Multi-center, Double-blind, Parallel-group, Randomized, Placebo-controlled, Three Doses, 40-week Extension to Studies ID-078A301 and ID-078A302 to Assess the Long Term Safety and Tolerability 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-078A303 - Multi-center, double-blind, parallel-group, randomized, 
placebo-controlled, three doses, 40-week extension to studies ID-078A301 and ID-
078A302 to assess the long-term safety and tolerability of ACT-541468 in adult and 
elderly subjects with insomnia disorder 
ClinicalTrials.gov Identifier:  
NCT03679884 
Date of document: 
17 February 2020 

TPL-100601_v01 
Daridorexant (ACT-541468) 
Insomnia Disorder 
Protocol ID-078A303 
Multi-center, double-blind, parallel-group, randomized, placebo-controlled, three 
doses, 40-week extension to studies ID-078A301 and ID-078A302 to assess the 
long-term safety and tolerability of ACT-541468 in adult and elderly subjects with 
insomnia disorder 
Study Phase: 
3 
EudraCT Number: 
2017-004644-38 
Status and version: 
Final Version 3 
Date: 
17 February 2020 
Document type 
Global protocol 
Idorsia document number 
(Doc No.): 
D-20.025
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The information contained in this document, especially unpublished data, is the property of the sponsor of 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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Insomnia Disorder 
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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 ORGANIZATION 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 
Daridorexant (ACT-541468) 
Indication 
Insomnia disorder 
Protocol number, study title 
ID-078A303 
Multi-center, double-blind, parallel-group, randomized, placebo-controlled, three doses, 
40-week extension to studies ID-078A301 and ID-078A302 to assess the long-term safety
and tolerability 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 ICH GCP 
guidelines. 
Title 
Name 
Date 
Signature 

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Insomnia Disorder 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
Daridorexant (ACT-541468) 
Indication 
Insomnia disorder 
Protocol number, study title 
ID-078A303 
Multi-center, double-blind, parallel-group, randomized, placebo-controlled, three doses, 
40-week extension to studies ID-078A301 and ID-078A302 to assess the long-term safety 
and tolerability 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. 
 
 
Principal 
Investigator 
Country 
Site 
number 
Town 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 

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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................11 
SUBSTANTIAL GLOBAL AMENDMENT 2 .................................................................14 
PROTOCOL SYNOPSIS ID-078A303 .............................................................................17 
PROTOCOL ......................................................................................................................27 
1 
BACKGROUND .........................................................................................................27 
1.1 
Insomnia disorder .........................................................................................27 
1.1.1 
Definition ..........................................................................................27 
1.1.2 
Epidemiology ....................................................................................27 
1.1.3 
Treatment ..........................................................................................27 
1.1.4 
Unmet medical need .........................................................................28 
1.2 
Study treatment: ACT-541468 .....................................................................28 
1.2.1 
The orexin system .............................................................................28 
1.2.2 
ACT-541468 properties ....................................................................29 
1.3 
Purpose and rationale of the study ................................................................29 
1.3.1 
Purpose of the study ..........................................................................29 
1.3.2 
Rationale for the study ......................................................................29 
1.4 
Summary of known and potential risks and benefits ....................................30 
1.4.1 
Benefits and risks of the study treatments ........................................30 
1.4.2 
Safety and risk-minimization measures taken in the present 
study ..................................................................................................31 
2 
STUDY OBJECTIVES ...............................................................................................32 
2.1 
Primary objective ..........................................................................................32 
2.2 
Exploratory objective ...................................................................................32 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................32 
3.1 
Study design .................................................................................................32 
3.1.1 
Study periods ....................................................................................33 
3.1.1.1 
Treatment phase ......................................................................33 
3.1.1.2 
Safety follow-up phase ............................................................34 
3.1.2 
Study duration ...................................................................................35 
3.2 
Study design rationale ..................................................................................35 
3.3 
Study committees .........................................................................................36 

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4 
SUBJECT POPULATION ..........................................................................................37 
4.1 
Subject population description .....................................................................37 
4.2 
Rationale for the selection of the study population ......................................37 
4.3 
Inclusion criteria ...........................................................................................37 
4.4 
Exclusion criteria ..........................................................................................37 
4.5 
Criteria for women of childbearing potential ...............................................38 
4.5.1 
Definition of childbearing potential ..................................................38 
4.5.2 
Acceptable methods of contraception ...............................................38 
5 
TREATMENTS ..........................................................................................................39 
5.1 
Study treatment .............................................................................................39 
5.1.1 
Investigational treatment and matching placebo: Description 
and rationale ......................................................................................39 
5.1.2 
Study treatment administration .........................................................39 
5.1.3 
Treatment assignment .......................................................................39 
5.1.4 
Blinding ............................................................................................40 
5.1.4.1 
Double-blind treatment period ................................................40 
5.1.4.2 
Run-out period .........................................................................41 
5.1.5 
Unblinding ........................................................................................41 
5.1.5.1 
Sponsor unblinding for interim and final analyses ..................41 
5.1.5.2 
Unblinding for IDMC review ..................................................41 
5.1.5.3 
Unblinding for suspected unexpected serious adverse 
reactions ...................................................................................41 
5.1.5.4 
Emergency procedure for unblinding ......................................42 
5.1.6 
Study treatment supply .....................................................................42 
5.1.6.1 
Study treatment packaging and labeling .................................42 
5.1.6.2 
Study treatment distribution and storage .................................42 
5.1.6.3 
Study treatment dispensing .....................................................43 
5.1.6.4 
Study treatment return and destruction ...................................43 
5.1.7 
Study treatment accountability and compliance with study 
treatment ...........................................................................................43 
5.1.7.1 
Study treatment accountability ................................................43 
5.1.7.2 
Study treatment compliance ....................................................44 
5.1.8 
Study treatment dose adjustments and interruptions ........................44 
5.1.9 
Premature discontinuation of study treatment ..................................44 
5.1.10 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................45 
5.1.11 
Study-specific measures for subject retention ..................................46 
5.2 
Previous and concomitant therapy ................................................................46 
5.2.1 
Definitions ........................................................................................46 

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5.2.2 
Reporting of previous/concomitant therapy in the eCRF .................46 
5.2.3 
Allowed concomitant therapy ...........................................................47 
5.2.4 
Forbidden concomitant therapy ........................................................47 
5.2.5 
Forbidden concomitant diet and activities ........................................47 
6 
STUDY ENDPOINTS ................................................................................................48 
6.1 
Safety endpoints ...........................................................................................48 
6.2 
Exploratory efficacy endpoints .....................................................................49 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................49 
7.1 
Study visits ...................................................................................................49 
7.1.1 
Visit 1 ................................................................................................49 
7.1.2 
Unscheduled visits ............................................................................50 
7.1.3 
Telephone calls between visits. ........................................................50 
7.2 
Study assessments .........................................................................................55 
7.2.1 
Demographics ...................................................................................56 
7.2.2 
Safety assessments ............................................................................56 
7.2.2.1 
Body weight and height ...........................................................56 
7.2.2.2 
Physical examination ...............................................................56 
7.2.2.3 
Vital signs ................................................................................57 
7.2.2.4 
Sheehan Disability Scale© .......................................................57 
7.2.2.5 
Columbia Suicide Severity Rating Scale©...............................57 
7.2.2.6 
Benzodiazepine Withdrawal Symptom Questionnaire ............57 
7.2.2.7 
Epworth Sleepiness Scale© ......................................................57 
7.2.2.8 
ECG assessment ......................................................................58 
7.2.3 
Efficacy assessments .........................................................................58 
7.2.3.1 
Sleep diary ...............................................................................58 
7.2.3.2 
Insomnia Severity Index© ........................................................59 
7.2.3.3 
Patient Global Assessment of Disease Severity ......................59 
7.2.3.4 
Patient Global Impression of Change ......................................59 
7.2.3.5 
Insomnia Daytime Symptoms and Impacts Questionnaire .....59 
7.2.4 
Laboratory assessments ....................................................................60 
7.2.4.1 
Type of laboratory ...................................................................60 
7.2.4.2 
Laboratory tests .......................................................................60 
8 
STUDY COMPLETION AND POST STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................62 
8.1 
Study completion as per protocol .................................................................62 
8.2 
Premature withdrawal from study ................................................................62 
8.3 
Premature termination or suspension of the study ........................................63 

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8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................63 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................64 
9.1 
Adverse events ..............................................................................................64 
9.1.1 
Definition of adverse events .............................................................64 
9.1.2 
Intensity of adverse events ................................................................65 
9.1.3 
Relationship to study treatment ........................................................66 
9.1.4 
Reporting of adverse events ..............................................................66 
9.1.5 
Follow-up of adverse events .............................................................66 
9.2 
Serious adverse events ..................................................................................66 
9.2.1 
Definitions of serious adverse events ...............................................66 
9.2.2 
Reporting of serious adverse events .................................................67 
9.2.3 
Follow-up of serious adverse events .................................................67 
9.2.4 
After the 30-day follow-up period ....................................................67 
9.2.5 
Reporting procedures ........................................................................67 
9.3 
Pregnancy .....................................................................................................68 
9.3.1 
Reporting of pregnancy ....................................................................68 
9.3.2 
Follow-up of pregnancy ....................................................................68 
9.4 
Study safety monitoring ................................................................................69 
10 STATISTICAL METHODS .......................................................................................69 
10.1 
Analysis sets .................................................................................................69 
10.1.1 
Enrolled Set .......................................................................................69 
10.1.2 
Full Analysis Set ...............................................................................69 
10.1.3 
Safety Set ..........................................................................................69 
10.1.4 
Treatment Withdrawal Set ................................................................70 
10.1.5 
Usage of the analysis sets .................................................................70 
10.2 
Variables .......................................................................................................70 
10.3 
Description of statistical analyses .................................................................70 
10.3.1 
Analysis of safety endpoints .............................................................70 
10.3.2 
Analysis of exploratory efficacy endpoints ......................................72 
10.3.3 
Subgroup analyses ............................................................................73 
10.4 
Interim analyses ............................................................................................73 
10.5 
Sample size ...................................................................................................73 
11 DATA HANDLING ....................................................................................................74 
11.1 
Data collection ..............................................................................................74 
11.2 
Maintenance of data confidentiality .............................................................75 
11.3 
Database management and quality control ...................................................75 

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12 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................76 
12.1 
Ethics and Good Clinical Practice ................................................................76 
12.2 
Independent Ethics Committee / Institutional Review Board ......................77 
12.3 
Informed consent ..........................................................................................77 
12.4 
Compensation to subjects and investigators .................................................78 
12.5 
Protocol adherence/compliance ....................................................................78 
12.6 
Protocol amendments ...................................................................................78 
12.7 
Essential documents and retention of documents .........................................79 
12.8 
Monitoring ....................................................................................................80 
12.9 
Investigator Site File .....................................................................................81 
12.10 
Audit .............................................................................................................81 
12.11 
Inspections ....................................................................................................81 
12.12 
Reporting of study results and publication ...................................................82 
13 REFERENCES ............................................................................................................83 
14 APPENDICES .............................................................................................................85 
 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule....................................................................52 
 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ...............................................................................................34 
Figure 2 
Probability of observing at least one adverse event ...................................74 
 
