Multi-center, Double-blind, Randomized, Placebo-controlled, Parallel-group, Polysomnography Study to Assess the Efficacy and Safety of ACT-541468 in Adult and Elderly Subjects With Insomnia Disorder
Phase: PHASE3
Conditions: Insomnia Disorder
Sponsor: Idorsia Pharmaceuticals Ltd.

 
 
Cover page 
 
 
 
 
Official Title: 
 
PROTOCOL ID-078A302 - Multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, polysomnography study to assess the efficacy and safety of  
ACT-541468 in adult and elderly subjects with insomnia disorder 
 
 
 
 
ClinicalTrials.gov Identifier:  
 
NCT03575104 
 
 
 
 
Date of document: 
 
8 November 2018 
 
 
 

TPL-100601_v01 
ACT-541468 
Insomnia Disorder 
Protocol ID-078A302 
Multi-center, double-blind, randomized, placebo-controlled, parallel-group, 
polysomnography study to assess the efficacy and safety of ACT-541468 in adult and 
elderly subjects with insomnia disorder 
Study Phase: 
3 
EudraCT Number: 
2017-004643-20 
Status and version: 
Final Version 5 
Date: 
8 November 2018 
Document type: 
Amended global protocol 
Idorsia document number 
(Doc No.): 
D-18.262
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 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, your personnel, and an independent ethics committee 
or institutional review board. 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 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 phone number 
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File 
 
 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
Some study activities will be delegated to Contract Research Organizations (CROs). 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 
 
Treatment name / number 
ACT-541468 
Indication 
Insomnia Disorder 
Protocol number, study title 
ID-078A302 
Multi-center, 
double-blind, 
randomized, 
placebo-controlled, 
parallel-group, 
polysomnography study to assess the efficacy and safety of ACT-541468 in adult and 
elderly subjects with insomnia disorder. 
 
I approve the terms and conditions relating to this study as defined in this protocol. I 
confirm that the information contained in this protocol is consistent with the current 
risk-benefit evaluation of ACT-541468, and with the ethical and scientific principles 
governing clinical research as set out in the Declaration of Helsinki and the International 
Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines. 
 
 
Title 
Name 
Date 
 
Signature 
 
 

ACT-541468 
Insomnia disorder 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
ACT-541468 
Indication 
Insomnia Disorder 
Protocol number, study title 
ID-078A302 
Multi-center, 
double-blind, 
randomized, 
placebo-controlled, 
parallel-group, 
polysomnography study to assess the efficacy and safety of ACT-541468 in adult and 
elderly subjects with insomnia disorder. 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form, 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 study 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. I confirm herewith that the sponsor 
is allowed to enter and utilize my professional contact details and function in an electronic 
database for internal purposes and for submission to health authorities worldwide. 
I am participating in the following sub-study (only for sites in Germany and the USA): 
PAtient Preferences StUdy in InSomnia (PAUSe) 
 
Principal 
Investigator 
Country 
Site 
number 
Town 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................12 
NON-SUBSTANTIAL GLOBAL AMENDMENT 4 .......................................................16 
PROTOCOL SYNOPSIS ID-078A302 .............................................................................18 
PROTOCOL ......................................................................................................................32 
1 
BACKGROUND .........................................................................................................32 
1.1 
Insomnia disorder .........................................................................................32 
1.1.1 
Definition ..........................................................................................32 
1.1.2 
Epidemiology ....................................................................................32 
1.1.3 
Treatment ..........................................................................................33 
1.1.4 
Unmet medical need .........................................................................34 
1.2 
Study treatment: ACT-541468 .....................................................................35 
1.2.1 
The orexin system .............................................................................35 
1.2.2 
ACT-541468 properties ....................................................................35 
1.2.2.1 
Nonclinical data .......................................................................35 
1.2.2.2 
Clinical studies ........................................................................36 
1.3 
Purpose and rationale of the study ................................................................39 
1.3.1 
Purpose of the study ..........................................................................39 
1.3.2 
Rationale for the study ......................................................................39 
1.4 
Summary of known and potential risks and benefits ....................................40 
1.4.1 
ACT-541468 .....................................................................................40 
1.4.2 
Safety and risk-minimization measures taken in the present 
study ..................................................................................................41 
2 
STUDY OBJECTIVES ...............................................................................................41 
2.1 
Primary objective ..........................................................................................42 
2.2 
Secondary objectives ....................................................................................42 
2.3 
Safety objectives ...........................................................................................42 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................42 
3.1 
Study design .................................................................................................42 
3.1.1 
Study periods ....................................................................................42 
3.1.1.1 
Screening phase .......................................................................42 
3.1.1.2 
Treatment phase ......................................................................43 
3.1.1.3 
Safety follow-up phase ............................................................43 

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3.1.2 
Study duration ...................................................................................44 
3.1.3 
Sub-study – Patient Preferences .......................................................45 
3.2 
Study design rationale ..................................................................................46 
3.2.1 
Core study .........................................................................................46 
3.2.2 
Patient preferences sub-study ...........................................................47 
3.3 
Study committees .........................................................................................47 
4 
SUBJECT POPULATION ..........................................................................................48 
4.1 
Subject population description .....................................................................48 
4.2 
Rationale for the selection of the study population ......................................48 
4.3 
Inclusion criteria ...........................................................................................49 
4.4 
Exclusion criteria ..........................................................................................50 
4.5 
Criteria for women of childbearing potential ...............................................52 
4.5.1 
Definition of childbearing potential ..................................................52 
4.5.2 
Acceptable methods of contraception ...............................................53 
5 
TREATMENTS ..........................................................................................................54 
5.1 
Study treatment .............................................................................................54 
5.1.1 
Investigational treatment and matching placebo: Description 
and rationale ......................................................................................54 
5.1.2 
Study treatment administration .........................................................54 
5.1.2.1 
Study treatment administration at site visits and at home .......54 
5.1.2.2 
Missed doses ............................................................................54 
5.1.3 
Treatment assignment .......................................................................54 
5.1.4 
Blinding ............................................................................................55 
5.1.4.1 
Run-in and run-out periods ......................................................55 
5.1.4.2 
Double-blind treatment period ................................................55 
5.1.5 
Unblinding ........................................................................................56 
5.1.5.1 
Unblinding for final analyses ..................................................56 
5.1.5.2 
Unblinding for IDMC review ..................................................56 
5.1.5.3 
Unblinding for suspected unexpected serious adverse 
reactions ...................................................................................56 
5.1.5.4 
Emergency procedure for unblinding ......................................56 
5.1.6 
Study treatment supply .....................................................................57 
5.1.6.1 
Study treatment packaging and labeling .................................57 
5.1.6.2 
Study treatment distribution and storage .................................57 
5.1.6.3 
Study treatment dispensing .....................................................57 
5.1.6.4 
Study treatment return and destruction ...................................57 
5.1.7 
Study treatment accountability and compliance with study 
treatment ...........................................................................................58 

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5.1.7.1 
Study treatment accountability ................................................58 
5.1.7.2 
Study treatment compliance ....................................................58 
5.1.8 
Study treatment dose adjustments and interruptions ........................59 
5.1.9 
Premature discontinuation of study treatment ..................................59 
5.1.10 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................60 
5.2 
Previous and concomitant therapy ................................................................60 
5.2.1 
Definitions ........................................................................................60 
5.2.2 
Reporting of previous/concomitant therapy in the eCRF .................60 
5.2.3 
Allowed concomitant therapy ...........................................................61 
5.2.4 
Forbidden concomitant therapy ........................................................61 
5.2.5 
Forbidden concomitant diet and activities ........................................61 
6 
STUDY ENDPOINTS ................................................................................................62 
6.1 
Primary efficacy endpoints ...........................................................................62 
6.2 
Secondary endpoints .....................................................................................62 
6.3 
Other efficacy endpoints ...............................................................................63 
6.4 
Exploratory endpoints ...................................................................................63 
6.5 
Safety endpoints ...........................................................................................64 
6.6 
Pharmacokinetic endpoints ...........................................................................65 
6.7 
Patient preferences exploratory endpoints ....................................................65 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................66 
7.1 
Study visits ...................................................................................................66 
7.1.1 
Screening ..........................................................................................66 
7.1.2 
Unscheduled visits ............................................................................66 
7.2 
Study assessments .........................................................................................70 
7.2.1 
Demographics ...................................................................................72 
7.2.2 
Efficacy assessments .........................................................................72 
7.2.2.1 
Polysomnography ....................................................................72 
7.2.2.2 
Sleep diary ...............................................................................74 
7.2.2.3 
Insomnia Severity Index© ........................................................74 
7.2.2.4 
Patient Global Assessment of Disease Severity (daytime 
symptoms) ...............................................................................75 
7.2.2.5 
Patient Global Impression of Change (daytime 
symptoms) ...............................................................................75 
7.2.2.6 
Patient Global Impression of Change (night-time 
symptoms) ...............................................................................75 
7.2.2.7 
Patient Global Impression of Severity (night-time 
symptoms) ...............................................................................76 

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7.2.2.8 
Insomnia Daytime Symptoms and Impacts Questionnaire .....76 
7.2.3 
Safety assessments ............................................................................76 
7.2.3.1 
Weight and height ...................................................................76 
7.2.3.2 
Physical examination ...............................................................76 
7.2.3.3 
Vital signs ................................................................................77 
7.2.3.4 
Coding sub-test© ......................................................................77 
7.2.3.5 
Sheehan Disability Scale© .......................................................77 
7.2.3.6 
Columbia Suicide Severity Rating Scale©...............................77 
7.2.3.7 
Benzodiazepine Withdrawal Symptom Questionnaire ............78 
7.2.3.8 
Mini International Neuropsychiatric Interview© .....................78 
7.2.3.9 
Mini Mental State Examination© ............................................78 
7.2.3.10 
Neurological examinations ......................................................79 
7.2.3.11 
Epworth Sleepiness Scale© ......................................................79 
7.2.3.12 
ECG assessment ......................................................................79 
7.2.4 
Patient preferences questionnaire .....................................................80 
7.2.5 
Laboratory assessments ....................................................................80 
7.2.5.1 
Type of laboratory ...................................................................80 
7.2.5.2 
Laboratory tests .......................................................................81 
7.2.6 
Pharmacokinetic assessments ...........................................................82 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................82 
8.1 
Study completion as per protocol .................................................................82 
8.2 
Premature withdrawal from study ................................................................82 
8.3 
Premature termination or suspension of the study ........................................83 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................84 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................84 
9.1 
Adverse events ..............................................................................................84 
9.1.1 
Definition of adverse events .............................................................84 
9.1.2 
Intensity of adverse events ................................................................85 
9.1.3 
Relationship to study treatment ........................................................86 
9.1.4 
Reporting of adverse events ..............................................................86 
9.1.5 
Follow-up of adverse events .............................................................86 
9.2 
Serious adverse events ..................................................................................87 
9.2.1 
Definitions of serious adverse events ...............................................87 
9.2.2 
Reporting of serious adverse events .................................................87 
9.2.3 
Follow-up of serious adverse events .................................................88 
9.2.4 
After the 30-day follow-up period ....................................................88 

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9.2.5 
Reporting procedures ........................................................................88 
9.3 
Pregnancy .....................................................................................................89 
9.3.1 
Reporting of pregnancy ....................................................................89 
9.3.2 
Follow-up of pregnancy ....................................................................89 
9.4 
Study safety monitoring ................................................................................89 
10 STATISTICAL METHODS .......................................................................................89 
10.1 
Analysis sets .................................................................................................90 
10.1.1 
Screened Analysis Set .......................................................................90 
10.1.2 
Full Analysis Set ...............................................................................90 
10.1.3 
Per-Protocol Set ................................................................................90 
10.1.4 
Safety Set ..........................................................................................90 
10.1.5 
Treatment Withdrawal Set ................................................................90 
10.1.6 
Pharmacokinetic Analysis Set ..........................................................90 
10.1.7 
Patient Preferences Analysis Set .......................................................90 
10.1.8 
Usage of the analysis sets .................................................................91 
10.2 
Variables .......................................................................................................91 
10.3 
Description of statistical analyses .................................................................91 
10.3.1 
Analysis of the primary and secondary efficacy variables ...............91 
10.3.1.1 
Overall testing strategy ............................................................91 
10.3.1.2 
Hypotheses and statistical model ............................................94 
10.3.1.3 
Handling of missing data .........................................................94 
10.3.1.4 
Supportive/sensitivity analyses ...............................................94 
10.3.2 
Analysis of other efficacy variables ..................................................95 
10.3.3 
Analysis of the safety variables ........................................................95 
10.3.4 
Analysis of pharmacokinetic variables .............................................96 
10.3.5 
Subgroup analyses ............................................................................97 
10.3.6 
Analysis of the patient preferences variable .....................................97 
10.4 
Interim analyses ............................................................................................97 
10.5 
Sample size ...................................................................................................97 
11 DATA HANDLING ....................................................................................................99 
11.1 
Data collection ..............................................................................................99 
11.2 
Maintenance of data confidentiality ...........................................................100 
11.3 
Database management and quality control .................................................100 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................101 
12.1 
Ethics and Good Clinical Practice ..............................................................101 
12.2 
Independent Ethics Committee / Institutional Review Board ....................101 
12.3 
Informed consent ........................................................................................102 

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12.4 
Compensation to subjects and investigators ...............................................103 
12.5 
Protocol adherence/compliance ..................................................................103 
12.6 
Protocol amendments .................................................................................103 
12.7 
Essential documents and retention of documents .......................................103 
12.8 
Monitoring ..................................................................................................104 
12.9 
Investigator Site File ...................................................................................105 
12.10 
Audit ...........................................................................................................106 
12.11 
Inspections ..................................................................................................106 
12.12 
Reporting of study results and publication .................................................106 
13 REFERENCES ..........................................................................................................108 
14 APPENDICES ...........................................................................................................115 
 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule .....................................................................67 
Table 2 
Sample size assumptions for primary and secondary endpoints .................98 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design.................................................................................................44 
Figure 2 
Hypothesis testing strategy ..........................................................................93 
Figure 3 
Effect of testing multiple null hypotheses on power at a given sample 
size ...............................................................................................................99 
 
 
 
 
 
 
 
 
 
 

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LIST OF APPENDICES 
 
Appendix 1 Alcohol restrictions during the study .........................................................115 
Appendix 2 Caffeine content of common beverages ....................................................116 
Appendix 3 Forbidden and restricted concomitant medications ...................................117 
Appendix 4 Coding sub-test© ........................................................................................120 
Appendix 5 Insomnia Severity Index© ..........................................................................121 
Appendix 6 Sheehan Disability Scale© .........................................................................122 
Appendix 7 Benzodiazepine Withdrawal Symptom Questionnaire ..............................123 
Appendix 8 Sleep Diary ................................................................................................124 
Appendix 9 Patient Global Assessment of Disease Severity and Patient Global 
Impression of Change, daytime symptoms ................................................126 
Appendix 10 Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C), night-time symptoms ..............................127 
Appendix 11 Insomnia Daytime Symptoms and Impacts Questionnaire ........................128 
Appendix 12 Epworth Sleepiness Scale© ........................................................................132 
Appendix 13 Mini Mental State Examination© ...............................................................133 
Appendix 14 PAtient preferences stUdy in inSomnia (PAUSe) .....................................135 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
Adverse event of special interest 
AHI  
Apnea/hypopnea index 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
AV  
Atrioventricular 
BMI  
Body mass index 
BP  
Blood pressure 
bpm  
Beats per minute 
BRA  
Benefit-risk assessment 
BWSQ  
Benzodiazepine Withdrawal Symptom Questionnaire 
CBT  
Cognitive behavioral therapy 
CFR  
Code of Federal Regulations (US) 
CNS  
Central nervous system 
CR  
Controlled-release 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
C-SSRS©  
Columbia Suicide Severity Rating Scale© 
CV%  
Coefficient of variation 
CYP  
Cytochrome P450 
DB  
Double-blind 
DCE  
Discrete Choice Experiment 
DoA  
Delegation of Authority 
DORA  
Dual orexin receptor antagonist 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 

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ECG  
Electrocardiogram/graphy 
eCRF  
Electronic Case Report Form 
EDS  
Excessive daytime sleepiness 
EMA  
European Medicines Agency 
Emax  
Maximum effect 
EODBT  
End-of-Double-Blind Treatment 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ESS©  
Epworth Sleepiness Scale© 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 
GABA  
Gamma-aminobutyric acid 
GCP  
Good Clinical Practice 
HR  
Heart rate 
IB  
Investigator’s Brochure 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IDSIQ  
Insomnia Daytime Symptoms and Impacts Questionnaire 
IEC  
Independent Ethics Committee 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISAC  
Independent Statistical Analysis Center 
ISB  
Independent Safety Board 
ISF  
Investigator Site File 
ISI©  
Insomnia Severity Index© 
LPS  
Latency to Persistent Sleep 
MAR  
Missing at random 

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MedDRA  
Medical Dictionary for Regulatory Activities 
MINI©  
Mini International Neuropsychiatric Interview© 
MMSE©  
Mini Mental State Examination© 
NOAEL  
No-observed-adverse-effect level 
PAUSe  
PAtient Preferences StUdy in InSomnia 
PD  
Pharmacodynamic(s) 
PGA-S  
Patient Global Assessment of Disease Severity 
PGI-C  
Patient Global Impression of Change 
PGI-S  
Patient Global Impression of Severity 
PI  
Principal Investigator 
PK  
Pharmacokinetic(s) 
PLMAI  
Periodic limb movement with arousal index 
PPS  
Per-Protocol Set 
PSG  
Polysomnography 
PT  
Preferred Term 
QS  
Quality System 
QTc  
Corrected QT interval 
QTcB  
QT interval corrected with Bazett’s formula 
QTcF  
QT interval corrected with Fridericia’s formula 
REM  
Rapid eye movement 
RSI  
Reference Safety Information 
RUT  
Random utility theory 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SD  
Standard deviation 
SDS©  
Sheehan Disability Scale© 
SIV  
Site Initiation Visit 
sLSO  
Subjective Latency to Sleep Onset 

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SMAA  
Stochastic multicriteria acceptability analysis 
SOC  
System Organ Class 
SpO2  
Blood oxygen saturation level by pulse oximetry 
SQ  
Sleep quality 
sTST  
Subjective Total Sleep Time 
SUSAR  
Suspected unexpected serious adverse reaction 
sWASO  
Subjective Wake After Sleep Onset 
SWS  
Slow wave sleep 
t½  
Half-life 
TEAE  
Treatment-emergent adverse event 
TST  
Total Sleep Time 
ULN  
Upper limit of normal 
USPI  
United States Package Insert 
VAS  
Visual analog scale(s) 
WASO  
Wake After Sleep Onset 

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PROTOCOL SYNOPSIS ID-078A302 
TITLE 
Multi-center, double-blind, randomized, placebo-controlled, parallel-
group, polysomnography study to assess the efficacy and safety of 
ACT-541468 in adult and elderly subjects with insomnia disorder 
OBJECTIVES 
Primary objectives 
To evaluate the efficacy of 10 mg and 25 mg ACT-541468 on 
objective sleep parameters in subjects with insomnia disorder. 
Secondary objectives 
To evaluate the efficacy of 10 mg and 25 mg ACT-541468 on 
subjective sleep parameters and next-day functioning in subjects with 
insomnia disorder. 
Safety objectives 
To assess the safety and tolerability of ACT-541468 in subjects with 
insomnia 
disorder 
during 
treatment 
and 
upon 
treatment 
discontinuation.  
DESIGN 
Multi-center, 
double-blind, 
randomized, 
placebo-controlled, 
parallel-group, Phase 3 study. 
PHASES 
The study comprises the following 3 phases: the screening phase, the 
treatment phase, and the safety follow-up phase. 
The screening phase starts with the signature of the informed consent 
form at Visit 1 and ends at Randomization (Visit 4), provided the 
subject fulfills all the eligibility criteria. It includes the Screening 
period and the Run-in period. The screening phase lasts 20 to 31 days. 
The Screening period starts with Visit 1 and ends at Visit 2. During 
the Screening period, the investigator verifies eligibility criteria and 
eligible subjects perform a one-night polysomnography (PSG) 
assessment. The Screening period lasts 7 to 18 days to allow time to 
perform all required procedures at Visit 1, the PSG assessment and 
collect the minimum number of eDiary entries (i.e., 7 days) between 
Visit 1 and Visit 2.  
The Run-in period starts with Visit 2 and ends at Randomization 
(i.e., Visit 4). At Visit 2 eligible subjects are allocated a 
single-blinded placebo treatment that is taken daily. During the 
Run-in period subjects come to the site for Visit 3, which consists of 

