Conditions: Insomnia Disorder
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 804
Healthy volunteers: no

Brief summary:
Study to assess the long term safety and tolerability of daridorexant in adult and elderly subjects suffering from difficulties to sleep

Detailed description:

Arms:
arm 1: Film-coated tablets administered orally, once daily in the evening arm 2: Film-coated tablets administered orally, once daily in the evening arm 3: Film-coated tablets administered orally, once daily in the evening arm 4: Film-coated tablets administered orally, once daily in the evening arm 5: Film-coated tablets administered orally, once daily in the evening

Interventions: intervention 1: Daridorexant 10 mg intervention 2: Daridorexant 25 mg intervention 3: Daridorexant 50 mg intervention 4: Placebo
Intervention descriptions: intervention 1: Daridorexant 10 mg film-coated tablets intervention 2: Daridorexant 25 mg film-coated tablets intervention 3: Daridorexant 50 mg film-coated tablets intervention 4: Matching placebo film-coated tablets

Protocol document:
SAP_002.pdf: 
 
 
Cover page 
 
 
 
 
Official Title: 
 
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT 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: 
 
20 July 2020 
 
 
 


 
 
 
TPL-100721_v02 
 
ACT-541468 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
FOR CLINICAL STUDY REPORT  
 
ID-078A303 
 
Version 3 
 
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 
 
 
Document Number: D-20.130 
 
20 July 2020 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 
 
 


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Revision history 
Version date 
Version 
Implemented change(s) 
9 May 2019 
1.0 
Initial version 
31 March 2020 
2.0 
• Section 2: Added interim analysis in the design. 
• Section 4.1.3: Clarified definition of treatment 
received. 
• Section 5.3.1: Included a summary based on the 
FAS. 
• Section 5.3.4: Clarified which ATC classification 
level will be presented. 
• Section 5.4.1: Updated summarized categories for 
the combined duration of double-blind study 
treatment. Added clarifications for the calculation 
of study treatment duration at the time of an 
interim analysis. 
• Section 5.4.2: Added a condition for the 
calculation of the total duration of treatment 
interruptions. 
• Updated calculation of treatment compliance if 
wallet not returned. eCRF collected compliance 
will not be listed. Added clarifications for the 
calculation of study treatment duration and total 
duration of treatment interruptions at the time of an 
interim analysis. Included categories for number of 
treatment interruptions. 
• Section 6.1: Added measurement for ISI© Total 
score. Added empirical cumulative distribution 
function plots and subgroup analyses for some 
efficacy endpoints. 
• Section 7: Clarified handling of EOT safety 
assessments in the event of premature study 
treatment discontinuation.  
• Section 7.2: Updated the definition of the reporting 
period for TEAE and added the summary of cases 
sent for ISB adjudication. 
• Section 7.4: Updated definition of subjects at risk 
of having a marked ECG abnormality for criteria 
based on change from baseline and clarified how 


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subjects will be counted. Added a sorting rules for 
ECG summaries. 
• Section 7.7: Updated the endpoints used to assess 
the potential of rebound insomnia. 
• Section 7.9: Added clarification for C-SSRS© 
analyses. Added a condition for the assignment of 
the assessments to a study period scheduled visit. 
• Section 7.10: Added clarification for analysis ESS© 
total score > 16. 
• Section 7.11: Added subgroups analyses for safety. 
• Section 10: Added interim analysis description.  
• Section11.2: Added a clarification and a condition 
for the double-blind study period definition. 
• Section 11.4: Clarified definition of baseline. 
• Section 11.7: New time window definition for 
PGA-S and PGI-C endpoints. 
• Section 12: Updated as previously mentioned 
changes are now included in the protocol 
amendment. 
• Section 14: Updated SAS® code 
20 July 2020 
• 3.0 
• Section 5.1.2: Added report of ongoing subjects at 
the time of interim analysis and added a summary 
to present disposition by visit of subjects in the 
double-blind study period at the cut-off.  
• Section 5.1.3: Added a Kaplan-Meir plot to 
summarize time from first dose of double-blind 
treatment to treatment discontinuation. 
• Section 5.2: Added summary for all PDs and 
important PDs related to COVID-19. 
• Section 5.4.1: Added a Kaplan-Meir plot to 
summarize time from treatment to study 
discontinuation. 
• Section 5.4.2: Added a condition for the calculation 
of the total duration of treatment interruptions. 
• Section 11.2: Added a condition to the 
double-blind study period definition and to the 
treatment withdrawal period definition. 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................7 
1 
INTRODUCTION .........................................................................................................9 
2 
STUDY DESIGN AND FLOW ....................................................................................9 
3 
OBJECTIVES .............................................................................................................11 
3.1 
Primary objective ..........................................................................................11 
3.2 
Exploratory objective ...................................................................................11 
4 
ANALYSIS SETS .......................................................................................................11 
4.1 
Definitions of analysis sets ...........................................................................11 
4.1.1 
Enrolled Set .......................................................................................11 
4.1.2 
Full Analysis Set ...............................................................................11 
4.1.3 
Safety Set ..........................................................................................12 
4.1.4 
Treatment Withdrawal Set ................................................................12 
4.2 
Usage of the analysis sets .............................................................................12 
5 
STUDY SUBJECTS VARIABLES AND ANALYSES ............................................13 
5.1 
Subject disposition ........................................................................................13 
5.1.1 
Subject not randomized ....................................................................13 
5.1.2 
Study disposition ...............................................................................13 
5.1.3 
Study and study treatment completion/discontinuation ....................14 
5.1.4 
Study enrollment ...............................................................................15 
5.2 
Protocol deviations .......................................................................................15 
5.3 
Subject characteristics ..................................................................................16 
5.3.1 
Demographics and baseline characteristics ......................................16 
5.3.2 
Baseline disease characteristics ........................................................16 
5.3.3 
Previous and concomitant diseases ...................................................17 
5.3.4 
Concomitant therapy .........................................................................17 
5.4 
Study treatment exposure and compliance ...................................................19 
5.4.1 
Study treatment exposure ..................................................................20 
5.4.2 
Study treatment compliance ..............................................................20 
6 
EFFICACY VARIABLES AND ANALYSES ...........................................................22 
6.1 
Analysis of exploratory efficacy variables ...................................................22 
7 
SAFETY VARIABLES AND ANALYSES ...............................................................26 


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7.1 
Overview of safety analyses including subgroup analyses ..........................26 
7.2 
Adverse events ..............................................................................................26 
7.3 
Laboratory tests ............................................................................................29 
7.4 
Electrocardiography ......................................................................................33 
7.5 
Vital signs and body weight .........................................................................35 
7.6 
Withdrawal symptoms ..................................................................................35 
7.7 
Rebound insomnia ........................................................................................35 
7.8 
Next-day residual effect ................................................................................36 
7.9 
Columbia Suicide Severity Rating Scale© ....................................................36 
7.10 
Epworth Sleepiness Scale© ...........................................................................37 
7.11 
Subgroup analysis of safety variables ..........................................................38 
8 
PHARMACOKINETIC VARIABLES AND ANALYSES .......................................38 
9 
GENERAL STATISTICAL METHODOLOGY ........................................................38 
9.1 
General rules for data presentations .............................................................38 
10 INTERIM ANALYSES ..............................................................................................39 
11 GENERAL DEFINITIONS AND DERIVATIONS ...................................................40 
11.1 
Treatment start and end dates .......................................................................40 
11.2 
Study periods ................................................................................................40 
11.3 
Treatment day and study day ........................................................................41 
11.4 
Baseline ........................................................................................................42 
11.5 
Change from baseline ...................................................................................42 
11.6 
Handling of data when subjective total sleep time is zero ...........................42 
11.7 
Time window definitions for calculating subjective endpoints ....................42 
12 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................44 
12.1 
Changes to the analyses planned in the study protocol ................................44 
12.2 
Changes in the conduct of the study / data collection ..................................44 
12.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................44 
12.4 
Additional analyses as compared to the study protocol ...............................45 
13 REFERENCES ............................................................................................................45 
14 APPENDICES .............................................................................................................46 


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LIST OF TABLES 
 
Table 1 
Imputation rules for an incomplete or missing concomitant therapy 
date ............................................................................................................ 19 
Table 2 
Insomnia Daytime Symptoms and Impacts Questionnaire description .... 23 
Table 3 
Imputation rules for an incomplete or missing AE date ............................ 29 
Table 4 
Marked abnormalities in laboratory parameters for reporting .................. 30 
Table 5 
Marked abnormalities in ECG parameters ................................................ 34 
Table 6 
Time windows (in days) to calculate weekly averages for certain 
subjective endpoints .................................................................................. 43 
Table 7 
Time windows (in days) for PGA-S and PGI-C measurements ................ 44 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design .............................................................................................. 10 
 
 
LIST OF APPENDICES 
 
Appendix 1 
SAS® code for Mixed Model for Repeated Measures............................... 46 
 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
ADaM
 
Analysis Data Model 
AE
 
Adverse event 
AESI 
 
Adverse event of special interest 
ALT 
 
Alanine aminotransferase 
AST 
 
Aspartate aminotransferase 
BMI 
 
Body mass index 
bpm 
 
Beats per minute 
BWSQ 
 
Benzodiazepine Withdrawal Symptom Questionnaire 
CI 
 
Confidence interval 
COVID-19 
 
Coronavirus disease 2019 
CSR 
 
Clinical study report 
C-SSRS© 
 
Columbia Suicide Severity Rating Scale© 
ECG 
 
Electrocardiogram/graphy 
eCRF 
 
Electronic case report form 
ENR 
 
Enrolled  
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  
HR 
 
Heart rate 
IDMC 
 
Independent Data Monitoring Committee 
IDSIQ 
 
Insomnia Daytime Symptoms and Impacts Questionnaire 
ISAC 
 
Independent Statistical Analysis Center 
ISB 
 
Independent Safety Board 
ISI© 
 
Insomnia Severity Index© 
LS 
 
Least squares 
MedDRA 
 
Medical Dictionary for Regulatory Activities 
NDA 
 
New Drug Application 
PD 
 
Protocol deviation 


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PGA-S 
 
Patient Global Assessment of Disease Severity 
PGI-C 
 
Patient Global Impression of Change 
PSG 
 
Polysomnography 
PT 
 
Preferred term 
SAE 
 
Serious adverse event 
SAP 
 
Statistical analysis plan 
SDS© 
 
Sheehan Disability Scale© 
SDTM 
 
Study Data Tabulation Model 
SI unit 
 
International System of Units 
sLSO 
 
Subjective latency to sleep onset 
SOC 
 
System organ class 
SS 
 
Safety Set 
sTST 
 
Subjective total sleep time 
sWASO 
 
Subjective wake after sleep onset 
TBIL 
 
Total bilirubin 
TEAE 
 
Treatment-emergent adverse event 
TWS 
 
Treatment Withdrawal Set 
ULN 
 
Upper limit of normal 
VAS 
 
Visual analog scale(s) 
WHO 
 
World Health Organization 


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1 
INTRODUCTION 
This SAP describes in detail the analyses and data presentation for the CSR for protocol 
ID-078A303. This study is a double-blind, joint extension study of each confirmatory 
study, i.e., ID-078A301 and ID-078A302. In the following text, the term “confirmatory 
study” (singular) will represent each of these studies (ID-078A301 and ID-078A302). 
Obvious corrections to address minor formatting errors or spelling mistakes may be 
performed at the time of analysis without amending this document or other related 
documents (e.g., mock shells).  
Data will be analyzed by Idorsia and/or designated Contract Research Organizations 
supervised by Idorsia using the SAS® version 9.4 or higher and R version 3.4.3 or higher.  
The analyses for the IDMC closed session meetings will be performed by an ISAC and are 
detailed in a separate SAP.  
Protocol ID-078A303, Final Version 3, dated 17 February 2020 was used as the basis at 
the time of writing this SAP. 
Unless noted otherwise, summaries will be produced by treatment group as described in 
Section 9.1. 
Only data collected on this extension study (ID-078A303) will be reported, however, some 
baseline data and subject characteristics data from the confirmatory study will be used. 
2 
STUDY DESIGN AND FLOW 
Subjects who complete double-blind study treatment and the run-out period of the 
confirmatory study, and who are willing to participate, will be eligible to enter the 
ID-078A303 extension study. 
The ID-078A303 study will be offered at every site participating in ID-078A301 and 
ID-078A302 (approximately 150 centers in 17 countries), and to every eligible subject. 
Subjects assigned to the placebo arm in the confirmatory study 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 of the confirmatory study will be taken into consideration 
for the randomization in the extension study).  
Subjects assigned to one of the ACT-541468 arms in the confirmatory study will continue 
on the same dose (but assigned a new randomization number).  
It was expected that approximately 1260 subjects (i.e., ~70% of the total subjects in the 
combined confirmatory studies) would enter the extension study after completing the 


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confirmatory study. The overall study design, including the transition from the 
confirmatory study, 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. 
 
