Conditions: Insomnia Disorder
Keywords: Insomnia Polysomnography
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 360
Healthy volunteers: no

Brief summary:
This study evaluates the dose response of ACT-541468 on the change of WASO from baseline to Days 1 and 2, assessed by PSG.

Detailed description:
This study consists of the following phases: screening phase; double-blind treatment phase; safety follow-up phase. Safety is monitored throughout the study.

Arms:
arm 1: Each subject receives one 5-mg ACT-541468 capusle (+ one placebo capsule), once daily in the evening for 4 weeks arm 2: Each subject receives one 10-mg ACT-541468 capusle (+ one placebo capsule), once daily in the evening for 4 weeks arm 3: Each subject receives one 25-mg ACT-541468 capsule (+ one placebo capsule), once daily in the evening) for 4 weeks arm 4: Each subject receives two 25-mg ACT-541468 capsules, once daily in the evening for 4 weeks arm 5: Each subject receives one 10-mg zolpidem capsule (+ one placebo capusle), once daily in the evening for 4 weeks arm 6: Each subject receives two placebo capsules, once daily in the evening for 4 weeks

Interventions: intervention 1: ACT-541468 5 mg intervention 2: ACT-541468 10 mg intervention 3: ACT-541468 25 mg intervention 4: Zolpidem intervention 5: Placebo 1 intervention 6: Placebo 2
Intervention descriptions: intervention 1: Capsule for oral administration containing ACT-541468 at a strength of 5 mg intervention 2: Capsule for oral administration containing ACT-541468 at a strength of 10 mg intervention 3: Capsule for oral administration containing ACT-541468 at a strength of 25 mg intervention 4: Over-encapsulated zolpidem tablet at a strength of 10 mg intervention 5: Placebo capsules matching ACT-541468 capsules intervention 6: Placebo capsules matching over-encapsulated zolpidem

Protocol document:
Prot_000.pdf: 
 
 
Study protocol AC-078A201 
 
 
Multi-center, double-blind, randomized, placebo-controlled, active-reference, 
parallel-group, polysomnography dose-response study to assess the efficacy and 
safety of ACT-541468 in adult subjects with insomnia disorder. 
 
 
ClinicalTrials.gov Identifier NCT02839200 
 
 
 
 
The study was sponsored was sponsored by Actelion Pharmaceuticals Ltd. 
Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018. 


TPL-000052_v11 
ACT-541468 
Insomnia Disorder 
Protocol AC-078A201 
Multi-center, double-blind, randomized, placebo-controlled, active-reference, 
parallel-group, polysomnography dose-response study to assess the efficacy and 
safety of ACT-541468 in adult subjects with insomnia disorder.  
Study Phase: 
2 
EudraCT Number: 
2016-000826-21 
Status and version: 
Final Version 3 
Date: 
16 December 2016 
Document type 
Global protocol 
Actelion document number 
(Doc No.): 
D-16.648
Confidentiality statement 
The information contained in this document, especially unpublished data, is the property of the sponsor of 
this study, Actelion 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 Actelion Pharmaceuticals Ltd, except to the extent necessary to obtain 
informed consent from those persons to whom the study treatment may be administered. 








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Insomnia disorder 
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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
ACT-541468 
Indication 
Insomnia disorder 
Protocol number, study title 
AC-078A201 
Multi-center, 
double-blind, 
randomized, 
placebo-controlled, 
active-reference, 
parallel-group, polysomnography dose-response study to assess the efficacy and safety of 
ACT-541468 in adult subjects with insomnia disorder. 
I agree to the terms and conditions relating to this study as defined in this protocol, the 
Case Report Form (CRF), 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 
wellbeing of the subjects). 
I agree to conduct this study in accordance with the Declaration of Helsinki principles, 
International Council for Harmonisation (ICH) Good Clinical Practice (GCP) guidelines, 
and applicable regulations and laws. I will obtain approval by an independent ethics 
committee or institutional review board (IEC/IRB) prior to study start and signed 
informed consent from all subjects included in this study. If an amendment to the 
protocol is necessary, I will obtain approval by an IEC/IRB and ensure approval by 
regulatory authorities has been obtained before the implementation of changes described 
in the amendment, and I will re-consent the subjects (if applicable). I will allow direct 
access to source documents and study facilities to sponsor representative(s), particularly 
Clinical Research Associate(s) (CRA[s]) and auditor(s), and agree to inspection by 
regulatory authorities or IEC/IRB representative(s). I will ensure that the study 
treatment(s) supplied by the sponsor is/are being used only as described in this protocol. I 
will ensure that all subjects have understood the nature, objectives, benefits, implications, 
risks and inconveniences for participating in this study. During the conduct of the study, I 
will constantly monitor the risk/benefit balance for an individual subject. 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. 
 
Country 
Site number 
Town 
Date 
 
Signature 
Principal 
Investigator 
 
 
 
 
 
 


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TABLE OF CONTENTS 
SPONSOR CONTACT DETAILS ......................................................................................2 
ACTELION CONTRIBUTORS TO THE PROTOCOL .....................................................2 
COORDINATING INVESTIGATOR.................................................................................2 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
TABLE OF CONTENTS .....................................................................................................6 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
NON-SUBSTANTIAL GLOBAL AMENDMENT 2 .......................................................17 
PROTOCOL SYNOPSIS AC-078A201 ............................................................................20 
PROTOCOL ......................................................................................................................35 
1 
BACKGROUND .........................................................................................................35 
 
Insomnia disorder .........................................................................................35 
1.1
1.1.1 
Definition ..........................................................................................35 
1.1.2 
Epidemiology ....................................................................................35 
1.1.3 
Treatment ..........................................................................................36 
1.1.4 
Unmet medical need .........................................................................37 
 
Study treatments ...........................................................................................38 
1.2
1.2.1 
ACT-541468 .....................................................................................38 
1.2.1.1 
The orexin system ...................................................................38 
1.2.1.2 
ACT-541468 properties ...........................................................38 
1.2.2 
Zolpidem ...........................................................................................42 
 
Purpose and rationale of the study ................................................................43 
1.3
1.3.1 
Purpose of the study ..........................................................................43 
1.3.2 
Rationale for the study ......................................................................43 
 
Summary of known and potential benefits and risks ....................................44 
1.4
1.4.1 
ACT-541468 .....................................................................................44 
1.4.2 
Zolpidem ...........................................................................................45 
1.4.3 
Safety and risk minimization measures taken in the present 
study ..................................................................................................46 


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2 
STUDY OBJECTIVES ...............................................................................................47 
 
Primary objective ..........................................................................................47 
2.1
 
Secondary objectives ....................................................................................47 
2.2
 
Other objectives ............................................................................................47 
2.3
3 
OVERALL STUDY DESIGN AND PLAN ...............................................................47 
 
Study design .................................................................................................47 
3.1
3.1.1 
Study phases .....................................................................................48 
3.1.1.1 
Screening Phase .......................................................................48 
3.1.1.2 
Treatment Phase ......................................................................48 
3.1.2 
Study duration ...................................................................................49 
 
Study design rationale ..................................................................................50 
3.2
 
Site personnel and their roles ........................................................................50 
3.3
 
Study committees .........................................................................................51 
3.4
4 
SUBJECT POPULATION ..........................................................................................51 
 
Subject population description .....................................................................51 
4.1
 
Rationale for the selection of the study population ......................................51 
4.2
 
Inclusion criteria ...........................................................................................52 
4.3
 
Exclusion criteria ..........................................................................................53 
4.4
 
Criteria for women of childbearing potential ...............................................55 
4.5
4.5.1 
Definition of childbearing potential ..................................................55 
4.5.2 
Acceptable methods of contraception ...............................................55 
5 
TREATMENTS ..........................................................................................................56 
 
Study treatment .............................................................................................56 
5.1
5.1.1 
Investigational treatment and matching placebo: Description 
and rationale ......................................................................................56 
5.1.2 
Active reference: Description and rationale .....................................56 
5.1.3 
Study treatment administration .........................................................56 
5.1.3.1 
Study treatment administration during the different study 
phases ......................................................................................57 
5.1.3.2 
Missed doses ............................................................................57 
5.1.4 
Treatment assignment .......................................................................58 
5.1.5 
Blinding ............................................................................................58 
5.1.5.1 
V2 (run-in) and V6 (run-out) ...................................................58 
5.1.5.2 
Double-blind treatment period ................................................58 
5.1.6 
Unblinding ........................................................................................59 
5.1.6.1 
Unblinding for final analyses ..................................................59 


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5.1.6.2 
Unblinding for IDMC review ..................................................59 
5.1.6.3 
Unblinding for suspected unexpected serious adverse 
reaction (SUSARs) ..................................................................59 
5.1.6.4 
Emergency procedure for unblinding ......................................59 
5.1.7 
Study treatment supply .....................................................................60 
5.1.7.1 
Study treatment packaging and labeling .................................60 
5.1.7.2 
Study treatment distribution and storage .................................60 
5.1.7.3 
Study treatment dispensing .....................................................60 
5.1.7.4 
Study treatment return and destruction ...................................60 
5.1.8 
Study treatment accountability and compliance with study 
treatment ...........................................................................................61 
5.1.8.1 
Study treatment accountability ................................................61 
5.1.8.2 
Study treatment compliance ....................................................61 
5.1.9 
Study treatment dose adjustments and interruptions ........................62 
5.1.10 
Premature discontinuation of double-blind study treatment .............62 
5.1.11 
Study-specific criteria for premature discontinuation of 
double-blind study treatment ............................................................63 
 
Previous and concomitant therapy ................................................................63 
5.2
5.2.1 
Definitions ........................................................................................63 
5.2.2 
Reporting of previous/concomitant therapy in the eCRF .................64 
5.2.3 
Allowed concomitant therapy ...........................................................64 
5.2.4 
Forbidden concomitant therapy ........................................................64 
5.2.5 
Forbidden concomitant diet and activities ........................................64 
6 
STUDY ENDPOINTS ................................................................................................65 
 
Efficacy endpoints ........................................................................................65 
6.1
6.1.1 
Primary efficacy endpoint .................................................................65 
6.1.2 
Secondary efficacy endpoints ...........................................................65 
6.1.3 
Other efficacy endpoints ...................................................................66 
 
Safety endpoints ...........................................................................................67 
6.2
 
Pharmacokinetic endpoints ...........................................................................68 
6.3
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................68 
 
Study visits ...................................................................................................68 
7.1
7.1.1 
Screening/re-screening ......................................................................68 
7.1.2 
Unscheduled visits ............................................................................68 
 
Study assessments .........................................................................................71 
7.2
7.2.1 
Demographics ...................................................................................72 
7.2.2 
Efficacy assessments .........................................................................72 
7.2.2.1 
Polysomnography ....................................................................72 


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7.2.2.2 
Sleep diary ...............................................................................74 
7.2.2.3 
Insomnia Severity Index© ........................................................75 
7.2.3 
Safety assessments ............................................................................75 
7.2.3.1 
Weight and height ...................................................................75 
7.2.3.2 
Vital signs ................................................................................75 
7.2.3.3 
Physical examination ...............................................................76 
7.2.3.4 
Digit Symbol Substitution Test© .............................................76 
7.2.3.5 
Sheehan Disability Scale© .......................................................77 
7.2.3.6 
Karolinska Sleepiness Scale ....................................................77 
7.2.3.7 
Columbia Suicide Severity Rating Scale©...............................77 
7.2.3.8 
Benzodiazepine Withdrawal Symptoms Questionnaire ..........78 
7.2.3.9 
Neurological examinations ......................................................78 
7.2.3.10 
ECG assessment ......................................................................78 
7.2.4 
Laboratory assessments ....................................................................79 
7.2.4.1 
Type of laboratory ...................................................................79 
7.2.4.2 
Laboratory tests .......................................................................80 
7.2.5 
Pharmacokinetic assessments ...........................................................81 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE ..........................................................................................................................81 
 
Study completion as per protocol .................................................................81 
8.1
 
Premature withdrawal from study ................................................................81 
8.2
 
Premature termination or suspension of the study ........................................82 
8.3
 
Medical care of subjects after study completion / withdrawal from 
8.4
study ..............................................................................................................83 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................83 
 
Adverse events ..............................................................................................83 
9.1
9.1.1 
Definition of adverse events .............................................................83 
9.1.2 
Intensity of adverse events ................................................................84 
9.1.3 
Relationship to study treatment ........................................................84 
9.1.4 
Reporting of adverse events ..............................................................85 
9.1.5 
Follow-up of adverse events .............................................................85 
 
Serious adverse events ..................................................................................85 
9.2
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 ....................................................86 
9.2.5 
Reporting procedures ........................................................................86 
 
Pregnancy .....................................................................................................87 
9.3


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9.3.1 
Reporting of pregnancy ....................................................................87 
9.3.2 
Follow-up of pregnancy ....................................................................87 
 
Study safety monitoring ................................................................................87 
9.4
10 STATISTICAL METHODS .......................................................................................88 
 
Analysis sets .................................................................................................88 
10.1
10.1.1 
Screened Analysis Set .......................................................................88 
10.1.2 
Randomized Analysis Set .................................................................88 
10.1.3 
Full Analysis Set ...............................................................................88 
10.1.4 
Modified Full Analysis Set ...............................................................88 
10.1.5 
Per-protocol Analysis Set .................................................................88 
10.1.6 
Safety Set ..........................................................................................89 
10.1.7 
Pharmacokinetic Analysis Set ..........................................................89 
10.1.8 
Usage of the analysis sets .................................................................89 
 
Variables .......................................................................................................90 
10.2
10.2.1 
Primary efficacy variable ..................................................................90 
10.2.2 
Secondary efficacy variables ............................................................90 
10.2.3 
Other efficacy variables ....................................................................91 
10.2.4 
Safety variables .................................................................................93 
10.2.5 
Other variables ..................................................................................94 
 
Description of statistical analyses .................................................................94 
10.3
10.3.1 
Overall testing strategy .....................................................................94 
10.3.2 
Analysis of the primary efficacy variable(s) .....................................95 
10.3.2.1 
Hypotheses and statistical model ............................................95 
10.3.2.2 
Handling of missing data .........................................................95 
10.3.2.3 
Main analysis ...........................................................................95 
10.3.2.4 
Supportive/sensitivity analyses ...............................................97 
10.3.3 
Analysis of secondary efficacy variables ..........................................97 
10.3.4 
Analysis of other efficacy variables ..................................................97 
10.3.4.1 
Subgroup analyses ...................................................................97 
10.3.5 
Analysis of the safety variables ........................................................97 
 
Interim analyses ..........................................................................................100 
10.4
 
Sample size .................................................................................................100 
10.5
11 DATA HANDLING ..................................................................................................101 
 
Data collection ............................................................................................101 
11.1
 
Maintenance of data confidentiality ...........................................................101 
11.2
 
Database management and quality control .................................................102 
11.3
12 PROCEDURES AND GOOD CLINICAL PRACTICE ...........................................102 


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Ethics and Good Clinical Practice ..............................................................102 
12.1
 
Independent Ethics Committee / Institutional Review Board ....................103 
12.2
 
Informed consent ........................................................................................103 
12.3
 
Compensation to subjects and investigators ...............................................104 
12.4
 
Protocol adherence/compliance ..................................................................104 
12.5
 
Protocol amendments .................................................................................104 
12.6
 
Essential documents and retention of documents .......................................104 
12.7
 
Monitoring ..................................................................................................106 
12.8
 
Investigator site file ....................................................................................107 
12.9
 
Audit ...........................................................................................................107 
12.10
 
Inspections ..................................................................................................107 
12.11
 
Reporting of study results and publication .................................................108 
12.12
13 REFERENCES ..........................................................................................................109 
14 APPENDICES ...........................................................................................................115 
 
 
LIST OF TABLES 
 
Table 1 
Capsules to be taken according to the treatment ........................................57 
Table 2 
Visit and assessment schedule....................................................................69 
Table 3 
Usage of analysis sets .................................................................................89 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design ...............................................................................................49 
Figure 2 
Modeled dose-response curves ...................................................................96 
 
 


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LIST OF APPENDICES 
 
Appendix 1 
Thresholds for marked laboratory abnormalities .....................................115 
Appendix 2 
Alcohol restrictions during the study .......................................................117 
Appendix 3 
Caffeine content of common beverages ...................................................118 
Appendix 4 
Forbidden and restricted concomitant medications ..................................119 
Appendix 5 
Digit Symbol Substitution Test© ..............................................................123 
Appendix 6 
Insomnia Severity Index©.........................................................................124 
Appendix 7 
Sheehan Disability Scale© ........................................................................125 
Appendix 8 
Karolinska Sleepiness Scale .....................................................................126 
Appendix 9 
Benzodiazepine Withdrawal Symptoms Questionnaire ...........................127 
Appendix 10 Sleep diary ................................................................................................128 
Appendix 11 Summary table of objectives, endpoints and variables ............................130 
 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AASM  
American Academy of Sleep Medicine 
AE  
Adverse event 
AHI  
Apnea/hypopnea index 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
AST  
Aspartate aminotransferase 
AUC  
Area under the plasma concentration-time curve 
AUC0-∞  
Area under the plasma concentration-time curve from zero to 
infinity 
BMI  
Body mass index 
BP  
Blood pressure 
bpm  
Beats per minute 
BCRP  
Breast Cancer Resistance Protein 
BWSQ  
Benzodiazepine Withdrawal Symptom Questionnaire 
CBT  
Cognitive behavioral therapy 
CI  
Confidence interval 
Cmax  
Maximum observed plasma concentration 
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 
CYP  
Cytochrome P450 
DDI  
Drug-drug interaction 
DoA  
Delegation of Authority 
DORA  
Dual orexin receptor antagonist 
DSM  
Diagnostic and Statistical Manual of Mental Disorders 
DSST©  
Digit Symbol Substitution Test 
ECG  
Electrocardiogram 


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eCRF  
Electronic Case Report Form 
ED50  
Effective dose that provides 50% of the maximum effect 
EMA  
European Medicines Agency 
Emax  
Maximum effect 
EODB  
End of Double-Blind Treatment 
EOS  
End of Study 
EOT  
End of Treatment 
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 
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 
KSS  
Karolinska Sleepiness Scale 
LPS  
Latency to Persistent Sleep 
MCT  
Multiple Contrast Test 
MedDRA  
Medical Dictionary for Regulatory Activities 
mFAS  
Modified Full Analysis Set 
NOAEL  
No-observed-adverse-effect level 
NOEL  
No-observed-effect level 
OTC  
Over-the-counter 


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OX1  
Orexin receptor 1 
OX2  
Orexin receptor 2 
PD  
Pharmacodynamic(s) 
P-gP  
P-glycoprotein 1 
PI  
Principal Investigator 
PK  
Pharmacokinetic(s) 
PLMAI  
Periodic Limb Movement with Arousal Index 
PPS  
Per-protocol Set 
PSG  
Polysomnography 
QS  
Quality System 
REM  
Rapid eye movement 
RSI  
Reference safety information 
SAD  
Single-ascending dose 
SAE  
Serious adverse event 
SAP  
Statistical Analysis Plan 
SDS©  
Sheehan Disability Scale 
SE  
Sleep Efficiency 
SIV  
Site initiation visit 
sLSO  
Subjective Latency to Sleep Onset 
SmPC  
Summary of Product Characteristics 
SOC  
System organ class 
SpO2  
Oxygen saturation by pulse oximetry 
SQ  
Sleep Quality 
SS  
Safety Set 
sTST  
Subjective Total Sleep Time 
SUSAR  
Suspected unexpected serious adverse reaction 
sWASO  
Subjective Wake after Sleep Onset 
SWS  
Slow wave sleep 
TEAE  
Treatment-emergent adverse event 
TST  
Total Sleep Time 
ULN  
Upper limit of the normal range 


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USPI  
US package insert 
V  
Visit 
VAS  
Visual analog scales 
WASO  
Wake After Sleep Onset 
 
 








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PROTOCOL SYNOPSIS AC-078A201 
TITLE 
Multi-center, double-blind, randomized, placebo-controlled, 
active-reference, 
parallel-group, 
polysomnography 
dose-response study to assess the efficacy and safety of 
ACT-541468 in adult subjects with insomnia disorder. 
OBJECTIVES 
Primary objective 
The primary objective of the study is to evaluate the 
dose-response of ACT-541468 on the change of Wake After 
Sleep Onset (WASO; minutes) assessed by polysomnography 
(PSG) after treatment on Days 1 and 2. 
Secondary objectives 
The secondary objective of the study is to evaluate the dose 
response of ACT-541468 on Latency to Persistent Sleep (LPS) 
on Days 1&2 and subjective Latency to Sleep Onset (sLSO) and 
subjective WASO (sWASO) at Week 4. 
DESIGN 
Multi-center, double-blind, randomized, placebo-controlled, 
active-reference, parallel-group, polysomnography 
dose-response Phase 2 study. 
PHASES 
Screening phase 
The screening phase lasts a minimum of 14 days and maximum 
of 28 days. It starts with the signing of the Informed Consent 
Form (ICF) and ends with subject randomization. It includes the 
screening period (from Day –28 to Day –7) and the run-in 
period (from Day –14 to Day –1). 
The screening period starts with Visit 1 (V1), which occurs 
between Day –28 and Day –14. V1 is followed by the 
completion of the screening sleep diary for at least 
7 consecutive days at home until Visit 2 (V2).  
The run-in period occurs between Day –14 and Day –1 and 
starts with V2. V2 consists of 2 consecutive PSG nights on 
single-blind placebo treatment occurring between Day –14 and 
Day –6. V2 is followed by 5 to 12 days at home with no 
treatment. A sleep diary must be completed for at least 
7 consecutive days from V2 to randomization.  
 