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2 PSG nights and is performed when the subject has completed the 
eDiary for at least 7 days and eligibility is confirmed. The Run-in 
period lasts 13 to 24 days, to allow collection of the minimum number 
of eDiary entries (i.e., 7 days), perform 2 PSG nights at Visit 3, and 
receive the eligibility confirmation from the PSG central reader.  
The double-blind (DB) treatment phase lasts 3 months. It starts at 
Randomization (Visit 4). DB study treatment is taken daily. A safety 
telephone call is performed at Visit 5 to collect information about 
adverse events (AEs) and concomitant medications. Sleep parameters 
of each subject are objectively assessed with 2 consecutive PSG 
nights at Visit 6 and Visit 8. A safety visit without PSG night will be 
performed at Visit 7. An eDiary is completed every day during the 
treatment phase. 
End-of-Double-Blind-Treatment (EODBT) is reached in the 
second morning of Visit 8. 
The safety follow-up phase starts after EODBT. It consists of a 
single-blind placebo run-out period of 7 days and a safety follow-up 
period.  
The Run-out period starts in the evening of Visit 9. Visit 9 consists 
of one PSG night on single-blind placebo treatment. Visit 9 is 
followed by 6 days at home with single-blind placebo treatment. The 
eDiary is completed every day during the Run-out period. The end of 
the Run-out period (End-of-Treatment [EOT]) is reached after all 
visit assessments have been performed at Visit 10. 
The Safety follow-up period starts after EOT and ends 30 days after 
the last dose of DB study treatment intake for subjects that are not 
enrolled in the ID-078A303 extension study. 
Subjects who complete DB study treatment and the Run-out period 
are eligible to enter the ID-078A303 extension study (if approved by 
the national health authorities and local Independent Ethics 
Committees / Institutional Review Boards). For these subjects, the 
safety follow-up period ends on the date of enrolment into 
ID-078A303.  
End-of-Study (EOS) for an individual subject is defined as the date 
of the 30-day follow-up telephone call (Visit 11) or the date of 
enrolment into the ID-078A303 extension study. If a subject is 

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prematurely discontinued from study treatment EOS is performed as 
planned on Day 115. If a subject withdraws consent and does not 
wish to participate in the study any longer, EOS is the date of consent 
withdrawal for this subject. If a subject is declared lost to follow-up, 
EOS is the date of last successful contact for this subject. 
PLANNED 
DURATION 
Approximately 18 months from first subject, first visit to last subject, 
last visit. 
SITE(S) / 
COUNTRY(IES) 
The study will be conducted at approximately 75 sites in 
10 countries. 
SUBJECTS / 
GROUPS 
Approximately 900 subjects will be randomized to either 10 mg or 
25 mg ACT-541468, or to placebo, in a 1:1:1 ratio. Treatment 
allocation will be stratified by age into 2 categories: < 65 and ≥ 65 
years. Approximately 40% of subjects will be elderly subjects (≥ 65 
years old), of which approximately 5% will be above 75 years old. 
These percentages will be monitored by the sponsor through the IRT. 
INCLUSION 
CRITERIA 
Criteria assessed at Visit 1: 
1. Signed informed consent prior to any study-mandated procedure. 
2. Male or female aged ≥ 18 years. 
3. Insomnia disorder according to Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition (DSM-5) criteria, as follows: 
3.1 The predominant complaint is dissatisfaction with sleep 
quantity or quality, associated with one (or more) of the 
following symptoms: 
• Difficulty initiating sleep. 
• Difficulty maintaining sleep, characterized by frequent 
awakenings or problems returning to sleep after 
awakenings. 
• Early-morning awakening with inability to return to 
sleep. 
3.2 The sleep disturbance causes clinically significant distress 
or impairment in social, occupational, educational, 
academic, behavioral, or other important areas of 
functioning. 
3.3 The sleep difficulty occurs despite adequate opportunity for 
sleep. 

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3.4 The insomnia is not better explained by and does not occur 
exclusively during the course of another sleep-wake 
disorder (e.g., narcolepsy, a breathing-related sleep 
disorder, a circadian rhythm sleep-wake disorder, a 
parasomnia). 
3.5 The insomnia is not attributable to the physiological effects 
of a substance (e.g., a drug of abuse, a medication). 
3.6 Coexisting mental disorders and medical conditions do not 
adequately explain the predominant complaint of insomnia. 
3.7 Self-reported history of all the following on at least 3 nights 
per week and for at least 3 months prior to Visit 1: 
3.7.1 ≥ 30 min to fall asleep, and 
3.7.2 Wake time during sleep ≥ 30 min, and 
3.7.3 Subjective Total Sleep Time (sTST) ≤ 6.5 h 
4. Insomnia Severity Index© score ≥ 15. 
5. Ability to communicate well with the investigator, to understand 
the study requirements and, as judged by the investigator, to be 
alert and oriented to person, place, time, and situation. 
Criteria assessed at Visit 3 
6. Meeting all the following sleep parameters on at least 3 nights out 
of 7 nights on the sleep diary completed at home between Visit 2 
and Visit 3: 
6.1 
≥ 30 min to fall asleep, and 
6.2 
Wake time during sleep ≥ 30 min, and 
6.3 
sTST of ≤ 6.5 h 
7. Usual bedtime between 21:30 and 00:30 as reported on sleep 
diary completed between Visit 2 and Visit 3. 
8. Regular time in bed between 6 and 9 h as reported on sleep diary 
completed between Visit 2 and Visit 3. 
9. Meeting all the following sleep parameters on the 2 PSG nights 
at Visit 3: 
9.1 
Mean Latency to Persistent Sleep (LPS) ≥ 20 min (with 
neither of the two nights < 15 min), and 
9.2 
Mean Wake After Sleep Onset (WASO) ≥ 30 min (with 
neither of the two nights < 20 min), and 
9.3 
Mean Total Sleep Time (TST) < 420 min 

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Criteria assessed at Visit 1, Visit 2, and Visit 4 
10. For women of childbearing potential, the following are required: 
• Negative serum pregnancy test (Visit 1). 
• Negative urine pregnancy test (Visit 2, Visit 4). 
• Agreement to use the contraception scheme as required by 
the protocol from Screening up to at least 30 days after last 
DB study treatment intake. 
EXCLUSION 
CRITERIA 
Criteria assessed at Visit 1 
1. Body mass index below 18.5 or above 40.0 kg/m2. 
2. Any lifetime history of sleep-related breathing disorder, including 
chronic obstructive pulmonary disease and sleep apnea. 
3. Cognitive behavioral therapy (CBT) for any indication is allowed 
only if the CBT started at least 1 month prior to Visit 3 and the 
subject agrees to continue this CBT throughout the study. 
4. Self-reported usual daytime napping ≥ 1 h per day, and ≥ 3 days 
per week. 
5. Acute or unstable psychiatric conditions (including but not 
restricted to anxiety disorder, major depression, bipolar disorder, 
schizophrenia, obsessive compulsive disorder, or depression) that 
are diagnosed by the Mini International Neuropsychiatric 
Interview© or that require pharmacological treatment for these 
disorders. N.B.: subjects with a history of major depressive 
disorder currently without any symptoms and not requiring 
treatment are eligible. 
6. Mini Mental State Examination© score < 25 in subjects 
≥ 50 years. 
7. Shift work within 2 weeks prior to the screening visit, or planned 
shift work during the study. 
8. Travel across ≥ 3 time zones within 2 weeks prior to the screening 
visit, or planned travel across ≥ 3 time zones during the study. 
9. Unstable medical condition, significant medical disorder or acute 
illness, ECG, hematology or biochemistry test results within 
1 month prior to the screening visit, which, in the opinion of the 
investigator, could affect the subject’s safety or interfere with the 
study assessments. 
10. Treatment with central nervous system-active drugs prohibited by 
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2 weeks, whichever is longer) prior to Visit 1, including over-the-
counter medication and herbal medicines. 
11. Diagnosis of alcohol or substance use disorder within 2 years 
prior to the screening visit or inability to refrain from drinking 
alcohol for at least 3 consecutive days. 
12. Heavy tobacco use (at least one pack of cigarettes a day or 
inability to refrain from smoking during the night).  
13. Caffeine consumption ≥ 600 mg per day or any caffeine 
consumption after 4 pm. 
14. Treatment with another investigational drug within 3 months 
prior to Visit 1, previous treatment with ACT-541468 or previous 
randomization in any trial involving ACT-541468. 
15. Known hypersensitivity or contraindication to drugs of the same 
class as the study treatment or to any excipients of the study drug 
formulation. 
16. Not able or willing to stop treatment with moderate or strong 
cytochrome P450 (CYP)3A4 inhibitors, or treatment with 
moderate or strong CYP3A4 inducers, within at least 1 week prior 
to Visit 2. 
17. Not able or willing to stop consumption of grapefruit, Seville 
(bitter) oranges or juices from those fruits within at least 1 week 
prior to Visit 2.  
Criteria assessed at PSG visit between Visit 1 and Visit 2 
18. Periodic limb movement disorder with arousal index (PLMAI) 
≥ 15/h (assessed on the 1st PSG night), restless legs syndrome, 
circadian rhythm disorder, rapid eye movement (REM) behavior 
disorder, or narcolepsy.  
19. Apnea/hypopnea index ≥ 15/h according to American Academy 
of Sleep Medicine criteria or event associated with blood oxygen 
saturation level by pulse oximetry (SpO2) < 80%, as assessed on 
the 1st PSG night. 
Criteria assessed at Visit 1 and Visit 3 
20. Aspartate aminotransferase and/or alanine aminotransferase > 2 × 
upper limit of normal (ULN) and/or direct bilirubin > 1.5 × ULN. 
21. Severe renal impairment: known or defined as estimated 
creatinine clearance < 30 mL/min/1.73 m2, according to the 
4-variable Modification of Diet in Renal Disease formula. 

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22. Hematology or biochemistry test results deviating from the 
normal range to a clinically relevant extent as per judgment of the 
investigator. 
23. Any of the following conditions related to ECG abnormalities: 
• A prolonged QT interval corrected with Bazett’s formula 
(QTcB) or QT interval corrected with Fridericia’s formula 
(QTcF) (greater than 450 ms). If QTcB or QTcF is greater than 
450 ms on the first ECG, a second ECG recording will be 
performed after at least 30 min. If QTcB or QTcF is greater 
than 450 ms on the second ECG, the subject is not eligible.  
• A history of additional risk factors for torsade de pointes (e.g., 
heart failure, hypokalemia, family history of long QT 
syndrome). 
• ECG with clinically significant atrioventricular (AV) 
conduction disturbance (e.g., second- or third-degree AV 
block), sick sinus syndrome, bradycardia (resting pulse 
< 40 bpm), or accessory bypass tract (e.g., Wolff-Parkinson-
White). 
Criterion assessed at Visit 1, Visit 2, Visit 3 and Visit 4 
24. 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 (Visit 1) and visit 
(Visit 2, Visit 3, Visit 4) version of the Columbia Suicide 
Severity Rating Scale© (C-SSRS©). 
• History of suicide attempt on the suicidal behavioral section 
of the lifetime version of the C-SSRS© (Visit 1). 
Criteria assessed at Visit 1, PSG visit between Visit 1 and 
Visit 2, Visit 2, Visit 3 and Visit 4 
25. For female subjects: pregnant, lactating or planning to become 
pregnant during projected duration of the study. 
26. Positive urine drug test (for benzodiazepines, barbiturates, 
cannabinoids, opiates, amphetamines, phencyclidine or cocaine) 
or presence of alcohol in exhaled breath as detected by 
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STUDY 
TREATMENTS 
Investigational treatment 
ACT-541468 tablets at strengths of 10 mg and 25 mg will be 
administered orally, once daily in the evening during the DB 
treatment period. 
Placebo 
ACT-541468-matching placebo will be administered orally, once 
daily in the evening during the single-blind run-in period, the DB 
treatment period and the single-blind run-out period. 
ENDPOINTS 
Primary efficacy endpoints 
The primary efficacy endpoints of this study are defined as: 
• the change from baseline to Month 1 in WASO (sleep 
maintenance) 
• the change from baseline to Month 3 in WASO  
• the change from baseline to Month 1 in LPS (sleep onset) 
• the change from baseline to Month 3 in LPS  
Baseline is defined as mean of the 2 PSG nights at Visit 3. Month 1 
and Month 3 are defined as the mean of the 2 PSG nights at Visit 6 
and Visit 8, respectively. 
LPS (min) is the time from start of recording to the beginning of the 
first continuous 20 epochs (i.e., 10 min) scored as non-awake, i.e., 
epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep 
stage 3 (slow wave sleep) or REM, as determined by PSG.  
WASO is the time (min) spent awake after onset of persistent sleep 
until lights on, as determined by PSG. 
Secondary efficacy endpoints 
The secondary efficacy endpoints of this study are defined as: 
• the change from baselinea to Month 1b in sTST. 
• the change from baselinea to Month 3c in sTST.  
• the change from baselinea to Month 1b in Insomnia Daytime 
Symptoms and Impacts Questionnaire (IDSIQ) sleepiness 
domain score. 
• the change from baselinea to Month 3c in IDSIQ sleepiness 
domain score.  

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a Baseline is the mean value based on the screening sleep diary / 
IDSIQ entries performed at home in the 7 days immediately 
preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries 
performed at home in the 7 days immediately preceding the first PSG 
at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries 
performed at home in the 7 days immediately preceding the first PSG 
at Visit 8. 
Safety endpoints 
In addition to the standardized collection of AEs, safety data specific 
to insomnia and its treatment will be assessed as follows:  
• Withdrawal effects (physical dependence) upon treatment 
discontinuation will be assessed based on the changes from last 
assessment on DB treatment (Visit 8, 2nd morning) to run-out 
period 
in 
the 
Benzodiazepine 
Withdrawal 
Symptom 
Questionnaire (BWSQ) total score (Visit 9 and Visit 10), the 
occurrence of relevant AEs and marked ECG abnormalities. 
• Rebound insomnia will be assessed based on objective sleep 
parameters (WASO, LPS, and TST) at Visit 9 as compared to 
Visit 3. It will also be assessed using subjective sleep parameters 
(subjective WASO [sWASO], subjective Latency to Sleep Onset 
[sLSO], and sTST) from run-out period as compared to baseline. 
• Next-day residual effects will be assessed based on changes from 
baseline (Visit 3) to Month 1 and Month 3 in: 
– 
Coding sub-test©  
– 
Sheehan Disability Scale© (SDS©) 
– 
Scores on the visual analog scale (VAS; mm) 
• Serious adverse events up to 30 days after DB study treatment 
discontinuation or until enrollment into the extension study. 
• Treatment-emergent AEs (TEAEs) up to 30 days after DB study 
treatment discontinuation or until enrollment into the extension 
study. 
• AEs leading to premature discontinuation of the DB study 
treatment. 
• AEs of special interest (AESIs) after adjudication by an 
Independent Safety Board (ISB): 

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– narcolepsy-like symptoms (i.e., excessive daytime sleepiness 
[EDS], cataplexy and complex sleep behavior events 
including hallucinations/sleep paralysis)  
– suicide/self-injury. 
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 
(Visit 8) in vital signs (mean of the 2 PSG nights in systolic and 
diastolic blood pressure [BP] and pulse rate). 
• Change from baseline (Visit 1) to Month 3 (Visit 8) in body 
weight. 
• Marked ECG abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 3 (Visit 8) and the end 
of run-out (Visit 10) in ECG variables. 
• Marked laboratory abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 
(Visit 8) in laboratory variables. 
• Occurrence of suicidal ideation and/or behavior on DB study 
treatment based on C-SSRS©. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
Analysis of the primary and secondary efficacy endpoints 
The Type I error rate will be controlled for the testing of multiple null 
hypotheses associated with the two primary endpoints (LPS and 
WASO) and two other endpoints (sTST and IDSIQ) assessed at 1 and 
3 months of treatment, and the two dose levels included in this study, 
i.e., 10 mg and 25 mg. 
The eight statistical null hypotheses associated with the primary 
efficacy endpoints are: 
Sleep maintenance: 
• H1WASO: Higher Dose – Placebo = 0 for WASO at Month 1 
• H2WASO: Higher Dose – Placebo = 0 for WASO at Month 3 
• H3WASO: Lower Dose – Placebo = 0 for WASO at Month 1 
• H4WASO: Lower Dose – Placebo = 0 for WASO at Month 3 
Sleep onset: 
• H1LPS: Higher Dose – Placebo = 0 for LPS at Month 1 

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• H2LPS: Higher Dose – Placebo = 0 for LPS at Month 3 
• H3LPS: Lower Dose – Placebo = 0 for LPS at Month 1 
• H4LPS: Lower Dose – Placebo = 0 for LPS at Month 3 
The eight statistical null hypotheses associated with the secondary 
efficacy endpoints are: 
Sleep quantity: 
• H1sTST: Higher Dose – Placebo = 0 for sTST at Month 1 
• H2sTST: Higher Dose – Placebo = 0 for sTST at Month 3 
• H3sTST: Lower Dose – Placebo = 0 for sTST at Month 1 
• H4sTST: Lower Dose – Placebo = 0 for sTST at Month 3 
Next-day performance: 
• H1IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 1 
• H2IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 3 
• H3IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 1 
• H4IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 3 
where ‘Higher Dose’, ‘Lower Dose’, and ‘Placebo’ represent the 
mean change from baseline for the given endpoint (WASO, LPS, 
sTST or IDSIQ sleepiness domain score) and time point (Month 1 or 
Month 3) for the 25 mg, 10 mg, and placebo treatment group, 
respectively. 
Each null hypothesis will be tested against the alternative hypothesis: 
that ACT-541468 improves WASO/LPS/sTST/ IDSIQ sleepiness 
domain score at the given dose (10 or 25 mg) and time point (Month 
1 or Month 3) compared to placebo. 
The order of testing and the alpha level applied to each null 
hypothesis will be based on the Bonferroni-based gatekeeping 
procedure [Bretz 2009], which will control the study-wise Type I 
error at a two-sided 5% significance level. To account for the 
concurrent evaluation (multiple comparison) of two distinct endpoint 
categories (i.e., sleep maintenance and sleep onset), a Bonferroni 

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correction is applied. Both endpoint categories will be tested at half 
of the two-sided 5% significance level. This supports the sponsor’s 
intention to make a superiority claim versus placebo for efficacy in 
either sleep maintenance and/or sleep onset. The remaining 
hypotheses will be tested following the gatekeeping strategy moving 
from Month 1 to Month 3 for higher dose ACT-541468 vs placebo 
and then from Month 1 to Month 3 for lower dose ACT-541468 vs 
placebo. The pre-specified proportion of alpha that will be distributed 
once a given null hypothesis (node) is rejected is shown on the arrow 
in the directed graph. If a certain null hypothesis cannot be rejected, 
the alpha level used for that test is absorbed at that node and not 
distributed further. 
The main analysis will be performed using the FAS. 
A longitudinal data analysis method (i.e., linear mixed effects model) 
will be used for the analysis of change from baseline in WASO, LPS, 
sTST, and IDSIQ scores, separately. All available data, regardless of 
occurrence 
of 
intercurrent 
events 
(e.g., 
study 
treatment 
discontinuation, the use of prohibited medication), will be included 
in the model. 
Analysis of the safety endpoints 
Adverse events: The number (%) of subjects experiencing a TEAE 
(including serious adverse events, AESIs after adjudication by the 
ISB, and AEs leading to premature discontinuation of the DB study 
treatment) will be summarized by System Organ Class and/or 
Preferred Term, and maximum intensity. 
Laboratory data: Observed values and changes from baseline to 
Month 1 and Month 3 in both hematology and blood chemistry 
laboratory parameters will be summarized. The number (%) of 
subjects having a marked laboratory abnormality during DB study 
treatment will be tabulated. 
Vital signs and weight: Observed values and changes from baseline 
to Month 1 and Month 3 in vital signs (mean of the two PSG nights 
in systolic and diastolic BP and pulse rate) and observed values and 
changes from baseline to Month 3 in body weight will be 
summarized.  