The study comprises 2 phases:  
• The double-blind treatment phase starts when the treatment is allocated (Visit 1) 
and lasts 40 weeks, until the EODBT at Visit 5. 
• The safety follow-up phase starts from the EODBT and ends 30 days after the last 
dose of double-blind study treatment with the EOS at Visit 7. It consists of the 
following two periods: 
– A single-blind placebo run-out period of 7 days (from the evening of Visit 5 until 
after all visit assessments have been performed at Visit 6 i.e., EOT). 
– 
A safety follow-up period (from EOT until EOS). 
See Section 11.2 for a detailed definition of study periods. 
An interim analysis will be conducted when all subjects who have not prematurely 
discontinue study treatment have reached Visit 3, to ensure 6 months of cumulative 
double-blind treatment (confirmatory and extension). 


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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, those in the extension study will only display 3-months.  
A second interim analysis focusing on safety may need to be conducted to fulfil 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.  
3 
OBJECTIVES 
3.1 Primary objective 
The primary objective of this extension study is to assess the long-term safety (including 
withdrawal symptoms and rebound insomnia) and tolerability of 10, 25 and 50 mg 
ACT-541468. 
3.2 Exploratory objective 
The exploratory objective is 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 IDSIQ) in subjects with insomnia disorder during 
long-term treatment. 
4 
ANALYSIS SETS 
4.1 Definitions of analysis sets 
A subject must have given informed consent before being included in any analysis set.  
The number of subjects in each analysis set defined below will be tabulated. 
4.1.1 Enrolled Set  
The ENR Set includes all subjects who have a subject identification number. Subject 
identification numbers assigned in the confirmatory studies will be identical in the 
extension study. 
Summaries based on the ENR Set will be presented as one group (i.e., all subjects), unless 
specified otherwise.  
For summaries by treatment group, subjects will be evaluated according to the treatment 
they have been assigned. 
4.1.2 Full Analysis Set  
The FAS includes all subjects assigned (i.e., randomized) to a study treatment.  


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In order to adhere to the intention-to-treat principle as much as possible:  
• Subjects will be evaluated according to the study treatment and strata they have been 
assigned to in the extension study.  
• All available data will be included. 
4.1.3 Safety Set 
The SS includes all subjects who received at least one dose of study treatment.  
Subjects will be evaluated according to the actual treatment they received in the extension 
study, which may differ from the randomly assigned treatment. 
Actual treatment received is defined as: 
• the assigned double-blind study treatment of this study when received at least once, 
• the first double-blind study treatment received in this study if the assigned double-blind 
study treatment of this study was never received. 
The data of any subjects who received a kit/treatment that was not assigned to them will 
be reviewed in detail and the impact to any statistical analyses will be discussed in the 
clinical study report. 
4.1.4 Treatment Withdrawal Set 
The TWS comprises all subjects included in the SS who received at least one dose of 
single-blind placebo treatment in the run-out period. 
Subjects will be evaluated according to the actual treatment they received as defined in 
Section 4.1.3. 
Any subject excluded because he/she did not receive at least one dose of single-blind 
placebo during the run-out period will be summarized and listed. 
4.2 Usage of the analysis sets 
The ENR Set will be used for subject disposition and demographic summaries. 
The analyses of efficacy endpoints, as well as baseline disease characteristics, will be 
performed using the FAS. 
The SS will be used for the analysis of safety endpoints, concomitant medications and 
study treatment exposure. 
The TWS will be used for the analysis of endpoints assessing withdrawal symptoms (e.g., 
BWSQ total score) and rebound insomnia (i.e., sTST). 


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5 
STUDY SUBJECTS VARIABLES AND ANALYSES 
5.1 Subject disposition 
5.1.1 Subject not randomized 
Subjects who discontinued before randomization will be summarized based on the ENR 
Set and will include:  
• Number and percentage of subjects not randomized (based on ‘Was the subject 
randomized?’ recorded as ‘No’ in the ‘Randomization’ page). 
• Primary reason for not being randomized (based on reason for not randomized 
entered on the ‘Randomization’ page).  
All reasons for a subject not being randomized will be listed using the ENR Set.  
5.1.2 Study disposition 
Study disposition will be summarized based on the ENR Set, presented by randomized 
treatment group and all enrolled subjects combined, and will include:  
• Number of subjects enrolled.  
• Number and percentage of subjects randomized (based on non-missing randomization 
number).  
• Number and percentage of subjects treated in the double-blind study period (based on 
non-missing ‘Treatment start date’ in the ‘Study Double-Blind Treatment Log’ page).  
• Number and percentage of subjects who completed the double-blind study period 
(based on ‘Reason for treatment stop’ entered as ‘Completion as per protocol’ in the 
‘Study Double-Blind Treatment Log’ page). 
• At the time of interim analysis: number and percentage of subjects ongoing in 
double-blind treatment at cut-off. 
• Number and percentage of subjects treated in the single-blind placebo treatment run-out 
period (based on a non-missing ‘Treatment start date’ in the ‘Study Single-Blind 
[Run-Out] Treatment Log’ page).  
• Number and percentage of subjects who completed the single-blind placebo treatment 
run-out period (based on ‘Reason for treatment stop’ entered as ‘Completion as per 
protocol’ in the ‘Study Single-Blind [Run-Out] Treatment Log’ page). 
• At the time of interim analysis: number and percentage of subjects ongoing in 
single-blind run-out treatment at cut-off. 
• Number and percentage of subjects who completed the study (based on ‘Did the subject 
complete the study?’ recorded as ‘Yes’ in the ‘End of Study Status’ page). 


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• At the time of interim analysis: number and percentage of subjects ongoing in the 
study treatment at cut-off. 
At the time of interim analysis, study disposition by visit of subjects in the double-blind 
study period at cut-off will be summarized based on FAS presented by randomized 
treatment group and all treatment groups combined, and will include: 
• Number and percentage of subjects randomized.  
• Number and percentage of subjects ongoing between randomization and Week 14 
(Visit 3) and discontinued study between randomization and Week 14 (Visit 3). 
• Number and percentage of subjects who completed Week 14 (Visit 3). 
• Number and percentage of subjects ongoing between Week 14 (Visit 3) and Week 27 
(Visit 4) and discontinued study between Week 14 (Visit 3) and Week 27 (Visit 4). 
• Number and percentage of subjects who completed Week 27 (Visit 4). 
• Number and percentage of subjects ongoing between Week 27 (Visit 4) and Week 40 
(Visit 5) and discontinued study between Week 27 (Visit 4) and Week 40 (Visit 5). 
• Number and percentage of subjects who completed Week 40 (Visit 5). 
5.1.3 Study and study treatment completion/discontinuation 
The following summary will be based on the FAS and presented by treatment group and 
all treatment groups combined:  
• Number and percentage of subjects who prematurely discontinued double-blind study 
treatment (based on reason for treatment stop entered as ‘Discontinuation’ in the ‘Study 
Double-Blind Treatment Log’ page).  
• Primary reason for premature double-blind study treatment discontinuation (based on 
reason for treatment discontinuation entered on the ‘Study Double-Blind Treatment 
Log’ page). 
All reasons for premature double-blind study treatment discontinuation will be listed based 
on the FAS. 
The following summary will be based on the FAS and presented by treatment group and 
all treatment groups combined:  
• Number and percentage of subjects who prematurely discontinued from the study 
(based on non-missing reason for stopping study entered in the ‘End-of-Study Status’ 
page).  
• Primary reason for premature discontinuation from the study (based on reason for 
stopping study entered in the ‘End-of-Study Status’ page).  


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All reasons for premature study discontinuation will be listed based on the FAS. 
The following summary will be based on the FAS and presented by treatment group and 
all treatment groups combined: 
• Number and percentage of subjects who prematurely discontinued single-blind placebo 
treatment in the run-out period (based on reason for treatment stop entered as 
‘Discontinuation’ in the ‘Study Single-Blind [Run-Out] Treatment Log’ page).  
• Primary reason for premature single-blind placebo treatment discontinuation in the 
run-out period (based on reason for treatment discontinuation entered on the ‘Study 
Single-Blind [Run-Out] Treatment Log’ page). 
All reasons for premature single-blind placebo treatment discontinuation in the run-out 
period will be listed based on the FAS. 
Time from randomization to study discontinuation will be summarized by treatment group 
using Kaplan-Meier plots in the FAS. For subjects who do not complete the study at the 
time of the interim analysis, time to study discontinuation will be censored at the cut-off 
date. 
5.1.4 Study enrollment 
The number and percentage of subjects enrolled as well as subjects enrolled but not 
randomized will be displayed by country and site based on the ENR Set. 
The number and percentage of subjects randomized will be displayed by country and site 
based on the FAS by treatment group and all treatment groups combined. 
The randomization scheme and codes will be listed for randomized subjects only using the 
FAS. 
5.2 Protocol deviations 
The FAS will be used for the summary of PDs.  
All PDs and important PDs will be summarized in separate tables as per pre-specified 
category (i.e., selection criteria, IMP, study conduct/procedure, forbidden medication, 
withdrawal criteria and other) by treatment group and all treatment groups combined. In 
addition, the same summary of all PDs and important PDs will only be provided separately 
for PDs related to COVID-19.  
A subject may have more than one protocol deviation in a given category, but the subject 
will be counted only once per protocol deviation category.  
A listing of PDs will be provided using the FAS. PDs related to COVID-19 will be flagged 
in the listing.  


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5.3 Subject characteristics 
Unless noted otherwise, summaries and listings described in this section will be based on 
the FAS.  
Summary tables will be produced by treatment group and all treatment groups combined. 
Data will be presented individually by subject in the listings. 
5.3.1 Demographics and baseline characteristics 
Demographic data at screening of the respective confirmatory study (ID-078A301 or 
ID-078A302) including age, sex, race, ethnicity, height, weight, BMI and region (US, 
other) will be summarized and listed using the ENR Set and using the FAS.  
The number and percentage of subjects randomized in each age category (< 18, 18 – < 65, 
65 – < 75, 75 – < 85, 65 – < 85, ≥ 85 years at screening of confirmatory study), in each 
BMI category (< 25, 25–30, > 30 kg/m2 at screening of confirmatory study), and in each 
region (US, other) will be further summarized using the ENR Set and using the FAS.  
The number of subjects treated in each age category (< 18, 18 – < 65, 65 – < 85 and  
≥ 85 years at screening of confirmatory study) by sex will be summarized based on the SS.  
5.3.2 Baseline disease characteristics 
Baseline disease characteristics will come from baseline disease characteristics of the 
confirmatory study and include: dissatisfaction with sleep quantity or quality (Y/N), 
difficulty initiating sleep (Y/N), difficulty maintaining sleep characterized by frequent 
awakenings or problems returning to sleep after awakenings (Y/N), early morning 
awakening with inability to return to sleep (Y/N) and sleep disturbance causing significant 
distress or impairment in social, occupational, educational, academic, behavioral, or other 
important areas of functioning (Y/N).  
These baseline disease characteristics, including the time since insomnia diagnosis (in 
years) at randomization of ID-078A301 or ID-078A302, will be listed and summarized. 
An incomplete (day or month missing) or missing insomnia diagnosis date will be imputed 
using the 15th day of the month (in case only the day is missing) or 1 July (in case day and 
month are missing).  
In the event that the insomnia diagnosis imputed date is after the randomization date of the 
confirmatory study, then the randomization date of the confirmatory study –1 day will be 
used as insomnia diagnosis date.  