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Treatment phase 
The treatment phase consists of a double-blind treatment 
period followed by a run-out period.  
The double-blind treatment period starts with the first dose of 
double-blind study treatment in the first evening of the 
Randomization Visit (V3, Day 1). The End of Double-Blind 
treatment is reached in the second morning of V5 (Day 30) 
after the last dose of double-blind study treatment and after all 
second morning assessments have been performed.  
The run-out period starts in the evening of Day 30 (V6) with 
the last dose of study treatment (single-blind placebo). The end 
of the run-out period corresponds to End of Treatment (EOT). 
EOT is reached after all morning assessments have been 
performed in the morning of Day 31 (V6).  
The safety follow-up phase starts after EOT (Day 31) and lasts 
at least 30 days (i.e., until Day 61, follow-up telephone call). 
End of Study (EOS) for a single subject is defined as the date 
of the 30-day follow-up telephone call (Day 61). If a subject 
withdraws consent and does not wish to participate in the study 
any longer, EOS is the date of consent withdrawal for this 
subject. If a subject is declared lost to follow-up, EOS is the 
date of last successful contact for this subject. 
The overall duration of participation in the study of a subject is 
expected to be approximately 12 weeks (see diagram below). 


ACT-541468 
Insomnia disorder 
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PLANNED DURATION 
Approximately 11 months from first subject first visit to last 
subject last visit. 
SITES / COUNTRIES 
Approximately 38 sites in 6 countries: 
ESP, GER, HUN, ISR, SWE, USA.  
SUBJECTS / GROUPS 
Approximately 300 subjects will be centrally randomized in 
6 groups in a 1:1:1:1:1:1 ratio stratified by gender; 50 subjects 
per group. 
INCLUSION CRITERIA 
1. Signed informed consent prior to any study-mandated 
procedure (V1). 
2. Male or female aged 18–64 years (inclusive) (V1). 
3. A woman of childbearing potential must provide:  
• Negative serum pregnancy test (V1). 
• Negative urine pregnancy test (V3). 
• Agreement to undertake pregnancy tests up to 30 days 
after EOT. 
• Agreement to use the contraception scheme as described 
in Section 4.5.2 of the protocol from Screening up to at 
least 30 days after EOT. 
4. Body mass index (BMI): 18.5 ≤ BMI (kg/m2) < 32.0 (V1). 
5. Insomnia disorder according to DSM-5 criteria (V1). 
6. Self-reported history of all of the following on at least 
3 nights per week and for at least 3 months prior to V1: 
• ≥ 30 minutes to fall asleep  
• Wake time during sleep ≥ 30 minutes  


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• Total sleep time (TST) ≤ 6.5 h 
7. Insomnia severity index (ISI©) score ≥ 15 (V1). 
8. Willing to comply with all aspects of the study protocol (V1, 
V2, V3). 
9. Ability to communicate well with the investigator and to 
understand the study requirements and judged by the 
investigator to be alert and oriented to person, place, time 
and situation (V1). 
10. Meeting the following sleep parameters on at least 3 nights 
out of 7 consecutive nights on the sleep diary completed at 
home between V1 and V2 (to be checked at V2): 
• ≥ 30 minutes to fall asleep  
• Wake time during sleep ≥ 30 minutes  
• TST ≤ 6.5 h 
11. Usual bedtime between 21:30 and 00:30 as reported on 
sleep diary completed between V1 and V2 (to be checked at 
V2). 
12. Regular time in bed between 6 and 9 hours as reported on 
sleep diary completed between V1 and V2 (to be checked at 
V2). 
13. Meeting the following sleep parameters on the 2 PSG nights 
(V2): 
• Mean LPS ≥ 20 min (with neither of the two nights 
< 15 min), and 
• Mean WASO ≥ 30 min (with neither of the two nights 
< 20 min), and 
• Mean TST < 420 minutes.  
EXCLUSION CRITERIA 
1. Any current sleep disorder(s) other than insomnia, or any 
lifetime history of related breathing disorder, periodic limb 
movement disorder, restless legs syndrome, circadian 
rhythm disorder, rapid eye movement (REM) behavior 
disorder, or narcolepsy (V1). 
2. Self-reported usual daytime napping ≥ 1 hour per day and 
≥ 3 days per week (V1). 
3. Caffeine 
consumption 
≥ 
600 
mg 
per 
day 
(V1) 
[see Appendix 3]. 
4. Shift work within 2 weeks prior to the screening visit, or 
planned shift work during the study (V1). 
5. Travel ≥ 3 time zones within 1 week prior to the screening 


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visit, or planned travel ≥ 3 time zones during study (V1). 
6. Pregnant, planning to become pregnant or lactating (V1, 
V3). 
7. Hematology or biochemistry test results deviating from the 
normal range to a clinically relevant extent as per judgment 
of the investigator (V1, V2). 
8. Aspartate aminotransferase and/or alanine aminotransferase 
> 2 × the upper limit of normal (ULN) and/or direct 
bilirubin > 1.5 × ULN (V1, V2). 
9. Severe renal impairment: known or defined as estimated 
creatinine clearance < 30 mL/min, according to the 
4-variable Modification of Diet in Renal Disease formula 
(V1, V2). 
10. Unstable medical condition, significant medical disorder or 
acute illness, 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 (V1). 
11. Systolic blood pressure > 150 mmHg and diastolic blood 
pressure > 90 mmHg (V1, V2). 
12. Resting pulse rate < 50 or ≥ 100 bpm (V1, V2). 
13. Any of the following conditions related to corrected QT 
(QTc) interval (V1, V2): 
• A prolonged QTc interval (QTc greater than 450 ms). If 
QTc is greater than 450 ms on the first ECG, a second 
ECG recording will be performed after at least 
30 minutes on the same day. If QTc 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).  
14. 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 Screening/Baseline 
version of the Columbia Suicide Severity Rating Scale 
(C-SSRS©) (V1, V2). 
• Lifetime history of suicide attempt (V1). 
15. Any known factor or disease that might interfere with 
treatment compliance, study conduct or interpretation of the 
results such as history of non-compliance to medical 


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regimen, psychiatric disease or neurological disorders which 
may impact sleep, motor performance, or cognition, 
including Parkinson disease, predementia, dementia, other 
neurodegenerative disorders, and stroke (V1). 
16. Treatment with another investigational drug within 1 month 
prior to V1. 
17. Known hypersensitivity or contraindication to drugs of the 
same class as the study treatment or to any excipients of the 
study drug formulation, or to zolpidem, including 
myasthenia gravis (V1). 
18. Treatment 
with 
prohibited 
central 
nervous 
system 
(CNS)-active drugs [as defined in Appendix 4] for 
5 half-lives of the respective drug (but at least 2 weeks) 
prior to V1 and until 24 hours after EOT (V6), including 
over-the-counter (OTC) medication and herbal medicines. 
19. Cognitive behavioral therapy (CBT) within one month prior 
to V1. 
20. Treatment with moderate to strong cytochrome P450 (CYP) 
3A4 inhibitors, CYP3A inducers, sensitive CYP3A4 
substrates, P-gP substrates, BCRP substrates, and CYP2B6 
substrates [as defined in Appendix 4] within 1 week prior to 
V1 until 24 h after EOT. 
21. Consumption of grapefruit or grapefruit juice within 1 week 
prior to V1 until 24 h after EOT. 
22. Diagnosis of alcohol or drug abuse or dependence within 
2 years prior to V1 or inability to refrain from drinking 
alcohol for at least 3 consecutive days (V1). 
23. Positive drug test (for benzodiazepines, barbiturates, 
cannabinoids, opiates, amphetamines, or cocaine) or 
presence of alcohol in exhaled breath as detected by 
breathalyzer test (V1, V2). 
24. Heavy tobacco use (≥ 10 cigarettes per day), and/or inability 
to refrain from smoking for at least 14 hours during the 
night (V1). 
25. Apnea/hypopnea index ≥ 10/h on the first PSG screening 
night according to American Academy of Sleep Medicine 
(AASM) criteria (V2). 
26. Apnea or hypopnea event (according to AASM criteria) 
associated with oxygen saturation by pulse oximetry < 80%, 
on the first PSG screening night (V2). 


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27. Periodic limb movement with arousal index ≥ 10/h on the 
first PSG screening night (V2). 
STUDY TREATMENTS 
Investigational treatment 
ACT-541468 capsules will be administered orally, once daily in 
the evening during the double-blind treatment period. 
ACT-541468 doses will include 5 mg, 10 mg, 25 mg and 
50 mg. Available dose strengths of ACT-541468 are 5 mg, 
10 mg and 25 mg.  
Reference and/or placebo 
Two capsules of ACT-541468-matching placebo will be 
administered orally once daily at V2 and V6. 
During the double-blind treatment period, subjects will receive 
orally once daily two capsules as shown in the table below.  
Treatment 
group 
Number 
(and dose 
strength) of 
ACT-5414
68 capsules 
Number of 
ACT-
541468-
matching 
placebo 
capsules 
Number 
of 
over-
encapsulated 
zolpidem 10 
mg capsules 
Number 
of 
over-encapsul
ated 
zolpidem-
matching 
placebo 
capsules 
ACT-541468 
5 mg 
1 (5 mg) 
1 
0 
0 
10 mg 
1 (10 mg) 
1 
0 
0 
25 mg 
1 (25 mg) 
1 
0 
0 
50 mg 
2 (25 mg) 
0 
0 
0 
Placebo 
0 
2 
0 
0 
Zolpidem 
0 
0 
1 
1 
CONCOMITANT 
THERAPY 
(MEDICATION, DIET, 
ACTIVITIES) 
The following concomitant therapies are forbidden during the 
study: 
• Treatment with another investigational drug until end of 
safety follow-up phase.  
• Prohibited 
CNS-active 
medications, 
including 
OTC 
medication and herbal medicines, until 24 hours after EOT 
[see Appendix 4]. 
• Treatment with moderate to strong CYP3A4 inhibitors, 


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CYP3A4 inducers, sensitive CYP3A4 substrates (i.e., have 
low bioavailability due to a marked first-pass effect), P-gP 
substrates, BCRP substrates and CYP2B6 substrates [see 
Appendix 4] until 24 hours after EOT. 
• CBT and other psychological therapies, excluding common 
advice related to sleep hygiene, until 24 hours after EOT.  
The following activities and diet are forbidden during the study: 
• Consumption of grapefruit and grapefruit juice until 
24 hours after EOT. 
• Consumption of food within 2 hours prior to study treatment 
intake. 
• Caffeine consumption [more details in Appendix 3]: 
– > 600 mg caffeine/day 
– after 4 pm on non-PSG nights 
– after 2 pm on the days of PSG nights.  
• 
Alcohol consumption [for definition of drinks see 
Appendix 2]: 
– > 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 (≥ 10 cigarettes per day), and smoking 
during PSG assessment at night. At home, it is 
recommended not to smoke or to use other tobacco 
products, including oral snuff tobacco, from 10 pm to 8 am. 
ENDPOINTS 
Primary efficacy endpoint 
The primary efficacy endpoint of this study is WASO, defined 
as the change of WASO from Baselinea to Days 1&2b as 
determined by PSG.  
WASO (min) is the time spent awake after onset of persistent 
sleep (see definition of LPS below) until lights on as determined 
by PSG.  
Total time in bed is fixed at 480 min (8 hours) during the PSG 
nights. The first screening PSG recording starts (lights off) 
within ± 30 minutes of usual bedtime (determined by sleep 
diary between V1 and V2); this time is then considered as the 
habitual bedtime and held constant ± 5 min throughout the 
study. PSG is recorded for 960 epochs of 30 seconds (8 hours) 


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from lights off until lights on. PSG recording is centrally scored 
by independent scorers.  
Where: 
a ’Baseline’ is the mean of the 2 PSG nights during the run-in 
period (V2).  
b ’Days 1&2’ are the mean of the corresponding 2 PSG 
treatment nights (V3).  
Secondary efficacy endpoints 
The secondary efficacy endpoints of this study are sleep 
initiation endpoints such as LPS and sLSO and a sleep 
maintenance endpoint such as subjective WASO (sWASO).  
Sleep-initiation endpoints 
Change from Baselinea to Days 1&2b in mean LPS.  
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-wake, 
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. 
Change from Baselinec to Week 4d in mean subjective sLSO. 
sLSO is the self-reported time to fall asleep, as reported in the 
sleep diary. 
Sleep-maintenance endpoint 
Change from Baselinec to Week 4d in mean sWASO.  
sWASO is the self-reported time spent awake after sleep onset 
as reported in the sleep diary. 
Where: 
a ’Baseline’ is the mean of the 2 PSG nights during the run-in 
period (V2).  
b ’Days 1&2’ is the mean of the corresponding 2 PSG 
treatment nights (V3).  
c ’Baseline’ is the mean value in the screening sleep diary 
entries at home between V2 and V3 across 7 consecutive 
days. 
d ’Week 4’ is the mean value based on the sleep diary entries at 
home across the last week of double-blind study treatment. 
 


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Other efficacy endpoints 
Other endpoints are described in Section 6.1.3. 
Safety endpoints 
• Treatment-emergent adverse events (TEAEs)‡ and serious 
adverse events (SAEs) up to 30 days after study treatment 
discontinuation. 
• Adverse events (AEs) leading to premature discontinuation 
of the double-blind study treatment. 
• TEAEs of special interest after adjudication by an 
Independent Safety Board (ISB): 
– Narcolepsy- like events (e.g., excessive daytime 
sleepiness, cataplexy) 
– Complex sleep behaviors events. 
– Suicidal thoughts and/or behaviors. 
• Change from baseline (mean of the two PSG nights at V2, 
run-in period) to the last value on double-blind study 
treatment in vital signs (systolic and diastolic blood 
pressures, pulse rate and body temperature)  
• Change from baseline (V1) to the last value on double-blind 
study treatment in body weight. 
• Treatment-emergent‡ ECG abnormalities. 
• Change from baseline (V2, second morning) to the last 
value on double-blind study treatment in ECG parameters.  
• Marked laboratory abnormalities on double-blind study 
treatment. 
• Change from baseline (V2, second morning) to the last 
value on double-blind study treatment in laboratory 
variables. 
• Rebound insomnia:  
– Change from baseline (V2) to the morning of V6 in 
WASO, TST and LPS. 
• Withdrawal symptoms: 
– Change from Day 30 to Day 31 in Benzodiazepine 
Withdrawal Symptom Questionnaire scores. 
– AEs and ECG abnormalities emerging from Day 30 to 
Day 31.  
• Change from baseline (mean of the two PSG nights at V2, 
run-in period) to Days 1&2, 15&16 and 28&29 in: 


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– Digit Symbol Substitution Test© performed in the 
morning, 30–60 minutes after lights on. 
– Sheehan Disability Scale© performed in the morning, 
30–60 minutes after lights on.  
– Karolinska Sleepiness Scale performed in the morning, 
30–60 minutes after lights on. 
• Change from baseline (V2, second morning) to the last 
value on double-blind study treatment in C-SSRS©. 
‡ A treatment-emergent AE is any AE temporally associated 
with the use of study treatment (from double-blind study 
treatment 
start 
until 
30 
days 
after 
study 
treatment 
discontinuation) whether or not considered by the investigator 
as related to study treatment. 
Pharmacokinetic endpoints 
ACT-541468 plasma concentrations (and possibly several of its 
metabolites) 9–10 h post-dose (morning after the second PSG 
night) at V3, V4, and V5. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 2. 
STATISTICAL 
METHODOLOGY 
Analysis sets: 
Screened Analysis Set 
This set includes all subjects who are screened and have a 
subject identification number. 
Randomized Analysis Set 
The Randomized Set includes all subjects who have been 
assigned to a study treatment. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects assigned to a 
study treatment and who received at least one dose of study 
treatment.  
Modified FAS 
The modified FAS (mFAS) includes all patients from the FAS 
who have at least one WASO assessment at Baseline and one at 
Days 1&2. 
Per-protocol Analysis Set 
The Per-protocol Analysis Set comprises all subjects from the 


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mFAS who have two consecutive WASO values at Baseline and 
at Days 1&2, and who complied with the protocol sufficiently to 
allow assessment of treatment effects.  
Safety Set 
The Safety Set (SS) includes all subjects who received at least 
one dose of study treatment. Subjects will be evaluated 
according to the actual treatment they received, which may 
differ from the randomly assigned treatment. 
PK Analysis Set 
The PK Analysis Set includes all subjects in the SS who have at 
least one PK sample collected after initiation of study drug. 
Methods 
The study is intended to select the dose that allows a clinically 
meaningful reduction of WASO compared to placebo. All 
analyses will be performed at a 0.05 type I error level 
(two-sided) using 95% confidence intervals (CIs). Secondary 
efficacy variables will also be analyzed at α = 0.05 (two-sided). 
Primary efficacy analysis 
This study includes 6 arms: a placebo, 4 doses of ACT-541468 
and an active reference. The active reference will be excluded 
from all statistical tests related to dose response, but will be 
compared separately versus placebo. 
The primary statistical analysis will be performed on the mFAS.  
The absolute change in WASO will be analyzed using the 
MCP-Mod approach [Bretz 2005, Pinheiro 2006] using a set of 
Multiple Contrast Tests (MCTs) to establish the existence of a 
dose response and a set of pre-specified dose-response models 
to describe the dose-response curve.  
Four candidate dose-response models will be considered: one 
linear, and three Emax models. The analysis will be performed 
using the R-package DoseFinding [Bornkamp 2016]. A 
dose-response relationship is demonstrated if at least one of the 
four MCTs has an adjusted p-value < 0.05. The best fitting 
model based on Akaike’s Information Criterion will be used to 
estimate the target dose, defined as the dose that achieves a 
placebo-corrected mean reduction from baseline of at least 
15 min with a 95% CI excluding 0. 


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The primary endpoint will be summarized at each time point by 
treatment group using the mean, median, standard deviation, 
standard error, quartiles, minimum, maximum and 95% 
confidence limits of mean.  
Secondary efficacy analyses 
Similarly, an MCP-Mod-based analysis will be conducted on 
the secondary endpoints. 
Treatment effect on secondary efficacy endpoints, except for the 
change of WASO from baseline over time, will also be assessed 
using a mixed model, with treatment, country, gender and age as 
fixed effects and patient as random covariate. 
Treatment effect on the change of WASO from baseline over 
time will be estimated using a repeated-measures mixed model. 
Further exploratory analysis will be conducted to assess the 
relationship of the changes between the perceived efficacy 
(subjective measures) and the objectives measures from PSG. 
Safety analysis 
Safety analyses will be performed on the SS [details defined in 
Section 10.1.6]. 
Adverse events: AEs in subjects who were screened but not 
randomized will be listed. 
The number and percentage of subjects experiencing TEAEs 
and SAEs will be tabulated by treatment group and by: 
• MedDRA system organ class (SOC) in alphabetical order 
and individual preferred term within each SOC, in 
descending order of incidence in the highest dose group. 
• Frequency of subjects with events coded with the same 
preferred term, in descending order of incidence in the 
highest dose group. 
TEAEs, AEs of special interest and SAEs will be tabulated as 
described above by severity and relationship to study treatment. 
AEs leading to premature discontinuation of the study treatment 
and AEs with outcome death will be summarized as described 
above.  


