Clinical trial NCT03545191
Conditions: Insomnia Disorder
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2018-06-04; Completion date: 2020-02-25
Enrollment: 930 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The main purpose of this study is to assess efficacy and safety of ACT-541468 (daridorexant) in adult and elderly subjects with insomnia disorder. Efficacy will be evaluated on objective and subjective sleep parameters.

Detailed description:

Arms: arm 1: None arm 2: None arm 3: None
Interventions: intervention 1: Daridorexant 25 mg intervention 2: Daridorexant 50 mg intervention 3: Placebo
Intervention descriptions: intervention 1: Daridorexant will be administered as tablets, orally, once daily in the evening. intervention 2: Daridorexant will be administered as tablets, orally, once daily in the evening. intervention 3: Matching placebo will be administered as tablets, orally, once daily in the evening.

Protocol documents:
Prot_000.pdf: 
Cover page 
Official Title: 
PROTOCOL ID-078A301 - Multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, polysomnography study to assess the efficacy and safety of  
ACT-541468 in adult and elderly subjects with insomnia disorder 
ClinicalTrials.gov Identifier:  
NCT03545191 
Date of document: 
30 July 2018 


TPL-100601_v01 
ACT-541468 
Insomnia Disorder 
Protocol ID-078A301 
Multi-center, double-blind, randomized, placebo-controlled, parallel-group, 
polysomnography study to assess the efficacy and safety of ACT-541468 in adult and 
elderly subjects with insomnia disorder 
Study Phase: 
3 
EudraCT Number: 
2017-004642-20 
Status and version: 
Final Version 4 
Date: 
30 July 2018 
Document type: 
Amended global protocol 
Idorsia document number 
(Doc No.): 
D-18.160
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The information contained in this document, especially unpublished data, is the property of the sponsor of 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. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 2/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
SPONSOR CONTACT DETAILS 
Sponsor 
Idorsia Pharmaceuticals Ltd 
Hegenheimermattweg 91 
CH-4123 Allschwil 
Switzerland 
 
+41 58 844 00 00 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
Toll phone number 
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File 
 
 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION 
Some study activities will be delegated to Contract Research Organizations (CROs). A 
list of site-specific contact details can be found in the Investigator Site File. 
 
 
 




ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 4/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
ACT-541468 
Indication 
Insomnia Disorder 
Protocol number, study title 
ID-078A301 
Multi-center, 
double-blind, 
randomized, 
placebo-controlled, 
parallel-group, 
polysomnography study to assess the efficacy and safety of ACT-541468 in adult and 
elderly subjects with insomnia disorder 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form, and any other protocol-related documents. I fully understand that any 
changes instituted by the investigator(s) without previous agreement with the sponsor 
would constitute a protocol deviation, including any ancillary studies or procedures 
performed on study subjects (other than those procedures necessary for the well-being of 
the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, ICH 
GCP guidelines, and applicable regulations and laws. I confirm herewith that the sponsor 
is allowed to enter and utilize my professional contact details and function in an electronic 
database for internal purposes and for submission to health authorities worldwide. 
I am participating in the following sub-study (only for sites in Germany and the USA): 
PAtient Preferences StUdy in InSomnia (PAUSe) 
 
Principal 
Investigator 
Country 
Site 
number 
Town 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 5/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................12 
NON-SUBSTANTIAL GLOBAL AMENDMENT 3 .......................................................16 
PROTOCOL SYNOPSIS ID-078A301 .............................................................................18 
PROTOCOL ......................................................................................................................32 
1 
BACKGROUND .........................................................................................................32 
1.1 
Insomnia disorder .........................................................................................32 
1.1.1 
Definition ..........................................................................................32 
1.1.2 
Epidemiology ....................................................................................32 
1.1.3 
Treatment ..........................................................................................33 
1.1.4 
Unmet medical need .........................................................................34 
1.2 
Study treatment: ACT-541468 .....................................................................35 
1.2.1 
The orexin system .............................................................................35 
1.2.2 
ACT-541468 properties ....................................................................35 
1.2.2.1 
Nonclinical data .......................................................................35 
1.2.2.2 
Clinical studies ........................................................................36 
1.3 
Purpose and rationale of the study ................................................................39 
1.3.1 
Purpose of the study ..........................................................................39 
1.3.2 
Rationale for the study ......................................................................39 
1.4 
Summary of known and potential risks and benefits ....................................40 
1.4.1 
ACT-541468 .....................................................................................40 
1.4.2 
Safety and risk-minimization measures taken in the present 
study ..................................................................................................41 
2 
STUDY OBJECTIVES ...............................................................................................41 
2.1 
Primary objective ..........................................................................................41 
2.2 
Secondary objectives ....................................................................................42 
2.3 
Safety objectives ...........................................................................................42 
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................42 
3.1 
Study design .................................................................................................42 
3.1.1 
Study periods ....................................................................................42 
3.1.1.1 
Screening phase .......................................................................42 
3.1.1.2 
Treatment phase ......................................................................43 
3.1.1.3 
Safety follow-up phase ............................................................43 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 6/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
3.1.2 
Study duration ...................................................................................44 
3.1.3 
Sub-study – Patient Preferences .......................................................45 
3.2 
Study design rationale ..................................................................................46 
3.2.1 
Core study .........................................................................................46 
3.2.2 
Patient preferences sub-study ...........................................................47 
3.3 
Study committees .........................................................................................47 
4 
SUBJECT POPULATION ..........................................................................................48 
4.1 
Subject population description .....................................................................48 
4.2 
Rationale for the selection of the study population ......................................48 
4.3 
Inclusion criteria ...........................................................................................48 
4.4 
Exclusion criteria ..........................................................................................50 
4.5 
Criteria for women of childbearing potential ...............................................52 
4.5.1 
Definition of childbearing potential ..................................................52 
4.5.2 
Acceptable methods of contraception ...............................................53 
5 
TREATMENTS ..........................................................................................................53 
5.1 
Study treatment .............................................................................................53 
5.1.1 
Investigational treatment and matching placebo: Description 
and rationale ......................................................................................53 
5.1.2 
Study treatment administration .........................................................54 
5.1.2.1 
Study treatment administration at site visits and at home .......54 
5.1.2.2 
Missed doses ............................................................................54 
5.1.3 
Treatment assignment .......................................................................54 
5.1.4 
Blinding ............................................................................................55 
5.1.4.1 
Run-in and run-out periods ......................................................55 
5.1.4.2 
Double-blind treatment period ................................................55 
5.1.5 
Unblinding ........................................................................................56 
5.1.5.1 
Unblinding for final analyses ..................................................56 
5.1.5.2 
Unblinding for IDMC review ..................................................56 
5.1.5.3 
Unblinding for suspected unexpected serious adverse 
reactions ...................................................................................56 
5.1.5.4 
Emergency procedure for unblinding ......................................56 
5.1.6 
Study treatment supply .....................................................................56 
5.1.6.1 
Study treatment packaging and labeling .................................57 
5.1.6.2 
Study treatment distribution and storage .................................57 
5.1.6.3 
Study treatment dispensing .....................................................57 
5.1.6.4 
Study treatment return and destruction ...................................57 
5.1.7 
Study treatment accountability and compliance with study 
treatment ...........................................................................................57 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 7/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
5.1.7.1 
Study treatment accountability ................................................57 
5.1.7.2 
Study treatment compliance ....................................................58 
5.1.8 
Study treatment dose adjustments and interruptions ........................58 
5.1.9 
Premature discontinuation of study treatment ..................................59 
5.1.10 
Study-specific criteria for interruption / premature 
discontinuation of study treatment ....................................................60 
5.2 
Previous and concomitant therapy ................................................................60 
5.2.1 
Definitions ........................................................................................60 
5.2.2 
Reporting of previous/concomitant therapy in the eCRF .................60 
5.2.3 
Allowed concomitant therapy ...........................................................60 
5.2.4 
Forbidden concomitant therapy ........................................................61 
5.2.5 
Forbidden concomitant diet and activities ........................................61 
6 
STUDY ENDPOINTS ................................................................................................62 
6.1 
Primary efficacy endpoints ...........................................................................62 
6.2 
Secondary endpoints .....................................................................................62 
6.3 
Other efficacy endpoints ...............................................................................63 
6.4 
Exploratory endpoints ...................................................................................63 
6.5 
Safety endpoints ...........................................................................................64 
6.6 
Pharmacokinetic endpoints ...........................................................................65 
6.7 
Patient preferences exploratory endpoints ....................................................65 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................65 
7.1 
Study visits ...................................................................................................65 
7.1.1 
Screening ..........................................................................................66 
7.1.2 
Unscheduled visits ............................................................................66 
7.2 
Study assessments .........................................................................................69 
7.2.1 
Demographics ...................................................................................71 
7.2.2 
Efficacy assessments .........................................................................71 
7.2.2.1 
Polysomnography ....................................................................71 
7.2.2.2 
Sleep diary ...............................................................................73 
7.2.2.3 
Insomnia Severity Index© ........................................................73 
7.2.2.4 
Patient Global Assessment of Disease Severity ......................74 
7.2.2.5 
Patient Global Impression of Change (daytime 
symptoms) ...............................................................................74 
7.2.2.6 
Patient Global Impression of Change (night-time 
symptoms) ...............................................................................74 
7.2.2.7 
Patient Global Impression of Severity .....................................75 
7.2.2.8 
Insomnia Daytime Symptoms and Impacts Questionnaire .....75 
7.2.3 
Safety assessments ............................................................................75 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 8/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
7.2.3.1 
Weight and height ...................................................................75 
7.2.3.2 
Physical examination ...............................................................75 
7.2.3.3 
Vital signs ................................................................................76 
7.2.3.4 
Coding sub-test© ......................................................................76 
7.2.3.5 
Sheehan Disability Scale© .......................................................76 
7.2.3.6 
Columbia Suicide Severity Rating Scale©...............................76 
7.2.3.7 
Benzodiazepine Withdrawal Symptom Questionnaire ............77 
7.2.3.8 
Mini International Neuropsychiatric Interview© .....................77 
7.2.3.9 
Mini Mental State Examination© ............................................77 
7.2.3.10 
Neurological examinations ......................................................78 
7.2.3.11 
Epworth Sleepiness Scale© ......................................................78 
7.2.3.12 
ECG assessment ......................................................................78 
7.2.4 
Patient preferences questionnaire .....................................................79 
7.2.5 
Laboratory assessments ....................................................................79 
7.2.5.1 
Type of laboratory ...................................................................79 
7.2.5.2 
Laboratory tests .......................................................................80 
7.2.6 
Pharmacokinetic assessments ...........................................................81 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................81 
8.1 
Study completion as per protocol .................................................................81 
8.2 
Premature withdrawal from study ................................................................81 
8.3 
Premature termination or suspension of the study ........................................82 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................83 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................83 
9.1 
Adverse events ..............................................................................................83 
9.1.1 
Definition of adverse events .............................................................83 
9.1.2 
Intensity of adverse events ................................................................84 
9.1.3 
Relationship to study treatment ........................................................85 
9.1.4 
Reporting of adverse events ..............................................................85 
9.1.5 
Follow-up of adverse events .............................................................85 
9.2 
Serious adverse events ..................................................................................85 
9.2.1 
Definitions of serious adverse events ...............................................85 
9.2.2 
Reporting of serious adverse events .................................................86 
9.2.3 
Follow-up of serious adverse events .................................................86 
9.2.4 
After the 30-day follow-up period ....................................................87 
9.2.5 
Reporting procedures ........................................................................87 
9.3 
Pregnancy .....................................................................................................88 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 9/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
9.3.1 
Reporting of pregnancy ....................................................................88 
9.3.2 
Follow-up of pregnancy ....................................................................88 
9.4 
Study safety monitoring ................................................................................88 
10 STATISTICAL METHODS .......................................................................................88 
10.1 
Analysis sets .................................................................................................88 
10.1.1 
Screened Analysis Set .......................................................................88 
10.1.2 
Full Analysis Set ...............................................................................89 
10.1.3 
Per-Protocol Set ................................................................................89 
10.1.4 
Safety Set ..........................................................................................89 
10.1.5 
Treatment Withdrawal Set ................................................................89 
10.1.6 
Pharmacokinetic Analysis Set ..........................................................89 
10.1.7 
Patient Preferences Analysis Set .......................................................89 
10.1.8 
Usage of the analysis sets .................................................................89 
10.2 
Variables .......................................................................................................90 
10.3 
Description of statistical analyses .................................................................90 
10.3.1 
Analysis of the primary and secondary efficacy variables ...............90 
10.3.1.1 
Overall testing strategy ............................................................90 
10.3.1.2 
Hypotheses and statistical model ............................................93 
10.3.1.3 
Handling of missing data .........................................................93 
10.3.1.4 
Supportive/sensitivity analyses ...............................................93 
10.3.2 
Analysis of other efficacy variables ..................................................94 
10.3.3 
Analysis of the safety variables ........................................................94 
10.3.4 
Analysis of pharmacokinetic variables .............................................95 
10.3.5 
Subgroup analyses ............................................................................96 
10.3.6 
Analysis of the patient preferences variable .....................................96 
10.4 
Interim analyses ............................................................................................96 
10.5 
Sample size ...................................................................................................96 
11 DATA HANDLING ....................................................................................................98 
11.1 
Data collection ..............................................................................................98 
11.2 
Maintenance of data confidentiality .............................................................99 
11.3 
Database management and quality control ...................................................99 
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................100 
12.1 
Ethics and Good Clinical Practice ..............................................................100 
12.2 
Independent Ethics Committee / Institutional Review Board ....................100 
12.3 
Informed consent ........................................................................................101 
12.4 
Compensation to subjects and investigators ...............................................102 
12.5 
Protocol adherence/compliance ..................................................................102 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 10/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
12.6 
Protocol amendments .................................................................................102 
12.7 
Essential documents and retention of documents .......................................102 
12.8 
Monitoring ..................................................................................................103 
12.9 
Investigator Site File ...................................................................................104 
12.10 
Audit ...........................................................................................................105 
12.11 
Inspections ..................................................................................................105 
12.12 
Reporting of study results and publication .................................................105 
13 REFERENCES ..........................................................................................................107 
14 APPENDICES ...........................................................................................................114 
 
 
 
LIST OF TABLES 
 
Table 1 
Visit and assessment schedule....................................................................67 
Table 2 
Sample size assumptions for primary and secondary endpoints ................97 
 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ...............................................................................................44 
Figure 2 
Hypothesis testing strategy .........................................................................92 
Figure 3 
Effect of testing multiple null hypotheses on power at a given 
sample size .................................................................................................98 
 
 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 11/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
LIST OF APPENDICES 
 
Appendix 1 
Alcohol restrictions during the study .......................................................114 
Appendix 2 
Caffeine content of common beverages ...................................................115 
Appendix 3 
Forbidden and restricted concomitant medications ..................................116 
Appendix 4 
Coding sub-test© .......................................................................................119 
Appendix 5 
Insomnia Severity Index©.........................................................................120 
Appendix 6 
Sheehan Disability Scale© ........................................................................121 
Appendix 7 
Benzodiazepine Withdrawal Symptom Questionnaire ............................122 
Appendix 8 
Sleep Diary ...............................................................................................123 
Appendix 9 
Patient Global Assessment of Disease Severity and Patient Global 
Impression of Change, daytime symptoms ..............................................125 
Appendix 10 Patient Global Impression of Severity (PGI-S) and Patient Global 
Impression of Change (PGI-C), night-time symptoms ............................126 
Appendix 11 Insomnia Daytime Symptoms and Impacts Questionnaire ......................127 
Appendix 12 Epworth Sleepiness Scale©.......................................................................131 
Appendix 13 Mini Mental State Examination© .............................................................132 
Appendix 14 PAtient preferences stUdy in inSomnia (PAUSe) ....................................134 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 12/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
Adverse event of special interest 
AHI  
Apnea/hypopnea index 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
AV  
Atrioventricular 
BMI  
Body mass index 
BP  
Blood pressure 
bpm  
Beats per minute 
BRA  
Benefit-risk assessment 
BWSQ  
Benzodiazepine Withdrawal Symptom Questionnaire 
CBT  
Cognitive behavioral therapy 
CFR  
Code of Federal Regulations (US) 
CNS  
Central nervous system 
CR  
Controlled-release 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR  
Clinical Study Report 
C-SSRS©  
Columbia Suicide Severity Rating Scale© 
CV%  
Coefficient of variation 
CYP  
Cytochrome P450 
DB  
Double-blind 
DCE  
Discrete Choice Experiment 
DoA  
Delegation of Authority 
DORA  
Dual orexin receptor antagonist 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders, Fifth 
Edition 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 13/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
ECG  
Electrocardiogram/graphy 
eCRF  
Electronic Case Report Form 
EDS  
Excessive daytime sleepiness 
EMA  
European Medicines Agency 
Emax  
Maximum effect 
EODBT  
End-of-Double-Blind Treatment 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ESS©  
Epworth Sleepiness Scale© 
FAS  
Full Analysis Set 
FDA  
Food and Drug Administration 
GABA  
Gamma-aminobutyric acid 
GCP  
Good Clinical Practice 
HR  
Heart rate 
IB  
Investigator’s Brochure 
ICF  
Informed consent form 
ICH  
International Council for Harmonisation 
IDMC  
Independent Data Monitoring Committee 
IDSIQ  
Insomnia Daytime Symptoms and Impacts Questionnaire 
IEC  
Independent Ethics Committee 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISAC  
Independent Statistical Analysis Center 
ISB  
Independent Safety Board 
ISF  
Investigator Site File 
ISI©  
Insomnia Severity Index© 
LPS  
Latency to Persistent Sleep 
MAR  
Missing at random 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 14/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
MedDRA  
Medical Dictionary for Regulatory Activities 
MINI©  
Mini International Neuropsychiatric Interview© 
MMSE©  
Mini Mental State Examination© 
NOAEL  
No-observed-adverse-effect level 
PAUSe  
PAtient Preferences StUdy in InSomnia 
PD  
Pharmacodynamic(s) 
PGA-S  
Patient Global Assessment of Disease Severity 
PGI-C  
Patient Global Impression of Change 
PGI-S  
Patient Global Impression of Severity 
PI  
Principal Investigator 
PK  
Pharmacokinetic(s) 
PLMAI  
Periodic limb movement with arousal index 
PPS  
Per-Protocol Set 
PSG  
Polysomnography 
PT  
Preferred Term 
QS  
Quality System 
QTc  
Corrected QT interval 
QTcB  
QT interval corrected with Bazett’s formula 
QTcF  
QT interval corrected with Fridericia’s formula 
REM  
Rapid eye movement 
RSI  
Reference Safety Information 
RUT  
Random utility theory 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SD  
Standard deviation 
SDS©  
Sheehan Disability Scale© 
SIV  
Site Initiation Visit 
sLSO  
Subjective Latency to Sleep Onset 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 15/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
SMAA  
Stochastic multicriteria acceptability analysis 
SOC  
System Organ Class 
SpO2  
Blood oxygen saturation level by pulse oximetry 
SQ  
Sleep quality 
sTST  
Subjective Total Sleep Time 
SUSAR  
Suspected unexpected serious adverse reaction 
sWASO  
Subjective Wake After Sleep Onset 
SWS  
Slow wave sleep 
t½  
Half-life 
TEAE  
Treatment-emergent adverse event 
TST  
Total Sleep Time 
ULN  
Upper limit of normal 
USPI  
United States Package Insert 
VAS  
Visual analog scale(s) 
WASO  
Wake After Sleep Onset 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 16/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 17/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 18/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
PROTOCOL SYNOPSIS ID-078A301 
TITLE 
Multi-center, double-blind, randomized, placebo-controlled, parallel-
group, polysomnography study to assess the efficacy and safety of 
ACT-541468 in adult and elderly subjects with insomnia disorder 
OBJECTIVES 
Primary objectives 
To evaluate the efficacy of 25 mg and 50 mg ACT-541468 on 
objective sleep parameters in subjects with insomnia disorder. 
Secondary objectives 
To evaluate the efficacy of 25 mg and 50 mg ACT-541468 on 
subjective sleep parameters and next-day functioning in subjects with 
insomnia disorder. 
Safety objectives 
To assess the safety and tolerability of ACT-541468 in subjects with 
insomnia 
disorder 
during 
treatment 
and 
upon 
treatment 
discontinuation. 
DESIGN 
Multi-center, 
double-blind, 
randomized, 
placebo-controlled, 
parallel-group, Phase 3 study. 
PHASES 
The study comprises the following 3 phases: the screening phase, the 
treatment phase, and the safety follow-up phase. 
The screening phase starts with the signature of the informed consent 
form at Visit 1 and ends at Randomization (Visit 4), provided the 
subject fulfills all the eligibility criteria. It includes the Screening 
period and the Run-in period. The screening phase lasts 20 to 31 days. 
The Screening period starts with Visit 1 and ends at Visit 2. During 
the Screening period, the investigator verifies eligibility criteria and 
eligible subjects perform a one-night polysomnography (PSG) 
assessment. The Screening period lasts 7 to 18 days to allow time to 
perform all required procedures at Visit 1, the PSG assessment and 
collect the minimum number of eDiary entries (i.e., 7 days) between 
Visit 1 and Visit 2.  
The Run-in period starts with Visit 2 and ends at Randomization 
(i.e., Visit 4). At Visit 2 eligible subjects are allocated a 
single-blinded placebo treatment that is taken daily. During the 
Run-in period subjects come to the site for Visit 3, which consists of 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 19/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
2 PSG nights and is performed when the subject has completed the 
eDiary for at least 7 days and eligibility is confirmed. The Run-in 
period lasts 13 to 24 days, to allow collection of the minimum number 
of eDiary entries (i.e., 7 days), perform 2 PSG nights at Visit 3, and 
receive the eligibility confirmation from the PSG central reader.  
The double-blind (DB) treatment phase lasts 3 months. It starts at 
Randomization (Visit 4). DB study treatment is taken daily. A safety 
telephone call is performed at Visit 5 to collect information about 
adverse events (AEs) and concomitant medications. Sleep parameters 
of each subject are objectively assessed with 2 consecutive PSG 
nights at Visit 6 and Visit 8. A safety visit without PSG night will be 
performed at Visit 7. An eDiary is completed every day during the 
treatment phase. 
End-of-Double-Blind-Treatment (EODBT) is reached in the 
second morning of Visit 8. 
The safety follow-up phase starts after EODBT. It consists of a 
single-blind placebo run-out period of 7 days and a safety follow-up 
period.  
The Run-out period starts in the evening of Visit 9. Visit 9 consists 
of one PSG night on single-blind placebo treatment. Visit 9 is 
followed by 6 days at home with single-blind placebo treatment. The 
eDiary is completed every day during the Run-out period. The end of 
the Run-out period (End-of-Treatment [EOT]) is reached after all 
visit assessments have been performed at Visit 10. 
The Safety follow-up period starts after EOT and ends 30 days after 
the last dose of DB study treatment intake for subjects that are not 
enrolled in the ID-078A303 extension study. 
Subjects who complete DB study treatment and the Run-out period 
are eligible to enter the ID-078A303 extension study (if approved by 
the national health authorities and local Independent Ethics 
Committees / Institutional Review Boards). For these subjects, the 
safety follow-up period ends on the date of enrolment into ID-
078A303. 
End-of-Study (EOS) for an individual subject is defined as the date 
of the 30-day follow-up telephone call (Visit 11) or the date of 
enrolment into the ID-078A303 extension study. If a subject is 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 20/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
prematurely discontinued from study treatment EOS is performed as 
planned on Day 115. If a subject withdraws consent and does not 
wish to participate in the study any longer, EOS is the date of consent 
withdrawal for this subject. If a subject is declared lost to follow-up, 
EOS is the date of last successful contact for this subject. 
PLANNED 
DURATION 
Approximately 18 months from first subject, first visit to last subject, 
last visit. 
SITE(S) / 
COUNTRY(IES) 
The study will be conducted at approximately 75 sites in 
10 countries. 
SUBJECTS / 
GROUPS 
Approximately 900 subjects will be randomized to either 25 mg or 
50 mg ACT-541468, or to placebo, in a 1:1:1 ratio. Treatment 
allocation will be stratified by age into 2 categories: < 65 and ≥ 65 
years. Approximately 40% of subjects will be elderly subjects (≥ 65 
years old), of which approximately 5% will be above 75 years old. 
These percentages will be monitored by the sponsor through the IRT. 
INCLUSION 
CRITERIA 
Criteria assessed at Visit 1: 
1. Signed informed consent prior to any study-mandated procedure. 
2. Male or female aged ≥ 18 years. 
3. Insomnia disorder according to Diagnostic and Statistical Manual 
of Mental Disorders, Fifth Edition (DSM-5) criteria, as follows: 
3.1 The predominant complaint is dissatisfaction with sleep 
quantity or quality, associated with one (or more) of the 
following symptoms: 
• Difficulty initiating sleep. 
• Difficulty maintaining sleep, characterized by frequent 
awakenings or problems returning to sleep after 
awakenings. 
• Early-morning awakening with inability to return to 
sleep. 
3.2 The sleep disturbance causes clinically significant distress 
or impairment in social, occupational, educational, 
academic, behavioral, or other important areas of 
functioning. 
3.3 The sleep difficulty occurs despite adequate opportunity for 
sleep. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 21/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
3.4 The insomnia is not better explained by and does not occur 
exclusively during the course of another sleep-wake 
disorder (e.g., narcolepsy, a breathing-related sleep 
disorder, a circadian rhythm sleep-wake disorder, a 
parasomnia). 
3.5 The insomnia is not attributable to the physiological effects 
of a substance (e.g., a drug of abuse, a medication). 
3.6 Coexisting mental disorders and medical conditions do not 
adequately explain the predominant complaint of insomnia. 
3.7 Self-reported history of all the following on at least 3 nights 
per week and for at least 3 months prior to Visit 1: 
3.7.1 ≥ 30 min to fall asleep, and 
3.7.2 Wake time during sleep ≥ 30 min, and 
3.7.3 Subjective Total Sleep Time (sTST) ≤ 6.5 h 
4. Insomnia Severity Index© score ≥ 15. 
5. Ability to communicate well with the investigator, to understand 
the study requirements and, as judged by the investigator, to be 
alert and oriented to person, place, time, and situation. 
Criteria assessed at Visit 3 
6. Meeting all the following sleep parameters on at least 3 nights out 
of 7 nights on the sleep diary completed at home between Visit 2 
and Visit 3: 
6.1 
≥ 30 min to fall asleep, and 
6.2 
Wake time during sleep ≥ 30 min, and 
6.3 
sTST of ≤ 6.5 h 
7. Usual bedtime between 21:30 and 00:30 as reported on sleep 
diary completed between Visit 2 and Visit 3. 
8. Regular time in bed between 6 and 9 h as reported on sleep diary 
completed between Visit 2 and Visit 3. 
9. Meeting all the following sleep parameters on the 2 PSG nights 
at Visit 3: 
9.1 
Mean Latency to Persistent Sleep (LPS) ≥ 20 min (with 
neither of the two nights < 15 min), and 
9.2 
Mean Wake After Sleep Onset (WASO) ≥ 30 min (with 
neither of the two nights < 20 min), and 
9.3 
Mean Total Sleep Time (TST) < 420 min 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 22/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
Criteria assessed at Visit 1, Visit 2, and Visit 4: 
10. For women of childbearing potential, the following are required: 
• Negative serum pregnancy test (Visit 1). 
• Negative urine pregnancy test (Visit 2, Visit 4). 
• Agreement to use the contraception scheme as required by 
the protocol from Screening up to at least 30 days after last 
DB study treatment intake. 
EXCLUSION 
CRITERIA 
Criteria assessed at Visit 1 
1. Body mass index below 18.5 or above 40.0 kg/m2. 
2. Any lifetime history of sleep-related breathing disorder, including 
chronic obstructive pulmonary disease and sleep apnea. 
3. Cognitive behavioral therapy (CBT) for any indication is allowed 
only if the CBT started at least 1 month prior to Visit 3 and the 
subject agrees to continue this CBT throughout the study. 
4. Self-reported usual daytime napping ≥ 1 h per day, and ≥ 3 days 
per week. 
5. Acute or unstable psychiatric conditions (including but not 
restricted to anxiety disorder, major depression, bipolar disorder, 
schizophrenia, obsessive compulsive disorder, or depression) that 
are diagnosed by the Mini International Neuropsychiatric 
Interview© or that require pharmacological treatment for these 
disorders. N.B.: subjects with a history of major depressive 
disorder currently without any symptoms and not requiring 
treatment are eligible. 
6. Mini Mental State Examination© score < 25 in subjects 
≥ 50 years. 
7. Shift work within 2 weeks prior to the screening visit, or planned 
shift work during the study. 
8. Travel across ≥ 3 time zones within 2 weeks prior to the screening 
visit, or planned travel across ≥ 3 time zones during the study. 
9. Unstable medical condition, significant medical disorder or acute 
illness, ECG, hematology or biochemistry test results within 
1 month prior to the screening visit, which, in the opinion of the 
investigator, could affect the subject’s safety or interfere with the 
study assessments. 
10. Treatment with central nervous system-active drugs prohibited by 
this protocol within 5 half-lives of the respective drug (or 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 23/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
2 weeks, whichever is longer) prior to Visit 1, including over-the-
counter medication and herbal medicines. 
11. Diagnosis of alcohol or substance use disorder within 2 years 
prior to the screening visit or inability to refrain from drinking 
alcohol for at least 3 consecutive days. 
12. Heavy tobacco use (at least one pack of cigarettes a day or 
inability to refrain from smoking during the night).  
13. Caffeine consumption ≥ 600 mg per day or any caffeine 
consumption after 4 pm. 
14. Treatment with another investigational drug within 3 months 
prior to Visit 1, previous treatment with ACT-541468 or previous 
randomization in any trial involving ACT-541468. 
15. Known hypersensitivity or contraindication to drugs of the same 
class as the study treatment or to any excipients of the study drug 
formulation. 
16. Not able or willing to stop treatment with moderate or strong 
cytochrome P450 (CYP)3A4 inhibitors, or treatment with 
moderate or strong CYP3A4 inducers, within at least 1 week prior 
to Visit 2. 
17. Not able or willing to stop consumption of grapefruit, Seville 
(bitter) oranges or juices from those fruits within at least 1 week 
prior to Visit 2.  
Criteria assessed at PSG visit between Visit 1 and Visit 2 
18. Periodic limb movement disorder with arousal index (PLMAI) 
≥ 15/h (assessed on the 1st PSG night), restless legs syndrome, 
circadian rhythm disorder, rapid eye movement (REM) behavior 
disorder, or narcolepsy.  
19. Apnea/hypopnea index ≥ 15/h according to American Academy 
of Sleep Medicine criteria or event associated with blood oxygen 
saturation level by pulse oximetry (SpO2) < 80%, as assessed on 
the 1st PSG night. 
Criteria assessed at Visit 1 and Visit 3 
20. Aspartate aminotransferase and/or alanine aminotransferase > 2 × 
upper limit of normal (ULN) and/or direct bilirubin > 1.5 × ULN. 
21. Severe renal impairment: known or defined as estimated 
creatinine clearance < 30 mL/min/1.73 m2, according to the 
4-variable Modification of Diet in Renal Disease formula. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 24/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
22. Hematology or biochemistry test results deviating from the 
normal range to a clinically relevant extent as per judgment of the 
investigator. 
23. Any of the following conditions related to ECG abnormalities: 
• A prolonged QT interval corrected with Bazett’s formula 
(QTcB) or QT interval corrected with Fridericia’s formula 
(QTcF) (greater than 450 ms). If QTcB or QTcF is greater 
than 450 ms on the first ECG, a second ECG recording will 
be performed after at least 30 min. If QTcB or QTcF is greater 
than 450 ms on the second ECG, the subject is not eligible.  
• A history of additional risk factors for torsade de pointes (e.g., 
heart failure, hypokalemia, family history of long QT 
syndrome). 
• ECG with clinically significant atrioventricular (AV) 
conduction disturbance (e.g., second- or third-degree AV 
block), sick sinus syndrome, bradycardia (resting pulse 
< 40 bpm), or accessory bypass tract (e.g., Wolff-Parkinson-
White). 
Criterion assessed at Visit 1, Visit 2, Visit 3 and Visit 4 
24. Any of the following conditions related to suicidality: 
• Any suicidal ideation with intent, with or without a plan, at 
screening, i.e., answering “Yes” to questions 4 or 5 on the 
suicidal ideation section of the lifetime (Visit 1) and visit 
(Visit 2, Visit 3, Visit 4) version of the Columbia Suicide 
Severity Rating Scale© (C-SSRS©). 
• 
History of suicide attempt on the suicidal behavioral section 
of the lifetime version of the C-SSRS© (Visit 1). 
Criteria assessed at Visit 1, PSG visit between Visit 1 and 
Visit 2, Visit 2, Visit 3 and Visit 4 
25. For female subjects: pregnant, lactating or planning to become 
pregnant during projected duration of the study. 
26. Positive urine drug test (for benzodiazepines, barbiturates, 
cannabinoids, opiates, amphetamines, phencyclidine or cocaine) 
or presence of alcohol in exhaled breath as detected by 
breathalyzer test. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 25/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
STUDY 
TREATMENTS 
Investigational treatment 
ACT-541468 tablets at strengths of 25 mg and 50 mg will be 
administered orally, once daily in the evening during the DB 
treatment period. 
Placebo 
ACT-541468-matching placebo will be administered orally, once 
daily in the evening during the single-blind run-in period, the DB 
treatment period and the single-blind run-out period. 
ENDPOINTS 
Primary efficacy endpoints 
The primary efficacy endpoints of this study are defined as: 
• the change from baseline to Month 1 in WASO (sleep 
maintenance) 
• the change from baseline to Month 3 in WASO  
• the change from baseline to Month 1 in LPS (sleep onset) 
• the change from baseline to Month 3 in LPS  
Baseline is defined as mean of the 2 PSG nights at Visit 3. Month 1 
and Month 3 are defined as the mean of the 2 PSG nights at Visit 6 
and Visit 8, respectively. 
LPS (min) is the time from start of recording to the beginning of the 
first continuous 20 epochs (i.e., 10 min) scored as non-awake, i.e., 
epochs scored as either sleep stage 1 (S1), sleep stage 2 (S2), sleep 
stage 3 (slow wave sleep) or REM, as determined by PSG.  
WASO is the time (min) spent awake after onset of persistent sleep 
until lights on, as determined by PSG. 
Secondary efficacy endpoints 
The secondary efficacy endpoints of this study are defined as: 
• the change from baselinea to Month 1b in sTST. 
• the change from baselinea to Month 3c in sTST.  
• the change from baselinea to Month 1b in Insomnia Daytime 
Symptoms and Impacts Questionnaire (IDSIQ) sleepiness 
domain score. 
• the change from baselinea to Month 3c in IDSIQ sleepiness 
domain score.  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 26/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
a Baseline is the mean value based on the screening sleep diary / 
IDSIQ entries performed at home in the 7 days immediately 
preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries 
performed at home in the 7 days immediately preceding the first PSG 
at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries 
performed at home in the 7 days immediately preceding the first PSG 
at Visit 8. 
Safety endpoints 
In addition to the standardized collection of AEs, safety data specific 
to insomnia and its treatment will be assessed as follows:  
• Withdrawal effects (physical dependence) upon treatment 
discontinuation will be assessed based on the changes from last 
assessment on DB treatment (Visit 8, 2nd morning) to run-out 
period 
in 
the 
Benzodiazepine 
Withdrawal 
Symptom 
Questionnaire (BWSQ) total score (Visit 9 and Visit 10), the 
occurrence of relevant AEs and marked ECG abnormalities. 
• Rebound insomnia will be assessed based on objective sleep 
parameters (WASO, LPS, and TST) at Visit 9 as compared to 
Visit 3. It will also be assessed using subjective sleep parameters 
(subjective WASO [sWASO], subjective Latency to Sleep Onset 
[sLSO], and sTST) from run-out period as compared to baseline. 
• Next-day residual effects will be assessed based on changes from 
baseline (Visit 3) to Month 1 and Month 3 in: 
– Coding sub-test©  
– Sheehan Disability Scale© (SDS©) 
– Scores on the visual analog scale (VAS; mm) 
• Serious adverse events up to 30 days after DB study treatment 
discontinuation or until enrollment into the extension study. 
• Treatment-emergent AEs (TEAEs) up to 30 days after DB study 
treatment discontinuation or until enrollment into the extension 
study. 
• AEs leading to premature discontinuation of the DB study 
treatment. 
• AEs of special interest (AESIs) after adjudication by an 
Independent Safety Board (ISB): 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 27/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
– narcolepsy-like symptoms (i.e., excessive daytime sleepiness 
[EDS], cataplexy and complex sleep behavior events 
including hallucinations/sleep paralysis)  
– suicide/self-injury. 
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 
(Visit 8) in vital signs (mean of the 2 PSG nights in systolic and 
diastolic blood pressure [BP] and pulse rate). 
• Change from baseline (Visit 1) to Month 3 (Visit 8) in body 
weight. 
• Marked ECG abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 3 (Visit 8) and the end 
of run-out (Visit 10) in ECG variables. 
• Marked laboratory abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 
(Visit 8) in laboratory variables. 
• Occurrence of suicidal ideation and/or behavior on DB study 
treatment based on C-SSRS©. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 1. 
STATISTICAL 
METHODOLOGY 
Analysis of the primary and secondary efficacy endpoints 
The Type I error rate will be controlled for the testing of multiple null 
hypotheses associated with the two primary endpoints (LPS and 
WASO) and two other endpoints (sTST and IDSIQ) assessed at 1 and 
3 months of treatment, and the two dose levels included in this study, 
i.e., 25 mg and 50 mg. 
The eight statistical null hypotheses associated with the primary 
efficacy endpoints are: 
Sleep maintenance: 
• H1WASO: Higher Dose – Placebo = 0 for WASO at Month 1 
• H2WASO: Higher Dose – Placebo = 0 for WASO at Month 3 
• H3WASO: Lower Dose – Placebo = 0 for WASO at Month 1 
• H4WASO: Lower Dose – Placebo = 0 for WASO at Month 3 
Sleep onset: 
• H1LPS: Higher Dose – Placebo = 0 for LPS at Month 1 
• H2LPS: Higher Dose – Placebo = 0 for LPS at Month 3 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 28/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
• H3LPS: Lower Dose – Placebo = 0 for LPS at Month 1 
• H4LPS: Lower Dose – Placebo = 0 for LPS at Month 3 
The eight statistical null hypotheses associated with the secondary 
efficacy endpoints are: 
Sleep quantity: 
• H1sTST: Higher Dose – Placebo = 0 for sTST at Month 1 
• H2sTST: Higher Dose – Placebo = 0 for sTST at Month 3 
• H3sTST: Lower Dose – Placebo = 0 for sTST at Month 1 
• H4sTST: Lower Dose – Placebo = 0 for sTST at Month 3 
Next-day performance: 
• H1IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 1 
• H2IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 3 
• H3IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 1 
• H4IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness 
domain score at Month 3 
where ‘Higher Dose’, ‘Lower Dose’, and ‘Placebo’ represent the 
mean change from baseline for the given endpoint (WASO, LPS, 
sTST or IDSIQ sleepiness domain score) and time point (Month 1 or 
Month 3) for the 50 mg, 25 mg, and placebo treatment group, 
respectively. 
Each null hypothesis will be tested against the alternative hypothesis: 
that ACT-541468 improves WASO/LPS/sTST/ IDSIQ sleepiness 
domain score at the given dose (25 or 50 mg) and time point (Month 
1 or Month 3) compared to placebo. 
The order of testing and the alpha level applied to each null 
hypothesis will be based on the Bonferroni-based gatekeeping 
procedure [Bretz 2009], which will control the study-wise Type I 
error at a two-sided 5% significance level. To account for the 
concurrent evaluation (multiple comparison) of two distinct endpoint 
categories (i.e., sleep maintenance and sleep onset), a Bonferroni 
correction is applied. Both endpoint categories will be tested at half 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 29/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
of the two-sided 5% significance level. This supports the sponsor’s 
intention to make a superiority claim versus placebo for efficacy in 
either sleep maintenance and/or sleep onset. The remaining 
hypotheses will be tested following the gatekeeping strategy moving 
from Month 1 to Month 3 for higher dose ACT-541468 vs placebo 
and then from Month 1 to Month 3 for lower dose ACT-541468 vs 
placebo. The pre-specified proportion of alpha that will be distributed 
once a given null hypothesis (node) is rejected is shown on the arrow 
in the directed graph. If a certain null hypothesis cannot be rejected, 
the alpha level used for that test is absorbed at that node and not 
distributed further. 
The main analysis will be performed using the FAS. 
A longitudinal data analysis method (i.e., linear mixed effects model) 
will be used for the analysis of change from baseline in WASO, LPS, 
sTST, and IDSIQ scores, separately. All available data, regardless of 
occurrence 
of 
intercurrent 
events 
(e.g., 
study 
treatment 
discontinuation, the use of prohibited medication), will be included 
in the model. 
Analysis of the safety endpoints 
Adverse events: The number (%) of subjects experiencing a TEAE 
(including serious adverse events, AESIs after adjudication by the 
ISB, and AEs leading to premature discontinuation of the DB study 
treatment) will be summarized by System Organ Class and/or 
Preferred Term, and maximum intensity. 
Laboratory data: Observed values and changes from baseline to 
Month 1 and Month 3 in both hematology and blood chemistry 
laboratory parameters will be summarized. The number (%) of 
subjects having a marked laboratory abnormality during DB study 
treatment will be tabulated. 
Vital signs and weight: Observed values and changes from baseline 
to Month 1 and Month 3 in vital signs (mean of the two PSG nights 
in systolic and diastolic BP and pulse rate) and observed values and 
changes from baseline to Month 3 in body weight will be 
summarized.  
Electrocardiograms: Observed values and changes from baseline to 
Month 3 for each ECG parameter (QTcB, QTcF, heart rate, PR, QRS) 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 30/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
will be summarized. The number (%) of subjects with a marked ECG 
abnormality during DB study treatment will be tabulated. 
Withdrawal symptoms: The BWSQ total score will be summarized 
using descriptive statistics for the observed values and changes from 
the last assessment on DB treatment (Visit 8, 2nd morning) to the 
beginning and the end of the treatment withdrawal period (in the 
morning at Visit 9 and at Visit 10, respectively). The number (%) of 
subjects having, separately, an AE and a marked ECG abnormality 
during the treatment withdrawal period will be tabulated. 
Insomnia rebound effect: The changes from baseline to the treatment 
withdrawal period (Visit 9, run-out) in objective sleep parameters 
(WASO, LPS, and TST) will be summarized using descriptive 
statistics. The changes from baseline (mean value based on the 
screening sleep diary entries performed at home in the 7 days 
immediately preceding the first PSG at Visit 3) to the treatment 
withdrawal period (after PSG night at Visit 9) in subjective sleep 
parameters (sWASO, sLSO, and sTST) will be summarized using 
descriptive statistics. 
Next-day residual effects: Observed values and changes from 
baseline to Month 1 and Month 3 in Coding sub-test©, SDS©, and 
VAS scores (mm) assessing morning sleepiness, daytime alertness, 
and daytime ability to function, will be summarized. 
C-SSRS©: Number (%) of subjects with suicidal ideation, suicidal 
behavior, and/or self-injurious behavior without suicidal intent based 
on the C-SSRS© during DB treatment will be tabulated. Shifts from 
baseline showing any changes in suicidal ideation and suicidal 
behavior during DB treatment will also be provided. 
STUDY 
COMMITTEES 
An Independent Data Monitoring Committee (IDMC) will have 
overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study, and making 
appropriate recommendations based on the reported data. This will 
ensure that the study is being conducted to the highest scientific and 
ethical standards. The IDMC will be fully operational prior to the 
enrollment of the first subject into the study. The composition and 
operation of the IDMC is described in the IDMC charter. 
An ISB will review and adjudicate in a blinded manner AESIs, i.e., 
narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 31/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
behavior events including. hallucinations/sleep paralysis), or 
suicide/self-injury. The composition and operation of the ISB is 
described in the ISB charter.  
SUB-STUDY 
A sub-study will be performed to collect patient preferences data. 
The Discrete Choice Experiment methodology aims to collect 
preferences for selected treatment outcomes in a subgroup of at least 
360 subjects in USA and Germany that are part of the approximately 
900 subjects enrolled in the ID-078A301 study, using the 
questionnaire for the PAtient Preferences StUdy in InSomnia 
(PAUSe) developed by Idorsia.  
STUDY 
EXTENSION 
Subjects who completed the study until EOT will have the possibility 
to participate in the extension study ID-078A303. The 9-month ID-
078A303 study will be available at each site and subjects will be 
treated for up to 12 months overall (i.e., including the treatment 
period of the confirmatory trial). 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 32/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
PROTOCOL 
1 
BACKGROUND 
1.1 Insomnia disorder 
1.1.1 Definition  
The definition of insomnia disorder used in the protocol is the one described in the 
Diagnostic and Statistical Manual of Mental Disorders, Fifth Edition (DSM-5) 
[APA 2013]: 
“Insomnia disorder is a predominant complaint of dissatisfaction with sleep quantity or 
quality, associated with difficulty initiating or maintaining sleep, or early morning 
awakening. Furthermore, the sleep disturbance is associated with significant social or 
functional distress or impairment. Sleep difficulty occurs at least 3 nights per week and is 
present for at least 3 months, and occurs despite adequate opportunity for sleep. The 
insomnia (a) is not better explained by, and does not occur exclusively during the course 
of another sleep-wake disorder, (b) it is not attributable to the physiological effect of a 
substance, and (c) is not explained by co-existing mental disorders or medical conditions.” 
1.1.2 Epidemiology 
Insomnia is a common problem. Population-based epidemiological studies suggest that 
30% or more of the general population complain of sleep disruption and approximately 
10% of the general population have complaints of sleep disruption with associated 
symptoms of distress or daytime functional impairment consistent with the diagnosis of 
insomnia disorder [NIH 2005, Roth 2007]. Insomnia symptoms (difficulties initiating 
sleep, early-morning awakenings, and dissatisfaction with sleep) increase with age. Factors 
associated with aging and not with age per se, such as depressed mood, respiratory 
symptoms, poor perceived health and physical disability are associated with the decrease 
in ability to sleep [Ohayon 2001].  
Insomnia disorder results in difficulty falling asleep or difficulty maintaining sleep, 
characterized by multiple or long awakenings during the sleep period, or early-morning 
awakenings. Difficulty maintaining sleep is the most common problem among patients 
with insomnia, occurring in approximately two-thirds of them [Neubauer 2014]. Studies 
have shown that the most common symptoms are combined difficulties to both fall and to 
stay asleep [Hohagen 1994]. Elderly patients are more likely to suffer from chronic 
insomnia characterized by difficulty maintaining sleep, rather than difficulty initiating 
sleep [McCall 2004]. 
Insomnia is associated with impairment in cognitive functioning, daytime fatigue, 
increased accident risk, and difficulties in interpersonal relationships [Balter 1991, 
Ancoli-Israel 1999, Rosenthal 1993, Zammit 1999, Fortier-Brochu 2014]. Insomnia 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 33/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
increases utilization of medical care [Simon 1997, Léger 2002, McCall 2004], has been 
correlated with chronic health issues and perceptions of poor health [Balter 1991, 
Ancoli-Israel 1999, Rosenthal 1993, Zammit 1999, Fortier-Brochu 2014], and in elderly 
subjects may also precipitate falls [McCall 2004]. Numerous studies have shown an 
association between insomnia and psychiatric disorders, specifically depression, anxiety, 
and other significant mental health conditions [Ford 1989, Benca 2004].  
1.1.3 Treatment 
The current standards of care encompass non-pharmacological therapies and 
pharmacotherapy [Schutte-Rodin 2008]. 
Non-pharmacological (psychological and behavioral) standard-of-care therapies for 
insomnia include a variety of treatment methods, such as cognitive behavioral therapy 
(CBT), stimulus control and relaxation training [Schutte-Rodin 2008]. Sleep hygiene 
therapy is often added to these treatment modalities.  
Prescription sleep medications (hypnotics) indicated for the treatment of insomnia include 
benzodiazepines, non-benzodiazepine benzodiazepine receptor agonists, melatonin 
agonists, the orexin receptor antagonist suvorexant, and low-dose doxepin.  
Benzodiazepines are a class of medications that bind to multiple gamma-aminobutyric acid 
(GABA) type A receptor subtypes [Lieberman 2007]. Drugs in this class, which includes 
flurazepam, temazepam, trialozam, estazolam, and quazepam, were previously commonly 
prescribed for insomnia. While the efficacy of these medications has been well 
documented, their usefulness is limited by adverse effects such as daytime sedation (e.g., 
morning or next-day hangover), cognitive impairment (including anterograde amnesia), 
motor dyscoordination, abuse liability, and dependence [Holbrook 2000, Buscemi 2007]. 
Benzodiazepines also alter sleep architecture: they prolong stage 2 sleep and may slightly 
reduce 
the 
relative 
amount 
of 
rapid 
eye 
movement 
(REM) 
sleep 
[Treat Guidel Med Lett 2009]. Their use has been associated with tolerance development 
and rebound insomnia upon withdrawal of medication [Kales 1978, Petursson 1981].  
Non-benzodiazepine benzodiazepine receptor agonists have a more targeted action on one 
or more GABA type A receptor subtypes, but the availability of these treatments highly 
varies across regions. Zolpidem, zolpidem controlled-release (CR) and zaleplon show 
affinity for the alpha-1 receptor subtype, while eszopiclone shows affinity for the alpha-2 
and -3 receptor subtypes [Nutt 2006]. All of these drugs reduce latency to sleep onset, but 
zolpidem CR and eszopiclone have also been shown to reduce Wake After Sleep Onset 
(WASO), 
reflecting 
an 
improvement 
in 
sleep 
maintenance 
[Ambien® USPI, 
Lunesta® USPI]. Although they have less impact on sleep architecture, possibly by virtue 
of their receptor selectivity, the drugs in this group have similar adverse effects as the 
benzodiazepines. In 2007 the US Food and Drug Administration (FDA) requested that all 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 34/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
manufacturers of hypnotic drug products strengthen their product labeling to include 
stronger language related to potential risks. These risks include severe allergic reactions 
(i.e., anaphylaxis) and complex sleep-related behaviors, which may include sleep-driving 
[FDA 2007].  
Newer hypnotics that do not act at the GABA receptor have been developed. The melatonin 
receptor agonist ramelteon is approved for insomnia in the US and in Japan, but not in 
Europe. Ramelteon reduces sleep latency and increases Total Sleep Time (TST), but has 
no effect on WASO [Kuriyama 2014], making it an inappropriate treatment for people with 
sleep maintenance problems [Simpson 2008]. Ramelteon is devoid of next-day residual 
effects, withdrawal or rebound insomnia and does not appear to be associated with abuse 
liability.  
Suvorexant is an oral dual orexin receptor antagonist (DORA) that was approved in the 
USA, Japan and Australia for the treatment of insomnia characterized by difficulties with 
sleep onset and/or sleep maintenance. Suvorexant is contraindicated in patients with 
narcolepsy. Next-day effects, including impaired driving performance, have been reported 
at 20 mg [Belsomra® USPI]. Next-day residual effects might be related to the long half-
life (t½ = 12 hours) of suvorexant [Citrome 2014]. Rebound insomnia or withdrawal signs 
upon drug discontinuation were not observed in clinical trials [Herring 2016]. 
Use of sleep medications increases with age and is highest in the elderly [Ohayon 2002, 
Ohayon 2010]. Despite the increased risk of falls, non-benzodiazepine benzodiazepine 
receptor agonists and generic antidepressants are among the most prescribed classes of 
medications for elderly patients in the US. 
1.1.4 Unmet medical need 
CBT is generally the recommended first-line treatment for insomnia disorder 
[Schutte-Rodin 2008]. However, this may not be the ideal course of treatment for all 
patients. Many patients with insomnia are not interested in CBT, and when they are, access 
to CBT may be limited by the lack of therapists with adequate training and experience, and 
the fact that CBT is time-consuming, costly, and its reimbursement is highly challenging 
[Pigeon 2007, Schutte-Rodin 2008].  
Insomnia disorder is a chronic disease and currently available treatments are limited to 
short-term use with the exception of eszopiclone and suvorexant (in the US). Caution and 
dose reduction are also often advised in the elderly. Pharmacological treatments that 
address sleep onset problems alone do not provide relief to people with sleep maintenance 
difficulties, and treatments indicated for those with sleep maintenance problems may be 
associated with risks of cognitive impairment, postural instability, or next-day residual 
sedation that may impair driving [Neubauer 2014]. Moreover, the use of benzodiazepines 
and benzodiazepine receptor agonists is associated with an increased risk of falling 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 35/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
[McCall 2004] leading to hip and femur fractures, increased disability, and use of 
healthcare resources.  
Overall, there is a need for a long-term pharmacological treatment for insomnia disorder 
that addresses the most prominent and pressing symptoms of insomnia without negatively 
impacting next-day functioning.  
1.2 Study treatment: ACT-541468 
1.2.1 The orexin system 
The orexin system is involved in the regulation of sleep and arousal by the central nervous 
system (CNS) and is currently being targeted in the development of new therapies for sleep 
disorders. 
The neuropeptides orexin-A and orexin-B are synthesized in the lateral hypothalamic areas 
[de Lecea 1998] and activate the orexin-1 and orexin-2 receptors [Kilduff 2000]. Nerve 
fibers from orexin neurons make projections to the basal forebrain, corticolimbic 
structures, and brainstem, particularly to those regions related to waking and regulation of 
sleep [Hagan 1999, Sakurai 2007]. Infusing exogenous orexins into cerebral ventricles in 
rats leads to enhanced behavioral activity, arousal, delayed onset of sleep, and maintenance 
of cortical activation [Hagan 1999, Samson 2010]. Orexin-producing neurons are active 
during wakefulness and fall quiet during sleep [Sakurai 2007]. Orexin-A levels in the 
cerebrospinal fluid of several species fluctuate according to circadian rhythms, being 
highest during active wake periods [Zeitzer 2003, Desarnaud 2004]. 
The absence of orexins is implicated in the genesis of narcolepsy, due to findings of low 
cerebral spinal fluid orexin levels in most patients with unequivocal narcolepsy with 
cataplexy [Mignot 2002] and near-complete destruction of orexin neurons in post-mortem 
brains of patients with narcolepsy-cataplexy [Thannickal 2000], coupled with the 
observation of behavioral phenotypes consistent with narcolepsy in multiple animal models 
of orexin deficiency or dysfunction [Lin 1999].  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 36/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 37/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 38/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 39/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
1.3 Purpose and rationale of the study 
1.3.1 Purpose of the study 
The main purpose of this Phase 3 study is to confirm that at least one dose of ACT-541468 
is well tolerated and efficacious in promoting sleep onset and/or sleep maintenance in 
subjects with insomnia disorder.  
1.3.2 Rationale for the study 
The orexin system is involved in the regulation of sleep and arousal. In two Phase 2 studies 
in subjects with insomnia disorder, ACT-541468 has shown objective and subjective 
improvements in sleep onset and sleep maintenance. 
The dose levels of 25 and 50 mg of ACT-541468 planned for this study were both 
investigated in Phase 2 studies, which demonstrated statistically significant reductions in 






ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 42/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
2.2 Secondary objectives 
To evaluate the efficacy of 25 mg and 50 mg ACT-541468 on subjective sleep parameters 
and next-day functioning in subjects with insomnia disorder. 
2.3 Safety objectives 
To assess the safety and tolerability of ACT-541468 in subjects with insomnia disorder 
during treatment and upon treatment discontinuation. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a 3-month, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, Phase 3 study to assess the efficacy and safety of two doses (25 mg and 
50 mg) of ACT-541468 in subjects with insomnia disorder.  
Approximately 900 subjects will be randomized to either 25 mg or 50 mg of ACT-541468, 
or to placebo, in a 1:1:1 ratio. Treatment allocation will be stratified by age into 2 
categories: < 65 and ≥ 65 years. Approximately 40% of subjects will be elderly subjects 
(≥ 65 years old), of which approximately 5% will be above 75 years old. These percentages 
will be monitored by the sponsor through the Interactive Response Technology (IRT) 
system. 
The study will be conducted at approximately 75 sites in 10 countries. 
In addition, a sub-study to collect data on the subject’s preferences will be performed, 
aiming to enroll at least 360 subjects both from the USA and Germany who are part of the 
approximately 900 subjects enrolled in the ID-078A301 study. That means that the study 
recruitment will end when approximately 900 subjects have been randomized in the 
ID-078A301 study.  
3.1.1 Study periods 
The study comprises the following 3 phases: the screening phase, the treatment phase, and 
the safety follow-up phase [see Figure 1]. 
3.1.1.1 Screening phase 
The screening phase starts with the signature of the informed consent form (ICF) at Visit 1 
and ends at Randomization at Visit 4, provided the subject fulfills all eligibility criteria. It 
includes the Screening period and the Run-in period. The screening phase lasts 20 to 
31 days. 
The Screening period starts with Visit 1 and ends with Visit 2. During the screening 
period, the investigator verifies the eligibility criteria and eligible subjects perform a 
one-night PSG assessment. The Screening period lasts 7 to 18 days to allow time to perform 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 43/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
all required procedures at Visit 1, the PSG assessment and collect the minimum number of 
eDiary entries (i.e., 7 days) between Visit 1 and Visit 2. 
The Run-in period starts with Visit 2 and ends at Randomization (i.e., Visit 4). At Visit 2 
eligible subjects are allocated a single-blinded placebo treatment that is taken daily. During 
the Run-in period subjects come to the site for Visit 3, which consists of 2 PSG nights and 
is performed when the subject has completed the eDiary for at least 7 days and eligibility 
is confirmed. The Run-in period lasts 13 to 24 days, to allow collection of the minimum 
number of eDiary entries (i.e., 7 days), perform 2 PSG nights at Visit 3, and receive the 
eligibility confirmation from the PSG central reader.  
3.1.1.2 Treatment phase 
The DB treatment phase lasts 3 months. It starts at Randomization (Visit 4). DB study 
treatment is taken daily. A safety telephone call is performed at Visit 5 to collect 
information about AEs and concomitant medications. Sleep parameters of each subject are 
objectively assessed with 2 consecutive PSG nights at Visit 6 and Visit 8. A safety visit 
without PSG night will be performed at Visit 7. An eDiary is completed every day during 
the treatment phase. 
End-of-Double-Blind-Treatment (EODBT) is reached in the second morning of Visit 8. 
3.1.1.3 Safety follow-up phase 
The safety follow-up phase starts after EODBT. It consists of a single-blind placebo Run-
out period of 7 days and a Safety follow-up period.  
The Run-out period starts in the evening of Visit 9. Visit 9 consists of one PSG night on 
single-blind placebo treatment. Visit 9 is followed by 6 days at home with single-blind 
placebo treatment. The eDiary is completed every day during the Run-out period. The end 
of the Run-out period (End-of-Treatment [EOT]) is reached after all visit assessments have 
been performed at Visit 10. 
The Safety follow-up period starts after EOT and ends 30 days after last dose of DB study 
treatment intake for subjects that are not enrolled in the ID-078A303 extension study. 
Subjects who complete DB study treatment and the Run-out period are eligible to enter the 
ID-078A303 extension study (if approved by the national health authorities and local 
Independent Ethics Committees / Institutional Review Boards [IECs/IRBs]). For these 
subjects, the Safety follow-up period ends at the date of enrolment into ID-078A303. 
End-of-Study (EOS) for an individual subject is defined as the date of the 30-day follow-
up telephone call (Visit 11, Day 115) or the date of enrollment into the ID-078A303 
extension study. If a subject is prematurely discontinued from study treatment, EOS is 
performed as planned on Day 115. If a subject withdraws consent and does not wish to 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 44/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
participate in the study any longer, EOS is the date of consent withdrawal for this subject. 
If a subject is declared lost to follow-up, EOS is the date of last successful contact for this 
subject.  
The visit schedule and protocol-mandated procedures are performed according to the table 
of assessments [Table 1] and are described in Section 7. 
The overall study design is depicted in [Figure 1]. 
Figure 1 
Study design  
 
V = Visit; ▬ = polysomnography nights; EODBT = End-of-Double-Blind-Treatment; EOS = End-of-Study; EOT = 
End-of-Treatment. 
 