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Electrocardiograms: Observed values and changes from baseline to 
Month 3 for each ECG parameter (QTcB, QTcF, heart rate, PR, QRS) 
will be summarized. The number (%) of subjects with a marked ECG 
abnormality during DB study treatment will be tabulated. 
Withdrawal symptoms: The BWSQ total score will be summarized 
using descriptive statistics for the observed values and changes from 
the last assessment on DB treatment (Visit 8, 2nd morning) to the 
beginning and the end of the treatment withdrawal period (in the 
morning at Visit 9 and at Visit 10, respectively). The number (%) of 
subjects having, separately, an AE and a marked ECG abnormality 
during the treatment withdrawal period will be tabulated. 
Insomnia rebound effect: The changes from baseline to the treatment 
withdrawal period (Visit 9, run-out) in objective sleep parameters 
(WASO, LPS, and TST) will be summarized using descriptive 
statistics. The changes from baseline (mean value based on the 
screening sleep diary entries performed at home in the 7 days 
immediately preceding the first PSG at Visit 3) to the treatment 
withdrawal period (after PSG night at Visit 9) in subjective sleep 
parameters (sWASO, sLSO, and sTST) will be summarized using 
descriptive statistics. 
Next-day residual effects: Observed values and changes from 
baseline to Month 1 and Month 3 in Coding sub-test©, SDS©, and 
VAS scores (mm) assessing morning sleepiness, daytime alertness, 
and daytime ability to function, will be summarized. 
C-SSRS©: Number (%) of subjects with suicidal ideation, suicidal 
behavior, and/or self-injurious behavior without suicidal intent based 
on the C-SSRS© during DB treatment will be tabulated. Shifts from 
baseline showing any changes in suicidal ideation and suicidal 
behavior during DB treatment will also be provided. 
STUDY 
COMMITTEES 
An Independent Data Monitoring Committee (IDMC) will have 
overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study, and making 
appropriate recommendations based on the reported data. This will 
ensure that the study is being conducted to the highest scientific and 
ethical standards. The IDMC will be fully operational prior to the 
enrollment of the first subject into the study. The composition and 
operation of the IDMC is described in the IDMC charter. 

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An ISB will review and adjudicate in a blinded manner AESIs, i.e., 
narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep 
behavior events including hallucinations / sleep paralysis), or 
suicide/self-injury. The composition and operation of the ISB is 
described in the ISB charter. 
SUB-STUDY 
A sub-study will be performed to collect patient preferences data. 
The Discrete Choice Experiment methodology aims to collect 
preferences for selected treatment outcomes in a subgroup of subjects 
in the USA and Germany, using the questionnaire for the PAtient 
Preferences StUdy in InSomnia (PAUSe) developed by Idorsia. The 
PAUSe sub-study aims to enroll at least 360 subjects within the 
Phase 3 program (i.e., ID-078A301 and ID-078A302). 
STUDY 
EXTENSION 
Subjects who completed the study until EOT will have the possibility 
to participate in the extension study ID-078A303. The 9-month 
ID-078A303 study will be available at each site and subjects will be 
treated for up to 12 months overall (i.e., including the treatment 
period of the confirmatory trial). 
 

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PROTOCOL 
1 
BACKGROUND 
1.1 Insomnia disorder 
1.1.1 Definition 
The definition of insomnia disorder used in the protocol is the one described in the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
[APA 2013]: 
“Insomnia disorder is a predominant complaint of dissatisfaction with sleep quantity or 
quality, associated with difficulty initiating or maintaining sleep, or early morning 
awakening. Furthermore, the sleep disturbance is associated with significant social or 
functional distress or impairment. Sleep difficulty occurs at least 3 nights per week and is 
present for at least 3 months, and occurs despite adequate opportunity for sleep. The 
insomnia (a) is not better explained by, and does not occur exclusively during the course 
of another sleep-wake disorder, (b) it is not attributable to the physiological effect of a 
substance, and (c) is not explained by co-existing mental disorders or medical conditions.” 
1.1.2 Epidemiology 
Insomnia is a common problem. Population-based epidemiological studies suggest that 
30% or more of the general population complain of sleep disruption and approximately 
10% of the general population have complaints of sleep disruption with associated 
symptoms of distress or daytime functional impairment consistent with the diagnosis of 
insomnia disorder [NIH 2005, Roth 2007]. Insomnia symptoms (difficulties initiating 
sleep, early-morning awakenings, and dissatisfaction with sleep) increase with age. Factors 
associated with aging and not with age per se, such as depressed mood, respiratory 
symptoms, poor perceived health and physical disability are associated with the decrease 
in ability to sleep [Ohayon 2001].  
Insomnia disorder results in difficulty falling asleep or difficulty maintaining sleep, 
characterized by multiple or long awakenings during the sleep period, or early-morning 
awakenings. Difficulty maintaining sleep is the most common problem among patients 
with insomnia, occurring in approximately two-thirds of them [Neubauer 2014]. Studies 
have shown that the most common symptoms are combined difficulties to both fall and to 
stay asleep [Hohagen 1994]. Elderly patients are more likely to suffer from chronic 
insomnia characterized by difficulty maintaining sleep, rather than difficulty initiating 
sleep [McCall 2004]. 
Insomnia is associated with impairment in cognitive functioning, daytime fatigue, 
increased accident risk, and difficulties in interpersonal relationships [Balter 1991, 
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increases utilization of medical care [Simon 1997, Léger 2002, McCall 2004], has been 
correlated with chronic health issues and perceptions of poor health [Balter 1991, 
Ancoli-Israel 1999, Rosenthal 1993, Zammit 1999, Fortier-Brochu 2014], and in elderly 
subjects may also precipitate falls [McCall 2004]. Numerous studies have shown an 
association between insomnia and psychiatric disorders, specifically depression, anxiety, 
and other significant mental health conditions [Ford 1989, Benca 2004].  
1.1.3 Treatment 
The current standards of care encompass non-pharmacological therapies and 
pharmacotherapy [Schutte-Rodin 2008]. 
Non-pharmacological (psychological and behavioral) standard-of-care therapies for 
insomnia include a variety of treatment methods, such as cognitive behavioral therapy 
(CBT), stimulus control and relaxation training [Schutte-Rodin 2008]. Sleep hygiene 
therapy is often added to these treatment modalities.  
Prescription sleep medications (hypnotics) indicated for the treatment of insomnia include 
benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, melatonin 
agonists, the orexin receptor antagonist suvorexant, and low-dose doxepin.  
Benzodiazepines are a class of medications that bind to multiple gamma-aminobutyric acid 
(GABA) type A receptor subtypes [Lieberman 2007]. Drugs in this class, which includes 
flurazepam, temazepam, trialozam, estazolam, and quazepam, were previously commonly 
prescribed for insomnia. While the efficacy of these medications has been well 
documented, their usefulness is limited by adverse effects such as daytime sedation (e.g., 
morning or next-day hangover), cognitive impairment (including anterograde amnesia), 
motor dyscoordination, abuse liability, and dependence [Holbrook 2000, Buscemi 2007]. 
Benzodiazepines also alter sleep architecture: they prolong stage 2 sleep and may slightly 
reduce 
the 
relative 
amount 
of 
rapid 
eye 
movement 
(REM) 
sleep 
[Treat Guidel Med Lett 2009]. Their use has been associated with tolerance development 
and rebound insomnia upon withdrawal of medication [Kales 1978, Petursson 1981].  
Non-benzodiazepine benzodiazepine receptor agonists have a more targeted action on one 
or more GABA type A receptor subtypes, but the availability of these treatments highly 
varies across regions. Zolpidem, zolpidem controlled-release (CR) and zaleplon show 
affinity for the alpha-1 receptor subtype, while eszopiclone shows affinity for the alpha-2 
and -3 receptor subtypes [Nutt 2006]. All of these drugs reduce latency to sleep onset, but 
zolpidem CR and eszopiclone have also been shown to reduce Wake After Sleep Onset 
(WASO), 
reflecting 
an 
improvement 
in 
sleep 
maintenance 
[Ambien® USPI, 
Lunesta® USPI]. Although they have less impact on sleep architecture, possibly by virtue 
of their receptor selectivity, the drugs in this group have similar adverse effects as the 
benzodiazepines. In 2007 the US Food and Drug Administration (FDA) requested that all 

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manufacturers of hypnotic drug products strengthen their product labeling to include 
stronger language related to potential risks. These risks include severe allergic reactions 
(i.e., anaphylaxis) and complex sleep-related behaviors, which may include sleep-driving 
[FDA 2007].  
Newer hypnotics that do not act at the GABA receptor have been developed. The melatonin 
receptor agonist ramelteon is approved for insomnia in the US and in Japan, but not in 
Europe. Ramelteon reduces sleep latency and increases Total Sleep Time (TST), but has 
no effect on WASO [Kuriyama 2014], making it an inappropriate treatment for people with 
sleep maintenance problems [Simpson 2008]. Ramelteon is devoid of next-day residual 
effects, withdrawal or rebound insomnia and does not appear to be associated with abuse 
liability.  
Suvorexant is an oral dual orexin receptor antagonist (DORA) that was approved in the 
USA, Japan and Australia for the treatment of insomnia characterized by difficulties with 
sleep onset and/or sleep maintenance. Suvorexant is contraindicated in patients with 
narcolepsy. Next-day effects, including impaired driving performance, have been reported 
at 20 mg [Belsomra® USPI]. Next-day residual effects might be related to the long half-
life (t½ = 12 hours) of suvorexant [Citrome 2014]. Rebound insomnia or withdrawal signs 
upon drug discontinuation were not observed in clinical trials [Herring 2016]. 
Use of sleep medications increases with age and is highest in the elderly [Ohayon 2002, 
Ohayon 2010]. Despite the increased risk of falls, non-benzodiazepine benzodiazepine 
receptor agonists and generic antidepressants are among the most prescribed classes of 
medications for elderly patients in the US. 
1.1.4 Unmet medical need 
CBT is generally the recommended first-line treatment for insomnia disorder 
[Schutte-Rodin 2008]. However, this may not be the ideal course of 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 is highly challenging 
[Pigeon 2007, Schutte-Rodin 2008].  
Insomnia disorder is a chronic disease and currently available treatments are limited to 
short-term use with the exception of eszopiclone and suvorexant (in the US). Caution and 
dose reduction are also often advised in the elderly. 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 
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[McCall 2004] leading to hip and femur fractures, increased disability, and use of 
healthcare resources.  
Overall, there is a need for a long-term pharmacological treatment for insomnia disorder 
that addresses the most prominent and pressing symptoms of insomnia without negatively 
impacting next-day functioning.  
1.2 Study treatment: ACT-541468 
1.2.1 The orexin system 
The orexin system is involved in the regulation of sleep and arousal by the central nervous 
system (CNS) and is currently being targeted in the development of new therapies for sleep 
disorders. 
The neuropeptides orexin-A and orexin-B are synthesized in the lateral hypothalamic areas 
[de Lecea 1998] and activate the orexin-1 and orexin-2 receptors [Kilduff 2000]. Nerve 
fibers from orexin neurons make projections to the basal forebrain, corticolimbic 
structures, and brainstem, particularly to those regions related to waking and regulation of 
sleep [Hagan 1999, Sakurai 2007]. Infusing exogenous orexins into cerebral ventricles in 
rats leads to enhanced behavioral activity, arousal, delayed onset of sleep, and maintenance 
of cortical activation [Hagan 1999, Samson 2010]. Orexin-producing neurons are active 
during wakefulness and fall quiet during sleep [Sakurai 2007]. Orexin-A levels in the 
cerebrospinal fluid of several species fluctuate according to circadian rhythms, being 
highest during active wake periods [Zeitzer 2003, Desarnaud 2004]. 
The absence of orexins is implicated in the genesis of narcolepsy, due to findings of low 
cerebral spinal fluid orexin levels in most patients with unequivocal narcolepsy with 
cataplexy [Mignot 2002] and near-complete destruction of orexin neurons in post-mortem 
brains of patients with narcolepsy-cataplexy [Thannickal 2000], coupled with the 
observation of behavioral phenotypes consistent with narcolepsy in multiple animal models 
of orexin deficiency or dysfunction [Lin 1999].  

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1.3 Purpose and rationale of the study 
1.3.1 Purpose of the study 
The main purpose of this Phase 3 study is to confirm that at least one dose of ACT-541468 
is well tolerated and efficacious in promoting sleep onset and/or sleep maintenance in 
subjects with insomnia disorder.  
1.3.2 Rationale for the study 
The orexin system is involved in the regulation of sleep and arousal. In two Phase 2 studies 
in subjects with insomnia disorder, ACT-541468 has shown objective and subjective 
improvements in sleep onset and sleep maintenance. 
The dose levels of 10 and 25 mg of ACT-541468 planned for this study were both 
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2.1 Primary objective 
To evaluate the efficacy of 10 mg and 25 mg ACT-541468 on objective sleep parameters 
in subjects with insomnia disorder. 
2.2 Secondary objectives 
To evaluate the efficacy of 10 mg and 25 mg ACT-541468 on subjective sleep parameters 
and next-day functioning in subjects with insomnia disorder. 
2.3 Safety objectives 
To assess the safety and tolerability of ACT-541468 in subjects with insomnia disorder 
during treatment and upon treatment discontinuation. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a 3-month, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, Phase 3 study to assess the efficacy and safety of two doses (10 mg and 
25 mg) of ACT-541468 in subjects with insomnia disorder.  
Approximately 900 subjects will be randomized to either 10 mg or 25 mg of ACT-541468, 
or to placebo, in a 1:1:1 ratio. Treatment allocation will be stratified by age into 2 
categories: < 65 and ≥ 65 years. Approximately 40% of subjects will be elderly subjects 
(≥ 65 years old), of which approximately 5% will be above 75 years old. These percentages 
will be monitored by the sponsor through the Interactive Response Technology (IRT) 
system. 
The study will be conducted at approximately 75 sites in 10 countries. 
In addition, a sub-study to collect data on the subject’s preferences will be performed, 
aiming to enroll at least 360 subjects both from the USA and Germany who are part of the 
approximately 1800 subjects enrolled in both ID-078A301 and ID-078A302 studies.  
3.1.1 Study periods 
The study comprises the following 3 phases: the screening phase, the treatment phase, and 
the safety follow-up phase [see Figure 1]. 
3.1.1.1 Screening phase 
The screening phase starts with the signature of the informed consent form (ICF) at Visit 1 
and ends at Randomization at Visit 4, provided the subject fulfills all eligibility criteria. It 
includes the Screening period and the Run-in period. The screening phase lasts 20 to 
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The Screening period starts with Visit 1 and ends with Visit 2. During the screening 
period, the investigator verifies the eligibility criteria and eligible subjects perform a 
one-night PSG assessment. The Screening period lasts 7 to 18 days to allow time to perform 
all required procedures at Visit 1, the PSG assessment and collect the minimum number of 
eDiary entries (i.e., 7 days) between Visit 1 and Visit 2. 
The Run-in period starts with Visit 2 and ends at Randomization (i.e., Visit 4). At Visit 2 
eligible subjects are allocated a single-blinded placebo treatment that is taken daily. During 
the Run-in period subjects come to the site for Visit 3, which consists of 2 PSG nights and 
is performed when the subject has completed the eDiary for at least 7 days and eligibility 
is confirmed. The Run-in period lasts 13 to 24 days, to allow collection of the minimum 
number of eDiary entries (i.e., 7 days), perform 2 PSG nights at Visit 3, and receive the 
eligibility confirmation from the PSG central reader.  
3.1.1.2 Treatment phase 
The DB treatment phase lasts 3 months. It starts at Randomization (Visit 4). DB study 
treatment is taken daily. A safety telephone call is performed at Visit 5 to collect 
information about AEs and concomitant medications. Sleep parameters of each subject are 
objectively assessed with 2 consecutive PSG nights at Visit 6 and Visit 8. A safety visit 
without PSG night will be performed at Visit 7. An eDiary is completed every day during 
the treatment phase. 
End-of-Double-Blind-Treatment (EODBT) is reached in the second morning of Visit 8. 
3.1.1.3 Safety follow-up phase 
The safety follow-up phase starts after EODBT. It consists of a single-blind placebo Run-
out period of 7 days and a Safety follow-up period.  
The Run-out period starts in the evening of Visit 9. Visit 9 consists of one PSG night on 
single-blind placebo treatment. Visit 9 is followed by 6 days at home with single-blind 
placebo treatment. The eDiary is completed every day during the Run-out period. The end 
of the Run-out period (End-of-Treatment [EOT]) is reached after all visit assessments have 
been performed at Visit 10. 
The Safety follow-up period starts after EOT and ends 30 days after last dose of DB study 
treatment intake for subjects that are not enrolled in the ID-078A303 extension study. 
Subjects who complete DB study treatment and the Run-out period are eligible to enter the 
ID-078A303 extension study (if approved by the national health authorities and local 
Independent Ethics Committees / Institutional Review Boards [IECs/IRBs]). For these 
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End-of-Study (EOS) for an individual subject is defined as the date of the 30-day 
follow-up telephone call (Visit 11, Day 115) or the date of enrollment into the ID-078A303 
extension study. If a subject is prematurely discontinued from study treatment, EOS is 
performed as planned on Day 115. If a subject withdraws consent and does not wish to 
participate in the study any longer, EOS is the date of consent withdrawal for this subject. 
If a subject is declared lost to follow-up, EOS is the date of last successful contact for this 
subject.  
The visit schedule and protocol-mandated procedures are performed according to the table 
of assessments [Table 1] and are described in Section 6.7. 
The overall study design is depicted in Figure 1. 
Figure 1 
Study design  
 
V = Visit; ▬ = polysomnography nights; EODBT = End-of-Double-Blind-Treatment; EOS = End-of-Study; EOT = 
End-of-Treatment. 
 