 
 

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LIST OF APPENDICES 
 
Appendix 1 
Alcohol restrictions during the study .........................................................85 
Appendix 2 
Caffeine content of common beverages .....................................................86 
Appendix 3 
Forbidden and restricted concomitant medications ....................................87 
Appendix 4 
Insomnia Severity Index©...........................................................................90 
Appendix 5 
Sheehan Disability Scale© ..........................................................................91 
Appendix 6 
Benzodiazepine Withdrawal Symptoms Questionnaire .............................92 
Appendix 7 
Sleep Diary .................................................................................................93 
Appendix 8 
Patient Global Assessment of Disease Severity and Patient Global 
Impression of Change .................................................................................95 
Appendix 9 
Insomnia Daytime Symptoms and Impacts Questionnaire ........................96 
Appendix 10 Epworth Sleepiness Scale©.......................................................................100 
 

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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
BP  
Blood pressure 
bpm  
Beats per minute 
BWSQ  
Benzodiazepine Withdrawal Symptom Questionnaire 
CBT  
Cognitive behavioral therapy 
CFR  
Code of Federal Regulations (US) 
CNS  
Central nervous system 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR  
Clinical study report 
C-SSRS©  
Columbia Suicide Severity Rating Scale© 
CYP  
Cytochrome P450 
DB  
Double-blind 
DoA  
Delegation of Authority 
DORA  
Dual orexin receptor antagonist 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 
ECG  
Electrocardiogram/graphy 
eCRF  
Electronic case report form 
EDS  
Excessive daytime sleepiness 
EMA  
European Medicines Agency 
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 

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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 
MedDRA  
Medical Dictionary for Regulatory Activities 
PGA-S  
Patient Global Assessment of Disease Severity 
PGI-C  
Patient Global Impression of Change 
PI  
Principal Investigator 
PK  
Pharmacokinetic 
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 
RSI  
Reference safety information 
SAE  
Serious adverse event 
SDS©  
Sheehan Disability Scale© 
SIV  
Site Initiation Visit 
sLSO  
Subjective Latency to Sleep Onset 
SOC  
System organ class 

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sTST  
Subjective Total Sleep Time 
SUSAR  
Suspected unexpected serious adverse reaction 
sWASO  
Subjective Wake After Sleep Onset 
TEAE  
Treatment-emergent adverse event 
USPI  
United States Package Insert 
VAS  
Visual analog scale(s) 
WASO  
Wake After Sleep Onset 
 
 
 

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SUBSTANTIAL GLOBAL AMENDMENT 2 
Amendment rationale 
This amendment applies to global protocol ID-078A303 Version 2 dated 4 July 2018. The 
resulting amended global protocol is Version 3 dated 17 February 2020. 
The main protocol change is related to the inclusion of an interim analysis for safety and 
efficacy to support global regulatory filings. The interim analysis will be conducted when 
all subjects who did not prematurely discontinue study treatment have reached Visit 3, to 
ensure at least 6 months of double-blind study treatment (confirmatory and extension 
studies). At this time, approximately 260 subjects will have been treated with daridorexant 
for 12 months. 
The submission of an NDA/MAA for daridorexant based on interim data from this study 
will potentially allow earlier access to daridorexant for patients with insomnia. 
A second interim analysis may be performed to fulfill the FDA requirement to submit 
updated safety data from ongoing studies 120 days after NDA submission, in case the study 
has not been completed by that time. 
The study will run until its completion (i.e., EOS for the last subject) to fulfill its primary 
objective and all data generated will be analyzed and reported in the final clinical study 
report, which will be available for regulatory authorities. Therefore, subjects enrolled later 
will equally benefit from the study.  
To maintain the integrity of the study after the interim analysis, participating subjects as 
well as investigators will remain blinded for the entire duration of the study. The sponsor 
personnel involved in data collection and medical monitoring of the study will also remain 
blinded until the end of the study.  
In addition to the protocol modifications required to support the interim analysis, the 
sponsor has made the following changes: 
 Clarification regarding the allowed methods of contraception: a formal documentation 
of a subject’s vasectomy or tubal occlusion/ligation is not necessary. The information 
can be obtained during the medical interview of the subject by the investigator. 
 Clarification regarding the definition and reporting of overdose, misuse, abuse and 
treatment error as an adverse event. 
 Clarification regarding the telephone calls to be performed monthly by the 
investigator/delegate. 
 Clarification that subgroup analyses will be conducted. 

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 Clarification regarding the reporting/transfer of ongoing medical history, adverse 
events, and concomitant therapies from the pivotal studies into the extension study 
database. 
 Clarification regarding some exploratory and safety endpoints. 
Furthermore, minor editorial changes have been made and typographical errors have been 
corrected.  
Changes to the protocol 
Two versions of the amended protocol will be prepared: 1) a clean version and 2) a Word 
comparison document, showing deletions and insertions in comparison to the previous 
protocol version. 
Amended protocol sections 
The main sections of the protocol affected by this amendment are listed below. Where 
applicable, the same changes have also been made to the corresponding sections of the 
protocol synopsis: 
3.1  
Study design 
3.2  
Study design rationale 
4.5.2  
Acceptable methods of contraception 
5.1.4.1 
Double-blind treatment period 
5.1.5.1 
Unblinding for interim analyses 
5.2.2 
Reporting of previous/concomitant therapy in the eCRF 
6.1 
Safety endpoints 
6.2 
Exploratory endpoints 
7.1.3 
Telephone calls between visits 
Table 1 
Table of assessments 
7.2.4.1 
Type of laboratory 
9.1.1  
Definition of adverse events 
10.3.3 
Subgroup analyses 
10.4  
Interim analysis 
11.3 
Database management and quality control 

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Summary of previous amendments 
Amendment 
Date 
Main reason(s) 
1 
4 July 2018 
Address the comment received on 26 June 2018 during the 
Voluntary Harmonization Procedure (VHP) review of this 
Clinical Trial Application (CTA) in the EU. 
 

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PROTOCOL SYNOPSIS ID-078A303 
TITLE 
Multi-center, 
double-blind, 
parallel-group, 
randomized, 
placebo-controlled, three doses, 40-week extension to studies 
ID-078A301 and ID-078A302 to assess the long-term safety 
and tolerability of ACT-541468 in adult and elderly subjects 
with insomnia disorder. 
OBJECTIVE 
To assess the long-term safety and tolerability of 10, 25 and 
50 mg ACT-541468. 
DESIGN 
Multi-center, 
double-blind, 
parallel-group, 
randomized, 
three-dose, 40-week extension to studies ID-078A301 and 
ID-078A302, Phase 3 study. 
PHASES 
The study starts at Visit 1, with the signature of the informed 
consent. The subject will receive the allocated treatment, 
provided all the eligibility criteria are met. 
ID-078A303 Visit 1 can be performed on the same day as the 
run-out, i.e., End-of-Treatment (EOT) of ID-078A301 or 
ID-078A302 studies, after all run-out assessments have been 
completed, or as an independent visit within a maximum of 
7 days after EOT. 
The study comprises a treatment phase and a safety follow-up 
phase: 
The double-blind (DB) treatment phase lasts 40 weeks, 
starting when the treatment is allocated. DB study treatment is 
taken daily.  
A safety telephone call is performed at Visit 2 (Day 7 to 
Day 14) to collect information about adverse events (AEs) and 
concomitant medications. Safety parameters of each subject 
are assessed at Visit 3 (Week 14), Visit 4 (Week 27) and at 
Visit 5 (Week 40).  
The sleep diary and Insomnia Daytime Symptoms and Impacts 
Questionnaire (IDSIQ) are completed at home daily during the 
last week of each consecutive 4-week DB study treatment 
period. Reminder telephone calls are scheduled within one 
week (preferably 2 days) before the week of questionnaire 
completion to increase the subject’s compliance with the diary. 

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During these telephone calls, the investigator/delegate is also 
encouraged to collect the results of the urine pregnancy tests 
performed at home. Alternatively, another telephone call can 
be set up to collect these data.  
End of Double-Blind Treatment (EODBT) is reached at 
Visit 5. 
The safety follow-up phase starts after EODBT and ends 
30 days after last dose of DB study treatment. 
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 5 (EODBT) 
with the intake of one dose of single-blind placebo treatment 
and ends after a total of 7 days of single-blind placebo intake 
(Visit 6). EOT is reached at Visit 6. 
The safety follow-up period starts after the run-out period and 
ends 30 days after last dose of DB study treatment.  
End-of-Study for an individual subject is defined as the date 
of the 30-day follow-up telephone call (Visit 7). The study 
duration for a single subject is expected to be approximately 
45 weeks. 
PLANNED DURATION 
Approximately 24 months from first subject, first visit to last 
subject, last visit. 
SITE(S) 
/ COUNTRY(IES) 
The study will be implemented at each site taking part in the 
ID-078A301 
and 
ID-078A302 
studies 
(approximately 
150 centers in 17 countries), depending on health authority / 
Independent Ethics Committee / Institutional Review Board 
approval.  
SUBJECTS / GROUPS / 
STUDY TREATMENTS 
Subjects assigned to the placebo arm in ID-078A301 or 
ID-078A302 studies will be randomized to receive either 
placebo or 25 mg ACT-541468 in a 1:1 ratio in the extension 
study. Treatment allocation will be stratified by age into 
2 categories: < 65 and ≥ 65 years (the age entered at the 
screening visit in the ID-078A301 or ID-078A302 studies will 
be taken into consideration for the ID-078A303 randomization 
of these subjects). Subjects assigned to the ACT-541468 arms 

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in the ID-078A301 or ID-078A302 studies will continue on the 
same dose (10, 25, or 50 mg) in the extension study. 
It is anticipated that approximately 1260 subjects will take part 
in the extension study. However, participation will be offered 
to all eligible subjects. 
INCLUSION CRITERIA 
For all the following criteria, time points in brackets refer to 
the visits when the criterion must be assessed. 
1. Signed informed consent prior to any study-mandated 
procedure (Visit 1).  
2. Having completed the DB study treatment and run-out 
period of ID-078A301 or ID-078A302 (Visit 1). 
3. For woman of childbearing potential, the following is 
required: 
 Negative urine pregnancy test (EOT of ID-078A301 
or ID-078A302 studies). 
 Agreement to use the contraception scheme as 
required by the protocol from Visit 1 up to at least 
30 days after EODBT. 
EXCLUSION CRITERIA 
For all the following criteria, timepoints in brackets refer to the 
visits when the criterion must be assessed. 
1. Unstable medical condition, significant medical disorder or 
acute illness, or ECG, Columbia Suicide Severity Rating 
Scale© (C-SSRS©), hematology or biochemistry test results 
in ID-078A301 and ID-078A302, which, in the opinion of 
the investigator, could affect the subject’s safety or 
interfere with the study assessments (Visit 1). 
2. For female subjects: lactating or planning to become 
pregnant over the duration of the study (Visit 1). 
3. Positive urine drug test (for benzodiazepines, barbiturates, 
cannabinoids, opiates, amphetamines, or cocaine) (Visit 1). 
STUDY TREATMENTS 
Investigational treatment 
ACT-541468 supplied as identical film-coated tablets at 
strengths of 10 mg, 25 mg and 50 mg will be administered 
orally, once daily at bedtime during the DB treatment period.  