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5.3.3 Previous and concomitant diseases  
Relevant medical history and current medical conditions will come from the respective 
confirmatory study (ID-078A301 or ID-078A302) and are coded using MedDRA 
terminology.  
Any disease or diagnosis is defined as previous if ‘Ongoing at informed consent signed’ is 
answered as ‘No’ in the eCRF of confirmatory studies or extension study.  
Medical history at screening of the confirmatory study (i.e., those procedures or diagnoses 
reported at screening of the respective confirmatory study or those recorded as ‘not 
ongoing’ in the eCRF at the signing of the informed consent of the extension study) and 
current medical conditions (i.e., those conditions recorded as ‘ongoing’ in the eCRF at the 
signing of the informed consent of the extension study ), excluding insomnia-related 
conditions and symptoms, will be summarized separately and listed.  
Summaries will be presented for each treatment group by primary SOC and PT.  
Medical history will be sorted by SOC and PT within each SOC by descending frequency 
based on all treatment groups combined.  
The MedDRA version used for reporting will be specified in the footnote of the applicable 
output. 
5.3.4 Concomitant therapy 
Therapies collected will be coded using the WHO Drug Global reference dictionary that 
employs the WHO ATC classification system. The WHO Drug Global version used for 
reporting will be specified in the footnote of the applicable output. 
Study concomitant therapies are any treatments that are either ongoing at the date the 
informed consent of the extension study was signed or initiated during the time from the 
date the informed consent of the extension study was signed up to EOS. The use of all 
study-concomitant therapies (including contraceptives and traditional and alternative 
medicines, e.g., plant-, animal-, or mineral-based medicines) is to be recorded in the 
‘Concomitant Medication’ page.  
Double-blind study treatment concomitant therapies (a subset of study-concomitant 
therapies) are any treatments that are either ongoing at the start of double-blind study 
treatment or initiated during the double-blind study period until 1 day after the last dose of 
double-blind study treatment.  
The number and percentage of subjects having taken at least one concomitant therapy will 
be summarized by ATC classification level 4 (or next highest available level) and 
individual preferred name within each ATC classification based on the SS.  


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Concomitant therapy will be sorted by ATC class and preferred name within each ATC 
class by descending frequency based on all treatment groups combined.  
Summary tables will be provided for study concomitant and double-blind study 
treatment-concomitant therapies separately. An additional summary table will be provided 
for double-blind study treatment concomitant therapies at baseline (i.e., therapy started on, 
or is ongoing at the double-blind study treatment start date). All concomitant therapies will 
be listed using the SS. The period (double-blind, run-out, Section 11.2) for which the 
concomitant therapy started will be displayed in the listing and those related to an adverse 
event (AE) will be flagged. 
An incomplete (day or month missing) or missing concomitant therapy date will be 
imputed as described in Table 1. The ‘lower limit’ and ‘upper limit’ refer to the earliest 
and latest possible dates, respectively. As an example: if concomitant therapy start date is 
MAR2017 (day missing), the lower limit is 01MAR2017 and the upper limit is 
31MAR2017; if concomitant therapy start date is 2017 (day and month missing), the lower 
limit is 01JAN2017 and the upper limit is 31DEC2017. 


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Table 1 
Imputation rules for an incomplete or missing concomitant therapy 
date 
Field 
Incomplete date 
Missing date 
Concomitant 
therapy end 
date 
The upper limit. 
No imputation; the therapy is 
considered as ongoing.  
Concomitant 
therapy start 
date 
The rules below apply in the order 
presented: 
1. For concomitant therapy reported as 
ongoing from the confirmatory study, 
the lower limit is used. 
2. If the (imputed) concomitant therapy 
end date is on or after the start of 
double-blind study treatment, and if the 
double-blind study treatment start falls 
within the upper and lower limits 
(inclusive), 
the 
double-blind 
study 
treatment start date is used. 
3. If the concomitant therapy resolution 
date is missing, and if the double-blind 
study treatment start falls within the 
upper and lower limits (inclusive), the 
double-blind study treatment start date is 
used. 
4. In all the other cases, the lower limit is 
used. 
Whichever is the earlier of 
the concomitant therapy end 
date or double-blind study 
treatment start date*. 
* If a concomitant therapy is reported as ongoing (from confirmatory study) and if the onset date is missing then the 
double-blind study start date of the confirmatory study is used. 
 
The purpose of imputing concomitant therapy dates is only to assign a concomitant therapy 
to a specific treatment phase for the summary tables and listings. However, only the actual 
dates as reported in the eCRF will be listed. No imputed date is considered in the medical 
evaluation of a concomitant therapy or an individual AE. 
5.4 Study treatment exposure and compliance 
Unless noted otherwise, summaries and listings described in this section will be based on 
the SS.  


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5.4.1 Study treatment exposure 
The duration of double-blind study treatment, and single-blind placebo run-out treatment 
(including categories: ≤ 4, > 4–8, > 8–12, > 12–16, > 16–20, > 20–24, > 24–28, > 28–32, 
> 32–36, > 36–40, > 40 weeks for double-blind study treatment; and 0, 1, 2, 3, 4, 5, 6, 7, 
8, 9, ≥ 10 days for single-blind placebo run-out treatment) and duration of double-blind 
study treatment in subject-years will be summarized for the extension study. The definition 
of a year is 365.25 days. 
The duration of treatment (in days) is defined as the difference between the respective 
(double-blind/run-out) treatment end date and the respective (double-blind/run-out) 
treatment start date plus one day. This calculation ignores periods of treatment interruption. 
Summary for run-out will be based on the TWS.  
Additionally, the duration of double-blind study treatment in the confirmatory and 
extension study is calculated as double-blind study treatment end date of the extension 
study – double-blind study treatment start date of the confirmatory study + 1 day (including 
categories: ≤ 12, > 12–16, > 16–20, > 20–24, > 24–28, > 28–32, > 32–36, > 36–40,  
> 40–44, > 44–48, > 48–52, > 52 weeks for double-blind study treatment in the 
confirmatory and extension study) and duration in subject-years will be summarized. 
Interruptions between studies including the run-out period will be ignored. This analysis 
excludes the subjects who switched from placebo to 25 mg. 
The calculation of study treatment duration at the time of an interim analysis will be slightly 
modified: for subjects who are still on study treatment at the interim cut-off date, this date 
will be used instead of the double-blind study treatment end date of the extension study. 
This also means that subjects who complete study treatment after the interim cut-off date 
will be considered as ‘study treatment ongoing ‘ for the interim report. 
Time from first dose of double-blind treatment to treatment discontinuation will be 
summarized using Kaplan-Meier plots in the SS. For subjects who did not complete the 
treatment at the time of the interim analysis, time to treatment discontinuation will be 
censored at the cut-off date. 
The duration of treatment along with reason for treatment stop will be listed. 
5.4.2 Study treatment compliance  
Study treatment compliance will be assessed through study treatment accountability.  
The following formula will be used to calculate compliance for both the double-blind study 
period and the run-out period:  
Study treatment compliance (%) = ([number of tablets dispensed – number of tablets 
returned*] / [treatment duration – total duration of treatment interruptions]) × 100 
* If a subject did not return his/her wallet (e.g., the wallet is lost), the study treatment compliance will not be calculated 
and the compliance for the period will be set to missing. 


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Treatment duration and total duration of treatment interruptions in the double-blind or 
run-out period are calculated using the dedicated eCRF page ‘Study Treatment Log’ as 
follows:  
• Treatment duration (days) = date of last drug intake of double-blind study treatment 
(run-out single-blind placebo treatment) – date of first drug intake of double-blind 
study treatment (run-out single-blind placebo treatment) + 1 day. 
• Total duration of treatment interruptions (days) is the sum of all treatment interruption 
durations. A treatment interruption duration = date restarted double-blind study 
treatment (run-out single-blind placebo treatment) – end date of double-blind study 
treatment (run-out single-blind placebo treatment) due to an interruption −1 day. For 
example, a subject stopped his treatment on 19MAR2019 and started again on 
23MAR2019, as the treatment is taken on the start and end date the calculation will be 
23MAR2019–19MAR2019 – 1 day = 3 days of interruption. Should the subject 
interrupt the treatment again for 7 days, the total duration of interruptions will be 
10 days. In case of a treatment interruption duration of 0 days, the interruption will be 
counted but the duration of 0 days will not be included in the summary for the duration 
of treatment interruption. For subjects who complete the study treatment for a given 
study period but end on an interruption before continuing study treatment in the next 
study period, the start date of the next study period is used as the date of restarted study 
treatment of the given study period. E.g., if a subject completed double-blind study 
treatment with an interruption on 23JUN2019 and then started the treatment withdrawal 
period on 26JUN2019, the duration of that treatment interruption will be  
(26JUN2019 – 23JUN2019) – 1 day = 2 days.  
The calculation of study treatment duration and total duration of treatment interruptions at 
the time of an interim analysis will be slightly modified: for subjects who are still on study 
treatment at the interim cut-off date, this date will be used instead of the last drug intake of 
double-blind study treatment (run-out single-blind placebo treatment). For subjects who 
have an ongoing treatment interruption at the interim cut-off date, the interim cut-off date 
will be used instead of the date restarted double-blind study treatment (run-out single-blind 
placebo treatment). Subjects who complete study treatment after the interim cut-off date 
will be considered as ‘study treatment ongoing’ for the interim report.  
The percentage of days treated is defined as follows:  
• Percentage of days treated: 100 × (treatment duration – total duration of treatment 
interruptions) ⁄ treatment duration. 
Study treatment compliance (including categories 0%, > 0% – < 50%, 50% – < 70%, 70% 
– < 80%, 80% – < 90%, 90% – < 100%, 100%, > 100%), number of treatment interruptions 
per subject by category (0, 1, 2, 3, 4, > 4 interruptions), duration of treatment interruptions 
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70% – < 80%, 80% – < 90%, 90% – < 100%, 100%) will be summarized for the 
double-blind and run-out period, separately. The summaries of the run-out period will be 
based on the TWS. 
The number and percentage of subjects who have treatment interruptions, and the 
corresponding reasons will be tabulated. 
Study treatment compliance, dispensing and accountability data will be listed. 
6 
EFFICACY VARIABLES AND ANALYSES 
Unless noted otherwise, the analyses of efficacy endpoints will be performed using the 
FAS. Efficacy data described below will be listed using the FAS. 
6.1 Analysis of exploratory efficacy variables 
The exploratory efficacy endpoints are measured on subject questionnaires and defined as: 
• Change from baselinea over timeb in sTST. 
• Change from baselinea over timeb in sLSO. 
• Change from baselinea over timeb in sWASO. 
• Change from baselinea over timeb in IDSIQ scores (i.e., total score; alert/cognition, 
mood and sleepiness domain scores). 
• Change from baselinea over timeb in the following visual analog scale (VAS) scores 
collected in the sleep diary: quality of the sleep, depth of the sleep, daytime alertness 
and daytime ability to function.  
• Change from baseline (baseline as defined in Section 11.4) to Visit 3 (Week 14), 
Visit 4 (Week 27) and Visit 5 (Week 40) in ISI© scores. 
– The number and percentage of subjects with ≥ 6 points decrease in ISI© total score 
from baseline to Visit 3 (Week 14), Visit 4 (Week 27) and Visit 5 (Week 40) will 
be tabulated.  
• Change from baselinea over timeb in number of self-reported awakenings. 
• Change from baseline (baseline as defined in Section 11.4) over time in PGA-S 
scores (daytime symptoms). 
• Change from baseline (baseline as defined in Section 11.4) over time in PGI-C scores 
(daytime symptoms). 
a For subjects randomized to placebo in ID-078A301 or ID-078A302 and who are randomized to 25 mg ACT-541468 
in this extension study, baseline is the mean value based on the last sleep diary / IDSIQ entries performed at home 
during a 7-day window (excluding any polysomnography [PSG] nights) in the confirmatory study. For all other 
subjects, baseline is the mean value based on the screening sleep diary / IDSIQ entries performed at home in the 7 days 
immediately preceding the first PSG at Visit 3 of the confirmatory studies. 
b Over time is the mean value of each time point defined in Table 6 (except for run-out week) based on the sleep diary / 
IDSIQ entries. According to the protocol it is planned to be completed at home daily during the last week of each 
consecutive 4-week double-blind study treatment period. 