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AEs and SAEs with onset between randomization and first day 
of study treatment will also be summarized.  
Listings will be provided for all reported AEs, including SAEs. 
In addition, separate listings will be provided for SAEs, for AEs 
leading to premature discontinuation of study treatment, and for 
AEs with outcome death. 
Laboratory variables: Descriptive summary statistics by visit 
and treatment group will be provided for observed values and 
absolute changes from baseline, in both hematology and blood 
chemistry laboratory tests. All central laboratory data will be 
taken into account regardless of whether they correspond to 
scheduled or unscheduled assessments. Local laboratory results 
will only be listed and not included in the safety analysis. 
Marked laboratory abnormalities will be summarized for each 
laboratory variable by treatment group providing their incidence 
and frequency. Absolute values and changes from baseline of 
laboratory values during the course of the study will be 
summarized using the location and scale summary statistics by 
treatment group. 
The number and percentage of subjects with treatment-emergent 
laboratory abnormalities will be tabulated by treatment group 
MCP-Mod approach will also be considered for assessing the 
dose-response relationship for insomnia rebound effect and for 
withdrawal symptoms. 
Other endpoints’ analysis 
Treatment effects on other endpoints will be evaluated and 
described in detail in the SAP. 
Subgroup analysis 
Subgroup analyses will be performed by gender. 


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STUDY COMMITTEES 
An Independent Data Monitoring Committee (IDMC) will 
monitor safety and efficacy data in an unblinded manner and 
make appropriate recommendations to ensure safety of the 
subjects, thus ensuring that the study is being conducted with 
the highest scientific and ethical standards. The IDMC will be 
fully operational prior to enrolment 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 AEs of 
special interest, i.e., narcolepsy-like events (e.g., excessive 
daytime sleepiness, cataplexy), complex sleep behavior events 
and suicidal thoughts and/or behaviors. The composition and 
operation of the ISB is described in the ISB charter.  
 
 
 


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PROTOCOL 
1 
BACKGROUND  
 Insomnia disorder 
1.1
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 [DSM-5 2013]: 
“Insomnia disorder is a 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]. Higher prevalence rates are found in clinical 
practices, where about one-half of respondents to a survey reported symptoms of sleep 
disruption [NIH 2005, Roth 2007]. 
Insomnia disorder may result 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], and 
some studies have shown that the most common constellation of symptoms is represented 
by patients who concurrently suffer from difficulty both falling and staying asleep 
[Hohagen 1994]. Evidence now suggests that people with sleep maintenance difficulties 
are among the most likely to experience daytime cognitive impairment and report 
comorbidities [Ohayon 2010]. Therefore, problems related to sleep maintenance 
insomnia impact the largest percentage of insomnia sufferers, and affect them most 
acutely.  
While the direct consequences of insomnia remain only partially understood, the 
comorbidities associated with insomnia have been examined in a number of studies. 
Individuals with insomnia report impairment in cognitive functioning, daytime fatigue, 


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increased accident risk, and difficulties in interpersonal relationships [Balter 1991, 
Ancoli-Israel 1999], Rosenthal 1993, Zammit 1999, Fortier-Brochu 2014]. Insomnia has 
also been correlated with increased utilization of medical care [Simon 1997, Léger 2002], 
chronic health issues, and perceptions of poor health [Balter 1991, Ancoli-Israel 1999], 
Rosenthal 1993, Zammit 1999, Fortier-Brochu 2014]. 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 pharmacotherapy and non-pharmacological 
therapies [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. 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 [Pigeon 2007, Schutte-Rodin 2008]. Pharmacological 
options may be warranted. 
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. 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 


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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 to the benzodiazepines. In 2007 the US FDA requested that all 
manufacturers of hypnotic drug products strengthen their product labeling to include 
stronger language related to potential risks. These risks include severe allergic reactions 
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.  
Low-dose doxepin (3 mg and 6 mg tablets) is indicated for insomnia characterized by 
difficulty with sleep maintenance. This drug appears to reduce wakefulness through a 
selective histamine-1 receptor blockade [Scharf 2008].  
Suvorexant is an oral dual orexin receptor antagonist (DORA) that was approved by the 
FDA in 2014 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]. Concerns related to driving safety led the FDA to approve suvorexant 
at a maximum dose of 20 mg per night [Vermeeren 2015], a lower dose than anticipated 
based on efficacy data with up to 40 mg. 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]. 
1.1.4 Unmet medical need 
There are effective and safe treatments for insomnia [Schutte-Rodin 2008]. 
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]. This represents an important unmet medical need. There is a need for a 
pharmacological treatment for insomnia disorder that addresses the most prominent and 
pressing symptoms of insomnia without negatively impacting next-day functioning. 
Results of nonclinical and early-phase clinical studies [ACT-541468 IB] warrant the 
evaluation of ACT-541468 as a sleep medication in order to investigate its efficacy and 




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1.2.2 Zolpidem 
Zolpidem is a non-benzodiazepine sleep medication, with a chemical structure unrelated 
to benzodiazepines. However, zolpidem shares some of the pharmacological properties of 
the benzodiazepines since it binds to the benzodiazepine receptor 1 [Stilnox® SmPC]. 
The zolpidem oral tablet formulation is indicated for short-term treatment of insomnia. In 
the United States it is indicated when insomnia is characterized by difficulties with sleep 
initiation; sleep latency has been shown to decrease for up to 35 days in controlled 
clinical studies. In Europe, zolpidem is indicated for the short-term treatment of insomnia 
in adults [Stilnox® SmPC]. 
Common undesirable effects of sleep medications have been described in Section 1.1.3. 
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drowsiness, dizziness, headaches, nausea and vomiting. The most commonly observed 
adverse reactions were drowsiness, dizziness and diarrhea. In addition to drowsiness, 
prolonged reaction time and impaired driving may occur the morning after therapy 
[EMA 2014]. As with benzodiazepines and non-benzodiazepine sleep medications, 
zolpidem may lose efficacy over time as well as induce dependence and complex sleep 
behaviors (such as sleep-driving) with amnesia for the events and hallucinations 
[Ambien® USPI, Stilnox® SmPC]. Zolpidem is contraindicated in patients with 
myasthenia gravis [Stilnox® SmPC]. 
In the United States, a lower dose than in the AC-078A201 study, 5 mg instead of 10 mg, 
is recommended as the initial dose in women and the dose to be considered in men 
[Ambien® USPI]. The recommendation of the lower starting dose of 5 mg was based on 
higher risk of next-morning impairment in patients taking initial doses of 10 mg, in 
particular with the extended release formulation of Ambien® [FDA 2013]. The 10 mg 
zolpidem dose group has been included in the proposed study AC-078A201 for assay 
validation as the efficacy and the safety of this dose have been well established in 
confirmatory clinical studies in adult patients with chronic insomnia [Stilnox® SmPC]. In 
order to ensure subject safety, sleepiness/alertness will be closely monitored and 
neurological examinations will be performed in the morning after each polysomnography 
(PSG) night at the sleep centers in this study. Based on the results of the neurological 
examination, the investigator will discuss with the subject and decide whether it is safe 
for the subject to leave the study center. 
 Purpose and rationale of the study 
1.3
1.3.1 Purpose of the study 
The main purpose of this dose response study is to define the ACT-541468 dose(s) which 
will show a favorable efficacy and safety profile and to assess the safety and tolerability 
of the compound in adult subjects with insomnia disorder. 
The efficacious dose will be established based on the change in objectively assessed 
WASO and safety data, such as next-day residual effect versus placebo.  
1.3.2 Rationale for the study 
ACT-541468 is a DORA. The orexin system is involved in the regulation of sleep and 
arousal.  
DORAs are efficacious in the treatment of insomnia disorder. Suvorexant, an oral 
DORA, demonstrated efficacy and was approved by the FDA in 2014 for the treatment of 
insomnia characterized by difficulties with sleep onset and/or sleep maintenance 
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improvements in sleep maintenance and TST compared with placebo in two studies in 
subjects with primary insomnia. 
The dose levels of 5, 10, 25 and 50 mg of ACT-541468 planned for this study were all 
investigated in Phase 1, with clear sleep-promoting effects starting at 25 mg in healthy 
subjects. The dose level of 50 mg is expected to cap the high-end of the dose-response 
relationship. The lowest dose level of 5 mg is not expected to exert a clinically relevant 
effect on sleep parameters.  
The ACT-541468 mechanism of action, the results of nonclinical studies and Phase 1 
studies in healthy young adults, and the limitations of the existing sleep medications 
justify the need for evaluating ACT-451468 in insomnia disorder and identifying 
efficacious and safe doses. 
 Summary of known and potential benefits and risks  
1.4
1.4.1 ACT-541468 
Based on the mechanism of action of ACT-541468, and current nonclinical data and data 
collected in Phase 1 studies in healthy adult and elderly subjects, a fast effect on sleep 
induction and a sustained effect on sleep maintenance are anticipated. Suvorexant, a 
compound with a similar mechanism of action, has been demonstrated to be efficacious 
in the treatment of insomnia without evidence of physical dependence or withdrawal 
symptoms after discontinuation of suvorexant.  
This study will be the first study with ACT-541468 in subjects with insomnia disorder. 
ACT-541468 crosses the blood–brain barrier and decreases wakefulness in rats and dogs, 
is associated with a short sleep latency, and increases sleep efficacy following oral 
administration. In particular, it shows a shorter latency to non-REM sleep and better sleep 
efficacy than suvorexant in rats, and shorter duration of sleep in dogs. REM and 
non-REM sleep are prolonged proportionately in rats and dogs, thus decreasing 
wakefulness 
while 
preserving 
natural 
sleep 
architecture. 
In 
humans, 
clear 
CNS-depressant effects were observed starting at the dose of 25 mg. A battery of 
objective and subjective PD tests showed a decrease in vigilance and attention, as well as 
in visuomotor coordination and postural stability. There were no relevant differences 
between PD effects measured on Day 1 compared to Day 5. No next-day residual effects 
were observed after multiple evening dose administration.  
The most frequently observed adverse drug reactions reported in the conducted studies 
involving approximately 110 healthy subjects exposed to ACT-541468 include headache, 
somnolence, fatigue and dizziness. Overall, the effects of 25 mg returned to baseline 
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• Compromised respiratory function. 
A dose of 10 mg without dose up-titration will be used in this study.  
The 10 mg zolpidem dose, which demonstrated efficacy in the pivotal trials supporting 
registration, is in the recommended dose range in all countries potentially participating in 
this trial. 
1.4.3 Safety and risk minimization measures taken in the present study  
A next-day sleepiness effect can be observed with zolpidem and potentially may occur 
with ACT-541468. On each of the mornings following drug administration in sleep 
centers, the subjects will undergo neurological examination based on the evaluation of 
gait, the Tandem Walking Test and the Romberg Test. Based on the results of the 
neurological examination, the investigator will discuss with the subject and decide 
whether it is safe for the subject to leave the study center. Next-day residual effect will 
also be evaluated with the Karolinska Sleepiness Scale and visual analog scales assessing 
sleepiness, to be completed by the subjects each morning. 
As required by current guidelines, the Columbia Suicide Severity Rating Scale 
(C-SSRS©) will be completed by the subjects on the second morning of the PSG nights at 
V2 to V5 and on the morning after the PSG night at V6 to assess suicidality prior to 
randomization and during the study treatment phase.  
Liver variables and other laboratory variables will be monitored in the study. 
Due to lack of data about interaction of ACT-541468 with food, the study treatment will 
be administered at least 2 hours after a meal. 
Two committees will be set up for the study: 
• An Independent Safety Board (ISB) will review and adjudicate in a blinded manner 
all AEs of special interest, i.e., narcolepsy-like events (e.g., excessive daytime 
sleepiness, cataplexy), complex sleep behavior events and suicidal thoughts and/or 
behaviors. 
• An Independent Data Monitoring Committee (IDMC) will monitor unblinded safety 
data in an unblinded manner and make appropriate recommendations to ensure safety 
of the subjects.  
It is the investigator’s responsibility to monitor the risk-benefit ratio of study treatment 
administration, as well as the degree of distress caused by study procedures on an 
individual subject level, and to discontinue study treatment or the study if, on balance, 
he/she believes that continuation would be detrimental to the subject’s well-being. 


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In conclusion, based on available data on the study drugs (ACT-541468 and zolpidem) 
and the risk minimization measures mandated by the protocol, the expected risk-benefit 
assessment supports the conduct of this 4-week treatment study in adult subjects with 
insomnia disorder. 
2 
STUDY OBJECTIVES 
 Primary objective 
2.1
The primary objective of the study is to evaluate the dose response of ACT-541468 on 
the change of WASO assessed by PSG after treatment on Days 1 and 2.  
 Secondary objectives 
2.2
The secondary objectives of the study are to evaluate the dose response of ACT-541468 
on Latency to Persistent Sleep (LPS) on Days 1&2, and subjective Latency to Sleep 
Onset (sLSO) and subjective WASO (sWASO) at Week 4.  
 Other objectives 
2.3
To explore the effect of ACT-541468 on sleep parameters during the study, sleep 
parameters will include various objective and subjective measures.  
To assess the safety and tolerability of oral administration of ACT-541468 in subjects 
with insomnia disorder. 
To explore the relationship between exposure (concentration of ACT-541468 
approximately 9–10 h post-dose at second morning of V3, V4, and V5) and safety. 
3 
OVERALL STUDY DESIGN AND PLAN 
 Study design 
3.1
This is a multi-center, double-blind, randomized, placebo-controlled, active-reference, 
parallel-group, polysomnography dose-response Phase 2 study in adult subjects with 
insomnia disorder. 
In order to have approximately 300 subjects randomized, approximately 750 subjects will 
be screened. Subjects will be randomized in a 1:1:1:1:1:1 ratio to oral fixed doses of 
either ACT-541468 5 mg, 10 mg, 25 mg, 50 mg, placebo or zolpidem 10 mg (estimated 
screen failure rate is up to 60%). Treatment allocation will be stratified by gender. The 
study will be conducted in approximately 38 sites in approximately 6 countries.  
Subjects who prematurely discontinue the study will not be replaced. Estimated dropout 
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No interim analysis is planned during the conduct of the study. Subjects who complete 
the study or prematurely discontinue the study will be treated with standard of care 
according to the investigator’s opinion.  
3.1.1 Study phases 
The study comprises the following consecutive phases: 
3.1.1.1 Screening Phase 
Screening phase: Lasts a minimum of 14 days and maximum of 28 days. It starts with 
the signing of the Informed Consent Form (ICF) and ends with subject randomization. It 
includes the screening period (from Day –28 to Day –7) and the run-in period (from 
Day –14 to Day –1). 
The screening period starts with Visit 1 (V1), which occurs between Day –28 and  
Day –14. V1 is followed by the completion of the screening sleep diary for at least 
7 consecutive days at home until Visit 2 (V2).  
The run-in period occurs between Day –14 and Day –1 and starts with V2. V2 consists 
of 2 consecutive PSG nights on single-blind placebo treatment occurring between  
Day –14 and Day –6. V2 is followed by 5 to 12 days at home with no treatment. A sleep 
diary must be completed for at least 7 consecutive days from V2 to randomization.  
3.1.1.2 Treatment Phase 
Treatment phase: Consists of a double-blind treatment period followed by a run-out 
period. 
The double-blind treatment period starts with the first dose of double-blind study 
treatment in the first evening of Randomization Visit (V3, Day 1). The End of 
Double-Blind treatment (EODB) is reached in the second morning of V5 (Day 30) after 
the last dose of double-blind study treatment and after all second morning assessments 
have been performed.  
The run-out period starts in the evening of Day 30 (V6) with the last dose of 
single-blind study treatment. The end of the run-out period corresponds to the End of 
Treatment (EOT). EOT is reached after all morning assessments have been performed in 
the morning of Day 31 (V6). 
Safety follow-up phase: Starts after EOT (Day 31) and lasts at least 30 days (i.e., until 
Day 61). 
End of Study (EOS) for a single subject is defined as the date of the 30-day follow-up 
telephone call (Day 61). 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 


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subject is declared lost to follow-up [see also Section 8.2], EOS is the date of last 
successful contact for this subject. 
Unscheduled visits are allowed to take place anytime during the study, in which case 
study-related information will be collected. 
The visit schedule and protocol-mandated procedures will be performed according to the 
table of assessments [Table 2] and are described in Section 7. 
The overall study design is depicted in Figure 1. 
Figure 1 
Study design  
 
V = Visit; ▬ = PSG nights; EODB = End of Double-Blind treatment; EOT = End of Treatment. 
 
3.1.2 Study duration 
The study starts with the first act of recruitment (i.e., ICF signed), and ends with the last 
visit of the last subject.  
The subjects will be treated for approximately 4 weeks. For an individual subject, the 
study is completed with EOS, Day 61 (30-day safety follow-up telephone call). The 
duration of participation in the study of a subject is expected to be approximately 
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 Study design rationale 
3.2
This is a multi-center, double-blind, randomized, placebo-controlled, active-reference, 
parallel-group, polysomnography dose-response study.  
The study is double-blind and randomized to prevent any possible bias in parameter 
assessment or analysis.  
The placebo arm will support the evaluation of the absolute efficacy of each 
ACT-541468 dose. One active reference treatment arm (zolpidem 10 mg) is included for 
assay validity.  
A parallel-group design is a well-established study design to assess efficacy, safety and 
tolerability in medical conditions, recommended by health authorities [EMA 2011].  
Subjects screened at V1 will complete a run-in period to confirm final eligibility and to 
perform baseline assessments, as well as to exclude subjects with major short-term 
fluctuation of their conditions.  
The subjects will be treated for four weeks with double-blind study treatment, an 
appropriate treatment duration to investigate the maintenance of the effect on sleep 
parameters and to assess ACT-541468 safety and tolerability prior to the onset of Phase 3 
clinical studies. 
Upon active treatment discontinuation, a one-day run-out period (V6) on single-blind 
placebo treatment is planned to investigate possible withdrawal effects and rebound 
insomnia, as recommended by health authorities [EMA 2011]. Rebound insomnia is the 
re-emergence of sleep symptoms, with a worse severity than at baseline level. 
Withdrawal symptoms are a set of physical symptoms and emotions that subjects 
experience after abrupt discontinuation or drastic reduction of a substance. 
 Site personnel and their roles  
3.3
Polysomnography technologists 
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 Clinilabs, 
NY). 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. 
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Documentation of technologists’ prior experience and training, and study-specific 
training, will be maintained at each clinical trial site. 
 Study committees 
3.4
An IDMC has overall responsibility for safeguarding the interests of subjects by 
monitoring, in an unblinded manner, 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 with 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 AEs of special interest, i.e., 
narcolepsy-like events (e.g., excessive daytime sleepiness, cataplexy), complex sleep 
behavior events and suicidal thoughts and/or behaviors. The composition and operation 
of the ISB is described in the ISB charter.  
4 
SUBJECT POPULATION 
 Subject population description  
4.1
This study will enroll adult male and female subjects (aged 18 to 64 years inclusive) with 
insomnia disorder. For more details on inclusion and exclusion criteria, see Sections 4.3 
and 4.4.  
Vulnerable subjects are non-eligible since the research can be carried out in a 
non-vulnerable group of subjects and no particular benefit has been anticipated for 
vulnerable subjects which would be different from that in the general population. 
Insufficient sleep quantity is defined in this study by self-reported history of ≥ 30 minutes 
to fall asleep, of wake time during sleep ≥ 30 minutes and of TST ≤ 6.5 hours 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 V1 and the first PSG assessment (V2). They will also be 
validated by objective PSG based criteria collected from 2 consecutive nights spent in a 
sleep laboratory during the run-in period. Poor Sleep Quality (SQ) is quantified by 
Insomnia Severity Index (ISI©) score ≥ 15 at screening.  
 Rationale for the selection of the study population  
4.2
The study will recruit adult subjects, from 18 to 64 years, inclusive. A separate 
dose-finding study will be performed in 50 elderly subjects. Studies in children of less 
than 12 years and adolescents will not be performed before efficacy and safety of 
ACT-541468 have been established in adults.  