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Placebo 
ACT-541468-matching placebo will be administered orally, 
once daily at bedtime during the DB treatment period and the 
single-blind run-out period. 
ENDPOINTS 
To evaluate long-term safety and efficacy of ACT-541468, 
data from ID-078A301 and ID-078A302 will be included for 
subjects entering this extension study. 
For subjects who received placebo in ID-078A301 or 
ID-078A302 that are randomized to 25 mg ACT-541468 in this 
extension study, baseline refers to assessments taken before 
start of ACT-541468 intake. For all other subjects, and unless 
stated otherwise, baseline refers to assessments performed 
before start of DB study treatment of study ID-078A301 or 
ID-078A302. 
Safety endpoints: 
 Serious adverse events (SAEs) up to 30 days after DB study 
treatment discontinuation. 
 Treatment-emergent AEs (TEAEs) up to 30 days after DB 
study treatment discontinuation. 
 AEs leading to premature discontinuation of the DB study 
treatment. 
 AEs of special interest (AESIs) after adjudication by 
Independent Safety Board (ISB): 
– 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 to Visit 3, Visit 4, Visit 5 and Visit 6 
in Epworth Sleepiness Scale© total score. 
 Change from baseline to Visit 3, Visit 4 and Visit 5 in vital 
signs (systolic and diastolic blood pressure [BP], and pulse 
rate). 
 Change from baseline to Visit 5 in body weight. 
 Marked ECG abnormalities on DB study treatment. 

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 Change from baseline to Visit 3, Visit 4, Visit 5 and Visit 6 
in ECG parameters.  
 Marked laboratory abnormalities on DB study treatment. 
 Change from baseline to Visit 3, Visit 4, Visit 5 and Visit 6 
in laboratory parameters. 
 Occurrence of suicidal ideation and/or behavior on DB 
study treatment and during the treatment withdrawal period 
based on C-SSRS©. 
 Withdrawal effects (physical dependence) upon treatment 
discontinuation will be assessed based on the changes from 
last assessment on DB treatment (Visit 5) to end of the 
run-out period (Visit 6) in the Benzodiazepine Withdrawal 
Symptom Questionnaire (BWSQ) total score, the 
occurrence 
of 
relevant 
AEs 
and 
marked 
ECG 
abnormalities. 
 Rebound insomnia will be assessed based on change from 
baseline to the run-out period in subjective Total Sleep 
Time (sTST). 
 Next-day residual effect will be assessed based on change 
from baseline to Visit 3, Visit 4 and Visit 5 in Sheehan 
Disability Scale© (SDS©) and change from baseline over 
time in morning sleepiness score on the sleep diary visual 
analog scale (VAS; mm). VAS scores are the subjects’ 
rating of their morning sleepiness (from ‘the way you feel 
this morning’), daytime alertness (from ‘your daytime 
alertness today’) and daytime ability to function (from 
‘your daily ability to function today’). 
Exploratory efficacy endpoints: 
 Change from baseline over time in sTST. sTST is the total 
sleep time, as reported in item 9 of the sleep diary. 
 Change from baseline over time in sLSO. sLSO is the 
self-reported time to fall asleep, as reported in item 5 of the 
sleep diary. 
 Change from baseline over time in subjective sleep 
maintenance (sWASO). sWASO is the self-reported time 
spent awake after sleep onset as reported in item 7 of the 
sleep diary. 

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 Change from baseline over time in IDSIQ scores (i.e., total 
score; alert/cognition, mood and sleepiness domain 
scores). 
 Change from baseline over time in sleep quality based on 
scores on the sleep diary VAS (mm). VAS scores are the 
subjects’ rating of ‘the quality of your sleep last night’ and 
‘the depth of your sleep last night’, daytime alertness and 
daytime ability to function questions. 
 Change from baseline to Visit 3, Visit 4 and Visit 5 in 
Insomnia Severity Index© (ISI©) scores. The number (%) 
of subjects with ≥ 6-point decrease in ISI© Total score from 
baseline to Visit 3, Visit 4 and Visit 5 will be tabulated. 
 Change from baseline over time in mean number of 
self-reported awakenings. 
 Change from baseline over time in Patient Global 
Assessment 
of 
Disease 
Severity 
scores 
(daytime 
symptoms). 
 Change from baseline over time in Patient Global 
Impression of Change scores (daytime symptoms). 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
To evaluate long-term safety and efficacy of ACT-541468, 
baseline data from ID-078A301 and ID-078A302 will be 
included for subjects entering this extension study. 
For subjects who received placebo in ID-078A301 or 
ID-078A302 that are randomized to 25 mg ACT-541468 in this 
extension study, baseline refers to assessments taken before 
start of ACT-541468 intake. For all other subjects, and unless 
stated otherwise, baseline refers to assessments performed 
before start of DB study treatment of study ID-078A301 or 
ID-078A302. 
Analysis of safety endpoints 
Analysis 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 

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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 preferred term (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 Visit 3, Visit 4, Visit 5 and Visit 6 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 body weight 
Observed values and changes from baseline to Visit 3, Visit 4 
and Visit 5 in vital signs (systolic and diastolic BP, and pulse 
rate) will be summarized. Observed values and changes from 
baseline to Visit 5 in body weight will be summarized. 
Electrocardiograms 
Observed values and changes from baseline to Visit 3, Visit 4, 
Visit 5 and Visit 6 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. 
The BWSQ total score will be summarized using descriptive 
statistics for the observed values and changes from the last 
assessment on treatment (Visit 5) to the end of the run-out 
period (Visit 6). 
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, 

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separately, an AE and a marked ECG abnormality during the 
treatment withdrawal period will be tabulated. 
Rebound insomnia  
The Treatment Withdrawal Set will be used to assess the 
potential for rebound insomnia. 
Changes from baseline to the treatment withdrawal period 
(Visit 6, Week 41) in sTST will be summarized using 
descriptive statistics. 
Next-day residual effect 
Observed values and changes from baseline to Visit 3, Visit 4 
and Visit 5 in SDS©, and sleep diary VAS scores (mm) 
assessing morning sleepiness (from ‘the way you feel this 
morning’), daytime alertness (from ‘your daytime alertness 
today’) and daytime ability to function (from ‘your daily ability 
to function today’), 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 and during the 
treatment withdrawal period will be tabulated. 
Shifts from baseline showing any changes in suicidal ideation 
and suicidal behavior during DB treatment and during the 
treatment withdrawal period 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. 
Epworth Sleepiness Scale© 
The change from baseline to Visit 3, Visit 4, Visit 5 and end of 
the run-out period Visit 6 in ESS© total score will be 
summarized. Observed values will also be summarized. 
Analysis of exploratory efficacy endpoints 
Analysis of the efficacy endpoints 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 

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sTST, sWASO, sLSO and IDSIQ scores (i.e., Total score; 
alert/cognition, mood, and sleepiness domain 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, age group (< 65; ≥ 65 years), 
treatment (10 mg; 25 mg; 50 mg; placebo), visit (Month 6; 
Month 9; Month 12), and the interaction of treatment by visit, 
and baseline by visit. 
An unstructured covariance matrix shared across treatment 
groups will be used to model the correlation among repeated 
measurements. A restricted maximum likelihood approach will 
be used to derive (unbiased) estimates of variance components. 
The Kenward-Roger approximation will be used to compute 
the denominator degrees of freedom and adjust standard errors 
[Kenward 1997]. 
Appropriate contrasts will be used to test the treatment 
differences of interest (e.g., the difference in least squares 
mean change from baseline of 10 mg vs placebo, 25 mg vs 
placebo and 50 mg vs placebo at Month 6). Baseline is the 
mean value based on the screening sleep diary / IDSIQ entries 
performed at home in the 7 days immediately preceding the 
first polysomnography at Visit 3 of the ID-078A301 or 
ID-078A302 study. Month 6 is the mean value based on the 
sleep diary / IDSIQ entries performed at home over the 7 days 
in Week 12 of the extension study; Month 9 and Month 12 is 
defined similarly. 
Observed values and changes from baseline over time in sTST, 
sWASO, sLSO and IDSIQ scores (i.e., total score; 
alert/cognition, mood and sleepiness domain scores) will be 
summarized. 
Summary statistics will be provided for other efficacy 
endpoints using number (%) of subjects for categorical 
variables and descriptive statistics (e.g., mean, standard 
deviation, median, min., max.) for continuous variables. 

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Interim analyses  
An interim analysis is planned to support global regulatory 
filings. 
The interim analysis will be conducted when all subjects who 
did not prematurely discontinue study treatment have reached 
Visit 3. 
A second interim analysis may be performed to fulfill the FDA 
requirement to submit updated safety data from ongoing 
studies 120 days after NDA submission, if the study has not 
been completed by that time. 
The interim analyses will include all safety and efficacy data.  
To maintain the integrity of the study after the interim analysis, 
participating subjects as well as investigators will remain fully 
blinded for the entire duration of the study. The sponsor 
personnel involved in data collection and medical monitoring 
of the study will also remain blinded until the end of the study.  
No adjustment for multiple testing is required as no formal 
interim analysis will be performed for determining whether to 
stop (or modify) the study (i.e., no hypothesis testing will be 
conducted ad interim). 
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. The IDMC will 
not be involved in any of the interim analyses described. 
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. 
 
 

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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) 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].  
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, and, in some regions, the orexin receptor antagonist suvorexant and low-dose 
doxepin.  
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 

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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 with insomnia 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 and benzodiazepine receptor agonists is associated 
with an increased risk of falling [McCall 2004] leading to hip and femur fractures, 
increased disability, and use of healthcare resources.  
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.  

