PGI-C (daily life) is indicative of the change in overall severity of daily life symptoms 
that the subject may have experienced due to their insomnia and nocturia over a period of 
4 weeks. The PGI-C (daily life) is a 1-item, 5-point scale that ranges from ‘Very much 
better’ to ‘Very much worse’. It will be completed by the subjects on the eDiary at Visit 4 
and Visit 8.  
6.3.3.4.5 Variable 
The PGI-C (daytime symptoms) scale ranges from 1–7, the PGI-C (nighttime symptoms) 
ranges from 1–7, and the PGI-C (daily life) ranges from 1–5. 
The same time window approach will be used for PGI-C (daytime symptoms) data as 
described in Section 6.3.3.4.2. 
6.3.3.4.6 Analysis 
The two PGI-C symptom scores will be summarized by week (Week 1, Week 2, Week 3, 
and Week 4). The PGI-C (daily life) score will be summarized for Week 4. 
6.3.3.5 IDSIQ endpoints 
IDSIQ is programmed on the eDiary and must be completed by the subject every day in 
the evening prior to completing the evening sleep diary. IDSIQ is structured in 3 domains 
(alert/cognition; mood; sleepiness) and contains 14 items overall, each based on an 
11-point Numeric Rating Scale. 
6.3.3.5.1 Variable 
The different IDSIQ domains are derived as shown in Table 5. 
Table 5 
Insomnia Daytime Symptoms and Impacts Questionnaire description 
Domain  
Scoring 
Minimum/Maximum Score 
Alert/Cognition 
Daily: Sum of Item 1*, Item 2*, Item 3, 
Item 9, Item 10*, Item 14* 
Minimum score: 0 
Maximum score: 60 
Higher score: greater burden of 
illness 
Weekly Average: Mean of the daily domain 
score over 7 days 
Mood 
Daily: Sum of Item 4, Item 5, Item 6, Item 7 
Minimum score: 0 
Maximum score: 40 
Higher score: greater burden of 
illness 
Weekly Average: Mean of the daily domain 
score over 7 days 


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Domain  
Scoring 
Minimum/Maximum Score 
Sleepiness 
Daily: Sum of Item 8*, Item 11, Item 12, 
Item 13 
Minimum score: 0 
Maximum score: 40 
Higher score: greater burden of 
illness 
Weekly Average: Mean of the daily domain 
score over 7 days 
Total score 
Daily: Sum of all domains above 
Minimum score: 0 
Maximum score: 140 
Higher score: greater burden of 
illness 
Weekly Average: Mean of the daily domain 
score over 7 days 
* Item 1, Item 2, Item 8, Item 10, and Item 14 scores are reverse-scored prior to summation. 
 
Baseline is the mean value based on the IDSIQ entries performed at home on the 7 days 
immediately preceding Visit 2. 
Week 1–Week 4 are defined as the mean values based on the IDSIQ entries performed 
during Days 2–8, 9–15, 16–22 and 23–29 in each treatment period, respectively. In order 
to calculate baseline and Week 1–Week 4 averages, at least two days of data must be 
available. Otherwise, baseline and weekly averages are considered as missing. 
6.3.3.5.2 Analysis 
For all IDSIQ scores, weekly averages and corresponding changes from baseline to  
Week 1–Week 4 will be summarized, by treatment. Changes from baseline to  
Week 1–Week 4 will also be analyzed for all IDSIQ scores based on an MMRM, as 
described in Section 6.1.3. 
6.3.3.6 Treatment satisfaction 
The Numeric Rating Scale collects information regarding treatment satisfaction during the 
clinical trial by asking the subjects to mark the number that best describes overall 
satisfaction on a scale from 0 (‘Not at all satisfied’) to 10 (‘Extremely satisfied). 
Self-reported treatment satisfaction is assessed on the morning of Visit 4 and Visit 8 on the 
eDiary. 
A paired t-test will be applied to the within-subject differences (daridorexant 50 mg vs 
placebo) to test for differences between the two treatments. The output will contain the 
mean estimate (including 95% CI) and the associated p-value. 
Treatment satisfaction will be summarized descriptively by treatment. 
6.3.3.7 Treatment preference 
The subjects will be asked at Visit 8 to select which treatment period (TP I or TP II) was 
preferred and complete it on the eDiary. Subjects that were not treated in TP II will be 
excluded from analysis. 