3.1.2 Study duration 
The study starts with the signature of the ICF at Visit 1 for the first subject enrolled and 
ends with the EOS of the last subject. Anticipated total study time is approximately 
18 months. 
Each subject will be treated for approximately 3 months. For an individual subject who 
does not decide to continue in the extension study, the study is completed with the EOS 
visit (safety follow-up telephone call at the end of follow-up) and the maximum duration 
of participation in the study of this subject is expected to be approximately 5 months.  
Subjects who completed the study until EOT are eligible to participate in the extension 
study ID-078A303. After the completion of the Run-out period, the 9-month ID-078A303 
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approval, and subjects will be treated for up to 12 months overall (i.e., including the 
treatment period of the confirmatory trial). For the subjects who decide to participate in the 
extension study, ID-078A302 is completed with the enrollment into ID-078A303. 
3.1.3 Sub-study – Patient Preferences 
A sub-study will be performed to collect patient preferences data.  
The Discrete Choice Experiment (DCE) methodology aims to collect preferences for 
selected treatment outcomes in a subgroup of subjects in the USA and Germany, using the 
questionnaire for the PAtient Preferences StUdy in InSomnia (PAUSe) developed by 
Idorsia. The PAUSe sub-study aims to enroll at least 360 subjects within the Phase 3 
program (i.e., ID-078A301 and ID-078A302). 
The questionnaire will present subjects with the following treatment outcomes: 
• Time to fall asleep 
• Total time asleep 
• Next day impairment 
• Dizziness/grogginess during the daytime 
• Abnormal thinking and behavioral changes 
• Falls in the night 
• Dependence 
The design of the DCE questionnaire was carried out in steps 1−3 below: 
1. Qualitative pilot (n = 24), where a mobile ethnography platform was used over a period 
of 10 days to collect patient experiences with insomnia in interactive sessions. This was 
followed by face-to-face interviews with patients to further discuss themes that 
emerged during the 10 days of interactive sessions (completed). 
2. Qualitative pilot (n = 24), where face-to-face interviews were conducted to ensure that 
the DCE outcomes and levels are associated with patients’ experiences with (and 
expectations for) insomnia, and that the proposed survey accurately describes these 
outcomes in an easily understandable manner (completed). 
3. Quantitative pilot (n = 200), where an online survey was conducted to elicit preferences 
from patients, using the PAUSe questionnaire. The data from the quantitative pilot will 
be used to update the priors of the Bayesian model and finalize the design of the 
sub-study. 
This sub-study has the following objectives: 1) To describe the stated preferences of 
insomnia disorder subjects within a clinical trial by applying the DCE technique; 2) To 
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the relationship between demographic, disease characteristics, previous medical history 
and elicited preferences among insomnia subjects. 
In addition, the results of the sub-study may contribute to the construction of a 
patient-oriented benefit-risk assessment model. 
3.2 Study design rationale 
3.2.1 Core study 
This is a multi-center, double-blind, randomized, placebo-controlled, parallel-group study. 
In accordance with the European Medicines Agency (EMA) guideline on medicinal 
products for the treatment of insomnia [EMA 2011] and the FDA guideline for the clinical 
evaluation of hypnotic drugs [FDA 1977], the study includes a placebo as a comparator to 
support the evaluation of the efficacy of each dose of ACT-541468. Moreover, it is an 
acceptable approach for a non-life-threatening condition. 
A parallel-group design is a well-established study design to assess efficacy and safety in 
medical conditions, recommended by health authorities [EMA 2011, FDA 1977]. 
The subjects will receive either a 10 or 25 mg daily dose of ACT-541468, or placebo DB 
study treatment. The doses to be tested for this study are based on a comprehensive set of 
data from Phase 1 and Phase 2 studies. A higher dose (50 mg) will be tested along with the 
25 mg dose in another separate Phase 3 study (i.e., ID-078A301). All three doses selected 
for this program have a favorable benefit-risk profile based on data collected so far during 
Phase 1 and Phase 2 studies in adults and elderly subjects. This will allow appropriate 
investigation of the sustained effect of ACT-541468 on sleep parameters and next-day 
performance as well as an optimized characterization of the safety profile of ACT-541468 
over a 3-month period, allowing full characterization of the benefit/risk ratio.  
The goal of the placebo run-in period is to increase the proportion of subjects in the clinical 
trial who will benefit due to taking active treatment, partly by reducing the placebo effect 
that will occur during the DB phase of the study and also aims to ensure sufficient stability 
of the subjects’ insomnia disorder and may reduce the impact of regression toward the 
mean.  
A run-out of 7 days is appropriate to assess withdrawal symptoms as it covers more than 
5 half-lives of ACT-541468. The duration of the run-out period is also compliant with the 
FDA guidance [FDA 1977], stating that a minimum of 3 nights of placebo withdrawal is 
necessary to assess withdrawal effects. To assess withdrawal symptoms, AEs and ECG 
abnormalities will be collected during the 7-day run-out period and subjects will complete 
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One PSG night is planned after the first day of treatment discontinuation and the sleep diary 
completed in the 3 days following treatment discontinuation will allow assessment of 
rebound insomnia on objective and subjective parameters, respectively. Thus, this 7-day 
run-out period allows to capture long-term withdrawal effects, as well as shorter-term 
potential rebound symptoms.  
3.2.2 Patient preferences sub-study 
Measuring patient preferences as an input to healthcare decisions has its foundations in two 
fields related to behavioral decision making, namely ‘decision theory’ and ‘decision 
analysis’. Research by Pauker et al. demonstrated that it was feasible to use decision 
analysis to understand individual treatment choices which were complicated by multiple 
uncertainties and personal values [Pauker 1981]. Increased understanding of individual 
values and preferences is critical for a number of reasons. Firstly, it enables the 
development of patient-specific recommendations and reliable decision aids, which are 
helpful both for patients and for doctors in advising patients and their carers or families. 
Secondly, understanding of patients’ preferences is the basis for shared decision-making, 
which in turn encourages patient compliance and health outcomes [Bowling 2001]. Lastly, 
understanding of preferences for health outcomes allows the design of transparent health 
policies, and informs resource allocation in healthcare, as these preferences can inform the 
judgment of cost-effectiveness of different treatments, for different patients [Coyle 2001]. 
DCEs are a form of stated preference method used by economists to explore how people 
make trade-offs between an intervention’s outcomes. They involve participants responding 
to a number of survey questions, in which they choose between alternative interventions, 
each described by a level of performance against the outcomes that influence choices. DCE 
has its microeconomic foundation in random utility theory (RUT), assuming that products 
can be valued in terms of their constituent outcomes and that respondents act in a utility 
maximizing manner, making choices contingent upon the outcome levels described in the 
exercise [Clark 2014, Tervonen 2017]. Consequently, the choice data can be analyzed 
using econometric methods compatible with RUT, which estimate how participants’ utility 
is influenced by changes in intervention outcomes. DCEs are frequently used in healthcare 
to address a wide range of health policy-related concerns, including identifying the 
trade-offs patients make when choosing between treatments, which can in turn be used to 
determine the probability that patients would prefer one treatment or another 
[Bridges 2011, Clark 2014]. 
3.3 Study committees 
An IDMC has overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study and making appropriate 
recommendations based on the reported data, thus ensuring that the study is being 
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operational prior to enrollment of the first subject into the study. The composition and 
operation of the IDMC is described in the IDMC charter. 
An ISB will review and adjudicate in a blinded manner AESIs, i.e., narcolepsy-like 
symptoms 
(EDS, 
cataplexy 
and 
complex 
sleep 
behavior 
events 
including 
hallucinations/sleep paralysis), or suicide/self-injury. The composition and operation of the 
ISB is described in the ISB charter.  
4 
SUBJECT POPULATION 
4.1 Subject population description 
This study will enroll adult and elderly (≥ 18 years), male and female subjects with 
insomnia disorder according to Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5). For more details on inclusion and exclusion criteria, see 
Sections 4.3 and 4.4.  
Insufficient sleep quantity is defined in this study by self-reported history of ≥ 30 min to 
fall asleep, of wake time during sleep ≥ 30 min and of subjective TST (sTST) ≤ 6.5 h during 
the night. Those 3 self-reported parameters must be present on at least 3 nights per week 
for at least 3 months prior to the screening visit and on the sleep diary sleep data collected 
during the period between Visit 2 and Visit 3. They will also be validated by objective 
PSG-based criteria collected from the Visit 3 PSG nights spent in a sleep laboratory during 
the run-in. Poor Sleep Quality (SQ) is defined as an Insomnia Severity Index© (ISI©) score 
≥ 15 at screening.  
4.2 Rationale for the selection of the study population 
In this study, adult (18–64 years) and elderly (≥ 65 years) subjects with insomnia as defined 
by DSM-5 will be included [see definition in Section 1.1.1], unless subject’s insomnia is 
associated with major comorbidities, especially comorbid neurological, affective or 
psychiatric disorders (e.g., severe or uncontrolled depression, anxiety or dementia) that 
may interfere with the efficacy and safety in the trial. 
Elderly people exhibit a different sleep pattern to younger adults [Ohayon 2004] and the 
sensitivity of elderly and younger adults to the PD properties of a compound may therefore 
differ in the long term. Thus, randomization will be stratified by age in both pivotal studies 
to ensure that tested doses are given to a proportion of elderly subjects (i.e., 40% with age 
≥ 65 years) and to ensure balance of the treatment groups within strata is achieved. 
Concomitant pharmacological treatments for insomnia or concomitant CNS-related 
medications are not allowed in the study. This approach will favor optimizing the 
evaluation of the safety and efficacy profile of ACT-541468 by avoiding any potential 
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4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject.  
Criteria assessed at Visit 1 
1. Signed informed consent prior to any study-mandated procedure. 
2. Male or female aged ≥ 18 years. 
3. Insomnia disorder according to DSM-5 criteria as follows:  
3.1 The predominant complaint is dissatisfaction with sleep quantity or quality, 
associated with one (or more) of the following symptoms: 
• Difficulty initiating sleep. 
• Difficulty maintaining sleep, characterized by frequent awakenings or 
problems returning to sleep after awakenings. 
• Early-morning awakening with inability to return to sleep. 
3.2 The sleep disturbance causes clinically significant distress or impairment in 
social, occupational, educational, academic, behavioral, or other important areas 
of functioning. 
3.3 The sleep difficulty occurs despite adequate opportunity for sleep. 
3.4 The insomnia is not better explained by and does not occur exclusively during 
the course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related 
sleep disorder, a circadian rhythm sleep-wake disorder, a parasomnia). 
3.5 The insomnia is not attributable to the physiological effects of a substance (e.g., 
a drug of abuse, a medication). 
3.6 Coexisting mental disorders and medical conditions do not adequately explain 
the predominant complaint of insomnia. 
3.7 Self-reported history of all the following on at least 3 nights per week and for at 
least 3 months prior to Visit 1: 
3.7.1 ≥ 30 min to fall asleep, and 
3.7.2 Wake time during sleep ≥ 30 min, and 
3.7.3 sTST ≤ 6.5 h 
4. ISI© score ≥ 15. 
5. 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. 
Criteria assessed at Visit 3 
6. Meeting all the following sleep parameters on at least 3 nights out of 7 nights on the 
sleep diary completed at home between Visit 2 and Visit 3: 
6.1 ≥ 30 min to fall asleep, and 
6.2 Wake time during sleep ≥ 30 min, and 

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6.3 sTST of ≤ 6.5 h 
7. Usual bedtime between 21:30 and 00:30, as reported on sleep diary completed between 
Visit 2 and Visit 3. 
8. Regular time in bed between 6 and 9 h, as reported on sleep diary completed between 
Visit 2 and Visit 3. 
9. Meeting all the following sleep parameters on the 2 PSG nights at Visit 3: 
9.1 Mean LPS ≥ 20 min (with none of the two nights < 15 min), and 
9.2 Mean WASO ≥ 30 min (with none of the two nights < 20 min), and 
9.3 Mean TST < 420 min 
Criterion assessed at Visit 1, Visit 2, and Visit 4 
10. For women of childbearing potential, the following is required: 
• Negative serum pregnancy test (Visit 1). 
• Negative urine pregnancy test (Visit 2, Visit 4). 
• Agreement to use the contraception scheme as required by the protocol from 
Screening up to at least 30 days after last study treatment intake. 
4.4 Exclusion criteria 
Criteria assessed at Visit 1 
1. Body mass index (BMI) below 18.5 or above 40.0 kg/m2. 
2. Any lifetime history of sleep-related breathing disorder, including chronic obstructive 
pulmonary disease and sleep apnea. 
3. Cognitive behavioral therapy (CBT) for any indication is allowed only if the CBT 
started at least 1 month prior to Visit 3 and the subject agrees to continue this CBT 
throughout the study. 
4. Self-reported usual daytime napping ≥ 1 hour per day, and ≥ 3 days per week. 
5. Acute or unstable psychiatric conditions (including but not restricted to anxiety 
disorder, major depression, bipolar disorder, schizophrenia, obsessive compulsive 
disorder or depression) that are diagnosed by the Mini International Neuropsychiatric 
Interview© (MINI©) or that require pharmacological treatment for these disorders. 
N.B.: subjects with a history of major depressive disorder currently without any 
symptoms and not requiring treatment are eligible. 
6. Mini Mental State Examination© (MMSE©) score < 25 in subjects ≥ 50 years. 
7. Shift work within 2 weeks prior to the screening visit, or planned shift work during the 
study. 
8. Travel across ≥ 3 time zones within 2 weeks prior to the screening visit, or planned 
travel across ≥ 3 time zones during study. 

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9. Unstable medical condition, significant medical disorder or acute illness, ECG, 
hematology or biochemistry test results within 1 month prior to the screening visit, 
which, in the opinion of the investigator, could affect the subject’s safety or interfere 
with the study assessments. 
10. Treatment with CNS-active drugs prohibited by this protocol for 5 half-lives of the 
respective drug (or 2 weeks, whichever is longer) prior to Visit 1, including 
over-the-counter medication and herbal medicines. 
11. Diagnosis of alcohol or substance use disorder within 2 years prior to the screening 
visit or inability to refrain from drinking alcohol for at least 3 consecutive days. 
12. Heavy tobacco use (at least one pack of cigarettes a day or inability to refrain from 
smoking during the night).  
13. Caffeine consumption ≥ 600 mg per day or any caffeine consumption after 4 pm. 
14. Treatment with another investigational drug within 3 months prior to Visit 1, previous 
treatment with ACT-541468 or previous randomization in any trial involving 
ACT-541468. 
15. Known hypersensitivity or contraindication to drugs of the same class as the study 
treatment or to any excipients of the study drug formulation. 
16. Not able or willing to stop treatment with moderate or strong CYP3A4 inhibitors, or 
treatment with moderate or strong CYP3A4 inducers, within at least 1 week prior to 
Visit 2. 
17. Not able or willing to stop consumption of grapefruit, Seville (bitter) oranges or juices 
from those fruits within at least 1 week prior to Visit 2.  
Criteria assessed at PSG visit between Visit 1 and Visit 2 
18. Periodic limb movement disorder with arousal index (PLMAI) ≥ 15/h (assessed on the 
1st PSG night), restless legs syndrome, circadian rhythm disorder, REM behavior 
disorder, or narcolepsy.  
19. Apnea/hypopnea index (AHI) ≥ 15/h according to American Academy of Sleep 
Medicine criteria or event associated with blood oxygen saturation level by pulse 
oximetry (SpO2) < 80%, as assessed on the 1st PSG night. 
Criteria assessed at Visit 1 and Visit 3 
20. AST and/or ALT > 2 × ULN and/or direct bilirubin > 1.5 × ULN. 
21. Severe renal impairment: known or defined as estimated creatinine clearance 
< 30 mL/min/1.73m2, according to the 4-variable Modification of Diet in Renal 
Disease formula. 
22. Hematology or biochemistry test results deviating from the normal range to a clinically 
relevant extent as per judgment of the investigator. 

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23. Any of the following conditions related to ECG abnormalities: 
• A prolonged QT interval corrected with Bazett’s formula (QTcB) or QT interval 
corrected with Fridericia’s formula (QTcF) (greater than 450 ms). If QTcB or QTcF 
is greater than 450 ms on the first ECG, a second ECG recording will be performed 
after at least 30 min. If QTcB or QTcF is greater than 450 ms on the second ECG, 
the subject is not eligible.  
• A history of additional risk factors for torsade de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
• ECG with clinically significant atrioventricular (AV) conduction disturbance (e.g., 
second or third-degree AV block), sick sinus syndrome, bradycardia (resting pulse 
< 40 bpm), or accessory bypass tract (e.g., Wolff-Parkinson-White). 
Criterion assessed at Visit 1, Visit 2, Visit 3 and Visit 4 
24. 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 
(Visit 1) and visit (Visit 2, Visit 3, Visit 4) version of the C-SSRS©. 
• History of suicide attempt on the suicidal behavioral section of the lifetime version 
of the C-SSRS© (Visit 1). 
Criteria assessed at Visit 1, PSG visit between Visit 1 and Visit 2, Visit 2, Visit 3 and 
Visit 4 
25. For female subjects: pregnant, lactating or planning to become pregnant during 
projected duration of the study. 
26. Positive urine drug test (for benzodiazepines, barbiturates, cannabinoids, opiates, 
amphetamines, phencyclidine or cocaine) or presence of alcohol in exhaled breath as 
detected by breathalyzer test. 
4.5 Criteria for women of childbearing potential 
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy, 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3 definition]), 
• Premature ovarian failure (confirmed by a specialist), XY genotype, Turner 
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The reason for not being of childbearing potential will be recorded in the electronic Case 
Report Form (eCRF). 
4.5.2 Acceptable methods of contraception 
For women of childbearing potential [see definition in Section 4.5.1], any of the following 
acceptable birth control methods are required: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
– Oral 
– Intravaginal 
– Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
– Oral 
– Injectable 
– Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Vasectomized male partner with documented post-vasectomy confirmation of the 
absence of sperm in the ejaculate.  
• Bilateral tubal occlusion (tubal occlusion / ligation at least 6 weeks prior to 
screening). 
• Sexual abstinence from intercourse with a male partner only when this is in line with 
the preferred lifestyle of the subject and if locally accepted as a reliable method of 
contraception. 
Rhythm methods, the use of a female condom, cervical cap, diaphragm or the partner’s use 
of a condom are not considered acceptable methods of contraception for this study. 
The method of birth control used must be recorded in the hospital charts.  
To ensure compliance, the study personnel must remind women of childbearing potential 
at each visit to use the methods of contraception defined for this study. The reminders must 
be documented in the hospital chart. 

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5 
TREATMENTS 
5.1 Study treatment 
The study drugs are ACT-541468 and ACT-541468-matching placebo. 
5.1.1 Investigational treatment and matching placebo: Description and rationale 
ACT-541468 or matching placebo will be administered as tablets, orally, once daily in the 
evening during the DB treatment period. ACT-541468-matching placebo will be 
administered as well during the run-in and the run-out period. At home, the study treatment 
will be taken at bedtime to mimic real life drug intake habits and at the site visits, the study 
treatment will be administered at least 2 h after the last meal and approximately 30 min 
before lights off to avoid a potential delay in ACT-541468 effects when administered with 
food which might bias objective endpoints. 
ACT-541468 is supplied by Idorsia as film-coated tablets at strengths of 10 mg and 25 mg. 
The rationale for the selection of these ACT-541468 doses is described in Section 1.3.2. 
The ACT-541468-matching placebo is supplied by Idorsia as identical tablets, formulated 
with the same inactive ingredients (excipients). 
5.1.2 Study treatment administration 
The tablet must not be broken or crushed. The date and time of treatment intake will be 
recorded in the sleep diary by the subject when taken at home and by the site personnel in 
the patient’s chart and the eCRF during the PSG nights. At Visit 2, the date of single-blind 
placebo treatment dispensing will also be recorded in the patient’s chart and the eCRF. 
5.1.2.1 Study treatment administration at site visits and at home 
During the PSG visits at the site, 1 tablet of study treatment will be taken at least 2 h after 
the last meal and approximately 30 min (± 5 min) before lights off, in the evening of each 
PSG night. 
At home, the tablet will be taken at bedtime.  
5.1.2.2 Missed doses 
If one or more doses have been missed, the next dose must be taken in the evening of the 
following day. 
5.1.3 Treatment assignment 
Each of the study sites will be assigned a unique site number and every subject will receive 
a unique subject number which identifies the subject throughout the study. 
At Visit 1, after the ICF has been signed, the investigator/delegate will contact the IRT 
system to get a subject number allocated to the subject. 

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During the run-in and run-out periods, subjects will receive single-blind placebo treatment. 
At Visit 2 and Visit 9, the investigator/delegate contacts the IRT system to assign the 
treatment wallet number. 
On the day of randomization (Visit 4), after having verified that the subject meets all 
inclusion criteria and none of the exclusion criteria, the investigator/delegate contacts the 
IRT to randomize the subject. The IRT assigns the treatment wallet number, which matches 
the treatment arm assigned per the randomization list. 
Subjects will be randomized in a 1:1:1 ratio to 10 or 25 mg of ACT-541468, or placebo, 
respectively (i.e., approximately 300 subjects per arm). Treatment allocation will be 
stratified by age into 2 categories: < 65 and ≥ 65 years. 
The randomization list is generated by an independent Contract Research Organization 
(CRO) and kept strictly confidential. 
5.1.4 Blinding 
5.1.4.1 Run-in and run-out periods 
During run-in and run-out periods, placebo treatment will be administered in a single-blind 
fashion. The subjects will remain blinded to the study treatment until the end of the 
ID-078A303 extension study. Subjects must not be informed about the change in treatment 
at the end of run-in and at the beginning of run-out. The investigator and study personnel, 
the monitors, Idorsia personnel, and CROs involved in the conduct of the study will be 
unblinded to the treatment provided during the run-in/run-out periods.  
5.1.4.2 Double-blind treatment period 
From Randomization until EODBT, the study will be performed in a DB fashion. The 
subjects, the investigator and site personnel, and the monitors will remain blinded to the 
study treatment until the end of the ID-078A303 extension study. Idorsia personnel 
responsible for clinical study supply distribution will monitor the depot stock levels in 
collaboration with the study team based on recruitment data and site activation. Site stocks 
will be maintained according to the settings in the IRT system.  
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to the IRT vendor and sponsor authorized persons (e.g., 
Quality assurance, Systems and compliance personnel, Bioanalytical Laboratory group) 
the Independent Statistical Analysis Center (ISAC) and the IDMC, who are not involved 
in the conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment wallets will be packaged in the same way. 

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To minimize the possibility of systematic unblinding, the results of PK data will not be 
communicated to the investigator and site study personnel, the subjects and Clinical 
Research Associates (CRAs) until the end of the ID-078A303 extension study. Results will 
be transferred by the sponsor Bioanalytical Laboratory group (for the PK data) to the 
sponsor and CRO personnel involved in the conduct of the study only after database lock. 
5.1.5 Unblinding 
5.1.5.1 Unblinding for final analyses 
Randomization information will be made available for data analysis only after database 
lock, in accordance with Idorsia Quality System (QS) documents. 
5.1.5.2 Unblinding for IDMC review 
An ISAC, not otherwise involved in the design, conduct and analysis of the study, will 
have access to the randomization code in order to prepare unblinded reports for IDMC 
review meetings during the course of the trial. The randomization code will be made 
available to the ISAC in accordance with the sponsor’s QS documents. 
5.1.5.3 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Idorsia Global Drug Safety will request the unblinding of the 
treatment assignment. The treatment assignment will not be communicated to site 
personnel or to the Idorsia Clinical Trial Team. Unblinded SUSAR information will be 
provided to respective health authorities and IECs/IRBs only. SUSARs will be reported to 
investigators in a blinded fashion. 
5.1.5.4 Emergency procedure for unblinding 
The investigator, study personnel and Idorsia personnel must remain blinded to the 
subject’s treatment assignment. 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 can receive 
the unblinded treatment assignment through the IRT. In these situations, the decision to 
unblind resides solely with the investigator. 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 Idorsia personnel. 
The occurrence of any unblinding during the study must be clearly justified and explained 
by the investigator. In all cases, Idorsia personnel must be informed of the unblinding 
procedure as soon as possible before or after the unblinding. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF. 