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Gender has been described in the literature as one of the intrinsic factors influencing 
response to sleep medications and the administration of the same dose of study drug 
might result in different drug exposure level in female and male subjects [FDA 2013]. 
Thus, stratification according to gender will be done and subgroup analysis will be 
performed. Since this study is the first trial of ACT-541468 conducted in subjects with 
insomnia disorder, concomitant treatments for insomnia (pharmacological or not) or 
concomitant medication active in the CNS are not allowed in the study to avoid 
confounding effects on safety and efficacy of the study treatments. 
 Inclusion criteria 
4.3
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 (V1, V2 and V3 in brackets refer to 
the visits when the criteria must be assessed): 
1. Signed informed consent prior to any study-mandated procedure (V1). 
2. Male or female aged 18–64 years (inclusive) (V1). 
3. A woman of childbearing potential must provide: 
• Negative serum pregnancy test (V1). 
• Negative urine pregnancy test (V3). 
• Agreement to undertake pregnancy tests up to 30 days after EOT. 
• Agreement to use the contraception scheme as described in Section 4.5.2 of the 
protocol from Screening up to at least 30 days after EOT. 
4. Body mass index (BMI): 18.5 ≤ BMI (kg/m2) < 32.0 (V1). 
5. Insomnia disorder according to DSM-5 criteria (V1). 
6. Self-reported history of all of the following on at least 3 nights per week and for at 
least 3 months prior to V1: 
• ≥ 30 minutes to fall asleep 
• Wake time during sleep ≥ 30 minutes 
• TST ≤ 6.5 h 
7. ISI© score ≥ 15 (V1). 
8. Willing to comply with all aspects of the study protocol (V1, V2, V3). 
9. Ability to communicate well with the investigator, to understand the study 
requirements and judged by the investigator to be alert and orientated to person, 
place, time and situation (V1). 
10. Meeting the following sleep parameters on at least 3 nights out of 7 consecutive 
nights on the sleep diary completed at home between V1 and V2 (to be checked at 
V2): 
• ≥ 30 minutes to fall asleep 
• Wake time during sleep ≥ 30 minutes 
• TST of ≤ 6.5 h 


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11. Usual bedtime between 21:30 and 00:30 as reported on sleep diary completed 
between V1 and V2 (to be checked at V2). 
12. Regular time in bed between 6 and 9 hours as reported on sleep diary completed 
between V1 and V2 (to be checked at V2). 
13. Meeting the following sleep parameters on the 2 PSG nights (V2): 
• Mean LPS ≥ 20 min (with none of the two nights < 15 min), and 
• Mean WASO ≥ 30 min (with none of the two nights < 20 min), and 
• Mean TST < 420 minutes 
 Exclusion criteria 
4.4
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any subject (V1, V2 and V3 in brackets refer to the visits 
when the criteria must be assessed): 
1. Any current sleep disorder(s) other than insomnia, or any lifetime history of related 
breathing disorder, periodic limb movement disorder, restless legs syndrome, 
circadian rhythm disorder, REM behavior disorder, or narcolepsy (V1). 
2. Self-reported usual daytime napping ≥ 1 hour per day, and ≥ 3 days per week (V1).  
3. Caffeine consumption ≥ 600 mg per day (V1) [see Appendix 3]. 
4. Shift work within 2 weeks prior to the screening visit, or planned shift work during 
study (V1). 
5. Travel ≥ 3 time zones within 1 week prior to the screening visit, or planned travel 
≥ 3 time zones during study (V1). 
6. Pregnant, planning to become pregnant or lactating (V1, V3). 
7. Hematology or biochemistry test results deviating from the normal range to a 
clinically relevant extent as per judgment of the investigator (V1, V2). 
8. AST and/or ALT > 2 × ULN and/or direct bilirubin > 1.5 × ULN (V1, V2). 
9. Severe renal impairment: known or defined as estimated creatinine clearance 
< 30 mL/min, according to the 4-variable Modification of Diet in Renal Disease 
formula (V1, V2). 
10. Unstable medical condition, significant medical disorder or acute illness, 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 (V1). 
11. Systolic blood pressure (BP) > 150 mmHg and diastolic BP > 90 mmHg (V1, V2). 
12. Resting pulse rate < 50 or ≥ 100 beats per minute (V1, V2). 
13. Any of the following conditions related to corrected QT (QTc) intervals (V1, V2): 
• 
A prolonged QTc interval (QTc greater than 450 ms). If QTc is greater than 
450 ms on the first ECG, a second ECG recording will be performed after at least 
30 minutes on the same day. If QTc is greater than 450 ms on the second ECG, 
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• 
A history of additional risk factors for torsade de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome). 
14. 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 
Screening/Baseline version of the C-SSRS© (V1, V2). 
• 
Lifetime history of suicide attempt (V1). 
15. Any known factor or disease that might interfere with treatment compliance, study 
conduct or interpretation of the results such as history of non-compliance to medical 
regimen, psychiatric disease or neurological disorders which may impact sleep, motor 
performance, or cognition, including Parkinson disease, predementia, dementia, other 
neurodegenerative disorders, and stroke (V1). 
16. Treatment with another investigational drug within 1 month prior to V1. 
17. Known hypersensitivity or contraindication to drugs of the same class as the study 
treatment or to any excipients of the study drug formulation, or to zolpidem, 
including myasthenia gravis (V1). 
18. Treatment with prohibited CNS-active drugs [as defined in Appendix 4] for 
5 half-lives of the respective drug (but at least 2 weeks) prior to V1 and until 24 h 
after EOT (V6), including over-the-counter (OTC) medication and herbal medicines. 
19. CBT within one month prior to V1. 
20. Treatment with moderate to strong CYP3A4 inhibitors, CYP3A4inducers, sensitive 
CYP3A4 substrates, P-gP substrates, BCRP substrates, and CYP2B6 substrates [as 
defined in Appendix 4] within 1 week prior to V1 until 24 h after EOT. 
21. Consumption of grapefruit or grapefruit juice within 1 week prior to V1 until 24 h 
after EOT.  
22. Diagnosis of alcohol or drug abuse or dependence within 2 years prior to the 
screening visit or inability to refrain from drinking alcohol for at least 3 consecutive 
days (V1). 
23. Positive drug test (for benzodiazepines, barbiturates, cannabinoids, opiates, 
amphetamines, or cocaine) or presence of alcohol in exhaled breath as detected by 
breathalyzer test (V1, V2). 
24. Heavy tobacco use (≥ 10 cigarettes per day), and/or inability to refrain from smoking 
for at least 14 hours during the night (V1).  
25. Apnea/hypopnea index (AHI) ≥ 10/h on the first PSG screening night according to 
American Academy of Sleep Medicine (AASM) criteria [Meoli 2001, CMS 2008] 
(V2).  
26. Apnea or hypopnea event (according to AASM criteria [Meoli 2001, CMS 2008]) 
associated with oxygen saturation by pulse oximetry (SpO2) < 80%, on the first PSG 
screening night (V2). 


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27. Periodic limb movement with arousal index (PLMAI) ≥ 10/h on the first PSG 
screening night (V2). 
 Criteria for women of childbearing potential 
4.5
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 eCRF.  
4.5.2 Acceptable methods of contraception 
Women of childbearing potential [see definition in Section 4.5.1] must follow the below 
contraception scheme from Screening up to at least 30 days after EOT: 
• 
Two methods of contraception, one from Group 1 and one from Group 2, defined as 
follows: 
o 
Group 1: Oral, implantable, transdermal, or injectable hormonal contraceptives 
or intrauterine devices. If a hormonal contraceptive is chosen from this group, it 
must be taken for at least 1 month prior to randomization. 
o 
Group 2: Diaphragm, female condom or cervical cap, partner’s use of a condom. 
OR 
• 
Sterilization of the male partner with documented post-vasectomy confirmation of 
the absence of sperm in the ejaculate.  
OR 
• 
Tubal sterilization (tubal occlusion / ligation at least 6 weeks prior to screening). 
OR 
• 
True abstinence from intercourse with a male partner only when this is in line with 
the preferred lifestyle of the subject. 
Rhythm methods or the partner’s use of a condom alone are not considered acceptable 
methods of contraception for this study. 


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The methods of birth control used (including non-pharmacological methods) must be 
recorded in the eCRF.  
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 
 Study treatment 
5.1
The study drugs are ACT-541468, over-encapsulated zolpidem, ACT-541468-matching 
placebo, and over-encapsulated zolpidem-matching placebo. Single-blind study drug will 
be administered at V2 and V6 and used for the swallow test at V1, if applicable. 
Double-blind study treatment will be administered from V3 to EODB (V5).  
5.1.1 Investigational treatment and matching placebo: Description and rationale 
ACT-541468 will be administered orally once daily in the evening during the 
double-blind treatment period. ACT-541468 doses will include: 5 mg, 10 mg, 25 mg and 
50 mg. The rationale for the selection of these ACT-541468 doses is described in 
Section 1.3.2.  
ACT-541468 is supplied by Actelion as the hydrochloride salt, in hard gelatin capsules at 
strengths of 5, 10 and 25 mg. The ACT-541468-matching placebo is supplied by Actelion 
as identical capsules, formulated with the same inactive ingredients (excipients) but 
without the active ingredient. 
5.1.2 Active reference: Description and rationale 
Zolpidem 10 mg will be administered orally once daily during the double-blind treatment 
period (V3 to EODB).  
Zolpidem is provided by Actelion as zolpidem tartrate, in over-encapsulated tablets of the 
commercially available Stilnox®. Each tablet contains 10 mg of zolpidem and excipients.  
In this study zolpidem will be administered at a dose of 10 mg. This dose has been well 
established in confirmatory clinical studies in adult subjects with chronic insomnia [see 
Section 1.2.2]. 
5.1.3 Study treatment administration 
In the absence of data evaluating food effects on ACT-541468 administration, the study 
treatment is recommended to be taken at least 2 hours after evening meal (including at 
V2 and V6). Each capsule will be swallowed whole. 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 eCRF during the PSG nights.  


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5.1.3.1 Study treatment administration during the different study phases 
5.1.3.1.1 Screening phase 
At V1, after signing the ICF and preferably prior any study mandated procedures, the 
subject will be given the option to perform a swallow test with two placebo capsules if 
he/she expresses any concern regarding his/her ability to swallow the study treatment. 
The test is to be done under the supervision of the site personnel and documented in the 
charts.  
At V2, 2 capsules of ACT-541468-matching placebo will be taken at the site. The 
capsules will be taken approximately 30 minutes before lights off (= habitual bedtime 
± 5 minutes), in the evening of each of the two PSG nights. 
5.1.3.1.2 Treatment phase 
During the double-blind treatment period, subjects will receive orally once daily two 
capsules as shown in Table 1.  
In the evening of a PSG night (V3, V4 and V5), the capsules will be taken at the site, 
approximately 30 minutes before lights off (= habitual bedtime ± 5 minutes). At home 
(from Day 3 to Day 14, and from Day 17 to Day 27) the capsules will be taken at 
bedtime.  
Table 1 
Capsules to be taken according to the treatment 
Treatment group 
Number (and 
dose strength) of 
ACT-541468 
capsules 
Number of ACT-
541468-matching 
placebo capsules 
Number of over-
encapsulated 
zolpidem 10 mg 
capsules 
Number of 
over-encapsulated 
zolpidem-
matching placebo 
capsules 
ACT-
541468 
5 mg 
1 (5 mg) 
1 
0 
0 
10 mg 
1 (10 mg) 
1 
0 
0 
25 mg 
1 (25 mg) 
1 
0 
0 
50 mg 
2 (25 mg) 
0 
0 
0 
Placebo 
0 
2 
0 
0 
Zolpidem 
0 
0 
1 
1 
 
During the run-out period, at V6, 2 capsules of ACT-541468-matching placebo will be 
taken approximately 30 minutes before lights off (= habitual bedtime ± 5 minutes), in the 
evening of the PSG night, at the site. 
5.1.3.2 Missed doses 
If one or more doses have been missed, the next dose must be taken in the evening of the 
following day. 


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5.1.4 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 V1 after the ICF has been fully signed, the investigator/delegate will contact the 
Interactive Response Technology (IRT) system to get a subject number allocated to the 
subject. 
At V2 (Days –14 to –6) and run out V6 (Day 30), subjects will receive single-blind 
placebo treatment.  
At randomization (V3, Day 1), after having verified that the subject meets all inclusion 
criteria and none of the exclusion criteria, the investigator/delegate contacts the IRT 
system to randomize the subject. The IRT system assigns a randomization number to the 
subject, and assigns the treatment kit number which matches the treatment arm assigned 
by the randomization list to the randomization number. 
The randomization list is generated by an independent CRO (ALMAC Clinical 
Technologies – see contact details on page 3 and in the IRT manual) and kept strictly 
confidential. 
5.1.5 Blinding 
5.1.5.1 V2 (run-in) and V6 (run-out) 
At V2 and V6, placebo treatment will be administered in a single-blind fashion. The 
subjects will remain blinded to the study treatment at least until study closure. The 
investigator and study personnel, the monitors, Actelion personnel, and CROs involved in 
the conduct of the study will be unblinded to treatment.  
5.1.5.2 Double-blind treatment period 
From V3 until EODB, the study will be performed in a double-blind fashion. The 
subjects, the investigator and study personnel, the monitors, Actelion personnel, and 
CROs involved in the conduct of the study will remain blinded to the study treatment. 
The Clinical Trial Supplies Manager 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 authorized persons who are not involved in the 
conduct of the study. 


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5.1.6 Unblinding 
5.1.6.1 Unblinding for final analyses  
Full randomization information will be made available for data analysis only after 
database closure in accordance with Actelion Quality System (QS) documents. 
5.1.6.2 Unblinding for IDMC review 
An Independent Statistical Analysis Center (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 review by the IDMC (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. 
5.1.6.3 Unblinding for suspected unexpected serious adverse reaction (SUSARs) 
If a suspected unexpected serious adverse reaction (SUSAR) occurs for a subject 
participating in the study, Actelion Global Drug Safety will request the unblinding of the 
treatment assignment. The treatment assignment will not be communicated to site 
personnel or to the Actelion Clinical Trial Team. Unblinded SUSAR information will be 
provided to respective health authorities and independent ethics committees (IECs) or 
institutional review board (IRBs) only. SUSARs will be reported to investigators in a 
blinded fashion. 
5.1.6.4 Emergency procedure for unblinding 
The investigator, study personnel and Actelion 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 it is 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 Actelion personnel. 
The occurrence of any unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, Actelion personnel must be informed as soon 
as possible before or after the unblinding. 
The circumstances leading to unblinding must be documented in the Investigator Site File 
(ISF) and eCRF. 


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5.1.7 Study treatment supply 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, GCP, and any local or national regulatory 
requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
5.1.7.1 Study treatment packaging and labeling 
Swallow test, V2 and V6: 
Study treatment is supplied as a site kit and provided in childproof bottles containing 
36 capsules.  
V3 to EODB: 
Study treatment is supplied as a subject kit containing 5 wallets. Each wallet contains 
capsules for 7 days of treatment (14 capsules).  
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.7.2 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. Temperature measurement devices for study 
treatment storage area are required.  
5.1.7.3 Study treatment dispensing 
The subjects will receive sufficient study treatment to cover the period from V3 up to 
EODB. If a wallet is lost or damaged, a replacement kit can be requested through the 
Treatment Replacement module of the IRT system. Subjects are asked to return all used, 
partially used and unused study treatment wallets at EODB. The protocol-mandated study 
treatment dispensing procedures must not be altered without prior written approval from 
Actelion. An accurate record of the date and amount of study treatment dispensed to each 
subject must be available for inspection at any time. 
5.1.7.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without 
prior written approval from Actelion. On an ongoing basis and/or on termination of the 
study, the CRA will collect used and unused treatment kits, which will be sent to the 
warehouse, where Actelion personnel or a deputy will check treatment reconciliation. In 
certain circumstances, used and unused study treatment containers may be destroyed at 
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personnel or the deputy, and written permission for destruction has been obtained from 
Actelion. 
5.1.8 Study treatment accountability and compliance with study treatment  
5.1.8.1 Study treatment accountability 
The inventory of study treatment dispensed to and returned by the subject (i.e., 
study-treatment accountability) must be performed by site personnel at each visit and 
before dispensing further study treatment. It is to be recorded by site personnel on the 
study-treatment dispensing and accountability log and in the eCRF, and checked by the 
CRA during site visits and at the end of the study. The study treatment accountability log 
in the eCRF will include at least the following information for each study treatment unit 
dispensed to the subject: 
At V2 (run-in) and V6 (run out):  
• 
Bottle number. 
• 
Number of capsules dispensed. 
Double-blind treatment period:  
• 
Dispensed subject kit number at randomization (V3, Day 1). 
• 
Date and number of capsules dispensed at randomization (V3, Day 1). 
• 
Date and number of capsules returned at EODB (V5, Day 30). 
All study treatment supplies, including partially used or empty wallets and bottles must 
be retained at the site for review by the CRA. 
If the subject forgets to bring the study treatment at V4, he/she will be assigned a new kit 
from the IRT and the subject must be instructed to not take any capsules from the 
remaining study treatment kit and to return it at EODB. 
5.1.8.2 Study treatment compliance 
Study treatment compliance is based on study treatment accountability. Study treatment 
compliance for the double-blind treatment period (Day 1 to EODB) will be calculated by 
site personnel using the below formula and entered in the eCRF. 
Compliance = [(number of capsules dispensed - number of capsules returned) / total 
number of capsules that must have been taken during the period*] × 100 
* The period is defined as from V3 (Day1) to EODB. The number of capsules that should 
have been taken is 58.  
During the double-blind treatment period (Day 1 to EODB), compliance is expected to be 
at least 70% per week. Compliance values below this will be considered as a protocol 


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deviation which will be reported in the eCRF 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. 
5.1.9 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 5.1.11. 
If study treatment is interrupted by the subject for any reason, he/she must immediately 
inform the investigator. 
Interruptions of study treatment must be kept as short as possible. 
Study treatment dose interruptions must be recorded in the eCRF. 
5.1.10 Premature discontinuation of double-blind study treatment 
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator, or Actelion personnel. The main reason for discontinuation must be 
documented in the eCRF and in the subject’s medical charts (e.g., tolerability- or 
efficacy-related if decision of the subject; due to pre-specified study treatment 
discontinuation criteria, an adverse event or lack of efficacy if decision of the 
investigator; study terminated if decision from Actelion). 
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 5.1.11. 