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Treatment preference will be summarized descriptively, overall and by treatment sequence. 
Odds ratios (including 95% CIs) and associated p-values will be added to the output. 
7 
SAFETY VARIABLES AND ANALYSES 
7.1 
Overview of safety analyses 
The SAF will be used for tables and listings of safety data, unless otherwise stated.  
Unless otherwise noted, only the treatment-emergent safety data will be considered in 
tables and figures. 
All safety data described below will be listed. 
7.2 
Adverse events 
TEAEs are defined as AEs that started or worsened on or after study treatment start date 
up to the EOT + 5 days (in each treatment period). AEs that start in TP I and continue into 
TP II will only be presented as TP I AEs, unless there is a worsening in TP II. AEs that 
start in the washout period (i.e., on day 6 of the washout period up to 1 day prior to start of 
TP II) and continue into TP II will not be presented for any of the treatment periods. 
AEs will be coded using MedDRA. The MedDRA version used for reporting will be 
specified in the footnote of the applicable output.  
The number (%) of study subjects experiencing a TEAE (including SAEs, AESI, and AEs 
leading to premature discontinuation and/or temporary interruption of study treatment) will 
be summarized by SOC and/or PT, and/or maximum intensity. 
AESIs, defined as AE PTs denoting ‘falls’ and ‘incontinence episodes’ will be summarized 
separately. 
A subject with multiple intensities reported for an AE will be summarized under the 
maximum intensity recorded for the event.  
Apart from the summaries of occurrences, where each event is counted, a subject with 
multiple occurrences of an AE is counted only once in the AE category (e.g., SOC, PT). If 
a single AE worsens on the same treatment, this event will be considered as one occurrence. 
AEs will be sorted by descending frequency, first based on daridorexant 50 mg, then based 
on placebo. After this sorting, SOCs are presented in alphabetical order and PTs are sorted 
alphabetically within each SOC. 
The following AE summary tables will be provided:  
• Treatment-emergent AEs; 
• TEAEs related to study treatment; 


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• AEs leading to premature discontinuation of study treatment; 
• AEs leading to temporary interruption of study treatment; 
• Treatment-emergent SAEs (including occurrences); 
• Treatment-emergent SAEs related to study treatment (including occurrences); 
• TEAEs with fatal outcome; 
• TEAEs related to study treatment with fatal outcome; 
• Total number of deaths; 
• Treatment-emergent AESIs; 
• AEs during the washout period. 
All AEs will be listed, with AESIs and SAEs being flagged in the AE listing.  
Separate listings will be provided for AEs leading to premature discontinuation of study 
treatment, AEs leading to temporary interruption of study treatment, SAEs, fatal AEs, and 
AESIs. 
All deaths will be listed, with cause of death, using the SCR.  
An AE listing, using the SCR, will also be provided for study subjects who were not 
randomized (i.e., screen failures) and study subjects who were randomized but did not take 
study treatment. This listing will therefore include any study subjects who discontinued the 
study due to an AE but did not receive any study treatment.  
Any other summary required for disclosure to the public database will be generated as 
appropriate. 
7.3 
Laboratory tests 
Local laboratory data will only be listed on the SCR as data is only included in the eCRF 
in case the investigator decides to collect the local lab data. 
7.4 
Vital signs, blood pressure and pulse rate 
The change from baseline to Week 4 in vital signs (systolic and diastolic blood pressure, 
and pulse rate) will be summarized based on the FAS by treatment. The observed values at 
baseline and each scheduled post-baseline visit will also be summarized for the FAS.   
7.5 
Columbia Suicide Severity Rating Scale©  
The C-SSRS© evaluates suicidal ideation and behaviors.  