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5.1.6 Study treatment supply 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, GCP, and any local or national regulatory 
requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.6.1 Study treatment packaging and labeling 
Study treatment (including placebo during run-in and run-out period) is provided as tablets 
and supplied in wallets. All pack types are childproof wallets containing 35 tablets. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.6.2 Study treatment distribution and storage 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label (i.e., 8–25 °C). Temperature measurement devices 
for study treatment storage area are required.  
5.1.6.3 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 wallets at each visit. If a treatment wallet is lost or damaged, a replacement wallet 
can be requested through the Treatment Replacement module of the IRT system. The 
protocol-mandated study treatment dispensing procedures may not be altered without prior 
written approval from Idorsia. In exceptional circumstances (e.g., if the subject lost the 
study treatment between two visits, or if the subject is unable to return to the site due to a 
medical emergency / hospitalization at another hospital), unscheduled dispensing and 
delivery of study treatment may occur outside of a scheduled visit. An accurate record of 
the date and amount of study treatment dispensed to each subject must be available for 
inspection at any time. 
5.1.6.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from Idorsia. On an ongoing basis and/or on termination of the study, the 
CRA will collect used and unused treatment wallets, which will be sent to the warehouse, 
where Idorsia personnel or a deputy will check treatment reconciliation. In certain 
circumstances, used and unused study treatment containers may be destroyed at the site 
once study treatment accountability is finalized and has been checked by Idorsia personnel 
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5.1.7 Study treatment accountability and compliance with study treatment 
5.1.7.1 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 at each visit and before 
dispensing further study treatment. It is to be recorded by site personnel on the study 
treatment dispensing and accountability log and in the eCRF, and checked by the CRA 
during site visits and at the end of the study. The study treatment accountability log in the 
eCRF will include at least the following information for each study treatment unit (i.e., 
wallet) dispensed to the subject: 
• Dispensed subject wallet number. 
• Date and number of tablets dispensed. 
• Date and number of tablets returned. 
All study treatment supplies, including partially used or empty wallets must be retained at 
the site for review by the CRA. 
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 wallet and to return it 
at the next visit. 
5.1.7.2 Study treatment compliance 
Study treatment compliance is based on study treatment accountability. Subjects also report 
their compliance in the eDiary every morning. Study treatment compliance for the Run-in 
period, the DB treatment period (Day 1 to EODBT) and the Run-out period will be 
separately calculated for each of these periods by site personnel using the below formula 
and entered in the eCRF: 
Compliance = [(number of tablets dispensed – number of tablets returned) / total number 
of tablets that needs to be taken during the period*] × 100 
* The period is defined as number of days during which study treatment should be taken as per actual visit 
dates. 
During the DB treatment period (Day 1 to EODBT), compliance is expected to be at least 
70%. Compliance values below this will be considered as a protocol deviation which will 
be reported in the Clinical Trial Management System by the CRA. The investigator 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 
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5.1.8 Study treatment dose adjustments and interruptions 
Study treatment dose adjustments are not permitted. 
Study treatment may be temporarily interrupted in response to an AE, a diagnostic or 
therapeutic procedure, a laboratory abnormality, or for administrative reasons. 
Study-specific criteria for interruption of study treatment are described in Section 5.1.10. 
If study treatment is interrupted by the subject for any reason, she/he must immediately 
inform the investigator. 
Interruptions of study treatment must be kept as short as possible.  
Study treatment interruptions must be recorded in the eCRF. 
5.1.9 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Idorsia personnel. The main reason for discontinuation must be 
documented in the eCRF and in the subject’s medical charts (e.g., AE, lack of efficacy). 
A subject has the right to prematurely discontinue study treatment at any time, without any 
justification, by withdrawal from study treatment only or by withdrawal from any further 
participation in the study (i.e., premature withdrawal from the study [see Section 8.2]). 
Although a subject is not obliged to give his/her reason for prematurely withdrawing from 
the treatment or the study, it is recommended that the investigator makes a reasonable effort 
to ascertain the reason(s), while fully respecting the subject’s rights. 
The investigator must 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 discontinuation of study treatment are described in 
Section 5.1.10. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until the planned EOS (Day 115), provided that the 
subject’s consent for this limited participation in the study has not been withdrawn. The 
subject is recommended to return for safety assessments [see Table 1] within one week of 
his/her last DB study treatment intake (N.B., next day residual assessments will only be 
performed if the subjects can be assessed within 24 h of last DB study drug intake). All 
subjects withdrawn from study treatment are encouraged to follow planned study 
procedures (e.g., visits, sleep diary and questionnaire completion) until EOS. In this case, 
the run-out period (including Visit 9 and Visit 10) will not be performed, and subjects will 
directly enter the follow-up period after Visit 8 (considered as EOT in the event of 
premature discontinuation). The phone call will be performed as planned 30 days (+ 7 days) 

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later, at Visit 11. This will decrease the amount of missing data which is important from a 
study integrity perspective. Subjects who prematurely discontinue study treatment or the 
study for any reason will not be replaced. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study and 
no further assessment will be collected after informed consent withdrawal. Subjects who 
die or are lost to follow-up are also considered as withdrawn from the study. Withdrawal 
from the study and follow-up medical care of subjects withdrawn from the study are 
described in Sections 8.2 and 8.4, respectively. 
5.1.10 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
At each visit, if there are signs of any AEs, the investigator must evaluate whether 
continuing treatment at home is compatible with the subject’s lifestyle and does not affect 
the subject’s safety. The investigator has the responsibility to decide whether it is safe for 
the subject to continue treatment in the study. 
If a subject becomes pregnant while on study drug, study drug must be permanently 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. 
Female subjects participating in the study and wishing to become pregnant during the study 
must discontinue study drug and continue contraception for at least 1 month.  
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to signing ICF. 
A therapy that is study-concomitant is any treatment that is ongoing or initiated after 
signing of informed consent, or initiated up to EOS. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at the 
start of DB study treatment or is initiated during the DB treatment period until 1 day after 
the last dose of DB treatment. 
5.2.2 Reporting of previous/concomitant therapy in the eCRF 
The use of all study-concomitant therapy (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will be recorded 
in the eCRF. Previous therapy must be recorded in the eCRF if discontinued less than 
30 days prior to signing of the ICF. The generic name, start/end dates of administration (as 

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well as whether it was ongoing at start of treatment and/or EOS), route, dose, and indication 
will be recorded in the eCRF. 
5.2.3 Allowed concomitant therapy 
CBT consists of a combination of cognitive therapy, behavioral, and educational 
interventions and is ideally delivered by a specially trained physician or a qualified 
psychotherapist. Given the shortage of certified sleep therapists, access to CBT is limited, 
particularly in Europe [Pigeon 2010, Schutte-Rodin 2008]. CBT for any indication is only 
allowed if the treatment started at least 1 month prior to Visit 3 and the subject agrees to 
continue this CBT throughout the study. Details about subject’s CBT or reason why CBT 
was not considered by the subject must be recorded in the eCRF. Initiation of CBT during 
the course of the study is not allowed. 
Therapies considered necessary for the subject’s well-being and not categorized as 
prohibited concomitant medications can be used in this study. However, initiation of new 
medication is to be discouraged and concomitant medication will preferably not be changed 
during the study. Non-sedating antihistamines (cetirizine, loratadine, desloratadine, 
fexofenadine and levocabastine) may be used a maximum of twice weekly for allergic 
symptoms. Inhaled or nasal corticosteroids are permitted. 
5.2.4 Forbidden concomitant therapy 
Subjects must not be withdrawn from medically necessary therapies in order to participate 
in the study. They must rather be considered as non-eligible to the study, both due to their 
medical condition and due to their requirement for these therapies. Several forbidden 
therapies are associated with excluded medical disorders (e.g., cardiovascular disease, 
Parkinson’s disease, stroke). 
The following concomitant therapies are forbidden during the study: 
• Treatment with another investigational drug until EOS. 
• Study-prohibited CNS-active medications from for 5 half-lives of the respective drug 
(but at least 2 weeks) prior to Visit 1 and until 24 hours after EOT [see Appendix 3]. 
• Treatment with moderate or strong CYP3A4 inhibitors, or moderate or strong CYP3A4 
inducers until 24 hours after EOT [see Appendix 3].  
5.2.5 Forbidden concomitant diet and activities 
The following activities and diet are forbidden during the study: 
• Consumption of grapefruit, Seville (bitter) oranges or juices from those fruits from 
1 week prior to Visit 2 until 24 h after the end of run-out period. 
• Caffeine consumption ≥ 600 mg caffeine/day or consumption of any caffeine after 
4 pm (after 2 pm on PSG nights) [see Appendix 2]. 

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• Alcohol consumption [see Appendix 1] 
− > 2 drinks a day 
− less than 3 hours before going to bed on non-PSG nights 
− within 24 hours prior to PSG night and during all PSG visits 
• Heavy tobacco use (at least one pack of cigarettes a day or inability to refrain from 
smoking during the night).  
• Driving or engaging in activities that require operating vehicles or dangerous 
machinery within 8 hours following study treatment intake for adult and elderly 
subjects. 
6 
STUDY ENDPOINTS 
The ID-078A302 trial is designed to assess safety and efficacy of ACT-541468 on 
objective and subjective endpoints.  
6.1 Primary efficacy endpoints 
The primary efficacy endpoints of this study are defined as: 
• the change from baseline to Month 1 in WASO (sleep maintenance) 
• the change from baseline to Month 3 in WASO 
• the change from baseline to Month 1 in LPS (sleep onset) 
• the change from baseline to Month 3 in LPS  
Baseline is defined as the mean of the 2 PSG nights at Visit 3. Month 1 and Month 3 are 
defined as the mean of the 2 PSG nights at Visit 6 and Visit 8, respectively. 
LPS (min) is the time from start of recording to the beginning of the first continuous 
20 epochs (i.e., 10 min) scored as non-awake, i.e., epochs scored as either sleep stage 
1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep [SWS]) or REM, as determined 
by PSG. 
WASO is the time (min) spent awake after onset of persistent sleep until lights on, as 
determined by PSG.  
6.2 Secondary endpoints 
The secondary efficacy endpoints of this study are defined as: 
• the change from baselinea to Month 1b in sTST 
• the change from baselinea to Month 3c in sTST 
• the change from baselinea to Month 1b in Insomnia Daytime Symptoms and Impacts 
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• the change from baselinea to Month 3c in IDSIQ sleepiness domain score  
a Baseline is the mean value based on the screening sleep diary / IDSIQ entries performed 
at home in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 8. 
6.3 Other efficacy endpoints 
• Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in TST. 
• Change from baselinea to Month 1b and Month 3c in subjective WASO (sWASO). 
• Change from baselinea to Month 1b and Month 3c in subjective Latency to Sleep Onset 
(sLSO). 
• Change from baselinea to Month 1b and Month 3c in IDSIQ scores (i.e., Total score; 
alert/cognition and mood domain scores). 
a Baseline is the mean value based on the screening sleep diary / IDSIQ entries performed 
at home in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 8. 
6.4 Exploratory endpoints 
For each variable, multiple aspects will be considered in the analysis, in particular changes 
from baseline at different time points.  
• WASO over time (by hour of the night and by quarter of the night) on each PSG night. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in SQ. SQ is the sleep quality 
as determined by scores on the VAS (mm) in the morning. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in duration of TST in each 
sleep stage (S1, S2, SWS and REM).  
• Change from baseline (Visit 3) to Month 1 and Month 3 in sleep architecture assessed 
as percentage of TST in each sleep stage (S1, S2, SWS, and REM) over the whole 
night, and for each quarter of the night.  

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• Change from baseline (Visit 3) to Month 1 and Month 3 in mean numbers of shifts from 
S2, SWS or REM to S1 or awake. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in ISI© scores. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in mean number of awakenings 
(defined as the number of awakenings between first epoch and last epoch not scored 
wake) as measured by PSG (will be summarized for the whole night, for each quarter 
of the night, and for each hour of the night). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in mean number of 
self-reported awakenings. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in Sleep Efficiency (defined 
as 100 × ([TST / time in bed]). 
• Change from baseline (Visit 1) to Month 1 and Month 3 in Patient Global Assessment 
of Disease Severity (PGA-S) scores (daytime symptoms). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in Patient Global Impression 
of Change (PGI-C) scores (daytime symptoms). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in PGI-C scores (night-time 
symptoms). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in Patient Global Impression 
of Severity (PGI-S) scores (night-time symptoms). 
6.5 Safety endpoints 
In addition to the standardized collection of AEs, safety data specific to insomnia and its 
treatment will be assessed as follows:  
• Withdrawal effects (physical dependence) upon treatment discontinuation will be 
assessed based on the changes from last assessment on DB treatment (Visit 8, 
2nd morning) to run-out period in the BWSQ total score (Visit 9 and Visit 10), the 
occurrence of relevant AEs and marked ECG abnormalities. 
• Rebound insomnia will be assessed based on objective sleep parameters (WASO, LPS 
and TST) at Visit 9 as compared to Visit 3. It will also be assessed using subjective 
sleep parameters (sWASO, sLSO and sTST) from run-out period as compared to 
baseline. 
• Next-day residual effect will be assessed based on changes from baseline (Visit 3) to 
Month 1 and Month 3 in: 
− Coding sub-test© 
− SDS© 
− Scores on the VAS (mm) 

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• SAEs up to 30 days after DB study treatment discontinuation or until enrollment into 
the extension study. 
• TEAEs up to 30 days after DB study treatment discontinuation or until enrollment into 
the extension study. 
• AEs leading to premature discontinuation of the DB study treatment. 
• AEs of special interest after adjudication by ISB: 
− narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep behavior 
events including hallucinations/sleep paralysis)  
− suicide/self-injury  
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8) in vital signs 
(mean of the 2 PSG nights in systolic and diastolic blood pressure [BP] and pulse rate). 
• Change from baseline (Visit 1) to Month 3 (Visit 8) in body weight. 
• Marked ECG abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 3 (Visit 8) and the end of the run-out period 
(Visit 10) in ECG parameters. 
• Marked laboratory abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8) in laboratory 
parameters. 
• Occurrence of suicidal ideation and/or behavior on DB study treatment based on 
C-SSRS©. 
6.6 Pharmacokinetic endpoints 
ACT-541468 plasma concentrations 9–10 h post-dose (morning after the second PSG night 
at Visit 6 and Visit 8) or in the event of excessive sleepiness based on the investigator’s 
opinion. 
6.7 Patient preferences exploratory endpoints 
The preferences resulting from the choice sets collected in the third section of the PAUSe 
questionnaire will be used to derive the following endpoints: 
• Partial value of each treatment outcome at Visit 4 and Visit 8. 
• Partial value function and weights for each treatment outcome at Visit 4 and Visit 8. 
• Total value score for each treatment at Visit 4 and Visit 8. 
• Change in total value score for each treatment from Visit 4 to Visit 8.  
• Probability that patients would prefer a treatment at Visit 4 and Visit 8. 
• Change in probability that patients would prefer a treatment from Visit 4 to Visit 8. 

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7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits 
The study visits are listed in Table 1. Screening will last 20 to 31 days. For all visits during 
the DB treatment phase, the subjects must be seen on the designated day and within a ± 2 
days visit window in comparison with randomization (Visit 4). A follow-up safety 
telephone call must be performed 30 days (+ 7 days) after last DB study treatment intake 
if the subject is not enrolled in the ID-078A303 extension study. 
7.1.1 Screening 
At Visit 1 subjects will discuss and sign the ICF, and will undergo initial eligibility 
assessments. The date on which the ICF is signed corresponds to the date of the screening 
visit (Visit 1). 
It is the responsibility of the investigator/delegate (the latter may or may not be a physician 
according to local legal requirements, in the EU it must be a physician) to obtain written 
informed consent from each subject participating in this study after adequate face-to-face 
explanation of the objectives, methods, and potential risks of the study. The subjects who 
agree to participate in the study and the investigator/delegate must sign the ICF prior to 
performing any study-related assessment or procedure.  
Subjects who are in the screening phase when the enrollment target has been met may still 
be randomized. 
It is not permitted to re-screen subjects. 
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., AE), appropriate assessments will be performed 
based on the judgment of the investigator. Results of ECGs and laboratory assessments, 
and changes in concomitant treatment will be recorded in the eCRF. After an unscheduled 
visit, the regular scheduled study visits must continue according to the planned visit and 
assessment schedule [Table 1]. 
 

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Table 1 
Visit and assessment schedule 
 
SCREENING PHASE (20–31 days) 
TREATMENT PHASE (82–86 days) 
FU PHASE (30–37 days) 
 
Screening period 
(7–18 days) 
Run-in period 
(13–24 days) 
Double-blind treatment (84 days ± 2 days13) 
Run-out period 
(7 days + 2 days) 
FU 
period  
(23 days 
+ 7 
days)16 
Visit 
1 
 
2 
3 
415 
5 
(phone call) 
6 
7 
8 
9 
10 
11 
(phone 
call) 
Target Study Days 
 
 
 
1st night 
2nd night 
1 
7 to 14 
1st night 13 
27/28 
2nd night 
28/29 
55 
1st night 13 
83/84 
2nd night 
84/85 
85/86 
92 
(+ 2 days) 
115 
(+ 7 
days) 
Evening(PM) /  
Morning (AM) 
 
PM 
AM 
 
PM 
AM 
PM 
AM 
 
 
PM 
AM 
PM 
AM 
 
PM 
AM 
PM 
AM 
PM 
AM 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
X 
X 
Physical examination, 
body weight and height 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
Vital signs 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X6 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
X 
 
Hematology, blood 
chemistry 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
X6 
 
 
 
 
Pregnancy test 1 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X6 
 
 
X 
 
Urine drug screen 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Alcohol test 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
PK sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
PSG 
 
X4 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
ISI© 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X6 
 
 
 
 
IDSIQ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sleep diary (incl. VAS) 2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological exam8 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
C-SSRS© 7 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
X6 
 
X 
X 
 
Coding sub-test© 7 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X14 
 
X 
 
 

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SCREENING PHASE (20–31 days) 
TREATMENT PHASE (82–86 days) 
FU PHASE (30–37 days) 
 
Screening period 
(7–18 days) 
Run-in period 
(13–24 days) 
Double-blind treatment (84 days ± 2 days13) 
Run-out period 
(7 days + 2 days) 
FU 
period  
(23 days 
+ 7 
days)16 
Visit 
1 
 
2 
3 
415 
5 
(phone call) 
6 
7 
8 
9 
10 
11 
(phone 
call) 
Target Study Days 
 
 
 
1st night 
2nd night 
1 
7 to 14 
1st night 13 
27/28 
2nd night 
28/29 
55 
1st night 13 
83/84 
2nd night 
84/85 
85/86 
92 
(+ 2 days) 
115 
(+ 7 
days) 
Evening(PM) /  
Morning (AM) 
 
PM 
AM 
 
PM 
AM 
PM 
AM 
 
 
PM 
AM 
PM 
AM 
 
PM 
AM 
PM 
AM 
PM 
AM 
 
 
ESS© 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
SDS© 7 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X6 
 
X 
 
 
BWSQ7 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X6 
 
X 
X 
 
MINI© 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
MMSE©10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGA-S11 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PGI-C11 daytime 
symptoms 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PGI-C11 night-time 
symptoms 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PGI-S11 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Patient Preferences17 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Contact IRT 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Randomization12 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IMP wallet(s) 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Study drug intake3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs and AEs 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. For women of childbearing potential, serum test at V1 and V8 and urine test at V2, V4, V6, V7, V10. 2. The hand-held device is handed out to the subject and completed at home daily from V1 to V10. 3. 
Daily placebo single-blind treatment during run-in and run-out periods, and daily double-blind study treatment during treatment phase. 4. The 1st PSG can be performed any nights between V1 and V2. It 
includes assessment of AHI, PLMAI, SpO2. 5. SAE and AE reporting and follow-up: all SAEs and AEs from signed ICF up to EOS. 6. In the event of permanent study treatment discontinuation, safety 
assessments of V8 are recommended to be performed within 7 days of last DB study drug intake. If the subject remains in the study, he or she will perform study visits and assessments as planned until EOS 
(Day 115), without the run-out period (including Visit 9 and Visit 10). 7. Approximately 30 to 60 minutes after PSG lights on. 8. Performed approximately 1 hour after lights on. 9. Height only at V1. 10. For 
elderly subjects only. 11. PGA-S, PGI-S and PGI-C (daytime symptoms and night-time symptoms questionnaires) will be completed at home once a week between V4 and EODBT. 12. Randomization will 
take place after all the V4 assessments have been performed and provided the subject fulfills all the eligibility criteria. 13. A time window of ± 2 days is allowed at each visit vs randomization visit (V4). 14. 
In the event of permanent study treatment discontinuation, next day residual assessment of V8 will only be performed if the subjects can be assessed within 24 h of last DB study drug intake. 15. Three 

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working days are required between V3 and V4 to obtain eligibility confirmation regarding objective sleep parameters. 16. If Run-out period exceeded by 2 days, then the follow-up period can only be 
exceeded by a maximum of 5 days; 17. Patient preferences sub-study (PAUSe) available for sites in Germany and in the USA only. 
AE = adverse event; AHI = apnea/hypopnea index; BWSQ = Benzodiazepine Withdrawal Symptom Questionnaire; C-SSRS© = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EODBT 
= End-of-Double-Blind-Treatment; EOS = End-of-Study; ESS© = Epworth Sleepiness Scale©; FU = Follow-up; ICF = Informed Consent Form; IDSIQ = Insomnia Daytime Symptoms and Impacts 
Questionnaire; IMP = Investigational Medicinal Product; IRT = Interactive Response Technology; ISI© = Insomnia Severity Index©; MINI© = Mini International Neuropsychiatric Interview©; MMSE© = 
Mini Mental State Examination©; PAUSe = PAtient Preferences StUdy in InSomnia; PGA-S = Patient Global Assessment of Disease Severity; PGI-C = Patient Global Impression of Change (daytime 
symptoms and night-time symptoms); PGI-S = Patient Global Impression of Severity; PK = pharmacokinetic; PLMAI = periodic limb movement with arousal index; PSG = polysomnography; SAE = 
serious adverse event; SDS© = Sheehan Disability Scale©; SpO2 = oxygen saturation by pulse oximetry; V = Visit; VAS = visual analog scale(s). 