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1.2.2 ACT-541468 properties 
ACT-541468 is a new potent and selective DORA that blocks the actions of the orexin 
neuropeptides at both orexin-1 and orexin-2 receptors. ACT-541468 shows similar potency 
on human, rat, and dog orexin receptors. ACT-541468 is not teratogenic, not genotoxic, 
not phototoxic, and showed no embryo-fetal toxicity. The nonclinical safety data and the 
resulting safety margins are considered adequate to support the safe use of ACT-541468 at 
doses of 10, 25, and 50 mg in clinical studies with a duration of up to 12 months.  
The human clinical experience with ACT-541468 consists of 11 completed Phase 1 studies 
and two completed Phase 2 studies. The Phase 2 program consisted of two Phase 2 studies. 
AC-078A201 was conducted in 360 adults (18 to 65 years old) treated for 1 month with 
one dose of double-blind (DB) study treatment and AC-078A202 was conducted in 
58 elderly subjects (≥ 65 years old) treated for 2 days with each dose of DB study treatment. 
Both studies demonstrated a dose-response effect on the change from baseline to Days 1&2 
in mean Wake After Sleep Onset (WASO). 
More detailed information can be found in the ID-078A301 and ID-078A302 protocols as 
well as in the Investigator’s Brochure (IB) [Daridorexant IB]. 
1.3 Purpose and rationale of the study 
1.3.1 Purpose of the study 
The main purpose of this Phase 3 extension study is to confirm that at least one dose of 
ACT-541468 is, in the long-term, well tolerated 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, 25, and 50 mg of ACT-541468 planned for this study were all 
investigated in Phase 2. The 10 mg dose is considered the minimal effective dose, 
providing clinical benefit in some patients, primarily on Latency to Persistent Sleep (LPS), 
in both adult and elderly subjects. The 25 mg and 50 mg doses provided a better effect on 
objective sleep parameters, and resulted in statistically significant reductions in mean 
WASO and in mean LPS at Days 1&2 compared with baseline, in both patient populations. 
These three doses were well tolerated and no significant safety findings emerged.  
The ID-078A303 study will be an extension of the two confirmatory ACT-541468 studies 
(i.e., ID-078A301 and ID-078A302) in adult and elderly subjects with insomnia disorder. 
This Phase 3 extension study aims to assess the long-term safety of ACT-541468 as 
required by ICH-E1 [ICH 1994], i.e., at least 300 subjects exposed to any dose of 

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ACT-541468 for 26 weeks and at least 100 subjects exposed for 52 weeks, combining the 
time of treatment of the confirmatory and extension studies. 
1.4 Summary of known and potential risks and benefits 
1.4.1 Benefits and risks of the study treatments 
Based on the mechanism of action of ACT-541468, nonclinical data, and data collected in 
Phase 1 and 2 studies in adult and elderly subjects, a shortened latency to sleep onset and 
a positive effect on sleep maintenance are anticipated. It is expected that the efficacy will 
be maintained long-term and some subjects may benefit from prolonged treatment of their 
insomnia. 
One year long-term treatment with ACT-541468 is not expected to induce additional risks 
compared with what was observed in Phase 2, as it has been demonstrated in previous 
Phase 1 studies that ACT-541468 does not accumulate in any organs.  
The most frequently observed treatment-emergent adverse events (TEAEs) reported in the 
conducted Phase 2 studies involving 418 subjects, out of which 297 were exposed to 
ACT-541468, included headache, somnolence, fatigue, and dizziness. Isolated cases of 
excessive daytime sleepiness (EDS) were observed. 
Considering the mode of action of DORAs and the known adverse reactions associated 
with the use of sleep medications, adverse events of special interest (AESIs) include: 
 Narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep behavior events 
including hallucinations/sleep paralysis). 
 Suicide/self-injury. 
These AESIs will be reviewed and adjudicated in a timely manner by the Independent 
Safety Board (ISB). 
The results of the AC-078-103 study have shown that ACT-541468 metabolism is mainly 
dependent on cytochrome P450 (CYP)3A4; co-administration of ACT-541468 and strong 
or moderate CYP3A4 inhibitors or inducers must be avoided [see Appendix 3]. 
ACT-541468 did not impair male or female fertility, was not teratogenic, and showed no 
embryo-fetal toxicity in animals. However, as the developmental and reproductive 
toxicology program of ACT-541468 is not yet fully complete, ACT-541468 must only be 
given to women of childbearing potential when the absence of pregnancy has been verified 
and a reliable method of contraception is practiced. Women of childbearing potential are 
required to use contraception during the whole study and for 30 days after discontinuation 
of ACT-541468. 

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Insomnia is not considered a life-threatening disease with irreversible morbidity if not 
treated immediately. It is hence considered acceptable and ethical to include a 
placebo-treated arm in a long-term trial of subjects with insomnia [ICH 2000]. Subjects are 
aware of the probability of being assigned to the placebo arm and of the therapeutic 
alternatives. However, to minimize the long-term exposure to placebo, patients who have 
been assigned to placebo in the confirmatory studies ID-078A301 and ID-078A302 will be 
randomized to either placebo or 25 mg ACT-541468 in ID-078A303.  
Subjects are encouraged to take the study drug as long as possible. However, if needed, 
withdrawal from study treatment and the use of standard-of-care will be accepted. In that 
case, subjects are encouraged to remain in the study until its completion to limit the amount 
of missing data and ensure the accuracy of the study results. The sponsor will continuously 
monitor missing treatment data, treatment discontinuation and withdrawal from the study.  
1.4.2 Safety and risk-minimization measures taken in the present study 
Next-day residual effects will be evaluated with the Sheehan Disability Scale© (SDS©), and 
a visual analog scale (VAS) assessing sleepiness. Suicidality will be assessed using the 
Columbia Suicide Severity Rating Scale© (C-SSRS©) at Visit 1, Visit 3, Visit 4, Visit 5 and 
Visit 6.  
As half of the subjects that were receiving placebo in the confirmatory studies will be 
randomized to 25 mg ACT-541468, and thus to a new treatment, in this study, a telephone 
call will be performed approximately 2 weeks after Visit 1 to collect adverse events (AEs) 
and concomitant medication. This will be done for all subjects, to maintain the blinding. 
Hematology and clinical chemistry laboratory variables will be monitored in the study. 
Two committees will be set up for the study:  
 An ISB will review and adjudicate all AESIs listed in Section 1.4.1 in a blinded manner.  
 An Independent Data Monitoring Committee (IDMC) will monitor safety and efficacy 
data in an unblinded manner. This committee will make appropriate recommendations 

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regarding continuation of the trial or potential modification to the sponsor to ensure 
data integrity and the safety of the subjects.  
A charter will provide a well-defined and structured process for each committee to operate 
effectively. 
It is the investigator’s responsibility to monitor the risk-benefit ratio of study treatment 
administration, as well as the degree of distress caused by study procedures on an 
individual subject level, and to discontinue study treatment or participation in the study if, 
on balance, he/she believes that continuation would be detrimental to the subject’s 
well-being. 
In conclusion, based on available data on ACT-541468 and the risk-minimization measures 
mandated by the protocol, the anticipated risk-benefit assessment supports the conduct of 
this 40-week treatment extension study in adult and elderly subjects with insomnia 
disorder. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The objective of this extension study is to assess the long-term safety and tolerability of 
10, 25 and 50 mg ACT-541468. 
2.2 Exploratory objective 
To evaluate the efficacy of 10 mg, 25 mg and 50 mg ACT-541468 on subjective sleep 
parameters (using an ad hoc sleep diary) and next-day functioning (using the dedicated 
Insomnia Daytime Symptoms and Impacts Questionnaire [IDSIQ]) in subjects with 
insomnia disorder during long-term treatment. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
Subjects who complete DB study treatment and the run-out period of the confirmatory 
studies ID-078A301 and ID-078A302, and who are willing to participate, will be eligible 
to enter the ID-078A303 extension study. 
Subjects assigned to the placebo arm in the ID-078A301 or ID-078A302 studies will be 
randomized to receive either placebo or 25 mg ACT-541468 in a 1:1 ratio in the extension 
study. Treatment allocation will be stratified by age into 2 categories: < 65 and ≥ 65 years 
(the age entered at the screening visit in the ID-078A301 or ID-078A302 studies will be 
taken into consideration for the ID-078A303 randomization of these subjects). Subjects 
assigned to one of the ACT-541468 arms in the ID-078A301 or ID-078A302 studies will 
receive the same dose in the extension study.  

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An interim analysis will be conducted when all subjects that did not prematurely 
discontinue study treatment have reached Visit 3, to ensure 6 months of cumulative 
double-blind treatment (confirmatory and extension). 
Subjects treated with placebo during the confirmatory studies and randomized to 
ACT-541468 25 mg are excluded from the conditions mentioned above as they will not 
all display 6-month data.  
A second interim analysis, focusing on safety, may need to be conducted to fulfill the FDA 
requirement to submit updated safety data from ongoing studies 120 days after NDA 
submission, if the study has not been completed by that time.  
It is expected that approximately 1260 subjects (i.e., ~70% of the total subjects in the 
combined confirmatory studies) having completed the confirmatory studies will enter the 
extension study. ID-078A303 will be offered at every site participating in ID-078A301 
and ID-078A302 (approximately 150 centers in 17 countries), and to every eligible 
subject. 
3.1.1 Study periods 
The study starts at Visit 1, with the signature of the informed consent. The subject will 
receive the allocated treatment, provided all the eligibility criteria are met. ID-078A303 
Visit 1 can be performed on the same day as End-of-Treatment (EOT) of ID-078A301 or 
ID-078A302 studies, after all run-out assessments have been completed, or as an 
independent visit within a maximum of 7 days after EOT.  
The study comprises a treatment phase and a safety follow-up phase [see Figure 1].  
3.1.1.1 Treatment phase 
The DB treatment phase lasts 40 weeks, starting when the treatment is allocated. DB 
study treatment is taken daily.  
A safety telephone call is performed at Visit 2 (Day 7 to Day 14) to collect information 
about AEs and concomitant medications. Safety parameters of each subject are assessed at 
Visit 3 (Week 14), Visit 4 (Week 27) and Visit 5 (Week 40). The sleep diary and IDSIQ 
are completed at home daily during the last week of each consecutive 4-week DB study 
treatment period. Reminder telephone calls are scheduled within one week (preferably 
2 days) before the week of questionnaire completion to increase the subject’s compliance 
with the diary. During these telephone calls, the investigator/delegate is also encouraged 
to collect the results of the urine pregnancy tests performed at home. Alternatively, another 
telephone call can be set up to collect these data. EODBT is reached at Visit 5. 

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3.1.1.2 Safety follow-up phase 
The safety follow-up phase starts after the End of Double-Blind Treatment (EODBT) and 
ends 30 days after last dose of DB study treatment. 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 5 with the intake of one dose of 
single-blind placebo treatment and ends after a total of 7 days of single-blind placebo intake 
(Visit 6). EOT is reached at Visit 6. 
The safety follow-up period starts after the run-out period and ends 30 days after last dose 
of DB study treatment. 
End-of-Study (EOS) for an individual subject is defined as the date of the 30-day 
follow-up telephone call (Visit 7). If a subject is prematurely discontinued from study 
treatment, EOS is performed as planned on Day 309. 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 will be performed according to the 
visit and assessment schedule [Table 1] and are described in Section 7. 
The overall study design is depicted in Figure 1. 
Figure 1 
Study design  
 
         Monthly telephone call 
EODBT = End of Double-Blind Treatment; EOS = End-of-Study; EOT = End-of-Treatment. 
* Subjects randomly assigned to the ACT-541468 arms in the confirmatory studies will receive the same dose in the 
extension study. 
** Subjects randomly assigned to the placebo arm in the confirmatory studies will be randomized to receive either 
placebo or 25 mg ACT-541468 in a 1:1 ratio in the extension study. 