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The C-SSRS© outcome categories are provided below. Each category has a binary response 
(yes/no).  
1 
Wish to be dead  
2 
Non-specific active suicidal thoughts  
3 
Active suicidal ideation with any methods (not plan) without intent to act  
4 
Active suicidal ideation with some intent to act, without specific plan  
5 
Active suicidal ideation with specific plan and intent  
6 
Preparatory acts or behavior  
7 
Aborted attempt  
8 
Interrupted attempt  
9 
Actual attempt (non-fatal)  
10 Completed suicide  
Categories 1–5 relate to suicidal ideation and a score of 0 is assigned if no suicidal ideation 
is present. Categories 6–10 relate to suicidal behavior.  
Self-injurious behavior without suicidal intent is also a C-SSRS© outcome (although not 
suicide-related) and has a binary response (yes/no).  
C-SSRS© data are collected at baseline, at Week 4 (in each treatment period), during the 
safety follow-up periods, and for premature treatment discontinuation. 
Based on the C-SSRS©, the number (%) of study subjects with suicidal ideation by category, 
suicidal behavior by category, suicidal ideation or suicidal behavior, and/or self-injurious 
behavior without suicidal intent will be tabulated by study phase. The worst C-SSRS© 
outcomes of Study Phase 1 (TP I; premature treatment discontinuation during TP I; and 
washout phase) will be derived, as well as the worst C-SSRS© outcomes of study phase 2 
(TP II; premature treatment discontinuation during TP II; and safety follow-up phase). 
Percentages will be based on the number of study subjects with at least one post-baseline 
C-SSRS© assessment.  
Shifts from baseline showing any change in suicidal ideation and suicidal behavior during 
the two study phases will be provided by treatment. Study subjects will be summarized 
under the worst of the following 3 categories, shown here in order from best to worst: 1) No 
suicidal ideation or behavior, 2) Suicidal ideation, and 3) Suicidal behavior (subjects with 
both suicidal ideation and suicidal behavior are also included in the suicidal behavior 
category). 
7.6 
Morning sleepiness (VAS) 
Morning sleepiness is analyzed as described in Section 6.3.1.2. 


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7.7 
Analysis of narratives 
The analyses of the subject narratives will be conducted based on a separate statistical 
analysis plan. 
8 
GENERAL STATISTICAL METHODOLOGY 
8.1 
General rules for data presentations 
Data are listed and summarized as described below.  
By-treatment tables will have the following header structure (label and order): 
Daridorexant 50 mg 
N = xxx 
Placebo 
N = xxx 
 
where N indicates the total number of subjects randomized to the respective treatment or 
treated with the respective treatment within the analysis set. 
If the treatment sequence is displayed, the header structure will be: 
Daridorexant 50 mg / Placebo 
N = xxx 
Placebo / Daridorexant 50 mg 
N = xxx 
 
where N indicates the total number of subjects randomized to the respective treatment 
sequence within the analysis set, unless otherwise specified. 
All listings will be sorted by randomized treatment sequence received, subject number 
(ascending) and, when appropriate, by visit / date of assessment (ascending). Listings 
related to the SCR will present a treatment label ‘screening failure’ to indicate study 
subjects who were not randomized and will be listed after the study subjects who were 
randomized or received study treatment, as relevant.  
Unless noted otherwise, the following descriptive statistics will be used to summarize data: 
number (%) of study subjects for categorical variables; descriptive statistics (number of 
non-missing values, mean, standard deviation, median, Q1, Q3, minimum, maximum) for 
continuous variables. 
8.2 
Handling of missing dates 
An incomplete date (day or month missing), or missing concomitant therapy / AE date, 
will be imputed as described in Table 6. The ‘lower limit’ and ‘upper limit’ refer to the 
earliest and latest possible dates, respectively.  
For example, if concomitant therapy start date / AE onset date is MAR2021 (day missing), 
the lower limit is 01MAR2021 and the upper limit is 31MAR2021; if concomitant therapy 
start date / AE onset date is 2021 (day and month missing), the lower limit is 01JAN2021 
and the upper limit is 31DEC2021. 


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Table 6 
Imputation rules for an incomplete or missing concomitant therapy or 
AE date 
Field 
Incomplete date 
Missing date 
Concomitant 
therapy end 
date / AE 
resolution date 
The upper limit. 
No imputation. The therapy / AE 
is considered as ongoing. 
Concomitant 
therapy start 
date / AE onset 
date 
The rules below apply in the order presented: 
1. If the (imputed) concomitant therapy / AE end 
date is on or after the start of study treatment, and 
if the study treatment start falls within the upper 
and lower limits (inclusive), the study treatment 
start date of the corresponding treatment period 
is used.* 
2. If the concomitant therapy end date / AE 
resolution date is missing, and if the study 
treatment start falls within the upper and lower 
limits (inclusive), the study treatment start date 
of the corresponding treatment period is used. # 
3. In all the other cases, the lower limit is used. 
Whichever is the earlier of the 
concomitant therapy end date or 
study treatment start date. 
If the start date is missing the AE 
will be assigned to both treatment 
periods. 
* If both treatment start dates (i.e., those for TP I and TP II) are within the lower and upper limit, the 
concomitant therapy / AE is duplicated and assigned to both treatment periods, i.e., once with 
treatment 1 start date and once with treatment 2 start date.) 
AE = adverse event; TP = treatment period. 
 