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sTST (in minutes) is based on the time reported by the subject in item 9 of the sleep diary 
i.e., the answer to the question “In total, how long did you sleep last night?”. 
sLSO (in minutes) is the self-reported time to fall asleep as reported in item 5 of the sleep 
diary, i.e., the answer to the question “How long did it take you to fall asleep?”. 
sWASO is the self-reported time spent awake after sleep onset as reported in item 7 of the 
sleep diary, i.e., the answer to the question “In total, how long did these awakenings last?”. 
The morning VAS consists of three questions: quality of subjects’ sleep, depth of sleep and 
sleepiness in the morning. The evening VAS consists of two questions: daytime alertness 
and ability to function. The VAS scores are collected in the sleep diary and answered on a 
continuous bipolar (or unipolar for sleepiness in the morning) scale ranging from  
0–100 points; for all questions, a higher score reflects a better outcome. 
The IDSIQ has 3 domains assessing Alert/Cognition, Mood, and Sleepiness [Table 2]. A 
total score can also be obtained. For each domain, the item responses in the respective 
domains are summed (each item is based on a categorical scale ranging from 0–10). Prior 
to summation, items 1, 2, 8, 10 and 14 must be reversed [see Table 2 for details regarding 
scoring]. For the Total score, all item responses are summed. 
Table 2 
Insomnia Daytime Symptoms and Impacts Questionnaire description 
Domain 
Scoring 
Minimum/Maximum score 
Alert/cognition 
Daily: sum of Item 1*, Item 2*, Item 3, 
Item 9, Item 10*, Item 14* 
Minimum score: 0 
Maximum score: 60 
Higher score: greater burden 
of illness 
Weekly average: mean of the daily 
domain score over 7 days 
Mood 
Daily: sum of Item 4, Item 5, Item 6, 
Item 7 
Minimum score: 0 
Maximum score: 40 
Higher score: greater burden 
of illness 
Weekly average: mean of the daily 
domain score over 7 days 
Sleepiness 
Daily: sum of Item 8*, Item 11, Item 12, 
Item 13 
Minimum score: 0 
Maximum score: 40 
Higher score: greater burden 
of illness 
Weekly average: mean of the daily 
domain score over 7 days 
Total score 
Daily: sum of all domains above 
Minimum score: 0 
Maximum score: 140 
Higher score: greater burden 
of illness 
Weekly average: mean of the daily 
domain score over 7 days 
* Item 1, Item 2, Item 8, Item 10, and Item 14 scores are reverse scored prior to summation. 
 


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A plot of the mean change from baseline over time (per month as defined in Table 6) for 
sTST, sWASO, sLSO and IDSIQ scores (i.e., Total score; Alert/Cognition, Mood and 
Sleepiness domain scores) will be provided together with a summary table.  
Observed values and change 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 by age group at screening in the confirmatory study (< 65; ≥ 65 years) and 
overall using descriptive statistics. 
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. Subjects who are randomized 
(switched) from placebo to 25 mg in this study will be excluded from this longitudinal 
analysis as their exposure to treatment and timing of assessments are not aligned with the 
other treatment groups.  
The analysis model will adjust for the baseline value of the relevant response variable 
(either sWASO, sLSO, sTST or IDSIQ scores), age group as per assigned strata (< 65; 
≥ 65 years), treatment (10 mg; 25 mg; 50 mg; placebo), visit (Month 6 [Week 12]; Month 9 
[Week 24]; Month 12 [Week 36]; as defined in Table 6), and the interaction of treatment 
by visit, and baseline by visit (SAS® code available in Appendix 1). 
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]. If this analysis fails to converge, the use of the 
heterogeneous Toeplitz covariance structure, shared across treatment groups, will be 
explored. 
Appropriate contrasts will be used to test the treatment differences of interest (i.e., the 
difference in least squares [LS] mean change from baseline between ACT-541468 10 mg 
vs placebo, ACT-541468 25 mg vs placebo and ACT-541468 50 mg vs placebo at Month 6, 
Month 9 and Month 12, see Appendix 1). 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 (Week 24) and Month 12 (Week 36) are defined similarly. 
The LS mean for each treatment group per time point will be displayed along with 
associated standard errors and 95% CIs. For each ACT-541468 dose level comparison with 
placebo, the placebo-adjusted LS mean will be displayed along with associated standard 
errors, 95% CI and unadjusted two-sided p-value.  


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Observed values and change from baseline over time in VAS scores, ISI©, number of 
self-reported awakening, PGA-S and PGI-C will also be summarized using descriptive 
statistics. 
Empirical cumulative distribution function plots of the observed cases of sWASO, sLSO, 
sTST and IDSIQ endpoints, separately, at Months 6, 9 and 12 for each treatment group will 
be provided. A summary will be provided showing the cumulative number and percentage 
of subjects meeting certain thresholds for sWASO, sLSO, sTST and IDSIQ endpoints, 
separately, for the observed range of values.  
For sTST, sWASO, sLSO, each IDSIQ domain and total scores, VAS scores and number 
of self-reported awakenings, subjects must have at least 2 days of data during each week 
to calculate a weekly mean. Otherwise, the mean value will be considered missing for that 
week. The approaches above imply implicit imputation: the missing data points are given 
the same value as the mean of the non-missing data points of that same time point or week. 
Subgroup analyses for sTST, sWASO, sLSO, each IDSIQ domain and total scores 
endpoints will be performed to investigate the consistency of the treatment effect (i.e., 
ACT-541468 vs placebo) across subgroups defined as: 
• Age at screening of confirmatory study: < 65, ≥ 65 years and < 75, ≥ 75 years. 
Specific subgroup analyses for sTST and each IDSIQ domain and total scores endpoints 
are defined below:  
• Sex: Male, female. 
• Region: US, other (non-US). 
• BMI at screening of confirmatory study: < 30, ≥ 30 kg/m2. 
• Race: White, Black or African American, Other*; 
* The ‘Other’ category will not be considered for subgroup analyses due to the mix of races and small number of subjects 
limiting the ability (i.e., low power) to detect differences between treatment groups. ‘Other’ includes: American Indian 
or Alaska Native, Native Hawaiian or other Pacific Islander, Asian and Other (Entry for multiple races was to be reported 
under category ‘Other’. Similarly, ‘Not permitted as per legislation/regulation’ was to be also grouped within this 
category ‘Other’). 
The same model as for the longitudinal analysis (i.e., linear mixed-effects model) will be 
fitted with the additional factor for subgroup, and the interaction of subgroup by treatment, 
subgroup by visit, and subgroup by treatment by visit. Subjects who are randomized 
(switched) from placebo to 25 mg in this study will be excluded from these longitudinal 
analyses.  
Of note, age group will not be included as a covariate in the model of the subgroup analyses 
by age. 


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Treatment effect estimates (LS mean and associated 95% CI for the ACT-541468 
comparison with placebo) at Month 6, 9 and 12 will be presented via forest plots.  
At the time of interim analysis, treatment will still be ongoing for some subjects so the 
efficacy beyond 6 months should be interpreted with caution. 
7 
SAFETY VARIABLES AND ANALYSES 
7.1 Overview of safety analyses including subgroup analyses 
Unless noted otherwise, the SS will be used for tables and listings of safety data. Safety 
data described below will be listed. 
In the event of permanent study treatment discontinuation, it is recommended per protocol 
to perform the safety assessments of Visit 5 within 7 days of the last double-blind study 
treatment intake. Although some subjects may be considered as being off study treatment, 
the time from the last double-blind study treatment intake to the Visit 5 assessments is 
expected to be short. Therefore, for subjects who prematurely discontinue treatment, the 
safety data (laboratory tests, ECG, vital signs) measured within 7 days of the last 
double-blind study treatment intake will be included as being taken during double-blind 
study treatment. A subject who prematurely discontinues treatment may continue the 
planned study visits until EOS, without the run-out period. Therefore, for subjects who 
prematurely discontinue treatment, the safety data (laboratory tests, ECG, vital signs) 
measured more than 7 days from the last double-blind study treatment intake will be 
excluded from analyses. 
Any unscheduled or re-test measurements will be excluded for determining last values 
during the double-blind treatment period. All scheduled, re-test and unscheduled 
measurements will be included for determining baseline values. 
7.2 Adverse events 
Unless noted otherwise, the AE summary tables will include TEAEs occurring during the 
extension study i.e., AEs that started or worsened on or after double-blind study treatment 
start date of the extension study up to 30 days after double-blind study treatment end date. 
An AE that started or worsened during any unplanned double-blind study treatment 
interruption (e.g., due to AE) will be considered as treatment-emergent. In addition, an AE 
that started or worsened during a planned double-blind study treatment interruption (i.e., 
the run-out period or safety follow-up period) that falls in the treatment-emergent time 
window defined above, will be considered as treatment-emergent. 
AEs will be coded using MedDRA. The MedDRA version used for reporting will be 
specified in the footnote of the applicable output.  