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A subject who prematurely discontinues study treatment is NOT considered as withdrawn 
from the study and will be followed up until EOS, provided that the subject’s consent for 
this limited participation in the study has not been withdrawn. 
The subject is recommended to return for an EODB visit within one week of last intake 
of study treatment and to agree to be called for a safety follow-up at least 30 days after 
the last intake of study treatment.  
A subject who prematurely discontinues study treatment and withdraws consent to 
participate in any further study assessments is considered as withdrawn from the study. 
Subjects who die or are lost to follow-up are also considered as withdrawn from the 
study. Withdrawal from the study and follow-up medical care of subjects withdrawn from 
the study is described in Sections 8.2 and 8.4, respectively. 
5.1.11 Study-specific criteria for premature discontinuation of double-blind study 
treatment 
On the second mornings of V3 and V4, the investigator will review with the subject the 
results of the safety evaluation after the two PSG nights [details described in 
Section 7.2.3] and evaluate the presence of any signs or symptoms of possible next-day 
residual effect or any other adverse event that the subject may have experienced. If there 
are signs of next-day residual effect or any other 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 leave the center and to continue 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.  
 Previous and concomitant therapy  
5.2
5.2.1 Definitions 
A previous therapy is any treatment for which the end date is prior to signing of informed 
consent.  
A therapy that is study-concomitant is any treatment that is ongoing or initiated after 
signing of informed consent, or initiated up to 30 days after study treatment 
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A therapy that is study treatment-concomitant is any treatment that is either ongoing at 
the start of double-blind study treatment or is initiated during the double-blind treatment 
period until 1 day after the last dose of double-blind study treatment.  
5.2.2 Reporting of previous/concomitant therapy in the eCRF  
The use of all study-concomitant therapies (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 informed consent.  
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 
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 preferably not be changed 
during the course of the study. 
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, stroke). 
The following concomitant therapies are forbidden during the study [see also 
Appendix 4]: 
• 
Treatment with another investigational drug until EOS.  
• 
Prohibited CNS-active medications, including OTC and herbal medicines, until 
24 hours after EOT. 
• 
Treatment with moderate to strong CYP3A4 inhibitors, CYP3A4 inducers, sensitive 
CYP3A4 substrates (i.e., have low bioavailability due to a marked first-pass effect), 
P-gP substrates, BCRP substrates and CYP2B6 substrates until 24 hours after EOT. 
CBT and other psychological therapies, excluding common advices related to sleep 
hygiene, until 24 hours after EOT.  
5.2.5 Forbidden concomitant diet and activities 
The following activities and diet are forbidden during the study: 
• 
Consumption of grapefruit and grapefruit juice until 24 hours after EOT. 


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• 
Consumption of food within 2 hours prior to study treatment intake. 
• 
Caffeine consumption [more details in Appendix 3]: 
– > 600 mg caffeine/day 
– after 4 pm on non-PSG nights 
– after 2 pm on the days of PSG nights.  
• 
Alcohol consumption [for definition of drinks, see Appendix 2]: 
– > 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 (≥ 10 cigarettes per day), and smoking during PSG assessment at 
night. At home, it is recommended not to smoke or to use other tobacco products 
including oral snuff tobacco from 10 pm to 8 am. 
6 
STUDY ENDPOINTS 
 Efficacy endpoints 
6.1
6.1.1 Primary efficacy endpoint 
The primary efficacy endpoint of this study is defined as the change of WASO (min) 
from Baselinea to Days 1&2b as determined by PSG.  
WASO is the time (min) spent awake after onset of persistent sleep (see definition of LPS 
in Section 6.1.2) until lights on as determined by PSG. WASO assessed by PSG is a sleep 
parameter evaluating sleep continuity. It is considered an adequate endpoint for 
dose-finding studies [EMA 2011].  
Total time in bed is fixed at 480 min (8 hours) during the PSG nights. The first screening 
PSG recording starts (lights off) within ± 30 minutes of usual bedtime (determined by 
sleep diary between V1 and V2); this time is then considered as the habitual bedtime and 
held constant ± 5 min throughout the study. PSG is recorded for 960 epochs of 
30 seconds (8 hours) from lights off until lights on. PSG recording is centrally scored by 
independent scorers.  
Where: 
a ’Baseline’ is the mean of the 2 PSG nights during the run-in period (V2).  
b ’Days 1&2’ is the mean of the corresponding 2 PSG treatment nights (V3).  
6.1.2 Secondary efficacy endpoints 
The secondary efficacy endpoints of this study are: sleep initiation endpoints such as LPS 
and sLSO and a sleep maintenance endpoint such as sWASO.  
Sleep-initiation endpoints: 
Change from Baselinea to Days 1&2b in mean LPS.  


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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-wake, 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. 
Change from Baselinec to Week 4d in mean sLSO.  
sLSO is the self-reported time to fall asleep, as reported in the sleep diary. 
Sleep-maintenance endpoint: 
Change from Baselinec to Week 4d in mean sWASO.  
sWASO is the self-reported time spent awake after sleep onset as reported in the sleep 
diary. 
Where: 
a ’Baseline’ is the mean of the 2 PSG nights during the run-in period (V2).  
b ’Days 1&2’ is the mean of the corresponding 2 PSG treatment nights (V3).  
c ’Baseline’ is the mean value in the screening sleep diary entries at home between 
V2 and V3 across 7 consecutive days. 
d ’Week 4’ is the mean value based on the sleep diary entries at home across the last 
week of double-blind study treatment. 
6.1.3 Other efficacy endpoints 
For each variable, multiple aspects will be considered in the analysis, in particular 
changes from baseline at different time points. Details are provided in Section 10.2.3:  
• 
WASO and sWASO, 
• 
LPS and sLSO, 
• 
TST and subjective TST (sTST),  
• 
SQ,  
• 
Sleep stages S1, S2, SWS and REM,  
• 
Shifts from S2, SWS or REM to S1 or awake, 
• 
Wake time during sleep, 
• 
Frequency of awakenings as measured by PSG and self-reported, 
• 
Sleep Efficiency (SE) (defined as 100 × ( TST / time in bed), 
• 
ISI© scores,  
• 
Next-day performance. 


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 Safety endpoints 
6.2
• TEAEs1 and SAEs up to 30 days after study treatment discontinuation. 
• AEs leading to premature discontinuation of the double-blind study treatment. 
• TEAEs of special interest after adjudication by ISB: 
– Narcolepsy-like events (e.g., excessive daytime sleepiness, cataplexy) 
– Complex sleep behaviors events. 
– Suicidal thoughts and/or behaviors. 
• Change from Baseline (mean of the two PSG nights at V2, run-in period) to the last 
value on double-blind study treatment in vital signs (systolic and diastolic BP, pulse 
rate and body temperature),  
• Change from baseline (V1) to the last value on double-blind study treatment in body 
weight. 
• Treatment-emergent ECG abnormalities from V3 until EOT. 
• Change from baseline (V2, second morning) to the last value on double-blind study 
treatment in ECG parameters.  
• Marked laboratory abnormalities on double-blind study treatment. 
• Change from baseline (V2, second morning) to the last value on double-blind study 
treatment in laboratory variables. 
• Rebound insomnia  
– Change from baseline (V2) to the morning of V6 in WASO, TST and LPS. 
• Withdrawal symptoms: 
– Change from Day 30 to Day 31 in the Benzodiazepine Withdrawal Symptom 
Questionnaire (BWSQ) scores. 
– AEs and ECG abnormalities emerging from Day 30 to Day 31.  
• Change from baseline (mean of the two PSG nights at V2, run-in period) to mean of 
the two PSG nights of V3 (Days 1&2), V4 (Days 15&16) and V5 (Days 28&29) in: 
– Digit Symbol Substitution Test (DSST©) performed in the morning,  
30–60 minutes after lights on. 
– Sheehan Disability Scale (SDS©) performed in the morning, 30–60 minutes after 
lights on. 
– Karolinska Sleepiness Scale (KSS) performed in the morning, 30–60 minutes after 
lights on. 
                                                 
1 A treatment-emergent AE is any AE temporally associated with the use of study treatment (from double-blind study 
treatment start until 30 days after study treatment discontinuation) whether or not considered by the investigator 
as related to study treatment. 
 


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• Change from baseline (V2, second morning) to the last value on double-blind study 
treatment in C-SSRS©. 
 Pharmacokinetic endpoints 
6.3
Concentration of ACT-541468 (and possibly several of its metabolites) approximately 
9–10 h post-dose at V3, V4, and V5.  
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
 Study visits  
7.1
The study visits are listed in Table 2. For all visits, the subjects must be seen on the 
designated day with an allowed visit window of ± 2 days. A follow-up safety telephone 
call must be performed 30 days (+ 7 days) after intake of the last dose of study treatment.  
7.1.1 Screening/re-screening 
Screening starts with the signing of the ICF. The date on which the first screening 
assessment is performed corresponds to the date of the Screening Visit (V1). 
It is the responsibility of the investigator/delegate to obtain written informed consent 
from each subject participating in this study after adequate face-to-face explanation of the 
objectives, methods, and potential hazards of the study. The subjects who agree to 
participate in the study and the investigator/delegate must sign the ICF prior to 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 permitted to re-screen subjects once, after discussion with Actelion. All screening 
assessments must then be repeated at the time of re-screening (or as agreed with 
Actelion). 
A swallow test will be proposed to subjects after signing the ICF and before starting any 
other study-mandated procedures. The swallow test will be optional; however, if a subject 
chooses to perform the swallow test but cannot swallow the study medication, the subject 
cannot participate in the run-in and has to be discontinued from the study.  
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study. Depending on the 
reason for the unscheduled visit (e.g., AE), appropriate assessments will be performed 
based on the judgment of the investigator. Results of ECG, laboratory assessments and 
change in concomitant treatment will be recorded in the eCRF. After an unscheduled 
visit, the regular scheduled study visits must continue according to the planned visit and 
assessment schedule [Table 2]. 
 


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Table 2 
Visit and assessment schedule 
 
SCREENING PHASE (14–28 days) 
TREATMENT PHASE  (29 days ± 2 days) 
FOLLOW-
UP 
PHASE 
VISITS Number 
1 
- 
2 
- 
3 
- 
4 
 
5 
6 
Safety  
follow-up8 
 
Name 
Screening 
period 
Run-in period 
PSG treatment nights 
At 
home 
PSG treatment nights  
At 
home 
Last PSG treatment nights / 
Permanent discontinuation6 
Run-out 
period 
 
Time 
Between 
Day –28 
and –14 
At 
home  
7 to 21 
Days 
1st night 
Day –14 to  
Day –7 
2nd night 
Day –13 to  
Day –6 
At home  
5 to 12 
Days 
 up to  
Day –1  
1st night 
Day 1 to  
Day 2 
2nd night 
Day 2 to  
Day 3 
Day  
3–14 
(± 2 
days) 
1st night 
Day 15 to 
Day 16 
2nd night 
Day 16 to 
Day 17 
Day  
17–27 
(± 2 
days) 
1st night 
Day 28 to 
Day 29 
2nd night 
Day 29 to 
Day 30 
Day 30 to 
Day 31 
Day 61  
(+ 7 
days) 
1st  
Evening 
1st 
Morning 
2nd 
Evening 
2nd 
Morning 
1st 
Evening 
1st 
Morning 
2nd 
Evening 
2nd 
Morning 
1st 
Evening 
1st 
Morning 
2nd 
Evening 
2nd 
Morning 
1st 
Evening 1st 
Morning 
2nd 
Evening 
2nd 
Morning 
 
Evening 
 
Morning 
 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion and 
exclusion 
criteria 
X 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Physical 
examination, 
body weight 
and height11 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
Vital signs and 
body 
temperature 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X6 
 
X 
 
12-lead ECG 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X6 
 
X 
 
Hematology, 
blood chemistry 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X6 
 
 
 
Pregnancy test 1 
X 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
X 
Drug and 
alcohol tests 
X 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 
 
PK sampling 
 
 
 
 
 
 
 
 
X10 
 
X 
 
 
X10 
 
X 
 
 
X10 
 
X 
 
 
 
PSG 
 
 
X4 
X 
 
X 
X 
 
X 
X 
 
X 
X 
X 
 
ISI© 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X6 
 
 
 
Sleep diary 
(incl. VAS) 2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
Neurological 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
X 
 


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1. For women of childbearing potential, serum test at V1 and 5 and urine test at V3, and 1 month after last dose of study drug intake. 2. The hand-held device is handed out to the subject, in order to be 
completed at home without interruption from V1 to V6. 3. Placebo single-blind treatment. 4. Includes assessment of AHI, PLMAI, SpO2. 5. SAE and AE reporting and follow-up: all SAE and AEs 
from signed ICF up to 30 days after double-blind study drug discontinuation. 6. In the event of permanent discontinuation, safety assessments of V5 are recommended to be performed within 24 hours 
of last study drug intake. 7. Approximately 30 to 60 minutes after PSG lights on. 8. Telephone call. 9. Performed approximately 1 hour after lights on. Repeat every 30 min until subject safe to leave 
center. 10. In the event of excessive sleepiness according to investigator opinion one hour after lights on in the morning after the first PSG night, it is recommended to draw a PK sample. 11. Height 
only at V1. 
 
AE = adverse event; AHI = apnea/hypopnea index; BWSQ = Benzodiazepine Withdrawal Symptom Questionnaire; C-SSRS = Columbia Suicide Severity Rating Scale; DSST = Digital Symbol 
Substitution Test; ECG = electrocardiogram; ICF = Informed Consent Form; KSS = Karolinska Sleepiness Scale; 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; VAS = visual analog scales. 
 
exam9 
C-SSRS©7 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X 
 
 
 
 
X6 
 
X 
 
DSST©7  
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X6 
 
 
 
SDS© 7 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X6 
 
 
 
KSS7 
 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X 
 
 
X 
 
X6 
 
 
 
BWSQ7 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
X 
 
 
 
 
X6 
 
X 
 
Randomization 
 
 
 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
intake 
 
 
X3 
 
X3 
 
 
X 
 
X 
 
X 
X 
 
X 
 
X 
X 
 
X 
 
X3 
 
 
Concomitant 
medications 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X6 
X 
X 
 
SAEs and AEs 5 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X 
 
X 
X 
X 
X6 
X 
X 
X 


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 Study assessments 
7.2
The mandatory study assessments are listed in Table 2.  
All study assessments are performed by qualified study personnel (medical, nursing, or 
specialist technical personnel) and are recorded in the 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: 
– Drug and alcohol test 
– Evening questionnaire in sleep diary (including visual analog scales [VAS]) 
– Recording of concomitant medications 
– AEs and SAEs 
– Study drug intake (30 minutes before lights off) 
• 
In the morning after a PSG night, after completion of normal morning routine (e.g., 
using the bathroom, eating breakfast): 
– Vital signs and body temperature 
– DSST©  
– ISI© (V5, second morning) 
– SDS© 
– KSS 
– C-SSRS© 
– BWSQ (only second morning at V2, V4, V5 and V6) 
– Morning questionnaire in sleep diary (including VAS) 
– Recording of concomitant medications 
– AEs and SAEs 
– Neurological examination* 
– Hematology and blood chemistry; PK sampling* (second morning) 
– 12-lead ECG (only second morning at V2, V3 and V5) 
* The neurological examination must be performed approximately 1 hour after lights on 
and repeated approximately every 30 min until the subject is safe to leave the center. In 
the event of excessive sleepiness according to investigator opinion one hour after lights 
on in the morning after the first PSG night, it is recommended to draw a PK sample. 
The following assessments will be analyzed by an external provider (results will be 
transferred to the Actelion database and to the investigators): 
• 
Laboratory parameters 
• 
ECG parameters 
• 
PSG recordings 


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• 
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 Actelion to whom these tasks are delegated. 
The set-up and oversight must be agreed upon with Actelion. 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 storage area. 
• 
Polysomnographic device. 
Use of hand-held device 
Patients will be required to complete the following questionnaires on a hand-held device:  
ISI©, SDS©, KSS, C-SSRS©, BWSQ, sleep diary and VAS.  
Sites will be properly trained on the accurate use of the hand-held device by an external 
CRO and are then expected to train their subjects on how to appropriately complete the 
questionnaires. Data collected from the hand-held device will be electronically 
transferred to Actelion by the CRO.  
For further details refer to the hand-held device manual.  
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 in the eCRF. Where possible, 
diagnoses and not symptoms will be recorded.  
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). The PSG data are evaluated and scored centrally 
by an independent scorer (expert from CRO Clinilabs, NY, not otherwise involved in the 
study). The technical requirements for montage and recording of the PSG are outlined in 
the PSG manual. The quality of PSG recordings is monitored and quality-controlled on 
an ongoing basis. 


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All PSG recordings are supervised by qualified technical personnel. The site and scorers 
that participate in this study must be certified by the CRO. 
The first screening PSG recording starts (lights off) within ± 30 minutes of usual bedtime 
(determined by sleep diary between V1 and V2); this time is then considered as the 
habitual bedtime and held constant (± 5 min) throughout the study. Study medication is 
administered 30 minutes (± 5 min) before the recording starts. The PSG recording is 
stopped after 480 minutes when 960 epochs of 30 seconds have been recorded. Two 
consecutive PSG nights take place at V2 (between Day –14 and Day –6), V3 (Days 1&2), 
V4 (Days 15&16) and V5 (Days 28&29). At V6 (Day 30), a single PSG night 
immediately follows V5. The first PSG screening night (V2) also includes AHI, PLMAI, 
and SpO2 assessments.  
The time in bed is fixed at 8 hours. 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 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 or 
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 minutes of recording are finished. 
After recording is stopped, the lights are turned on and the subject is awakened. The 
subject is then allowed to go to the bathroom and to get dressed. Within 30–60 minutes 
vital signs are measured and subject is asked to perform the morning assessments. The 
presence of any AE or change in concomitant medication will be checked. Based on the 
results of the neurological examination, the investigator will discuss with the subject and 
decide whether it is safe for the subject to leave the study center.  
The centers are required to transfer PSG data to the CRO responsible for central scoring, 
after each second PSG night. During the run-in Period, PSG data obviously not fitting 
eligibility criteria 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. The CRO will score 
the PSG data immediately upon receipt and the center will receive the complete 
Eligibility Assessment (mean WASO, mean LPS, mean TST, AHI, PLMAI, and the 
presence of any apnea/hypopnea event associated with SpO2 < 80%) within 3 business 
days following file receipt by the CRO. Based on this information, the investigator 
assesses the subject’s potential eligibility. 


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After the last PSG night in the run-out period, results of all the PSG nights for the subject 
(V2, V3, V4, V5 and V6) are sent to Actelion from the CRO. The following sleep 
variables will be assessed by PSG: WASO, LPS, TST, sleep stages S1 (called N1 in the 
scoring procedures of Clinilabs Manual), S2 (N2), SWS (N3) and REM (R), and Wake 
time during sleep (W). The definitions of the sleep variables are given in the scoring 
procedures of the Clinilabs Manual. 
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 
Clinilabs, NY). 
7.2.2.2 Sleep diary 
The sleep diary is provided to the subject at V1 as an electronic hand-held device 
programmed in the subject’s language, and must be completed every day at home and at 
the site until V6. 
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 ERT).  
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.  
During the Screening period, the subject's answer to the sleep diary question “What time 
did you go to bed last night?” is expected to be in the time window of 21:30 to 00:30, for 
at least 50% of the nights, and the median of these values defined as the usual bedtime 
(used to set the habitual bedtime) is also expected to be in the same time window. The 
subject's regular time in bed (i.e. time calculated from “What time did you go to bed last 
night?” until “What time did you get out of bed this morning?”) is expected to be in the 
time window of 6 to 9 hours, for at least 50% of the nights. 
For further details, see Appendix 10. 
7.2.2.2.2 Visual analog scales 
The VAS collect information on quality of sleep, depth of sleep, morning sleepiness, 
daytime alertness, and daytime ability to function by asking the subjects to report their 
feelings by placing a mark on a visual analog scale. 


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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 10. 
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 functioning [see Appendix 6]. 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 subjective-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.  
Actelion has been granted a license agreement for the use of the ISI©. 
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 (V1) and recorded in the eCRF. 
Body weight will be measured at Screening (V1) and EODB, and recorded in the eCRF. 
BMI will be calculated at V1 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 Vital signs 
Systolic and diastolic BP, pulse rate and body temperature will be measured 
non-invasively at each study visit from screening (V1) to V6. Vital signs will be 
measured with the subject either in a supine or sitting position. It is recommended to 
allow the subject to rest for at least 5 minutes, and to use the same position (supine or 
sitting) throughout the trial for an individual subject. The right or left arm may be used, 
but it is recommended to use the same arm throughout the trial. 
Vital sign measurements and conditions will be collected in the eCRF. 