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3.1.2 Study duration 
The study starts with the signature of the Informed Consent Form (ICF) at Visit 1 for the 
first subject enrolled and ends with the EOS of the last subject. The anticipated total study 
time is approximately 24 months. 
Each subject will be treated for approximately 40 weeks in study ID-078A303, and will 
therefore receive 12 months of cumulative treatment combining ID-078A301/ID-078A302 
and the extension study. For an individual subject, the study is completed with the EOS 
visit (Visit 7; 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 
45 weeks.  
3.2 Study design rationale 
In accordance with the 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 inclusion of a placebo arm in this extension study allows a better 
discrimination between the background rate of AEs and that of AEs potentially attributable 
to the study drug. 
A parallel-group design is an appropriate design to assess the continuous exposure to 
ACT-541468 in the wake of studies ID-078A301 and ID-078A302, and is accepted by 
health authorities [EMA 2011, FDA 1977]. 
The treatment allocation ratio will allow the collection of maximum information on safety 
and efficacy of the medium dose of ACT-541468, the 25 mg dose. The number of subjects 
allocated to ACT-541468 10 mg and 50 mg is also adequate to ensure an appropriate 
characterization of the safety profile of those doses over a 52-week period. In addition, 
study ID-078A303 provides an appropriate investigation of the sustained effect of 
ACT-541468 on both sleep parameters and next-day performance at the three dose levels 
studied.  
A blinded placebo run-out period of 7 days allows the assessment of withdrawal symptoms 
after a long-term treatment period as it covers more than 5 half-lives of either 10, 25, or 
50 mg ACT-541468. The duration of the run-out period is also compliant with FDA 
guidance [FDA 1977] stating that a minimum of 3 nights of placebo withdrawal is 
necessary to assess withdrawal effects. To assess withdrawal effects AEs and ECG 
abnormalities will be collected during the 7-day run-out period and subjects will complete 
the Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) at Visit 6. The 
completion of the sleep diary from at least 3 days following treatment discontinuation will 
allow the assessment of rebound insomnia based on subjective parameters. Thus, this 7-day 
run-out period allows potential long-term withdrawal effects to be captured, as well as 
potential shorter-term rebound symptoms. 

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Importantly, the study will provide long-term efficacy data as required by the EMA 
guideline on medicinal products for the treatment of insomnia [EMA 2011]. The study will 
assess the maintenance of the treatment effect over time beyond the 3 months of the 
confirmatory trials: efficacy will be assessed by subjective endpoints describing sleep 
parameters (subject’s diary) and next-day functioning (IDSIQ) for 26 weeks (6 months) 
and up to 52 weeks of overall treatment, combining the time of treatment of the 
confirmatory and extension studies. Enrolled subjects will have to fill in the two 
questionnaires during the last 7 days of each consecutive 4-week DB study treatment 
period. This is to collect relevant subjective data without adding too much burden for the 
subjects. 
An interim analysis will be performed after completion of the pivotal studies and when all 
subjects have performed Visit 3. One additional interim analysis may be performed as 
required by health authorities (FDA) if the study is still ongoing, to provide additional 
safety information. 
After the planned interim analysis, sites and subjects will remain blinded to the treatment 
allocation while the study continues to collect data on the entire population for 52 weeks. 
This approach allows an early analysis of the efficacy and safety data after 6 months of 
exposure of the entire study population collected in a blinded way. These data will support 
the initial filing with health authorities for ACT-541468 without triggering early 
termination of the study. Therefore, subjects enrolled later will equally benefit from the 
study along with ACT-541468 being potentially available earlier on the market for the 
patients. 
To maintain the integrity of the study, the sponsor personnel involved in the data collection 
and medical monitoring of the study will not be involved in the interim analysis and will 
remain blinded until the completion of the study without having access to the results of the 
interim analysis [see Section 5.1.4.1]. 
3.3 Study committees 
An 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 to the sponsor based on the reported data. This will ensure that the study 
is being conducted to the highest scientific and ethical standards and will protect the safety 
and well-being of the subjects. 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. The IDMC will not be involved in any interim analysis. 
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 

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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 the DSM-5 definition, having completed the DB study 
treatment and run-out period of the confirmatory studies ID-078A301 or ID-078A302. For 
more details on inclusion and exclusion criteria, see Sections 4.3 and 4.4.  
4.2 Rationale for the selection of the study population 
Adult (18–64 years) and elderly (≥ 65 years) subjects with insomnia as defined by DSM-5 
who have completed the ID-078A301 or ID-078A302 study will be included, unless 
presenting a significant medical condition which in the opinion of the investigator could 
affect the subject’s safety or interfere with the study assessments. This will allow the 
collection of long-term safety and tolerability information across a broad population. 
4.3 Inclusion criteria 
For all the following criteria, time points in brackets refer to the visits when the criterion 
must be assessed. 
1. Signed informed consent prior to any study-mandated procedure (Visit 1).  
2. Completion of the DB study treatment and run-out period of ID-078A301 or 
ID-078A302 (Visit 1). 
3. For woman of childbearing potential, the following is required: 
 Negative urine pregnancy test (EOT of ID-078A301 or ID-078A302 studies). 
 Agreement to use the contraception scheme as required by the protocol from 
Visit 1 up to at least 30 days after EODBT. 
4.4 Exclusion criteria 
For all the following criteria, time points in brackets refer to the visits when the criterion 
must be assessed. 
1. Unstable medical condition, significant medical disorder or acute illness, or ECG, 
C-SSRS©, hematology or biochemistry test results in ID-078A301 or ID-078A302 
study, which, in the opinion of the investigator, could affect the subject’s safety or 
interfere with the study assessments (Visit 1). 
2. For female subjects: lactating or planning to become pregnant during the study 
(Visit 1). 

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3. Positive urine drug test (for benzodiazepines, barbiturates, cannabinoids, opiates, 
amphetamines, or cocaine) (Visit 1). 
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 
syndrome, uterine agenesis. 
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 
 Bilateral tubal occlusion (tubal occlusion / ligation at least 6 weeks prior to screening; 
information can be obtained via the medical interview of the subject). 
 Vasectomized partner with documented post-vasectomy confirmation of the absence of 
sperm in the ejaculate (information can be obtained via the medical interview of the 
subject). 

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 Sexual abstinence from intercourse with a male partner only if it 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. 
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 during the treatment period as 
tablets, orally, once daily at bedtime. ACT-541468-matching placebo will be administered 
as well during the run-out period. 
ACT-541468 is supplied by Idorsia as identical film-coated tablets at strengths of 10 mg, 
25 mg and 50 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 daily during the last week of each consecutive 
4-week DB study treatment period (the first 4-week treatment period starts at Day 1 after 
randomization of the subject at Visit 1) during the DB treatment phase and daily during the 
run-out period.  
If one or more doses have been missed, the next dose must be taken in the evening of the 
following day. 
The last dose of study treatment will be taken the evening before Visit 6. 
5.1.3 Treatment assignment 
Subjects assigned to the placebo arm in the ID-078A301 and ID-078A302 studies will be 
randomized to receive either placebo or 25 mg ACT-541468 in a 1:1 ratio in the extension 
study. Treatment allocation will be stratified by age into 2 categories: < 65 and ≥ 65 years 

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(the age entered at the screening visit in the ID-078A301 or ID-078A302 studies will be 
taken into consideration for the ID-078A303 randomization of these subjects). Subjects 
assigned to the ACT-541468 arms in the ID-078A301 and ID-078A302 studies will receive 
the same dose in the extension study.  
At Visit 1, after the ICF has been signed and after having verified that the subject meets all 
inclusion criteria and none of the exclusion criteria, the investigator/delegate contacts the 
Interactive Response Technology (IRT) to obtain the treatment kit numbers assigned to the 
subject. The IRT assigns the treatment kit number, which matches the treatment arm 
assigned per the randomization list. Subject number assigned in the confirmatory studies 
will be identical in the extension study.  
At Visit 3, Visit 4 and Visit 5, the investigator/delegate contacts the IRT and the treatment 
kit, which matches the treatment arm assigned per the randomization list, will be dispensed 
to the subject. During the run-out period, subjects will receive single-blind placebo 
treatment.  
The randomization list is generated by an independent Contract Research Organization 
(CRO) and kept strictly confidential.  
5.1.4 Blinding 
5.1.4.1 Double-blind treatment period 
From Randomization (Visit 1) 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 ID-078A303 final data analysis, the randomization lists of 
studies ID-078A301 and ID-078A302 (and thus, also ID-078A303) are kept strictly 
confidential, and accessible to the IRT vendor, the sponsor authorized persons (i.e., 
dedicated persons from Quality Assurance, Systems and Compliance personnel, as well as 
from the Bioanalytical Laboratory group) the Independent Statistical Analysis Center 
(ISAC), and the IDMC. None of those people are involved in the conduct of the three 
studies.  
In order to maintain the blinding of the study, a different team will be responsible for the 
conduct of the extension study. In particular, the sponsor staff that had access to the 
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analysis will not be involved in the conduct of the extension study until its final database 
closure. The process will be duly documented in Idorsia Quality System (QS) documents. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment kits will be packaged in the same way. 
5.1.4.2 Run-out period 
During the run-out period, placebo treatment will be administered in a single-blind fashion. 
The subjects will remain blinded to the study treatment until EOT. Subjects must not be 
informed about the change in treatment at the beginning of the run-out period.  
The investigators 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-out 
period.  
5.1.5 Unblinding 
5.1.5.1 Sponsor unblinding for interim and final analyses 
Randomization information will be made available for interim analysis after interim 
database closure, in accordance with Idorsia QS documents. 
The randomization list will not be shared with investigators and site personnel until the end 
of the study and the final analysis to maintain the blind.  
Sponsor personnel involved in data collection and medical monitoring of the study before 
and after interim analysis will also remain blinded, in accordance with Idorsia QS 
documents (i.e., Blinding Management Plan). 
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 Idorsia’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 Independent Ethics Committees / Institutional 
Review Boards (IECs/IRBs) only. SUSARs will be reported to investigators in a blinded 
fashion. 

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5.1.5.4 Emergency procedure for unblinding 
The investigator, study personnel and Idorsia personnel must remain blinded to the 
subject’s treatment assignment as defined in Section 5.1.4. 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 interests of the 
subject, the investigator is invited to discuss the intended unblinding with Idorsia 
personnel. 
The occurrence of any emergency unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, Idorsia personnel must be informed of the 
unblinding decision as soon as possible before or after the unblinding. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF). 
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 the run-out period) is provided as tablets and 
supplied in 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. The treatment wallets will display the study 
number on the front label to ensure only the ID-078A303 study treatment wallets are 
provided to the subjects. 
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.  

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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 
Clinical Research Associate (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 or the deputy, and written permission for destruction has been 
obtained from Idorsia. 
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. 

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If the subject forgets to bring the remaining study treatment to a study visit, he/she must be 
instructed to not take any tablets from the remaining study treatment 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. Study treatment 
compliance for the treatment period (Visit 1 to EODBT) and the run-out period will be 
separately calculated for each of these periods by site personnel using the formula below: 
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 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 
source documents. 
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, he/she 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  
Maintenance of subjects in the study is important from a study integrity perspective. It is 
recommended to advise the subject to remain in the study even if he/she wishes to be 
withdrawn from study treatment. This will decrease the amount of missing data and 
increase the reliability of the study results. Measures in place to increase subject retention 
in the study are described in Section 5.1.11. 

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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 to be withdrawn 
from the study and will be followed up until the planned EOS (Day 309), 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 study treatment intake and to agree to follow planned study procedures (e.g., 
visits, sleep diary and questionnaire completion) until EOS. In this case, the run-out period 
(including Visit 6) will not be performed, and subjects will directly enter the follow-up 
period after Visit 5 (considered as EOT in the event of premature discontinuation). The 
telephone call will be performed as planned 30 days (+7 days) later, at Visit 7. This will 
decrease the amount of missing data, helping to maintain study integrity. 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 to be 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 to be 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. 