The purpose of imputing concomitant therapy / AE dates is only to assign a concomitant 
therapy / AE to a specific study period for the summary tables. No imputed date is 
considered in the medical evaluation of an AE or of a causal relationship between a 
concomitant therapy and an individual AE.  
9 
INTERIM ANALYSES  
No interim analysis will be performed.   
10 GENERAL DEFINITIONS AND DERIVATIONS 
10.1 Treatment start and end dates  
Study treatment start or end date is the earliest or latest date, respectively, of dose intake 
recorded on the ‘Study Treatment Log’ page for the corresponding treatment period.   
10.2 Study periods  
The screening period is defined as the time from the informed consent date until one day 
before the study treatment start date of TP I, or date of screening failure.  


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The treatment periods are defined as the time from the day of study treatment start until the 
day of EOT (Week 4), or, for those who prematurely discontinued study treatment (i.e., 
those without an EOT date), until the day of study treatment end date.  
Provided the subject starts the second treatment, the washout period is defined as the time 
from one day after the end of TP I until the day before start of TP II.  
The safety follow-up period is defined as the time from one day after the end of the last 
treatment period until end of safety follow-up period / EOS date (for both treatment 
periods). 
10.3 Treatment day and Study day  
The Treatment day for an assessment or event will be calculated using the study treatment 
start date of the corresponding treatment period as reference. 
For assessments/events occurring on or after the start date of study treatment, Treatment 
day will be positive and will be calculated as:  
• Treatment day (days) = Date of assessment/event – Start date of study treatment 
+ 1 day 
The first day of study treatment is Treatment day 1. 
Study day will be calculated as:  
• Study day (days) = Date of assessment/event – Start date of study treatment in TP I  
For all assessments/events occurring prior to the start date of TP I, Study day will be 
negative. Study day will be displayed in the data listings as appropriate.  
10.4 Baseline  
Baseline is the last non-missing assessment performed or value measured before or on the 
day of the first dose of any study treatment, unless otherwise defined in the specific analysis 
section.  
Study subjects with no data for a given parameter before the first treatment administration 
will have a missing baseline (and missing change from baseline) for this parameter.  
10.5 Change from baseline  
The change from baseline is defined as the post-baseline value (any assessment performed 
after baseline and up to EOS) minus the baseline value. A positive number indicates an 
increase compared to baseline.  


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11 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
11.1 Changes to the analyses planned in the study protocol 
Not applicable. 
11.2 Changes in the conduct of the study / data collection 
Not applicable. 
11.3 Clarifications concerning endpoint definitions and related variables or 
statistical methods 
Analyses for the key voiding endpoints ‘Total nocturnal voiding volume’ and ‘Total 
number of nocturnal voids’ were updated to address potential inconsistencies in the Minze 
Health voiding data. 
Due to issues involving the weekly PGA and PGI endpoint data collection, a time window 
approach was introduced. Analyses remain the same. 
Some minor clarifications were added for C-SSRS© analyses. 
Two of the PDs were updated for the definition of the PPS population. 
Generally, some minor clarifications were added to the SAP, e.g. outputs repeated on a 
different population. 
The duration of the safety follow-up period was set to 5 days (instead of the 5–10 days 
specified in the protocol). 
11.4 Additional analyses to those planned in the study protocol 
Baseline disease characteristics summary tables were added for the RND and FAS. 
A table summarizing the duration of the washout period was added. 
The study discontinuations summary table will also be produced for the FAS. 
Analyses for ISI©, VAS scales and IDSIQ scales will be repeated based on an MMRM for 
the FAS. 
An analysis by treatment period was added for the missing data patterns of the primary 
endpoint and for the compliance summary table. 
Two sensitivity analyses each were added for ‘Total nocturnal voiding volume’ and ‘Total 
number of nocturnal voids’ to account for missing and inconsistent data. 
For the time to first nocturnal void, a Kaplan-Meier plot was added for all subjects at 
baseline. 


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An analysis was added for the total nocturnal voiding volume plus the morning void 
volume. 