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7.2 Study assessments 
The mandatory study assessments are listed in Table 1. 
All study assessments are performed by qualified study personnel (medical, nursing, or 
specialist technical personnel), and are recorded in the medical history and eCRF unless 
otherwise specified. Study assessments performed during unscheduled visits will also be 
recorded in the eCRF.  
The following order of assessments is recommended:  
• In the evening before a PSG night: 
– Urine drug screen and alcohol test 
– IDSIQ 
– Evening questionnaire in sleep diary (including VAS) 
– PGA-S daytime symptoms (in the first evening at Visits 3, 6 and 8) 
– PGI-C daytime symptoms (in the first evening at Visits 3, 6 and 8) 
– Recording of concomitant medications 
– AEs and SAEs 
– Study drug intake (30 minutes before lights off) 
• In the morning after a PSG night (subject fasted): 
– 
Blood samples (hematology and blood chemistry, only second morning at 
Visits 3, 6 and 8; PK, only second morning at Visits 6 and 8.  
• In the morning after a PSG night and after completion of normal morning routine 
(e.g., using the bathroom, eating breakfast): 
– Vital signs  
– C-SSRS© (only second morning at Visits 3, 6 and 8) 
– Coding sub-test© 
– ISI© (only second morning at Visits 3, 6 and 8) 
– ESS© 
– SDS© 
– BWSQ (only second morning at Visits 3, 6, 8 and 9) 
– Morning questionnaire in sleep diary (including VAS) 
– PGI-S night-time symptoms (in the first morning at Visits 3, 6 and 8) 
– PGI-C night-time symptoms (in the first morning at Visits 3, 6 and 8) 
– Recording of concomitant medications 
– AEs and SAEs 
– Neurological examination 
– 12-lead ECG (only second morning at Visits 3 and 8) 
– Patient preferences questionnaire (PAUSe; only second morning at Visit 8) 

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The following assessments will be analyzed by an external provider (results will be 
transferred to the Idorsia database and to the investigators): 
• Laboratory parameters 
• ECG parameters 
• PSG recordings 
• Questionnaires completed using a hand-held device (listed below). 
If the Principal Investigator (PI) delegates any study procedure/assessment for a subject, to 
an external facility, he/she must inform Idorsia to whom these tasks are delegated. The set-
up and oversight must be agreed upon with Idorsia. The supervision of any external 
facilities remains the responsibility of the PI. 
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available prior to the screening of 
the first subject. Calibration certificates of other equipment must be available as per local 
requirements: 
• Temperature measurement devices for study treatment and sample storage area. 
• Polysomnographic device. 
Use of hand-held and tablet devices 
Subjects will be required to complete the following questionnaires on a hand-held device:  
Epworth Sleepiness Scale© (ESS©), ISI©, SDS©, BWSQ, IDSIQ, PGA-S daytime 
symptoms, PGI-C daytime and night-time symptoms, PGI-S night-time symptoms, sleep 
diary (including VAS). 
Subjects will be required to complete the following questionnaires on a tablet at the site:  
Patient preferences questionnaire (PAUSe). 
Investigators, delegated physicians, specialist nurses or nurse practitioners trained 
according to local requirements and local clinical practice will be required to complete the 
following questionnaires on a tablet at the site: C-SSRS©, MMSE©. 
Sites will be properly trained on the accurate use of the hand-held and tablet devices by the 
sponsor or an external CRO and are then expected to train their subjects on how to 
appropriately complete the questionnaires. Data collected from the hand-held devices will 
be electronically transferred to Idorsia by the CRO.  
For further details refer to the tablet and hand-held devices manual.  

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7.2.1 Demographics 
Demographic data to be collected in the eCRF for all subjects include: age, sex, race and 
ethnicity. Relevant medical history / current medical conditions (e.g., chronic and ongoing 
acute conditions, serious past conditions) present before signing informed consent will be 
recorded on the medical history page. Where possible, diagnoses and not symptoms will 
be recorded. 
Characteristics of insomnia will be captured on a specific Diagnosis eCRF page. 
Subject’s information regarding CBT will be captured on a specific Medical History eCRF 
page.  
For subjects who failed screening, the following data will be collected in the eCRF if 
available: 
• Demographics (i.e., age, sex, race and ethnicity)  
• Informed consent date 
• Reason for screening failure 
• AEs. 
7.2.2 Efficacy assessments 
7.2.2.1 Polysomnography 
PSG data will be used to assess objective sleep parameters (WASO and LPS) as well as 
data on sleep architecture (sleep stages).  
PSG recordings must be performed by technologists who are familiar with the recording 
techniques described in the investigator site operations manual for the acquisition, 
processing, scoring, archiving, and transfer of digital PSG data (provided by the central 
scoring CRO). The quality of PSG recordings is monitored and quality-controlled on an 
ongoing basis. Technologists must be able to follow the procedures in this manual in order 
to produce technically acceptable tracings. Technologists are not required to be registered 
PSG technologists. Technologists must receive study-specific training prior to their 
participation in the study. Documentation of technologists’ prior experience and training, 
and study-specific training will be maintained at each clinical trial site. The sites and 
scorers that participate in this study must be certified by the CRO. The center conditions 
must allow an undisturbed environment and PSG recordings must be conducted in a sleep 
laboratory environment that meets the guidelines for sleep disorder centers [aasmnet.org]. 
During the Screening period, a PSG night will be performed if the subject meets all 
inclusion criteria and none of the exclusion criteria checked so far, and assesses AHI, 
PLMAI, and SpO2. At Visit 3, the first PSG recording starts (lights off) within ± 30 min of 

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usual bedtime (determined by sleep diary between Visit 2 and Visit 3); this time is then 
considered as the habitual bedtime and held constant (± 15 min) throughout the study. 
Study medication is administered 30 min (± 5 min) before the recording starts. The PSG 
recording is stopped after 480 min when 960 epochs of 30 seconds have been recorded. 
PSGs will be performed as per the visit and assessment schedule [Table 1].  
During the PSG recording, the subject is requested to stay in bed and remains connected to 
the recording equipment. However, if the subject needs to go to the bathroom, he/she may 
do so and will be disconnected for this short time from the recording device. Alternatively, 
urine flasks or bedpans may be provided. The subject must be re-connected as quickly as 
possible. The time during which the subject is disconnected will be scored as time awake. 
The subject is not permitted to perform any cognitive activity (such as reading, listening to 
radio, etc.), and is recommended not to have a watch or access to any clock. The lights 
remain switched off until the 480 min of recording are finished. After recording is stopped, 
the lights are turned on and the subject is awakened and asked to perform the morning 
assessments.  
The centers are required to transfer PSG data to the CRO responsible for central scoring, 
after the Visit 3 PSG visit and after Visit 6, Visit 8 and Visit 9 PSG visits. During the 
screening phase, PSG data obviously not fitting eligibility criteria at the first PSG and at 
Visit 3 according to site scoring (more than 10% deviation from protocol range) are not 
required to be sent for central scoring. If anything prevents any PSG night being scored, 
the center must contact the monitor for instructions. After Visit 3, the CRO will score the 
PSG data obtained at the first PSG and at Visit 3 immediately upon receipt and the center 
will receive the complete Eligibility Assessment (AHI, PLMAI, and the presence of any 
apnea/hypopnea or event associated with SpO2 < 80% as assessed at Visit 1, and WASO, 
LPS and TST as assessed at Visit 3) within 3 business days following file receipt by the 
CRO. These PSG data are evaluated and scored centrally by an independent scorer (expert 
from central reading CRO, not otherwise involved in the study). Based on this information, 
the investigator assesses the subject’s potential eligibility. 
Results of all PSG nights (1st PSG, Visit 3, Visit 6, Visit 8, and Visit 9) for the randomized 
subjects are sent to Idorsia from the central scoring CRO. The following sleep variables 
assessed by PSG include but are not limited to: WASO, LPS, TST, sleep stages S1 (also 
called N1), S2 (N2), SWS (N3), REM (R), and Wake time during sleep (W). The 
definitions of the sleep variables are given in the scoring procedures of the central scoring 
CRO manual. 
The sponsor reserves the right to request the sites to provide PSG data from the 1st PSG 
night of screened failed subjects to further characterize the patient population. In such case, 
the sites will be informed in due time.  

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For more detailed information, refer to the investigator site operations manual for the 
acquisition, processing, scoring, archiving, and transfer of digital PSG data (provided by 
central scoring CRO). 
7.2.2.2 Sleep diary 
The sleep diary (also called eDiary) 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 at screening and until Visit 10. 
The self-administered sleep diary includes a morning and evening questionnaire, and VAS.  
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 (provided by CRF Health).  
7.2.2.2.1 Morning and evening questionnaire 
These questions collect information on self-reported sleep characteristics (sleep induction 
and maintenance), habitual napping, bedtime, and timing of study treatment intake.  
The subject’s answer to the sleep diary question “What time did you get into bed?” is 
expected to be in the time window of 21:30 to 00:30 for at least 50% of the nights between 
Visit 2 and Visit 3. The median of the values falling into the time window of 21:30 to 00:30 
is defined as the usual bedtime and will be used to set the habitual bedtime. The subject’s 
regular time in bed (i.e., time calculated from “What time did you get into bed?” until 
“What time did you get out of bed for the day?”) is expected to be in the time window of 
6 to 9 h, for at least 50% of the nights between Visit 2 and Visit 3. 
For further details, see Appendix 8. 
7.2.2.2.2 Visual analog scales 
The VAS collects information on quality of sleep, depth of sleep, morning sleepiness, 
daytime alertness, and daytime ability to function by asking the subjects to report their 
feelings by placing a mark on a visual analog scale. 
Self-reported quality of sleep, depth of sleep and morning sleepiness are assessed in the 
morning. Self-reported daytime alertness and daytime ability to function are assessed in 
the evening. 
For further details, see Appendix 8. 
7.2.2.3 Insomnia Severity Index© 
The ISI© assesses the severity of a patient’s insomnia by scoring the severity of sleep onset 
and sleep maintenance difficulties and any insomnia-related interference with daytime 

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functioning [see Appendix 5]. 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 hand-held device at Visit 1, Visit 3, Visit 6, and Visit 8.  
7.2.2.4 Patient Global Assessment of Disease Severity (daytime symptoms) 
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 his/her insomnia over the 7 days preceding the PGA-
S. It is a self-administered question programmed on the hand-held device and is to be 
completed at Visit 1, Visit 2, Visit 3 1st evening, Visit 6 1st evening, Visit 8 1st evening, 
Visit 10, and weekly in the evening at home from Visit 4 until EODBT.  
For further details, see Appendix 9. 
7.2.2.5 Patient Global Impression of Change (daytime symptoms) 
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 his/her 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 self-administered question on the hand-held device and is to 
be completed at Visit 3 1st evening, Visit 6 1st evening, Visit 8 1st evening, Visit 10, and 
weekly in the evening at home from Visit 4 until EODBT. 
For further details, see Appendix 9. 
7.2.2.6 Patient Global Impression of Change (night-time symptoms) 
The PGI-C (night-time symptoms) is a question concerning the change in the subject’s 
insomnia symptoms at night (e.g., trouble falling asleep, total time asleep, or number of 
times they wake up) over the past week (7 nights) preceding the PGI-C night-time 
symptoms compared to the week before the subject started treatment. The PGI-C 
night-time symptoms is a self-administered question on the hand-held device and is to be 
completed at Visit 3 1st morning, Visit 6 1st morning, Visit 8 1st morning, Visit 10, and 
weekly in the morning at home from Visit 4 until EODBT. 
For further details, see Appendix 10. 

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7.2.2.7 Patient Global Impression of Severity (night-time symptoms) 
The PGI-S is a question concerning the overall severity of the subject’s night-time 
symptoms (e.g., trouble falling asleep, total time asleep, or number of times they wake up) 
that the subject may have experienced due to his/her insomnia over the past week (7 nights) 
preceding the PGI-S. It is a self-administered question programmed on the hand-held 
device and is to be completed at Visit 1, Visit 2, Visit 3 1st morning, Visit 6 1st morning, 
Visit 8 1st morning, Visit 10 and weekly in the morning at home from Visit 4 until EODBT. 
For further details, please see Appendix 10. 
7.2.2.8 Insomnia Daytime Symptoms and Impacts Questionnaire 
The IDSIQ is programmed on the electronic hand-held device in the subject’s language, 
and must be completed every day in the evening before the evening sleep diary by the 
subject without study staff input or interference from Screening (Visit 1) until EOT 
(Visit 10). 
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 numeric 
rating scale. This tool is based on an existing instrument, the Daytime Insomnia Symptom 
Scale [Buysse 2007]. The psychometric validation of the IDSIQ instrument was performed 
in study ID-078A203. 
For further details, see Appendix 11. 
7.2.3 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 
7.2.3.1 Weight and height 
Height will be measured at Screening only (Visit 1) and recorded in the eCRF. 
Body weight will be measured at Screening (Visit 1) and EODBT visit (Visit 8), and 
recorded in the eCRF. BMI will be calculated at Visit 1 according to the BMI formula 
(weight in kg/m2) and displayed automatically upon entry of weight and height in the 
eCRF.  
7.2.3.2 Physical examination 
Physical examination will be performed at Screening (Visit 1) and EODBT visit (Visit 8) 
according to site standard medical practice for subjects with insomnia disorders. 
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Information for all physical examinations must be included in the source documentation at 
the study site. The observations will not be directly reported in the eCRF. Clinically 
significant findings that are present prior to signing of ICF must be recorded on the Medical 
History eCRF form. Clinically significant physical examination findings made after 
signing of informed consent that meet the definition of an AE [Section 9.1.1] must be 
recorded on the AE form of the eCRF. 
7.2.3.3 Vital signs 
Systolic and diastolic BP and pulse rate will be measured non-invasively at each study visit 
from Screening (Visit 1) to EOT (Visit 10).  
Vital signs measurements will be collected in the eCRF. 
7.2.3.4 Coding sub-test© 
The Coding sub-test©, formerly known as Digit Symbol Substitution Test, is a measure of 
attention, perceptual speed, motor speed, visual scanning and memory.  
On a sheet of paper, the subject is given 120 seconds to complete as many substitutions as 
possible, entering a symbol in numbered boxes according to a key shown on the top of the 
sheet (9 symbols).  
The Coding sub-test© is performed at Visit 3, Visit 6, Visit 8 and Visit 9. The number of 
correct substitutions is recorded as the total Coding sub-test© score and collected in the 
eCRF. 
For further details, see Appendix 4. 
7.2.3.5 Sheehan Disability Scale© 
The SDS© consists of 3 questions on impairment of work, social life, and family life / home 
responsibilities [see Appendix 6; Sheehan 1996]. The SDS© is a self-administered 
questionnaire on the hand-held device performed at Visit 3, Visit 6, Visit 8 and Visit 9.  
7.2.3.6 Columbia Suicide Severity Rating Scale© 
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 
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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. 
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. The C-SSRS© will be completed at all study visits except Visit 
5 and Visit 11 (i.e., telephone calls). At Visit 1 (Screening) the C-SSRS© will be completed 
for the subject lifetime history of suicidal ideation and behaviors. At all other visits, the C-
SSRS© will be completed for ideation and behaviors since the previous visit.  
At each visit, the investigator, a delegated physician, a specialist nurse or a nurse 
practitioner, trained according to local requirements and local clinical practice will 
complete this questionnaire with the subject on a tablet and assess the findings. 
7.2.3.7 Benzodiazepine Withdrawal Symptom Questionnaire 
The BWSQ assesses the main symptoms which might be experienced by subjects during 
withdrawal from benzodiazepines [see Appendix 7; Tyrer 1990]. The questionnaire 
consists of 20 items. The symptoms will be rated from 0 (No), 1 (Yes-moderate) to 
2 (Yes-severe). The questionnaire will be self-administered using the hand-held device at 
Visit 3, Visit 6, Visit 8, Visit 9 and Visit 10. 
7.2.3.8 Mini International Neuropsychiatric Interview© 
The MINI© is a psychiatric examination [Sheehan 1999] and will identify subjects with 
exclusionary psychiatric conditions. The MINI© will be administered at Screening (Visit 1) 
by the investigator, a delegated physician, a specialist nurse or a nurse practitioner, trained 
according to local requirements and local clinical practice. The MINI© Version 7.0.2 will 
be administered on paper to ascertain the psychiatric diagnoses, and any clinically relevant 
psychiatric conditions will be reported in the eCRF. 
7.2.3.9 Mini Mental State Examination© 
The MMSE© is a simplified, scored form of the cognitive mental status examination [see 
Appendix 13; Folstein 1975]. The MMSE© assesses orientation, attention, immediate and 
short-term recall, language, and the ability to follow simple verbal and written commands. 
The MMSE© will be administered at Screening (Visit 1) for subjects ≥ 50 years at the site 
on a tablet by the investigator, a delegated physician, a specialist nurse or a nurse 
practitioner, trained according to local requirements and local clinical practice. A subject 
with a score between 25 and 30 will be eligible and a subject with a score below 25 has 
greater cognitive impairment and will be excluded. 