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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. 
5.1.11 Study-specific measures for subject retention 
Subjects withdrawn from study treatment are encouraged to remain in the study until its 
completion.  
In order to ensure a high level of compliance with the study procedures, subjects that are 
under DB treatment and subjects that prematurely discontinued will be called within one 
week (preferably 2 days) before each 4-week DB study treatment period during which the 
completion of the sleep diary, IDSIQ, Patient Global Assessment of Disease Severity 
(PGA-S) and Patient Global Impression of Change (PGI-C) is required. The investigator 
will call the subject to remind him/her to complete the different questionnaires on the 
hand-held device as instructed, check there is no issue with the study treatment (if 
applicable) and remind the subject to keep the appointments at the sleep center. An alert 
email is sent to the investigator to remind him/her to call the subjects. 
A reminder is also programmed on the hand-held device the day before the completion 
must be started and every day during the completion period. 
Investigators are encouraged to discuss with the subjects the importance of remaining in 
the study for data accuracy purposes and scientific relevance of the study results. 
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 study treatment or is initiated during the 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.  

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Previous/concomitant therapy recorded in the ID-078A301 or ID-078A302 study and still 
ongoing at enrollment in the ID-078A303 study will be automatically transferred on a 
specific eCRF page into the ID-078A303 database. Concomitant therapies initiated in the 
extension study will be recorded in the ID-078A303 eCRF. The generic name, start/end 
dates of administration (as well as whether it was ongoing at EOS), route, dose, and 
indication will be recorded in the eCRF. 
5.2.3 Allowed concomitant therapy 
Therapies considered necessary for the subject’s well-being and not categorized as 
prohibited concomitant medications can be used in this study.  
5.2.4 Forbidden concomitant therapy 
Subjects must not be withdrawn from medically necessary therapies in order to participate 
in the study. The following concomitant therapies are forbidden during this study and a 
complete list of forbidden medications is provided in Appendix 3: 
 Treatment with another investigational drug until EOS. 
 Study-prohibited CNS-active medications at least 1 week prior to Visit 1 and until 
24 hours after EOT. 
 Treatment with moderate or strong CYP3A4 inhibitors or moderate to strong 
CYP3A4 inducers at least 1 week prior to Visit 1 until 24 hours after EOT.  
5.2.5 Forbidden concomitant diet and activities 
The following activities and diet are forbidden during the study: 
 Consumption of grapefruit, Seville (bitter) oranges and juices from those fruits from 
1 week prior to Visit 1 until 24 hours after the end of the run-out period.  
 Caffeine consumption > 600 mg caffeine/day.  
 Alcohol consumption > 2 drinks a day. 
 Heavy tobacco use (at least one pack of cigarettes per 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 after study treatment intake. 
The investigator should also advise the subject about the risks of taking the study drug prior 
to traveling across several time zones or working night shifts. The appropriate safety 
measures for these specific cases will also be explained. 

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6 
STUDY ENDPOINTS 
To evaluate long-term safety and efficacy of ACT-541468, data from ID-078A301 and 
ID-078A302 for subjects entering this extension study will be included. 
For subjects who received placebo in ID-078A301 or ID-078A302 that are randomized to 
25 mg ACT-541468 in this extension study, baseline refers to assessments taken before 
start of ACT-541468 intake. For all other subjects, and unless stated otherwise, baseline 
refers to assessments performed before start of DB study treatment of study ID-078A301 
or ID-078A302. 
6.1 Safety endpoints 
 Serious adverse events (SAEs) up to 30 days after study DB treatment discontinuation. 
 TEAEs up to 30 days after DB study treatment discontinuation. 
 AEs leading to premature discontinuation of the DB study treatment. 
 AESIs 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 to Visit 3, Visit 4, Visit 5 and Visit 6 in Epworth Sleepiness 
Scale (ESS)© total score. 
 Change from baseline to Visit 3, Visit 4 and Visit 5 in vital signs (systolic and diastolic 
blood pressure [BP], and pulse rate). 
 Change from baseline to Visit 5 in body weight. 
 Marked ECG abnormalities on DB study treatment. 
 Change from baseline to Visit 3, Visit 4, Visit 5 and Visit 6 in ECG parameters.  
 Marked laboratory abnormalities on DB study treatment. 
 Change from baseline to Visit 3, Visit 4, Visit 5 and Visit 6 in laboratory parameters. 
 Occurrence of suicidal ideation and/or behavior on DB study treatment and during the 
treatment withdrawal period based on C-SSRS©. 
 Withdrawal effects (physical dependence) upon treatment discontinuation will be 
assessed based on the changes from last assessment on DB treatment (Visit 5) to end 
of the run-out period (Visit 6) in the BWSQ total score, the occurrence of relevant AEs 
and marked ECG abnormalities.  
 Rebound insomnia will be assessed based on change from baseline to the run-out period 
in subjective Total Sleep Time (sTST).  

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 Next-day residual effects will be assessed based on change from baseline to Visit 3, 
Visit 4 and Visit 5 in SDS© and change from baseline over time in morning sleepiness 
score on the sleep diary VAS (mm). VAS scores are the subjects’ rating of their 
morning sleepiness (from ‘the way you feel this morning’), daytime alertness (from 
‘your daytime alertness today’) and daytime ability to function (from ‘your daily ability 
to function today’). 
6.2 Exploratory efficacy endpoints 
 Change from baseline over time in sTST. sTST is the total sleep time as reported in 
item 9 of the sleep diary. 
 Change from baseline over time in sLSO. sLSO is the self-reported time to fall asleep 
as reported in item 5 of the sleep diary. 
 Change from baseline over time in subjective sleep maintenance (sWASO). sWASO is 
the self-reported time spent awake after sleep onset as reported in item 7 of the sleep 
diary. 
 Change from baseline over time in IDSIQ scores (i.e., total score; alert/cognition, mood 
and sleepiness domain scores). 
 Change from baseline over time in sleep quality based on scores on the sleep diary VAS 
(mm). VAS scores are the subjects’ ratings of ‘the quality of your sleep last night’, ‘the 
depth of your sleep last night’, daytime alertness and daytime ability to function 
questions. 
 Change from baseline to Visit 3, Visit 4 and Visit 5 in Insomnia Severity Index© (ISI©) 
scores. 
The number (%) of subjects with ≥ 6-point decrease in ISI© Total score from baseline 
to Visit 3, Visit 4 and Visit 5 will be tabulated. 
 Change from baseline over time in mean number of self-reported awakenings. 
 Change from baseline over time in PGA-S scores (daytime symptoms). 
 Change from baseline over time in PGI-C scores (daytime symptoms). 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits  
The study visits are listed in Table 1. For all visits during the DB treatment phase, the 
subjects must be seen on the designated day and within a ± 7 days visit window in 
comparison with randomization.  
7.1.1 Visit 1 
At Visit 1, subjects will discuss and sign the ICF, and will undergo eligibility assessments 
based on the results from the tests performed at EODBT and EOT in the ID-078A301 and 

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ID-078A302 studies. Visit 1 can be performed either at the same time as EOT of the 
ID-078A301 or ID-078A302 study, after all assessments related to EOT are done, or as an 
independent visit within a maximum of 7 days after EOT. Treatment allocation will occur 
at Visit 1, provided the subject is eligible. The DB study treatment is to be started in the 
evening of 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.  
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 ECG, laboratory assessments, and 
change 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]. 
Pharmacokinetic (PK) samples can be collected at the discretion of the investigator in the 
event of emergence of an AE (e.g., EDS). 
The date and the time of blood sample collection will be entered in the eCRF as an 
unscheduled visit. The date and time of the last study treatment dosing before blood draw 
will be entered as well. 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 for PK sample analysis. 
Alcohol tests can be performed at the discretion of the investigator at any time in the event 
of suspicion of exaggerated alcohol consumption (i.e., above the accepted threshold 
defined in Appendix 1). 
Details about the collection, sampling, storage, and shipment procedures can be found in 
the laboratory manual. 
7.1.3 Telephone calls between visits. 
Questionnaires are to be completed at home during the last week of each consecutive 
4-week DB treatment period. 

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The investigator/delegate will call the subject within 1 week (preferably 2 days) before 
each 4-week DB study treatment period to remind him/her to switch on / charge the 
hand-held device and complete the questionnaires. During these telephone calls, the 
investigator/delegate is also encouraged to collect the results of the urine pregnancy tests 
performed at home and information regarding potential AEs. Alternatively, another 
telephone call can be set up to collect these data.  

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AE = adverse event; BWSQ= Benzodiazepine Withdrawal Symptom Questionnaire; C-SSRS© = Columbia Suicide Severity Rating Scale©; DB = double-blind; ECG = electrocardiogram; EODBT = End of 
Double-Blind Treatment; EOT = End-of-Treatment; ESS© = Epworth Sleepiness Scale©; ICF = Informed Consent Form; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; IMP = 
Investigational Medicinal Product; IRT = Interactive Response Technology; ISI© = Insomnia Severity Index©; PGA-S = Patient Global Assessment of Disease Severity; PGI-C = Patient Global 
Impression of Change; SAE = serious adverse event; SDS© = Sheehan Disability Scale©;VAS = visual analog scale(s); WOCBP = women of childbearing potential. 

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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. 
Visit 1 of ID-078A303 can be performed at the same time as EOT of the ID-078A301 or 
ID-078A302 studies. Eligibility criteria will be assessed based on the latest test results 
available, i.e., 
 EODBT (hematology and biochemistry, physical examination, body weight, ECG) and 
EOT (vital signs, pregnancy test, urine drug screen, C-SSRS©, ESS©) of the 
ID-078A301 or ID-078A302 studies if Visit 1 happens on the same day as EOT. 
 EODBT (hematology and biochemistry, physical examination, body weight, ECG) and 
EOT (vital signs, pregnancy test) of the ID-078A301 or ID-078A302 studies if Visit 1 
happens another day than EOT. In this case, the C-SSRS©, the ESS© and the urine drug 
screen must be performed again at the time of Visit 1.  
The following assessments will be analyzed by an external provider (results will be 
transferred to Idorsia and integrated into the clinical database and to the investigators): 
 Laboratory parameters. 
 ECG parameters. 
 Questionnaires completed using a hand-held device (listed below). 
If the investigator delegates any study procedure/assessment for a subject to an external 
facility, he/she must inform Idorsia and specify 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 investigator. 
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available prior to the enrolment 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. 
Use of hand-held and tablet devices 
Subjects will be required to complete the following questionnaires on a hand-held device: 
ESS©, ISI©, SDS©, BWSQ, IDSIQ, sleep diary (including VAS), PGA-S and PGI-C. 