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The number and percentage of subjects experiencing a TEAE occurring during the 
extension study (including SAEs, AESIs after adjudication by the ISB, and AEs leading to 
premature discontinuation or temporary interruption of double-blind study treatment) will 
be summarized by SOC and/or PT, and/or maximum intensity.  
Each AESI category (i.e., excessive daytime sleepiness, cataplexy, complex sleep behavior 
including hallucinations/sleep paralysis, suicide/self-injury, narcolepsy-like symptoms) 
will be summarized by PT separately. 
A subject with multiple intensities reported for an AE will be summarized under the 
maximum intensity recorded for the event.  
Apart from the summaries of occurrences, where each event is counted, a subject with 
multiple occurrences of an AE is counted only once in the AE category (e.g., SOC, PT). If 
a single AE worsens on the same treatment group, then this event will be considered as one 
occurrence.  
AEs will be sorted by descending frequency, first in the ACT-541468 50 mg dose level, 
then in the ACT-541468 25 mg dose level, then in the ACT-541468 10 mg, then in the 
placebo treatment group, and finally in the ex-placebo/ACT-541468 25 mg. After this 
ordering, SOCs are presented in alphabetical order with PT sorted within SOC in 
alphabetical order. 
The following AE summary tables will be provided:  
• TEAEs,  
• TEAEs during the double-blind study perioda,  
• TEAEs occurring (i.e., that started or worsened) during the treatment withdrawal 
period (based on the TWS),  
• TEAEs during the double-blind study perioda related to study treatment as assessed 
by the investigator and/or sponsor,  
• AEs leading to premature discontinuation of double-blind study treatment,  
• AEs leading to temporary interruption of double-blind study treatment,  
• Treatment emergent SAEs (including occurrences),  
• Treatment emergent SAEs related to study treatment (including occurrences), 
• Most frequent (threshold to be defined at time of reporting) non-serious TEAEs 
(including occurrences),  
• Treatment emergent AESIs after ISB adjudication, 
• TEAEs during the double-blind study perioda related to abuse (as defined in the 
document Search specifications for safety monitoring), 


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• TEAEs during the double-blind study perioda based on selected Standardized 
MedDRA Queries or pre-defined search criteria (as defined in the document Search 
specifications for safety monitoring), 
• TEAEs with fatal outcome, 
• Total number of deaths (those occurring on or after double-blind study treatment start 
date of the extension study up to 30 days after double-blind study treatment end date). 
a Includes only those TEAEs occurring (i.e., that started or worsened) during the 
double-blind study period [see Section 12.2].  
All AEs will be listed including AEs recorded as ongoing at the start of double-blind study 
treatment.  
An AE listing will be provided also for subjects who were not randomized and subjects 
who were randomized but did not take double-blind study treatment. Subjects who were 
not randomized due to an AE or discontinued the study due to an AE will be reported in 
that listing. In addition, a separate listing will be provided for deaths with cause of death 
using the ENR Set.  
AEs submitted for adjudication will be listed flagging separately: AEs that were 
adjudicated as an AESI and AEs that were considered an AESI as per the investigator’s 
judgment. 
The number of subjects (including occurrences) with at least one case submitted for ISB 
adjudication will be summarized and listed.  
An incomplete (day or month missing) or missing AE date will be imputed as described in 
Table 3. The ‘lower limit’ and ‘upper limit’ refer to the earliest and latest possible dates, 
respectively. As an example: if AE onset date is MAR2017 (day missing), the lower limit 
is 01MAR2017 and the upper limit is 31MAR2017; if AE onset date is 2017 (day and 
month missing), the lower limit is 01JAN2017 and the upper limit is 31DEC2017. 


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Table 3 
Imputation rules for an incomplete or missing AE date  
Field 
Incomplete date 
Missing date 
AE 
resolution 
date 
The upper limit. 
No imputation; the AE is 
considered as ongoing. 
AE 
onset 
date 
The rules below apply in the order 
presented: 
1. For AEs reported as ongoing from the 
confirmatory study, the lower limit is 
used. 
2. If the (imputed) AE end date is on or 
after the start of double-blind study 
treatment, and if the double-blind study 
treatment start falls within the upper and 
lower limits (inclusive), the double-blind 
study treatment start date is used. 
3. If the AE resolution date is missing, 
and if the double-blind study treatment 
start falls within the upper and lower 
limits (inclusive), the double-blind study 
treatment start date is used. 
4. In all the other cases, the lower limit is 
used. 
Whichever is the earlier of 
the AE resolution date or 
double-blind study treatment 
start date*. 
AE = adverse event. 
*If an AE is reported as ongoing (from confirmatory study) and if the onset date is missing then the double-blind study 
start date of the confirmatory study should be used.  
 
The purpose of imputing AE dates is only to assign an AE to a specific treatment phase for 
the summary tables and listings. However, only the actual dates as reported in the eCRF 
will be listed. No imputed date is considered in the medical evaluation of an AE.  
7.3 Laboratory tests 
Laboratory analyses are based on data received from the central laboratory. Laboratory 
data will be converted into SI units. Unless noted otherwise, summaries and listings will 
include scheduled, re-test and unscheduled assessments.  


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Descriptive summary statistics for each scheduled visit (re-test excluded) will be provided 
for observed values and change from baseline (baseline as defined in Section 11.4) in both 
hematology and blood chemistry laboratory parameters.  
The change from baseline to the last value (re-test and unscheduled assessments excluded) 
in the double-blind study period for hematology and blood chemistry parameters will be 
summarized.  
Marked laboratory abnormalities are defined in Table 4. The number and percentage of 
subjects with marked laboratory abnormalities during double-blind study treatment will be 
tabulated. In the event of multiple occurrences, a subject will be counted only once but may 
be reported in more than one marked laboratory abnormality criterion of a given parameter.  
Percentages will be based on the number of subjects at risk, i.e., those having at least one 
post-baseline value for a given parameter.  
Shift from baseline to worst value post-baseline based on laboratory normal ranges will be 
provided for the following laboratory parameters: 
• Liver enzymes: ALT, AST, gamma-glutamyl transpeptidase and TBIL.  
• Thyroid hormones: thyroid-stimulating hormone, free triiodothyronine and free 
thyroxine.  
• Lipids: total cholesterol and triglycerides.  
• Hematology: leucocytes, neutrophils, lymphocytes, and eosinophils.  
All laboratory data for subjects with at least one marked laboratory abnormality during 
double-blind study treatment will be listed. Any local laboratory data collected will be 
listed separately. 
Table 4 
Marked abnormalities in laboratory parameters for reporting 
Laboratory 
parameter 
Criteria for marked laboratory abnormalities 
Hematology (SI unit) 
Hemoglobin (g/L) 
< 100  
< 80  
> 20 above ULN or > 20 above baseline if baseline > ULN  
> 40 above ULN or > 40 above baseline if baseline > ULN  
Hematocrit (%) 
< 32% (Male); < 28% (Female)  
< 20%  
> 60% (Male); > 55% (Female)  


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Laboratory 
parameter 
Criteria for marked laboratory abnormalities 
> 65%  
Platelets (109/L) 
< 75  
< 50  
> 600  
> 999  
Leucocytes (109/L) 
< 3.0  
< 2.0  
> 20.0  
> 100.0  
Neutrophils (109/L) 
< 1.5  
< 1.0  
Eosinophils (109/L) 
> 5.0  
Eosinophils (%) 
> 5%  
Lymphocytes (109/L) 
< 0.8  
< 0.5  
> 4.0  
> 20.0  
Reticulocyte (%) 
> 2.5%  
Blood chemistry (SI unit) 
ALT (U/L) 
> 3 × ULN  
> 5 × ULN  
> 10 × ULN  
AST (U/L) 
> 3 × ULN  
> 5 × ULN  
> 10 × ULN  
ALP (U/L) 
> 2.5 × ULN  
> 5 × ULN  
Total 
bilirubin 
(mol/L) 
> 2 × ULN  
> 5 × ULN  
Creatinine (mol/L) 
> 1.5 × ULN or > 1.5 × baseline if baseline > ULN 
> 3 × ULN or > 3 × baseline if baseline > ULN  


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Laboratory 
parameter 
Criteria for marked laboratory abnormalities 
Creatinine 
clearance 
(ml/min/1.73 m2) 
< 30 
< 60 
Albumin (g/L) 
< 30  
< 20  
Calcium (mmol/L) 
< 2.0  
< 1.75  
> 2.9  
> 3.1  
Potassium (mmol/L) 
< 3.2  
< 3.0  
> 5.5  
> 6.0  
Sodium (mmol/L) 
< 130  
> 150  
> 155  
Chloride (mmol/L) 
< 74  
> 131  
Creatine kinase (μg/L) > 5 × ULN  
> 10 × ULN  
Gamma-glutamyl 
transferase (U/L) 
> 2.5 × ULN  
> 5 × ULN  
Blood urea nitrogen 
(mmol/L) 
> 2.5 × ULN  
> 5 × ULN  
Uric acid (μmol/L) 
> 590  
> 720  
Glucose (mmol/L) 
< 3  
< 2.2  
> 8.9 
> 13.9 
TSH (mIU/L) 
< 0.28 
> 6.6 
Free T3 (pmol/L) 
< 2.8 
> 7.8 
Total T3 (nmol/L) 
< 0.9 


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Laboratory 
parameter 
Criteria for marked laboratory abnormalities 
> 3.6 
Free T4 (pmol/L) 
< 7.2 
> 24 
Total T4 (nmol/L) 
< 53 
> 210 
Triglycerides 
> 5.7 mmol/L 
Total cholesterol 
> 2  ULN 
ALP = alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI unit = International 
System of Units; TSH = thyroid-stimulating hormone; T3 = triiodothyronine; T4 = thyroxine; ULN = upper limit of 
normal.  
 
Elevated liver parameters during double-blind study treatment will be summarized: the 
number and percentage of subjects meeting the criteria defined below within a given central 
laboratory sample will be tabulated by treatment group. Percentages will be based on the 
number of subjects at risk, i.e., those having at least one post-baseline value for all 
parameters within the given criteria. 
• AST or ALT > 3 × ULN. 
• AST or ALT > 5 × ULN. 
• AST or ALT > 10 × ULN. 
• TBIL > 1.5 × ULN and > 2 × ULN. 
• ALP > 1.5 × ULN. 
• (ALT or AST > 3 × ULN) and (TBIL > 1.5 × ULN). 
• (ALT or AST > 3 × ULN) and (TBIL > 2 × ULN). 
7.4 Electrocardiography 
Unless noted otherwise, ECG summaries and listings will include scheduled, re-test and 
unscheduled assessments.  
Descriptive summary statistics for each scheduled visit (re-test excluded) will be provided 
for observed values and change from baseline (baseline as defined in Section 11.4) to 
Visit 3 (Week 14), Visit 4 (Week 27), Visit 5 (Week 40) and Visit 6 (Week 41) in ECG 
parameters (QT corrected according to Fridericia’s formula, QT corrected according to 
Bazett’s formula, heart rate, PR, and QRS). 
Marked ECG abnormalities are defined in Table 5. The following summaries will be 
provided for each ECG parameter: 


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• Number and percentage of subjects having a marked ECG abnormality during the 
double-blind study period, 
• Number and percentage of subjects having a marked ECG abnormality during the 
treatment withdrawal period (based on the TWS).  
For the summaries above, percentages will be based on the number of subjects at risk: those 
having at least one post-baseline value in the study period under consideration per ECG 
parameter for criteria based on post-baseline values only, or those having a baseline value 
and at least one post-baseline value in the study period under consideration per ECG 
parameter for criteria based on change from baseline. For non-mutually exclusive criteria 
(i.e., HR < 45 bpm and < 50 bpm), a subject will be counted only once in the event of 
multiple occurrences but may be reported in more than one marked ECG abnormality 
criterion of a given parameter. For mutually exclusive criteria (e.g., HR and QTc), only the 
subject’s worst post-baseline value (or worst change from baseline value) will be counted. 
ECG findings during the double-blind study period and during the treatment withdrawal 
period (based on the TWS) will be summarized separately and listed.  
ECG abnormality categories and findings will be sorted by descending frequency, first in 
the ACT-541468 50 mg dose level, then in the ACT-541468 25 mg dose level, then in the 
ACT-541468 10 mg, then in the placebo treatment group, and finally in the 
ex-placebo/ACT-541468 25 mg. After this sorting, ECG abnormality categories will be 
presented in alphabetical order with ECG finding sorted within ECG abnormality category 
in alphabetical order.  
All ECG values for subjects with at least one marked ECG abnormality during double-blind 
study period or during the treatment withdrawal period will be listed.  
Table 5 
Marked abnormalities in ECG parameters 
ECG parameter 
Criteria for marked ECG abnormalities 
QTcF, QTcB (ms) 
> 450 and ≤ 480  
> 480 and ≤ 500  
> 500  
> 30 and ≤ 60 increase from baseline  
> 60 increase from baseline 
HR (bpm) 
< 45  
< 50  
> 10 and ≤ 20 decrease from baseline  
> 20 decrease from baseline  
PR (ms) 
> 200  
QRS (ms) 
> 110  
bpm = beats per minute; ECG = electrocardiogram; HR = heart rate; QTcB = QT corrected according to Bazett’s 
formula; QTcF = QT according to Fridericia’s formula.  