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7.2.3.10 Neurological examinations 
At 1st PSG night, Visit 3, Visit 6, Visit 8, and Visit 9, a set of examinations must be 
performed approximately 1 hour after lights on [see Section 7.2]. The neurological 
examinations will be done by the investigator, a delegated physician, a specialist nurse or 
a nurse practitioner, trained according to local requirements and local clinical practice. The 
following examinations will be performed to detect a possible next-day residual effect: 
• Gait 
• Tandem walking 
• Romberg test 
In the event of clinically significant findings, the set of examinations must be repeated 
approximately every 30 min. until the subject is considered safe to leave the center and the 
investigator must ensure appropriate safety follow-up of the subject. All clinically 
significant findings must be recorded as AEs in the eCRF.  
Neurological examinations are recorded on the eCRF. 
7.2.3.11 Epworth Sleepiness Scale© 
The ESS© is a validated questionnaire designed to provide a subjective measure of daytime 
sleepiness [Johns 1991]. The ESS© [see Appendix 12] will be self-administered at site 
visits (Visit 1, Visit 2, Visit 3, Visit 6, Visit 8, and Visit 10) on a hand-held device to assess 
daytime sleepiness. All clinically significant findings must be recorded as AEs in the eCRF. 
7.2.3.12 ECG assessment 
A standard 12-lead ECG is to be performed at Visit 1, in the second morning of Visit 3, 
Visit 8 and at Visit 10. 
12-lead ECG will be recorded at rest with the subject in the supine position. Data records 
will be sent to the evaluation center for central reading.  
Details will be provided in the 12-lead ECG laboratory manual.  
The following parameters will be evaluated: PQ or PR (ms), QRS (ms), QT (ms), heart rate 
(HR; bpm), and rhythm. QTc (ms) will be calculated according to: 
• Bazett’s formula: QTcB = QT / (RR)1/2 
and 
• Fridericia’s formula: QTcF = QT / (RR)1/3, where RR = 60 / HR 
If the central review of the ECG detects a prolonged QTcB and/or QTcF interval greater 
than 450 ms for a subject at screening (Visit 1 or Visit 3), the ECG must be repeated (at 
least 30 min after first ECG). If the central review confirms that the repeated ECG shows 

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a QTcB and/or QTcF interval greater than 450 ms, the subject cannot be enrolled into the 
study.  
Clinically significant findings detected after signing of ICF which meet the definition of 
an AE must be recorded in the eCRF.  
ECG data collected by the CRO will be electronically transferred to Idorsia.  
7.2.4 Patient preferences questionnaire 
The DCE methodology requires the presentation of several possible comparative scenarios, 
(i.e., Treatment A and Treatment B) showing specific treatment outcomes (benefits and 
risks). After each treatment scenario, subjects will be asked to make choices about the type 
of treatment they would be willing to take. The patient preferences questionnaire is 
programmed on the tablet site device in the subject’s language (i.e., US English for USA 
and German for Germany), and if subjects consent to participate to this sub-study, must be 
completed at Randomization (Visit 4) and at EODBT visit (Visit 8, 2nd morning). 
For further details, see Appendix 14. 
7.2.5 Laboratory assessments 
7.2.5.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests until EOS, including follow-up tests due to abnormal 
laboratory findings and laboratory tests performed at unscheduled visits. 
Local laboratory results of the parameters described in Section 7.2.5.2 will only be 
collected in exceptional circumstances (e.g., hospitalization of the subject due to a medical 
emergency). The local laboratory results (with the corresponding normal ranges) must be 
recorded in the eCRF. 
If a central laboratory sample is lost or cannot be analyzed for whatever reason, it is 
recommended to the investigator to collect an additional sample as soon as possible for 
repeat analysis. 
No repeat test is allowed if the subject does not meet the eligibility criteria. 
Central laboratory reports will be sent to the investigator. In the event of specific 
(pre-defined) laboratory abnormalities, the central laboratory will alert Idorsia personnel 
and the concerned site personnel. 
All laboratory reports must be reviewed, signed, and dated by the investigator or delegate 
within 10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 

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considered clinically significant or not. Clinically significant laboratory findings present 
before signing of the ICF must be recorded on the Medical History page of the eCRF. Any 
clinically significant laboratory abnormalities detected after signing of ICF must be 
reported as an AE or SAE as appropriate [see Section 9], and must be followed up until the 
value returns to within the normal range or is stable, or until the change is no longer 
clinically significant. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. Blood samples will 
be drawn under fasted condition (i.e., before breakfast) at Visit 3, Visit 6, Visit 7 and 
Visit 8. 
7.2.5.2 Laboratory tests 
Hematology 
• Hemoglobin  
• Hematocrit  
• Erythrocytes  
• Reticulocyte 
• Leukocytes with differential counts 
• Platelets  
Clinical chemistry 
• ALT  
• AST  
• Alkaline phosphatase  
• Creatine kinase  
• Total and direct bilirubin  
• Gamma-glutamyl transferase  
• Creatinine and creatinine clearance 
• Blood urea nitrogen  
• Uric acid  
• Glucose  
• Cholesterol, triglycerides  
• Sodium, potassium, chloride, calcium  
• Albumin  
• Thyroid hormones, i.e., triiodothyronine (total and free) and thyroxine (total and 
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Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed at Screening 
(Visit 1) and on the second morning of Visit 8. A urine pregnancy test will be performed 
on Visit 2, Visit 4, on the first evening of Visit 6, Visit 7 and at run-out (Visit 10). If 
pregnancy is suspected during the study, a serum pregnancy test must be performed 
immediately. 
Other tests 
The urine drug screening kits (testing for presence of benzodiazepines, barbiturates, 
cannabinoids, opiates, amphetamines, phencyclidine or cocaine) and the breathalyzer for 
alcohol detection in the exhaled breath will be provided by the central laboratory. Should 
any technical issue arise with the breathalyzer, alcohol saliva tests will be provided to be 
used as back-up. 
Study drug is administered as described in Section 5 only if the results of the pregnancy 
tests and other tests are negative.  
7.2.6 Pharmacokinetic assessments 
PK samples will be collected in the morning after the second PSG night, after lights on, 
approximately 9–10 h post-dose (i.e., 30–90 min after lights on) at Visit 6 and Visit 8 or in 
the event of excessive sleepiness based on the investigator’s opinion. 
The date and the time of blood sample collection will be entered in the eCRF. The date and 
time of the last study treatment dosing before blood draw will be entered in the eCRF. The 
site personnel will ship the plasma samples to the central laboratory. The central laboratory 
will ship the samples to Idorsia Drug Metabolism and Pharmacokinetics department, who 
are in charge of the PK sample analysis. 
Details about the collection, sampling, storage, and shipment procedures can be found in 
the laboratory manual. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol 
A subject who completes the study treatment phase and the safety follow-up phase is 
considered to have completed the study as per protocol. Subjects who completed the study 
until the end of the run-out period will have the possibility to participate in the extension 
study ID-078A303 and will complete the safety follow-up phase at the end of the extension.  
8.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn from study if they state an intention to 

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withdraw further participation in all components of the study (i.e., withdrawal of consent), 
die, or are lost to follow-up. If a subject withdraws consent, no further data will be collected 
in the eCRF from the date of withdrawal onward. Withdrawal from the study may also 
result from a decision by Idorsia for any reason, including premature termination or 
suspension of the study. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual failed. The site must take preventive measures to avoid 
a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted if the subject 
cannot be reached). If the subject cannot be reached, the site must make a reasonable effort 
to contact the subject, document all attempts, and enter the loss of follow-up information 
into the eCRF. The following methods must be used: at least three telephone calls must be 
placed to the last available telephone number and one registered letter must be sent by post 
to the last available home address. Additional methods may be acceptable if they are 
compliant with local rules/regulations (e.g., a visit by site personnel to the subject’s home), 
respecting the subject’s right to privacy. If the subject is still unreachable after all contact 
attempts listed above, he/she will be considered to be lost to follow-up. 
If premature withdrawal occurs for any reason, the reason (if known) for premature 
withdrawal from the study (e.g., withdrawal by subject, AE, lost to follow-up, death) must 
be recorded in the eCRF. 
If, for whatever reason (except death or loss-to-follow-up), a subject is withdrawn from the 
study, the investigator should make efforts to schedule a last appointment / telephone 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 / telephone call 
will be recorded in the subjects’ medical records but it will not be collected 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 8.4. 
8.3 Premature termination or suspension of the study 
Idorsia 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 prematurely suspended or terminated, Idorsia will promptly inform the 
investigators, IECs/IRBs and health authorities, as appropriate, and provide the reasons for 
the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Idorsia – must promptly inform all enrolled subjects and ensure their 

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appropriate treatment and follow-up, as described in Section 8.4. Idorsia may inform the 
investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates the participation in the study without 
prior agreement from Idorsia, the investigator must promptly inform Idorsia personnel and 
the IEC/IRB, and provide both with a detailed written explanation of the termination or 
suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify Idorsia personnel and provide a detailed written 
explanation of the termination or suspension. 
8.4 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/delegate will explain to subjects what treatment / medical care is 
necessary and available according to local regulations. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
9.1.1 Definition of adverse events 
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 course of the study, whether or not considered by the investigator as related to 
study treatment. 
A TEAE is any AE temporally associated with the use of study treatment (i.e., emerging 
from DB study treatment initiation until up to 30 days after DB study treatment 
discontinuation or until enrollment into the extension study) whether or not considered by 
the investigator as related to study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of 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 following 
the signing of informed consent. 

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• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the course 
of the study, or led to interruption or permanent discontinuation of study treatment. 
Overdose, misuse, abuse of the study treatment and study treatment errors will be reported 
as an AE. 
The ISB will adjudicate treatment-emergent AESIs which are similar to, or indicate: 
• narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep behavior events 
including hallucinations/sleep paralysis) 
• suicide/self-injury 
A treatment-emergent AESI is any AESI emerging from DB study treatment initiation until 
up to 30 days after DB study treatment discontinuation or until enrollment into the 
extension study. 
9.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the eCRF. 
Any increases in intensity of an AE during the study will be reported in the eCRF.  
The three categories of intensity are defined 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. 

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A mild, moderate, or severe AE may or may not be serious [see Section 9.2.1]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations. 
9.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by the investigator. 
9.1.4 Reporting of adverse events 
The investigator will ask the subject to report all AEs at each study visit, including the 
telephone calls.  
All AEs with an onset date after signing of informed consent and up to EOS for subjects 
that are not enrolled in ID-078A303 extension study must be recorded on AE pages of the 
eCRF. 
All AEs with an onset date after signing of informed consent, and up to enrollment in the 
ID-078A303 (i.e., ID-078A302 EOT) for subjects that are participating in the extension 
study, must be recorded on AE pages of the ID-078A302 eCRF. 
9.1.5 Follow-up of adverse events 
AEs still ongoing more than 30 days after EOS for subjects that are not enrolled in the 
ID-078A303 extension study must be followed up until they are no longer considered 
clinically relevant or until stabilization. The follow-up information obtained after the 
subject’s EOS telephone call will not be collected by Idorsia. 
For subjects enrolled in ID-078A303, AEs that are ongoing at ID-078A302 EOT will be 
followed up in the extension study and reported in the ID-078A303 eCRF on a dedicated 
page. 

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9.2 Serious adverse events 
9.2.1 Definitions of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one 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 or prolongation of existing hospitalization. 
• 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 when, based upon appropriate medical judgment, they may jeopardize the 
subject, and may require medical or surgical intervention to prevent one 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 informed consent) 
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. 
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
9.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent up to EOS must be reported on AE 
pages in the eCRF and on an SAE form, regardless of the investigator-attributed causal 
relationship with study treatment or study-mandated procedures. 
All SAEs with an onset date after signing of informed consent and up to enrollment in 
ID-078A303 (i.e., ID-078A302 EOT) for subjects that are participating in the extension 
study must be recorded on AE pages of the ID-078A302 eCRF. 
An SAE is defined as related to protocol-mandated procedures if it appears to have a 
reasonable possibility of a causal relationship to either the study design or to 

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protocol-mandated procedures (e.g., discontinuation of a subject’s previous treatment 
during a washout period, leading to exacerbation of underlying disease). 
9.2.3 Follow-up of serious adverse events 
SAEs still ongoing more than 30 days after EOS must be followed up until resolution or 
stabilization, or until the event outcome is provided. The follow-up information obtained 
after the subject’s EOS telephone call must be reported to Idorsia Global Drug Safety, but 
it is not recorded in the eCRF. 
For subjects enrolled in ID-078A303, SAEs that are ongoing at ID-078A302 EOT will be 
followed up in the extension study and reported in the ID-078A303 eCRF on a dedicated 
page. 
9.2.4 After the 30-day follow-up period 
New SAEs occurring after the 30-day follow-up period must be reported to Idorsia Global 
Drug Safety within 24 hours of the investigator’s knowledge of the event, only if 
considered by the investigator to be causally related to previous exposure to the study 
treatment. 
9.2.5 Reporting procedures 
All SAEs must be reported by the investigator to Idorsia Global Drug Safety within 
24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be related 
to study treatment. 
The SAE forms must be sent to Idorsia Global Drug Safety (contact details are provided 
on the SAE form). The investigator 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 also be reported within 
24 hours of receiving it. Idorsia Global Drug Safety personnel may contact the investigator 
to obtain further information. 
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The expectedness of an adverse reaction is determined by Idorsia in the reference safety 
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[ACT-541468 IB]. Any SAE that is assessed as related and unexpected against the RSI of 
the ACT-541468 IB [ACT-541468 IB] is known as a SUSAR and must be reported by 
Idorsia to concerned health authorities (including the EudraVigilance database if the study 
is conducted in Europe), IECs/IRBs and investigators. 
9.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. 
9.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring after study 
start (i.e., signing of informed consent) up to EOS must be reported within 24 hours of the 
investigator’s knowledge of the event. 
Pregnancies must be reported on the Idorsia Pregnancy form, which is faxed to Idorsia 
Global Drug Safety (see contact details provided on the Pregnancy form), and on an AE 
page in the eCRF. 
9.3.2 Follow-up of pregnancy 
Pregnancies must be followed-up to their conclusion for all randomized subjects and the 
outcome must be reported to Idorsia Global Drug Safety. 
Any AE associated with the pregnancy occurring during the follow-up period after DB 
study treatment discontinuation must be reported on separate AE pages in the eCRF. Any 
SAE occurring during the pregnancy must be reported on an SAE form as described in 
Section 9.2.5. 
9.4 Study safety monitoring 
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific examinations as required) is monitored and reviewed on a continuous basis 
by the Idorsia Clinical Team (in charge of ensuring subjects’ safety as well as data quality). 
In addition, an IDMC and an ISB are monitoring safety data [see Section 3.2.2]. 
10 STATISTICAL METHODS 
All statistical analyses will be conducted by Idorsia or by designated CROs supervised by 
Idorsia. 
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. 

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10.1 Analysis sets 
A subject must have given informed consent before being included in any analysis set. 
10.1.1 Screened Analysis Set 
The Screened Analysis Set includes all subjects who entered screening and have a subject 
identification number. 
10.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects assigned to a DB study treatment. In 
order to adhere to the intention-to-treat principle as much as possible: 
• 
Subjects are evaluated according to the treatment and strata they have been assigned 
to, which may differ from the treatment they have received; 
• 
All available data are included. 
10.1.3 Per-Protocol Set 
The Per-Protocol Set (PPS) comprises all subjects from the FAS who complied with the 
protocol sufficiently to be likely to exhibit the treatment effects. Criteria for sufficient 
compliance include exposure to treatment, availability of measurements, and absence of 
major protocol deviations that have an impact on the treatment effect. The full list of criteria 
will be finalized before unblinding treatment codes. 
10.1.4 Safety Set 
The Safety Set includes all subjects who received at least one dose of DB study treatment. 
Subjects will be evaluated according to the actual treatment they received, which may 
differ from the randomly assigned treatment. 
10.1.5 Treatment Withdrawal Set 
The Treatment Withdrawal Set comprises all subjects included in the Safety Set who 
received single-blind placebo treatment in the run-out period. 
10.1.6 Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set (PK Set) includes all subjects in the Safety Set who 
have at least 1 PK sample collected after initiation of DB study treatment. Subjects 
receiving placebo will be excluded from the PK set. 
10.1.7 Patient Preferences Analysis Set 
The Patient Preferences Analysis Set includes all subjects in the Safety Set who have 
answered at least one patient preferences questionnaire after initiation of study treatment. 

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10.1.8 Usage of the analysis sets 
The analyses of efficacy endpoints including baseline and disease characteristics will be 
performed using the FAS, and the PPS for certain sensitivity analyses. 
The Safety Set will be used for the analysis of safety endpoints (including previous and 
concomitant medications, and study treatment exposure). 
Subject data will be listed using the Safety Set, unless otherwise specified. 
The Treatment Withdrawal Set will be used for the analysis of endpoints used to assess 
withdrawal symptoms (e.g., BWSQ total score) and rebound insomnia (e.g., objective and 
subjective sleep parameters: WASO, LPS, TST, sWASO, sLSO, and sTST). 
The analysis of ACT-541468 plasma concentrations 9–10 h post-dose will be performed 
using the PK Set. 
The Patient Preferences Analysis Set will be used for the analysis of endpoints to assess 
patient preferences. 
10.2 Variables 
Detailed description of study efficacy and safety variables (endpoints) can be found in 
Section 6 of this protocol. 
10.3 Description of statistical analyses 
10.3.1 Analysis of the primary and secondary efficacy variables 
10.3.1.1 Overall testing strategy 
The Type I error rate will be controlled for the testing of multiple null hypotheses 
associated with the primary and secondary endpoints assessed at 1 and 3 months of 
treatment and the two dose levels included in this study, i.e., 10 mg and 25 mg. 
The eight statistical null hypotheses associated with the primary efficacy endpoints are: 
Sleep maintenance: 
• H1WASO: Higher Dose – Placebo = 0 for WASO at Month 1 
• H2WASO: Higher Dose – Placebo = 0 for WASO at Month 3 
• H3WASO: Lower Dose – Placebo = 0 for WASO at Month 1 
• H4WASO: Lower Dose – Placebo = 0 for WASO at Month 3 
Sleep onset: 
• H1LPS: Higher Dose – Placebo = 0 for LPS at Month 1 
• H2LPS: Higher Dose – Placebo = 0 for LPS at Month 3 

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• H3LPS: Lower Dose – Placebo = 0 for LPS at Month 1 
• H4LPS: Lower Dose – Placebo = 0 for LPS at Month 3 
The eight statistical null hypotheses associated with the secondary efficacy endpoints are: 
Sleep quantity: 
• H1sTST: Higher Dose – Placebo = 0 for sTST at Month 1 
• H2sTST: Higher Dose – Placebo = 0 for sTST at Month 3 
• H3sTST: Lower Dose – Placebo = 0 for sTST at Month 1 
• H4sTST: Lower Dose – Placebo = 0 for sTST at Month 3 
Next day performance: 
• H1IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 1 
• H2IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 3 
• H3IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 1 
• H4IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 3 
where ‘Higher Dose’, ‘Lower Dose’, and ‘Placebo’ represent the mean change from 
baseline for the given endpoint (WASO, LPS, sTST or IDSIQ sleepiness domain score) 
and time point (Month 1 or Month 3) for the 25 mg, 10 mg and placebo treatment group, 
respectively. 
Each null hypothesis will be tested against the alternative hypothesis: that ACT-541468 
improves WASO / LPS / sTST / IDSIQ sleepiness domain score at the given dose (10 or 
25 mg) and time point (Month 1 or Month 3) compared to placebo. 
The order of testing and the alpha level applied to each null hypothesis will be based on 
the Bonferroni-based gatekeeping procedure [Bretz 2009] (shown in Figure 2 below as a 
directed graph) that will control the study-wise Type I error at a two-sided 5% significance 
level. To account for the concurrent evaluation (multiple comparison) of two distinct 
endpoint categories (i.e., sleep maintenance and sleep onset) a Bonferroni correction is 
applied. Both endpoint categories will be tested at half of the two-sided 5% significance 
level. This supports the sponsor’s intention to make a superiority claim versus placebo for 
efficacy in either a sleep maintenance and/or sleep onset indication. The remaining 
hypotheses will be tested following the gatekeeping strategy moving from Month 1 to 
Month 3 for higher dose ACT-541468 vs placebo and then from Month 1 to Month 3 for 
lower dose ACT-541468 vs placebo. The pre-specified proportion of alpha that will be 
distributed once a given null hypothesis (node) is rejected is shown on the arrow in the 
directed graph. If a certain null hypothesis cannot be rejected, then the alpha level used for 
that test is absorbed at that node and not distributed further. 

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Figure 2 
Hypothesis testing strategy 
 

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10.3.1.2 Hypotheses and statistical model 
The main analysis will be performed using the FAS. 
A longitudinal data analysis method (i.e., linear mixed effects model) will be used for the 
analysis of change from baseline in WASO, LPS, sTST, and IDSIQ scores, separately. All 
available data, regardless of occurrence of intercurrent events (e.g., study treatment 
discontinuation, the use of prohibited medication), will be included in the model. 
The analysis model will adjust for the baseline value of the relevant response variable 
(either WASO, LPS, sTST or IDSIQ sleepiness domain score), age group (< 65; 
≥ 65 years), treatment (higher dose; lower dose; placebo), time point (Month 1; Month 3), 
and the interaction of treatment by time point, and baseline by time point. 
To evaluate the efficacy hypotheses, appropriate contrasts will be used to test the treatment 
differences of interest (i.e., the difference in Least Squares mean change from baseline 
between higher dose ACT-541468 vs placebo and lower dose ACT-541468 vs placebo at 
Month 1 and Month 3). An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. This approach relies on the missing at random 
(MAR) assumption. 
A term for ‘center’ is not included in the statistical model due to the low numbers of 
subjects expected in many centers. Randomization was not stratified by center for the same 
reason. 
10.3.1.3 Handling of missing data 
For WASO and LPS values, if one of the two values is missing either for baseline, Month 1 
or Month 3, the single value available will be used as the mean for this time point. 
Otherwise, the mean value will be considered missing for that time point. 
For sTST values, subjects must have at least 3 days of data during each week to calculate 
a weekly mean. Otherwise, the mean value will be considered missing for that week. 
For IDSIQ sleepiness domain scores, subjects must have at least 4 days of data during each 
week to calculate a weekly mean. Otherwise, the mean value will be considered missing 
for that week. 
Note that the above implies implicit imputation: the missing data point(s) is(are) given the 
same value as the mean of the non-missing data point(s) of that same week or time point. 
10.3.1.4 Supportive/sensitivity analyses 
The impact of deviations from the MAR assumption underlying the linear mixed effects 
model as well as the incidence and pattern of missing values will be explored in order to 
evaluate the possible impact on results and will be described in the SAP. 