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Investigators, a delegated physician, a specialist nurse or a nurse practitioner, trained 
according to local requirements and local clinical practice, will be required to complete the 
following questionnaires on a tablet at site: C-SSRS©. 
In addition to the telephone call, a reminder will be sent on each hand-held device the day 
before questionnaire completion is required and every day during the completion period. 
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.  
7.2.1 Demographics 
Demographic data will not be collected again in the eCRF for the extension study. The 
investigator/delegate only needs to confirm the subject’s age that was entered at Visit 1 in 
ID-078A301 or ID-078A302 study in the IRT system. 
For subjects who are not eligible, the following data will be recorded in the eCRF if 
available: 
 Informed consent date 
 Reason for non-eligibility 
 AEs 
7.2.2 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 
7.2.2.1 Body weight and height 
Body weight will be measured at EODBT (Visit 5) and will be recorded in the eCRF.  
Height will not be measured again and values will be taken from Visit 1 in the ID-078A301 
or ID-078A302 studies.  
7.2.2.2 Physical examination 
Physical examination will be performed at Visit 3, Visit 4 and EODBT visit (Visit 5) 
according to site standard medical practice for subjects with insomnia disorders. 
Other exams will be performed if indicated, based on medical history and/or symptoms. 
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 

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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.  
7.2.2.3 Vital signs 
Systolic and diastolic BP and pulse rate will be measured non-invasively at Visit 3, Visit 4, 
Visit 5 and Visit 6.  
Vital sign measurements will be collected in the eCRF. 
7.2.2.4 Sheehan Disability Scale© 
The SDS© consists of 3 questions on impairment of work, social life, and family life / home 
responsibilities [see Appendix 5; Sheehan 1999]. The SDS© is a self-administered 
questionnaire on the hand-held device. It will be completed at Visit 1, Visit 3, Visit 4, 
Visit 5 and Visit 6. 
7.2.2.5 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].  
The C-SSRS© will be completed at Visit 3, Visit 4, Visit 5 and Visit 6.  
At Visit 1, if this visit does not happen on the same day as EOT of the ID-078A301 and 
ID-078A302 studies, the C-SSRS© will be completed for suicidal ideation and behaviors 
since the last visit in the confirmatory studies ID-078A301 and ID-078A302 (i.e., EOT). 
Otherwise, the C-SSRS© does not need to be repeated at Visit 1. At all other visits, the 
C-SSRS© will be completed for suicidal 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. 
7.2.2.6 Benzodiazepine Withdrawal Symptom Questionnaire 
The BWSQ assesses the main symptoms which might be experienced by subjects during 
withdrawal from benzodiazepines [see Appendix 6; Tyrer 1990]. The questionnaire will be 
self-administered using the hand-held device at Visit 5 and Visit 6. 
7.2.2.7 Epworth Sleepiness Scale© 
The ESS© is a validated questionnaire designed to provide a subjective measure of daytime 
sleepiness [Johns 1991]. The ESS© [see Appendix 10] will be self-administered at Visit 3, 
Visit 4, Visit 5 and Visit 6 on a hand-held device to assess daytime sleepiness. The 
assessment must also be performed at Visit 1 if this visit is not performed on the same day 
as EOT of the ID-078A301 and ID-078A302 studies. All clinically significant findings 
must be recorded as AEs in the eCRF. 

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7.2.2.8 ECG assessment 
A standard 12-lead ECG is to be performed at Visit 3, Visit 4, Visit 5 and Visit 6. 
A 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 
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.  
7.2.3 Efficacy assessments 
7.2.3.1 Sleep diary 
The sleep diary will be uploaded onto an electronic hand-held device (also called eDiary) 
and will be kept by the subject from the confirmatory studies to the extension study. Sleep 
diaries will be available in the subject’s language, and must be completed daily throughout 
the last week of each consecutive 4-week period during the treatment period and daily 
during the run-out period. 
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 the external service provider).  
7.2.3.1.1 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.  
For further details, see Appendix 7. 

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7.2.3.1.2 Visual analog scales 
The VAS collect 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 7. 
7.2.3.2 Insomnia Severity Index© 
The ISI© assesses the severity of a subject’s insomnia by scoring the severity of sleep onset 
and sleep maintenance difficulties and any insomnia-related interference with daytime 
functioning [see Appendix 4]. The ISI© will be completed by the subject on the hand-held 
device at Visit 1, Visit 3, Visit 4 and Visit 5.  
7.2.3.3 Patient Global Assessment of Disease Severity 
The PGA-S 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 completion. 
It is a self-administered question programmed on the hand-held device, and is to be 
completed once during the last week of each consecutive 4-week period during the DB 
treatment period and at Visit 6.  
For further details, see Appendix 8. 
7.2.3.4 Patient Global Impression of Change 
The PGI-C 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 compared 
to the week before he/she started treatment. The PGI-C is a self-administered question on 
the hand-held device, and is to be completed once during the last week of each consecutive 
4-week period during the DB treatment period and at Visit 6. 
For further details, see Appendix 8. 
7.2.3.5  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 daily by the subject throughout the last week of each consecutive 
4-week period during the DB treatment period and the run-out period starting from Visit 1, 
without study staff input or interference.  
For further details, see Appendix 9. 

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7.2.4 Laboratory assessments 
7.2.4.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits. 
Local laboratory results of the parameters described in Section 7.2.4.2 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 at Visit 3, Visit 4 and Visit 5 
for whatever reason, it is recommended to the investigator to collect an additional sample 
as soon as possible for repeat analysis.  
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 
considered clinically significant or not. 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 at Visit 3, Visit 4, Visit 5 and Visit 6. 
7.2.4.2 Laboratory tests 
Hematology 

Hemoglobin

Hematocrit

Erythrocytes

Reticulocytes

Leukocytes with differential counts

Platelets

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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 free), 
and thyroid-stimulating hormone. 
Pregnancy test 
Results from the urine pregnancy test performed at EOT of the ID-078A301 or 
ID-078A302 studies will be taken into account to check the eligibility of the subject at 
Visit 1. If Visit 1 does not happen on the same day as EOT, a urine pregnancy test must be 
performed again. If pregnancy is suspected during the study, a serum pregnancy test must 
be performed immediately. 
A serum pregnancy test for women of childbearing potential will be performed at EODBT 
(Visit 5). A urine pregnancy test will be performed at Visit 3, Visit 4 and Visit 6. In 
addition, 2 urine pregnancy tests will be provided to women of childbearing potential at 
Visit 1, Visit 3 and Visit 4. These tests will have to be performed monthly at home. The 
investigator/delegate will call the subject to ask about the result of the test. This call can be 
performed at the same time as the reminder phone call for completion of the eDiary or 
separately, as appropriate. Results of the pregnancy tests performed at home will be 
recorded in the eCRF. 
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. Urine 
drug screen is performed at Visit 3, Visit 4, Visit 5 and Visit 6 and must also be performed 
at Visit 1 if this visit is not performed on the same day as EOT of the ID-078A301 or ID-
078A302 studies. Alcohol tests can be performed at the discretion of the investigator at any 
time in the event of suspicion of exaggerated alcohol consumption (i.e., above the accepted 

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threshold defined in Appendix 1). 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 5.1.2 only if the results of the pregnancy 
tests and other tests are negative.  
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.  
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 
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. 
Investigators are encouraged to explain the importance of remaining in the study to the 
subjects withdrawn from study treatment. The occurrence of missing data due to a subject’s 
withdrawal from the study treatment must be minimal, to ensure accuracy of the results. 
Study-specific measures are in place to maximize subject’s compliance with the study 
treatment and procedures [see Section 5.1.11]. 
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. 

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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, the 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 
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 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. 

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9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
9.1.1 Definition of adverse events 
The study will deal with AEs, TEAEs, and treatment-emergent AESIs. 
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. A TEAE is any 
AE emerging from randomization in the ID-078A303 study until up to 30 days after DB 
study treatment discontinuation in 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. 
 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 dose reduction, interruption or permanent discontinuation of 
study treatment. 
An overdose is defined as intake of more than the maximum recommended dose. In the 
context of this clinical study, it corresponds to the intake of more than one tablet per night 
and the subject explicitly reports overdose. The verbatim term of the corresponding AE 
should specify whether the intake was intentional or accidental, the number of nights it 
occurred, the number of tablets taken at once and the root cause leading to overdose. 
Misuse and abuse of the study treatment and study treatment error will be reported as an 
AE/SAE as determined by the principal investigator. Study treatment abuse is defined as 

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any intentional, non-therapeutic use of the study treatment, even once, for the purpose 
of achieving a desirable psychological or physiological effect. 
Study treatment misuse is defined as any intentional therapeutic use of the study 
treatment in an inappropriate way (e.g., taking a tablet during the day). Misuse specifically 
excludes those events that meet the definition of an abuse event.  
Study treatment error is defined as any preventable unintentional error or inappropriate 
medication use while it is in the control of the subject. 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 in 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.  
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. 
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. 

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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 
All AEs with an onset date after signing of informed consent and up to EOS must be 
recorded on AE pages of the eCRF. 
AEs that started during the course of the ID-078A301 or ID-078A302 studies and that are 
still ongoing at enrollment in the ID-078A303 will be automatically transferred into the 
AE pages of the ID-078A303 eCRF.  
Any increase of intensity will be reported as a new AE in the eCRF. No new AE is required 
to be reported if there is a decrease of intensity. 
9.1.5 Follow-up of adverse events 
AEs still ongoing more than 30 days after EODBT 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 in the eCRF. 
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. 

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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. 
SAEs that started during the course of the ID-078A301 or ID-078A302 studies and that are 
still ongoing at enrollment in the ID-078A303 will be kept open in the eCRF of the 
ID-078A301 or ID-078A302 studies and reported in the ID-078A303 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 
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 EODBT 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. 
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. 

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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 
information (RSI) section provided in the most recent version of the IB for ACT-541468 
[Daridorexant IB]. Any SAE that is assessed as related and unexpected against the RSI of 
the 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 and the outcome must be reported to 
Idorsia Global Drug Safety for all randomized subjects. 

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Any AE associated with the pregnancy occurring during the follow-up period after 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 will review and adjudicate safety data [see Section 3.3]. 
10 STATISTICAL METHODS 
All statistical analyses will be conducted by Idorsia or by designated CROs supervised by 
Idorsia. 
For subjects who received placebo in ID-078A301 or ID-078A302 who are randomized to 
25 mg ACT-541468 in this extension study, baseline refers to assessments performed 
before randomization or start of ACT-541468 intake. For all other subjects, and unless 
stated otherwise, baseline refers to assessments performed before start of DB study 
treatment of study ID-078A301 or ID-078A302. 
A Statistical Analysis Plan will provide full details of the analyses, data displays, and 
algorithms to be used for data derivations. 
10.1 Analysis sets 
A subject must have given informed consent before being included in any analysis set. 
10.1.1 Enrolled Set  
The Enrolled Set includes all subjects who have a subject identification number in the 
extension study (same as in the confirmatory study). 
10.1.2 Full Analysis Set  
The Full Analysis Set (FAS) includes all subjects assigned to a study treatment in the 
extension study. Subjects will be evaluated according to the study treatment they have been 
assigned. 
10.1.3 Safety Set  
The Safety Set includes all subjects who received at least one dose of study treatment in 
the extension study. Subjects will be evaluated according to the actual treatment they 
received. 

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10.1.4 Treatment Withdrawal Set  
The Treatment Withdrawal Set comprises all subjects from the Safety Set who received 
single-blind placebo treatment in the run-out period of the extension study. 
10.1.5 Usage of the analysis sets 
The analyses of efficacy endpoints including baseline and disease characteristics will be 
performed using the FAS. 
The Safety Set will be used for the analysis of safety endpoints (including previous and 
concomitant medications, and study treatment exposure). 
The Treatment Withdrawal Set will be used for the analysis of endpoints assessing 
withdrawal symptoms (e.g., BWSQ total score) and rebound insomnia (e.g., sTST). 
10.2 Variables 
Detailed descriptions 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 safety endpoints 
Analysis 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 preferred term (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 Visit 3, Visit 4, Visit 5 and Visit 6 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. 