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12 REFERENCES 
[D-23.307] A multi-center, double-blind, randomized, placebo-controlled, 2-way 
cross-over post approval study to investigate the efficacy of daridorexant in subjects 
with insomnia and comorbid nocturia. Idorsia Pharmaceuticals Ltd; Global Protocol 
ID-078A401, 4 September 2023. 
[Bladt 2022] Bladt L, De Win G, Wachter S. Accuracy validation of a novel automated 
bladder diary device, Minze Diary Pod. Eur Urol. 2022 Feb;81:S151.  
[Bright 2014] Bright E, Cotterill N, Drake M, Abrams P. Developing and validating the 
International Consultation on Incontinence Questionnaire bladder diary. Eur Urol. 
2014 Aug;66(2):294–300. 
[ICH 2019] ICH Harmonised Guideline. Addendum on estimands and sensitivity analysis 
in clinical trials to the guideline on statistical principles for clinical trials – E9(R1). 
20 November 2019 [accessed on 25 May 2024]. Available from: 
 
https://database.ich.org/sites/default/files/E9-R1_Step4_Guideline_2019_1203.pdf 
[Kenward 1997] Kenward MG, Roger JH. Small sample inference for fixed effects from 
restricted maximum likelihood. Biometrics. 1997 Sep;53(3):983–97. 
[Mignot 2022] Mignot E, Mayleben D, Fietze I, Leger D, Zammit G, Bassetti CLA, et al. 
Safety and efficacy of daridorexant in patients with insomnia disorder: results from 
two multicentre, randomised, double-blind, placebo-controlled, phase 3 trials. Lancet 
Neurol. 2022 Feb;21(2):125–39. Erratum in: Lancet Neurol. 2022 Apr 5. 
[Shaw 2005] Shaw J, Johnson JA, Coons SJ. US Valuation of the EQ-5D Health States 
Development and Testing of the D1 Valuation Model. Med Care 2005;43:203–220. 


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13 APPENDICES 
13.1 Revision history 
Version date 
Version 
Implemented change(s) 
5 July 2023 
1 
New 
30 May 2024 
2 
Changes as described in Section 11. 
 
13.2 SAS® code for mixed model for repeated measures 
This model is used, for example, for the main analyses of the primary endpoint. Assuming 
the data are in ‘long’ format (i.e., one row for each subject/visit), example SAS® statements 
for the primary endpoint analysis are: 
proc mixed data=data; 
class SUBJID TRT VIS PERIOD; 
 
model CHG = BASE TRT VIS PERIOD TRT*VIS / ddfm=kr; 
 
random int / subject=SUBJID; 
 
repeated VIS / subject=SUBJID*TRT type=un; 
 
lsmeans TRT*VIS / diff cl; 
 
estimate ‘daridorexant 50 mg vs placebo at Week 4’ TRT 1 -1 TRT*VIS 0 0 0 1 0 
0 0 -1 / cl; 
run; 
The dataset ‘data’ includes baseline as well as changes (CHG) from baseline to Weeks 1, 
2, 3, and 4 (VIS). Furthermore, TRT equals 1 and 2 for daridorexant 50 mg and placebo, 
respectively, and PERIOD equals 1 and 2 for TP I and TP II. 
13.3 SAS® code for Kaplan-Meier analyses 
This model is used, for example, for the voiding diary analyses. The duration is the time 
from bedtime to first void, for example. The status of 0 is assigned to censored patients. 
proc lifetest data=data; 
 
time duration*status(0);  
 
strata treatment;  
run; 
13.4 Reference data for EQ-5D-3L 
The 5-digit sequence of the EQ-5D-3L questionnaire will be assigned a score, as presented 
in Table 7.  


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Table 7 
EQ-5D-3L Coding 
Combination 
Value 
11111 
1.000 
11211 
0.860 
21111 
0.854 
11112 
0.844 
21211 
0.843 
11212 
0.833 
11121 
0.827 
21112 
0.827 
12111 
0.825 
11221 
0.816 
12211 
0.814 
21121 
0.810 
22111 
0.808 
11122 
0.800 
12112 
0.797 
21212 
0.794 
12121 
0.781 
21221 
0.778 
22211 
0.775 
11222 
0.768 
12212 
0.765 
21122 
0.761 
22112 
0.759 
12221 
0.748 
22121 
0.742 
12122 
0.732 
21222 
0.708 
22212 
0.705 
22221 
0.689 
12222 
0.678 
22122 
0.672 
11311 
0.626 
21311 
0.619 
11312 
0.609 