3.1.2 Study duration 
The study starts with the signature of the ICF at Visit 1 for the first subject enrolled and 
ends with the EOS of the last subject. Anticipated total study time is approximately 
18 months. 
Each subject will be treated for approximately 3 months. For an individual subject who 
does not decide to continue in the extension study, the study is completed with the EOS 
visit (safety follow-up telephone call at the end of follow-up) and the maximum duration 
of participation in the study of this subject is expected to be approximately 5 months.  
Subjects who completed the study until EOT are eligible to participate in the extension 
study ID-078A303. After the completion of the Run-out period, the 9-month ID-078A303 
extension study will be available at each site, depending on health authority / IEC / IRB 
approval, and subjects will be treated for up to 12 months overall (i.e., including the 
treatment period of the confirmatory trial). For the subjects who decide to participate in the 
extension study, ID-078A301 is completed with the enrollment into ID-078A303. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 45/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
3.1.3 Sub-study – Patient Preferences 
A sub-study will be performed to collect patient preferences data. 
The Discrete Choice Experiment (DCE) methodology aims to collect preferences for 
selected treatment outcomes in a subgroup of at least 360 subjects in USA and Germany 
using the questionnaire for the PAtient Preferences StUdy in InSomnia (PAUSe) developed 
by Idorsia.  
The questionnaire will present subjects with the following treatment outcomes: 
• Time to fall asleep 
• Total time asleep  
• Next day impairment 
• Dizziness/grogginess during the daytime 
• Abnormal thinking and behavioral changes 
• Falls in the night  
• Dependence 
The design of the DCE questionnaire was carried out in steps 1−3 below:  
1. Qualitative pilot (n = 24), where a mobile ethnography platform was used over a period 
of 10 days to collect patient experiences with insomnia in interactive sessions. This was 
followed by face-to-face interviews with patients to further discuss themes that 
emerged during the 10 days of interactive sessions (completed). 
2. Qualitative pilot (n = 24), where face-to-face interviews were conducted to ensure that 
the DCE outcomes and levels are associated with patients’ experiences with (and 
expectations for) insomnia, and that the proposed survey accurately describes these 
outcomes in an easily understandable manner (completed). 
3. Quantitative pilot (n = 200), where an online survey was conducted to elicit preferences 
from patients, using the PAUSe questionnaire. The data from the quantitative pilot will 
be used to update the priors of the Bayesian model and finalize the design of the sub-
study. 
This sub-study has the following objectives: 1) To describe the stated preferences of 
insomnia disorder subjects within a clinical trial by applying the DCE technique; 2) To 
describe the impact of treatment on the preferences of insomnia subjects; 3) To describe 
the relationship between demographic, disease characteristics, previous medical history 
and elicited preferences among insomnia subjects. 
In addition, the results of the sub-study may contribute to the construction of a 
patient-oriented benefit-risk assessment model.  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 46/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
3.2 Study design rationale 
3.2.1 Core study 
This is a multi-center, double-blind, randomized, placebo-controlled, parallel-group study. 
In accordance with the European Medicines Agency (EMA) guideline on medicinal 
products for the treatment of insomnia [EMA 2011] and the FDA guideline for the clinical 
evaluation of hypnotic drugs [FDA 1977], the study includes a placebo as a comparator to 
support the evaluation of the efficacy of each dose of ACT-541468. Moreover, it is an 
acceptable approach for a non-life-threatening condition. 
A parallel-group design is a well-established study design to assess efficacy and safety in 
medical conditions, recommended by health authorities [EMA 2011, FDA 1977]. 
The subjects will receive either a 50 or 25 mg daily dose of ACT-541468, or placebo DB 
study treatment. The doses to be tested for this study are based on a comprehensive set of 
data from Phase 1 and Phase 2 studies. A lower dose (10 mg), identified as the minimum 
effective dose in Phase 2, will be tested along with the 25 mg dose in another separate 
Phase 3 study (i.e., ID-078A302). All three doses selected for this program have a favorable 
benefit-risk profile based on data collected so far during Phase 1 and Phase 2 studies in 
adults and elderly subjects. This will allow appropriate investigation of the sustained effect 
of ACT-541468 on sleep parameters and next-day performance as well as an optimized 
characterization of the safety profile of ACT-541468 over a 3-month period, allowing full 
characterization of the benefit/risk ratio.  
The goal of the placebo run-in period is to increase the proportion of subjects in the clinical 
trial who will benefit due to taking active treatment, partly by reducing the placebo effect 
that will occur during the DB phase of the study and also aims to ensure sufficient stability 
of the subjects’ insomnia disorder and may reduce the impact of regression toward the 
mean.  
A run-out of 7 days is appropriate to assess withdrawal symptoms as it covers more than 5 
half-lives of ACT-541468. The duration of the run-out period is also compliant with the 
FDA guidance [FDA 1977], stating that a minimum of 3 nights of placebo withdrawal is 
necessary to assess withdrawal effects. To assess withdrawal symptoms, AEs and ECG 
abnormalities will be collected during the 7-day run-out period and subjects will complete 
the Benzodiazapine Withdrawal Symptom Questionnaire (BWSQ) at Visit 9 and Visit 10. 
One PSG night is planned after the first day of treatment discontinuation and the sleep diary 
completed in the 3 days following treatment discontinuation will allow assessment of 
rebound insomnia on objective and subjective parameters, respectively. Thus, this 7-day 
run-out period allows to capture long-term withdrawal effects, as well as shorter-term 
potential rebound symptoms. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 47/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
3.2.2 Patient preferences sub-study 
Measuring patient preferences as an input to healthcare decisions has its foundations in two 
fields related to behavioral decision making, namely ‘decision theory’ and ‘decision 
analysis’. Research by Pauker et al. demonstrated that it was feasible to use decision 
analysis to understand individual treatment choices which were complicated by multiple 
uncertainties and personal values [Pauker 1981]. Increased understanding of individual 
values and preferences is critical for a number of reasons. Firstly, it enables the 
development of patient-specific recommendations and reliable decision aids, which are 
helpful both for patients and for doctors in advising patients and their carers or families. 
Secondly, understanding of patients’ preferences is the basis for shared decision-making, 
which in turn encourages patient compliance and health outcomes [Bowling 2001]. Lastly, 
understanding of preferences for health outcomes allows the design of transparent health 
policies, and informs resource allocation in healthcare, as these preferences can inform the 
judgment of cost-effectiveness of different treatments, for different patients [Coyle 2001]. 
DCEs are a form of stated preference method used by economists to explore how people 
make trade-offs between an intervention’s outcomes. They involve participants responding 
to a number of survey questions, in which they choose between alternative interventions, 
each described by a level of performance against the outcomes that influence choices. DCE 
has its microeconomic foundation in random utility theory (RUT), assuming that products 
can be valued in terms of their constituent outcomes and that respondents act in a utility 
maximizing manner, making choices contingent upon the outcome levels described in the 
exercise [Clark 2014, Tervonen 2017]. Consequently, the choice data can be analyzed 
using econometric methods compatible with RUT, which estimate how participants’ utility 
is influenced by changes in intervention outcomes. DCEs are frequently used in healthcare 
to address a wide range of health policy-related concerns, including identifying the trade-
offs patients make when choosing between treatments, which can in turn be used to 
determine the probability that patients would prefer one treatment or another [Bridges 
2011, Clark 2014]. 
3.3 Study committees 
An IDMC has overall responsibility for safeguarding the interests of subjects by 
monitoring safety and efficacy data obtained in the study and making appropriate 
recommendations based on the reported data, thus ensuring that the study is being 
conducted to the highest scientific and ethical standards. The IDMC will be fully 
operational prior to enrollment of the first subject into the study. The composition and 
operation of the IDMC is described in the IDMC charter. 
An ISB will review and adjudicate in a blinded manner AESIs, i.e., narcolepsy-like 
symptoms 
(EDS, 
cataplexy 
and 
complex 
sleep 
behavior 
events 
including 
hallucinations/sleep paralysis), or suicide/self-injury. The composition and operation of the 
ISB is described in the ISB charter.  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 48/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
4 
SUBJECT POPULATION 
4.1 Subject population description 
This study will enroll adult and elderly (≥ 18 years), male and female subjects with 
insomnia disorder according to Diagnostic and Statistical Manual of Mental Disorders, 
Fifth Edition (DSM-5). For more details on inclusion and exclusion criteria, see 
Sections 4.3 and 4.4.  
Insufficient sleep quantity is defined in this study by self-reported history of ≥ 30 min to 
fall asleep, of wake time during sleep ≥ 30 min and of subjective TST (sTST) ≤ 6.5 h during 
the night. Those 3 self-reported parameters must be present on at least 3 nights per week 
for at least 3 months prior to the screening visit and on the sleep diary sleep data collected 
during the period between Visit 2 and Visit 3. They will also be validated by objective 
PSG-based criteria collected from the Visit 3 PSG nights spent in a sleep laboratory during 
the run-in. Poor Sleep Quality (SQ) is defined as an Insomnia Severity Index© (ISI©) score 
≥ 15 at screening.  
4.2 Rationale for the selection of the study population 
In this study, adult (18–64 years) and elderly (≥ 65 years) subjects with insomnia as defined 
by DSM-5 will be included [see definition in Section 1.1.1], unless subject’s insomnia is 
associated with major comorbidities, especially comorbid neurological, affective or 
psychiatric disorders (e.g., severe or uncontrolled depression, anxiety or dementia) that 
may interfere with the efficacy and safety in the trial. 
Elderly people exhibit a different sleep pattern to younger adults [Ohayon 2004] and the 
sensitivity of elderly and younger adults to the PD properties of a compound may therefore 
differ in the long term. Thus, randomization will be stratified by age in both pivotal studies 
to ensure that tested doses are given to a proportion of elderly subjects (i.e., 40% with age 
≥ 65 years) and to ensure balance of the treatment groups within strata is achieved. 
Concomitant pharmacological treatments for insomnia or concomitant CNS-related 
medications are not allowed in the study. This approach will favor optimizing the 
evaluation of the safety and efficacy profile of ACT-541468 by avoiding any potential 
confounding effects due to background co-medications. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject.  
Criteria assessed at Visit 1 
1. Signed informed consent prior to any study-mandated procedure. 
2. Male or female aged ≥ 18 years. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 49/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
3. Insomnia disorder according to DSM-5 criteria as follows: 
3.1 The predominant complaint is dissatisfaction with sleep quantity or quality, 
associated with one (or more) of the following symptoms: 
• Difficulty initiating sleep. 
• Difficulty maintaining sleep, characterized by frequent awakenings or 
problems returning to sleep after awakenings. 
• Early-morning awakening with inability to return to sleep. 
3.2 The sleep disturbance causes clinically significant distress or impairment in 
social, occupational, educational, academic, behavioral, or other important 
areas of functioning. 
3.3 The sleep difficulty occurs despite adequate opportunity for sleep. 
3.4 The insomnia is not better explained by and does not occur exclusively during 
the course of another sleep-wake disorder (e.g., narcolepsy, a breathing-related 
sleep disorder, a circadian rhythm sleep-wake disorder, a parasomnia). 
3.5 The insomnia is not attributable to the physiological effects of a substance (e.g., 
a drug of abuse, a medication). 
3.6 Coexisting mental disorders and medical conditions do not adequately explain 
the predominant complaint of insomnia. 
3.7  Self-reported history of all the following on at least 3 nights per week and for 
at least 3 months prior to Visit 1: 
3.7.1 ≥ 30 min to fall asleep, and 
3.7.2 Wake time during sleep ≥ 30 min, and 
3.7.3 sTST ≤ 6.5 h 
4. ISI© score ≥ 15. 
5. Ability to communicate well with the investigator, to understand the study 
requirements and judged by the investigator to be alert and oriented to person, place, 
time, and situation. 
Criteria assessed at Visit 3 
6. Meeting all the following sleep parameters on at least 3 nights out of 7 nights on the 
sleep diary completed at home between Visit 2 and Visit 3: 
6.1 
≥ 30 min to fall asleep, and 
6.2 
Wake time during sleep ≥ 30 min, and 
6.3 
sTST of ≤ 6.5 h 
7. Usual bedtime between 21:30 and 00:30, as reported on sleep diary completed between 
Visit 2 and Visit 3. 
8. Regular time in bed between 6 and 9 h, as reported on sleep diary completed between 
Visit 2 and Visit 3. 
9. Meeting all the following sleep parameters on the 2 PSG nights at Visit 3: 
9.1 
Mean LPS ≥ 20 min (with none of the two nights < 15 min), and 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 50/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
9.2 
Mean WASO ≥ 30 min (with none of the two nights < 20 min), and 
9.3 
Mean TST < 420 min 
Criterion assessed at Visit 1, Visit 2, and Visit 4 
10. For women of childbearing potential, the following is required: 
• Negative serum pregnancy test (Visit 1). 
• Negative urine pregnancy test (Visit 2, Visit 4). 
• Agreement to use the contraception scheme as required by the protocol from 
Screening up to at least 30 days after last study treatment intake. 
4.4 Exclusion criteria 
Criteria assessed at Visit 1 
1. Body mass index (BMI) below 18.5 or above 40.0 kg/m2. 
2. Any lifetime history of sleep-related breathing disorder, including chronic obstructive 
pulmonary disease and sleep apnea. 
3. Cognitive behavioral therapy (CBT) for any indication is allowed only if the CBT 
started at least 1 month prior to Visit 3 and the subject agrees to continue this CBT 
throughout the study. 
4. Self-reported usual daytime napping ≥ 1 hour per day, and ≥ 3 days per week. 
5. Acute or unstable psychiatric conditions (including but not restricted to anxiety 
disorder, major depression, bipolar disorder, schizophrenia, obsessive compulsive 
disorder or depression) that are diagnosed by the Mini International Neuropsychiatric 
Interview© (MINI©) or that require pharmacological treatment for these disorders. 
N.B.: subjects with a history of major depressive disorder currently without any 
symptoms and not requiring treatment are eligible. 
6. Mini Mental State Examination© (MMSE©) score < 25 in subjects ≥ 50 years. 
7. Shift work within 2 weeks prior to the screening visit, or planned shift work during the 
study. 
8. Travel across ≥ 3 time zones within 2 weeks prior to the screening visit, or planned 
travel across ≥ 3 time zones during study. 
9. Unstable medical condition, significant medical disorder or acute illness, ECG, 
hematology or biochemistry test results within 1 month prior to the screening visit, 
which, in the opinion of the investigator, could affect the subject’s safety or interfere 
with the study assessments. 
10. Treatment with CNS-active drugs prohibited by this protocol for 5 half-lives of the 
respective drug (or 2 weeks, whichever is longer) prior to Visit 1, including 
over-the-counter medication and herbal medicines. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 51/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
11. Diagnosis of alcohol or substance use disorder within 2 years prior to the screening 
visit or inability to refrain from drinking alcohol for at least 3 consecutive days. 
12. Heavy tobacco use (at least one pack of cigarettes a day or inability to refrain from 
smoking during the night).  
13. Caffeine consumption ≥ 600 mg per day or any caffeine consumption after 4 pm. 
14. Treatment with another investigational drug within 3 months prior to Visit 1, previous 
treatment with ACT-541468 or previous randomization in any trial involving 
ACT-541468. 
15. Known hypersensitivity or contraindication to drugs of the same class as the study 
treatment or to any excipients of the study drug formulation. 
16. Not able or willing to stop treatment with moderate or strong CYP3A4 inhibitors, or 
treatment with moderate or strong CYP3A4 inducers, within at least 1 week prior to 
Visit 2. 
17. Not able or willing to stop consumption of grapefruit, Seville (bitter) oranges or juices 
from those fruits within at least 1 week prior to Visit 2.  
Criteria assessed at PSG visit between Visit 1 and Visit 2 
18. Periodic limb movement disorder with arousal index (PLMAI) ≥ 15/h (assessed on the 
1st PSG night), restless legs syndrome, circadian rhythm disorder, REM behavior 
disorder, or narcolepsy.  
19. Apnea/hypopnea index (AHI) ≥ 15/h according to American Academy of Sleep 
Medicine criteria or event associated with blood oxygen saturation level by pulse 
oximetry (SpO2) < 80%, as assessed on the 1st PSG night. 
Criteria assessed at Visit 1 and Visit 3 
20. AST and/or ALT > 2 × ULN and/or direct bilirubin > 1.5 × ULN. 
21. Severe renal impairment: known or defined as estimated creatinine clearance 
< 30 mL/min/1.73m2, according to the 4-variable Modification of Diet in Renal 
Disease formula. 
22. Hematology or biochemistry test results deviating from the normal range to a clinically 
relevant extent as per judgment of the investigator. 
23. Any of the following conditions related to ECG abnormalities: 
• A prolonged QT interval corrected with Bazett’s formula (QTcB) or QT interval 
corrected with Fridericia’s formula (QTcF) (greater than 450 ms). If QTcB or QTcF 
is greater than 450 ms on the first ECG, a second ECG recording will be performed 
after at least 30 min. If QTcB or QTcF is greater than 450 ms on the second ECG, 
the subject is not eligible.  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 52/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
• A history of additional risk factors for torsade de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
• ECG with clinically significant atrioventricular (AV) conduction disturbance (e.g., 
second- or third-degree AV block), sick sinus syndrome, bradycardia (resting pulse 
< 40 bpm), or accessory bypass tract (e.g., Wolff-Parkinson-White). 
Criterion assessed at Visit 1, Visit 2, Visit 3 and Visit 4 
24. Any of the following conditions related to suicidality: 
• Any suicidal ideation with intent, with or without a plan, at screening, i.e., 
answering “Yes” to questions 4 or 5 on the suicidal ideation section of the lifetime 
(Visit 1) and visit (Visit 2, Visit 3, Visit 4) version of the C-SSRS©. 
• History of suicide attempt on the suicidal behavioral section of the lifetime version 
of the C-SSRS© (Visit 1). 
Criteria assessed at Visit 1, PSG visit between Visit 1 and Visit 2, Visit 2, Visit 3 and 
Visit 4 
25. For female subjects: pregnant, lactating or planning to become pregnant during 
projected duration of the study. 
26. Positive urine drug test (for benzodiazepines, barbiturates, cannabinoids, opiates, 
amphetamines, phencyclidine or cocaine) or presence of alcohol in exhaled breath as 
detected by breathalyzer test. 
4.5 Criteria for women of childbearing potential 
4.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential unless she meets at least one of the 
following criteria: 
• Previous bilateral salpingectomy, bilateral salpingo-oophorectomy or hysterectomy, 
• Postmenopausal (defined as 12 consecutive months with no menses without an 
alternative medical cause [ICH M3 definition]), 
• Premature ovarian failure (confirmed by a specialist), XY genotype, Turner 
syndrome, uterine agenesis, 
The reason for not being of childbearing potential will be recorded in the electronic Case 
Report Form (eCRF). 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 53/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
4.5.2 Acceptable methods of contraception 
For women of childbearing potential [see definition in Section 4.5.1], any of the following 
acceptable birth control methods are required: 
• Combined (estrogen- and progestogen-containing) hormonal contraception associated 
with inhibition of ovulation: 
– Oral 
– Intravaginal 
– Transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulation: 
– Oral 
– Injectable 
– Implantable 
• Intrauterine device 
• Intrauterine hormone-releasing system 
• Vasectomized male partner with documented post-vasectomy confirmation of the 
absence of sperm in the ejaculate.  
• Bilateral tubal occlusion (tubal occlusion / ligation at least 6 weeks prior to screening). 
• Sexual abstinence from intercourse with a male partner only when this is in line with 
the preferred lifestyle of the subject and if locally accepted as a reliable method of 
contraception. 
Rhythm methods, the use of a female condom, cervical cap, diaphragm or the partner’s use 
of a condom are not considered acceptable methods of contraception for this study. 
The method of birth control used must be recorded in the hospital charts.  
To ensure compliance, the study personnel must remind women of childbearing potential 
at each visit to use the methods of contraception defined for this study. The reminders must 
be documented in the hospital chart. 
5 
TREATMENTS 
5.1 Study treatment 
The study drugs are ACT-541468 and ACT-541468-matching placebo. 
5.1.1 Investigational treatment and matching placebo: Description and rationale 
ACT-541468 or matching placebo will be administered as tablets, orally, once daily in the 
evening during the DB treatment period. ACT-541468-matching placebo will be 
administered as well during the run-in and the run-out period. At home, the study treatment 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 54/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
will be taken at bedtime to mimic real life drug intake habits and at the site visits, the study 
treatment will be administered at least 2 h after the last meal and approximately 30 min 
before lights off to avoid a potential delay in ACT-541468 effects when administered with 
food which might bias objective endpoints. 
ACT-541468 is supplied by Idorsia as film-coated tablets at strengths of 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 when taken at home and by the site personnel in 
the patient’s chart and the eCRF during the PSG nights. At Visit 2, the date of single-blind 
placebo treatment dispensing will also be recorded in the patient’s chart and the eCRF. 
5.1.2.1 Study treatment administration at site visits and at home 
During the PSG visits at the site, 1 tablet of study treatment will be taken at least 2 h after 
the last meal and approximately 30 min (± 5 min) before lights off, in the evening of each 
PSG night. 
At home, the tablet will be taken at bedtime.  
5.1.2.2 Missed doses 
If one or more doses have been missed, the next dose must be taken in the evening of the 
following day. 
5.1.3 Treatment assignment 
Each of the study sites will be assigned a unique site number and every subject will receive 
a unique subject number which identifies the subject throughout the study. 
At Visit 1, after the ICF has been signed, the investigator/delegate will contact the IRT 
system to get a subject number allocated to the subject. 
During the run-in and run-out periods, subjects will receive single-blind placebo treatment. 
At Visit 2 and Visit 9, the investigator/delegate contacts the IRT system to assign the 
treatment wallet number. 
On the day of randomization (Visit 4), after having verified that the subject meets all 
inclusion criteria and none of the exclusion criteria, the investigator/delegate contacts the 
IRT to randomize the subject. The IRT assigns the treatment wallet number, which matches 
the treatment arm assigned per the randomization list. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 55/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
Subjects will be randomized in a 1:1:1 ratio to 25 or 50 mg of ACT-541468, or placebo, 
respectively (i.e., approximately 300 subjects per arm). Treatment allocation will be 
stratified by age into 2 categories: < 65 and ≥ 65 years. 
The randomization list is generated by an independent Contract Research Organization 
(CRO) and kept strictly confidential. 
5.1.4 Blinding 
5.1.4.1 Run-in and run-out periods 
During run-in and run-out periods, placebo treatment will be administered in a single-blind 
fashion. The subjects will remain blinded to the study treatment until the end of the 
ID-078A303 extension study. Subjects must not be informed about the change in treatment 
at the end of run-in and at the beginning of run-out. The investigator and study personnel, 
the monitors, Idorsia personnel, and CROs involved in the conduct of the study will be 
unblinded to the treatment provided during the run-in/run-out periods.  
5.1.4.2 Double-blind treatment period 
From Randomization until EODBT, the study will be performed in a DB fashion. The 
subjects, the investigator and site personnel, and the monitors will remain blinded to the 
study treatment until the end of the ID-078A303 extension study. Idorsia personnel 
responsible for clinical study supply distribution will monitor the depot stock levels in 
collaboration with the study team based on recruitment data and site activation. Site stocks 
will be maintained according to the settings in the IRT system.  
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to the IRT vendor and sponsor authorized persons (e.g., 
Quality assurance, Systems and compliance personnel, Bioanalytical Laboratory group) 
the Independent Statistical Analysis Center (ISAC) and the IDMC, who are not involved 
in the conduct of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment wallets will be packaged in the same way. 
To minimize the possibility of systematic unblinding, the results of PK data will not be 
communicated to the investigator and site study personnel, the subjects and Clinical 
Research Associates (CRAs) until the end of the ID-078A303 extension study. Results will 
be transferred by the sponsor Bioanalytical Laboratory group (for the PK data) to the 
sponsor and CRO personnel involved in the conduct of the study only after database lock. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 56/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
5.1.5 Unblinding 
5.1.5.1 Unblinding for final analyses 
Randomization information will be made available for data analysis only after database 
lock, in accordance with Idorsia Quality System (QS) documents. 
5.1.5.2 Unblinding for IDMC review 
An ISAC, not otherwise involved in the design, conduct and analysis of the study, will 
have access to the randomization code in order to prepare unblinded reports for IDMC 
review meetings during the course of the trial. The randomization code will be made 
available to the ISAC in accordance with the sponsor’s QS documents. 
5.1.5.3 Unblinding for suspected unexpected serious adverse reactions 
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Idorsia Global Drug Safety will request the unblinding of the 
treatment assignment. The treatment assignment will not be communicated to site 
personnel or to the Idorsia Clinical Trial Team. Unblinded SUSAR information will be 
provided to respective health authorities and IECs/IRBs only. SUSARs will be reported to 
investigators in a blinded fashion. 
5.1.5.4 Emergency procedure for unblinding 
The investigator, study personnel and Idorsia personnel must remain blinded to the 
subject’s treatment assignment. The identity of the study treatment may be revealed only 
if the subject experiences a medical event, the management of which would require 
knowledge of the blinded treatment assignment. In this case, the investigator can receive 
the unblinded treatment assignment through the IRT. In these situations, the decision to 
unblind resides solely with the investigator. Whenever possible, and if it does not interfere 
with (or does not delay) any decision in the best interest of the subject, the investigator is 
invited to discuss the intended unblinding with Idorsia personnel. 
The occurrence of any unblinding during the study must be clearly justified and explained 
by the investigator. In all cases, Idorsia personnel must be informed of the unblinding 
procedure as soon as possible before or after the unblinding. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF. 
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. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 57/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.6.1 Study treatment packaging and labeling 
Study treatment (including placebo during run-in and run-out period) is provided as tablets 
and supplied in wallets. All pack types are childproof wallets containing 35 tablets. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.6.2 Study treatment distribution and storage 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label (i.e., 8–25 °C). Temperature measurement devices 
for study treatment storage area are required.  
5.1.6.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period up to the next 
scheduled visit. Subjects are asked to return all used, partially used, and unused study 
treatment wallets at each visit. If a treatment wallet is lost or damaged, a replacement wallet 
can be requested through the Treatment Replacement module of the IRT system. The 
protocol-mandated study treatment dispensing procedures may not be altered without prior 
written approval from Idorsia. In exceptional circumstances (e.g., if the subject lost the 
study treatment between two visits, or if the subject is unable to return to the site due to a 
medical emergency / hospitalization at another hospital), unscheduled dispensing and 
delivery of study treatment may occur outside of a scheduled visit. An accurate record of 
the date and amount of study treatment dispensed to each subject must be available for 
inspection at any time. 
5.1.6.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without prior 
written approval from Idorsia. On an ongoing basis and/or on termination of the study, the 
CRA will collect used and unused treatment wallets, which will be sent to the warehouse, 
where Idorsia personnel or a deputy will check treatment reconciliation. In certain 
circumstances, used and unused study treatment containers may be destroyed at the site 
once study treatment accountability is finalized and has been checked by Idorsia personnel 
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 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 58/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
dispensing further study treatment. It is to be recorded by site personnel on the study 
treatment dispensing and accountability log and in the eCRF, and checked by the CRA 
during site visits and at the end of the study. The study treatment accountability log in the 
eCRF will include at least the following information for each study treatment unit (i.e., 
wallet) dispensed to the subject: 
• Dispensed subject wallet number. 
• Date and number of tablets dispensed. 
• Date and number of tablets returned. 
All study treatment supplies, including partially used or empty wallets must be retained at 
the site for review by the CRA. 
If the subject forgets to bring the remaining study treatment to a study visit, he/she must be 
instructed to not take any tablets from the remaining study treatment wallet and to return it 
at the next visit. 
5.1.7.2 Study treatment compliance 
Study treatment compliance is based on study treatment accountability. Subjects also report 
their compliance in the eDiary every morning. Study treatment compliance for the Run-in 
period, the DB treatment period (Day 1 to EODBT) and the Run-out period will be 
separately calculated for each of these periods by site personnel using the below formula 
and entered in the eCRF: 
Compliance = [(number of tablets dispensed – number of tablets returned) / total number 
of tablets that needs to be taken during the period*] × 100 
* The period is defined as number of days during which study treatment should be taken as per actual visit 
dates. 
During the DB treatment period (Day 1 to EODBT), compliance is expected to be at least 
70%. Compliance values below this will be considered as a protocol deviation which will 
be reported in the Clinical Trial Management System by the CRA. The investigator must 
discuss the non-compliance with the subject to clarify the reasons and to take appropriate 
actions to avoid re-occurrence. This discussion and its outcome must be documented in the 
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. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 59/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
If study treatment is interrupted by the subject for any reason, she/he must immediately 
inform the investigator. 
Interruptions of study treatment must be kept as short as possible.  
Study treatment interruptions must be recorded in the eCRF. 
5.1.9 Premature discontinuation of study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Idorsia personnel. The main reason for discontinuation must be 
documented in the eCRF and in the subject’s medical charts (e.g., AE, lack of efficacy). 
A subject has the right to prematurely discontinue study treatment at any time, without any 
justification, by withdrawal from study treatment only or by withdrawal from any further 
participation in the study (i.e., premature withdrawal from the study [see Section 8.2]). 
Although a subject is not obliged to give his/her reason for prematurely withdrawing from 
the treatment or the study, it is recommended that the investigator makes a reasonable effort 
to ascertain the reason(s), while fully respecting the subject’s rights. 
The investigator must discontinue study treatment for a given subject if, on balance, he/she 
believes that continued administration would be contrary to the best interests of the subject. 
Study-specific criteria for discontinuation of study treatment are described in 
Section 5.1.10. 
A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until the planned EOS (Day 115), provided that the 
subject’s consent for this limited participation in the study has not been withdrawn. The 
subject is recommended to return for safety assessments [see Table 1] within one week of 
his/her last DB study treatment intake (N.B., next day residual assessments will only be 
performed if the subjects can be assessed within 24 h of last DB study drug intake). All 
subjects withdrawn from study treatment are encouraged to follow planned study 
procedures (e.g., visits, sleep diary and questionnaire completion) until EOS. In this case, 
the run-out period (including Visit 9 and Visit 10) will not be performed, and subjects will 
directly enter the follow-up period after Visit 8 (considered as EOT in the event of 
premature discontinuation). The phone call will be performed as planned 30 days (+ 7 days) 
later, at Visit 11. This will decrease the amount of missing data which is important from a 
study integrity perspective. Subjects who prematurely discontinue study treatment or the 
study for any reason will not be replaced. 
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study and 
no further assessment will be collected after informed consent withdrawal. Subjects who 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 60/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
die or are lost to follow-up are also considered as withdrawn from the study. Withdrawal 
from the study and follow-up medical care of subjects withdrawn from the study are 
described in Sections 8.2 and 8.4, respectively. 
5.1.10 Study-specific criteria for interruption / premature discontinuation of study 
treatment 
At each visit, if there are signs of any AEs, the investigator must evaluate whether 
continuing treatment at home is compatible with the subject’s lifestyle and does not affect 
the subject’s safety. The investigator has the responsibility to decide whether it is safe for 
the subject to continue treatment in the study. 
If a subject becomes pregnant while on study drug, study drug must be permanently 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. 
Female subjects participating in the study and wishing to become pregnant during the study 
must discontinue study drug and continue contraception for at least 1 month.  
5.2 Previous and concomitant therapy 
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to signing ICF. 
A therapy that is study-concomitant is any treatment that is ongoing or initiated after 
signing of informed consent, or initiated up to EOS. 
A therapy that is study treatment-concomitant is any treatment that is either ongoing at the 
start of DB study treatment or is initiated during the DB treatment period until 1 day after 
the last dose of DB treatment. 
5.2.2 Reporting of previous/concomitant therapy in the eCRF 
The use of all study-concomitant therapy (including contraceptives and traditional and 
alternative medicines, e.g., plant-, animal-, or mineral-based medicines) will be recorded 
in the eCRF. Previous therapy must be recorded in the eCRF if discontinued less than 
30 days prior to signing of the ICF. The generic name, start/end dates of administration (as 
well as whether it was ongoing at start of treatment and/or EOS), route, dose, and indication 
will be recorded in the eCRF. 
5.2.3 Allowed concomitant therapy 
CBT consists of a combination of cognitive therapy, behavioral, and educational 
interventions and is ideally delivered by a specially trained physician or a qualified 
psychotherapist. Given the shortage of certified sleep therapists, access to CBT is limited, 
particularly in Europe [Pigeon 2010, Schutte-Rodin 2008]. CBT for any indication is only 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 61/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
allowed if the treatment started at least 1 month prior to Visit 3 and the subject agrees to 
continue this CBT throughout the study. Details about subject’s CBT or reason why CBT 
was not considered by the subject must be recorded in the eCRF. Initiation of CBT during 
the course of the study is not allowed. 
Therapies considered necessary for the subject’s well-being and not categorized as 
prohibited concomitant medications can be used in this study. However, initiation of new 
medication is to be discouraged and concomitant medication will preferably not be changed 
during the study. Non-sedating antihistamines (cetirizine, loratadine, desloratadine, 
fexofenadine and levocabastine) may be used a maximum of twice weekly for allergic 
symptoms. Inhaled or nasal corticosteroids are permitted. 
5.2.4 Forbidden concomitant therapy 
Subjects must not be withdrawn from medically necessary therapies in order to participate 
in the study. They must rather be considered as non-eligible to the study, both due to their 
medical condition and due to their requirement for these therapies. Several forbidden 
therapies are associated with excluded medical disorders (e.g., cardiovascular disease, 
Parkinson’s disease, stroke). 
The following concomitant therapies are forbidden during the study: 
• Treatment with another investigational drug until EOS. 
• Study-prohibited CNS-active medications from for 5 half-lives of the respective drug 
(but at least 2 weeks) prior to Visit 1 and until 24 hours after EOT [see Appendix 3]. 
• Treatment with moderate or strong CYP3A4 inhibitors, or moderate or strong CYP3A4 
inducers until 24 hours after EOT [see Appendix 3].  
5.2.5 Forbidden concomitant diet and activities 
The following activities and diet are forbidden during the study: 
• Consumption of grapefruit, Seville (bitter) oranges or juices from those fruits from 
1 week prior to Visit 2 until 24 h after the end of run-out period. 
• Caffeine consumption ≥ 600 mg caffeine/day or consumption of any caffeine after 4 pm 
(after 2 pm on PSG nights) [see Appendix 2]. 
• Alcohol consumption [see Appendix 1] 
− > 2 drinks a day 
− less than 3 hours before going to bed on non-PSG nights 
− within 24 hours prior to PSG night and during all PSG visits 
• Heavy tobacco use (at least one pack of cigarettes a day or inability to refrain from 
smoking during the night).  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 62/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
• Driving or engaging in activities that require operating vehicles or dangerous 
machinery within 8 hours following study treatment intake for adult and elderly 
subjects. 
6 
STUDY ENDPOINTS 
The ID-078A301 trial is designed to assess safety and efficacy of ACT-541468 on 
objective and subjective endpoints.  
6.1 Primary efficacy endpoints 
The primary efficacy endpoints of this study are defined as: 
• the change from baseline to Month 1 in WASO (sleep maintenance) 
• the change from baseline to Month 3 in WASO 
• the change from baseline to Month 1 in LPS (sleep onset) 
• the change from baseline to Month 3 in LPS  
Baseline is defined as the mean of the 2 PSG nights at Visit 3. Month 1 and Month 3 are 
defined as the mean of the 2 PSG nights at Visit 6 and Visit 8, respectively. 
LPS (min) is the time from start of recording to the beginning of the first continuous 
20 epochs (i.e., 10 min) scored as non-awake, i.e., epochs scored as either sleep stage 
1 (S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep [SWS]) or REM, as determined 
by PSG.  
WASO is the time (min) spent awake after onset of persistent sleep until lights on, as 
determined by PSG. 
6.2 Secondary endpoints 
The secondary efficacy endpoints of this study are defined as: 
• the change from baselinea to Month 1b in sTST 
• the change from baselinea to Month 3c in sTST  
• the change from baselinea to Month 1b in Insomnia Daytime Symptoms and Impacts 
Questionnaire (IDSIQ) sleepiness domain score 
• the change from baselinea to Month 3c in IDSIQ sleepiness domain score  
a Baseline is the mean value based on the screening sleep diary / IDSIQ entries performed 
at home in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 6. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 63/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 8. 
6.3 Other efficacy endpoints 
• Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in TST. 
• Change from baselinea to Month 1b and Month 3c in subjective WASO (sWASO). 
• Change from baselinea to Month 1b and Month 3c in subjective Latency to Sleep Onset 
(sLSO). 
• Change from baselinea to Month 1b and Month 3c in IDSIQ scores (i.e., Total score; 
alert/cognition and mood domain scores). 
a Baseline is the mean value based on the screening sleep diary / IDSIQ entries performed 
at home in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 8. 
6.4 Exploratory endpoints 
For each variable, multiple aspects will be considered in the analysis, in particular changes 
from baseline at different time points.  
• WASO over time (by hour of the night and by quarter of the night) on each PSG night. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in SQ. SQ is the sleep quality 
as determined by scores on the VAS (mm) in the morning. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in duration of TST in each 
sleep stage (S1, S2, SWS and REM).  
• Change from baseline (Visit 3) to Month 1 and Month 3 in sleep architecture assessed 
as percentage of TST in each sleep stage (S1, S2, SWS, and REM) over the whole 
night, and for each quarter of the night.  
• Change from baseline (Visit 3) to Month 1 and Month 3 in mean numbers of shifts from 
S2, SWS or REM to S1 or awake. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in ISI© scores. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in mean number of awakenings 
(defined as the number of awakenings between first epoch and last epoch not scored 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 64/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
wake) as measured by PSG (will be summarized for the whole night, for each quarter 
of the night, and for each hour of the night). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in mean number of 
self-reported awakenings. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in sWASO. 
• Change from baseline (Visit 3) to Month 1 and Month 3 in Sleep Efficiency (defined 
as 100 × ([TST / time in bed]). 
• Change from baseline (Visit 1) to Month 1 and Month 3 in Patient Global Assessment 
of Disease Severity (PGA-S) scores (daytime symptoms). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in Patient Global Impression 
of Change (PGI-C) scores (daytime symptoms). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in PGI-C scores (night-time 
symptoms). 
• Change from baseline (Visit 3) to Month 1 and Month 3 in Patient Global Impression 
of Severity (PGI-S) scores (night-time symptoms). 
6.5 Safety endpoints 
In addition to the standardized collection of AEs, safety data specific to insomnia and its 
treatment will be assessed as follows:  
• Withdrawal effects (physical dependence) upon treatment discontinuation will be 
assessed based on the changes from last assessment on DB treatment (Visit 8, 
2nd morning) to run-out period in the BWSQ total score (Visit 9 and Visit 10), the 
occurrence of relevant AEs and marked ECG abnormalities. 
• Rebound insomnia will be assessed based on objective sleep parameters (WASO, LPS 
and TST) at Visit 9 as compared to Visit 3. It will also be assessed using subjective 
sleep parameters (sWASO, sLSO and sTST) from run-out period as compared to 
baseline. 
• Next-day residual effect will be assessed based on changes from baseline (Visit 3) to 
Month 1 and Month 3 in: 
− Coding sub-test© 
− SDS© 
− Scores on the VAS (mm) 
• SAEs up to 30 days after DB study treatment discontinuation or until enrollment into 
the extension study. 
• TEAEs up to 30 days after DB study treatment discontinuation or until enrollment into 
the extension study. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 65/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
• AEs leading to premature discontinuation of the DB study treatment. 
• AEs of special interest after adjudication by ISB: 
− narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep behavior 
events including hallucinations/sleep paralysis)  
− suicide/self-injury  
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8) in vital signs 
(mean of the 2 PSG nights in systolic and diastolic blood pressure [BP] and pulse rate). 
• Change from baseline (Visit 1) to Month 3 (Visit 8) in body weight. 
• Marked ECG abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 3 (Visit 8) and the end of the run-out period 
(Visit 10) in ECG parameters. 
• Marked laboratory abnormalities on DB study treatment. 
• Change from baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8) in laboratory 
parameters. 
• Occurrence of suicidal ideation and/or behavior on DB study treatment based on 
C-SSRS©. 
6.6 Pharmacokinetic endpoints 
ACT-541468 plasma concentrations 9–10 h post-dose (morning after the second PSG night 
at Visit 6 and Visit 8) or in the event of excessive sleepiness based on the investigator’s 
opinion. 
6.7 Patient preferences exploratory endpoints 
The preferences resulting from the choice sets collected in the third section of the PAUSe 
questionnaire will be used to derive the following endpoints: 
• Partial value of each treatment outcome at Visit 4 and Visit 8. 
• Partial value function and weights for each treatment outcome at Visit 4 and Visit 8. 
• Total value score for each treatment at Visit 4 and Visit 8. 
• Change in total value score for each treatment from Visit 4 to Visit 8.  
• Probability that patients would prefer a treatment at Visit 4 and Visit 8. 
• Change in probability that patients would prefer a treatment from Visit 4 to Visit 8. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits 
The study visits are listed in Table 1. Screening will last 20 to 31 days. For all visits during 
the DB treatment phase, the subjects must be seen on the designated day and within a ± 2 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 66/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
days visit window in comparison with randomization (Visit 4). A follow-up safety 
telephone call must be performed 30 days (+ 7 days) after last DB study treatment intake 
if the subject is not enrolled in the ID-078A303 extension study. 
7.1.1 Screening 
At Visit 1 subjects will discuss and sign the ICF, and will undergo initial eligibility 
assessments. The date on which the ICF is signed corresponds to the date of the screening 
visit (Visit 1). 
It is the responsibility of the investigator/delegate (the latter may or may not be a physician 
according to local legal requirements, in the EU it must be a physician) to obtain written 
informed consent from each subject participating in this study after adequate face-to-face 
explanation of the objectives, methods, and potential risks of the study. The subjects who 
agree to participate in the study and the investigator/delegate must sign the ICF prior to 
performing any study-related assessment or procedure.  
Subjects who are in the screening phase when the enrollment target has been met may still 
be randomized. 
It is not permitted to re-screen subjects. 
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., AE), appropriate assessments will be performed 
based on the judgment of the investigator. Results of ECGs and laboratory assessments, 
and changes in concomitant treatment will be recorded in the eCRF. After an unscheduled 
visit, the regular scheduled study visits must continue according to the planned visit and 
assessment schedule [Table 1]. 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 67/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
Table 1 
Visit and assessment schedule 
 
SCREENING PHASE (20–31 days) 
TREATMENT PHASE (82–86 days) 
FU PHASE (30–37 days) 
 
Screening period  
(7–18 days) 
Run-in period  
(13–24 days) 
Double-blind treatment (84 days ± 2 days13) 
Run-out period 
(7 days + 2 days) 
FU period  
(23 days + 
7 days)17 
Visit 
1 
 
2 
3 
416 
5 
(phone call) 
6 
7 
8 
9 
10 
11 
(phone call) 
Target Study Days 
 
 
 
1st night 
2nd night 
1 
7 to 14 
1st night 13 
27/28 
2nd night 
28/29 
55 
1st night 13 
83/84 
2nd night 
84/85 
85/86 
92 
(+ 2 days) 
115 
(+ 7 days) 
Evening(PM) /  
Morning (AM) 
 
PM 
AM 
 
PM 
AM 
PM 
AM 
 
 
PM 
AM 
PM 
AM 
 
PM 
AM 
PM 
AM 
PM 
AM 
 
 
Informed consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and exclusion 
criteria 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
Concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X6 
X 
X 
X 
X 
Physical examination, body 
weight and height 9 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
 
Vital signs 
X 
 
X 
X 
 
X 
 
X 
X 
 
 
X 
 
X 
X 
 
X 
 
X6 
 
X 
X 
 
12-lead ECG 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
X 
 
Hematology, blood 
chemistry 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
X 
 
 
 
X6 
 
 
 
 
Pregnancy test 1 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
X6 
 
 
X 
 
Urine drug screen 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
Alcohol test 
X 
X 
 
X 
X 
 
X 
 
X 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
X 
 
PK sampling 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
PSG 
 
X4 
 
X 
X 
 
 
X 
X 
 
X 
X 
X 
 
 
ISI© 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X6 
 
 
 
 
IDSIQ 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Sleep diary (incl. VAS)2 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Neurological exam8 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
C-SSRS© 7 
X 
 
 
X 
 
 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
X6 
 
X 
X 
 
Coding sub-test© 7 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X15 
 
X 
 
 
ESS© 
X 
 
 
X 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X 
 
 
X 
 
SDS© 7 
 
 
 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
 
X 
 
X6 
 
X 
 
 
BWSQ7 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
 
X6 
 
X 
X 
 
MINI© 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 68/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
SCREENING PHASE (20–31 days) 
TREATMENT PHASE (82–86 days) 
FU PHASE (30–37 days) 
 
Screening period  
(7–18 days) 
Run-in period  
(13–24 days) 
Double-blind treatment (84 days ± 2 days13) 
Run-out period 
(7 days + 2 days) 
FU period  
(23 days + 
7 days)17 
Visit 
1 
 
2 
3 
416 
5 
(phone call) 
6 
7 
8 
9 
10 
11 
(phone call) 
Target Study Days 
 
 
 
1st night 
2nd night 
1 
7 to 14 
1st night 13 
27/28 
2nd night 
28/29 
55 
1st night 13 
83/84 
2nd night 
84/85 
85/86 
92 
(+ 2 days) 
115 
(+ 7 days) 
Evening(PM) /  
Morning (AM) 
 
PM 
AM 
 
PM 
AM 
PM 
AM 
 
 
PM 
AM 
PM 
AM 
 
PM 
AM 
PM 
AM 
PM 
AM 
 
 
MMSE©10 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PGA-S11 
X 
 
 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PGI-C11 daytime symptoms 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PGI-C11 night-time 
symptoms 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
PGI-S11 
X 
 
 
X 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
 
Patient Preferences14 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
Contact IRT 
X 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Randomization12 
 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Dispense IMP wallet(s) 
 
 
 
X 
 
 
 
 
X 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
Study drug intake3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
SAEs and AEs 5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
1. For women of childbearing potential, serum test at V1 and V8 and urine test at V2, V4, V6, V7, V10. 2. The hand-held device is handed out to the subject and completed at home daily from V1 to V10. 
3. Daily placebo single-blind treatment during run-in and run-out periods, and daily double-blind study treatment during treatment phase. 4. The 1st PSG can be performed any nights between V1 and V2. It 
includes assessment of AHI, PLMAI, SpO2. 5. SAE and AE reporting and follow-up: all SAEs and AEs from signed ICF up to EOS. 6. In the event of permanent study treatment discontinuation, safety 
assessments of V8 are recommended to be performed within 7 days of last DB study drug intake. If the subject remains in the study, he or she will perform study visits and assessments as planned until EOS 
(Day 115), without the run-out period (including Visit 9 and Visit 10). 7. Approximately 30 to 60 minutes after PSG lights on. 8. Performed approximately 1 hour after lights on. 9. Height only at V1. 10. For 
elderly subjects only. 11. PGA-S, PGI-S and PGI-C (daytime symptoms and night-time symptoms questionnaires) will be completed at home once a week between V4 and EODBT. 12. Randomization will 
take place after all the V4 assessments have been performed and provided the subject fulfills all the eligibility criteria. 13. A time window of ± 2 days is allowed at each visit vs randomization visit (V4). 
14. Patient preferences sub-study (PAUSe) available for sites in Germany and in the USA only. 15. In the event of permanent study treatment discontinuation, next day residual assessment of V8 will only be 
performed if the subjects can be assessed within 24 h of last DB study drug intake. 16. Three working days are required between V3 and V4 to obtain eligibility confirmation regarding objective sleep parameters. 
17. If Run-out period exceeded by 2 days, then the follow-up period can only be exceeded by a maximum of 5 days.  
 