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7.5 Vital signs and body weight 
Each summary will include only scheduled assessments (re-test excluded) and listings will 
include both scheduled and unscheduled assessments.  
The change from baseline (baseline as defined in Section 11.4) to Visit 3 (Week 14), Visit 4 
(Week 27), Visit 5 (Week 40) and the run-out period Visit 6 (Week 41) in vital signs 
(systolic and diastolic blood pressure, and pulse rate) will be summarized. The observed 
values at baseline and each scheduled post-baseline visit will also be summarized.  
The change from baseline (baseline as defined in Section 11.4) to Visit 5 (Week 40; or last 
value on study) in body weight will be summarized.  
7.6 Withdrawal symptoms 
The TWS will be used to assess the potential for withdrawal symptoms. 
The BWSQ assesses the main symptoms which might be experienced by subjects during 
withdrawal from benzodiazepines. The questionnaire consists of 20 items with each item 
rated by the subject as either 0 (No), 1 (Yes–moderate) to 2 (Yes–severe). The BWSQ total 
score (possible range: 0–40) for the observed values and change from the last available 
assessment on double-blind study treatment to the end of the treatment withdrawal period 
will be summarized. Observed values will also be summarized.  
The number and percentage of subjects with a BWSQ total score above 20 will be tabulated 
by visit. The number and percentage of subjects with one or more BWSQ symptom scored 
as ‘severe’ will be tabulated by visit. 
In addition, withdrawal symptoms after double-blind study treatment discontinuation will 
be assessed through the incidence of AEs, and marked ECG abnormalities, occurring 
during the treatment withdrawal period [see Section 11.2]. As described in their respective 
sections, the incidence of AEs [Section 7.2] and marked ECG abnormalities [Section 7.4] 
occurring during the treatment withdrawal period (between Visit 5 and Visit 6) will be 
summarized. 
7.7 Rebound insomnia 
The TWS will be used to assess the potential for rebound insomnia. 
The change from baseline (baseline as defined in Section 6.1) to the treatment withdrawal 
period (Visit 6, Week 41, see Section 11.7) in the subjective sleep parameter sTST will be 
summarized using descriptive statistics.  
Empirical cumulative distribution function plots of this subjective sleep parameter for each 
treatment group will be provided together with a summary showing the cumulative number 
and percentage of subjects meeting certain thresholds for the observed range of values. 


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7.8 Next-day residual effect 
Sheehan Disability Scale©  
The SDS© consists of three questions on impairment of work, social life, and family  
life / home responsibilities each on a 10-point scale. The three items will be summed into 
a single dimensional measure of global functional impairment that ranges from 
0 (unimpaired) to 30 (highly impaired). Number of days lost (school, work or normal daily 
responsibilities) and number of days underproductive (school, work or normal daily 
responsibilities) are also collected and will be summarized.  
The change from baselinea to Visit 3 (Week 14), Visit 4 (Week 27), Visit 5 (Week 40) and 
run-out period Visit 6 (Week 41) in each SDS© item (impairment of work, social life, 
family life / home responsibilities, number of days lost and number of days 
underproductive) and Total score will be summarized. The Total score will be calculated 
only for subjects with all the three items available: impairment of work, social life and 
family life / home responsibilities. Observed values will also be summarized.  
a For subjects entering ID-078A303 and assigned to the same treatment arm as that of the 
confirmatory studies (ACT-541468 10 mg, 25 mg, or 50 mg, or placebo), baseline is the 
mean of the two PSG morning assessments at Visit 3 of the run-in period in the 
confirmatory study. For subjects entering ID-078A303 who received placebo in the 
confirmatory studies and who are randomized (switched) to 25 mg of ACT-541468 in the 
extension study, baseline is as defined in Section 11.4. 
Visual Analog Scales  
The change from baseline over time (baseline and over time as defined in Section 6.1) in 
morning sleepiness VAS score will be summarized. Observed values will also be 
summarized.  
7.9 Columbia Suicide Severity Rating Scale©  
The C-SSRS© is an instrument that evaluates suicidal ideation and behaviors.  
The C-SSRS© outcome categories are provided below. Each category has a binary response 
(yes/no) and are numbered and ordered for convenience.  
1. 
Wish to be Dead  
2. 
Non-specific Active Suicidal Thoughts  
3. 
Active Suicidal Ideation with Any Methods (Not Plan) without Intent to Act  
4. 
Active Suicidal Ideation with Some Intent to Act, without Specific Plan  
5. 
Active Suicidal Ideation with Specific Plan and Intent  
6. 
Preparatory Acts or Behavior  
7. 
Aborted Attempt  
8. 
Interrupted Attempt  
9. 
Actual Attempt (Non-Fatal)  
10. 
Completed Suicide  


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Self-injurious behavior without suicidal intent is also a C-SSRS© outcome (although not 
suicide-related) and has a binary response (yes/no).  
Categories 1–5 relate to suicidal ideation and a score of 0 is assigned if no suicidal ideation 
is present. Categories 6–10 relate to suicidal behavior.  
Based on the C-SSRS©, the number and percentage of subjects with suicidal ideation by 
category, suicidal behavior by category, suicidal ideation or behavior and/or self-injurious 
behavior without suicidal intent, 1) during the double-blind study period and 2) during the 
treatment withdrawal period (based on TWS) will be tabulated separately. Percentages will 
be based on the number of subjects with at least one post-baseline C-SSRS© assessment, 
in the corresponding period. The assessment will be assigned to a study period based on a 
scheduled visit as follows: V1 (Day 1) = not assigned any study period; V3 (Week 14), V4 
(Week 27) and V5 (Week 40) = double-blind study period; V6 (Week 41) = Treatment 
withdrawal (or Run-out) period. 
Shift from baseline (baseline as defined in Section 11.4) showing any change in suicidal 
ideation and suicidal behavior, 1) during the double-blind study period and 2) during the 
treatment withdrawal period (based on TWS), will be provided separately. 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, and 3) Suicidal 
behavior (subjects with both suicidal ideation and suicidal behavior are included in the 
suicidal behavior category and not in the suicidal ideation category). Suicidal ideation 
includes any one of the five suicidal ideation events (categories 1–5). Suicidal behavior 
includes any one of the five suicidal behavior events (categories 6–10). 
7.10 Epworth Sleepiness Scale© 
The ESS© is a validated questionnaire designed to provide a subjective measure of daytime 
sleepiness. The ESS© consists of eight situations on chances of dozing; each situation is 
evaluated with a score that ranges from 0 (never dozing) to 3 (high chance of dozing). The 
eight items will be summed into a total score of daytime sleepiness.  
The change from baseline (baseline as defined in Section 11.4) to Visit 3 (Week 14), Visit 4 
(Week 27), Visit 5 (Week 40) and end of the run-out period Visit 6 (Week 41) in ESS© 
total score will be summarized. Observed values will also be summarized.  
The number and percentage of subjects meeting the criteria defined below will be 
tabulated: 
• ESS© total score > 16 at last value before start of treatment in the extension (it 
corresponds to last value before start of treatment collected on Day 1 of extension study 
or in the confirmatory study), Visit 3 (Week 14), Visit 4 (Week 27), Visit 5 (Week 40) 
and end of the run-out period (Visit 6, Week 41). 


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• ESS© total score > 4 points increase from previous visit at Visit 3 (Week 14), Visit 4 
(Week 27), Visit 5 (Week 40) and end of the run-out period (Visit 6, Week 41). 
7.11 Subgroup analysis of safety variables  
Summaries of TEAEs occurring (i.e., that started or worsened) during the double-blind 
study period [see Section 12.3] by SOC and PT will be performed on the following 
subgroups: 
Age at screening of confirmatory study  
< 65, ≥ 65 years and <75; ≥75 
BMI at screening of confirmatory study 
< 25, 25–30, > 30 kg/m2  
Sex  
 
 
 
 
 
Male, female 
Race  
 
 
 
 
White, Black or African American, Other* 
 
* The ‘Other’ category will not be considered for subgroup analyses due to the mix of races and small number of subjects limiting the 
ability (i.e., low power) to detect differences between treatment groups. ‘Other’ includes: American Indian or Alaska Native, Native 
Hawaiian or other Pacific Islander, Asian and Other (Entry for multiple races was to be reported under category ‘Other’. Similarly, ‘Not 
permitted as per legislation/regulation’ was to be also grouped within this category ‘Other’). 
8 
PHARMACOKINETIC VARIABLES AND ANALYSES 
Pharmacokinetic data, i.e., plasma concentrations of ACT-541468 (collected at the 
discretion of the investigator) will only be listed. 
9 
GENERAL STATISTICAL METHODOLOGY 
9.1 General rules for data presentations 
Data are listed and summarized as described below.  
The tables for ID-078A303 will use the following header structure (label and order): 
ACT-541468  
10 mg 
N = xxx 
ACT-541468  
25 mg 
N = xxx 
ACT-541468  
50 mg 
N = xxx 
Placebo 
N = xxx 
Ex-placebo/ACT-541468 
25 mg 
N = xxx 
 
• ACT-541468 10 mg: subjects continuing in the extension trial at the same dose level 
of 10 mg  
• ACT-541468 25 mg: subjects continuing in the extension trial at the same dose level 
of 25 mg  
• ACT-541468 50 mg: subjects continuing in the extension trial at the same dose level 
of 50 mg  


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• Placebo: subjects continuing in the extension trial assigned to placebo arm 
• Ex-placebo/ACT-541468 25 mg: subjects continuing in the extension trial that switch 
from placebo to 25 mg  
Where N indicates the total number randomized or treated appropriate to the analysis set 
in the corresponding treatment group, unless otherwise specified.  
All listings will be sorted by randomized treatment or actual treatment received 
(appropriate to the analysis set), country, subject number (ascending) and, when 
appropriate, by visit / date of assessment (ascending).  
Listings based on the ENR Set will present a treatment group label “Subject not 
randomized” for subjects who were not randomized and will be listed after the subjects 
who were randomized.  
Unless noted otherwise, the following descriptive statistics will be used to summarize data: 
number and percentage of subjects for categorical variables or descriptive statistics 
(number of non-missing values, mean, standard deviation, median, Q1, Q3, minimum, 
maximum) for continuous variables. 
10 INTERIM ANALYSES  
This study includes an IDMC and ISB that will assess safety of ACT-541468 on a regular 
basis as per IDMC and ISB charters, respectively.  
Safety and efficacy data supporting the review by IDMC will be provided by Idorsia for 
the part of analyses that are blinded and by an ISAC for the unblinded part. 
An interim analysis was introduced as part of amendment protocol Version 3, dated 
17 February 2020, 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 fulfil the FDA requirement to submit 
updated safety data 120 days after NDA submission from ongoing studies, in case the study 
has not been completed by that time. 
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.  
The interim analysis will be based upon a snapshot of the clinical trial database and will 
include all clean safety and efficacy data as of approximately end of July (a cut-off date 