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Vital signs and body weight 
Observed values and changes from baseline to Visit 3, Visit 4, Visit 5 and Visit 6 in vital 
signs (systolic and diastolic BP, and pulse rate) will be summarized. Observed values and 
changes from baseline to Visit 5 in body weight will be summarized. 
Electrocardiograms 
Observed values and changes from baseline to Visit 3, Visit 4, Visit 5 and Visit 6 for each 
ECG parameter (QTcB, QTcF, HR, PR, QRS) will be summarized. The number (%) of 
subjects with 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. 
The BWSQ total score will be summarized using descriptive statistics for the observed 
values and changes from the last assessment on treatment (Visit 5) to the end of the run-
out period (Visit 6). 
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 experiencing, separately, an AE 
and a marked ECG abnormality during the treatment withdrawal period will be tabulated. 
Rebound insomnia 
The Treatment Withdrawal Set will be used to assess the potential for rebound insomnia. 
The changes from the baseline to the treatment withdrawal period (Visit 6, Week 41) in 
sTST will be summarized using descriptive statistics. 
Next-day residual effect 
Observed values and changes from baseline to Visit 3, Visit 4 and Visit 5 in SDS©, and 
sleep diary VAS scores (mm) assessing morning sleepiness (from ‘the way you feel this 
morning’), daytime alertness (from ‘your daytime alertness today’) and daytime ability to 
function (from ‘your daily ability to function today’), 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 and during 
the treatment withdrawal period will be tabulated. 
Shifts from baseline showing any changes in suicidal ideation and suicidal behavior during 
DB treatment and during the treatment withdrawal period will also be provided. Subjects 

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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. 
Epworth Sleepiness Scale© 
The change from baseline to Visit 3, Visit 4, Visit 5 and end of the run-out period Visit 6 
in ESS© total score will be summarized. Observed values will also be summarized.  
10.3.2 Analysis of exploratory efficacy endpoints 
Analysis of the efficacy endpoints 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 sTST, sWASO, sLSO and IDSIQ scores (i.e., total 
score; alert/cognition, mood and sleepiness domain 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, age 
group (< 65; ≥ 65 years), treatment (10 mg; 25 mg; 50 mg; placebo), visit (Month 6; 
Month 9; Month 12), and the interaction of treatment by visit, and baseline by visit. 
An unstructured covariance matrix shared across treatment groups will be used to model 
the correlation among repeated measurements. A restricted maximum likelihood approach 
will be used to derive (unbiased) estimates of variance components. The Kenward-Roger 
approximation will be used to compute the denominator degrees of freedom and adjust 
standard errors [Kenward 1997]. 
Appropriate contrasts will be used to test the treatment differences of interest (e.g., the 
difference in least squares mean change from baseline between 10 mg vs placebo, 25 mg 
vs placebo and 50 mg vs placebo at Month 6). Baseline is the mean value based on the 
screening sleep diary / IDSIQ entries performed at home in the 7 days immediately 
preceding the first polysomnography at Visit 3 of the confirmatory study. Month 6 is the 
mean value based on the sleep diary / IDSIQ entries performed at home over the 7 days in 
Week 12 of the extension study; Month 9 and Month 12 is defined similarly. 
Observed values and changes from baseline over time in sTST, sWASO, sLSO and IDSIQ 
scores (i.e., total score; alert/cognition, mood and sleepiness domain scores) will be 
summarized. 
Summary statistics will be provided for other efficacy endpoints using number (%) of 
subjects for categorical variables and descriptive statistics (e.g., mean, standard deviation, 
median, min., max.) for continuous variables. 

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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 

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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). 
Entries recorded by the subject on the hand-held device (i.e., ESS©, sleep diary (including 
VAS), ISI©, IDSIQ, PGA-S, PGI-C, SDS©, BWSQ) as well as the physician-reported 
global assessment on a tablet at site (i.e., C-SSRS©) 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 subjects’ metadata or 
answers in physician-reported assessments. Site personnel will not be allowed to alter 
subject-generated data, unless requested to do so by the subject. A data correction form 
will be completed by the site personnel to request any data changes and sent to the CRO 
provider, who 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 subject 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 

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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. Should discrepant data be 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) 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 and hand-held device data will be processed through a central 
laboratory / CRO and the results will be electronically sent to Idorsia. 
Should local laboratory data be generated, 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 and previous/concomitant 
therapies are coded using the latest version of WHODrug 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. 

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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]. 
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 

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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. 
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. 
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 clinical study report (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. 

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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 as long as is necessary to comply with 
Idorsia’s requirements (i.e., as specified in the clinical study agreement), and national 
and/or 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 documents 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 containing 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 

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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 Principal Investigator (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. 
The SIV must be completed before the site can start the enrollment 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 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. 

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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. 
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 the inspector(s) and allow access 
to all study documentation (e.g., subject records) and study facilities. 

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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 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. 
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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13 REFERENCES 
[Daridorexant IB] Investigator’s Brochure for daridorexant, version 7. Idorsia 
Pharmaceuticals Ltd; January 2020. 
[APA 2013] American Psychiatric Association. Diagnostic and statistical manual of 
mental disorders, Fifth Edition. Arlington, VA: American Psychiatric Publishing; 
2013. 
[Belsomra® USPI] Belsomra® (suvorexant) US Package Insert. United States Food and 
Drug Administration full prescribing information. Revised 8/2014. Accessed on 25 
April 2018. Available from: 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204569s000lbledt.pdf 
[Citrome 2014] Citrome L. Suvorexant for insomnia: a systematic review of the efficacy 
and safety profile for this newly approved hypnotic - what is the number needed to 
treat, number needed to harm and likelihood to be helped or harmed? Int J Clin Pract 
2014;68(12):1429-41.  
[EMA 2011] European Medicines Agency guideline on medicinal products for the 
treatment of insomnia. EMA/CHMP/16274/2009 Rev. 1. 7 February 2011. Accessed 
on 25 April 2018. Available from: 
http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/201
1/02/WC500102351.pdf 
[FDA 1977] Food and Drug Administration (US): Guidelines for the clinical evaluation of 
hypnotic drugs. September 1977. Accessed on 25 April 2018. Available from: 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM071711.pdf 
[Herring 2016] Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et 
al. Suvorexant in patients with insomnia: Results from two 3-month randomized 
controlled clinical trials. Biol Psychiatry 2016;79(2):136-48. 
[ICH 1994] ICH Tripartite Guideline. The Extent of Population Exposure to Assess 
Clinical Safety - E1. Accessed on 4 May 2018. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E1/Step4/E1_Guideline.pdf 
[ICH 2000] ICH Tripartite Guideline. Choice of Control Group and Related Issues in 
Clinical Trials - E10. Accessed on 4 May 2018. Available from: 
http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Efficacy/
E10/Step4/E10_Guideline.pdf 

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[Johns 1991] Johns MW. A new method for measuring daytime sleepiness: the Epworth 
Sleepiness Scale. Sleep 1991;14(6):540-5. 
[Kenward 1997] Kenward MG, Roger JH. Small sample inference for fixed effects from 
restricted maximum likelihood. Biometrics 1997;53:983-97. 
[McCall 2004] McCall WV. Sleep in the elderly: Burden, diagnosis, and treatment. Prim 
Care Companion J Clin Psychiatry 2004;6(1):9–20. 
[Neubauer 2014] Neubauer DN. New and emerging pharmacotherapeutic approaches for 
insomnia. Int Rev Psychiatry 2014;26(2):214-24. 
[NIH 2005] National Institutes of Health, State-of-the-Science Conference Statement on 
Manifestations and Management of Chronic Insomnia in Adults. NIH Consensus and 
State-of-the-Science Statements. 2005 Jun;13-15;22(2):1-30. 
[Ohayon 2002] Ohayon MM, Smirne S. Prevalence and consequences of insomnia 
disorders in the general population of Italy. Sleep Med. 2002;3(2):115–20. 
[Ohayon 2010] Ohayon MM, Sagales T. Prevalence of insomnia and sleep characteristics 
in the general population of Spain. Sleep Med. 2010;11(10):1010–8. 
[Pigeon 2007] Pigeon WR, Crabtree VM, Scherer MR. The future of behavioral sleep 
medicine. J Clin Sleep Med 2007;3(1):73-9. 
[Posner 2007] Posner K, Oquendo MA, Gould M, Stanley B, Davies M. Columbia 
Classification Algorithm of Suicide Assessment (C-CASA): classification of suicidal 
events in the FDA’s pediatric suicidal risk analysis of antidepressants. Am J 
Psychiatry 2007 Jul;164(7):1035-43. 
[Roth 2007] Roth T. Insomnia: Definition, prevalence, etiology, and consequences. J Clin 
Sleep Med 2007;3 Suppl 5:S7-10. 
[Schutte-Rodin 2008] Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical 
guideline for the evaluation and management of chronic insomnia in adults. J Clin 
Sleep Med 2008;4:487–504. 
[Sheehan 1999] Sheehan D, Janavs J, Baker R, Harnett-Sheehan K, Knapp E, Sheehan M. 
MINI international neuropsychiatric interview. J Clin Psychiatry 1999:60(18):39-60. 
[Tyrer 1990] Tyrer P, Murphy S, Riley P. The Benzodiazepine Withdrawal Symptom 
Questionnaire. J Affect Disord 1990;19:53-61 
 
 

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14 APPENDICES 
Appendix 1 
Alcohol restrictions during the study 
The subjects will be instructed to limit alcohol to a maximum of 2 drinks per day. 
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 caffeinated 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.
The use of CNS-active drugs is forbidden or restricted at least 1 week prior to Visit 1
and until 24 hours after EOT.
Drug Class 
Examples 
Forbidden 
/ Restricted 
Comment 
Antihistamines 
Sedating: e.g., carbinoxamine, 
triprolidine HCl, acrivastine, 
azatadine, chlorpheniramine, 
doxylamine, hydroxyzine, ketotifen, 
promethazine & timeprazine, 
diphenhydramine HCl. 
F 
Psychotropics 
Stimulants: e.g., amphetamine 
derivatives, ephedrine derivatives, 
modafinil, armodafinil, 
methylphenidate, aripiprazole, 
pramipexole, levodopa. 
F 
Antipsychotics, including depot 
neuroleptics: e.g., quetiapine, 
olanzapine. 
F 
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. 
F 
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) 

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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 
Isotrenitoin  
Systemic glucocorticoids: e.g., 
dexamethasone, methylprednisone, 
prednisone. 
Diet pills (prescription and OTC). 
F 
R 
 
 
F 
Continuous treatment 
limited to 1 week. Inhaled 
corticosteroids are 
permitted 
 
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. 
GABA = gamma-aminobutyric acid; NSAID = nonsteroidal anti-inflammatory drug; OTC = over-the-counter. 
 

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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 1 
and are forbidden until 24 hours after EOT.  
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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