AE = adverse event; AHI = apnea/hypopnea index; BWSQ = Benzodiazepine Withdrawal Symptom Questionnaire; C-SSRS© = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EODBT = 
End-of-Double-Blind-Treatment; EOS = End-of-Study; ESS© = Epworth Sleepiness Scale©; FU = Follow-up; ICF = Informed Consent Form; IDSIQ = Insomnia Daytime Symptoms and Impacts Questionnaire; 
IMP = Investigational Medicinal Product; IRT = Interactive Response Technology; ISI© = Insomnia Severity Index©; MINI© = Mini International Neuropsychiatric Interview©; MMSE© = Mini Mental State 
Examination©; PAUSe = PAtient Preferences StUdy in InSomnia; PGA-S = Patient Global Assessment of Disease Severity; PGI-C = Patient Global Impression of Change (daytime symptoms and night-time 
symptoms); PGI-S = Patient Global Impression of Severity; PK = pharmacokinetic; PLMAI = periodic limb movement with arousal index; PSG = polysomnography; SAE = serious adverse event; SDS© = 
Sheehan Disability Scale©; SpO2 = oxygen saturation by pulse oximetry; V = Visit; VAS = visual analog scale(s). 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 69/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
7.2 Study assessments 
The mandatory study assessments are listed in Table 1.  
All study assessments are performed by qualified study personnel (medical, nursing, or 
specialist technical personnel), and are recorded in the medical history and eCRF unless 
otherwise specified. Study assessments performed during unscheduled visits will also be 
recorded in the eCRF. 
The following order of assessments is recommended:  
• In the evening before a PSG night: 
– Urine drug screen and alcohol test 
– IDSIQ 
– Evening questionnaire in sleep diary (including VAS) 
– PGA-S daytime symptoms (in the first evening at Visits 3, 6 and 8) 
– PGI-C daytime symptoms (in the first evening at Visits 3, 6 and 8) 
– Recording of concomitant medications 
– AEs and SAEs 
– Study drug intake (30 minutes before lights off) 
• In the morning after a PSG night (subject fasted): 
– Blood samples (hematology and blood chemistry, only second morning at 
Visits 3, 6 and 8; PK, only second morning at Visits 6 and 8.  
• In the morning after a PSG night and after completion of normal morning routine 
(e.g., using the bathroom, eating breakfast): 
– Vital signs  
– C-SSRS© (only second morning at Visits 3, 6 and 8) 
– Coding sub-test© 
– ISI© (only second morning at Visits 3, 6 and 8) 
– ESS© 
– SDS© 
– BWSQ (only second morning at Visits 3, 6, 8 and 9) 
– Morning questionnaire in sleep diary (including VAS) 
– PGI-S night-time symptoms (in the first morning at Visits 3, 6 and 8) 
– PGI-C night-time symptoms (in the first morning at Visits 3, 6 and 8) 
– Recording of concomitant medications 
– AEs and SAEs 
– Neurological examination 
– 12-lead ECG (only second morning at Visits 3and 8) 
– Patient preferences questionnaire PAUSe (only second morning at Visit 8) 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 70/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
The following assessments will be analyzed by an external provider (results will be 
transferred to the Idorsia database and to the investigators): 
• Laboratory parameters 
• ECG parameters 
• PSG recordings 
• Questionnaires completed using a hand-held device (listed below). 
If the Principal Investigator (PI) delegates any study procedure/assessment for a subject, to 
an external facility, he/she must inform Idorsia to whom these tasks are delegated. The set-
up and oversight must be agreed upon with Idorsia. The supervision of any external 
facilities remains the responsibility of the PI. 
Calibration certificates / evidence of equipment maintenance for the below-listed 
equipment used to perform study assessments must be available prior to the screening of 
the first subject. Calibration certificates of other equipment must be available as per local 
requirements: 
• Temperature measurement devices for study treatment and sample storage area. 
• Polysomnographic device. 
Use of hand-held and tablet devices 
Subjects will be required to complete the following questionnaires on a hand-held device:  
Epworth Sleepiness Scale© (ESS©), ISI©, SDS©, BWSQ, IDSIQ, PGA-S daytime 
symptoms, PGI-C daytime and night-time symptoms, PGI-S night-time symptoms, sleep 
diary (including VAS). 
Subjects will be required to complete the following questionnaires on a tablet at site:  
Patient preferences questionnaire (PAUSe). 
Investigators, delegated physicians, specialist nurses or nurse practitioners trained 
according to local requirements and local clinical practice will be required to complete the 
following questionnaires on a tablet at the site: C-SSRS©, MMSE©. 
Sites will be properly trained on the accurate use of the hand-held and tablet devices by the 
sponsor or an external CRO and are then expected to train their subjects on how to 
appropriately complete the questionnaires. Data collected from the hand-held devices will 
be electronically transferred to Idorsia by the CRO.  
For further details refer to the tablet and hand-held devices manual.  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 71/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
7.2.1 Demographics 
Demographic data to be collected in the eCRF for all subjects include: age, sex, race and 
ethnicity. Relevant medical history / current medical conditions (e.g., chronic and ongoing 
acute conditions, serious past conditions) present before signing informed consent will be 
recorded on the medical history page. Where possible, diagnoses and not symptoms will 
be recorded. 
Characteristics of insomnia will be captured on a specific Diagnosis eCRF page.  
Subject’s information regarding CBT will be captured on a specific Medical History eCRF 
page. 
For subjects who failed screening, the following data will be collected in the eCRF if 
available: 
• Demographics (i.e., age, sex, race and ethnicity)  
• Informed consent date 
• Reason for screening failure 
• AEs. 
7.2.2 Efficacy assessments 
7.2.2.1 Polysomnography 
PSG data will be used to assess objective sleep parameters (WASO and LPS) as well as 
data on sleep architecture (sleep stages).  
PSG recordings must be performed by technologists who are familiar with the recording 
techniques described in the investigator site operations manual for the acquisition, 
processing, scoring, archiving, and transfer of digital PSG data (provided by the central 
scoring CRO). The quality of PSG recordings is monitored and quality-controlled on an 
ongoing basis. Technologists must be able to follow the procedures in this manual in order 
to produce technically acceptable tracings. Technologists are not required to be registered 
PSG technologists. Technologists must receive study-specific training prior to their 
participation in the study. Documentation of technologists’ prior experience and training, 
and study-specific training will be maintained at each clinical trial site. The sites and 
scorers that participate in this study must be certified by the CRO. The center conditions 
must allow an undisturbed environment and PSG recordings must be conducted in a sleep 
laboratory environment that meets the guidelines for sleep disorder centers [aasmnet.org]. 
During the Screening period, a PSG night will be performed if the subject meets all 
inclusion criteria and none of the exclusion criteria checked so far, and assesses AHI, 
PLMAI, and SpO2. At Visit 3, the first PSG recording starts (lights off) within ± 30 min of 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 72/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
usual bedtime (determined by sleep diary between Visit 2 and Visit 3); this time is then 
considered as the habitual bedtime and held constant (± 15 min) throughout the study. 
Study medication is administered 30 min (± 5 min) before the recording starts. The PSG 
recording is stopped after 480 min when 960 epochs of 30 seconds have been recorded. 
PSGs will be performed as per the visit and assessment schedule [Table 1].  
During the PSG recording, the subject is requested to stay in bed and remains connected to 
the recording equipment. However, if the subject needs to go to the bathroom, he/she may 
do so and will be disconnected for this short time from the recording device. Alternatively, 
urine flasks or bedpans may be provided. The subject must be re-connected as quickly as 
possible. The time during which the subject is disconnected will be scored as time awake. 
The subject is not permitted to perform any cognitive activity (such as reading, listening to 
radio, etc.), and is recommended not to have a watch or access to any clock. The lights 
remain switched off until the 480 min of recording are finished. After recording is stopped, 
the lights are turned on and the subject is awakened and asked to perform the morning 
assessments.  
The centers are required to transfer PSG data to the CRO responsible for central scoring, 
after the Visit 3 PSG visit and after Visit 6, Visit 8 and Visit 9 PSG visits. During the 
screening phase, PSG data obviously not fitting eligibility criteria at the first PSG and at 
Visit 3 according to site scoring (more than 10% deviation from protocol range) are not 
required to be sent for central scoring. If anything prevents any PSG night being scored, 
the center must contact the monitor for instructions. After Visit 3, the CRO will score the 
PSG data obtained at the first PSG and at Visit 3 immediately upon receipt and the center 
will receive the complete Eligibility Assessment (AHI, PLMAI, and the presence of any 
apnea/hypopnea or event associated with SpO2 < 80% as assessed at Visit 1, and WASO, 
LPS and TST as assessed at Visit 3) within 3 business days following file receipt by the 
CRO. These PSG data are evaluated and scored centrally by an independent scorer (expert 
from central reading CRO, not otherwise involved in the study). Based on this information, 
the investigator assesses the subject’s potential eligibility. 
Results of all PSG nights (1st PSG, Visit 3, Visit 6, Visit 8, and Visit 9) for the randomized 
subjects are sent to Idorsia from the central scoring CRO. The following sleep variables 
assessed by PSG include but are not limited to: WASO, LPS, TST, sleep stages S1 (also 
called N1), S2 (N2), SWS (N3), REM (R), and Wake time during sleep (W). The 
definitions of the sleep variables are given in the scoring procedures of the central scoring 
CRO manual. 
The sponsor reserves the right to request the sites to provide PSG data from the 1st PSG 
night of screened failed subjects to further characterize the patient population. In such case, 
the sites will be informed in due time.  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 73/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
For more detailed information, refer to the investigator site operations manual for the 
acquisition, processing, scoring, archiving, and transfer of digital PSG data (provided by 
central scoring CRO). 
7.2.2.2 Sleep diary 
The sleep diary (also called eDiary) will be uploaded into an electronic hand-held device 
and given to the subjects at Visit 1. Sleep diaries will be available in the subject’s language, 
and must be completed daily from Visit 1 at screening and until Visit 10. 
The self-administered sleep diary includes a morning and evening questionnaire, and VAS.  
For further information about the set-up and the use of the sleep diary on the hand-held 
device, refer to the investigator site electronic Clinical Outcome Assessment study 
information guide (provided by CRF Health).  
7.2.2.2.1 Morning and evening questionnaire 
These questions collect information on self-reported sleep characteristics (sleep induction 
and maintenance), habitual napping, bedtime, and timing of study treatment intake.  
The subject’s answer to the sleep diary question “What time did you get into bed?” is 
expected to be in the time window of 21:30 to 00:30 for at least 50% of the nights between 
Visit 2 and Visit 3. The median of the values falling into the time window of 21:30 to 00:30 
is defined as the usual bedtime and will be used to set the habitual bedtime. The subject’s 
regular time in bed (i.e., time calculated from “What time did you get into bed?” until 
“What time did you get out of bed for the day?”) is expected to be in the time window of 
6 to 9 h, for at least 50% of the nights between Visit 2 and Visit 3. 
For further details, see Appendix 8. 
7.2.2.2.2 Visual analog scales 
The VAS collects information on quality of sleep, depth of sleep, morning sleepiness, 
daytime alertness, and daytime ability to function by asking the subjects to report their 
feelings by placing a mark on a visual analog scale. 
Self-reported quality of sleep, depth of sleep and morning sleepiness are assessed in the 
morning. Self-reported daytime alertness and daytime ability to function are assessed in 
the evening. 
For further details, see Appendix 8. 
7.2.2.3 Insomnia Severity Index© 
The ISI© assesses the severity of a patient’s insomnia by scoring the severity of sleep onset 
and sleep maintenance difficulties and any insomnia-related interference with daytime 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 74/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
functioning [see Appendix 5]. The assessment is on a 5-point scale (0–4), where the 
composite score is obtained by summing the 7 rated dimensions measuring the subject’s 
perception of his or her insomnia. A score of 15–21 indicates a moderate level of insomnia 
and a score of 22–28 indicates severe insomnia. An ISI© total score < 10 indicates that the 
subject’s subjectively-rated insomnia symptoms, daytime impairment, and quality of life 
have improved to the minimal-to-none range [Morin 1993, Scharf 2007]. The ISI© will be 
completed by the subject on the hand-held device at Visit 1, Visit 3, Visit 6, and Visit 8.  
7.2.2.4 Patient Global Assessment of Disease Severity (daytime symptoms) 
The PGA-S (daytime symptoms) is a question concerning the overall severity of daytime 
symptoms (e.g., sleepiness) and impacts (e.g., effort to perform daily activities) that the 
subject may have experienced due to his/her insomnia over the 7 days preceding the PGA-
S. It is a self-administered question programmed on the hand-held device and is to be 
completed at Visit 1, Visit 2, Visit 3 1st evening, Visit 6 1st evening, Visit 8 1st evening, 
Visit 10, and weekly in the evening at home from Visit 4 until EODBT.  
For further details, see Appendix 9. 
7.2.2.5 Patient Global Impression of Change (daytime symptoms) 
The PGI-C (daytime symptoms) is a question concerning the change in overall severity of 
daytime symptoms (e.g., sleepiness) and impacts (e.g., effort to perform daily activities) 
that the subject may have experienced due to his/her insomnia over the 7 days preceding 
the PGI-C daytime symptoms compared to the week before he/she started treatment. The 
PGI-C daytime symptoms is a self-administered question on the hand-held device and is to 
be completed at Visit 3 1st evening, Visit 6 1st evening, Visit 8 1st evening, Visit 10, and 
weekly in the evening at home from Visit 4 until EODBT. 
For further details, see Appendix 9. 
7.2.2.6 Patient Global Impression of Change (night-time symptoms) 
The PGI-C (night-time symptoms) is a question concerning the change in the subject’s 
insomnia symptoms at night (e.g., trouble falling asleep, total time asleep, or number of 
times they wake up) over the past week (7 nights) preceding the PGI-C night-time 
symptoms compared to the week before the subject started treatment. The PGI-C 
night-time symptoms is a self-administered question on the hand-held device and is to be 
completed at Visit 3 1st morning, Visit 6 1st morning, Visit 8 1st morning, Visit 10, and 
weekly in the morning at home from Visit 4 until EODBT. 
For further details, see Appendix 10. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 75/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
7.2.2.7 Patient Global Impression of Severity (night-time symptoms) 
The PGI-S is a question concerning the overall severity of the subject’s night-time 
symptoms (e.g., trouble falling asleep, total time asleep, or number of times they wake up) 
that the subject may have experienced due to his/her insomnia over the past week (7 nights) 
preceding the PGI-S. It is a self-administered question programmed on the hand-held 
device and is to be completed at Visit 1, Visit 2, Visit 3 1st morning, Visit 6 1st morning, 
Visit 8 1st morning, Visit 10 and weekly in the morning at home from Visit 4 until EODBT. 
For further details, please see Appendix 10. 
7.2.2.8 Insomnia Daytime Symptoms and Impacts Questionnaire 
The IDSIQ is programmed on the electronic hand-held device in the subject’s language, 
and must be completed every day in the evening before the evening sleep diary by the 
subject without study staff input or interference from Screening (Visit 1) until EOT 
(Visit 10). 
The IDSIQ is structured in 3 domains (i.e., alertness/cognition; negative mood; 
tiredness/sleepiness) and contains overall 14 items, each based on an 11-point numeric 
rating scale. This tool is based on an existing instrument, the Daytime Insomnia Symptom 
Scale [Buysse 2007]. The psychometric validation of the IDSIQ instrument was performed 
in study ID-078A203. 
For further details, see Appendix 11. 
7.2.3 Safety assessments 
The definitions, reporting and follow-up of AEs, SAEs and pregnancies are described in 
Section 9. 
7.2.3.1 Weight and height 
Height will be measured at Screening only (Visit 1) and recorded in the eCRF. 
Body weight will be measured at Screening (Visit 1) and EODBT visit (Visit 8), and 
recorded in the eCRF. BMI will be calculated at Visit 1 according to the BMI formula 
(weight in kg/m2) and displayed automatically upon entry of weight and height in the 
eCRF.  
7.2.3.2 Physical examination 
Physical examination will be performed at Screening (Visit 1) and EODBT visit (Visit 8) 
according to site standard medical practice for subjects with insomnia disorders. 
Other exams will be performed if indicated, based on medical history and/or symptoms. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 76/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
Information for all physical examinations must be included in the source documentation at 
the study site. The observations will not be directly reported in the eCRF. Clinically 
significant findings that are present prior to signing of ICF must be recorded on the Medical 
History eCRF form. Clinically significant physical examination findings made after 
signing of informed consent that meet the definition of an AE [Section 9.1.1] must be 
recorded on the AE form of the eCRF. 
7.2.3.3 Vital signs 
Systolic and diastolic BP and pulse rate will be measured non-invasively at each study visit 
from Screening (Visit 1) to EOT (Visit 10).  
Vital signs measurements will be collected in the eCRF. 
7.2.3.4 Coding sub-test© 
The Coding sub-test©, formerly known as Digit Symbol Substitution Test, is a measure of 
attention, perceptual speed, motor speed, visual scanning and memory.  
On a sheet of paper, the subject is given 120 seconds to complete as many substitutions as 
possible, entering a symbol in numbered boxes according to a key shown on the top of the 
sheet (9 symbols).  
The Coding sub-test© is performed at Visit 3, Visit 6, Visit 8 and Visit 9. The number of 
correct substitutions is recorded as the total Coding sub-test© score and collected in the 
eCRF. 
For further details, see Appendix 4. 
7.2.3.5 Sheehan Disability Scale© 
The SDS© consists of 3 questions on impairment of work, social life, and family life / home 
responsibilities [see Appendix 6; Sheehan 1996]. The SDS© is a self-administered 
questionnaire on the hand-held device performed at Visit 3, Visit 6, Visit 8 and Visit 9.  
7.2.3.6 Columbia Suicide Severity Rating Scale© 
The C-SSRS© is an instrument that reports the presence and severity of both suicidal 
ideation and behaviors [Posner 2007]. Suicidal ideation is classified on a 5-item scale:  
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (not plan) without intent to act 
4. Active suicidal ideation with some intent to act, without specific plan 
5. Active suicidal ideation with specific plan and intent 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 77/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
The C-SSRS© also captures information about the intensity of ideation, specifically the 
frequency, duration, controllability, deterrents, and reasons for the most severe types of 
ideation. In addition, the C-SSRS© captures information using yes/no question and answers 
on suicidal behaviors, specifically actual, interrupted, and aborted attempts; preparatory 
acts or behaviors; and if suicidal behaviors were present during the assessment period. 
More than one classification can be selected provided they represent separate episodes. For 
actual attempts only, the actual or potential lethality is classified for the initial, most lethal, 
and most recent attempts. The C-SSRS© will be completed at all study visits except Visit 
5 and Visit 11 (i.e., telephone calls). At Visit 1 (Screening) the C-SSRS© will be completed 
for the subject lifetime history of suicidal ideation and behaviors. At all other visits, the C-
SSRS© will be completed for ideation and behaviors since the previous visit.  
At each visit, the investigator, a delegated physician, a specialist nurse or a nurse 
practitioner, trained according to local requirements and local clinical practice will 
complete this questionnaire with the subject on a tablet and assess the findings. 
7.2.3.7 Benzodiazepine Withdrawal Symptom Questionnaire 
The BWSQ assesses the main symptoms which might be experienced by subjects during 
withdrawal from benzodiazepines [see Appendix 7; Tyrer 1990]. The questionnaire 
consists of 20 items. The symptoms will be rated from 0 (No), 1 (Yes-moderate) to 
2 (Yes-severe). The questionnaire will be self-administered using the hand-held device at 
Visit 3, Visit 6, Visit 8, Visit 9 and Visit 10. 
7.2.3.8 Mini International Neuropsychiatric Interview© 
The MINI© is a psychiatric examination [Sheehan 1999] and will identify subjects with 
exclusionary psychiatric conditions. The MINI© will be administered at Screening (Visit 1) 
by the investigator, a delegated physician, a specialist nurse or a nurse practitioner, trained 
according to local requirements and local clinical practice. The MINI© Version 7.0.2 will 
be administered on paper to ascertain the psychiatric diagnoses, and any clinically relevant 
psychiatric conditions will be reported in the eCRF. 
7.2.3.9 Mini Mental State Examination© 
The MMSE© is a simplified, scored form of the cognitive mental status examination [see 
Appendix 13; Folstein 1975]. The MMSE© assesses orientation, attention, immediate and 
short-term recall, language, and the ability to follow simple verbal and written commands. 
The MMSE© will be administered at Screening (Visit 1) for subjects ≥ 50 years at the site 
on a tablet by the investigator, a delegated physician, a specialist nurse or a nurse 
practitioner, trained according to local requirements and local clinical practice. A subject 
with a score between 25 and 30 will be eligible and a subject with a score below 25 has 
greater cognitive impairment and will be excluded. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 78/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
7.2.3.10 Neurological examinations 
At 1st PSG night, Visit 3, Visit 6, Visit 8, and Visit 9, a set of examinations must be 
performed approximately 1 hour after lights on [see Section 7.2]. The neurological 
examinations will be done by the investigator, a delegated physician, a specialist nurse or 
a nurse practitioner, trained according to local requirements and local clinical practice. The 
following examinations will be performed to detect a possible next-day residual effect: 
• Gait 
• Tandem walking 
• Romberg test 
In the event of clinically significant findings, the set of examinations must be repeated 
approximately every 30 min. until the subject is considered safe to leave the center and the 
investigator must ensure appropriate safety follow-up of the subject. All clinically 
significant findings must be recorded as AEs in the eCRF.  
Neurological examinations are recorded on the eCRF. 
7.2.3.11 Epworth Sleepiness Scale© 
The ESS© is a validated questionnaire designed to provide a subjective measure of daytime 
sleepiness [Johns 1991]. The ESS© [see Appendix 12] will be self-administered at site 
visits (Visit 1, Visit 2, Visit 3, Visit 6, Visit 8, and Visit 10) on a hand-held device to assess 
daytime sleepiness. All clinically significant findings must be recorded as AEs in the eCRF. 
7.2.3.12 ECG assessment 
A standard 12-lead ECG is to be performed at Visit 1, in the second morning of Visit 3, 
Visit 8 and at Visit 10. 
12-lead ECG will be recorded at rest with the subject in the supine position. Data records 
will be sent to the evaluation center for central reading.  
Details will be provided in the 12-lead ECG laboratory manual.  
The following parameters will be evaluated: PQ or PR (ms), QRS (ms), QT (ms), heart rate 
(HR; bpm), and rhythm. QTc (ms) will be calculated according to: 
• Bazett’s formula: QTcB = QT / (RR)1/2 
and 
• Fridericia’s formula: QTcF = QT / (RR)1/3, where RR = 60 / HR 
If the central review of the ECG detects a prolonged QTcB and/or QTcF interval greater 
than 450 ms for a subject at screening (Visit 1 or Visit 3), the ECG must be repeated (at 
least 30 min after first ECG). If the central review confirms that the repeated ECG shows 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 79/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
a QTcB and/or QTcF interval greater than 450 ms, the subject cannot be enrolled into the 
study.  
Clinically significant findings detected after signing of ICF which meet the definition of 
an AE must be recorded in the eCRF.  
ECG data collected by the CRO will be electronically transferred to Idorsia.  
7.2.4 Patient preferences questionnaire 
The DCE methodology requires the presentation of several possible comparative scenarios, 
(i.e., Treatment A and Treatment B) showing specific treatment outcomes (benefits and 
risks). After each treatment scenario, subjects will be asked to make choices about the type 
of treatment they would be willing to take. The patient preferences questionnaire is 
programmed on the tablet site device in the subject’s language (i.e., US English for USA 
and German for Germany), and if subjects consent to participate to this sub-study, must be 
completed at Randomization (Visit 4) and at EODBT visit (Visit 8, 2nd morning). 
For further details, see Appendix 14. 
7.2.5 Laboratory assessments 
7.2.5.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests until EOS, including follow-up tests due to abnormal 
laboratory findings and laboratory tests performed at unscheduled visits. 
Local laboratory results of the parameters described in Section 7.2.5.2 will only be 
collected in exceptional circumstances (e.g., hospitalization of the subject due to a medical 
emergency). The local laboratory results (with the corresponding normal ranges) must be 
recorded in the eCRF. 
If a central laboratory sample is lost or cannot be analyzed for whatever reason, it is 
recommended to the investigator to collect an additional sample as soon as possible for 
repeat analysis. 
No repeat test is allowed if the subject does not meet the eligibility criteria. 
Central laboratory reports will be sent to the investigator. In the event of specific 
(pre-defined) laboratory abnormalities, the central laboratory will alert Idorsia personnel 
and the concerned site personnel. 
All laboratory reports must be reviewed, signed, and dated by the investigator or delegate 
within 10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 80/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
considered clinically significant or not. Clinically significant laboratory findings present 
before signing of the ICF must be recorded on the Medical History page of the eCRF. Any 
clinically significant laboratory abnormalities detected after signing of ICF must be 
reported as an AE or SAE as appropriate [see Section 9], and must be followed up until the 
value returns to within the normal range or is stable, or until the change is no longer 
clinically significant. 
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. Blood samples will 
be drawn under fasted condition (i.e., before breakfast) at Visit 3, Visit 6, Visit 7 and 
Visit 8. 
7.2.5.2 Laboratory tests 
Hematology 
• Hemoglobin  
• Hematocrit  
• Erythrocytes  
• Reticulocyte 
• Leukocytes with differential counts 
• Platelets  
Clinical chemistry 
• ALT  
• AST  
• Alkaline phosphatase  
• Creatine kinase  
• Total and direct bilirubin  
• Gamma-glutamyl transferase  
• Creatinine and creatinine clearance 
• Blood urea nitrogen  
• Uric acid  
• Glucose  
• Cholesterol, triglycerides  
• Sodium, potassium, chloride, calcium  
• Albumin  
• Thyroid hormones, i.e., triiodothyronine (total and free) and thyroxine (total and free), 
and thyroid-stimulating hormone. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 81/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed at Screening 
(Visit 1) and on the second morning of Visit 8. A urine pregnancy test will be performed 
on Visit 2, Visit 4, on the first evening of Visit 6, Visit 7 and at run-out (Visit 10). If 
pregnancy is suspected during the study, a serum pregnancy test must be performed 
immediately. 
Other tests 
The urine drug screening kits (testing for presence of benzodiazepines, barbiturates, 
cannabinoids, opiates, amphetamines, phencyclidine or cocaine) and the breathalyzer for 
alcohol detection in the exhaled breath will be provided by the central laboratory. Should 
any technical issue arise with the breathalyzer, alcohol saliva tests will be provided to be 
used as back-up.  
Study drug is administered as described in Section 5 only if the results of the pregnancy 
tests and other tests are negative.  
7.2.6 Pharmacokinetic assessments 
PK samples will be collected in the morning after the second PSG night, after lights on, 
approximately 9–10 h post-dose (i.e., 30–90 min after lights on) at Visit 6 and Visit 8 or in 
the event of excessive sleepiness based on the investigator’s opinion. 
The date and the time of blood sample collection will be entered in the eCRF. The date and 
time of the last study treatment dosing before blood draw will be entered in the eCRF. The 
site personnel will ship the plasma samples to the central laboratory. The central laboratory 
will ship the samples to Idorsia Drug Metabolism and Pharmacokinetics department, who 
are in charge of the PK sample analysis. 
Details about the collection, sampling, storage, and shipment procedures can be found in 
the laboratory manual. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol 
A subject who completes the study treatment phase and the safety follow-up phase is 
considered to have completed the study as per protocol. Subjects who completed the study 
until the end of the run-out period will have the possibility to participate in the extension 
study ID-078A303 and will complete the safety follow-up phase at the end of the extension.  
8.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn from study if they state an intention to 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 82/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
withdraw further participation in all components of the study (i.e., withdrawal of consent), 
die, or are lost to follow-up. If a subject withdraws consent, no further data will be collected 
in the eCRF from the date of withdrawal onward. Withdrawal from the study may also 
result from a decision by Idorsia for any reason, including premature termination or 
suspension of the study. 
Subjects are considered as lost to follow-up if all reasonable attempts by the investigator 
to communicate with the individual failed. The site must take preventive measures to avoid 
a subject being lost to follow-up (e.g., document different ways of contact such as 
telephone number, home address, email address, person to be contacted if the subject 
cannot be reached). If the subject cannot be reached, the site must make a reasonable effort 
to contact the subject, document all attempts, and enter the loss of follow-up information 
into the eCRF. The following methods must be used: at least three telephone calls must be 
placed to the last available telephone number and one registered letter must be sent by post 
to the last available home address. Additional methods may be acceptable if they are 
compliant with local rules/regulations (e.g., a visit by site personnel to the subject’s home), 
respecting the subject’s right to privacy. If the subject is still unreachable after all contact 
attempts listed above, he/she will be considered to be lost to follow-up. 
If premature withdrawal occurs for any reason, the reason (if known) for premature 
withdrawal from the study (e.g., withdrawal by subject, AE, lost to follow-up, death) must 
be recorded in the eCRF. 
If, for whatever reason (except death or loss-to-follow-up), a subject is withdrawn from the 
study, the investigator should make efforts to schedule a last appointment / telephone call 
to assess the safety and well-being of the subject, collect unused study treatment and 
discuss follow-up medical care. Data obtained during this last appointment / telephone call 
will be recorded in the subjects’ medical records but it will not be collected in the eCRF. 
The investigator must provide follow-up medical care for all subjects who are prematurely 
withdrawn from the study, or must refer them for appropriate ongoing care, as described 
in Section 8.4. 
8.3 Premature termination or suspension of the study 
Idorsia reserves the right to terminate the study at any time globally or locally. Investigators 
can terminate the participation of their site in the study at any time. 
If the study is prematurely suspended or terminated, Idorsia will promptly inform the 
investigators, IECs/IRBs and health authorities, as appropriate, and provide the reasons for 
the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Idorsia – must promptly inform all enrolled subjects and ensure their 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 83/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
appropriate treatment and follow-up, as described in Section 8.4. Idorsia may inform the 
investigator of additional procedures to be followed in order to ensure that adequate 
consideration is given to the protection of the subjects’ interests. 
In addition, if the investigator suspends or terminates the participation in the study without 
prior agreement from Idorsia, the investigator must promptly inform Idorsia personnel and 
the IEC/IRB, and provide both with a detailed written explanation of the termination or 
suspension. 
If the IEC/IRB suspends or terminates its approval / favorable opinion of the study, the 
investigator must promptly notify Idorsia personnel and provide a detailed written 
explanation of the termination or suspension. 
8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment / medical care is 
necessary and available according to local regulations. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
9.1.1 Definition of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A TEAE is any AE temporally associated with the use of study treatment (i.e., emerging 
from DB study treatment initiation until up to 30 days after DB study treatment 
discontinuation or until enrollment into the extension study) whether or not considered by 
the investigator as related to study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of the study even 
though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen following 
the signing of informed consent. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 84/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or worsened 
during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the course 
of the study, or led to interruption or permanent discontinuation of study treatment. 
Overdose, misuse, abuse of the study treatment and study treatment errors will be reported 
as an AE. 
The ISB will adjudicate treatment-emergent AESIs which are similar to, or indicate: 
• narcolepsy-like symptoms (i.e., EDS, cataplexy and complex sleep behavior events 
including hallucinations/sleep paralysis) 
• suicide/self-injury 
A treatment-emergent AESI is any AESI emerging from DB study treatment initiation until 
up to 30 days after DB study treatment discontinuation or until enrollment into the 
extension study. 
9.1.2 Intensity of adverse events 
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on specific AE pages of the eCRF. 
Any increases in intensity of an AE during the study will be reported in the eCRF.  
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort and usually interferes with daily activities. The 
subject may not be able to continue in the study, and treatment or intervention is usually 
needed. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 85/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
A mild, moderate, or severe AE may or may not be serious [see Section 9.2.1]. These terms 
are used to describe the intensity of a specific event. Medical judgment should be used on 
a case-by-case basis. 
Seriousness, rather than intensity assessment, determines the regulatory reporting 
obligations. 
9.1.3 Relationship to study treatment 
Each AE must be assessed by the investigator as to whether or not there is a reasonable 
possibility of causal relationship to the study treatment, and reported as either related or 
unrelated. The determination of the likelihood that the study treatment caused the AE will 
be provided by the investigator. 
9.1.4 Reporting of adverse events 
The investigator will ask the subject to report all AEs at each study visit, including the 
telephone calls.  
All AEs with an onset date after signing of informed consent and up to EOS for subjects 
that are not enrolled in ID-078A303 extension study must be recorded on AE pages of the 
eCRF. 
All AEs with an onset date after signing of informed consent, and up to enrollment in the 
ID-078A303 (i.e., ID-078A301 EOT) for subjects that are participating in the extension 
study, must be recorded on AE pages of the ID-078A301 eCRF. 
9.1.5 Follow-up of adverse events 
AEs still ongoing more than 30 days after EOS for subjects that are not enrolled in the 
ID-078A303 extension study must be followed up until they are no longer considered 
clinically relevant or until stabilization. The follow-up information obtained after the 
subject’s EOS telephone call will not be collected by Idorsia. 
For subjects enrolled in ID-078A303, AEs that are ongoing at ID-078A301 EOT will be 
followed up in the extension study and reported in the ID-078A303 eCRF on a dedicated 
page. 
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. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 86/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
• Life-threatening: Refers to an event in which the subject was at risk of death at the time 
of the event. It does not refer to an event that hypothetically might have caused death 
had it been more severe. 
• Requiring in-patient hospitalization or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: Refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject, and may require medical or surgical intervention to prevent one of the outcomes 
listed in the definitions above. 
The following reasons for hospitalization are not considered as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing informed consent) surgery 
or standard monitoring of a pre-existing disease or medical condition that did not 
worsen, e.g., hospitalization for coronary angiography in a subject with stable angina 
pectoris. 
However, complications that occur during hospitalization are AEs or SAEs (e.g., if a 
complication prolongs hospitalization). 
9.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent up to EOS must be reported on AE 
pages in the eCRF and on an SAE form, regardless of the investigator-attributed causal 
relationship with study treatment or study-mandated procedures. 
All SAEs with an onset date after signing of informed consent and up to enrollment in 
ID-078A303 (i.e., ID-078A301 EOT) for subjects that are participating in the extension 
study must be recorded on AE pages of the ID-078A301 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 EOS must be followed up until resolution or 
stabilization, or until the event outcome is provided. The follow-up information obtained 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 87/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
after the subject’s EOS telephone call must be reported to Idorsia Global Drug Safety, but 
it is not recorded in the eCRF. 
For subjects enrolled in ID-078A303, SAEs that are ongoing at ID-078A301 EOT will be 
followed up in the extension study and reported in the ID-078A303 eCRF on a dedicated 
page. 
9.2.4 After the 30-day follow-up period 
New SAEs occurring after the 30-day follow-up period must be reported to Idorsia Global 
Drug Safety within 24 hours of the investigator’s knowledge of the event, only if 
considered by the investigator to be causally related to previous exposure to the study 
treatment. 
9.2.5 Reporting procedures 
All SAEs must be reported by the investigator to Idorsia Global Drug Safety within 
24 hours of the investigator’s first knowledge of the event. 
All SAEs must be recorded on an SAE form, irrespective of the study treatment received 
by the subject, and whether or not this event is considered by the investigator to be related 
to study treatment. 
The SAE forms must be sent to Idorsia Global Drug Safety (contact details are provided 
on the SAE form). The investigator must complete the SAE form in English, and must 
assess the event’s causal relationship to the study treatment. 
Any relevant information from source documents regarding the SAE, e.g., hospital notes 
or discharge summaries, etc., must be summarized on the SAE form. 
Follow-up information about a previously reported SAE must also be reported within 
24 hours of receiving it. Idorsia Global Drug Safety personnel may contact the investigator 
to obtain further information. 
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The expectedness of an adverse reaction is determined by Idorsia in the reference safety 
information (RSI) section provided in the most recent version of the IB for ACT-541468 
[ACT-541468 IB]. Any SAE that is assessed as related and unexpected against the RSI of 
the ACT-541468 IB [ACT-541468 IB] is known as a SUSAR and must be reported by 
Idorsia to concerned health authorities (including the EudraVigilance database if the study 
is conducted in Europe), IECs/IRBs and investigators. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 88/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
9.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued. The investigator must counsel the subject and discuss the risks of continuing 
with the pregnancy and the possible effects on the fetus. 
9.3.1 Reporting of pregnancy 
Irrespective of the treatment received by the subject, any pregnancy occurring after study 
start (i.e., signing of informed consent) up to EOS must be reported within 24 hours of the 
investigator’s knowledge of the event. 
Pregnancies must be reported on the Idorsia Pregnancy form, which is faxed to Idorsia 
Global Drug Safety (see contact details provided on the Pregnancy form), and on an AE 
page in the eCRF. 
9.3.2 Follow-up of pregnancy 
Pregnancies must be followed-up to their conclusion for all randomized subjects and the 
outcome must be reported to Idorsia Global Drug Safety. 
Any AE associated with the pregnancy occurring during the follow-up period after DB 
study treatment discontinuation must be reported on separate AE pages in the eCRF. Any 
SAE occurring during the pregnancy must be reported on an SAE form as described in 
Section 9.2.5. 
9.4 Study safety monitoring 
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific examinations as required) is monitored and reviewed on a continuous basis 
by the Idorsia Clinical Team (in charge of ensuring subjects’ safety as well as data quality). 
In addition, an IDMC and an ISB are monitoring safety data [see Section 3.3]. 
10 STATISTICAL METHODS 
All statistical analyses will be conducted by Idorsia or by designated CROs supervised by 
Idorsia. 
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. 
10.1 Analysis sets 
A subject must have given informed consent before being included in any analysis set. 
10.1.1 Screened Analysis Set 
The Screened Analysis Set includes all subjects who entered screening and have a subject 
identification number. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 89/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
10.1.2 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects assigned to a DB study treatment. In 
order to adhere to the intention-to-treat principle as much as possible: 
• Subjects are evaluated according to the treatment and strata they have been assigned 
to, which may differ from the treatment they have received; 
• All available data are included. 
10.1.3 Per-Protocol Set 
The Per-Protocol Set (PPS) comprises all subjects from the FAS who complied with the 
protocol sufficiently to be likely to exhibit the treatment effects. Criteria for sufficient 
compliance include exposure to treatment, availability of measurements, and absence of 
major protocol deviations that have an impact on the treatment effect. The full list of criteria 
will be finalized before unblinding treatment codes. 
10.1.4 Safety Set 
The Safety Set includes all subjects who received at least one dose of DB study treatment. 
Subjects will be evaluated according to the actual treatment they received, which may 
differ from the randomly assigned treatment. 
10.1.5 Treatment Withdrawal Set 
The Treatment Withdrawal Set comprises all subjects included in the Safety Set who 
received single-blind placebo treatment in the run-out period. 
10.1.6 Pharmacokinetic Analysis Set 
The Pharmacokinetic Analysis Set (PK Set) includes all subjects in the Safety Set who 
have at least 1 PK sample collected after initiation of DB study treatment. Subjects 
receiving placebo will be excluded from the PK set. 
10.1.7 Patient Preferences Analysis Set 
The Patient Preferences Analysis Set includes all subjects in the Safety Set who have 
answered at least one patient preferences questionnaire after initiation of study treatment. 
10.1.8  Usage of the analysis sets 
The analyses of efficacy endpoints including baseline and disease characteristics will be 
performed using the FAS, and the PPS for certain sensitivity analyses. 
The Safety Set will be used for the analysis of safety endpoints (including previous and 
concomitant medications, and study treatment exposure). 
Subject data will be listed using the Safety Set, unless otherwise specified. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 90/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
The Treatment Withdrawal Set will be used for the analysis of endpoints used to assess 
withdrawal symptoms (e.g., BWSQ total score) and rebound insomnia (e.g., objective and 
subjective sleep parameters: WASO, LPS, TST, sWASO, sLSO, and sTST). 
The analysis of ACT-541468 plasma concentrations 9–10 h post-dose will be performed 
using the PK Set. 
The Patient Preferences Analysis Set will be used for the analysis of endpoints to assess 
patient preferences. 
10.2 Variables 
Detailed description of study efficacy and safety variables (endpoints) can be found in 
Section 6 of this protocol.  
10.3 Description of statistical analyses 
10.3.1 Analysis of the primary and secondary efficacy variables 
10.3.1.1 Overall testing strategy 
The Type I error rate will be controlled for the testing of multiple null hypotheses 
associated with the primary and secondary endpoints assessed at 1 and 3 months of 
treatment and the two dose levels included in this study, i.e., 25 mg and 50 mg. 
The eight statistical null hypotheses associated with the primary efficacy endpoints are: 
Sleep maintenance: 
• H1WASO: Higher Dose – Placebo = 0 for WASO at Month 1 
• H2WASO: Higher Dose – Placebo = 0 for WASO at Month 3 
• H3WASO: Lower Dose – Placebo = 0 for WASO at Month 1 
• H4WASO: Lower Dose – Placebo = 0 for WASO at Month 3 
Sleep onset: 
• H1LPS: Higher Dose – Placebo = 0 for LPS at Month 1 
• H2LPS: Higher Dose – Placebo = 0 for LPS at Month 3 
• H3LPS: Lower Dose – Placebo = 0 for LPS at Month 1 
• H4LPS: Lower Dose – Placebo = 0 for LPS at Month 3 
The eight statistical null hypotheses associated with the secondary efficacy endpoints are: 
Sleep quantity: 
• H1sTST: Higher Dose – Placebo = 0 for sTST at Month 1 
• H2sTST: Higher Dose – Placebo = 0 for sTST at Month 3 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 91/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
• H3sTST: Lower Dose – Placebo = 0 for sTST at Month 1 
• H4sTST: Lower Dose – Placebo = 0 for sTST at Month 3 
Next day performance: 
• H1IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 1 
• H2IDSIQ: Higher Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 3 
• H3IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 1 
• H4IDSIQ: Lower Dose – Placebo = 0 for IDSIQ sleepiness domain score at Month 3 
where ‘Higher Dose’, ‘Lower Dose’, and ‘Placebo’ represent the mean change from 
baseline for the given endpoint (WASO, LPS, sTST or IDSIQ sleepiness domain score) 
and time point (Month 1 or Month 3) for the 50 mg, 25 mg and placebo treatment group, 
respectively. 
Each null hypothesis will be tested against the alternative hypothesis: that ACT-541468 
improves WASO / LPS / sTST / IDSIQ sleepiness domain score at the given dose (25 or 
50 mg) and time point (Month 1 or Month 3) compared to placebo. 
The order of testing and the alpha level applied to each null hypothesis will be based on 
the Bonferroni-based gatekeeping procedure [Bretz 2009] (shown in Figure 2 below as a 
directed graph) that will control the study-wise Type I error at a two-sided 5% significance 
level. To account for the concurrent evaluation (multiple comparison) of two distinct 
endpoint categories (i.e., sleep maintenance and sleep onset) a Bonferroni correction is 
applied. Both endpoint categories will be tested at half of the two-sided 5% significance 
level. This supports the sponsor’s intention to make a superiority claim versus placebo for 
efficacy in either a sleep maintenance and/or sleep onset indication. The remaining 
hypotheses will be tested following the gatekeeping strategy moving from Month 1 to 
Month 3 for higher dose ACT-541468 vs placebo and then from Month 1 to Month 3 for 
lower dose ACT-541468 vs placebo. The pre-specified proportion of alpha that will be 
distributed once a given null hypothesis (node) is rejected is shown on the arrow in the 
directed graph. If a certain null hypothesis cannot be rejected, then the alpha level used for 
that test is absorbed at that node and not distributed further. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 92/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
Figure 2 
Hypothesis testing strategy 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 93/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
10.3.1.2 Hypotheses and statistical model 
The main analysis will be performed using the FAS. 
A longitudinal data analysis method (i.e., linear mixed effects model) will be used for the 
analysis of change from baseline in WASO, LPS, sTST, and IDSIQ scores, separately. All 
available data, regardless of occurrence of intercurrent events (e.g., study treatment 
discontinuation, the use of prohibited medication), will be included in the model. 
The analysis model will adjust for the baseline value of the relevant response variable 
(either WASO, LPS, sTST or IDSIQ sleepiness domain score), age group (< 65; 
≥ 65 years), treatment (higher dose; lower dose; placebo), time point (Month 1; Month 3), 
and the interaction of treatment by time point, and baseline by time point. 
To evaluate the efficacy hypotheses, appropriate contrasts will be used to test the treatment 
differences of interest (i.e., the difference in Least Squares mean change from baseline 
between higher dose ACT-541468 vs placebo and lower dose ACT-541468 vs placebo at 
Month 1 and Month 3). An unstructured covariance matrix will be used to model the 
correlation among repeated measurements. This approach relies on the missing at random 
(MAR) assumption. 
A term for ‘center’ is not included in the statistical model due to the low numbers of 
subjects expected in many centers. Randomization was not stratified by center for the same 
reason. 
10.3.1.3 Handling of missing data 
For WASO and LPS values, if one of the two values is missing either for baseline, Month 1 
or Month 3, the single value available will be used as the mean for this time point. 
Otherwise, the mean value will be considered missing for that time point. 
For sTST values, subjects must have at least 3 days of data during each week to calculate 
a weekly mean. Otherwise, the mean value will be considered missing for that week. 
For IDSIQ sleepiness domain scores, subjects must have at least 4 days of data during each 
week to calculate a weekly mean. Otherwise, the mean value will be considered missing 
for that week. 
Note that the above implies implicit imputation: the missing data point(s) is(are) given the 
same value as the mean of the non-missing data point(s) of that same week or time point. 
10.3.1.4 Supportive/sensitivity analyses 
The impact of deviations from the MAR assumption underlying the linear mixed effects 
model as well as the incidence and pattern of missing values will be explored in order to 
evaluate the possible impact on results and will be described in the SAP. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 94/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
The analysis performed for the primary and secondary endpoints will be repeated using the 
PPS in order to assess the effect protocol deviations have on the results. 
10.3.2 Analysis of other efficacy variables 
Summary statistics will be provided for other efficacy endpoints using either number (%) 
of subjects for categorical variables or descriptive statistics (e.g., mean, SD, median, min., 
max.) for continuous variables. Further details will be described in the SAP. 
10.3.3 Analysis of the safety variables 
Analyses of safety endpoints will be performed using the Safety Set, unless noted 
otherwise. 
Adverse events 
AEs will be coded using MedDRA. The number (%) of subjects experiencing a TEAE 
(including SAEs, AESIs after adjudication by the ISB, and AEs leading to premature 
discontinuation of the DB study treatment) will be summarized by System Organ Class 
(SOC) and/or PT, and maximum intensity. A subject with multiple intensities reported for 
an AE will be summarized under the maximum intensity recorded for the event. A subject 
with multiple occurrences of an AE is counted only once in the AE category (e.g., SOC, 
PT). 
Laboratory data 
Laboratory analyses will be based on data received from the central laboratory. Observed 
values and changes from baseline to Month 1 and Month 3 in both hematology and blood 
chemistry laboratory parameters will be summarized. The number (%) of subjects having 
a marked laboratory abnormality during DB study treatment will be tabulated. 
Vital signs and weight 
Observed values and changes from baseline to Month 1 and Month 3 in vital signs (mean 
of the two PSG nights in systolic and diastolic BP, and pulse rate) will be summarized. 
Observed values and changes from baseline to Month 3 in body weight will be summarized. 
Electrocardiograms 
Observed values and changes from baseline to Month 3 for each ECG parameter (QTcB, 
QTcF, heart rate, PR, QRS) will be summarized. The number (%) of subjects having a 
marked ECG abnormality during DB study treatment will be tabulated. 
Withdrawal symptoms 
The Treatment Withdrawal Set will be used to assess the potential for withdrawal 
symptoms. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 95/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
The BWSQ total score will be summarized using descriptive statistics for the observed 
values and changes from the last assessment on DB treatment (Visit 8, 2nd morning) to the 
beginning and the end of the treatment withdrawal period (in the morning at Visit 9 and at 
Visit 10, respectively). 
In addition, withdrawal symptoms after DB study treatment withdrawal will be assessed 
through the incidence of AEs and marked ECG abnormalities occurring during the 
treatment withdrawal period. The number (%) of subjects having, separately, an AE and a 
marked ECG abnormality during the treatment withdrawal period will be tabulated. 
Insomnia rebound effect 
The Treatment Withdrawal Set will be used to assess the potential for rebound insomnia. 
The changes from baseline to the treatment withdrawal period (Visit 9, run-out) in 
objective sleep parameters (WASO, LPS and TST) will be summarized using descriptive 
statistics. 
The changes from baseline (mean value based on the screening sleep diary entries 
performed at home in the 7 days immediately preceding the first PSG at Visit 3) to the 
treatment withdrawal period (after PSG night at Visit 9) in subjective sleep parameters 
(sWASO, sLSO, and sTST) will be summarized using descriptive statistics. 
Next-day residual effect 
Observed values and changes from baseline to Month 1 and Month 3 in Coding sub-test©, 
SDS©, and VAS scores (mm) assessing morning sleepiness, daytime alertness and daytime 
ability to function, will be summarized. 
C-SSRS© 
Number (%) of subjects with suicidal ideation, suicidal behavior, and/or self-injurious 
behavior without suicidal intent based on the C-SSRS© during DB treatment will be 
tabulated. 
Shifts from baseline showing any changes in suicidal ideation and suicidal behavior during 
DB treatment will also be provided. Subjects will be summarized under the worst of the 
following three categories, shown here in the order from best to worst: 1) No suicidal 
ideation or behavior, 2) Suicidal ideation only, and 3) Suicidal ideation and behavior. 
10.3.4 Analysis of pharmacokinetic variables 
PK analyses will be performed using the PK Set. 
Descriptive statistics (n, mean, standard deviation, coefficient of variation [CV%], m 
[number of non-zero concentrations], geometric mean, geometric standard deviation, 
geometric CV%, median, minimum and maximum) of the ACT-541468 plasma 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 96/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
concentrations collected approximately 9–10 h post-dose (morning after the second PSG 
night) at Visit 6 and Visit 8 will be provided. 
Exposure-safety analysis 
The exposure-safety relationship will be explored using C9–10h (plasma concentrations of 
ACT-541468 in the morning after the second PSG night at Visit 6 and Visit 8) and will be 
based on the PK Set. Safety parameters considered for this analysis will likely include 
selected AEs (e.g., somnolence), changes from baseline in Coding sub-test©, SDS©, VAS 
scores (mm) assessing morning sleepiness, daytime alertness and daytime ability to 
function, and other parameters as relevant. Further details will be described in the SAP. 
10.3.5 Subgroup analyses 
Subgroup analyses will be conducted to explore the uniformity of the overall treatment 
effects with regards to efficacy and safety variables, and will be described in the SAP. 
10.3.6 Analysis of the patient preferences variable 
Discrete choice data from the PAUSe sub-study will be analyzed using multinomial logit, 
random parameter logit, latent class and heteroscedastic conditional logit models. 
Socio-demographic and clinical characteristics, and health literacy and numeracy data will 
be collected from the study participants, and used as covariates for assessing preference 
and scale heterogeneity. The results of the DCE may be used to specify the weights and 
partial value functions in a quantitative benefit-risk assessment (BRA) of insomnia 
treatments. The BRA will be run both deterministically and probabilistically and will 
facilitate a stochastic multicriteria acceptability analysis (SMAA). The SMAA will involve 
running up to 10,000 iterations of the BRA, each time sampling weights and performance 
inputs from pre-specified distributions. Further details on analysis of the PAUSe sub-study 
will be provided in a separate SAP. 
10.4 Interim analyses 
No formal interim analysis will be performed for determining whether to stop (or modify) 
the study early (i.e., no hypothesis testing will be conducted ad interim). Therefore, no 
adjustment for multiple testing is required. This study includes an IDMC and ISB that will 
assess the safety of ACT-541468 on a regular basis as per the IDMC and ISB charters, 
respectively. To support the review of the safety and efficacy data by the IDMC, blinded 
data will be provided by Idorsia (or designated CRO) for the open sessions, and unblinded 
data will be provided by the ISAC for the closed sessions. 
10.5 Sample size 
The assumptions used to calculate sample size are provided in Table 2. 




ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 98/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
reference. Consequently, 900 subjects will provide at least 90% power to detect an effect 
size of 0.37 for testing 9 independent null hypotheses. 
Figure 3 
Effect of testing multiple null hypotheses on power at a given sample 
size 
 
11 DATA HANDLING 
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timeliness of the data reported. All source documents are recommended to be completed 
in a neat, legible manner to ensure accurate interpretation of the data. Data reported in the 
eCRF derived from source documents must be consistent with the source documents. 
eCRF data will be reported through electronic data capture (a web-based tool). The 
investigator and site personnel will be trained to enter and edit the data via a secure 
network, with secure access features (username, password, and identification – an 
electronic password system). A complete electronic audit trail will be maintained. The 
50
60
70
80
90
100
Effect size = 0.37
Number of independent null hypotheses
Power (%)
based on two-sample z-test (alpha = 2.5% two-sided)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
N = 350 per group
N = 300 per group
N = 250 per group


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 99/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
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, VAS, ISI©, 
IDSIQ, PGA-S daytime symptoms, PGI-C daytime and night-time symptoms, PGI-S 
night-time symptoms, SDS©, BWSQ) and on paper (i.e., Coding sub-test©) as well as the 
physician-reported global assessment on a tablet at site (i.e., C-SSRS©, MMSE©, PAUSe) 
and on paper (i.e., MINI©) are considered source data. Site personnel will review and 
ensure completeness and readability of the subjects’ entries. Site personnel will be allowed 
to instigate correction or deletion of subject metadata or answers in physician-reported 
assessments. Site personnel will not be allowed to alter subject-generated data. A data 
correction form will be completed by the site personnel to request any data changes and 
sent to the CRO provider that will process the changes as per CRO data management 
procedures. 
Subject screening and enrollment data will be completed for all subjects (i.e., eligible and 
non-eligible) through the IRT system and eCRF. 
For each subject enrolled, regardless of study treatment initiation, an eCRF must be 
completed and signed by the investigator/delegate. This also applies to those subjects who 
fail to complete the study. If a subject withdraws from the study, the reason must be noted 
on the eCRF. 
11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
Idorsia and any CROs, subjects must be identified only by number and never by their name 
or initials, date of birth, hospital numbers, or any other identifier. The investigator/delegate 
must keep a subject identification code list at the site, showing the screening/randomization 
number, the subject’s name, date of birth, and address or any other locally accepted 
identifiers. Documents identifying the subjects (e.g., signed ICFs) must not be sent to 
Idorsia, and must be kept in strict confidence by the investigator/delegate. 
11.3 Database management and quality control 
eCRFs will be used for all subjects. The investigators will have access to the site eCRF 
data until the database is locked. Thereafter, they will have read-only access. The eCRF 
must be kept current to reflect subject status at any time point during the course of the 
study. 
While entering the data, the investigator/delegate will be instantly alerted to data queries 
by validated programmed checks. Additional data review will be performed by Idorsia 
personnel on an ongoing basis to look for unexpected patterns in data and for study 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 100/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
monitoring. If discrepant data are detected, a query specifying the problem and requesting 
clarification will be issued and visible to the investigator/delegate via the eCRF. All 
electronic queries visible in the system either require a data correction (when applicable) 
and a response from the investigator/delegate to clarify the queried data directly in the 
eCRF, or simply a data correction in the eCRF.  
This process will continue until database closure. 
The investigator/delegate must, on request, supply Idorsia with any required background 
data from the study documentation or clinical records. This is particularly important when 
errors in data transcription are suspected. In the event of health authority queries, it is also 
necessary to have access to the complete study records, provided that subject 
confidentiality is protected. 
Laboratory samples, ECGs, PSGs and hand-held device data will be processed through a 
central laboratory / CRO and the results will be electronically sent to Idorsia. 
If local laboratory data is obtained, as may be required per protocol in certain instances, it 
must be entered in the eCRF by the site personnel. 
AEs are coded according to the latest version of MedDRA used by Idorsia. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made as described in the 
appropriate Idorsia QS documents. After database closure, the investigator will receive the 
eCRFs of the subjects of his/her site (including the audit trail) on electronic media or as a 
paper copy. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
12.1 Ethics and Good Clinical Practice 
Idorsia personnel and the investigators will ensure that the study is conducted in full 
compliance with ICH-GCP Guidelines, the principles of the “Declaration of Helsinki”, and 
with the laws and regulations of the country in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed, and the date of 
approval. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 101/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
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 
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., 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 102/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
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. Study subjects will be reimbursed for the study-related expenses 
(e.g., travel costs, meals, hotel), and may be offered financial compensation for their 
participation in the study only to the extent permitted by applicable local regulations. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB and/or the 
regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform Idorsia or its 
representative in a timely manner. The investigator/delegate must document and explain 
any deviation from the approved protocol. Deviations considered to be a violation of 
ICH-GCP must be reported to the IEC/IRB and regulatory authorities according to Idorsia 
or (overruling) local requirements. 
All protocol deviations will be reported in the CSR. IECs/IRBs will be provided with 
listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, according 
to their requirements. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. A number of attributes are considered of universal importance 
to source data and the records that hold those data. These include that the data and records 
are accurate, legible, contemporaneous, original (or certified copy), attributable, complete, 
consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subjects’ source documents. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 103/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
These records must be kept by the investigator for 25 years to comply with Idorsia’s 
requirements (i.e., as specified in the clinical study agreement), and national and/or 
international regulations, whichever would be the longest period. If the investigator cannot 
guarantee this archiving requirement at the site for any or all of the documents, special 
arrangements, respecting the data confidentiality, must be made between the investigator 
and Idorsia to store these documents outside the site, so that they can be retrieved in the 
event of a regulatory inspection. No study document should be destroyed without prior 
written approval from Idorsia. Should the investigator wish to assign the study records to 
another party, or move them to another location, Idorsia must be notified in advance. 
If the site is using an electronic/computerized system to store subject medical records, it 
can be used for the purpose of the clinical study if it is validated (as per US 21 CFR Part 11 
or equivalent standard) and if the CRA has been provided personal and restricted access to 
study subjects only, to verify consistency between electronic source data and the eCRF 
during monitoring visits. 
If the site is using an electronic/computerized system to store subject medical records but 
it could not be confirmed that the system is validated or if the CRA could not be provided 
access to the system, the site is requested to print the complete set of source data needed 
for verification by the CRA. The printouts must be numbered, stapled together with a 
coversheet, signed and dated by the investigator/delegate to confirm that these certified 
copies are exact copies having the same information as the original source data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per Idorsia’s instructions. If it were not possible for the 
CRA to observe this process, it would not be possible to rely on the site’s certified copies 
and therefore the site cannot be selected for the clinical study. 
12.8 Monitoring 
Prior to study start, a Site Initiation Visit (SIV) will be performed after the required 
essential study documents are approved by Idorsia. The study treatment will be shipped to 
the site upon approval of the required essential documents. 
The PI must ensure that all site personnel involved in the study are present during the SIV 
and will dedicate enough time to it. Site Information Technology support should also be 
available during the SIV. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 104/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
The SIV must be completed before the site can start the screening of study subjects. 
Following the SIV, a copy of the completed initiation visit report and follow-up letter will 
be provided to the PI and filed in the ISF. 
During the study, the CRA will contact and visit the site regularly and must be permitted, 
on request, to have access to study facilities and all source documents needed to verify 
adherence to the protocol and the completeness, consistency, and accuracy of the data being 
entered in the eCRFs and other protocol-related documents. Idorsia monitoring standards 
require full verification that informed consent has been provided, verification of adherence 
to the inclusion/exclusion criteria, documentation of SAEs, and the recording of the main 
efficacy, safety, and tolerability endpoints. Additional checks of the consistency of the 
source data with the eCRFs will be performed according to the study-specific monitoring 
guidelines. The frequency of the monitoring visits will be based on subject recruitment rate 
and critical data-collection times. 
The PI must ensure that the eCRF is completed after a subject’s visit (site visit or telephone 
call), and that all requested subject files (e.g., ICFs, medical notes/charts, other 
documentation verifying the activities conducted for the study) are available for review by 
the CRA. The required site personnel must be available during monitoring visits and allow 
adequate time to meet with the CRA to discuss study-related issues. 
The investigator agrees to cooperate with the CRA(s) to ensure that any issues detected in 
the course of these monitoring visits are resolved. If the subject is hospitalized or dies in a 
hospital other than the study site, the investigator is responsible for contacting that hospital 
in order to document the SAE, in accordance with local regulations. 
A close-out visit will be performed for any initiated site when there are no more active 
subjects and all follow-up issues have been resolved. If a site does not enroll any subjects, 
the close-out visit may be performed prior to study database closure at the discretion of 
Idorsia. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of contents listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is filed. 
This note to file should be present in the specific tab of the document in the ISF. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 105/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Idorsia. If the site needs to transfer the 
ISF to another location and/or if site facility can no longer store the ISF, the PI must 
immediately inform Idorsia. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 
12.10 Audit 
Idorsia’s Pharmaceutical Development group representatives or delegates may audit the 
investigator site (during the study or after its completion). The purpose of this visit will be 
to determine the investigator’s adherence to ICH-GCP, the protocol, and applicable 
regulations; adherence to Idorsia’s requirements (e.g., standard operating procedures) will 
also be verified. Prior to initiating this audit, the investigator will be contacted by Idorsia 
to arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health authorities and/or IECs/IRBs may also conduct an inspection of this study (during 
the study or after its completion) at the site. 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform Idorsia (usually via the CRA) that such a request has been made. 
The investigator and site personnel must cooperate with inspector(s) and allow access to 
all study documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication 
Idorsia will post the key elements of this protocol and the summary of results on Idorsia’s 
Clinical Trial Register and within the required timelines on publicly accessible databases 
(e.g., clinicaltrials.gov, EU database), as required by law and regulation. 
Study results will be documented in a CSR (the PAUSe sub-study results will be reported 
in a separate CSR) that will be signed by Idorsia representatives and the Coordinating 
Investigator. 
In accordance with the Good Publication Practices and ethical practice, the results of the 
study will be submitted for publication in a peer-reviewed journal. Study results can be 
submitted for presentation at a congress before submission to a peer-reviewed journal. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 106/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
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. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 107/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
13 REFERENCES 
[D-15.653] Double-blind, placebo-controlled, randomized, single ascending dose study to 
investigate the tolerability, safety, pharmacokinetics, pharmacodynamics, absolute 
bioavailability, mass balance, and metabolism of ACT-541468 in healthy male 
subjects. Actelion Pharmaceuticals Ltd. Clinical Study Report AC-078-101. 4 March 
2016. 
[D-16.087] A single-center, open-label, randomized, two-way crossover study to 
investigate the effect of multiple-dose diltiazem on the pharmacokinetics of a single 
dose of 25 mg ACT-541468 in healthy male subjects. Actelion Pharmaceuticals Ltd. 
Clinical Study Report AC-078-103. 28 April 2016.  
[D-16.386] Double-blind, placebo-controlled, randomized study to investigate the 
tolerability, safety, pharmacokinetics, and pharmacodynamics of ACT-541468: Part 
A: Multiple-ascending doses in healthy young adults after morning administration; 
Part B: Single-ascending doses in healthy elderly subjects after morning 
administration; Part C: Repeated doses in both healthy young adults and elderly 
subjects after evening administration. Actelion Pharmaceuticals Ltd. Clinical Study 
Report AC-078-102. 7 November 2016. 
[D-17.098] A single-center, open-label study to investigate the food effect on the 
pharmacokinetics of ACT-541468 and the effect of single- and multiple-dose 
ACT-541468 on the pharmacokinetics of midazolam and its metabolite 
1-hydroxymidazolam in healthy male subjects. Idorsia Pharmaceuticals Ltd. Clinical 
Study Report AC-078-104. 28 November 2017. 
[ACT-541468 IB] Investigator’s Brochure for ACT-541468 version 5. Idorsia 
Pharmaceuticals Ltd. January 2018. 
[aasmnet.org] American Academy of Sleep Medicine Standards and Guidelines for the 
Practice of Sleep Medicine, [regularly updated]. Available from: 
 
http://www.aasmnet.org 
[Ambien® USPI] Ambien® (zolpidem) US Package Insert. United States Food and Drug 
Administration full prescribing information; 
https://www.accessdata.fda.gov/drugsatfda_docs/label/2017/019908s038lbl.pdf  
[Ancoli-Israel 1999] Ancoli-Israel S, Roth T. Characteristics of insomnia in the United 
States: results of the 1991 National Sleep Foundation Survey. Sleep. 1999;22 Suppl 
2:S354-58. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 108/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
[APA 2013] American Psychiatric Association. Diagnostic and statistical manual of 
mental disorders, Fifth Edition. Arlington, VA: American Psychiatric Publishing; 
2013. 
[Balter 1991] Balter MB, Uhlenhuth EHJ. The beneficial and adverse effects of hypnotics. 
J Clin Psychiatry. 1991;52 Suppl:16-23.  
[Belsomra® USPI] Belsomra® (suvorexant) US Package Insert. United States Food and 
Drug Administration full prescribing information; 
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/204569s000lbledt.pdf 
[Benca 2004] Benca RM, Ancoli-Israel S, Moldofsky H. Special considerations in 
insomnia diagnosis and management: depressed, elderly, and chronic pain 
populations. J Clin Psychiatry. 2004;65 Suppl 8:26-35. 
[Bowling 2001] Bowling A, Ebrahim S. Measuring patients’ preferences for treatment and 
perceptions of risk. Quality in Health Care. 2001;10(Supplement 1):i2–i8 
[Bretz 2009] Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to 
sequentially rejective multiple test procedures. Stat Med. 2009;28:586-604. 
[Bridges 2011] Bridges JFP, Hauber AB, Marshall D, Lloyd A, Prosser L.A, Regier DA, 
et al. Conjoint Analysis Applications in Health—a Checklist: A Report of the ISPOR 
Good Research Practices for Conjoint Analysis Task Force, Value in Health 
2011;14,403– 413. 
[Buscemi 2007] Buscemi N, Vandermeer B, Friesen C, Bialy L, Tubman M, Ospina M, et 
al. The efficacy and safety of drug treatments for chronic insomnia in adults: a meta-
analysis of RCTs. J Gen Intern Med. 2007;22(9):1335-50. 
[Buysse 2007] Buysse DJ, Thompson W, Scott J, Franzen PL, Germain A, Hall M, et al. 
Daytime symptoms in primary insomnia: a prospective analysis using ecological 
momentary assessment. Sleep Med. 2007 Apr;8(3):198–208. 
[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.  
[Clark 2014] Clark MD, Determann D, Petrou S, Moro D, de Bekker-Grob EW. Discrete 
choice experiments in health economics: a review of the literature. 
Pharmacoeconomics. 2014;32(9):883-902. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 109/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
[Coyle 2001] Coyle D, Wells G, Graham I, et al. The impact of risk on preference values: 
Implications for evaluations of postmenopausal osteoporosis therapy. Value in 
Health. 2001;4(5):385–91.  
[de Lecea 1998] de Lecea L, Kilduff TS, Peyron C, Gao X, Foye PE, Danielson PE, et al. 
The hypocretins: hypothalamus-specific peptides with neuroexcitatory activity. Proc 
Natl Acad Sci USA. 1998;95:322–7. 
[Desarnaud 2004] Desarnaud F, Murillo-Rodriguez E, Lin L, Xu M, Gerashchenko D, 
Shiromani SN, et al. The diurnal rhythm of hypocretin in young and old F344 rats. 
Sleep. 2004;27:851–6. 
[EMA 2011] European Medicines Agency guideline on medicinal products for the 
treatment of insomnia. EMA/CHMP/16274/2009 Rev. 1. 7 February 2011. 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): Guideline for the clinical evaluation of 
hypnotic drugs. September 1977; Available from: 
 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformatio
n/Guidances/UCM071711.pdf 
[FDA 2007] Food and Drug Administration (US) Requests Label Change for All Sleep 
Disorder Drug Products. Available from: 
 
https://www.ptcommunity.com/news/20170421/fda-requests-label-change-all-
sleep-disorder-drug-products 
[FDA 2017] Food and Drug Administration (US): Assessment of Abuse Potential of 
Drugs. January 2017; Available from:  
https://www.fda.gov/downloads/drugs/guidancecomplianceregulatoryinformation/g
uidances/ucm198650.pdf 
[Folstein 1975] Folstein MF, Folstein SE, McHugh PR. “Mini-mental state”: A practical 
method for grading the cognitive state of patients for the clinician. J. Psychiat. Res. 
1975;12:189-98 
[Ford 1989] Ford DE, Kamerow DB. Epidemiologic study of sleep disturbances and 
psychiatric disorders. An opportunity for prevention? JAMA. 1989;262(11): 
1479-84. 
[Fortier-Brochu 2014] Fortier-Brochu E, Morin CM. Cognitive impairment in individuals 
with insomnia: clinical significance and correlates. Sleep. 2014;37(11):1787-98.  