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7.2.3.3 Physical examination 
Physical examination is to be performed at screening (V1) and on second morning of V5 
(recommended within 24 hours after last dose of double-blind study drug intake). It 
includes the examination of the following body systems: 
• 
Head, ear, nose and throat 
• 
Eyes 
• 
Neck 
• 
Cardiovascular system 
• 
Respiratory system 
• 
Abdomen 
• 
Skin 
• 
Extremities 
• 
Neurological system 
• 
Musculoskeletal system.  
Other exams will be performed if indicated, based on medical history and/or symptoms. 
Information for all physical examinations must be included in the source documentation 
at the study site. The observations must be recorded according to body system. In the 
event of an abnormality, the related signs (e.g., systolic murmur) and not the diagnosis 
(e.g., mitral valve insufficiency) must be recorded in the eCRF. Clinically relevant 
findings (other than those related to insomnia disorder), including smoking habits, that 
are present prior to signing of informed consent, must be recorded on the Medical History 
eCRF form. Physical examination findings made after signing of informed consent, 
which meet the definition of an AE [Section 9.1.1] must be recorded on the AE form of 
the eCRF. 
7.2.3.4 Digit Symbol Substitution Test© 
The DSST© 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 number of correct substitutions is recorded as the total DSST© score. 
Actelion has been granted a license agreement for the use of the DSST©. For further 
details, see Appendix 5. 


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7.2.3.5 Sheehan Disability Scale© 
The SDS© consist of 3 questions on impairment of work, social life, and family life/home 
responsibilities [see Appendix 7] [Sheehan 1996]. The SDS© is a self-administered 
questionnaire on the hand-held device.  
Actelion has been granted the license agreement for the use SDS©.  
7.2.3.6 Karolinska Sleepiness Scale  
The Karolinska Sleepiness Scale (KSS) will be used to assess next-day alertness [see 
Appendix 8]. The subject will be asked to mark his/her sleepiness on a 9-point scale. The 
scale has a range from 1 being ‘very alert’ to 9 being ‘very sleepy, great effort to keep 
awake, fighting sleep’. The KSS is a self-administered questionnaire on the hand-held 
device. 
7.2.3.7 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 
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. At V1 (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 will review the responses provided by the subject and 
assess the findings. The scale will be self-administered using the hand-held device in 
presence of an adequately trained staff member.  


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Actelion has been granted the license agreement for the use of the electronic C-SSRS©.  
7.2.3.8 Benzodiazepine Withdrawal Symptoms Questionnaire 
The BWSQ, also called the Tyrer Withdrawal Symptoms Questionnaire, assesses the 
main symptoms which might be experienced by subjects during withdrawal from 
benzodiazepines [see Appendix 9] [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. 
7.2.3.9 Neurological examinations 
In the morning following each PSG night (V2, V3, V4, V5 and V6), 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 
The set of examinations will be repeated approximately every 30 minutes until the subject is 
safe to leave the center [also see Section 7.2]. The time when the subjects is considered 
safe to leave the center will be recorded in the eCRF.  
7.2.3.10 ECG assessment 
A standard 12-lead ECG is to be performed, at V1, in the second morning of V2, V3 and 
V5, and in the morning of V6. 
12-lead ECG will be recorded at rest with the subject in the supine position for a 
5-minute period. 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: QTc = QT / (RR)1/2 
and 
• Fridericia’s formula: QTc = QT / (RR)1/3, where RR = 60 / HR 


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If the central review of the ECG detects a prolonged QTc interval greater than 450 ms for 
a subject at screening (V1, V2), ECG must be repeated (at least 30 minutes after first 
ECG). If the central review confirms that the repeated ECG shows a QTC interval greater 
than 450 ms, the subject cannot be enrolled into the study.  
Clinically relevant findings made after randomization which meet the definition of an AE 
must be recorded in the eCRF.  
ECG data collected by the CRO will be electronically transferred to Actelion.  
7.2.4 Laboratory assessments 
7.2.4.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits.  
Exceptional circumstances which will require recording of local laboratory results of the 
parameters described in Section 7.2.4.2 (with corresponding normal ranges), include 
hospitalization of the subject due to a medical emergency and missing central laboratory 
results from a scheduled or unscheduled visit.  
If one central laboratory sample is lost or cannot be analyzed for whatever reason, the 
investigator will collect an additional sample as soon as possible for repeat analysis, 
unless a local laboratory sample was collected within the same time-window and these 
test results are available. 
Central laboratory reports will be sent to the investigator. In the event of specific 
(pre-defined) laboratory abnormalities, the central laboratory will alert Actelion 
personnel and the concerned site personnel. Alert flags that will trigger such notifications 
are displayed in Appendix 1. 
All laboratory reports must be reviewed, signed and dated by the investigator or delegate 
within 10 working days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the laboratory report whether abnormal values are 
considered clinically relevant or not. Clinically relevant laboratory findings that are 
known at the time of signing of informed consent must be recorded on the Medical 
History page of the eCRF. Any clinically relevant laboratory abnormalities detected after 
signing of informed consent must be reported as an AE or SAE as appropriate [see 
Section 9], and must be followed until the value returns to within the normal range or is 
stable, or until the change is no longer clinically relevant.  
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 


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7.2.4.2 Laboratory tests 
Hematology 
• Hemoglobin (g/L) 
• Hematocrit (L/L) 
• Erythrocytes (109/L) 
• Reticulocyte (%) 
• Leukocytes with differential counts (109/L) 
• Platelets (109/L) 
• Prothrombin time and International Normalized Ratio 
Clinical chemistry 
• ALT (U/L) 
• AST (U/L) 
• Alkaline phosphatase (U/L) 
• Creatine kinase (µg/L) 
• Total and direct bilirubin (μmol/L) 
• Gamma-glutamyl transferase (U/L) 
• Creatinine (μmol/L) 
• Blood urea nitrogen (mmol/L) 
• Uric acid (μmol/L) 
• Glucose (mmol/L) 
• Cholesterol, triglycerides (mmol/L) 
• Sodium, potassium, chloride, calcium (mmol/L) 
• Albumin (g/L) 
• Thyroid hormones, i.e., triiodothyronine (T3; total and free) and thyroxine (T4; total 
and free), and thyroid stimulating hormone. 
Pregnancy test 
A serum pregnancy test for women of childbearing potential will be performed at 
screening and on the second morning of V5. A urine pregnancy test will be performed at 
randomization (V3) and 30 days after last dose of double-blind study drug intake (safety 
follow-up). The urine pregnancy test kit will be provided by the central laboratory. 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 or cocaine) and the breathalyzer for alcohol 
detection in the exhaled breath will be provided by the central laboratory. 


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Study drug is administered as described in Section 5 only if the results of the pregnancy 
tests and other tests are negative.  
7.2.5 Pharmacokinetic assessments 
PK samples will be collected in the morning after the second PSG night, after lights on, 
approximately 9–10 hours post-dose at randomization (V3, Day 3), V4 (Day 17), and V5 
(Day 30, EODB). In the event of excessive sleepiness according to investigator opinion 
one hour after lights on in the morning after the first PSG night, it is also recommended 
to draw a PK sample. 
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 Actelion Preclinical Drug Metabolism and 
Pharmacokinetics department, who are in charge of the PK analysis. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT/MEDICAL 
CARE 
 Study completion as per protocol 
8.1
A subject who completes the study treatment phase and the safety follow-up phase is 
considered to have completed the study as per protocol.  
 Premature withdrawal from study  
8.2
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost 
to follow-up. If a subject withdraws consent from the study, no further data will be 
collected in the eCRF from the date of withdrawal onward. The investigator may 
withdraw a subject from the study (without regard to the subject’s consent) if, on balance, 
he/she believes that continued participation in the study would be contrary to the best 
interests of the subject. Withdrawal from the study may also result from a decision by 
Actelion 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 


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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, along with who made the decision (subject, investigator, or 
Actelion personnel) must be recorded in the eCRF, if known. 
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. 
 Premature termination or suspension of the study 
8.3
Actelion 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 a study is prematurely suspended or terminated, Actelion will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the 
reasons for the suspension or termination. 
If the study is suspended or prematurely terminated for any reason, the investigator – in 
agreement with Actelion – must promptly inform all enrolled subjects, and ensure their 
appropriate treatment and follow-up, as described in Section 8.4. Actelion 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 a study without prior agreement 
from Actelion, the investigator must promptly inform Actelion 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 a study, the 
investigator must promptly notify Actelion personnel and provide a detailed written 
explanation of the termination or suspension. 


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 Medical care of subjects after study completion / withdrawal from study 
8.4
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local regulations. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
 Adverse events 
9.1
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 treatment-emergent AE is any AE temporally associated with the use of study 
treatment (from double-blind study treatment initiation until 30 days after study treatment 
discontinuation) whether or not considered by the investigator as related to study 
treatment. 
AEs include: 
• Exacerbation of a pre-existing disease. 
• Increase in frequency or intensity of a pre-existing episodic disease or medical 
condition. 
• Disease or medical condition detected or diagnosed during the course of the study 
even though it may have been present prior to the start of the study. 
• Continuous persistent disease or symptoms present at study start that worsen 
following the signing of informed consent. 
• Abnormal assessments, e.g., change on physical examination, ECG findings, if they 
represent a clinically significant finding that was not present at study start or 
worsened during the course of the study. 
• Laboratory test abnormalities if they represent a clinically significant finding, 
symptomatic or not, which was not present at study start or worsened during the 
course of the study or led to dose reduction, interruption or permanent discontinuation 
of study treatment. 
Overdose, misuse, abuse of the study treatment and study treatment errors will be 
reported as an AE.  


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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 form of the eCRF. 
If the intensity of an AE worsens during study treatment administration, only the worst 
intensity must be reported on the AE form. If the AE lessens in intensity, no change in 
the severity is required to be reported. 
For AEs ongoing at the start of study treatment, if the intensity worsens after the start of 
study treatment, new AE data must be reported adding a new log line on the AE form. 
The onset date reported on the new log line corresponds to the date of worsening in 
intensity. 
The three categories of intensity are defined as follows: 
 Mild 
The event may be noticeable to the subject. It does not usually influence daily activities, 
and normally does not require intervention. 
 Moderate 
The event may make the subject uncomfortable. Performance of daily activities may be 
influenced, and intervention may be needed. 
 Severe 
The event may cause noticeable discomfort, and usually interferes with daily activities. 
The subject may not be able to continue in the study, and treatment or intervention is 
usually needed. 
A mild, moderate, or severe AE may or may not be serious [see Section 9.2.1]. These 
terms are used to describe the intensity of a specific event. Medical judgment must 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. 


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9.1.4 Reporting of adverse events  
All AEs with an onset date after signing of informed consent and up to 30 days after 
study treatment discontinuation must be recorded on the specific AE form of the eCRF.  
9.1.5 Follow-up of adverse events  
AEs still ongoing more than 30 days after study treatment discontinuation 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 Actelion. 
 Serious adverse events  
9.2
9.2.1 Definitions of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the 
following criteria: 
• Fatal. 
• Life-threatening: refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe. 
• Requiring inpatient 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). 


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9.2.2 Reporting of serious adverse events 
All SAEs occurring after signing of informed consent up to 30 days after study treatment 
discontinuation 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. 
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 study treatment discontinuation must be 
followed up until resolution or stabilization, or until the event outcome is provided. The 
follow-up information obtained after the subject’s EOS telephone call must be reported to 
Actelion Global Drug Safety, but it is not recorded in the eCRF. 
9.2.4 After the 30-day follow-up period 
New SAEs occurring after the 30-day follow-up period must be reported to the Actelion 
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 Actelion 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 Actelion 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. Actelion Global Drug Safety personnel may contact the 
investigator to obtain further information. 


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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 the sponsor in the RSI section 
provided in the most recent version of the IB for ACT-541468 [ACT-541468 IB] and the 
Stilnox® SmPC for zolpidem [Stilnox® SmPC]. Any SAE that is assessed as related and 
unexpected against the RSI of the ACT-541468 IB [ACT-541468 IB] or the 
Stilnox® SmPC [Stilnox® SmPC] is known as a SUSAR and must be reported by 
Actelion to concerned health authorities (including the EudraVigilance database if the 
study is conducted in Europe), IECs/IRBs and investigators.  
 Pregnancy  
9.3
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 30 days following study treatment 
discontinuation must be reported within 24 hours of the investigator’s knowledge of the 
event. 
Pregnancies must be reported on the Actelion Pregnancy form, which is faxed to Actelion 
Global Drug Safety (see contact details provided on the Actelion Pregnancy form), and 
on an AE form in the eCRF. 
9.3.2 Follow-up of pregnancy 
Any pregnancies must be followed up to their conclusion and the outcome must be 
reported to Actelion Global Drug Safety. 
Any AE associated with the pregnancy occurring during the follow-up period after study 
treatment discontinuation must be reported on separate AE pages in the eCRF. Any SAE 
occurring during the pregnancy must be reported on an SAE form as described in 
Section 9.2.5. 
 Study safety monitoring 
9.4
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 Actelion 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 3.4]. 


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10 STATISTICAL METHODS 
All statistical analyses will be conducted by Actelion or by designated CROs supervised 
by Actelion. 
A Statistical Analysis Plan (SAP) will provide full details of the analyses, data displays, 
and algorithms to be used for data derivations. 
 Analysis sets 
10.1
10.1.1 Screened Analysis Set 
The Screened Analysis Set includes all subjects who are screened and have a subject 
identification number. 
10.1.2 Randomized Analysis Set 
The Randomized Analysis Set includes all subjects who have been assigned to a study 
treatment. 
10.1.3 Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects from the Randomized Analysis Set who 
received at least one dose of study treatment.  
In order to adhere to the intention-to-treat principle: 
• Subjects will be evaluated according to the study treatment they have been assigned 
to (which may be different from the study treatment they actually receive), 
• All available data are included. 
10.1.4 Modified Full Analysis Set 
The modified FAS (mFAS) includes all patients from the FAS and who have at least one 
WASO assessment at baseline and one at Days 1&2. 
10.1.5 Per-protocol Analysis Set 
The Per-protocol Analysis Set (PPS) comprises all subjects from the mFAS, who have 
two consecutive WASO values at Baseline and at Days 1&2, and who complied with the 
protocol sufficiently to allow relevant assessment of 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 detailed in the SAP, and at the latest 
before breaking the treatment blind. 


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10.1.6 Safety Set 
The Safety Set (SS) includes all subjects who received at least one dose of study 
treatment. Subjects will be evaluated according to the actual treatment they received, 
which may differ from the randomly assigned treatment. 
10.1.7 Pharmacokinetic Analysis Set 
The PK Analysis Set includes all subjects in the SS who have at least one PK sample 
collected after initiation of study drug. 
10.1.8 Usage of the analysis sets 
The primary efficacy analysis will be performed on the mFAS based on treatment as 
randomized. Secondary and exploratory efficacy endpoint analyses will be performed on 
the FAS, while PPS will be used for sensitivity analyses. 
Safety analyses will be performed on the SS based on treatment as received. 
Subject listings will be based on the SS, unless otherwise specified. Subject disposition 
will be described for the Screened Analysis Set. 
Table 3 describes the analysis sets used for the analysis of each data set. 
Table 3 
Usage of analysis sets 
 
Screened 
Set 
Randomized 
Set 
FAS 
mFAS 
PPS 
SS 
PK 
Set 
Patient disposition 
X 
 
 
 
 
 
 
Baseline and disease characteristics 
 
(x) 
X 
(x) 
 
 
(x) 
Previous and concomitant 
medication 
 
 
 
 
 
X 
 
Study drug exposure 
 
 
 
 
(x) 
X 
 
Primary efficacy endpoint 
 
 
 
X 
(x) 
 
 
Secondary and exploratory efficacy 
endpoints 
 
 
X 
 
 
 
 
Safety and tolerability 
 
 
 
 
 
X 
 
PK data 
 
 
 
 
 
 
X 
Note: X: main analysis, (x): sensitivity analysis to be conducted only if > 10% difference of set size with set used for 
main analysis. 
FAS = Full Analysis Set; mFAS = modified Full Analysis Set; PK = pharmacokinetic; PPS = Per-protocol Set, SS = 
Safety Set. 
 


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 Variables 
10.2
The absolute change from Baseline to time T is defined as the algebraic difference 
between the value observed at time T minus the value at baseline. 
Unless specified otherwise, the Baseline value is defined as the arithmetic mean of the 
last two values collected during the screening phase prior to randomization.  
For variables that are collected only once at each visit (e.g., laboratory parameters), the 
unique pre-randomization value collected at V2 will be used as the baseline value. 
10.2.1 Primary efficacy variable 
The primary efficacy endpoint relates to sleep maintenance and is assessed through the 
absolute change in minutes of WASO from Baselinea to Days 1&2b. 
WASO is defined in Section 6.1.1. 
Where: 
a ’Baseline’ is the mean of the 2 PSG nights during the run-in period (V2).  
b ’Days 1&2’ is the mean of the corresponding 2 PSG treatment nights (V3).  
Missing values 
No imputation will be performed for missing WASO values.  
If one of the two values is missing either for Baseline or for Days 1&2, the only available 
value will be used for this time point, however for the PPS analysis, only assessments 
with two values at each time point will be considered.  
10.2.2 Secondary efficacy variables 
The secondary efficacy endpoints include LPS, sLSO and sWASO using the variables 
below:  
Sleep-initiation endpoints: 
• LPS absolute change from Baselinea to Days 1&2b. 
• sLSO absolute change from Baselinec to Week 4d. 
Sleep-maintenance endpoint: 
• sWASO absolute change from Baselinec to Week 4d. 
LPS, sWASO and sLSO are defined in Section 6.1.2. 
Where: 
a ’Baseline’ is the mean of the 2 PSG nights during the run-in period (V2).  
b ’Days 1&2’ is the mean of the corresponding 2 PSG treatment nights (V3).  


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c ’Baseline’ is the mean value in the screening sleep diary entries at home between 
V2 and V3 across 7 consecutive days. 
d ’Week 4’ is the mean value based on the sleep diary entries at home across the last 
week of double-blind study treatment. 
Missing values 
Same as for the primary endpoint, no imputation are to be used for secondary endpoints. 
10.2.3 Other efficacy variables 
Other exploratory efficacy endpoints include:  
• WASO and sWASO, 
• LPS and sLSO, 
• TST and sTST, 
• SQ, 
• Sleep stages S1, S2, SWS and REM,  
• Shifts from S2, SWS or REM to S1 or awake, 
• Wake time during sleep, 
• Frequency of awakenings as measured by PSG and self-reported, 
• SE (defined as 100 × (TST / time in bed), 
• ISI© scores, 
• Next-day performance. 
For each variable, multiple aspects will be considered in the analysis:  
Sleep-maintenance endpoint: 
• WASO absolute change from Baselinea to Days 15&16e, and to Days 28&29f, 
• WASO over time (by hour of the night and by quarter of the night), 
• sWASO absolute change from Baselinec to Weeks 1&2&3g. 
Sleep-initiation endpoint: 
• LPS absolute change from Baselinea to Days 15&16e, and to Days 28&29f, 
• sLSO absolute change from Baselinec to Weeks 1&2&3g. 
Total sleep time endpoint:  
• TST absolute change from Baselinea to Days 1&2b, Days 15&16e, Days 28&29f. 
• sTST absolute change from Baselinec to Weeks 1&2&3&4h. 
TST is the amount of actual sleep time (time spent in epochs scored as non-wake), as 
determined by PSG. sTST is the self-reported time spent asleep, as reported in the sleep 
diary. 


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Sleep quality (SQ):  
• Change from Baselinec to Weeks 1&2&3&4h in SQ. 
SQ is the sleep quality as determined by scores on the VAS.  
Sleep architecture:  
• Meani duration and mean percent of TST of each sleep stage (S1, S2, SWS and REM) 
for the whole night, and for each quarter of the night. 
• Meani latency to each sleep stage (S1, S2, SWS, and REM).  
Sleep continuity: 
• Meani number and frequency of shifts from S2, SWS or REM to S1 or wake for the 
whole night. 
• Meani wake time during sleep: time spent in epochs scored as wake between LPS and 
last epoch not scored wake for the whole night. 
• Meani frequency of awakenings: number of awakenings between first epoch and last 
epoch not scored wake for the whole night, by hour of the night and by quarter of the 
night. 
• Change from Baselinec to Weeks 1&2&3&4h in self-reported number of awakenings. 
Sleep efficiency (SE): 
• SE absolute change from Baselinea to: Day 1&2b, Day 15&16e and Day 28&29f.  
SE is defined as 100 × (TST [min] / time in bed [min]). 
Insomnia severity 
• Change from Baseline (V1) to the second morning of V5 (Day 30) in ISI© scores.  
Next-day performance 
• Change from Baselinec to Weeks 1&2&3&4h in next-day performance assessed at 
home by scores on the VAS assessing morning sleepiness, daytime alertness and 
daytime ability to function.  
Where: 
a ‘Baseline’ is the mean of the 2 PSG nights during the run-in period (V2).  
b ‘Days 1&2’ are the mean of the corresponding 2 PSG treatment nights (V3).  
c ‘Baseline’ is the mean value in the screening sleep diary entries at home prior to 
start of study treatment between V2 and V3 across 7 consecutive days. 
d ‘Week 4’ is the mean value based on the sleep diary entries at home across the last 
week of double-blind study treatment. 
e ‘Days 15&16’ is the mean of the corresponding 2 PSG treatment nights (V4). 