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22222 
0.597 
11321 
0.592 
21312 
0.592 
12311 
0.590 
21321 
0.575 
22311 
0.573 
11322 
0.565 
12312 
0.563 
11113 
0.550 
11213 
0.550 
12321 
0.546 
21113 
0.543 
21213 
0.533 
13111 
0.529 
13211 
0.529 
21322 
0.527 
22312 
0.524 
23111 
0.522 
11123 
0.517 
12113 
0.514 
13112 
0.512 
23211 
0.512 
22321 
0.508 
11223 
0.506 
12213 
0.503 
13212 
0.501 
21123 
0.499 
12322 
0.497 
22113 
0.497 
13121 
0.496 
23112 
0.495 
13221 
0.485 
23121 
0.478 
12123 
0.470 
13122 
0.468 
21223 
0.467 
22213 
0.465 


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11131 
0.463 
11231 
0.463 
23212 
0.463 
21131 
0.456 
11313 
0.452 
11132 
0.446 
23221 
0.446 
21231 
0.446 
21313 
0.445 
31111 
0.442 
31211 
0.442 
12223 
0.438 
22322 
0.437 
13222 
0.436 
11232 
0.435 
22123 
0.432 
13311 
0.431 
23122 
0.430 
21132 
0.429 
12131 
0.427 
31112 
0.426 
23311 
0.424 
11323 
0.418 
12231 
0.416 
12313 
0.416 
31212 
0.415 
13312 
0.414 
22131 
0.410 
31121 
0.409 
32111 
0.407 
21323 
0.401 
12132 
0.400 
22313 
0.399 
31221 
0.398 
13321 
0.397 
21232 
0.397 
23312 
0.397 


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32211 
0.396 
31122 
0.382 
23321 
0.380 
32112 
0.379 
22223 
0.378 
22231 
0.378 
23222 
0.376 
12323 
0.372 
13322 
0.370 
12232 
0.368 
11331 
0.365 
32121 
0.363 
22132 
0.361 
21331 
0.358 
13113 
0.355 
13213 
0.354 
31222 
0.350 
23113 
0.348 
11332 
0.348 
32212 
0.347 
31311 
0.344 
23213 
0.337 
22323 
0.333 
23322 
0.331 
21332 
0.331 
32221 
0.330 
12331 
0.329 
31312 
0.327 
13123 
0.321 
32122 
0.314 
22331 
0.312 
31321 
0.311 
13223 
0.310 
32311 
0.308 
22232 
0.308 
23123 
0.304 
12332 
0.302 


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11133 
0.289 
11233 
0.289 
13313 
0.286 
31322 
0.283 
21133 
0.282 
32312 
0.281 
23313 
0.279 
23223 
0.272 
21233 
0.271 
31113 
0.268 
13131 
0.268 
31213 
0.268 
13231 
0.268 
32321 
0.264 
22332 
0.263 
23131 
0.261 
32222 
0.260 
12133 
0.253 
13323 
0.253 
13132 
0.251 
23231 
0.250 
33111 
0.247 
33211 
0.247 
12233 
0.242 
13232 
0.240 
22133 
0.236 
23323 
0.235 
31123 
0.235 
23132 
0.234 
32113 
0.232 
33112 
0.230 
31223 
0.224 
32213 
0.222 
11333 
0.220 
33212 
0.220 
32322 
0.216 
21333 
0.214 


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33121 
0.214 
22233 
0.204 
33221 
0.203 
23232 
0.202 
31313 
0.199 
13331 
0.199 
23331 
0.193 
32123 
0.188 
33122 
0.186 
12333 
0.184 
13332 
0.182 
31131 
0.181 
31231 
0.181 
33311 
0.178 
22333 
0.167 
31323 
0.166 
23332 
0.165 
31132 
0.165 
32313 
0.164 
33312 
0.162 
32223 
0.156 
33222 
0.154 
31232 
0.154 
32131 
0.145 
33321 
0.145 
32231 
0.135 
13133 
0.123 
13233 
0.123 
32323 
0.120 
32132 
0.118 
33322 
0.118 
23133 
0.117 
31331 
0.112 
23233 
0.106 
33113 
0.102 
33213 
0.102 
31332 
0.096 


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32232 
0.086 
13333 
0.084 
23333 
0.077 
32331 
0.077 
33123 
0.069 
33313 
0.063 
33223 
0.058 
32332 
0.049 
31133 
0.037 
31233 
0.036 
33323 
0.030 
33131 
0.016 
33231 
0.015 
32133 
0.001 
33132 
-0.001 
31333 
-0.003 
32233 
-0.010 
33232 
-0.012 
33331 
-0.024 
32333 
-0.038 
33332 
-0.040 
33133 
-0.100 
33233 
-0.100 
33333 
-0.109