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 110/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
[Hagan 1999] Hagan JJ, Leslie RA, Patel S, Evans ML, Wattam TA, Holmes S, et al. 
Orexin A activates locus coeruleus cell firing and increases arousal in the rat. Proc 
Natl Acad Sci USA. 1999;96:10911–6. 
[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. 
[Hohagen 1994] Hohagen F, Käppler C, Schramm E, Riemann D, Weyerer S, Berger M. 
Sleep onset insomnia, sleep maintaining insomnia and insomnia with early morning 
awakening-temporal stability of subtypes in a longitudinal study on general practice 
attenders. Sleep. 1994;17(6):551-4.  
[Holbrook 2000] Holbrook AM, Crowther R, Lotter A, Cheng C, King D. Meta-analysis 
of benzodiazepine use in the treatment of insomnia. CMAJ. 2000;162(2):225-33. 
[Johns 1991] Johns MW. A new method for measuring daytime sleepiness: the Epworth 
Sleepiness Scale. Sleep. 1991;14(6):540-5. 
[Kales 1978] Kales A, Scharf MB, Kales JD. Rebound insomnia: a new clinical syndrome. 
Science. 1978;201(4360):1039-41.  
[Kilduff 2000] Kilduff TS, Peyron C. The hypocretin/orexin ligand-receptor system: 
implications for sleep and sleep disorders. Trends Neurosci. 2000;23:359–65. 
[Kuriyama 2014] Kuriyama A, Honda M, Hayashino Y. Ramelteon for the treatment of 
insomnia in adults: a systematic review and meta-analysis. Sleep Med. 
2014;15(4):385-92.  
[Léger 2002] Léger D, Guilleminault C, Bader G, Lévy E, Paillard M. Medical and socio-
professional impact of insomnia. Sleep. 2002;25(6):625-9. 
[Lieberman 2007] Lieberman JA. Update on the safety considerations in the management 
of insomnia with hypnotics: incorporating modified-release formulations into 
primary care. Prim Care Companion J Clin Psychiatry. 2007;9(1):25-31. 
[Lin 1999] Lin L, Faraco J, Li R, Kadotani H, Rogers W, Lin X, et al. The sleep disorder 
canine narcolepsy is caused by a mutation in the hypocretin (orexin) receptor 2 gene. 
Cell. 1999;98(3):365-76. 
[Lunesta® USPI] Lunesta® (eszopiclone) US Package Insert. United States Food and Drug 
Administration full prescribing information;  
http://www.accessdata.fda.gov/drugsatfda_docs/label/2014/021476s030lbl.pdf 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 111/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
[McCall 2004] McCall WV. Sleep in the elderly: Burden, diagnosis, and treatment. Prim 
Care Companion J Clin Psychiatry. 2004;6(1):9–20. 
[Mignot 2002] Mignot E, Lammers GJ, Ripley B, Okun M, Nevsimalova S, Overeem S, et 
al. The role of cerebrospinal fluid hypocretin measurement in the diagnosis of 
narcolepsy and other hypersomnias. Arch Neurol. 2002;59(10):1553–62. 
[Morin 1993] Morin CM, Kowatch RA, Barry T, Walton E. Cognitive-behavior therapy 
for late-life insomnia. J Consult Clin Psychol. 1993;61(1):137-46.  
[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. 
[Nutt 2006] Nutt D. GABAA receptors: subtypes, regional distribution, and function. J 
Clin Sleep Med. 2006;2(2):Suppl S7-11.  
[Ohayon 2001] Ohayon MM, Zulley J, Guilleminault C, Smirne S, Priest RG. How age 
and daytime activities are related to insomnia in the general population: 
consequences for older people. J Am Geriatr Soc. 2001;49(4):360–6. 
[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 2004] Ohayon MM, Carskadon MA, Guilleminault C, Vitiello MV. 
Meta-analysis of quantitative sleep parameters from childhood to old age in healthy 
individuals: developing normative sleep values across the human lifespan. Sleep. 
2004;27(7):1255–73. 
[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. 
[Pauker 1981] Pauker SG, McNeil BJ. Impact of patient preferences on the selection of 
therapy. J Chronic Dis. 1981; 34(2–3):77–86 
[Petursson 1981] Petursson H, Lader MH. Benzodiazepine dependence. Br J Addict. 
1981;76(2):133-45. 
[Pigeon 2007] Pigeon WR, Crabtree VM, Scherer MR. The future of behavioral sleep 
medicine. J Clin Sleep Med. 2007;3(1):73-9. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 112/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 
[Pigeon 2010] Treatment of adult insomnia with cognitive-behavioral therapy. J Clin 
Psychol. 2010;66(11):1148–60. 
[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. 
[Rosenthal 1993] Rosenthal L, Roehrs TA, Rosen A, Roth T. Level of sleepiness and total 
sleep time following various time in bed conditions. Sleep. 1993;16(3): 
226-32 
[Roth 2007] Roth T. Insomnia: Definition, Prevalence, Etiology, and Consequences. J Clin 
Sleep Med. 2007;3 Suppl 5:S7-10. 
[Sakurai 2007] Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep and 
wakefulness. Nat Rev Neurosci. 2007;8:171–81. 
[Samson 2010] Samson WK, Bagley SL, Ferguson AV, White MM. Orexin receptor 
subtype activation and locomotor behaviour in the rat. Acta Physiol (Oxf). 
2010;198:313–24. 
[Scharf 2007] Scharf MB, Black J, Hull S, Landin R, Farber R. Long-term nightly 
treatment with indiplon in adults with primary insomnia: results of a double-blind, 
placebo-controlled, 3-month study. Sleep. 2007;30(6):743-52.  
[Schutte-Rodin 2008] Schutte-Rodin S, Broch L, Buysse D, Dorsey C, Sateia M. Clinical 
guideline for the evaluation and management of chronic insomnia in adults. J Clin 
Sleep Med. 2008;4:487–504. 
[Sheehan 1996] Sheehan DV, Harnett-Sheehan K, Raj BA. The measurement of disability. 
Int Clin Psychopharmacol 1996;11 Suppl 3:S89-95  
[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. 
[Simon 1997] Simon GE, VonKorff M. Prevalence, burden, and treatment of insomnia in 
primary care. Am J Psychiatry. 1997;154(10):1417-23. 
[Simpson 2008] Simpson D, Curran MP. Ramelteon: a review of its use in insomnia. 
Drugs. 2008;68(13):1901-19. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 113/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
[Tervonen 2017] Tervonen T, Gelhorn H, Sri Bhashyam S, et al. MCDA swing weighting 
and discrete choice experiments for elicitation of patient benefit-risk preferences: a 
critical assessment. Pharmacoepidemiol Drug Saf. 2017;1–9. 
[Thannickal 2000] Thannickal TC, Moore RY, Nienhuis R, Ramanathan L, Gulyani S, 
Aldrich M, et al. Reduced number of hypocretin neurons in human narcolepsy. 
Neuron. 2000;27(3):469–74. 
[Treat Guidel Med Lett 2009] Drugs for insomnia. Treat Guidel Med Lett. 2009;7:23-6. 
[Tyrer 1990] Tyrer P, Murphy S, Riley P. The Benzodiazepine Withdrawal Symptom 
Questionnaire. J Affect Disord. 1990;19:53-61 
[Zammit 1999] Zammit GK, Weiner J, Damato N, Sillup GP, McMillan CA. Quality of 
life in people with insomnia. Sleep. 1999;22 Suppl 2:S379-85. 
[Zeitzer 2003] Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, Mignot E. 
Circadian and homeostatic regulation of hypocretin in a primate model: implications 
for the consolidation of wakefulness. J Neurosci. 2003;23:3555–60. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 114/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
14 APPENDICES 
Appendix 1 
Alcohol restrictions during the study 
The subjects must not drink alcohol for at least 24 hours prior to the start of the PSG 
assessments, as well as during the PSG assessments including the morning after the second 
PSG assessment, until they leave the center. 
On non-PSG nights, the subjects will be instructed to limit alcohol to a maximum of 
2 drinks per day, and to refrain from drinking alcohol at least 3 hours before going to bed. 
A drink is defined as: 
a.
A bottle/can of 33 cl / 12 ounces of beer (≈14 grams alcohol)
b.
A glass of 10–12 cl / 4 ounces of wine (≈12 grams alcohol)
c.
A small glass of 3–4 cl / 1 ounce of liquor (≈9 grams alcohol)


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 115/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
Appendix 2 
Caffeine content of common beverages 
The content of caffeine in common caffeine beverages is approximately: 
a.
A standard cup of brewed or restaurant-style coffee contains approximately
150–200 mg caffeine.
b.
A can of most soda drinks (unless decaffeinated soda drinks) contains approximately
50 mg caffeine.
c.
A can of energy drink contains approximately 150–200 mg caffeine.


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 116/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
Appendix 3 
Forbidden and restricted concomitant medications 
1.
Forbidden (F) or restricted (R) concomitant medications due to CNS side effects.
To be eligible, subjects must not be treated with CNS-active drugs for 5 half-lives of
the respective drug (but at least 2 weeks) prior to Visit 1. The use of CNS-active
drugs is forbidden or restricted until 24 hours after EOT (Visit 10).
Drug Class 
Examples 
Forbidden / 
Restricted 
Comment 
Centrally Acting 
Anticholinergics 
e.g., tropatepine, oxybutynin,
solifenacin, dimenhydrinate,
dextrometorphan.
F 
Antihistamines 
Sedating: e.g., carbinoxamine, 
triprolidine HCl, acrivastine, 
azatadine, chlorpheniramine, 
doxylamine, hydroxyzine, ketotifen, 
promethazine & timeprazine, 
diphenhydramine HCl. 
F 
Non-sedating: e.g., cetirizine, 
desloratidine, fexofenadine, 
levocabasteine, loratidine. 
R 
Non-sedating 
antihistamines may be used 
maximum twice weekly for 
allergic symptoms. 
Psychotropics 
Stimulants: e.g., amphetamine 
derivatives, ephedrine derivatives, 
modafinil, armodafinil, 
methylphenidate, aripiprazole, 
pramipexole, levodopa. 
F 
Antidepressants: e.g., bupropion, 
citalopram, doxepin, duloxetine, 
escitalopram, fluoxetine, 
fluvoxamine, nefazodone, 
paroxetine, sertraline, trazodone, 
amitriptyline, clomipramine, 
desipramine, imipramine, 
mirtazapine, nortriptyline, 
trimipramine, venlafaxine, 
hydracarbazine, moclobemide, 
selegiline. 
F 
Antipsychotics, including depot 
neuroleptics: e.g., quetiapine, 
olanzapine. 
F 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 117/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
Anxiolytics: e.g., alprazolam, 
buspirone, clorazepate, diazepam, 
flurazepam, lorazepam, midazolam, 
quazepam, temazepam, triazolam. 
F 
Hypnotics: e.g., ramelteon, 
suvorexant, zolpidem and OTC. 
F 
Cholinesterase inhibitors: e.g., 
donepezil, galantamine. 
Mood stabilizers, e.g., 
carbamazepine, gabapentin, 
lamotrigine, lithium, oxcarbazepine, 
pregabalin, valproic acid, tiagabine. 
F 
Opioids/Narcotics: e.g., codeine, 
oxycodone, heroin, marijuana. 
R 
Use of narcotics for pain 
relief must be avoided if 
there are effective 
alternative medications 
(such as NSAIDs) 
Centrally acting muscle relaxants 
with psychotropic effects: e.g., 
methocarbamol, tetrazepam. 
R 
Use of centrally acting 
muscle relaxants must be 
avoided if there are 
effective alternative 
medications (such as 
NSAIDs) 
Herbal preparations with possible 
psychotropic effects: e.g., St John’s 
Wort, valerian, passiflora, 
hypericum. 
F 
Others: e.g., tryptophan, melatonin. 
F 
Anticonvulsants 
Barbiturates, benzodiazepines, 
GABA analogs, hydantoins 
phenyltriazines (e.g., lamotrigine) 
succinimides (e.g., ethosuximide) 
F 
Other 
Warfarin, heparin, ticlopidine 
F 
Isotrenitoin  
F 
Systemic glucocorticoids: e.g., 
dexamethasone, methylprednisone, 
prednisone. 
F 
Inhaled corticosteroids are 
permitted 
Diet pills (prescription and OTC). 
F 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 118/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
Pseudoephedrine 
R 
May only be used before 
2 pm, and no more than 
twice a week. Dosage is 
limited to 30 mg of active 
ingredient in each tablet. 
Extended release 
formulations are forbidden. 
Anti-emetics: e.g., domperidone, 
metoclopramide. 
F 
GABA = gamma-aminobutyric acid; NSAID = nonsteroidal anti-inflammatory drug; OTC = over-the-counter. 
2.
Non-exhaustive list of forbidden concomitant medications and diets due to potential
drug interactions with CYP3A4 (moderate and strong inhibitors, inducers).
Those medications must be discontinued no later than within 1 week prior to Visit 2
and are forbidden until 24 hours after EOT (Visit 10).
CYP3A4 moderate and strong inhibitors and CYP3A4 moderate and strong inducers: 
Inhibitors of CYP3A4 
Inducers of CYP3A4 
HIV antivirals: atazanavir, boceprevir, cobicistat, 
darunavir, delaviridine, fosamprenavir, indinavir, 
lopinavir, nelfinavir, ritonavir, saquinavir, 
telaprevir 
HIV antivirals: efavirenz, etravirine 
Antibiotics: ciprofloxacin, clarithromycin, 
erythromycin, norfloxacin, quinupristin, 
telithromycin, troleandomycin 
Antibiotics: nafcillin, rifabutin, rifampin 
Antifungal: fluconazole, itraconazole, 
ketoconazole, posaconazole, voriconazole 
CNS-active: fluvoxamine, nefazodone 
CNS-active: carbamazepine, fenobarbital, 
modafinil, phenytoin, St. John’s Wort 
Cardiovascular: amiodarone, diltiazem, 
dronedarone, verapamil 
Cardiovascular: bosentan 
Aprepitant, conivaptan, cimetidine, imatinib 
Grapefruit and grapefruit juice 
Seville oranges (bitter) and Seville oranges juice 
CNS = central nervous system; CYP = cytochrome P450; HIV = human immunodeficiency virus. 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 119/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 




ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 121/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 122/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 123/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 124/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 125/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 126/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 127/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 128/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 129/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 130/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 131/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 




ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 133/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 
 
 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 134/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 135/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 136/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 137/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 138/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 139/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 140/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 141/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 142/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 143/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 144/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 145/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 146/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 147/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 148/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 149/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 150/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 151/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 152/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 


ACT-541468 
Insomnia disorder 
Protocol ID-078A301 
Version 4 
30 July 2018, page 153/153 
Confidential 
EudraCT 2017-004642-20 
Doc No D-18.160 

SAP_001.pdf: 
 
 
Cover page 
 
 
 
 
Official Title: 
 
STATISTICAL ANALYSIS PLAN FOR CLINICAL STUDY REPORT  
ID-078A301 - Multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, polysomnography study to assess the efficacy and safety 
of ACT-541468 in adult and elderly subjects with insomnia disorder 
 
 
 
 
ClinicalTrials.gov Identifier:  
 
NCT03545191 
 
 
 
 
Date of document: 
 
25 March 2020 
 
 
 


 
 
 
TPL-100721_v02 
 
 
 
ACT-541468 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
FOR CLINICAL STUDY REPORT  
 
ID-078A301 
 
Version 4 
 
Multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, polysomnography study to assess the efficacy and safety 
of ACT-541468 in adult and elderly subjects with insomnia disorder 
 
 
 
 
Document Number: D-20.054 
 
 
25 March 2020 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 
 
 


ACT-541468 
ID-078A301 
25 March 2020, page 2/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Revision history 
Version date 
Version 
Implemented change(s) 
16 January 2019 
1 
Initial version 
7 August 2019 
2 
 Section 4.1.4: Clarified definition of treatment 
received. 
 Section 5.4.2: Updated the calculation of treatment 
compliance. 
 Section 6.1.7: Updated the Markov Chain Monte 
Carlo (MCMC) imputation model to conform with 
the multivariate normal distribution assumption 
(SAS® code updated accordingly in Section 15).  
 Section 6.3: Added boxplots for sleep architecture 
parameters, and added measurement for Insomnia 
Severity Index© (ISI©) Total score. 
 Section 7.2: Updated the definition of the reporting 
period for treatment-emergent adverse events 
(TEAE), and added the summary of cases sent for 
Independent Safety Board (ISB) adjudication. 
 Section 7.7: Updated the endpoints used to assess 
the potential of rebound insomnia. 
20 February 2020 
3 
 Section 5.4.1: Updated summarized categories for 
the duration of double-blind study treatment. 
 Section 5.4.2: Updated the calculation of treatment 
compliance if wallet not returned. 
 Section 6.1.7: Updated the multiple imputation 
procedure to avoid imputing nonsensical values 
(SAS® code updated accordingly in Section 15).  
 Section 6.3: Added a summary for total sleep time 
by quarter of the night and sleep onset latency. 
Added boxplots for total sleep time and % of total 
sleep time by each quarter of the night. 
 Section 7: Clarified the handling of End-of-
Treatment (EOT) safety assessments in the event of 
premature study treatment discontinuation.  
 Section 7.2: Summary of TEAE added back in.  
 Section 7.4: Updated the definition of subjects at 
risk of having a marked ECG abnormality during 
the treatment withdrawal period. 


ACT-541468 
ID-078A301 
25 March 2020, page 3/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 Section 12.4: Clarified the definition of baseline. 
 Section 13.4: Mentioned additional analysis for vital 
signs and the Columbia-Suicide Severity Rating 
Scale (C-SSRS). 
25 March 2020 
4 
 Section 5.3.4: Clarified which Anatomical 
Therapeutic Chemical (ATC) classification level 
will be presented.  
 Section 5.4.2: Added a condition for the calculation 
of the total duration of treatment interruptions. 
 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 
subjects will be counted. 
 Section 7.9: Added a condition for the assignment 
of the assessments to a study period based on 
scheduled visits. 
 Section 12.2: Added a condition of the double-blind 
(DB) study period definition. 
 Section 15.4: Updated SAS® code for the jump to 
reference (J2R) method. 
 
 
 


ACT-541468 
ID-078A301 
25 March 2020, page 4/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................8 
1 
INTRODUCTION .......................................................................................................10 
2 
STUDY DESIGN AND FLOW ..................................................................................10 
3 
OBJECTIVES .............................................................................................................11 
3.1 
Primary objectives ........................................................................................12 
3.2 
Secondary objectives ....................................................................................12 
3.3 
Safety objectives ...........................................................................................12 
4 
ANALYSIS SETS .......................................................................................................12 
4.1 
Definitions of analysis sets ...........................................................................12 
4.1.1 
Screened analysis set ........................................................................12 
4.1.2 
Full analysis set .................................................................................12 
4.1.3 
Per-protocol set .................................................................................13 
4.1.4 
Safety set ...........................................................................................13 
4.1.5 
Treatment withdrawal set ..................................................................13 
4.1.6 
Pharmacokinetic analysis set ............................................................13 
4.2 
Usage of the analysis sets .............................................................................14 
5 
STUDY SUBJECTS’ VARIABLES AND ANALYSES ...........................................14 
5.1 
Subject disposition ........................................................................................14 
5.1.1 
Screening failures .............................................................................14 
5.1.2 
Study disposition ...............................................................................15 
5.1.3 
Study and study treatment completion/discontinuation ....................16 
5.1.4 
Study enrollment ...............................................................................16 
5.2 
Protocol deviations .......................................................................................17 
5.3 
Subject characteristics ..................................................................................17 
5.3.1 
Demographics and baseline characteristics ......................................17 
5.3.2 
Baseline disease characteristics ........................................................17 
5.3.3 
Previous and concomitant diseases at screening ...............................18 
5.3.4 
Previous and concomitant therapy ....................................................18 
5.4 
Study treatment exposure and compliance ...................................................20 
5.4.1 
Exposure ...........................................................................................20 
5.4.2 
Study treatment compliance ..............................................................21 
6 
EFFICACY VARIABLES AND ANALYSES ...........................................................22 
6.1 
Analysis of the primary and secondary variables .........................................22 


ACT-541468 
ID-078A301 
25 March 2020, page 5/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
6.1.1 
Primary efficacy endpoints ...............................................................22 
6.1.2 
Secondary efficacy endpoints ...........................................................23 
6.1.3 
Overall testing strategy and hypotheses ............................................23 
6.1.4 
Statistical model ................................................................................26 
6.1.5 
Handling of partially missing data ....................................................28 
6.1.6 
Descriptive analyses .........................................................................28 
6.1.7 
Sensitivity analyses ...........................................................................28 
6.1.8 
Supportive analyses ..........................................................................31 
6.1.9 
Subgroup analyses ............................................................................32 
6.2 
Analysis of other efficacy variables .............................................................32 
6.3 
Analysis of exploratory variables .................................................................33 
6.4 
Estimating minimal clinically important differences ...................................36 
6.5 
Patient preferences exploratory endpoints ....................................................36 
7 
SAFETY VARIABLES AND ANALYSES ...............................................................36 
7.1 
Overview of safety analyses including subgroup analyses ..........................36 
7.2 
Adverse events ..............................................................................................37 
7.3 
Laboratory tests ............................................................................................39 
7.4 
Electrocardiography ......................................................................................43 
7.5 
Vital signs and body weight .........................................................................44 
7.6 
Withdrawal symptoms ..................................................................................44 
7.7 
Rebound insomnia ........................................................................................45 
7.8 
Next-day residual effect ................................................................................45 
7.9 
Columbia-Suicide Severity Rating Scale© ...................................................46 
7.10 
Epworth Sleepiness Scale© ...........................................................................47 
7.11 
Subgroup analysis of safety variables ..........................................................48 
8 
PHARMACOKINETIC VARIABLES AND ANALYSES .......................................48 
9 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES .............................48 
9.1 
Exposure-safety analyses ..............................................................................48 
9.2 
Exposure-efficacy analyses ..........................................................................49 
10 GENERAL STATISTICAL METHODOLOGY ........................................................49 
10.1 
Handling of partially missing data ................................................................49 
10.2 
General rules for data presentations .............................................................49 
11 INTERIM ANALYSES ..............................................................................................50 
12 GENERAL DEFINITIONS AND DERIVATIONS ...................................................50 
12.1 
Treatment start and end dates .......................................................................50 


ACT-541468 
ID-078A301 
25 March 2020, page 6/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
12.2 
Study periods ................................................................................................50 
12.3 
Treatment day and Study day .......................................................................51 
12.4 
Baseline ........................................................................................................52 
12.5 
Change from baseline ...................................................................................52 
12.6 
Handling of data when total sleep time is zero .............................................52 
12.7 
Missing data patterns ....................................................................................52 
12.8 
Time window definitions for calculating subjective endpoints ....................53 
13 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................54 
13.1 
Changes to the analyses planned in the study protocol ................................54 
13.2 
Changes in the conduct of the study / data collection ..................................55 
13.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................55 
13.4 
Additional analyses as compared to the study protocol ...............................55 
14 REFERENCES ............................................................................................................56 
15 APPENDICES .............................................................................................................57 
15.1 
SAS® code for Mixed Model for Repeated Measures ..................................57 
15.2 
SAS® code for multiple imputation with MCMC for monotone 
missingness mechanism ................................................................................57 
15.3 
SAS® code for multiple imputation under MAR assumption .......................57 
15.4 
SAS® code for multiple imputation under MNAR assumption for 
jump to reference method .............................................................................58 
15.5 
SAS® code for multiple imputation under MNAR assumption for 
delta-adjusted (tipping point) ........................................................................59 
 
 
 
 


ACT-541468 
ID-078A301 
25 March 2020, page 7/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
LIST OF TABLES 
 
Table 1 
Imputation rules for an incomplete or missing concomitant therapy date ..... 20 
Table 2 
Insomnia Daytime Symptoms and Impacts Questionnaire description ......... 33 
Table 3 
Imputation rules for an incomplete or missing AE date ................................ 39 
Table 4 
Marked abnormalities in laboratory parameters for reporting ....................... 40 
Table 5 
Marked abnormalities in ECG parameters ..................................................... 44 
Table 6 
Meaning of the first and last PSG end date at Visits 3, 6 and 8 ..................... 53 
Table 7 
Time windows (in days) to calculate weekly averages for certain 
subjective endpoints ....................................................................................... 54 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design for ID-078A301 ........................................................................ 11 
Figure 2 
Hypothesis testing strategy ............................................................................ 25 
 
 
 
 


ACT-541468 
ID-078A301 
25 March 2020, page 8/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
BMI  
Body mass index 
BWSQ  
Benzodiazepine Withdrawal Symptom Questionnaire 
CI  
Confidence interval 
CSR  
Clinical study report 
C-SSRS©  
Columbia-Suicide Severity Rating Scale© 
DB  
Double-blind 
ECG  
Electrocardiogram/graphy 
eCRF  
Electronic case report form 
EODBT  
End-of-Double-Blind-Treatment 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
ESS©  
Epworth Sleepiness Scale© 
FAS  
Full analysis set 
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© 
J2R  
Jump to reference 
LPS  
Latency to Persistent Sleep 
LS  
Least squares 
MAR  
Missing at random 
MCMC  
Markov Chain Monte Carlo 
MedDRA  
Medical Dictionary for Regulatory Activities 
MI  
Multiple imputation 
MMRM  
Mixed model for repeated measures 


ACT-541468 
ID-078A301 
25 March 2020, page 9/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
MNAR  
Missing not at random 
PD  
Protocol deviation 
PGA-S  
Patient Global Assessment of Disease Severity 
PGI-C  
Patient Global Impression of Change 
PGI-S  
Patient Global Impression of Severity 
PK  
Pharmacokinetic 
PPS  
Per-protocol set 
PSG  
Polysomnography 
PT  
Preferred term 
REM  
Rapid eye movement 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SCR set  
Screened analysis set 
SD  
Standard deviation 
SDS©  
Sheehan Disability Scale© 
SI  
Standard international 
sLSO  
Subjective Latency to Sleep Onset 
SOC  
System organ class 
SS  
Safety set 
sTST  
Subjective Total Sleep Time 
sWASO  
Subjective Wake After Sleep Onset 
SWS  
Slow wave sleep 
TBIL  
Total bilirubin 
TEAE  
Treatment-emergent adverse event 
TST  
Total Sleep Time 
TWS  
Treatment withdrawal set 
ULN  
Upper limit of normal 
VAS  
Visual analog scale(s) 
WASO  
Wake After Sleep Onset 
WHO  
World Health Organization 
 


ACT-541468 
ID-078A301 
25 March 2020, page 10/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
1 
INTRODUCTION 
This statistical analysis plan (SAP) describes in detail the analyses and data presentation 
for the clinical study report (CSR) prepared for ID-078A301.  
Obvious corrections to address minor formatting errors or spelling mistakes may be 
performed at the time of analysis without amending this and related documentation (e.g., 
mock shells).  
Data will be analyzed by Idorsia and/or designated contract research organizations 
supervised by Idorsia using SAS® version 9.4 or higher and R version 3.4.3 or higher.  
The analyses for the Independent Data Monitoring Committee (IDMC) closed session 
meetings will be performed by an Independent Statistical Analysis Center (ISAC) and are 
detailed in a separate SAP.  
Protocol ID-078A301, Final Version 4, dated 30 July 2018 was used when writing this 
SAP. 
A sub-study will be performed to collect data on subject preferences, which aims to enroll 
at least 360 subjects from the USA and Germany who are part of the approximately 
900 subjects enrolled in the ID-078A301. The statistical analyses of the sub-study will be 
detailed in a separate document and reported separately.  
Unless noted otherwise, summaries will be produced by treatment group [see Section 10.2]. 
2 
STUDY DESIGN AND FLOW 
This is a 3-month, multi-center, double-blind, randomized, placebo-controlled, 
parallel-group, Phase 3 study to assess the efficacy and safety of two doses (25 mg and 
50 mg) of ACT-541468 in subjects with insomnia disorder. 
Approximately 900 subjects per study will be randomized to either 25 mg ACT-541468, 
50 mg ACT-541468 or placebo, in a 1:1:1 ratio.  
Treatment allocation is further stratified by age into two categories: < 65 and ≥ 65 years. 
Approximately 40% of subjects will be elderly subjects (≥ 65 years old), of which 
approximately 5% will be above 75 years old. 
The study will be conducted at approximately 75 sites in 10 countries. 
The study design is shown in Figure 1. 


ACT-541468 
ID-078A301 
25 March 2020, page 11/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Figure 1 
Study design for ID-078A301 
 
▬ = polysomnography nights; EODBT = End-of-Double-Blind-Treatment; EOS = End-of-Study; EOT = End-of-
Treatment, V = Visit. 
 
The study comprises the following 3 phases: the screening phase, the treatment phase and 
the safety follow-up phase.  
The screening phase starts with the signing of the informed consent form at Visit 1 and 
ends at Randomization at Visit 4. It includes the Screening period (from Visit 1 to Visit 2) 
and the Run-in period (from Visit 2 to Visit 4).  
The double-blind (DB) treatment phase starts with the first dose of DB study treatment 
in the first evening of the randomization visit (Visit 4) and lasts until the second morning 
of Visit 8 after all second morning assessments have been performed, i.e., 
End-of-Double-Blind-Treatment (EODBT). 
The safety follow-up phase starts from EODBT and lasts until End-of-Study (EOS). It 
consists of a single-blind placebo Run-out period (from the evening of Visit 9 until after 
all visit assessments have been performed at Visit 10, i.e., End-of-Treatment [EOT]) and a 
Safety follow-up period (from EOT until EOS). 
See Section 12.2 for detailed definitions of the study periods. 
Subjects who do not prematurely discontinue DB study treatment and who complete the 
Run-out period will be eligible to enter the ID-078A303 extension study. The statistical 
analyses for ID-078A303 CSR will be detailed in a separate document and reported 
separately.  
3 
OBJECTIVES 
The main objectives of the study are to assess efficacy and safety of ACT-541468 in 
subjects with insomnia disorder. 


ACT-541468 
ID-078A301 
25 March 2020, page 12/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Efficacy will be evaluated primarily by the drug effects on sleep onset and sleep 
maintenance. 
3.1 Primary objectives 
To evaluate the efficacy of 25 mg and 50 mg ACT-541468 on objective sleep parameters 
in subjects with insomnia disorder. 
3.2 Secondary objectives 
To evaluate the efficacy of 25 mg and 50 mg ACT-541468 on subjective sleep parameters 
and next-day functioning in subjects with insomnia disorder. 
3.3 Safety objectives 
To assess the safety and tolerability of ACT-541468 in subjects with insomnia disorder 
during treatment and upon treatment discontinuation. 
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. Any subject 
excluded along with reason(s) for exclusion from Per-protocol set (PPS), Treatment 
withdrawal set (TWS), or Pharmacokinetic (PK) analysis set will be summarized and listed. 
4.1.1 Screened analysis set 
The Screened analysis set (SCR set) comprises all subjects who entered screening and have 
a subject identification number.  
Summaries based on the SCR 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 to. 
4.1.2 Full analysis set 
The Full analysis set (FAS) comprises all subjects assigned (i.e., randomized) to a DB 
study treatment.  
In order to adhere to the intention-to-treat principle as much as possible:  
 Subjects will be evaluated according to the treatment and strata they have been 
assigned to, which may differ from the treatment they received.  
 All available data will be included. 


ACT-541468 
ID-078A301 
25 March 2020, page 13/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
4.1.3 Per-protocol set 
The PPS comprises all subjects from the FAS who received at least one dose of DB study 
treatment and who complied with the protocol sufficiently to be likely to exhibit the 
treatment effects.  
Criteria for sufficient compliance: 
 Absence of major protocol deviations (i.e., those leading to exclusion from the PPS), 
as defined in a separate protocol deviation (PD) document that will be finalized 
before unblinding treatment codes.  
 DB study treatment compliance is ≥ 70% (as calculated in Section 5.4.2). 
Subjects not meeting the criteria for sufficient compliance will be excluded from the PPS. 
Subjects will be evaluated according to the treatment they have been assigned and actual 
stratum they belong to. 
4.1.4 Safety set 
The Safety set (SS) comprises all subjects who received at least one dose of DB study 
treatment.  
Subjects will be evaluated according to the actual treatment they received, which may 
differ from the randomly assigned treatment. 
Actual treatment received is defined as: 
 the assigned DB study treatment when received at least once, 
 the first DB study treatment received if the assigned DB study treatment was never 
received. 
4.1.5 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, which may 
differ from the randomly assigned treatment. 
4.1.6 Pharmacokinetic analysis set 
The PK set comprises all subjects in the SS who have at least one PK sample collected 
after initiation of DB study treatment.  
Subjects will be evaluated according to the actual treatment they received. Subjects 
receiving placebo will be excluded from the PK set. 


ACT-541468 
ID-078A301 
25 March 2020, page 14/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
4.2 Usage of the analysis sets 
The analyses of efficacy endpoints as well as demographic and baseline disease 
characteristics will be performed using the FAS, and the PPS for certain sensitivity 
analyses. 
The SS will be used for the analysis of safety endpoints (including previous and 
concomitant medications, and study treatment exposure). 
The TWS will be used for the analysis of endpoints used to assess withdrawal symptoms 
(e.g., Benzodiazepine Withdrawal Symptom Questionnaire [BWSQ] Total score) and 
rebound insomnia (i.e., objective sleep parameters Wake After Sleep Onset [WASO], 
Latency to Persistent Sleep [LPS] and subjective TST [sTST]). 
The PK set will be used for the analysis of ACT-541468 plasma concentrations 9–10 h 
post-dose. 
5 
STUDY SUBJECTS’ VARIABLES AND ANALYSES 
5.1 Subject disposition 
5.1.1 Screening failures 
Screening failures will be summarized based on the SCR set and will include:  
 Number (%) of subjects who discontinued during the screening phase (based on ‘Was 
the subject randomized?’ recorded as ‘No’ in the ‘Randomization’ page); this 
summary will be broken down as follows: 
– Number (%) of subjects who discontinued during the Screening period (based on 
‘Was the subject randomized?’ recorded as ‘No’ in the ‘Randomization’ page, and 
missing ‘Treatment start date’ in the ‘Study Single-Blind [Run-In] Treatment 
Log’ page).  
– Number (%) of subjects who discontinued during the Run-in period (based on 
‘Was the subject randomized?’ recorded as ‘No’ in the ‘Randomization’ page, and 
a non-missing ‘Treatment start date’ in the ‘Study Single-Blind [Run-In] 
Treatment Log’ page). 
 Primary reason for screening phase discontinuation (based on reason for not 
randomized entered on the ‘Randomization’ page); this summary will be broken 
down as follows: 
– Primary reason for Screening period discontinuation (based on reason for not 
randomized entered on the ‘Randomization’ page for subjects missing ‘Treatment 
start date’ in the ‘Study Single-Blind [Run-In] Treatment Log’ page). 
– Primary reason for Run-in period discontinuation (based on reason for not 
randomized entered on the ‘Randomization’ page for subjects with a non-missing 
‘Treatment start date’ in the ‘Study Single-Blind [Run-In] Treatment Log’ page). 


ACT-541468 
ID-078A301 
25 March 2020, page 15/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
– Primary reason for premature single-blind placebo treatment discontinuation in 
the run-in period (based on reason for treatment discontinuation entered on the 
‘Study Single-Blind [Run-In] Treatment Log’ page). 
All reasons for screening failure will be listed using the SCR set.  
Of note, subjects are not permitted to be re-screened. 
5.1.2 Study disposition  
Study disposition will be summarized based on the SCR set, presented by randomized 
treatment group and all screened subjects combined, and will include:  
 Number of subjects screened.  
 Number (%) of subjects treated in the single-blind placebo treatment run-in period 
(based on a non-missing ‘Treatment start date’ in the ‘Study Single-Blind [Run-In] 
Treatment Log’ page).  
 Number (%) of subjects who completed single-blind placebo treatment run-in period 
(based on ‘Reason for treatment stop’ entered as ‘Completion as per protocol’ in the 
‘Study Single-Blind [Run-In] Treatment Log’ page). 
 Number (%) of subjects randomized (based on non-missing randomization number).  
 Number (%) of subjects treated in the DB study period (based on non-missing 
‘Treatment start date’ in the ‘Study Double Blind Treatment Log’ page).  
 Number (%) of subjects who completed the DB study period (based on ‘Reason for 
treatment stop’ entered as ‘Completion as per protocol’ in the ‘Study Double Blind 
Treatment Log’ page). 
 Number (%) 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 (%) of subjects who completed 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). 
 Number (%) of subjects completing the study (based on ‘Did the subject complete the 
study?’ recorded as ‘Yes’ in the ‘End of Study Status’ page). 
 Number (%) of subjects completing the study and not entering the extension study 
(based on ‘Did the subject complete the study?’ recorded as ‘Yes’ in the ‘End of 
Study Status’ page, and ‘Did the subject sign the informed consent to participate in 
the extension study?’ recorded as ‘No’ in the ‘Study Extension’ page). 
 Number (%) of subjects entering the extension study (based on ‘Did the subject sign 
the informed consent to participate in the extension study?’ recorded as ‘Yes’ in the 
‘Study Extension’ page). 