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will be fixed to ensure all subject data up to and including Visit 3 are included). All visits 
and assessments that have been done before and on this cut-off date will be considered for 
the interim analysis. All analyses described in this SAP will be performed for the interim 
analysis. 
SDTM dataset will be based on the snapshot of the clinical database and may include data 
beyond the cut-off date. Then, ADaM datasets will be produced including only data up to 
the date of the interim cut-off. 
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).  
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Treatment start and end dates  
Unless noted otherwise, treatment start and end dates mentioned throughout this document 
are in reference to the treatment received in the extension study. 
Double-blind study treatment start or end date is the earliest or latest, respectively, date of 
dose intake recorded on the ‘Study Double-Blind Treatment Log’ page. Double-blind study 
treatment start or end date of the confirmatory study is the earliest or latest, respectively, 
date of dose intake recorded on the ‘Study Double-Blind Treatment Log’ page of either 
study ID-078A301 or study ID-078A302. 
Run-out single-blind placebo treatment start and end date is the earliest and latest date of 
dose intake recorded on the ‘Study Single-Blind (Run-Out) Treatment Log’ page.  
11.2 Study periods  
The enrollment period is defined as the time from the informed consent date until one day 
before double-blind study treatment start date.  
The double-blind study period is defined as the time from the day of double-blind study 
treatment start until the day of EODBT (Visit 5) or for those who prematurely discontinued 
double-blind study treatment (i.e., those without an EODBT date), until one day after 
double-blind study treatment end date (if the treatment is taken before midnight), or the 
day of double-blind study treatment end date (if the treatment is taken after midnight). 
Time of treatment intake between 00:00 and 11:59 is considered as ‘after midnight’, while 
a time between 12:00 and 23:59 is considered as ‘before midnight’. For any missing or 
incomplete time, it is presumed that the treatment was taken before midnight. For subjects 
lost to follow-up, the EOS date will be used as the end of DB study treatment. For subjects 
who complete double-blind study treatment with an interruption before continuing the 
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single-blind placebo treatment start date – 1 day. For subjects who prematurely discontinue 
treatment, the safety data (laboratory tests, ECG and vital signs) assessment up to 7 days 
after last drug intake are considered in the definition of double-blind study period [see 
Section 7.1].  
For those subjects in the TWS, the treatment withdrawal period (or the run-out period) is 
defined as the time from one day after the end of the double-blind study period to the latter 
of seven days after the end of the double-blind study period or Visit 6 date. If the latter of 
the two dates falls after the EOS date, then the EOS date will be used. 
The safety follow-up period is defined as the time from one day after the end of the 
treatment withdrawal period for those starting the treatment withdrawal period (i.e., 
subjects in the TWS) until the EOS date; or from one day after the end of double-blind 
study period for those not starting the treatment withdrawal period until the EOS date. 
11.3 Treatment day and study day  
The treatment day for an assessment or event will be calculated using the double-blind 
study treatment start date as reference.  
For assessments/events occurring on or after the start date of double-blind study treatment, 
the treatment day will be positive and will be calculated as:  
Treatment day (days) = Date of assessment/event – Start date of double-blind study 
treatment + 1 day. 
The first day of double-blind study treatment is Treatment Day 1. 
For all assessment/events occurring prior to the start date of double-blind study treatment, 
the treatment day will be negative and calculated as:  
Treatment day (days) = Date of assessment/event – Start date of double-blind study 
treatment.  
The study day for an assessment or event will be calculated using the randomization date 
as reference.  
For assessments/events occurring on or after the randomization date, the study day will be 
positive and calculated as:  
Study day (days) = Date of assessment/event – randomization date + 1 day. 
The day of randomization date is Study Day 1. 
For all assessment/events occurring prior to the randomization date, study day will be 
negative and calculated as:  


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Study day (days) = Date of assessment/event – randomization date. 
Treatment day and/or study day will be displayed in the data listings as appropriate.  
11.4 Baseline  
Unless otherwise defined in the specific analysis section, baseline is defined as follows: 
1. For subjects entering ID-078A303 and assigned to the same treatment arm as that of 
the confirmatory studies (ACT-541468 10 mg, 25 mg, or 50 mg, or placebo), baseline 
is the last non-missing assessment performed or value measured before or on the day 
of first dose of double-blind study treatment in the confirmatory study. 
2. For subjects entering ID-078A303 who received placebo in the confirmatory studies 
and who are randomized (switched) to 25 mg of ACT-541468 in the extension study, 
baseline is the last non-missing assessment performed or value measured before or on 
the day of first dose of double-blind study treatment in the extension study. This could 
be either data collected at Visit 1 of the extension study or collected in the confirmatory 
study. An assessment taken on the day of the double-blind study treatment start date is 
considered a baseline assessment and is not considered a post-baseline assessment in 
the double-blind study period. 
Subjects with no data on a particular parameter before the first treatment administration 
will have a missing baseline (and change from baseline) for this parameter. 
11.5 Change from baseline  
The change from baseline is defined as post-baseline value (any assessment performed 
after baseline and up to EOS) minus baseline value. A positive number indicates an 
increase as compared to baseline.  
11.6 Handling of data when subjective total sleep time is zero  
If the sTST is recorded as zero:  
• sWASO is set as missing since subject is never at risk.  
• sLSO is set as 480 minutes.  
11.7 Time window definitions for calculating subjective endpoints  
Values falling in the following time window will be used to calculate weekly averages for 
the subjective endpoints:  
Run out: the 7 consecutive days immediately following the evening of Visit 5 (i.e., 7-day 
window = [Treatment withdrawal period start date; Minimum (Treatment withdrawal 
period start date + 6 days; Visit 6 date)]).  


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Table 6 defines the time windows used to calculate weekly averages for certain subjective 
measures that will be summarized over time. These subjective measures include sTST, 
sWASO, sLSO, IDSIQ scores (i.e., total score; alert/cognition, mood and sleepiness 
domain scores), VAS scores and number of self-reported awakenings. 
Weekly averages will be calculated using the data recorded in a 7-day window. The 7-day 
window for a given week begins on the first date the subjective measure is recorded in the 
given time window [see last column in Table 6]. For example, if a subject starts to record 
data on Study Day 17 of the time window then only values recorded from Study Day 17 to 
Study Day 23 (7-day window) will be considered. If a subject starts to record data on Study 
Day 27, only values recorded from Study Day 27 to Study Day 33 (7-day window) will be 
considered. The first date is specific to each type of subjective measure (e.g., for a given 
subject, a 7-day window from Study Day 17 to Study Day 23 could be considered for sTST 
at Week 4, while for IDSIQ scores at Week 4, a 7-day window from Study Day 27 to 
Study Day 33 may be considered). Note: values recorded by the subject beyond the 
considered 7-day window will not be considered in the calculation of the weekly average. 
Table 6 
Time windows (in days) to calculate weekly averages for certain 
subjective endpoints 
Week 
Reference 7-day window 
(Study day) 
Time window 
(Study day) 
4 
22–28 
(17; 27) 
8 
50–56 
(45; 55) 
12* 
78–84 
(73; 83) 
16 
106–112 
(101; 111) 
20 
134–140 
(129; 139) 
24* 
162–168 
(157; 167) 
28 
190–196 
(185; 195) 
32 
218–224 
(213; 223) 
36* 
246–252 
(241; 251) 
40 
274–280 
(269; 279) 
* Week 12, 24 and 36 correspond to Month 6, 9 and 12, respectively. 
Values from the run-out period will not be included.  
 
For PGA-S and PGI-C, Table 7 defines the time windows to report the values collected. 
All values falling in the time window defined will be considered for the analysis of these 


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endpoints. However, if more than one value falls into the time window, then only the first 
value will be used for the analysis.  
Table 7 
Time windows (in days) for PGA-S and PGI-C measurements  
Week 
Reference 7-day window 
(Study day) 
Time window 
(Study day) 
4 
22–28 
(20; 35) 
8 
50–56 
(48; 63) 
12* 
78–84 
(76; 91) 
16 
106–112 
(104; 119) 
20 
134–140 
(132; 147) 
24* 
162–168 
(160; 175) 
28 
190–196 
(188; 203) 
32 
218–224 
(216; 231) 
36* 
246–252 
(244; 259) 
40 
274–280 
(272;287) 
* Week 12, 24 and 36 correspond to Month 6, 9 and 12, respectively. 
Values from the run-out period will not be included.  
PGA-S = Patient Global Assessment of Disease Severity; PGI-C = Patient Global Impression of Change. 
 
12 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL 
12.1 Changes to the analyses planned in the study protocol 
Not applicable. 
12.2 Changes in the conduct of the study / data collection 
Not applicable. 
12.3 Clarifications concerning endpoint definitions and related variables or 
statistical methods 
Summary tables for TEAEs related to study treatment, TEAEs related to abuse and TEAEs 
based on selected Standardized MedDRA Queries or pre-defined search criteria will 
include only those TEAEs occurring during the double-blind study period. 


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12.4 Additional analyses as compared to the study protocol 
Not applicable. 
13 REFERENCES 
[Kenward 1997] Kenward MG, Roger JH. Small sample inference for fixed effects from 
restricted maximum likelihood. Biometrics 1997;53(3):983–97. 
 


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14 APPENDICES 
Appendix 1 
SAS® code for Mixed Model for Repeated Measures  
ods output sliceDiffs=lsd2;   
proc mixed data=data; 
            class SUBJID AGE TRT VIS; 
            model CHG = BASE AGE TRT VIS TRT*VIS BASE*VIS/ ddfm= kr; 
            repeated VIS / subject=SUBJID type=un; 
lsmeans TRT*VIS / cl alpha=0.05; 
            slice TRT*VIS / sliceby=VIS diff=control(‘PLACEBO’ ‘Month12’) cl;   
run;  
ods output close;   
 
/* The following code could be used as reference */ 
 

Prot_001.pdf: 
Cover page 
Official Title: 
ADDENDUM TO PROTOCOL ID-078A303 -  
Exceptional measures to ensure subject safety and counteract 
potential trial conduct disruption due to the COVID-19 pandemic 
ClinicalTrials.gov Identifier:  
NCT03679884
Date of document: 
8 April 2020 


TPL-100601_v03
ADDENDUM TO PROTOCOL 
ID-078A303 
Exceptional measures to ensure subject safety and counteract 
potential trial conduct disruption due to the COVID-19 
pandemic 
Document Number: D-20.065 
8 April 2020 
Property of Idorsia Pharmaceuticals Ltd 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Idorsia Pharmaceuticals Ltd 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ........................................................... 3
1 
INTRODUCTION ........................................................................................................ 4
2 
RECOMMENDATIONS AND INSTRUCTIONS ...................................................... 4
2.1
Flexibility regarding site visits for subjects who can still go to sites ............ 4
2.2
Conduct of remote visits for subjects who cannot, are not allowed to, 
or are not willing to travel to the investigator’s site ...................................... 5
2.3
Provisions for subjects infected with SARS-CoV-2 ...................................... 6
2.4
Evaluation of the study endpoints ................................................................. 7
2.4.1
Safety endpoints ................................................................................. 7
2.4.1.1
Withdrawal effects (only at run-out Visit 6) [protocol 
sections 7.2.2.6 and 7.2.2.8] ..................................................... 7
2.4.1.2
Rebound insomnia (only at run-out Visit 6) [protocol 
section 7.2.3.1] ......................................................................... 7
2.4.1.3
Next day residual effects [protocol sections 7.2.2.4 and 
7.2.3.1.2] ................................................................................... 7
2.4.1.4
Occurrence of AESIs [protocol section 7.2.2.5] ...................... 8
2.4.2
Efficacy endpoints [protocol section 7.2.3] ....................................... 8
2.4.3
Impact on statistical analyses [protocol section 10] .......................... 8
2.5
Reporting of protocol deviations related to the COVID-19 pandemic .......... 8
2.6
Monitoring ..................................................................................................... 8


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE 
 
Adverse event 
AESI 
 
Adverse Event of Special Interest 
BWSQ 
 
Benzodiazepine Withdrawal Symptoms Questionnaire 
COVID-19 
 
Coronavirus disease 2019 
CRA 
 
Clinical research associate 
C-SSRS 
 
Columbia Suicide Severity Rating Scale 
DDI 
 
Drug-drug interaction 
ECG 
 
Electrocardiogram/graphy 
eCRF 
 
Electronic case report form 
EDS 
 
Excessive Daytime Sleepiness 
FDA 
 
Food and Drug Administration 
GCP 
 
Good Clinical Practice 
HMA 
 
Heads of Medicines Agencies 
ICH 
 
International Council for Harmonisation 
IDSIQ 
 
Insomnia Daytime Symptoms and Impact Questionnaire 
IEC 
 
Independent ethics committee 
IRB 
 
Institutional review board 
PD 
 
Protocol deviation 
PI 
 
Principle Investigator 
SARS-CoV-2 
 
Severe acute respiratory syndrome coronavirus 2 
SDS 
 
Sheehan Disability Scale 
SDV 
 
Source data verification 
VAS 
 
Visual Analog Scale 
WHO 
 
World Health Organization 
 
 