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f ‘Days 28&29’ is the mean of the corresponding 2 PSG treatment nights (V5).  
g ‘Weeks 1&2&3’ is the mean value based on the sleep diary entries at home while 
on double-blind study treatment at Week 1, Week 2 and Week 3. 
h ‘Weeks 1&2&3&4’ is the mean value based on the sleep diary entries at home 
while on double-blind study treatment at Week 1, Week 2, Week 3 and Week 4. 
i mean values calculated based on the 2 PSG treatment nights of each visits. 
Endpoints and related variables are also summarized in Appendix 11. 
10.2.4 Safety variables 
Safety analysis will be conducted on the SS, and will include all safety data collected up 
to 30 days after study drug discontinuation. 
Adverse events: 
An AE is defined as any event, which is recorded on the AE eCRF module regardless of 
the onset date. 
TEAEs are those with onset date/time ≥ start date/time of double-blind study treatment 
and ≤ 30 days, after end of study treatment. AEs, including AEs of special interest, with 
onset prior to study treatment which worsened during the treatment phase will also be 
reported as TEAEs. 
Laboratory data: 
Laboratory analyses are based on data received from the central laboratory. All 
transferred central laboratory data are taken into account regardless of whether they 
correspond to scheduled or unscheduled assessments. Baseline laboratory test refers to 
the latest laboratory test performed prior to start of double-blind study treatment.  
Missing values: 
No imputation is performed for missing values. If laboratory data are missing at the EOT 
Visit, the results of the latest available post-baseline laboratory tests performed prior to 
EOT date/time are used for the analysis.  
The handling of missing or incomplete dates/time of AEs and assessments will be 
described in the SAP.  
No other imputation will be performed for safety parameters except for laboratory values 
at EOT. 
ECG: 
• Clinically abnormal ECG on double-blind study treatment, 
• Change in ECG parameters on double-blind study treatment, 
• Treatment-emergent ECG abnormalities. 


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Withdrawal symptoms: 
Withdrawal symptoms will be assessed by change from V5 to V6.  
• BWSQ results, 
• Incidence of AEs and ECG abnormalities. 
Insomnia rebound: 
In order to assess the potential rebound insomnia, for each of the variables, the change 
from the worst PSG night of V2 to V6 in WASO, TST, and LPS will be analyzed 
specifically. 
Other safety parameters of interest: 
Change from V2 (mean of the two PSG nights at V2, run-in period) to Days 1&2, 15&16 
and 28&29 in: 
• KSS performed in the morning, 30–60 minutes after lights on. 
• DSST© performed in the morning, 30–60 minutes after lights on. 
• SDS© performed in the morning, 30–60 minutes after lights on. 
Change from V2 (second morning) to the last value on double-blind study treatment in 
C-SSRS©. 
Vital signs: 
Change from Baseline (mean of the two PSG nights at V2, run-in period) to the last value 
on double-blind study treatment in vital signs (temperature, BP, pulse rate, and body 
weight). 
10.2.5 Other variables 
Pharmacokinetic 
Plasma concentrations of ACT-541468 (9–10 h post-dose) at V3, V4 and V5 will be 
collected. 
 Description of statistical analyses 
10.3
10.3.1 Overall testing strategy 
The study is intended to select the dose that allows a clinically meaningful reduction of 
WASO compared to placebo. All analyses will be performed at a 0.05 type I error level 
(two-sided) using 95% confidence intervals (CIs). Secondary efficacy variables will also 
be analyzed at α = 0.05 (two-sided).  


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10.3.2 Analysis of the primary efficacy variable(s) 
10.3.2.1 Hypotheses and statistical model  
This study has 6 arms: a placebo, 4 doses of ACT-541468 and an active reference. The 
active reference will be excluded from all statistical tests related to dose-response, but 
will be compared descriptively separately versus placebo. 
The study is using an MCP-Mod approach [Bretz 2005, Pinheiro 2006] which combines a 
multiple comparison procedure to assess the efficacy of the drug versus placebo and a 
modeling step to further identify the dose that is most likely to provide the expected level 
of efficacy (as defined by the primary efficacy endpoint). This approach has been 
qualified by the EMA as “an efficient statistical methodology for model-based design and 
analysis of phase II dose finding studies under model uncertainty” [EMA 2013]. 
The maximum mean reduction in WASO from baseline to Days 1 and 2 with an 
ACT-541468 dose is assumed to be 25 minutes (standard deviation = 40 minutes) longer 
than placebo. 
The null hypothesis of an absence of a dose-response relationship for change from 
baseline in WASO will be tested at a two-sided significance level of 5% against the 
alternative hypothesis of existence of a dose response. 
Dose selection to be used in future clinical trials will be done in consideration of the 
statistical results and clinically meaningful criteria. 
10.3.2.2 Handling of missing data 
For any given visit, if one of the two WASO values is missing, the available value will be 
used as the mean for the period. If both values are missing, no imputation will be 
considered. Further imputation rules may be defined in the SAP. 
10.3.2.3 Main analysis 
The primary statistical analysis will be performed on the mFAS.  
The absolute change in WASO will be analyzed using the MCP-Mod approach 
[Bretz 2005, Pinheiro 2006] using a set of Multiple Contrast Tests (MCTs) to establish 
the existence of a dose-response and a set of pre-specified dose-response models to 
describe the dose-response relationship.  
Four candidate dose response models will be considered: one linear, and three Emax 
models. Figure 2 shows the candidate dose-response curves for the mean reduction from 
baseline in WASO. 
The analysis will be performed using the R-package ‘DoseFinding’ [Bornkamp 2016]. 
For each candidate model, a t-statistic is derived based on a linear combination of the 




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10.3.2.4 Supportive/sensitivity analyses 
Sensitivity analyses will be conducted on the PPS if this analysis set differs from the 
mFAS significantly (e.g., > 10%). Change from baseline to Days 1&2 in mean WASO 
will also be analyzed using an ANCOVA model with the same factors as the main 
analysis [Section 10.3.2.3] with possible addition of region, race and age. Each of the 
4 doses of ACT-541468 will be compared to placebo applying Dunnett’s test.  
The active comparator will be compared separately versus placebo using an ANCOVA 
model of Days 1&2 mean WASO value with a factor for treatment group (placebo or 
active comparator) and a covariate for Baseline mean WASO and gender. 
10.3.3 Analysis of secondary efficacy variables 
Similarly, an MCP-Mod-based analysis will be conducted on the secondary endpoints. 
Treatment effect on secondary efficacy endpoints, except for the change of WASO from 
Baseline over time, will also be assessed using a mixed model, with treatment, region, 
gender and age as fixed effects and patient as random covariate. 
Treatment effect on the change of WASO from baseline over time will be estimated using 
a repeated-measures mixed model. 
Further exploratory analysis will be conducted to assess the relationship of the changes 
between the perceived efficacy (subjective measures) and the objectives measures from 
PSG. 
10.3.4 Analysis of other efficacy variables 
Descriptive statistics will be provided for all the exploratory variables either as frequency 
and percentage for categorical variables or using descriptive statistics for continuous 
variables as well as 95% CIs.  
Additional exploratory analysis that may be performed will be described in full detail in 
the SAP. 
10.3.4.1 Subgroup analyses 
Subgroup analyses will be performed by gender. This will be done using the ANCOVA 
described above. Additional subgroup analyses will be described in the SAP. 
10.3.5 Analysis of the safety variables 
All safety analyses will be performed on the SS, by treatment, using descriptive statistics. 
All safety data will be listed, with flags for quantitative abnormalities.  
Analysis of safety and tolerability endpoints 


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Safety and tolerability quantitative endpoints will be summarized using descriptive 
statistics (mean, standard deviation, median, 1st and 3rd quartiles, minimum, and 
maximum) while frequency counts and proportions will be used for categorical data. 
Unless stated otherwise, percentages will be computed on the total sample size of the 
given treatment arm. 
For shift analyses, only subjects with values at both considered time points (i.e., baseline 
and last value on double-blind treatment) will be included.  
Adverse events 
AEs in subjects who were screened but not randomized will be listed. 
The number and percentage of subjects experiencing TEAEs and SAEs will be tabulated 
by treatment group and by: 
• MedDRA system organ class (SOC) in alphabetical order and individual preferred 
term within each SOC, in descending order of incidence in the highest dose group. 
• Frequency of subjects with events coded with the same preferred term, in descending 
order of incidence in the highest dose group. 
TEAEs, AEs of special interest and SAEs will be tabulated as described above by 
severity and relationship to study treatment. AEs leading to premature discontinuation of 
the study treatment and AEs with outcome death will be summarized as described above.  
AEs and SAEs with onset between randomization and first day of study treatment will 
also be summarized.  
Listings will be provided for all reported AEs, including SAEs. In addition, separate 
listings will be provided for SAEs, for AEs leading to premature discontinuation of study 
treatment, and for AEs with outcome death.  
Laboratory variables 
Descriptive summary statistics by visit and treatment group will be provided for observed 
values and absolute changes from baseline, in both hematology and blood chemistry 
laboratory tests. All laboratory data transferred are taken into account regardless of 
whether they correspond to scheduled (per protocol) or unscheduled assessments. Marked 
laboratory abnormalities will be summarized for each laboratory variable by treatment 
group providing their incidence and frequency. Absolute values and changes from 
baseline of laboratory values during the course of the study will be summarized using 
summary statistics by treatment group. 
The number and percentage of subjects with treatment-emergent laboratory abnormalities 
will be tabulated by treatment group 


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ECG 
Incidence of clinically abnormal ECG on double-blind study treatment as well as 
treatment-emergent ECG abnormalities will be tabulated (frequency and percentage).  
On-treatment change in ECG parameters will be described using descriptive statistics. 
Withdrawal symptoms 
Change of BWSQ from V5 to V6 will be described through shift tables (V5 vs V6) and 
summarized using descriptive statistics.  
MCP-Mod approach will be used to assess the dose-response relationship for the change 
from V5 to V6 of BWSQ.  
Incidence of AEs and ECG abnormalities occurring between V5 and V6 will be 
summarized. As for BWSQ, an MCP-Mod approach will be used to determine the dose 
response of the occurrence of any of those events. 
Insomnia rebound effect 
In order to assess the potential rebound insomnia, descriptive statistics are provided for 
the change from the worst PSG screening night to V6 in WASO, TST, and LPS. 
Similarly to withdrawal symptoms, MCP-Mod will be used to assess the dose-response 
relationship for the occurrence of worsening of any of the 3 parameters. 
Vital signs 
Change from baseline to the last value on double-blind study treatment will be 
summarized. 
Other safety parameters of interest 
Change from V2 (morning of run-in PSG nights) to Days 1&2, 15&16 and 28&29 
(morning) in KSS, DSST©, and in SDS© will be summarized. 
Similarly, change from V2 (morning of run-in second PSG night) to V5 (morning of 
second PSG night) C-SSRS© will be summarized. 
All scale analyses will be performed according to their respective manual and 
interpretation guides. 
Exposure-safety analysis 
The exposure-safety relationship will be explored using C9-10h (plasma concentrations of 
ACT-541468 in the morning of the second PSG night at V3, V4, and V5) and will be 
based on the PK set. Safety parameters considered for this analysis will include selected 
AEs (e.g., somnolence), changes from baseline in DSST and other parameters as relevant. 
Further details will be provided in the SAP. 


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Pharmacokinetic 
Plasma concentrations of ACT-541468 will be analyzed by descriptive statistics, 
including arithmetic mean, standard deviation, minimum, maximum, and median. 
 Interim analyses 
10.4
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 regular basis as per IDMC and ISB charter, 
respectively. Safety and efficacy data supporting the review by IDMC will be provided 
by Actelion for the part of analyses that are blinded and by an ISAC for the unblinded 
part. 
 Sample size 
10.5
The following sample size calculations are based on MCP-Mod methodology 
[Pinheiro 2006]. Computations were performed in R version 3.1.2 using the 
‘DoseFinding’ package. 
Assuming the maximum mean reduction in WASO from baseline to Day 1&2 with an 
ACT-541468 dose is 25 minutes larger than with placebo (standard deviation 
= 40 minutes), and values from 8% of subjects are not available for analysis, a sample 
size of approximately 250 (i.e., 50 subjects per arm allocated in a 1:1:1:1:1 ratio) 
provides between 89–92% power (power is 90% when averaged over all candidate 
models; see Figure 2] to reject the null hypothesis of no dose-response at a 5% two-sided 
significance level, while the alternative hypothesis is that a dose-response relationship 
exists. 
Assuming the maximum mean reduction in WASO is considered to be 20 minutes larger 
than with placebo, a sample size of 71 subjects per arm (with no dropout) are required. 
This number drops to 32 subjects per arm if we consider a maximum mean reduction of 
30 minutes compared to placebo. 
50 subjects will also be randomly assigned to the zolpidem arm. This sample size 
provides 80% power to detect a difference in mean reduction in WASO from baseline to 
Days 1&2 of 23 minutes versus placebo (50 subjects with no dropout) at a 5% two-sided 
significance level using a two-sample independent t-test assuming a common standard 
deviation of 40 minutes. 
This study is powered to detect a dose-response signal given the pre-defined set of 
candidate dose-response curves shown in Figure 2. The study is not specifically powered 
to show the superiority of individual doses of ACT-541468 compared to placebo nor to 
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11 DATA HANDLING 
 Data collection 
11.1
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 captured via electronic data capture (using the Rave system provided 
by Medidata Solutions, Inc., a web-based tool). The investigator and site personnel will 
be trained to enter and edit the data via a secure network, with secure access features 
(username, password, and identification – an electronic password system). A complete 
electronic audit trail will be maintained. The investigator/delegate will approve the data 
(i.e., confirm the accuracy of the data recorded) using an electronic signature (ref. to US 
21 CFR Part 11). 
Entries recorded by the subject on the hand-held device (i.e., sleep diary, VAS, ISI©, 
C-SSRS©, KSS, SDS©, BWSQ) and on paper (i.e., DSST©) are considered source data. 
Site personnel will review and ensure completeness and readability of the subject’s 
entries. 
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. 
 Maintenance of data confidentiality 
11.2
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 Actelion 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 Actelion, and must be kept in strict confidence by the 
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 Database management and quality control 
11.3
Electronic CRFs will be used for all subjects. The investigators will have access to the 
site eCRF data until the database is closed. 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 Actelion 
personnel on an ongoing basis to look for unexpected patterns in data and for study 
monitoring. If discrepant data are detected, a query specifying the problem and requesting 
clarification will be issued and visible to the investigator/delegate via the eCRF. All 
electronic queries visible in the system either require a data correction (when applicable) 
and a response from the investigator/delegate to clarify the queried data directly in the 
eCRF, or simply a data correction in the eCRF. The investigator/delegate must, on 
request, supply Actelion 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 case of health authority queries, it is also necessary to 
have access to the complete study records, provided that subject confidentiality is 
protected. 
This process will continue until database closure. 
Laboratory samples, ECGs, PSGs and hand-held device data will be processed through a 
central laboratory / CRO and the results will be sent electronically to Actelion.  
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. 
Adverse events are coded according to the latest MedDRA version used by Actelion. 
After the database has been declared complete and accurate, the database will be closed. 
Any changes to the database after that time may only be made as described in the 
appropriate Actelion QS documents. After database closure, the investigator will receive 
the eCRFs of the subjects of his/her site (including all data changes made) on electronic 
media or as a paper copy. 
12 PROCEDURES AND GOOD CLINICAL PRACTICE 
 Ethics and Good Clinical Practice 
12.1
Actelion 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 research is conducted. 


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 Independent Ethics Committee / Institutional Review Board 
12.2
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed, and the date of 
approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 
A list of members participating in the IEC/IRB meetings must be provided, including the 
names, qualifications, and functions of these members. If that is not possible, the attempts 
made to obtain this information along with an explanation as to why it cannot be obtained 
or disclosed must be documented in the study documentation.  
If a member of the study personnel was present during an IEC/IRB meeting, it must be 
clear that this person did not vote. 
 Informed consent 
12.3
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. In European countries, the informed consent must 
be obtained by a physician. 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 trial 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 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 
Actelion. A study physician must always be involved in the consent process. 
The subject and authorized site personnel listed on the DoA form supplied by Actelion 
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 
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A copy of the signed and dated ICF is given to the subject; the original is filed in the site 
documentation. The informed consent process must be fully documented in the subject’s 
medical records. This must include at a minimum the study reference, the subject 
number, the date and, if applicable, time when the subject was first introduced to the 
study, the date and, if applicable, time of consent, who participated in the consent 
discussion, who consented the subject, and any additional person present during the 
consent process (e.g., subject’s family member[s]), and the information that a copy of the 
signed ICF was given to the subject. 
 Compensation to subjects and investigators 
12.4
Actelion 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. 
 Protocol adherence/compliance 
12.5
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 Actelion 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 
Actelion or (overruling) local requirements. 
All protocol deviations will be reported in the Clinical Study Report (CSR). IECs/IRBs 
will be provided with listings of protocol deviations as per local requirements.  
 Protocol amendments 
12.6
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. 
 Essential documents and retention of documents 
12.7
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 


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that the data and records are accurate, legible, contemporaneous, original (or certified 
copy), attributable, complete, consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for as long as is necessary to comply with 
Actelion’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 Actelion 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 Actelion. Should the investigator wish 
to assign the study records to another party, or move them to another location, Actelion 
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 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 print-outs 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 subject’s data. The 
printouts will be considered as the official clinical study records and must be filed either 
with the subject 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 Actelion’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. 


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 Monitoring 
12.8
Prior to study start, a site initiation visit (SIV) will be performed after the required 
essential study documents are approved by Actelion. 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. 
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. Actelion 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 Actelion. 


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 Investigator site file 
12.9
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of contents listing the essential documents. All study-related 
documentation must be maintained in the ISF. 
In some cases, exceptions can be discussed with the CRA regarding the filing of the study 
documents outside the ISF. It should be clearly documented where each document is 
filed. This note to file should be present in the specific tab of the document in the ISF. 
The ISF must be stored in a secure and access-restricted area during and after the study. It 
must be kept by the site for as long as needed to comply with any applicable rules and 
regulations, ICH-GCP, as well as instructions from Actelion. 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 Actelion. 
If the PI will change, or if the site will relocate, the CRA must be notified as soon as 
possible. 
 Audit 
12.10
Actelion’s Global Quality Management representatives may audit the investigator site 
(during the study or after its completion). The purpose of this visit will be to determine 
the investigator’s adherence to ICH-GCP, the protocol, and applicable regulations; 
adherence to Actelion’s requirements (e.g., standard operating procedures) will also be 
verified. Prior to initiating this audit, the investigator will be contacted by Actelion 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. 
 Inspections 
12.11
Health authorities and/or IEC/IRB 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 Actelion, (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. 