ACT-541468 
ID-078A301 
25 March 2020, page 16/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
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 (%) of subjects who prematurely discontinued DB study treatment (based on 
reason for treatment stop entered as ‘Discontinuation’ in the ‘Study Double Blind 
Treatment Log’ page).  
 Primary reason for premature DB study treatment discontinuation (based on reason 
for treatment discontinuation entered on the ‘Study Double Blind Treatment Log’ 
page). 
All reasons for premature DB 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 (%) 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).  
All reasons for premature study discontinuation will be listed based on the FAS. 
The following summary will be based on the TWS and presented by treatment group and 
all treatment groups combined: 
 Number (%) 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 TWS. 
5.1.4 Study enrollment 
The number (%) 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. 


ACT-541468 
ID-078A301 
25 March 2020, page 17/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
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, 
Investigational Medicinal Product, study conduct/procedure, forbidden medication, 
withdrawal criteria and other) by treatment group and all treatment groups combined.  
A subject with multiple occurrences of a protocol deviation is counted only once per 
protocol deviation category.  
A listing of protocol deviations will be provided using the FAS. 
5.3 Subject characteristics 
Unless noted otherwise, summaries and listings described in this section will be based on 
the FAS.  
Summaries will be produced by treatment group and all treatment groups combined. Data 
will be listed individually by subject. 
5.3.1 Demographics and baseline characteristics 
Demographic data at screening, including age, sex, race, ethnicity, height, weight, body 
mass index (BMI) and region (US, other), will be summarized and listed.  
The number (%) of subjects randomized in each age category (< 18, 18 – < 65, 65 – < 75, 
75 – < 85, 65 – < 85, ≥ 85 years at screening), in each BMI category (< 25, 25 – 30, 
> 30 kg/m2 at screening), and in each region (US, other) will be further summarized.  
The number of subjects treated in each age category (< 18, 18 – < 65, 65 – < 85 and 
≥ 85 years at screening) by sex will be summarized based on the SS.  
5.3.2 Baseline disease characteristics 
Baseline disease characteristics 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, 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 (if only the day is missing) or 1st of July (if day and month 
are missing).  


ACT-541468 
ID-078A301 
25 March 2020, page 18/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
If the insomnia diagnosis imputed date is after the randomization date, then the 
randomization date –1 day will be used as insomnia diagnosis date.  
5.3.3 Previous and concomitant diseases at screening 
Relevant medical history and current medical conditions will be coded using MedDRA 
terminology.  
Any disease or diagnosis is defined as previous if ‘Ongoing at informed consent signed’ is 
answered as ‘No’; all other diseases/diagnoses are considered as study concomitant (where 
answer is ‘Yes’).  
Medical history and current (ongoing) medical conditions, excluding insomnia-related 
conditions and symptoms, will be summarized separately and listed. Summaries will be 
presented for each treatment group by primary system organ class (SOC) and preferred 
term (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 Previous and concomitant therapy 
Therapies collected will be coded using the WHO Drug Global reference dictionary that 
employs the WHO Anatomical Therapeutic Chemical (ATC) classification system. The 
WHO Drug Global version used for reporting will be specified in the footnote of the 
applicable output.  
Previous therapies are any treatments for which the end date is prior to signing of the 
informed consent form. A previous therapy is to be recorded in the ‘Previous/Concomitant 
Medication’ page if discontinued less than 30 days prior to signing of the informed consent 
form, however, all previous therapies recorded will be reported.  
Study-concomitant therapies are any treatments that are either ongoing at the signing of 
informed consent, or initiated during the time from the signing of informed consent 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 ‘Previous/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 DB study treatment or 
initiated during the DB study period until 1 day after the last dose of DB study treatment.  
Number (%) of subjects having taken at least one previous or concomitant therapy will be 
summarized by ATC classification level 4 (or next highest available level) and individual 
preferred name within each ATC classification based on the SS. Previous and concomitant 


ACT-541468 
ID-078A301 
25 March 2020, page 19/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
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 previous, study-concomitant and DB study 
treatment-concomitant therapies separately. An additional summary table will be provided 
for DB study treatment concomitant therapies at Baseline (i.e., therapy started on, or is 
ongoing at, the DB study treatment start date). All concomitant therapies will be listed 
using the SS. The period (e.g., run-in, DB, run-out [Section 12.2]) for which the 
concomitant therapy started will be displayed in the listing and those related to an adverse 
event (AE) will be flagged. 
The number (%) of subjects currently on cognitive behavioral therapies and reasons for not 
using cognitive behavioral therapy will be summarized and listed using both the FAS and 
the SCR set. Cognitive behavioral therapy is not coded. 
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. 


ACT-541468 
ID-078A301 
25 March 2020, page 20/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
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. If the (imputed) concomitant therapy end date 
is on or after the start of DB study treatment, and 
if the DB study treatment start falls within the 
upper and lower limits (inclusive), the DB study 
treatment start date is used. 
2. If the (imputed) concomitant therapy end date 
is on or after the start of run-in single-blind 
placebo treatment, and if the run-in single-blind 
placebo treatment start falls within the upper and 
lower limits (inclusive), the run-in single-blind 
placebo treatment start date is used. 
3. If the concomitant therapy resolution date is 
missing, and: 
a. if the DB study treatment start falls within the 
upper and lower limits (inclusive), the DB study 
treatment start date is used; 
else: 
b. if the run-in single-blind placebo treatment 
start falls within the upper and lower limits 
(inclusive), the run-in single-blind placebo 
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 
DB study treatment start date. 
DB = double-blind. 
 
The purpose of imputing concomitant therapy dates is only to assign a concomitant therapy 
to a specific treatment phase for the summary tables. No imputed date is considered in the 
medical evaluation of a concomitant therapy causal relationship to 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.  
5.4.1 Exposure 
The duration of single-blind placebo run-in treatment, DB study treatment, and single-blind 
placebo run-out treatment (including categories: ≤ 1, > 1 – 2, > 2 – 3, > 3 – 4, > 4 – 6, 


ACT-541468 
ID-078A301 
25 March 2020, page 21/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
> 6 – 8, > 8 – 10, > 10 – 11, > 11 – 12, > 12 – 13, > 13 weeks for DB study treatment; 0, 
> 0 – 2, > 2 – 5, > 5 – 9, > 9 – 14, > 14 – 20, > 20 days for single-blind placebo run-in 
treatment; and 0, 1, 2, 3, 4, 5, 6, 7, 8, 9, ≥ 10 days for single-blind placebo run-out 
treatment) and duration in subject-years will be summarized. The definition of a year is 
365.25 days.  
The duration of treatment (in days) is defined as the difference between the respective 
(run-in/DB/run-out) treatment end date and the respective (run-in/DB/run-out) treatment 
start date plus one day. This calculation ignores periods of treatment interruption. The 
summary for run-out will be based on the TWS. 
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.  
Study treatment compliance per wallet dispensed is entered in the electronic case report 
form (eCRF) for the Run-in period, the DB study period, and the Run-out period and will 
only be listed.  
The following formula will be used to calculate compliance for each of these periods: 
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 wallet (e.g., it is lost), compliance will not be calculated and 
the compliance for the period will be set to missing. 
Treatment duration and total duration of treatment interruptions in Run-in, DB, or Run-out 
periods are calculated using the dedicated eCRF page ‘Study Treatment Log’ as follows:  
 Treatment duration (days) = date of last drug intake of DB study treatment 
(run-in / run-out single-blind placebo treatment) – date of first drug intake of DB 
study treatment (run-in / run-out single-blind placebo treatment) + 1 day. 
 Total duration of treatment interruptions (days) is the sum of all the treatment 
interruptions’ durations. A treatment interruption duration = date restarted DB study 
treatment (run-in / run-out single-blind placebo treatment) – end date of DB study 
treatment (run-in / run-out single-blind placebo treatment) due to an interruption 
1 day. For example, if a subject stopped his/her treatment on 19MAR2019 and started 
again on 23MAR2019, as the treatment is taken on the start and end dates, 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. 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, 


ACT-541468 
ID-078A301 
25 March 2020, page 22/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
the start date of the next study period will be used as the date restarted study treatment 
of the given study period. E.g., if a subject completed DB 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 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 and percentage of days treated (including categories 0%, > 0% – < 50%, 50% 
– < 70%, 70% – < 80%, 80% – < 90%, 90% – < 100%, 100%) will be summarized for 
Run-in, DB and Run-out periods, separately. The summaries of the Run-out period will be 
based on the TWS. 
The number (%) 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 the primary and secondary variables 
6.1.1 Primary efficacy endpoints 
The primary efficacy endpoints of this study are measured during polysomnography (PSG) 
nights and defined as: 
 Change from baseline to Month 1 in WASO (sleep maintenance). 
 Change from baseline to Month 3 in WASO. 
 Change from baseline to Month 1 in LPS (sleep onset). 
 Change from baseline to Month 3 in LPS. 
LPS is the time (in minutes) from start of recording to the beginning of the first continuous 
20 epochs (i.e., 10 min) scored as non-awake, i.e., epochs scored as either sleep stage 1 
(S1), sleep stage 2 (S2), sleep stage 3 (slow wave sleep [SWS]), or rapid eye movement 
(REM), as determined by PSG. 


ACT-541468 
ID-078A301 
25 March 2020, page 23/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
WASO is the time (in minutes) spent awake after onset of persistent sleep until lights on, 
as determined by PSG. 
Baseline is the mean of the two PSG nights at Visit 3 during the Run-in period. Month 1 
and Month 3 are the mean of the two PSG nights at Visit 6 and Visit 8, respectively. 
6.1.2 Secondary efficacy endpoints 
The secondary efficacy endpoints of this study are measured on patient questionnaires and 
defined as: 
 
Change from baselinea to Month 1b in sTST. 
 
Change from baselinea to Month 3c in sTST.  
 
Change from baselinea to Month 1b in IDSIQ Sleepiness domain score. 
 Change from baselinea to Month 3c in IDSIQ Sleepiness domain score. 
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?”. 
The Insomnia Daytime Symptoms and Impacts Questionnaire (IDSIQ) is a patient-reported 
outcome measure structured in 3 domains (Alertness/Cognition; Mood; Sleepiness). The 
IDSIQ Sleepiness domain score is based on the sum of the responses reported by the subject 
for 4 items: item 8, 11, 12, and 13. Item 8 score is reversed prior to summing [see 
Section 6.2]. The IDSIQ Sleepiness domain score can range from 0 to 40 (whole numbers 
only) with higher scores indicating greater burden during the daytime. 
a Baseline is the mean value based on the screening sleep diary / IDSIQ entries performed 
at home in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 8. 
6.1.3 Overall testing strategy and hypotheses 
The Type I error rate will be controlled for the testing of multiple null hypotheses 
associated with the primary and secondary endpoints assessed at 1 and 3 months of 
treatment and the two dose levels included in this study (i.e., 25 mg and 50 mg). 
The eight statistical null hypotheses associated with the primary efficacy endpoints are: 
Sleep maintenance: 
 
H1WASO: Higher Dose – Placebo = 0 for WASO at Month 1. 
 
H2WASO: Higher Dose – Placebo = 0 for WASO at Month 3. 
 
H3WASO: Lower Dose – Placebo = 0 for WASO at Month 1. 


ACT-541468 
ID-078A301 
25 March 2020, page 24/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 H4WASO: Lower Dose – Placebo = 0 for WASO at Month 3. 
Sleep onset: 
 
H1LPS: Higher Dose – Placebo = 0 for LPS at Month 1. 
 
H2LPS: Higher Dose – Placebo = 0 for LPS at Month 3. 
 
H3LPS: Lower Dose – Placebo = 0 for LPS at Month 1. 
 H4LPS: Lower Dose – Placebo = 0 for LPS at Month 3. 
The eight statistical null hypotheses associated with the secondary efficacy endpoints are: 
Sleep quantity: 
 
H1sTST: Higher Dose – Placebo = 0 for sTST at Month 1. 
 
H2sTST: Higher Dose – Placebo = 0 for sTST at Month 3. 
 
H3sTST: Lower Dose – Placebo = 0 for sTST at Month 1. 
 H4sTST: Lower Dose – Placebo = 0 for sTST at Month 3. 
Next-day performance: 
 
H1IDSIQ: Higher Dose – Placebo = 0 for IDSIQ Sleepiness domain score at Month 1. 
 
H2IDSIQ: Higher Dose – Placebo = 0 for IDSIQ Sleepiness domain score at Month 3. 
 
H3IDSIQ: Lower Dose – Placebo = 0 for IDSIQ Sleepiness domain score at Month 1. 
 H4IDSIQ: Lower Dose – Placebo = 0 for IDSIQ Sleepiness domain score at Month 3. 
where ‘Higher Dose’, ‘Lower Dose’ and ‘Placebo’ represent the mean change from 
baseline for the given endpoint (WASO, LPS, sTST or IDSIQ Sleepiness domain score) 
and time point (Month 1 or Month 3) for the 50 mg, 25 mg and placebo treatment group, 
respectively. 
Each null hypothesis will be tested against the alternative hypothesis that ACT-541468 
improves the respective endpoint at the given dose and time point compared to placebo. 
The order of testing and the alpha level applied to each null hypothesis will be based on 
the Bonferroni-based gatekeeping procedure [Bretz 2009] (shown in Figure 2 as a directed 
graph) that will control the study-wise Type I error at a two-sided 5% significance level.  
To account for the concurrent evaluation (multiple comparison) of two distinct endpoint 
categories (i.e., sleep maintenance and sleep onset) a Bonferroni correction is applied. Both 
endpoint categories will be tested at half of the two-sided 5% significance level. This 
supports the sponsor’s intention to make a superiority claim vs placebo for efficacy in 
either a sleep maintenance and/or sleep onset indication.  
The remaining hypotheses will be tested following the gatekeeping strategy moving from 
Month 1 to Month 3 for higher dose ACT-541468 vs placebo and then from Month 1 to 
Month 3 for lower dose ACT-541468 vs placebo. The pre-specified proportion of alpha 
(weight) that will be distributed once a given null hypothesis (node) is rejected is shown 


ACT-541468 
ID-078A301 
25 March 2020, page 25/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
on the arrow in the directed graph. If a certain null hypothesis cannot be rejected, then the 
alpha level used for that test is absorbed at that node and not distributed further. 
Figure 2 
Hypothesis testing strategy 
 
 


ACT-541468 
ID-078A301 
25 March 2020, page 26/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
The graph is sequentially updated after rejection of a hypothesis following the algorithm 
below (algorithm 1 presented in Bretz 2009): 
 
0. Set I = M. 
 
1. Let j=arg miniꞓI pi / αi 
 
2. pj ≤ αj, reject Hj ; otherwise stop. 
 
3. Update the graph: 
 
 
I → I \ {j} 
 
 
αl → {𝛼𝑙 + 𝛼𝑗 𝑔𝑗𝑙 , 𝑙 𝜖 𝐼 
0            𝑜𝑡ℎ𝑒𝑟𝑤𝑖𝑠𝑒 
 
 
 
glk → {
𝑔𝑙𝑘+ 𝑔𝑙𝑗𝑔𝑗𝑘
1− 𝑔𝑙𝑗𝑔𝑗𝑙 , 𝑙, 𝑘 𝜖 𝐼, 𝑙≠𝑘
0                          𝑜𝑡ℎ𝑒𝑟𝑤𝑖𝑠𝑒
 
 
 
4. If |I|≥ 1, go to step 1; otherwise stop. 
Where g are the weights, α the local significance, p the observed unadjusted two-sided 
p-values from the statistical model [see Section 6.1.4] for M null hypotheses and I denotes 
the associated index set (i.e., the given set of non-rejected null hypotheses to be tested).  
The initial graph and the algorithm unequivocally define the multiple test strategy because 
the test decisions are independent of the rejection sequence [Bretz 2009]. In other words, 
the final result (i.e., the rejection or non-rejection of a given null hypothesis) will always 
be the same regardless of the order in which the hypotheses are tested. 
6.1.4 Statistical model 
All available data, regardless of the occurrence of any type of potential intercurrent event 
(e.g., study treatment discontinuation for any reason, the use of prohibited medication for 
any reason) will be included in the analyses. This approach (labeled in ICH E9[R1] as the 
treatment policy strategy) aligns, as close as possible, to the intention-to-treat principle, 
and is believed to provide an estimate of the treatment effect that is appropriate for 
regulatory and clinical decision-making. 
The occurrence of intercurrent events in ID-078A301 is expected to be low. In the Phase 2 
study (AC-078A201) of 1-month duration, no subjects (out of 356) took prohibited 
medication during treatment, and 3.9% (14 subjects) discontinued treatment prematurely. 
In 4 subjects, treatment discontinuation was due to AEs: 2 subjects on 10 mg ACT-541468, 
1 subject on 50 mg ACT-541468, and 1 subject on 10 mg zolpidem. 7 subjects 
discontinued treatment for ‘Other’ reasons (withdrawal of consent, 2 subjects; subject 
randomized in error / randomization criteria not met, 4 subjects; change in subject’s work 
schedule, 1 subject). In addition, 3 subjects discontinued DB study treatment with no 


ACT-541468 
ID-078A301 
25 March 2020, page 27/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
reason provided. No differences across treatment groups in the reasons or rates of 
premature treatment discontinuation was evident. However, it is acknowledged that the 
rate of intercurrent events is likely to be slightly higher in the Phase 3 studies due to the 
increased number of centers and the longer duration (3 months) for some of the endpoints. 
It is expected that the type and occurrence of intercurrent events are similar across 
treatment groups. Therefore, the efficacy data collected following the occurrences of a 
intercurrent events are, on average, likely to be similar across treatment groups, diluting 
the treatment effect slightly. However, this seems reasonable since occurrence of 
intercurrent events are more likely due to unfavorable conditions, again providing an 
estimate of the treatment effect that is appropriate for regulatory and clinical 
decision-making. 
Moreover, to ensure the estimand based on the treatment policy strategy can be estimated 
with minimal assumptions about missing data, efforts are being made to retain subjects in 
the trial and adhere to the schedule of assessments regardless of the occurrence of an 
intercurrent event. 
A longitudinal data analysis method (i.e., linear mixed effects model) will be used for the 
analysis of change from baseline in WASO, LPS, sTST and IDSIQ Sleepiness domain 
score, separately.  
The analysis model will adjust for the baseline value of the relevant response variable 
(either WASO, LPS, sTST or IDSIQ Sleepiness domain score), age group (< 65; 
≥ 65 years), treatment (higher dose; lower dose; placebo), visit (Month 1; Month 3), and 
the interaction of treatment by visit, and baseline by visit [see SAS® code in Section 15.1]. 
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].  
To evaluate the efficacy hypotheses, 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 higher dose ACT-541468 vs placebo and lower dose ACT-541468 vs placebo, 
both at Month 1 and Month 3 [see Section 15.1]). 
The LS mean for each treatment group per time point will be displayed along with 
associated standard errors and 95% confidence intervals (CIs). For each ACT-541468 dose 
level comparison with placebo, the placebo-adjusted LS mean will be displayed along with 
associated standard error, 95% CI and unadjusted two-sided p-value.  


ACT-541468 
ID-078A301 
25 March 2020, page 28/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
6.1.5 Handling of partially missing data 
Section 10.1 explains how the primary and secondary efficacy endpoints are derived in the 
event of partially missing data. 
The (partially) missing data patterns of each primary and secondary efficacy endpoint will 
be shown with a shift table for each treatment group. The table will show the shifts in the 
number of available WASO, LPS, sTST or IDSIQ Sleepiness domain score values from 
baseline to Month 1, and from baseline to Month 3, respectively.  
6.1.6 Descriptive analyses 
Empirical cumulative distribution function plots of the observed cases of the primary and 
secondary efficacy endpoints for each treatment group will be provided. The primary and 
secondary efficacy endpoints along with their observed values will be summarized by age 
group (< 65; ≥ 65 years) and overall using descriptive statistics. A summary will be 
provided showing the cumulative number and percentage of subjects meeting a certain 
threshold for WASO, LPS, sTST and IDSIQ Sleepiness domain score, separately, for the 
observed range of values.  
A plot of the mean change from baseline over time (per week, as defined in Table 7) for 
sTST and IDSIQ Sleepiness domain score will be provided together with a summary table.  
6.1.7 Sensitivity analyses 
The incidence and pattern of missing values will be explored to assess the appropriateness 
of the statistical analysis and possible impact on results. The observed missing data patterns 
for WASO, LPS, sTST and IDSIQ Sleepiness domain score at Baseline, Month 1 and 
Month 3 will be presented for each treatment group. The missing data patterns will be 
sorted from completely missing to completely observed by the order of the first occurrence 
of missing data.  
The mean change from baseline of the primary and secondary efficacy endpoints will be 
plotted over time (to Month 1 and to Month 3) for study completers and for premature 
study withdrawals by treatment group and by reason for study discontinuation together 
with a summary table. A cumulative incidence plot will be provided showing the timing 
(relative to randomization date) and reasons for premature DB study treatment 
discontinuation and premature study discontinuation, separately, by treatment group. 
Based on the exploration of the observed missing data patterns, further sensitivity analyses 
to those described below may be performed. 
The linear mixed effects model (or mixed model for repeated measures [MMRM]) relies 
on the missing at random (MAR) assumption. That is, conditional on the statistical model 
and observed values of the outcome (e.g., change from baseline WASO), the probability 
of missing data does not depend on the unobserved values of that outcome. Consequently, 


ACT-541468 
ID-078A301 
25 March 2020, page 29/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
the subject’s missing values are estimated based on similar subjects who remain in the 
study. 
Performing the main analysis under MAR is not likely to bias results in favor of 
ACT-541468 to an important degree, especially if the proportion of withdrawals are similar 
across treatment groups (or not significantly greater in the ACT-541468 groups), and 
subjects who withdraw early for a given reason tend to have similar outcomes before 
withdrawal (e.g., less favorable than completers) across treatment groups. In addition, 
assuming missing data are MAR in the placebo group is considered conservative; subjects 
who withdraw are expected to have worse efficacy over time compared to those placebo 
subjects that remain, whose data will constitute the basis for the imputed values for the 
withdrawn subjects. Furthermore, a placebo effect is expected to increase (improve) over 
time, particularly in those subjects on placebo who remain in the study. 
Sensitivity analysis will be performed to assess the robustness of the conclusions of the 
main analysis to departures from the MAR assumption. For this, models that assume 
missing not at random (MNAR) will be used [Mallinckrodt 2013]. These models will be 
based on the multiple imputation (MI) methodology [Rubin 1987] and will be specifically 
used to assess the bias that can result when the outcomes for subjects who discontinue 
differ from those who complete. Sensitivity analyses will be performed for the analysis of 
change from baseline in WASO, LPS, sTST and IDSIQ Sleepiness domain score, 
separately.  
As a general approach, imputations will be performed on observed values (baseline, 
Month 1 and Month 3) specifying a minimum and a maximum threshold to avoid 
imputation of nonsensical values. The boundaries will range from 0 to 480 for WASO, LPS 
and sTST, and from 0 to 40 for IDSIQ Sleepiness domain score. When an intended imputed 
value is outside the defined boundaries, this value will be discarded, and the procedure will 
draw another value for imputation. The maximum number of discarded values will be set 
to 100 for each imputed dataset. The imputed dataset will not be produced if more than 
100 values have been discarded. If more than 20% of the planned imputed datasets are not 
produced, the results for that analysis will not be shown as this would likely lead to 
unreliable conclusions. Once all the multiply-imputed datasets are produced, the change 
from baseline to Month 1 and Month 3 will be calculated.  
In all the MI analyses described below a preliminary step will be performed to obtain a 
monotone missing data pattern [see Section 12.7]. That is, any non-monotone (or 
intermediate) missing data will be imputed using the Markov Chain Monte Carlo (MCMC) 
methodology [Schafer 1997] under MAR assumptions within each treatment group. This 
assumption is considered reasonable given that subjects are expected to miss intermediate 
visits due to reasons unrelated to their insomnia disorder (e.g., scheduling conflicts), or 
have missing intermediate values due to technical problems (e.g., PSG not fully recorded 
due to power outage). In addition, the proportion of non-monotone missing data is expected 


ACT-541468 
ID-078A301 
25 March 2020, page 30/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
to be infrequent and imputing these few values using the MCMC method is not expected 
to compromise the validity of the sensitivity analyses. The MCMC imputation will be 
performed by treatment group and the variables included in the model are age (as 
continuous), baseline, Month 1 values and Month 3 values. The MCMC methodology 
assumes a multivariate normal distribution over these variables [see SAS® code in 
Section 15.2]. 
As a reference for the sensitivity analyses under MNAR (described below), the main 
analyses will be repeated using MI methodology under MAR. Imputation for monotone 
missing data will be performed sequentially, one visit at a time using the linear regression 
method [Ratitch 2013]. A linear regression model will be fitted sequentially for each visit 
(i.e., Month 1 and then Month 3) with treatment (higher dose; lower dose; placebo), age 
group (< 65; ≥ 65 years), baseline and any prior visit (i.e., Month 1 when fitting the linear 
regression model to Month 3 values) as predictors. Missing values are then replaced for 
each visit sequentially (i.e., Month 1 and then Month 3) by predictions from the respective 
linear regression model [Rubin 1987]. Note that values imputed at Month 1 are included 
when fitting the linear regression model to Month 3 values. The resulting multiple data sets 
are analyzed using the same statistical model as for the primary analysis (i.e., linear mixed 
effects model with the same factors). Results from these analyses are combined using 
Rubin’s methodology [Rubin 1987; see SAS® code in Section 15.3]. The results obtained 
from this MI analysis are expected to be similar to the main MMRM analysis since both 
methods rely on the same MAR assumption. 
Two sensitivity analyses assuming MNAR will be performed: A control-based imputation 
method called jump to reference (J2R) [Carpenter 2013], and a delta-adjusted imputation 
method [Yan 2009]. Each method differs in its assumption about the monotone missing 
data of the ACT-541468 groups. However, for both methods, subjects from the placebo 
group that discontinue the study are assumed to evolve in the same way as placebo subjects 
who remain in the study (i.e., MAR is assumed for the placebo group). As explained above, 
this assumption is considered conservative. 
The J2R imputation method can be considered conservative (and more conservative than 
the methods above based on the MAR assumption) as it assumes that subjects discontinuing 
study from the ACT-541468 groups exhibit the same future evolution as placebo subjects. 
The same sequential procedure using linear regression models for imputing monotone 
missing data as described above will be used. However, predictions to replace the missing 
values in the ACT-541468 groups will be based on data from the placebo subjects only. As 
such, the factor for treatment is omitted from the sequential regression models. After 
imputation, the multiply-imputed datasets are then analyzed via standard MI analysis. Note 
that the same linear mixed effects model as in the main analysis will be used [see SAS® 
code in Section 15.4]. 


ACT-541468 
ID-078A301 
25 March 2020, page 31/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
A delta-adjusted imputation method will be used to progressively stress test the MAR 
assumption of the main analysis. That is, a tipping-point analysis will be performed to see 
how severe departures from the MAR assumption must be to overturn the conclusions of 
the main analysis (i.e., the point where significant results become non-significant). The 
assumption here is that subjects from the ACT-541468 groups who discontinue from study 
would have, on average, their observed efficacy score worsened by some amount (delta) 
compared with the efficacy observed from subjects of the same ACT-541468 group that 
remain in the study. A series of analyses with progressively increasing deltas (δWASO/LPS = 
15, 30, 45, 60; δsTST = –20, –40, –60, –80; δIDSIQ = 2.5, 5, 7.5, 10; from less conservative to 
more conservative) will be performed. The delta adjustment will only be made to the 
multiply-imputed values (based on the MAR assumption) for the subjects in the 
ACT-541468 groups. Note that a delta of zero corresponds to the standard MAR-based MI 
analysis that is described above to obtain a reference for the sensitivity analyses. Again, 
the same linear mixed effects model as in the main analysis will be used [see SAS® code 
in Section 15.5].  
For all the analyses above using MI methodology, the seed is set to 708695 and 
100 multiply-imputed datasets are created. The decision of imputing 100 datasets was 
taken from O’Kelly [O’Kelly 2014], where it is stated that number of imputations should 
typically be between 20 and 100 (simulations performed by Graham [Graham 2007]). 
Similar recommendations were provided by others [Bodner 2008, Von Hippel 2009, 
White 2011].  
For the main analysis and each planned sensitivity analysis, the LS mean estimate of the 
difference in change from baseline between higher dose ACT-541468 vs placebo and lower 
dose ACT-541468 vs placebo both at Month 1 and Month 3 will be provided, together with 
its estimated standard error and associated p-value. The LS mean estimate of the change 
from baseline for each treatment group at Month 1 and Month 3 will also be provided, 
together with its estimated standard error and associated p-value. 
A plot over time for the primary and secondary efficacy endpoints showing the LS mean 
of each treatment group per imputation method (i.e., MAR; J2R; delta-adjusted including 
δ = 0) will be provided.  
6.1.8 Supportive analyses 
The main analysis performed for the primary and secondary efficacy endpoints 
[Section 6.1.4] will be repeated using the PPS to assess the effect protocol deviations may 
have on the results. Of note, these analyses rely on the MAR assumption.  
The impact of any deviation from the assumption that the covariance structure is similar 
across treatment groups will be investigated by re-running the main analyses using two 
additional types of covariance structures. Firstly, the assumption of a common 
within-group standard deviation (SD) will be relaxed by using an unstructured covariance 


ACT-541468 
ID-078A301 
25 March 2020, page 32/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
matrix that is specific to each treatment group. Secondly, the more restrictive Toeplitz 
structure, shared across treatment groups, will be used. The Toeplitz structure requires 
fewer parameters to be estimated and will be considered as the main statistical analysis 
model if the model described in Section 6.1.4 fails to converge.  
6.1.9 Subgroup analyses 
Subgroup analyses for the primary and secondary efficacy endpoints will be performed to 
investigate the consistency of the treatment effect (i.e., ACT-541468 vs placebo) across 
subgroups defined by: 
Age:   
< 65, ≥ 65 years 
Sex:   
Male, female 
Region: 
US, other (non-US) 
The same model as for the main analysis (MMRM) will be fitted per subgroup. Of note, 
age group will not be included as a covariate in the model for subgroup analysis by age. 
Treatment effect estimates (LS mean plus 95% CI) will be presented via forest plots. 
6.2 Analysis of other efficacy variables 
The following efficacy endpoints along with their observed values will be summarized by 
age group (< 65; ≥ 65 years) and overall using descriptive statistics: 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in Total 
Sleep Time (TST). 
 Change from baselinea to Month 1b and Month 3c in subjective WASO (sWASO). 
 Change from baselinea to Month 1b and Month 3c in subjective Latency to Sleep 
Onset (sLSO). 
 Change from baselinea to Month 1b and Month 3c in IDSIQ scores (i.e., Total score; 
Alert/Cognition and Mood domain scores). 
a Baseline is the mean value based on the screening sleep diary / IDSIQ entries performed 
at home in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary / IDSIQ entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 8. 
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?”. 
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?”. 


ACT-541468 
ID-078A301 
25 March 2020, page 33/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Section 10.1 explains how these endpoints are derived in the event of partially missing 
data.  
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 to 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. 
 
A plot of the mean change from baseline over time (per week, as defined in Table 7) for 
sWASO, sLSO and IDSIQ scores (i.e., Total score; Alert/Cognition and Mood domain 
scores) will be provided together with a summary table.  
The same model as for the main analysis, MMRM [Section 6.1.4], will be fitted for these 
efficacy endpoints. The LS mean for each treatment group 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 
error, 95% CI and unadjusted two-sided p-value.  
6.3 Analysis of exploratory variables 
The following exploratory endpoints will be summarized along with their observed values 
at the respective time points: 


ACT-541468 
ID-078A301 
25 March 2020, page 34/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in WASO 
over time (by hour of the night and by quarter of the night). 
 Change from baselinea (Visit 3) to Month 1b and Month 3c in the following visual 
analog scale (VAS) scores collected in the sleep diary: quality of the sleep, depth of 
the sleep, daytime alertness and ability to function.  
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in 
duration of TST in each sleep stage (S1, S2, SWS and REM) over the whole night, 
and for each quarter of the night. 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in sleep 
architecture assessed as percentage of TST in each sleep stage (S1, S2, SWS, and 
REM) over the whole night, and for each quarter of the night.  
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in sleep 
onset latency. 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in 
numbers of shifts from S2, SWS or REM to S1 or awake. 
 Change from baseline (Visit 3) to Month 1 and Month 3 in Insomnia Severity Index© 
(ISI©) scores. 
– The number (%) of subjects with ≥ 6 points decrease in ISI© Total score from 
baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8) will be tabulated.  
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in number 
of awakenings (defined as the number of awakenings between first epoch and last 
epoch not scored wake) as measured by PSG (will be summarized for the whole 
night, for each quarter of the night, and for each hour of the night). 
 Change from baselinea (Visit 3) to Month 1b and Month 3c in number of self-reported 
awakenings. 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in Sleep 
Efficiency (defined as 100  [TST (min) / time in bed (min)]) where time in bed is 
fixed to 480 min during the PSG nights. 
 Change from baseline (Visit 3) to Month 1 (Visit 6 or, if that is missing, week 4 of the 
questionnaire) and Month 3 (Visit 8 or, if that is missing, week 12 of the 


ACT-541468 
ID-078A301 
25 March 2020, page 35/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
questionnaire) in Patient Global Assessment of Disease Severity (PGA-S) scores 
(daytime symptoms). 
 Change from baseline (Visit 3) to Month 1 (Visit 6 or, if that is missing, week 4 of the 
questionnaire) and Month 3 (Visit 8 or, if that is missing, week 12 of the 
questionnaire) in Patient Global Impression of Change (PGI-C) scores (daytime 
symptoms). 
 Change from baseline (Visit 3) to Month 1 (Visit 6 or, if that is missing, week 4 of the 
questionnaire) and Month 3 (Visit 8 or, if that is missing, week 12 of the 
questionnaire) in PGI-C scores (night-time symptoms). 
 Change from baseline (Visit 3) to Month 1 (Visit 6 or, if that is missing, week 4 of the 
questionnaire) and Month 3 (Visit 8 or, if that is missing, week 12 of the 
questionnaire) in Patient Global Impression of Severity (PGI-S) scores (night-time 
symptoms). 
a Baseline is the mean value based on the screening sleep diary entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary entries performed at home in the 
7 days immediately preceding the first PSG at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary entries performed at home in the 
7 days immediately preceding the first PSG at Visit 8. 
Section 10.1 explains how these endpoints, except for ISI©, are derived in the event of 
partially missing data. 
Additionally, the following PSG measurements will be summarized: 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in 
duration (min) of TST in each sleep stage (S1, S2, SWS and REM) by quarter of the 
night. 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in 
duration (min) from lights off to the first epoch of each sleep stage (S1, S2, SWS and 
REM). 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in 
duration of time (min) from onset of persistent sleep (LPS) to the first epoch of REM 
sleep. 