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1 
INTRODUCTION 
As a consequence of the pandemic of respiratory infectious disease (COVID-19; declared 
a pandemic by the WHO on 11 March 2020) caused by a novel coronavirus 
(SARS-CoV-2), Idorsia provided instructions and guidance in communication letters sent 
to investigators participating in the ID-078A303 study on 19 March 2020 and 
31 March 2020. These measures and instructions are in line with health authority 
guidelines (FDA, HMA and individual national health authorities) released in March 2020 
on how to address the challenges caused by the pandemic itself.  
These measures, which also constitute PDs, are introduced to preserve subject safety, trial 
integrity and interpretability, as well as compliance with regulatory requirements. 
Idorsia tracks all these deviations from the protocol as “PDs related to COVID-19”. This 
will allow, at the end of the trial, a reconstruction of the impact that such deviations had on 
the trial integrity and interpretability. This requires that the instructions and measures 
included in this addendum continue to be collected as PDs as per original protocol 
definition, and will be identified as due to COVID-19 even after the implementation of this 
addendum.  
The objective of this addendum is to document those measures and instructions in the 
protocol. The addendum applies to those sites affected by the COVID-19 outbreak and 
is limited to the time during which such sites are affected.  
This addendum is therefore limited in scope and in duration.  
The recommendations and instructions that have been provided to the investigators are 
described below with reference to the protocol section affected. 
2 
RECOMMENDATIONS AND INSTRUCTIONS 
2.1 Flexibility regarding site visits for subjects who can still go to sites 
For subjects ongoing in ID-078A303: 
 If the subject can travel to the investigator’s site, the investigator should: 
 Ensure the subject’s safety on his/her way to the site by following local/country 
regulations (e.g., not using public transportation). Alternatively, subjects can use 
taxis or private cars, the cost of which will be reimbursed by Idorsia. 
 Perform the on-site visit assessments according to the protocol. 
 An on-site visit is always preferable. Therefore, this may mean that the visit 
windows need to be extended, as long as the subject has enough study treatment. 
Study treatment can be delivered to the subject’s home, following the instructions 
as in Section 2.2. The reason for this delayed scheduled visit must be documented 
in the subject’s medical charts. 


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For subjects potentially transitioning from ID-078A302 to ID-078A303 [protocol 
section 7.1.1]: 
 New enrollment in the extension study is allowed only if Visit 1 in ID-078A303, as 
well as Visit 10 in ID-078A302 can happen on-site.  
2.2 Conduct of remote visits for subjects who cannot, are not allowed to, or 
are not willing to travel to the investigator’s site 
 If the subject cannot, is not allowed to, or is not willing to travel to the investigator’s 
site, the clinic visit(s) can be replaced by a telephone call or video call: to keep close 
contact with subjects (remote visits), these visits should be at least as frequent as the 
protocol-mandated clinic visits.  
 The investigator should notify the IEC / IRB in advance of remote visits if this is a 
local requirement. 
Before the telephone call or video call visit:  
 If the study treatment needs to be delivered to the subject’s home, the investigator 
should ensure the following:  
 Obtain subject’s verbal consent by telephone to provide his/her name and home 
address to the courier service responsible for delivering study treatment and 
pregnancy tests [protocol section 5.1.6.3].  
 The date and time that verbal consent was obtained is documented in the subject’s 
medical records.  
 Make sure that women of childbearing potential have enough home urine 
pregnancy kits (send them along with study medications to the subject’s home if 
necessary) and remind them to perform the test monthly [protocol section 7.2.4.2]. 
 If the approval must be in writing, according to the site’s local regulation, please 
act accordingly and document it in the subject’s medical charts. 
 Arrange for the delivery of study treatment (in accordance with local regulation) to 
the subject’s home in advance. 
 Local laboratory assessments are not to be performed in study ID-078A303 at 
regions/sites that are impacted by the pandemic, unless it is judged by the investigator 
as unavoidable, to preserve the subjects’ safety. Should a sample be analyzed by a local 
laboratory, the investigator should send a prescription to the subject’s home to take to 
the laboratory to ensure that the protocol requirements, laboratory manual and eCRF 
completion guidelines are followed [protocol section 7.2.4]. 
During the telephone call or video call visit [protocol section 7]: 
 The investigator will interview the subject for: 
 Occurrence of any new AEs or worsening of existing ones. 


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 When asking about the occurrence of AEs, please follow the same process as for a 
site visit, i.e., use an open-ended question, such as: 
o “Have you had any signiﬁcant medical problems since the last study visit?” 
 Collection of additional information about AESI as applicable. AESI include: 
o Narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep behavior 
events including hallucinations / sleep paralysis), 
o Suicide / self-injury.  
 Checking for next day residual effects [see Section 2.4]. 
 Assessing withdrawal and rebound (only applicable to Visit 6) [see Section 2.4]. 
 Completion of the C-SSRS questionnaire. 
 If closer monitoring of any of the above symptoms is required but not possible, 
depending on the severity of the symptoms observed and the investigator’s 
assessment of the benefit-risk for the subject participation in the trial, the 
investigator can consider discontinuing treatment while trying to maintain the 
subject in the study [protocol section 5.1.9]. 
 Changes in any ongoing medication or start of new medication(s). 
 Check compliance with study medication and potential overdose or other 
medication error(s) [protocol sections 5.1.7 and 9.1.1]. 
 The telephone or video contact must be entered under the visit it replaces (e.g., if 
the assessments were intended for Visit 3, please use the Visit 3 form) and 
documented in detail (day, time and conversation) in the subject’s medical charts. 
All assessments not performed must be entered as “Not done”.  
 Should any additional telephone calls be performed to ensure the subject’s safety 
that are not part of the regular visit plan, the call must be entered as an unscheduled 
visit (‘UNS’) in the eCRF and documented in detail (day and reason for the ‘UNS’) 
in the subject’s medical charts. 
 For Visit 6 please also refer to Section 2.4 
2.3 Provisions for subjects infected with SARS-CoV-2 
Testing for SARS-CoV-2 should follow local guidance. Mandatory testing is not requested 
for this study.  
Should a subject become infected with SARS-CoV-2 / contract COVID-19:  
 Information about COVID-19 infection, whether positively confirmed with a 
SARS-CoV-2 test or not, and its corresponding diagnosis (symptoms or pneumonia 
related to COVID-19) as well as administered medications will be collected on the AE 
and Concomitant Medication pages of the eCRF. 


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 If a subject is without symptoms and remains asymptomatic, study treatment can be 
continued as per protocol. 
 If a subject is presenting mild symptoms, study treatment can be continued as per 
protocol and the subject should be closely monitored. Should the symptoms worsen, 
study treatment should be interrupted. 
 If a subject develops severe symptoms or requires hospitalization for COVID-19, the 
subject should be discontinued from study treatment. 
 When shipping blood samples from subjects who tested positive or had high potential 
to test positive for SARS-CoV-2 virus infection to the Study Central Laboratory, the 
central laboratory manual and the most up-to-date COVID-19 regional guidance should 
be followed.  
Drug-drug interaction with medications used to treat COVID-19 
Certain treatments used for COVID-19, such as lopinavir/ritonavir (strong CYP3A4 
inhibitor) are contraindicated in association with daridorexant. Please refer to the 
Investigator’s Brochure and the protocol for more details on potential DDIs with 
daridorexant. Please try to avoid using such treatments for at least 24 h after last dose intake 
of daridorexant.  
2.4 Evaluation of the study endpoints 
2.4.1 Safety endpoints 
If the investigators are not able to arrange site visits to perform the safety evaluations 
planned at each visit during the period that the site is affected by the COVID-19 pandemic, 
the following should be implemented: 
2.4.1.1 Withdrawal effects (only at run-out Visit 6) [protocol sections 7.2.2.6 and 
7.2.2.8]  
Withdrawal effects are assessed via BWSQ scores, occurrence of relevant AEs and marked 
ECG abnormalities upon treatment discontinuation. If no on-site visits are possible, 
withdrawal effects will only be assessed by relevant AEs upon treatment discontinuation. 
2.4.1.2 Rebound insomnia (only at run-out Visit 6) [protocol section 7.2.3.1] 
Rebound insomnia is assessed via subjective sleep parameters collected through the 
subject’s sleep diary. The hand-held device is automatically programmed to display the 
sleep diary when entries are expected from the subject, therefore, those data can still be 
collected and analyzed without disruption. 
2.4.1.3 Next day residual effects [protocol sections 7.2.2.4 and 7.2.3.1.2] 
Next day residual effects are assessed via the SDS questionnaire and VAS scores collected 
in the hand-held device. The SDS requires manual activation at each visit. As no remote 
activation can be performed, if an on-site visit cannot be performed, those data will not be 


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collected and analyzed. The VAS is automatically programmed to be displayed when 
entries are expected from the subject, therefore, those data can still be collected and 
analyzed without disruption. 
2.4.1.4 Occurrence of AESIs [protocol section 7.2.2.5] 
If an on-site visit is replaced by a telephone/video call, investigators should collect any 
new occurrence or worsening of AE, including AESIs (as defined above). The C-SSRS 
should also be completed during this call. Therefore, no disruption should be noted in the 
evaluation of this safety endpoint. 
2.4.2 Efficacy endpoints [protocol section 7.2.3] 
Efficacy endpoints are collected through the subject’s entries in the sleep diary and the 
completion of the IDSIQ questionnaire. The hand-held device is automatically 
programmed to display the sleep diary when entries are expected from the subject, 
therefore, those data can still be collected and analyzed without disruption. The 
investigator/delegate is encouraged to remind the subject to complete the sleep diary and 
IDSIQ at each call performed. 
2.4.3 Impact on statistical analyses [protocol section 10] 
The sample size in ID-078A303 is driven by subjects rolling over from ID-078A301 / 
ID-078A302. The number of subjects rolling over from ID-078A302 may be impacted 
during the COVID-19 pandemic: subjects who are unable to perform their visit (Visit 10) 
in ID-078A302 and did not have their eligibility criteria assessed at the site for this 
extension study cannot roll over. 
No changes to the current planned analyses are foreseen. All observed data will be 
summarized as planned. The missing-at-random assumption of the linear mixed-effects 
model is considered appropriate for any missing data due to the COVID-19 pandemic. 
2.5 Reporting of protocol deviations related to the COVID-19 pandemic 
Protocol deviations due to COVID-19 are expected to occur during the pandemic and fall 
under the ICH GCP 4.5.4 “The investigator may implement a deviation from, or change 
of, the protocol to eliminate an immediate hazard(s) to trial subjects”. Any protocol 
deviation occurring due to COVID-19 must be documented according to ICH GCP 4.5.3 
and be clearly recorded as related to COVID-19. All protocol deviations will be reported 
to the sponsor, IEC/IRB and regulatory authorities according to local requirements.  
2.6 Monitoring 
If on-site monitoring cannot be performed by the CRA as described in protocol section 12.8 
and if acceptable under local law with the IEC/IRB, the CRA will conduct remote 
monitoring and remote SDV, provided that the subject’s confidentiality is maintained 
throughout the process [as per protocol section 11.2] and all local approvals to do so are in 
place. If remote monitoring or remote SDV are not allowed, alternatives as applicable, 
according to local regulations, might be agreed with the PI to ensure data integrity.  

Prot_000.pdf: 
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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Doc No D-20.025 
 
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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Doc No D-20.025 
 
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 
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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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