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The analysis performed for the primary and secondary endpoints will be repeated using the 
PPS in order to assess the effect protocol deviations have on the results. 
10.3.2 Analysis of other efficacy variables 
Summary statistics will be provided for other efficacy endpoints using either number (%) 
of subjects for categorical variables or descriptive statistics (e.g., mean, SD, median, min., 
max.) for continuous variables. Further details will be described in the SAP. 
10.3.3 Analysis of the safety variables 
Analyses of safety endpoints will be performed using the Safety Set, unless noted 
otherwise. 
Adverse events 
AEs will be coded using MedDRA. The number (%) of subjects experiencing a TEAE 
(including SAEs, AESIs after adjudication by the ISB, and AEs leading to premature 
discontinuation of the DB study treatment) will be summarized by System Organ Class 
(SOC) and/or PT, and maximum intensity. A subject with multiple intensities reported for 
an AE will be summarized under the maximum intensity recorded for the event. A subject 
with multiple occurrences of an AE is counted only once in the AE category (e.g., SOC, 
PT). 
Laboratory data 
Laboratory analyses will be based on data received from the central laboratory. Observed 
values and changes from baseline to Month 1 and Month 3 in both hematology and blood 
chemistry laboratory parameters will be summarized. The number (%) of subjects having 
a marked laboratory abnormality during DB study treatment will be tabulated. 
Vital signs and weight 
Observed values and changes from baseline to Month 1 and Month 3 in vital signs (mean 
of the two PSG nights in systolic and diastolic BP, and pulse rate) will be summarized. 
Observed values and changes from baseline to Month 3 in body weight will be summarized. 
Electrocardiograms 
Observed values and changes from baseline to Month 3 for each ECG parameter (QTcB, 
QTcF, heart rate, PR, QRS) will be summarized. The number (%) of subjects having a 
marked ECG abnormality during DB study treatment will be tabulated. 
Withdrawal symptoms 
The Treatment Withdrawal Set will be used to assess the potential for withdrawal 
symptoms. 

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The BWSQ total score will be summarized using descriptive statistics for the observed 
values and changes from the last assessment on DB treatment (Visit 8, 2nd morning) to the 
beginning and the end of the treatment withdrawal period (in the morning at Visit 9 and at 
Visit 10, respectively). 
In addition, withdrawal symptoms after DB study treatment withdrawal will be assessed 
through the incidence of AEs and marked ECG abnormalities occurring during the 
treatment withdrawal period. The number (%) of subjects having, separately, an AE and a 
marked ECG abnormality during the treatment withdrawal period will be tabulated. 
Insomnia rebound effect 
The Treatment Withdrawal Set will be used to assess the potential for rebound insomnia. 
The changes from baseline to the treatment withdrawal period (Visit 9, run-out) in 
objective sleep parameters (WASO, LPS and TST) will be summarized using descriptive 
statistics. 
The changes from baseline (mean value based on the screening sleep diary entries 
performed at home in the 7 days immediately preceding the first PSG at Visit 3) to the 
treatment withdrawal period (after PSG night at Visit 9) in subjective sleep parameters 
(sWASO, sLSO, and sTST) will be summarized using descriptive statistics. 
Next-day residual effect 
Observed values and changes from baseline to Month 1 and Month 3 in Coding sub-test©, 
SDS©, and VAS scores (mm) assessing morning sleepiness, daytime alertness and daytime 
ability to function, will be summarized. 
C-SSRS© 
Number (%) of subjects with suicidal ideation, suicidal behavior, and/or self-injurious 
behavior without suicidal intent based on the C-SSRS© during DB treatment will be 
tabulated. 
Shifts from baseline showing any changes in suicidal ideation and suicidal behavior during 
DB treatment will also be provided. Subjects will be summarized under the worst of the 
following three categories, shown here in the order from best to worst: 1) No suicidal 
ideation or behavior, 2) Suicidal ideation only, and 3) Suicidal ideation and behavior. 
10.3.4 Analysis of pharmacokinetic variables 
PK analyses will be performed using the PK Set. 
Descriptive statistics (n, mean, standard deviation, coefficient of variation [CV%], m 
[number of non-zero concentrations], geometric mean, geometric standard deviation, 
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concentrations collected approximately 9–10 h post-dose (morning after the second PSG 
night) at Visit 6 and Visit 8 will be provided. 
Exposure-safety analysis 
The exposure-safety relationship will be explored using C9–10h (plasma concentrations of 
ACT-541468 in the morning after the second PSG night at Visit 6 and Visit 8) and will be 
based on the PK Set. Safety parameters considered for this analysis will likely include 
selected AEs (e.g., somnolence), changes from baseline in Coding sub-test©, SDS©, VAS 
scores (mm) assessing morning sleepiness, daytime alertness and daytime ability to 
function, and other parameters as relevant. Further details will be described in the SAP. 
10.3.5 Subgroup analyses 
Subgroup analyses will be conducted to explore the uniformity of the overall treatment 
effects with regards to efficacy and safety variables and will be described in the SAP. 
10.3.6 Analysis of the patient preferences variable 
Discrete choice data from the PAUSe sub-study will be analyzed using multinomial logit, 
random parameter logit, latent class and heteroscedastic conditional logit models. 
Socio-demographic and clinical characteristics, and health literacy and numeracy data will 
be collected from the study participants, and used as covariates for assessing preference 
and scale heterogeneity. The results of the DCE may be used to specify the weights and 
partial value functions in a quantitative benefit-risk assessment (BRA) of insomnia 
treatments. The BRA will be run both deterministically and probabilistically and will 
facilitate a stochastic multicriteria acceptability analysis (SMAA). The SMAA will involve 
running up to 10,000 iterations of the BRA, each time sampling weights and performance 
inputs from pre-specified distributions. Further details on analysis of the PAUSe sub-study 
will be provided in a separate SAP. 
10.4 Interim analyses 
No formal interim analysis will be performed for determining whether to stop (or modify) 
the study early (i.e., no hypothesis testing will be conducted ad interim). Therefore, no 
adjustment for multiple testing is required. This study includes an IDMC and ISB that will 
assess the safety of ACT-541468 on a regular basis as per the IDMC and ISB charters, 
respectively. To support the review of the safety and efficacy data by the IDMC, blinded 
data will be provided by Idorsia (or designated CRO) for the open sessions, and unblinded 
data will be provided by the ISAC for the closed sessions. 
10.5 Sample size 
The assumptions used to calculate sample size are provided in Table 2. 

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Figure 3 
Effect of testing multiple null hypotheses on power at a given sample 
size 
 
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timeliness of the data reported. All source documents are recommended to be completed 
in a neat, legible manner to ensure accurate interpretation of the data. Data reported in the 
eCRF derived from source documents must be consistent with the source documents. 
eCRF data will be reported through electronic data capture (a web-based tool). 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/delegate will approve the data (i.e., confirm the accuracy of the data recorded) 
using an electronic signature (ref. to US 21 CFR Part 11). 
50
60
70
80
90
100
Effect size = 0.37
Number of independent null hypotheses
Power (%)
based on two-sample z-test (alpha = 2.5% two-sided)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
N = 350 per group
N = 300 per group
N = 250 per group

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Entries recorded by the subject on the hand-held device (i.e., ESS©, sleep diary, VAS, ISI©, 
IDSIQ, PGA-S daytime symptoms, PGI-C daytime and night-time symptoms, PGI-S 
night-time symptoms, SDS©, BWSQ) and on paper (i.e., Coding sub-test©) as well as the 
physician-reported global assessment on a tablet at site (i.e., C-SSRS©, MMSE©, PAUSe) 
and on paper (i.e., MINI©) are considered source data. Site personnel will review and 
ensure completeness and readability of the subjects’ entries. Site personnel will be allowed 
to instigate correction or deletion of subject metadata or answers in physician-reported 
assessments. Site personnel will not be allowed to alter subject-generated data. A data 
correction form will be completed by the site personnel to request any data changes and 
sent to the CRO provider that will process the changes as per CRO data management 
procedures. 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be noted 
on the eCRF. 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
Idorsia and any CROs, subjects must be identified only by number and never by their name 
or initials, date of birth, hospital numbers, or any other identifier. The investigator/delegate 
must keep a subject identification code list at the site, showing the screening/randomization 
number, the subject’s name, date of birth, and address or any other locally accepted 
identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be sent to 
Idorsia, and must be kept in strict confidence by the investigator/delegate. 
11.3 Database management and quality control 
eCRFs will be used for all subjects. The investigators will have access to the site eCRF 
data until the database is locked. Thereafter, they will have read-only access. The eCRF 
must be kept current to reflect subject status at any time point during the course of the 
study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Idorsia 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. If discrepant data are detected, a query specifying the problem and requesting 
clarification will be issued and visible to the investigator/delegate via the eCRF. All 
electronic queries visible in the system either require a data correction (when applicable) 

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and a response from the investigator/delegate to clarify the queried data directly in the 
eCRF, or simply a data correction in the eCRF.  
This process will continue until database closure. 
The investigator/delegate must, on request, supply Idorsia 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 
confidentiality is protected. 
Laboratory samples, ECGs, PSGs and hand-held device data will be processed through a 
central laboratory / CRO and the results will be electronically sent to Idorsia. 
If local laboratory data is obtained, as may be required per protocol in certain instances, it 
must be entered in the eCRF by the site personnel. 
AEs are coded according to the latest version of MedDRA used by Idorsia. 
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 Idorsia QS documents. After database closure, the investigator will receive the 
eCRFs of the subjects of his/her site (including the audit trail) on electronic media or as a 
paper copy. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
Idorsia personnel and the investigators will ensure that the study is conducted in full 
compliance with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki”, and 
with the laws and regulations of the country in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, 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 to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 

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A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  
If a member of the study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
12.3 Informed consent 
It is the responsibility of the investigator/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/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 shall be paid to the information needs of specific subject populations and of 
individual subjects, as well as to the methods used to give the information. Adequate time 
shall be given for the subject to consider his or her decision to participate in the study and 
it shall be verified that the subject has understood the information (e.g., by asking the 
subject to explain what is going to happen). 
The ICF will be provided in the country local language(s). 
Site personnel authorized (according to local regulation) to participate in the consent 
process and/or to obtain consent from the subject will be listed on the Delegation of 
Authority (DoA) form supplied by Idorsia. A study physician must always be involved in 
the consent process. In European countries, the informed consent must be obtained by a 
physician. 
The subject and authorized site personnel listed on the DoA form supplied by Idorsia must 
sign, personally date, and time (if the first study-mandated procedure is to be performed on 
the same day informed consent is obtained) the ICF before any study-related procedures 
(i.e., any procedures required by the protocol) begin.  
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 number, 
the date and, if applicable, time when the subject was first introduced to the study, the date 
and, if applicable, time of consent, who participated in the consent discussion, who 
consented the subject, and any additional person 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. 

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12.4 Compensation to subjects and investigators 
Idorsia provides insurance in order 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 compensation of the subject in the event of study-related injuries will comply with 
applicable regulations. Study subjects will be reimbursed for the study-related expenses 
(e.g., travel costs, meals, hotel), and may be offered financial compensation for their 
participation in the study only to the extent permitted by applicable local regulations. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB 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. 
If a protocol deviation occurs, the investigator/delegate will inform Idorsia or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to Idorsia 
or (overruling) local requirements. 
All protocol deviations will be reported in the CSR. IECs/IRBs will be provided with 
listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according 
to their requirements. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for 25 years to comply with Idorsia’s 
requirements (i.e., as specified in the clinical study agreement), and national and/or 

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international regulations, whichever would be the longest period. If the investigator 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 
and Idorsia to store these documents outside the site, so that they can be retrieved in the 
event of a regulatory inspection. No study document should be destroyed without prior 
written approval from Idorsia. Should the investigator wish to assign the study records to 
another party, or move them to another location, Idorsia must be notified in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per US 21 CFR Part 11 
or equivalent standard) and if the CRA has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the eCRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
access to the system, 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 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Idorsia’s instructions. If it were not possible for the 
CRA to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, a Site Initiation Visit (SIV) will be performed after the required 
essential study documents are approved by Idorsia. The study treatment will be shipped to 
the site upon approval of the required essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the SIV. 

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The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the PI 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. Idorsia monitoring standards 
require full verification that informed consent has been provided, verification of adherence 
to the inclusion/exclusion criteria, documentation of SAEs, and the recording of the main 
efficacy, safety, and tolerability endpoints. Additional checks of the consistency of the 
source data with the eCRFs will be performed according to the study-specific monitoring 
guidelines. The frequency of the monitoring visits will be based on subject recruitment rate 
and critical data-collection times. 
The PI must ensure that the eCRF is completed after a subject’s visit (site visit or telephone 
call), 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(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a 
hospital other than the study site, the investigator is responsible for contacting that hospital 
in order to document the SAE, in accordance with local regulations. 
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 enroll any subjects, 
the close-out visit may be performed prior to study database closure at the discretion of 
Idorsia. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of contents listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is filed. 
This note to file should be present in the specific tab of the document in the ISF. 

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The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Idorsia. If the site needs to transfer the 
ISF to another location and/or if site facility can no longer store the ISF, the PI must 
immediately inform Idorsia. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 
12.10 Audit 
Idorsia’s Pharmaceutical Development group representatives or delegates 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 Idorsia’s requirements (e.g., standard operating procedures) will 
also be verified. Prior to initiating this audit, the investigator will be contacted by Idorsia 
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. 
12.11 Inspections 
Health authorities and/or IECs/IRBs may also conduct an inspection of this study (during 
the study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform Idorsia (usually via the CRA) that such a request has been made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication 
Idorsia will post the key elements of this protocol and the summary of results on Idorsia’s 
Clinical Trial Register and within the required timelines on publicly accessible databases 
(e.g., clinicaltrials.gov, EU database), as required by law and regulation. 
Study results will be documented in a CSR (the PAUSe sub-study results from both 
ID-078A301 and ID-078A302 studies will be reported in a separate CSR) that will be 
signed by Idorsia representatives and the Coordinating Investigator. 
In accordance with the Good Publication Practices and ethical practice, 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. 

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

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14 APPENDICES 
Appendix 1 
Alcohol restrictions during the study 
The subjects must not drink alcohol for at least 24 hours prior to the start of the PSG 
assessments, as well as during the PSG assessments including the morning after the second 
PSG assessment, until they leave the center. 
On non-PSG nights, the subjects will be instructed to limit alcohol to a maximum of 
2 drinks per day, and to refrain from drinking alcohol at least 3 hours before going to bed. 
A drink is defined as: 
a. A bottle/can of 33 cL / 12 ounces of beer (≈14 grams alcohol)
b. A glass of 10–12 cL / 4 ounces of wine (≈12 grams alcohol)
c.
A small glass of 3–4 cL / 1 ounce of liquor (≈9 grams alcohol)

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Appendix 2 
Caffeine content of common beverages 
The content of caffeine in common caffeine beverages is approximately: 
a.
A standard cup of brewed or restaurant-style coffee contains approximately
150–200 mg caffeine.
b. A can of most soda drinks (unless decaffeinated soda drinks) contains approximately
50 mg caffeine.
c.
A can of energy drink contains approximately 150–200 mg caffeine.

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Appendix 3 
Forbidden and restricted concomitant medications 
1.
Forbidden (F) or restricted (R) concomitant medications due to CNS side effects.
To be eligible, subjects must not be treated with CNS-active drugs for 5 half-lives of
the respective drug (but at least 2 weeks) prior to Visit 1. The use of CNS-active
drugs is forbidden or restricted until 24 hours after EOT (Visit 10).
Drug Class 
Examples 
Forbidden 
/ Restricted 
Comment 
Centrally Acting 
Anticholinergics 
e.g., tropatepine, oxybutynin,
solifenacin, dimenhydrinate,
dextromethorphan.
F 
Antihistamines 
Sedating: e.g., carbinoxamine, 
triprolidine HCl, acrivastine, 
azatadine, chlorpheniramine, 
doxylamine, hydroxyzine, ketotifen, 
promethazine & timeprazine, 
diphenhydramine HCl. 
F 
Non-sedating: e.g., cetirizine, 
desloratidine, fexofenadine, 
levocabasteine, loratidine. 
R 
Non-sedating 
antihistamines may be used 
maximum twice weekly for 
allergic symptoms. 
Psychotropics 
Stimulants: e.g., amphetamine 
derivatives, ephedrine derivatives, 
modafinil, armodafinil, 
methylphenidate, aripiprazole, 
pramipexole, levodopa. 
F 
Antidepressants: e.g., bupropion, 
citalopram, doxepin, duloxetine, 
escitalopram, fluoxetine, 
fluvoxamine, nefazodone, 
paroxetine, sertraline, trazodone, 
amitriptyline, clomipramine, 
desipramine, imipramine, 
mirtazapine, nortriptyline, 
trimipramine, venlafaxine, 
hydracarbazine, moclobemide, 
selegiline. 
F 
Antipsychotics, including depot 
neuroleptics: e.g., quetiapine, 
olanzapine. 
F 

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Anxiolytics: e.g., alprazolam, 
buspirone, clorazepate, diazepam, 
flurazepam, lorazepam, midazolam, 
quazepam, temazepam, triazolam. 
F 
Hypnotics: e.g., ramelteon, 
suvorexant, zolpidem and OTC. 
F 
Cholinesterase inhibitors: e.g., 
donepezil, galantamine. 
Mood stabilizers, e.g., 
carbamazepine, gabapentin, 
lamotrigine, 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, valerian, passiflora, 
hypericum. 
F 
Others: e.g., tryptophan, melatonin. 
F 
Anticonvulsants 
Barbiturates, benzodiazepines, 
GABA analogs, hydantoins 
phenyltriazines (e.g., lamotrigine) 
succinimides (e.g., ethosuximide) 
F 
Other 
Warfarin, heparin, ticlopidine 
F 
Isotrenitoin  
F 
Systemic glucocorticoids: e.g., 
dexamethasone, methylprednisone, 
prednisone. 
F 
Inhaled corticosteroids are 
permitted 
Diet pills (prescription and OTC). 
F 

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Pseudoephedrine 
R 
May only be used before 
2 pm, and no more than 
twice a week. Dosage is 
limited to 30 mg of active 
ingredient in each tablet. 
Extended release 
formulations are forbidden. 
Anti-emetics: e.g., domperidone, 
metoclopramide. 
F 
GABA = gamma-aminobutyric acid; NSAID = nonsteroidal anti-inflammatory drug; OTC = over-the-counter. 
2.
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 within 1 week prior to Visit 2
and are forbidden until 24 hours after EOT (Visit 10).
CYP3A4 moderate and strong inhibitors and CYP3A4 moderate and strong inducers: 
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 
Grapefruit and grapefruit juice 
Seville oranges (bitter) and Seville oranges juice 
CNS = central nervous system; CYP = cytochrome P450; HIV = human immunodeficiency virus. 

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Insomnia disorder 
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Version 5 
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Insomnia disorder 
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Version 5 
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EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 123/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
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EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
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Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 126/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 127/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 128/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 129/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 130/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 131/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 132/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 133/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 134/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 135/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 136/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 
 
 
 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 137/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 
 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 138/154 
Confidential 
EudraCT 2017-004643-20 
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Insomnia disorder 
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Version 5 
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EudraCT 2017-004643-20 
Doc No D-18.262 
 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 140/154 
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EudraCT 2017-004643-20 
Doc No D-18.262 
 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 141/154 
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EudraCT 2017-004643-20 
Doc No D-18.262 
 
 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 142/154 
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EudraCT 2017-004643-20 
Doc No D-18.262 
 
 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
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EudraCT 2017-004643-20 
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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 144/154 
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EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 145/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 146/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 147/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 148/154 
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EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 149/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 150/154 
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EudraCT 2017-004643-20 
Doc No D-18.262 

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Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 151/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 152/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 153/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262 
 
 

ACT-541468 
Insomnia disorder 
Protocol ID-078A302 
Version 5 
8 November 2018, page 154/154 
Confidential 
EudraCT 2017-004643-20 
Doc No D-18.262