ACT-541468 
ID-078A301 
25 March 2020, page 36/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in 
duration of time (min) from sleep onset (LSO) to the first epoch of REM sleep. 
 Change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 (mean of the 
2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) in 
duration of wakefulness (min) from onset of persistent sleep (LPS) till the last epoch 
of sleep prior lights on. 
Boxplots of the change from baseline (mean of the 2 PSG nights at Visit 3) to Month 1 
(mean of the 2 PSG nights at Visit 6) and Month 3 (mean of the 2 PSG nights at Visit 8) 
will be provided for the following: 
 Duration of TST (min) in each sleep stage over the whole night, and by quarter of the 
night. 
 % of TST spent in each sleep stage over the whole night, and by quarter of the night.  
 Latency (min) to each sleep stage over the whole night. 
 Duration of REM sleep (min) by quarter of the night. 
 Duration of S1 sleep (min) by quarter of the night. 
 Duration of the S2 sleep (min) by quarter of the night. 
 Duration of SWS sleep (min) by quarter of the night. 
 WASO (min) by quarter of the night. 
Boxplots will also be provided for the observed values at Baseline (mean of the 2 PSG 
nights at Visit 3), Month 1 (mean of the 2 PSG nights at Visit 6) and Month 3 (mean of the 
2 PSG nights at Visit 8) for the % of TST spent in each sleep stage over the whole night. 
6.4 Estimating minimal clinically important differences  
This analysis will be described in a separate document and reported separately.  
6.5 Patient preferences exploratory endpoints  
This analysis will be described in a separate document and reported separately.  
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 to perform 
the safety assessments of Visit 8 within 7 days of the last DB study treatment intake. 
Although some subjects may be considered as being off study treatment, the time from the 


ACT-541468 
ID-078A301 
25 March 2020, page 37/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
last DB study treatment intake to the Visit 8 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 DB study treatment intake will be included 
as being taken during DB 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 DB study treatment intake 
will be excluded from analyses. 
7.2 Adverse events 
Unless noted otherwise, the AE summary tables will include treatment-emergent AEs 
(TEAEs): AEs that started or worsened on or after DB study treatment start date up to the 
earlier of 30 days after DB study treatment end date or the date of enrollment into the 
ID-078A303 extension study. An AE that started or worsened during any planned or 
unplanned study treatment interruption (e.g., run-out, safety follow-up) that is falling 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.  
The number (%) of subjects experiencing a TEAE (including serious AEs [SAEs], AEs of 
special interest [AESIs] after adjudication by the Independent Safety Board [ISB], and AEs 
leading to premature discontinuation or temporary interruption of DB 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 highest ACT-541468 
dose level, then in the next highest ACT-541468 dose level, and finally in the placebo 
treatment group. After this sorting, SOCs are presented in alphabetical order with PT sorted 
within SOC in alphabetical order. 
The following AE summary tables will be provided:  
 Treatment-emergent AEs. 
 Treatment-emergent AEs during the DB study perioda. 


ACT-541468 
ID-078A301 
25 March 2020, page 38/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 AEs occurring (i.e., that started or worsened) during the Run-in period. 
 AEs occurring (i.e., that started or worsened) during the treatment withdrawal period 
(based on the TWS). 
 TEAEs during the DB study perioda related to study treatment. 
 AEs leading to premature discontinuation of DB study treatment. 
 AEs leading to temporary interruption of DB study treatment. 
 Treatment-emergent SAEs (including occurrences). 
 Treatment-emergent SAEs related to study treatment (including occurrences). 
 Disclosure to public database purposes: most frequent (threshold to be defined at time 
of reporting) non-serious TEAEs (including occurrences). 
 Treatment-emergent AESIs after ISB adjudication. 
 TEAEs during the DB study perioda related to abuse (as defined in the document 
Search specifications for safety monitoring). 
 TEAEs during the DB study perioda based on selected Standardised MedDRA 
Queries or pre-defined search criteria (as defined in the document Search 
specifications for safety monitoring). 
 TEAEs with fatal outcome. 
 TEAEs related to study treatment with fatal outcome. 
 Total number of deaths (those occurring on or after DB study treatment start date up 
to the earlier of 30 days after DB study treatment end date or the date of enrollment 
into the ID-078A303 extension study). 
a Includes only those TEAEs occurring (i.e., that started or worsened) during the DB study 
period [see Section 12.2].  
All AEs will be listed as well as all deaths with cause of death. Any death will be listed 
using the SCR set. In addition, separate listings will be provided for SAEs.  
An AE listing will be provided also for subjects who were not randomized (i.e., screen 
failures) and subjects who were randomized but did not take DB study treatment to report 
any subjects who discontinued run-in single-blind placebo treatment or discontinued the 
study, respectively, due to AE.  
AEs submitted for adjudication will be listed flagging, separately, AEs that were 
adjudicated as an AESI and AEs that were considered an AESI by the investigator. 
The number of subjects (including occurrences) with at least one case submitted for ISB 
adjudication will be summarized and listed.  


ACT-541468 
ID-078A301 
25 March 2020, page 39/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
An incomplete (day or month missing) or missing AE date will be imputed as described in 
the 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. 
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. If the (imputed) AE end date is on or after the start 
of DB study treatment, and if the DB study treatment 
start falls within the upper and lower limits 
(inclusive), the DB study treatment start date is used. 
2. If the (imputed) AE end date is on or after the start 
of run-in single-blind placebo treatment, and if the 
run-in single-blind placebo treatment start falls 
within the upper and lower limits (inclusive), the 
run-in single-blind placebo treatment start date is 
used. 
3. If the AE resolution date is missing, and: 
a. if the DB study treatment start falls within the 
upper and lower limits (inclusive), the DB study 
treatment start date is used; 
else: 
b. if the run-in single-blind placebo treatment start 
falls within the upper and lower limits (inclusive), the 
run-in single-blind placebo 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 DB 
study treatment start date. 
AE = adverse event; DB = double-blind. 
 
The purpose of imputing AE dates is only to assign an AE to a specific treatment phase for 
the summary tables. 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.  


ACT-541468 
ID-078A301 
25 March 2020, page 40/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Descriptive summary statistics for each scheduled visit (re-test excluded) will be provided 
for observed values and change from baseline in both hematology and blood chemistry 
laboratory parameters.  
The change from baseline to last value (re-test and unscheduled assessments excluded) in 
the DB study period for hematology and blood chemistry parameters will be summarized.  
Marked laboratory abnormalities are defined in Table 4 below. The number (%) of subjects 
with marked laboratory abnormalities during DB study treatment will be tabulated. 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: alanine aminotransferase (ALT), aspartate aminotransferase (AST), 
gamma-glutamyl transferase and total bilirubin (TBIL).  
 Thyroid hormones: Thyroid-stimulating hormone, free T3 and free T4. 
 Lipids: total cholesterol and triglycerides. 
 Hematology: leukocytes, neutrophils, lymphocytes, eosinophils. 
All laboratory data for subjects with at least one marked laboratory abnormality during DB 
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)  
> 65%  
Platelets (109/L) 
< 75  
< 50  
> 600  
> 999  
Leukocytes (109/L) 
< 3.0  
< 2.0  


ACT-541468 
ID-078A301 
25 March 2020, page 41/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Laboratory parameter 
Criteria for marked laboratory abnormalities 
> 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 
Alkaline phosphatase (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 
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 


ACT-541468 
ID-078A301 
25 March 2020, page 42/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Laboratory parameter 
Criteria for marked laboratory abnormalities 
> 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 
> 3.6 
Free T4 (pmol/L) 
< 7.2 
> 24 
Total T4 (nmol/L) 
< 53 
> 210 
Triglycerides 
> 5.7 mmol/L 
Total cholesterol 
> 2  ULN 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; SI = standard international; 
TSH = thyroid-stimulating hormone; T3 = triiodothyronine; T4 = thyroxine; ULN = upper limit of normal.  
 
Elevated liver parameters during DB study treatment will be summarized: the number (%) 
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 × upper limit of normal (ULN) 
 AST or ALT > 5 × ULN 
 AST or ALT > 10 × ULN 


ACT-541468 
ID-078A301 
25 March 2020, page 43/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 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 in ECG parameters (QT corrected according 
to Fridericia’s formula, QT corrected according to Bazett’s formula, heart rate, PR, QRS). 
Marked ECG abnormalities are defined in Table 5. The following summaries will be 
provided for each ECG parameter: 
 Number (%) of subjects with a marked ECG abnormality during the DB study period. 
 Number (%) of subjects with a marked ECG abnormality during the treatment 
withdrawal period (based on the TWS).  
Percentages will be based on the number of subjects at risk, i.e., 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, PR, and 
QRS), a subject will be counted only once in case of multiple occurrences but may be 
reported in more than one marked ECG abnormality criterion of a given parameter. For 
mutually exclusive criteria (i.e., QTc), only the subject’s worst post-baseline value (or 
worst change from baseline value) will be counted. 
ECG findings during the DB 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 highest ACT-541468 dose 
level, then in the next highest ACT-541468 dose level, and finally in the placebo treatment 
group. 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 the DB study 
period or during the treatment withdrawal period will be listed.  


ACT-541468 
ID-078A301 
25 March 2020, page 44/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
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 interval corrected according to 
Bazett’s formula; QTcF = QT interval corrected according to Fridericia’s formula. 
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 (mean of the two PSG nights at Visit 3, run-in period) to Month 1 
(mean of the two PSG nights at Visit 6), Month 2 (Visit 7), Month 3 (mean of the two PSG 
nights at Visit 8) and Run-out period (Visit 9 and Visit 10) 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 (Visit 1 or last value before DB study treatment) to Visit 8 (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 to 40) for 
the change from the last available assessment on DB study treatment to the beginning and 
the end of the treatment withdrawal period (in the morning at Visit 9 and at Visit 10, 
respectively) will be summarized. Observed values will also be summarized.  
The number (%) of subjects with a BWSQ Total score above 20 will be tabulated by visit. 


ACT-541468 
ID-078A301 
25 March 2020, page 45/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
The number (%) of subjects with one or more BWSQ symptom scored as ‘severe’ will be 
tabulated by visit. 
In addition, withdrawal symptoms after DB study treatment discontinuation will be 
assessed through the incidence of AEs, and marked ECG abnormalities, occurring during 
the treatment withdrawal period [see Section 12.2]. As described in their respective section, 
the incidence of AEs [Section 7.2] and marked ECG abnormalities [Section 7.4] occurring 
during the treatment withdrawal period (between Visit 9 and Visit 10) will be summarized. 
7.7 Rebound insomnia 
The TWS will be used to assess the potential for rebound insomnia. The change from 
baseline (Visit 3) to the treatment withdrawal period (Visit 9, run-out) in objective sleep 
parameters (WASO and LPS) will be summarized. The change from baseline (mean value 
based on the screening sleep diary entries performed at home in the 7 days immediately 
preceding the first PSG at Visit 3) to the treatment withdrawal period (after PSG night at 
Visit 9 [see Section 12.8]) in the subjective sleep parameter sTST will be summarized. 
Empirical cumulative distribution function plots of these objective and subjective sleep 
parameters for each treatment group will be provided, together with a summary showing 
the cumulative number and percentage of subjects meeting a certain threshold for the 
observed range of values.  
7.8 Next-day residual effect 
Coding sub-test© 
The Coding sub-test© is a measure of attention, perceptual speed, motor speed, visual 
scanning and memory. The total Coding sub-test© score is the number of correct symbols 
entered.  
The change from baseline (mean of the two PSG morning assessments at Visit 3, run-in 
period) to Month 1 and Month 3 (mean of the two PSG morning assessments at Visit 6 and 
Visit 8, respectively), and Run-out period (Visit 9) in total Coding sub-test© score will be 
summarized. Observed values will also be summarized.  
Sheehan Disability Scale© 
The Sheehan Disability Scale© (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.  
The change from baseline (mean of the two PSG morning assessments at Visit 3, run-in 
period) to Month 1 and Month 3 (mean of the two PSG morning assessments at Visit 6 and 


ACT-541468 
ID-078A301 
25 March 2020, page 46/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Visit 8, respectively), and Run-out period (Visit 9) 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.  
Visual analog scales 
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 to 
100 points; for all questions, a higher score reflects a better outcome. 
The change from baselinea (Visit 3) to Month 1b and Month 3c in morning sleepiness VAS 
score will be summarized. Observed values will also be summarized.  
a Baseline is the mean value based on the screening sleep diary entries performed at home 
in the 7 days immediately preceding the first PSG at Visit 3. 
b ‘Month 1’ is the mean value based on the sleep diary entries performed at home in the 
7 days immediately preceding the first PSG at Visit 6. 
c ‘Month 3’ is the mean value based on the sleep diary entries performed at home in the 
7 days immediately preceding the first PSG at Visit 8. 
Neurological examination  
The time from treatment until the subject is considered safe to leave the center the next day 
will be summarized for each scheduled PSG visit. 
7.9 Columbia-Suicide Severity Rating Scale©  
The Columbia-Suicide Severity Rating Scale© (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 below 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  


ACT-541468 
ID-078A301 
25 March 2020, page 47/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
9 – Actual Attempt (non-fatal)  
10 – Completed Suicide  
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 (%) of subjects with suicidal ideation by category, 
suicidal behavior by category, suicidal ideation or suicidal behavior, and/or self-injurious 
behavior without suicidal intent 1) during DB study treatment and 2) during the treatment 
withdrawal period (based on the 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: Visit 1 = not assigned to any study period; Visit 2 = Screening 
period; Visit 3 and Visit 4 = Run-in period; Visit 6, Visit 7 and Visit 8 = DB study period; 
Visit 9 and Visit 10 = Treatment withdrawal (or Run-out) period. 
Shift from baseline showing any change in suicidal ideation and suicidal behavior 1) during 
the DB study period and 2) during the treatment withdrawal period (based on the 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 also included in the suicidal behavior 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 Epworth Sleepiness Scale© (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 (Visit 3) to Month 1 (Visit 6), Month 3 (Visit 8) and end of 
run-out period (Visit 10) in ESS© Total score will be summarized. Observed values will 
also be summarized.  
The number (%) of subjects meeting the criteria defined below will be tabulated: 
 ESS© Total score > 16 at Baseline (Visit 3), Month 1 (Visit 6), Month 3 (Visit 8) and 
end of Run-out period (Visit 10). 


ACT-541468 
ID-078A301 
25 March 2020, page 48/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 ESS© Total score > 4 points increase from previous visit at Month 1 (Visit 6), 
Month 3 (Visit 8) and end of Run-out period (Visit 10). 
7.11 Subgroup analysis of safety variables  
Summaries of TEAEs occurring (i.e., that started or worsened) during the DB study period 
[see Section 12.2] by SOC and PT will be performed on the following subgroups: 
Age:  < 65, ≥ 65 years 
BMI: < 25, 25–30, > 30 kg/m2 
8 
PHARMACOKINETIC VARIABLES AND ANALYSES 
PK analyses will be performed using the PK set.  
Descriptive statistics (n, mean, SD, coefficient of variation [CV%], m [number of non-zero 
concentrations], geometric mean, geometric SD, geometric CV%, median, minimum and 
maximum) of the ACT-541468 plasma concentrations collected approximately 9–10 h 
post-dose in the morning after the second PSG night at Visit 6 and Visit 8 by age categories 
will be provided. These concentration values will also be displayed graphically by visit and 
ACT-541468 treatment group: scatter plots vs BMI (with a linear regression line) by sex; 
boxplots for age categories (< 65, ≥ 65 years) and all ages combined; empirical cumulative 
distribution functions, together with a summary showing the cumulative number and 
percentage of subjects meeting a certain threshold for the observed range of values; and 
probability density functions. 
Concentration values below the lower limit of quantification will be displayed in listings 
as “BLQ” and handled as zero in the calculations for mean, CV%, SD, median, minimum, 
and maximum, but handled as missing for the calculation of the geometric mean, 
geometric SD and geometric CV%. 
All individual ACT-541468 plasma concentration data will be listed. 
9 
PHARMACOKINETIC/PHARMACODYNAMIC ANALYSES 
9.1 Exposure-safety analyses 
The exposure-safety relationship will be explored using C9–10h (plasma concentrations of 
ACT-541468 in the morning after the second PSG night at Visit 6 and Visit 8) and will be 
based on the PK set. Scatter plots will be provided to explore the relationship between the 
concentration of ACT-541468 and Coding sub-test© and VAS score assessing morning 
sleepiness. These safety endpoints include only values assessed in the morning or evening 
after the second PSG night at Visit 6 and Visit 8.  
Descriptive statistics [as per Section 10.1] of the ACT-541468 plasma concentrations 
collected approximately 9–10 h post-dose in the morning after the second PSG night at 


ACT-541468 
ID-078A301 
25 March 2020, page 49/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Visit 6 and Visit 8 will be provided for subjects with and without clinically significant 
findings for neurological examination at the matching time point. 
9.2 Exposure-efficacy analyses 
The exposure-efficacy relationship will be explored using C9–10h (plasma concentrations of 
ACT-541468 in the morning after the second PSG night at Visit 6 and Visit 8) and will be 
based on the PK set. Scatter plots will be provided to explore the relationship between the 
concentration of ACT-541468 and WASO, LPS, sTST, IDSIQ Sleepiness domain score 
and VAS scores assessing sleep quality, sleep depth, daytime alertness and daytime ability 
to function. These efficacy endpoints include only values assessed during or in the morning 
after the second PSG night at Visit 6 and Visit 8.  
10 GENERAL STATISTICAL METHODOLOGY 
10.1 Handling of partially missing data  
Partially missing data for primary endpoint WASO and LPS values, and for variables like 
TST, number of shifts from S2, SWS or REM to S1 or awake, number of awakenings, 
Coding sub-test©, SDS©, or neurological examination, will be handled as follows: if one of 
the two values is missing either for baseline, Month 1 or Month 3, the single value available 
will be used as the mean for this time point. Otherwise, the mean value will be considered 
missing for that time point. 
For sTST, sWASO, sLSO, IDSIQ total and domain 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: missing data points are given the same 
value as the mean of the non-missing data points of that same time point or week. 
10.2 General rules for data presentations 
Data are listed and summarized as described below.  
The tables will use the following header structure (label and order): 
ACT-541468 25 mg 
N = xxx 
ACT-541468 50 mg 
N = xxx 
Placebo 
N = xxx 
 
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 related to the SCR set will 
present a treatment group label “screening failure” to indicate subjects who were not 


ACT-541468 
ID-078A301 
25 March 2020, page 50/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
randomized and will be listed after the subjects who were randomized or received DB study 
treatment, as relevant.  
Unless noted otherwise, the following descriptive statistics will be used to summarize data: 
number (%) of subjects for categorical variables or descriptive statistics (number of 
non-missing values, mean, SD, median, Q1, Q3, minimum, maximum) for continuous 
variables. 
11 INTERIM ANALYSES  
No formal interim analysis will be performed for determining whether to stop (or modify) 
the study early (i.e., no hypothesis testing will be conducted ad interim). Therefore, no 
adjustment for multiple testing is required. This study includes an IDMC and ISB that will 
assess safety of ACT-541468 on a regular basis as per the IDMC and ISB charters, 
respectively. Safety and efficacy data supporting the review by the IDMC will be provided 
by Idorsia for the part of analyses that are blinded and by an ISAC for the unblinded part. 
12 GENERAL DEFINITIONS AND DERIVATIONS 
12.1 Treatment start and end dates  
Run-in single-blind placebo treatment start or end date is the earliest or latest, respectively, 
date of dose intake recorded on the ‘Study Single-Blind (Run-In) Treatment Log’ page.  
DB 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.  
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.  
12.2 Study periods  
The Screening period is defined as the time from the informed consent date until one day 
before the Run-in period start date.  
The Run-in period is defined as the time from the start of the run-in single-blind placebo 
treatment to one day before start of DB study treatment or, for those not starting DB study 
treatment, to run-in single-blind placebo treatment end date.  
The DB study period is defined as the time from the day of DB study treatment start until 
the day of EODBT (Visit 8, 2nd morning), or, for those who prematurely discontinued DB 
study treatment (i.e., those without an EODBT date), until one day after DB study treatment 
end date (if the treatment is taken before midnight) or the day of DB 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 who complete DB study treatment with an 


ACT-541468 
ID-078A301 
25 March 2020, page 51/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
interruption before continuing the run-out single-blind placebo treatment, the end of DB 
study period is the run-out single-blind placebo treatment start date – 1 day. 
For those subjects in the TWS, the treatment withdrawal period (or Run-out period) is 
defined as the time from one day after the end of the DB study period to the latter of seven 
days after the end of the DB study period or Visit 10 date. 
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 EOS date; or from one day after the end of the DB study period 
for those not starting the treatment withdrawal period until EOS date. 
12.3 Treatment day and Study day  
The Treatment day for an assessment or event will be calculated using the DB study 
treatment start date as reference. 
For assessments/events occurring on or after the start date of DB study treatment, 
Treatment day will be positive and will be calculated as:  
Treatment day (days) = Date of assessment/event – Start date of DB study treatment 
+ 1 day 
The first day of DB study treatment is Treatment day 1. 
For all assessment/events occurring prior to the start date of DB study treatment, Treatment 
day will be negative and will be calculated as:  
Treatment day (days) = Date of assessment/event – Start date of DB 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, Study day will be 
positive and will be 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 will be calculated as:  
Study day (days) = Date of assessment/event – randomization date 
Treatment day and/or Study day will be displayed in the data listings as appropriate.  


ACT-541468 
ID-078A301 
25 March 2020, page 52/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
12.4 Baseline  
Baseline is the last non-missing assessment performed or value measured before or on the 
day of first dose of DB study treatment, unless otherwise defined in the specific analysis 
section.  
An assessment done on the day of the DB study treatment start date is considered a baseline 
assessment and is not considered a post-baseline assessment in the DB 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.  
12.5 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.  
12.6 Handling of data when total sleep time is zero  
If the TST is recorded as zero (i.e., subject did not fall asleep during the night), then:  
 WASO is set as missing since subject is never at risk, and  
 LPS is set as 480 minutes which is equal to the duration of time in bed.  
If the sTST is recorded as zero, then similarly:  
 sWASO is set as missing, and 
 sLSO is set as 480 minutes.  
12.7 Missing data patterns 
Monotone missing data pattern: Given a dataset with variables, Y1, Y2, …, Yt (in that 
order) and Vj is missing for a particular subject, then all subsequent variables Vk, k > j, are 
missing for that subject. In addition, given the same dataset and Vj is observed for a 
particular subject, then all previous variables Vk, k < j, are also observed for that subject. 
Monotone missing data patterns are typically encountered when a subject prematurely 
withdraws from a study and is expected to be more likely seen than non-monotone missing 
data patterns.  
In the examples below, an ‘X’ indicates that the variable is observed in the corresponding 
group and a ‘.’ means that the variable is missing.  
Example of monotone missing data patterns: 
Subject 
Y1 
Y2 
Y3 
1 
X 
X 
X 
2 
X 
X 
. 
3 
X 
. 
. 


ACT-541468 
ID-078A301 
25 March 2020, page 53/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
When missing data are non-monotone, data can also be missing at intermediate visits (i.e., 
missing a given visit, but observed again at the next visit). Non-monotone missing data 
patterns are commonly turned into monotone missing data patterns using MI (based on 
MCMC), which are then subsequently analyzed using MI methods based on monotone 
missing data.  
Example of non-monotone missing data patterns: 
Subject 
Y1 
Y2 
Y3 
1 
X 
X 
X 
2 
. 
X 
X 
3 
. 
. 
X 
4 
. 
X 
. 
5 
X 
. 
X 
12.8 Time window definitions for calculating subjective endpoints  
The meaning of the first PSG end date and the last PSG end date at a given visit (Visit 3, 
Visit 6 and Visit 8) are shown in Table 6.  
Table 6 
Meaning of the first and last PSG end date at Visits 3, 6 and 8 
Visit 3, Visit 6 and Visit 8  
First PSG 
Last PSG 
Start date 
(evening) 
End date 
(morning) 
Start date 
(evening) 
End date 
(morning) 
 
Values falling in the following time windows will be used to calculate weekly averages for 
the subjective endpoints; values from PSG night will not be included:  
Screening: the 7 consecutive days immediately preceding the Run-in single-blind placebo 
treatment start date but after PSG end date at Visit 1 (morning) (i.e., 7-day window = [Max. 
(Run-in single-blind placebo treatment start date – 7 days; PSG end date at Visit 1 
[morning]); Run-in single-blind placebo treatment start date − 1 day]).  
Baseline (Run-in period): the 7 consecutive days immediately preceding the first PSG at 
Visit 3, but after Run-in single-blind placebo treatment start date (i.e., 7-day window = 
[Max. (End date of first PSG at Visit 3 – 7 days; Run-in single-blind placebo treatment 
start date); End date of first PSG at Visit 3 − 1 day]). The time window for Baseline may 
be less than 7 days. Baseline will be missing for any subjects without a PSG at Visit 3.  
Month 1: the 7 consecutive days immediately preceding the first PSG at Visit 6 (i.e., 7-day 
window = [End date of first PSG at Visit 6 – 7 days; End date of first PSG at Visit 6 – 
1 day]). For subjects missing PSG at Visit 6, the 7-day window = [Study day 23; Study 
day 29]. 
Month 3: the 7 consecutive days immediately preceding the first PSG morning at (Visit 8 
i.e., 7-day window = [End date of first PSG at Visit 8 – 7 days; End date of first PSG at 


ACT-541468 
ID-078A301 
25 March 2020, page 54/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
Visit 8 – 1 day]). For subjects missing PSG at Visit 8, the 7-day window = [Study day 79; 
Study day 85]. 
Run-out: the 7 consecutive days immediately following the PSG morning at Visit 9 (i.e., 
7-day window = [Date of PSG morning at Visit 9 + 1 day; Min. (Date of PSG morning at 
Visit 9 + 7 days; Visit 10 date)]). For subjects missing PSG at V9, the 7-day window = 
[Treatment withdrawal period start date; Min. (Treatment withdrawal period start date + 
6 days; Visit 10 date)]. 
Table 7 defines the time windows used to calculate weekly averages for certain subjective 
measures that will be summarized per week. These subjective measures include sTST, 
sWASO, sLSO and IDSIQ scores (i.e., Total score; Alert/Cognition, Mood and Sleepiness 
domain scores). 
Table 7 
Time windows (in days) to calculate weekly averages for certain 
subjective endpoints 
Week 
Study day (7-day window) 
1 
2–8 
2 
9–15 
3 
16–22 
4* 
23–29 
5 
30–36 
6 
37–43 
7 
44–50 
8 
51–57 
9 
58–64 
10 
65–71 
11 
72–78 
12* 
79–85 
* These days might not be the same as in the definition above (Month 1, Month 3). 
Values from PSG nights and Run-out period will not be included. 
 
13 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
13.1 Changes to the analyses planned in the study protocol 
The baseline for PGA-S scores (daytime symptoms) is defined from Visit 3 and not from 
Visit 1 as stated in the protocol. 
Assessments for potential rebound insomnia will be based only on WASO, LPS and sTST 
for consistency with the primary and secondary endpoints. TST, sWASO and sLSO have 
been removed.  


ACT-541468 
ID-078A301 
25 March 2020, page 55/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
13.2 Changes in the conduct of the study / data collection 
Not applicable. 
13.3 Clarifications concerning endpoint definitions and related variables or 
statistical methods 
The VAS scores related to depth of sleep, daytime alertness and ability to function will be 
analyzed as efficacy variables [Section 6.3] and not as safety variables. The VAS score 
remaining as a safety variable is the question from the sleep diary related to morning 
sleepiness [Section 7.8].  
TEAEs that started or worsened during the safety follow-up period will only be listed. 
Summary tables for TEAEs, TEAEs related to study treatment, TEAEs related to abuse 
and TEAEs based on selected Standardised MedDRA Queries or pre-defined search criteria 
will include only those TEAEs occurring during the DB study period. 
The handling of the missing data for the weekly calculation of the subjective endpoints, 
which includes the secondary endpoints, will be aligned: subjects must have at least 2 days 
of data during each week to calculate a weekly mean [Section 10.1]. 
13.4 Additional analyses as compared to the study protocol 
A summary of the number (%) of subjects with ≥ 6 points decrease in ISI© Total score from 
baseline (Visit 3) to Month 1 (Visit 6) and Month 3 (Visit 8) is added to the analysis of 
exploratory variables [Section 6.3].  
The change from baseline to Month 2 (Visit 7) and to Run-out period (Visit 9 and 10) is 
added to the vital signs analyses [Section 7.5]. 
A summary of the neurological examination results is added to the next-day residual effect 
analysis [Section 7.8]. 
The occurrence of suicidal ideation and/or behavior during the treatment withdrawal period 
is added to C-SSRS© analysis [Section 7.9]. 
A summary of the ESS© [Section 7.10] is added to the safety analyses. 
Exposure-efficacy analysis is added to the pharmacokinetic/pharmacodynamic analyses 
[Section 9.2]. 


ACT-541468 
ID-078A301 
25 March 2020, page 56/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
14 REFERENCES 
[Bodner 2008] Bodner TE. What Improves with Increased Missing Data Imputations? 
Structural Equation Modeling 2008;15(4):651–75. 
[Bretz 2009] Bretz F, Maurer W, Brannath W, Posch M. A graphical approach to 
sequentially rejective multiple test procedures. Stat Med 2009;28(4):586–604. 
[Carpenter 2013] Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials 
with protocol deviation: a framework for relevant accessible assumptions and 
inference via multiple imputation. J Biopharm Stat 2013;23(6):1352–71. 
[Graham 2007] Graham JW, Olchowski AE, Gilreath TD. How many imputations are 
really needed? Some practical clarifications of multiple imputation theory. Prev 
Sci 2007;8(3):206–13. 
[Kenward 1997] Kenward MG, Roger JH. Small sample inference for fixed effects from 
restricted maximum likelihood. Biometrics 1997;53(3):983–97. 
[Mallinckrodt 2013] Mallinckrodt C, Roger J, Chuang-stein C, Molenberghs G. Missing 
data: turning guidance into action. Stat Biopharm Res 2013;4:369–82. 
[O’Kelly 2014] O’Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for 
Practitioners. 1st ed. Wiley; 2014. 
[Ratitch 2013] Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from 
clinical assumptions to statistical analysis using pattern mixture models. Pharm Stat 
2013;12:337–47. 
[Rubin 1987] Rubin DB. Multiple imputation for nonresponse in surveys. New York: John 
Wiley & Sons; 1987. 
[Schafer 1997] Schafer JL. Analysis of incomplete multivariate data. New York: Chapman 
& Hall; 1997. 
[Von Hippel 2009] Von Hippel PT. How to impute interactions, squares, and other 
transformed variables. Sociological Methodology 2009;39(1):265–91. 
[White 2011] White IR, Royston P, Wood AM. Multiple imputation using chained 
equations: issues and guidance for practice. Stat Med 2011;30(4):377–399. 
[Yan 2009] Yan X, Lee S, Li N. Missing data handling methods in medical device clinical 
trials. J Biopharm Stat 2009;19:1085–98. 
 


ACT-541468 
ID-078A301 
25 March 2020, page 57/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
15 APPENDICES 
15.1 SAS® code for Mixed Model for Repeated Measures  
proc mixed data=data; 
 
class SUBJID AGEGR TRT VIS; 
 
model CHG = BASE AGEGR TRT VIS TRT*VIS BASE*VIS / ddfm=kr;  
 
lsmeans TRT*VIS / diff cl; 
 
repeated VIS / subject=SUBJID type=un; 
 
estimate ‘25 mg vs placebo at month1’ TRT 1 0 -1 TRT*VIS 1 0 0 0 -1 0 / cl; 
 
estimate ‘25 mg vs placebo at month3’ TRT 1 0 -1 TRT*VIS 0 1 0 0 0 -1 / cl; 
 
estimate ‘50 mg vs placebo at month1’ TRT 0 1 -1 TRT*VIS 0 0 1 0 -1 0 / cl; 
 
estimate ‘50 mg vs placebo at month3’ TRT 0 1 -1 TRT*VIS 0 0 0 1 0 -1 / cl; 
run; 
/* contrasts are built considering the following treatment order: low dose, high dose, 
placebo */ 
15.2 SAS® code for multiple imputation with MCMC for monotone 
missingness mechanism 
ods graphic on; 
proc mi data=data_wide nimpute=100 seed=708695 minimum=. 0 0 0 maximum=. 480 
480 480 out=data_mono;  
 
by _TRT_;  
 
var AGE BASE OBSM1 OBSM3; /* age is continuous */ 
 
mcmc impute= monotone plots=(trace(mean(OBSM1 OBSM3))); 
run; 
ods graphic off; 
15.3 SAS® code for multiple imputation under MAR assumption 
/* multiple imputation */ 
proc mi data=data_mono nimpute=1 seed=708695 minimum=. . 0 0 0 maximum=. . 480 
480 480 out=data_mi noprint; 
 
by _IMPUTATION_; /* flag variable for imputation from proc mi */ 
   
class TRT AGEGR; 
var TRT AGEGR BASE OBSM1 OBSM3; 
   
monotone regression; 
run; 
 
/* analyze and combine the results */ 
ods 
output 
lsmeans=mixparms 
diffs=diffparms(where=(_TRT=‘PLACEBO’ 
and 
VIS=_VIS)); 
proc mixed data=data_mi_long; 


ACT-541468 
ID-078A301 
25 March 2020, page 58/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
 
by _IMPUTATION_; /* flag variable for imputation from proc mi */ 
 
class SUBJID AGEGR TRT VIS; 
 
model CHG = BASE AGEGR TRT VIS TRT*VIS BASE*VIS / ddfm=kr; 
 
lsmeans TRT*VIS / diff cl; 
 
repeated VIS / subject=SUBJID type=un; 
run; 
proc mianalyze parms=mixparms; 
   
class TRT VIS; 
   
modeleffects TRT*VIS; 
run; 
proc mianalyze parms =diffparms; 
   
class TRT VIS; 
   
modeleffects TRT*VIS; 
run; 
15.4 SAS® code for multiple imputation under MNAR assumption for jump 
to reference method 
/*** multiple imputation ***/ 
 
/* OBSM1 */ 
proc mi data=data_mono nimpute=1 seed=708695 minimum=. . 0 0 maximum=. . 480 480 
out=data_mi2 noprint; 
 
by _IMPUTATION_; /* flag variable for imputation from proc mi */ 
   
class TRT AGEGR; 
   
var AGEGR BASE OBSM1;   
 
   
monotone regression; 
 
mnar model (OBSM1 / modelobs=(TRT=‘placebo’)); 
run; 
 
/* OBSM3 */ 
proc mi data=data_mi2 nimpute=1 seed=708695 minimum=. . 0 0 maximum=. . 480 480 
out=data_mi3 noprint; 
 
by _IMPUTATION_; /* flag variable for imputation from proc mi */ 
   
class TRT AGEGR; 
   
var AGEGR BASE OBSM3;   
 
   
monotone regression; 
 
mnar model (OBSM3 / modelobs=(TRT=‘placebo’)); 
run; 


ACT-541468 
ID-078A301 
25 March 2020, page 59/59 
Confidential 
Statistical Analysis Plan  
for Clinical Study Report 
Version 4 
Doc No D-20.054 
 
15.5 SAS® code for multiple imputation under MNAR assumption for 
delta-adjusted (tipping point) 
%macro midata(data=, smin=, smax=, sinc=, out=); 
data &out; 
 
set _null_; 
run; 
/*------------ # of shift values ------------*/ 
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil ); 
/*------- Imputed data for each shift -------*/ 
%do jc=0 %to &ncase; 
%let sj= %sysevalf( &smin + &jc * &sinc); 
proc mi data=&data seed=708695 nimpute=1 minimum=. . 0 0 0 maximum=. . 480 480 
480 out=outmi; 
 
by _IMPUTATION_; /* flag variable for imputation from proc mi */ 
 
class TRT AGEGR; 
 
monotone regression; 
 
mnar adjust(OBSM1 / shift=&sj adjustobs=(TRT = ‘ACT-541468 25mg’)); 
 
mnar adjust(OBSM1 / shift=&sj adjustobs=(TRT = ‘ACT-541468 50mg’)); 
 
mnar adjust(OBSM3 / shift=&sj adjustobs=(TRT = ‘ACT-541468 25mg’)); 
 
mnar adjust(OBSM3 / shift=&sj adjustobs=(TRT = ‘ACT-541468 50mg’)); 
 
var TRT AGEGR BASE OBSM1 OBSM3; 
run; 
data outmi; 
 
set outmi; 
 
Shift= &sj; 
run; 
data &out; 
 
set &out outmi; 
run; 
%end; 
%mend midata; 
 
%midata(data=data_mono, smin=0, smax=60, sinc=15, out=data_mi4); /* shifts for 
WASO */