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 Reporting of study results and publication 
12.12
Actelion will post the key elements of this protocol and the summary of results on 
Actelion’s Clinical Trial Register and within the required timelines on publically 
accessible databases (e.g., clinicaltrials.gov, EU database), as required by law and 
regulation. 
Study results will be documented in a CSR that will be signed by Actelion representatives 
and the Coordinating Investigator (or PI for single-center studies). 
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. 
The Coordinating Investigator and the Steering Committee, if any, will have the 
opportunity to review the analysis of the data and to discuss the interpretation of the 
study results with Actelion personnel prior to submission to a peer-reviewed journal or 
presentation at a congress. 
Authorship will be determined in accordance with the International Committee of 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 
Actelion and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted 
to Actelion for review at least 30 days prior to submission for publication or presentation 
at a congress. Upon review, Actelion 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. 
Actelion’s Policy on Scientific Publications can be found at: 
http://www.actelion.com/documents/corporate/policies-charters/policy-scientific-
publications.pdf 


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Version 3 
16 December 2016, page 109/131 
Confidential 
EudraCT 2016-000826-21 
Doc No D-16.648 
 
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Doc No D-16.648 
 
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Doc No D-16.648 
 
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[Herring 2016] Herring WJ, Connor KM, Ivgy-May N, Snyder E, Liu K, Snavely DB, et 
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Sleep Onset Insomnia, Sleep Maintaining Insomnia and Insomnia With Early 
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[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. 
[Huedo-Medina 2012] Huedo-Medina TB, Kirsch I, Middlemass J, Klonizakis M, 
Siriwardena AN. Effectiveness of non-benzodiazepine hypnotics in treatment of 
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[Lieberman 2007] Lieberman JA. Update on the safety considerations in the management 
of insomnia with hypnotics: incorporating modified-release formulations into 
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gene. Cell. 1999;98(3):365-76. 


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Doc No D-16.648 
 
[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 
[Meoli 2001] Meoli AL, Casey KR, Clark RW, Coleman JA Jr, Fayle RW, Troell RJ, et 
al. Hypopnea in sleep-disordered breathing in adults. Sleep 2001;24(4):469-70. 
[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. International Review of 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 Jun13-15;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.  
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studies combining multiple comparisons and modeling procedures. J Biopharm 
Stat. 2006;16(5):639-56. 
[Posner 2007] Suicidality issues in clinical trials: Columbia suicidal adverse event 
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[Roth 2007] Roth T. Insomnia: Definition, Prevalence, Etiology, and Consequences. 
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[Sakurai 2007] Sakurai T. The neural circuit of orexin (hypocretin): maintaining sleep 
and wakefulness. Nat Rev Neurosci 2007;8:171-81. 


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Doc No D-16.648 
 
[Samson 2010] Samson WK, Bagley SL, Ferguson AV, White MM. Orexin receptor 
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[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, 
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Doc No D-16.648 
 
[Zeitzer 2003] Zeitzer JM, Buckmaster CL, Parker KJ, Hauck CM, Lyons DM, Mignot E. 
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EudraCT 2016-000826-21 
Doc No D-16.648 
 
14 
APPENDICES  
Appendix 1 
Thresholds for marked laboratory abnormalities 
Parameters 
Sex 
Conventional US Reporting of Reference Ranges 
SI Reporting Reference Ranges 
Units 
Ref 
Range 
Low 
Ref  
Range 
High 
Flag 
L 
at 
Flag 
H 
at 
Flag 
LL 
at 
Flag 
HH 
at 
Call  
Alert 
Low 
at 
Call 
Alert 
High 
at 
Units 
Ref 
Range 
Low 
Ref 
Range 
High 
Flag 
L 
at 
Flag 
H 
at 
Flag 
LL 
at 
Flag 
HH 
at 
Call 
Alert 
Low 
at 
Call 
Alert 
High 
at 
Hematology 
White blood cells   
M/F 103/uL 
4.5 
11 
4.4 
11.1 
1.9 
22 
NA 
NA 
109/L 
4.5 
11 
4.4 
11.1 
1.9 
22 
NA 
NA 
Red blood cells  
M 
106/uL 
4.5 
5.9 
4.49 
5.91 
NA 
NA 
NA 
NA 
1012/L 
4.5 
5.9 
4.49 5.91 
NA NA 
NA 
NA 
Red blood cells  
F 
106/uL 
3.8 
5.2 
3.79 
5.21 
NA 
NA 
NA 
NA 
1012/L 
3.8 
5.2 
3.79 5.21 
NA NA 
NA 
NA 
Hemoglobin  
M 
g/dL 
13 
17.5 
12.9 
17.6 
6.9 
19 
NA 
NA 
g/L 
130 
175 
129 
176 
69 
190 
NA 
NA 
Hemoglobin  
F 
g/dL 
11.5 
16 
11.4 
16.1 
6.9 
19 
NA 
NA 
g/L 
115 
160 
114 
161 
69 
190 
NA 
NA 
Hematocrit  
M 
% 
41.6 
54.1 
41.5 
54.2 
21 
60 
21 
60 
L/L 
0.416 
0.541 0.415 0.542 0.21 0.6 
0.21 
0.6 
Hematocrit  
F 
% 
36.4 
48.9 
36.3 
49 
21 
60 
21 
60 
L/L 
0.364 
0.489 0.363 0.49 0.21 0.6 
0.21 
0.6 
Platelets 
M/F 103/uL 
130 
400 
129 
401 
49 
1000 
NA 
NA 
109/L 
130 
400 
129 
401 
49 1000 
NA 
NA 
Absolute Neutrophil Count 
M/F 103/uL 
1.8 
7.7 
1.7 
7.8 
0.5 
15.4 
NA 
NA 
109/L 
1.8 
7.7 
1.7 
7.8 
0.5 15.4 
NA 
NA 
Absolute Lymphocyte Count 
M/F 103/uL 
1 
4.8 
0.9 
4.9 
NA 
NA 
NA 
NA 
109/L 
1 
4.8 
0.9 
4.9 
NA NA 
NA 
NA 
Absolute Monocyte Count 
M/F 103/uL 
0.1 
0.8 
0 
0.9 
NA 
NA 
NA 
NA 
109/L 
0.1 
0.8 
0 
0.9 
NA NA 
NA 
NA 
Absolute Eosinophil Count 
M/F 103/uL 
0 
0.5 
NA 
0.6 
NA 
NA 
NA 
NA 
109/L 
0 
0.5 
NA 
0.6 
NA NA 
NA 
NA 
Absolute Basophil Count 
M/F 103/uL 
0 
0.2 
NA 
0.3 
NA 
NA 
NA 
NA 
109/L 
0 
0.2 
NA 
0.3 
NA NA 
NA 
NA 
Percent Neutrophils 
M/F 
% 
40 
70 
39.9 
70.1 
NA 
NA 
NA 
NA 
% 
40 
70 
39.9 70.1 
NA NA 
NA 
NA 
Percent Lymphocytes 
M/F 
% 
22.2 
43.6 
22.1 
43.7 
NA 
NA 
NA 
NA 
% 
22.2 
43.6 
22.1 43.7 
NA NA 
NA 
NA 
Percent Monocytes 
M/F 
% 
2 
12 
1.9 
12.1 
NA 
NA 
NA 
NA 
% 
2 
12 
1.9 
12.1 
NA NA 
NA 
NA 
Percent Eosinophils 
M/F 
% 
0 
4.5 
NA 
4.6 
NA 
NA 
NA 
NA 
% 
0 
4.5 
NA 
4.6 
NA NA 
NA 
NA 
Percent Basophils 
M/F 
% 
0 
1.8 
NA 
1.9 
NA 
NA 
NA 
NA 
% 
0 
1.8 
NA 
1.9 
NA NA 
NA 
NA 
Reticulocytes  
M/F 
% 
0.2 
2.3 
0.1 
2.4 
NA 
NA 
NA 
NA 
% 
0.2 
2.3 
0.1 
2.4 
NA NA 
NA 
NA 
Protime  
M/F seconds 
9.4 
13 
9.3 
13.1 
NA 
NA 
NA 
100.1 
seconds 
9.4 
13 
9.3 
13.1 
NA NA 
NA 100.1 
INR  
M/F 
N/A 
0.8 
1.2 
0.79 
1.21 
NA 
NA 
NA 
5 
N/A 
0.8 
1.2 
0.79 1.21 
NA NA 
NA 
5 


ACT-541468 
Insomnia disorder 
Protocol AC-078A201 
Version 3 
16 December 2016, page 116/131 
Confidential 
EudraCT 2016-000826-21 
Doc No D-16.648 
 
Parameters 
Sex 
Conventional US Reporting of Reference Ranges 
SI Reporting Reference Ranges 
Units 
Ref 
Range 
Low 
Ref  
Range 
High 
Flag 
L 
at 
Flag 
H 
at 
Flag 
LL 
at 
Flag 
HH 
at 
Call  
Alert 
Low 
at 
Call 
Alert 
High 
at 
Units 
Ref 
Range 
Low 
Ref 
Range 
High 
Flag 
L 
at 
Flag 
H 
at 
Flag 
LL 
at 
Flag 
HH 
at 
Call 
Alert 
Low 
at 
Call 
Alert 
High 
at 
Clinical Chemistry 
Alanine aminotransferase  
M 
U/L 
0 
44 
NA 
45 
NA 
132 
NA 
NA 
U/L 
0 
44 
NA 
45 
NA 132 
NA 
NA 
Alanine aminotransferase  
F 
U/L 
0 
33 
NA 
34 
NA 
99 
NA 
NA 
U/L 
0 
33 
NA 
34 
NA 
99 
NA 
NA 
Albumin 
M/F 
g/dL 
3.5 
5.2 
3.4 
5.3 
2.0 
7.1 
2.0 
7.1 
g/L 
35 
52 
34 
53 
20 
71 
20 
71 
Alkaline phosphatase  
M 
U/L 
53 
129 
52 
130 
NA 
440 
NA 
NA 
U/L 
53 
129 
52 
130 
NA 440 
NA 
NA 
Alkaline phosphatase  
F 
U/L 
42 
98 
41 
99 
NA 
440 
NA 
NA 
U/L 
42 
98 
41 
99 
NA 440 
NA 
NA 
Aspartate aminotransferase  
M  
U/L 
14 
39 
13 
40 
NA 
117 
NA 
NA 
U/L 
14 
39 
13 
40 
NA 117 
NA 
NA 
Aspartate aminotransferase  
F 
U/L 
14 
34 
13 
35 
NA 
102 
NA 
NA 
U/L 
14 
34 
13 
35 
NA 102 
NA 
NA 
Bilirubin, direct 
M/F 
mg/dL 
0.0 
0.3 
NA 
0.4 
NA 
3.0 
NA 
NA 
umol/L 
0.0 
5.1 
NA 
5.2 
NA 51.3 
NA 
NA 
Bilirubin, total 
M/F 
mg/dL 
0.3 
1.2 
0.2 
1.3 
NA 
3.3 
NA 
NA 
umol/L 
5.1 
20.5 
5.0 
20.6 
NA 56.5 
NA 
NA 
Blood Urea Nitrogen (BUN) 
M/F 
mg/dL 
9 
23 
8 
24 
NA 
70 
NA 
NA 
mmol/L 
3.2 
8.2 
3.1 
8.3 
NA 25.0 
NA 
NA 
Calcium 
M/F 
mg/dL 
8.6 
10.2 
8.5 
10.3 
6.8 
12.0 
6.8 
14.0 
mmol/L 
2.15 
2.55 
2.14 
2.56 
1.70 3.00 
1.70 
3.50 
Chloride  
M/F 
mmol/L 
99 
109 
98 
110 
74 
131 
NA 
NA 
mmol/L 
99 
109 
98 
110 
74 
131 
NA 
NA 
Cholesterol, total 
M/F 
mg/dL 
0 
199 
NA 
200 
NA 
602 
NA 
NA 
mmol/L 
0.0 
5.2 
NA 
5.3 
NA 15.6 
NA 
NA 
Creatinine 
M 
mg/dL 
0.70 
1.30 
0.69 
1.31 
NA 
3.00 
NA 
NA 
umol/L 
62 
115 
61 
116 
NA 265 
NA 
NA 
Creatinine 
F 
mg/dL 
0.50 
1.10 
0.49 
1.11 
NA 
3.00 
NA 
NA 
umol/L 
44 
97 
43 
98 
NA 265 
NA 
NA 
Creatine kinase 
M 
U/L 
32 
294 
31 
295 
NA 
525 
NA 
NA 
U/L 
32 
294 
31 
295 
NA 525 
NA 
NA 
Creatine kinase 
F 
U/L 
33 
211 
32 
212 
NA 
525 
NA 
NA 
U/L 
33 
211 
32 
212 
NA 525 
NA 
NA 
GGT 
M 
U/L 
0 
54 
NA 
55 
NA 
162 
NA 
NA 
U/L 
0 
54 
NA 
55 
NA 162 
NA 
NA 
GGT 
F 
U/L 
0 
37 
NA 
38 
NA 
111 
NA 
NA 
U/L 
0 
37 
NA 
38 
NA 111 
NA 
NA 
Glucose, Random 
M/F 
mg/dL 
60 
140 
59 
141 
40 
360 
NA 
NA 
mmol/L 
3.3 
7.8 
3.2 
7.9 
2.2 20.0 
NA 
NA 
Potassium (K) 
M/F 
mmol/L 
3.5 
5.1 
3.4 
5.2 
2.5 
6.5 
2.5 
6.5 
mmol/L 
3.5 
5.1 
3.4 
5.2 
2.5 
6.5 
2.5 
6.5 
Sodium (Na) 
M/F 
mmol/L 
136 
145 
135 
146 
119 
161 
NA 
NA 
mmol/L 
136 
145 
135 
146 
119 161 
NA 
NA 
Triglycerides 
M/F 
mg/dL 
0 
149 
NA 
150 
NA 
NA 
NA 
NA 
mmol/L 
0.00 
1.68 
NA 
1.69 
NA NA 
NA 
NA 
Uric acid 
F 
mg/dL 
2.3 
6.6 
2.2 
6.7 
NA 
13.1 
NA 
NA 
umol/L 
137 
393 
136 
394 
NA 780 
NA 
NA 
Thyroid stimulating hormone (TSH) 
M/F 
µIU/mL 
0.35 
5.50 
0.34 
5.51 
NA 
NA 
NA 
NA 
mIU/L 
0.35 
5.50 
0.34 
5.51 
NA NA 
NA 
NA 
Triiodothyronine, Free (FT3) 
M/F 
pg/mL 
2.3 
4.2 
2.2 
4.3 
NA 
NA 
NA 
NA 
pmol/L 
3.5 
6.5 
3.4 
6.6 
NA NA 
NA 
NA 
Triiodothyronine, Total (T3) 
M/F 
ng/dL 
60 
181 
59.9 
181.1 
NA 
NA 
NA 
NA 
nmol/L 
0.9 
2.8 
0.8 
2.9 
NA NA 
NA 
NA 
Thyroxine, Free (FT4) 
M/F 
ng/dL 
0.9 
1.8 
0.8 
1.9 
NA 
NA 
NA 
NA 
pmol/L 
11.6 
23.2 
11.5 
23.3 
NA NA 
NA 
NA 
Thyroxine, Total (T4) 
M/F 
µg/dL 
4.5 
10.9 
4.4 
11.0 
NA 
NA 
NA 
NA 
nmol/L 
58 
141 
57 
142 
NA NA 
NA 
NA 


ACT-541468 
Insomnia disorder 
Protocol AC-078A201 
Version 3 
16 December 2016, page 117/131 
Confidential 
EudraCT 2016-000826-21 
Doc No D-16.648 
 
Appendix 2 
Alcohol restrictions during the study 
The subjects must not drink alcohol 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 bottle/can of 33 cl / 12 ounces of beer (≈14 grams alcohol) 
• A glass of 10–12 cl / 4 ounces of wine (≈12 grams alcohol) 
• A small glass of 3–4 cl / 1 ounce of liquor (≈9 grams alcohol) 
 
 
 
 


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Insomnia disorder 
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Version 3 
16 December 2016, page 118/131 
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Doc No D-16.648 
 
Appendix 3 
Caffeine content of common beverages 
The content of caffeine in common caffeine beverages is approximately: 
• A standard cup of brewed or restaurant-style coffee contains approximately  
150–200 mg caffeine.  
• A can of most soda drinks (unless decaffeinated soda drinks) contains approximately 
50 mg caffeine. 
• A can of energy drink contains approximately 150–200 mg caffeine. 
 
 
 


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Insomnia disorder 
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16 December 2016, page 119/131 
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Appendix 4 
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 V1. The use of CNS-active drugs is 
forbidden or restricted until 24 hours after EOT (V6). 
Drug Class 
Examples 
Forbidden / 
Restricted 
Comment 
Centrally Acting 
Anticholinergics and 
Antihistamines 
OTC Histamine1-Antihistamines, 
e.g.: 
Diphenhydramine HCl  
Carbinoxamine  
Dimenhydrinate  
Triprolidine HCl  
Hydroxizine  
F 
 
Antihistamines 
Sedating 
Non-sedating (loratidine, 
fexofenadine) 
F 
R 
Non-sedating antihistamines 
may be used maximum 
twice weekly for allergic 
symptoms. 
Psychotropics 
Stimulants: 
Amphetamines 
Modafinil, armodafinil 
Methylphenidate 
F 
 
 
Antidepressants 
F 
 
 
Antipsychotics, including depot 
neuroleptics 
F 
 
 
Anxiolytics, e.g.: 
Lorazepam 
Alprazolam 
Buspirone 
F 
 
 
Sleep medications, e.g.: 
Prescribed zolpidem and other sleep 
medicines, suvorexant, ramelteon 
and OTC  
F 
 
 
MAOIs 
F 
 
 
Melatonin 
F 
 


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16 December 2016, page 120/131 
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Mood stabilizers, e.g.: 
Lamotrigine 
Gabapentin 
Lithium 
Oxcarbazepine 
Carbamazepine 
Valproic acid 
F 
 
 
Narcotics 
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  
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 Johns 
Wort, valerian, passiflora 
F 
 
 
Tryptophan 
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 
F 
 
 
Diet Pills (prescription and OTC) 
F 
 
 
Pseudoephedrine 
R 
May only be used before 
2 pm, and no more than 
twice a week. Dosage is 
limited to 30 mg of active 
ingredient in each tablet. 
Extended release 
formulations are forbidden. 
GABA = gamma-aminobutyric acid; MAOI = monoamine oxidase inhibitor; NSAID = nonsteroidal anti-inflammatory 
drug; OTC = over-the-counter. 
 


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Insomnia disorder 
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16 December 2016, page 121/131 
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2. Non-exhaustive list of forbidden concomitant medications and diets due to potential 
drug interactions with CYP3A4 (moderate and strong inhibitors, inducers and 
sensitive substrates), with P-gP substrates, with BCRP substrates, and with CYP2B6 
substrates. 
Those medications must be discontinued no later than within 1 week prior to V1 and 
are forbidden until 24 hours after EOT (V6).  
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 
 
CYP3A4 substrates: alfentanil, apixaban, budesonide, buspirone, cisapride, crizotinib, 
cyclosporine, darifenacin, dihydroergotamine, domperidone, dronedarone, erlotinib, 
ergotamine, erythromycin, felodipine, fentanyl, halofantrine, ketamine, lovastatin, 
lurasidone, maraviroc, midazolam, nifedipine, nisoldipine, oxycodone, quetiapine, 
saquinavir, sildenafil, simvastatin, sirolimus, tacrolimus, terfenadine, ticagrelor, 
tipranavir/ritonavir, tolvaptan, triazolam, vardenafil, verapamil. 
P-gP substrates: aliskiren, ambrisentan, colchicine, dabigatran etexilate, digoxin, 
everolimus, fexofenadine, imatinib, lapatinib, maraviroc, nilotinib, posaconazole, 
ranolazine, saxagliptin, sirolimus, sitagliptin, talinolol, tolvaptan, topotecan. 


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Insomnia disorder 
Protocol AC-078A201 
Version 3 
16 December 2016, page 122/131 
Confidential 
EudraCT 2016-000826-21 
Doc No D-16.648 
 
BCRP 
substrates: 
imatinib, 
irinotecan, 
lapatinib, 
methotrexate, 
mitoxantrone, 
rosuvastatin, sulfasalazine, topotecan. 
CYP2B6 substrates: bupropion, cyclophosphamide, efavirenz, irinotecan, ketamine, 
promethazine, propofol, selegiline, valproic acid. 
 
 
 


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Insomnia disorder 
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Version 3 
16 December 2016, page 123/131 
Confidential 
EudraCT 2016-000826-21 
Doc No D-16.648 
 
Appendix 5 
Digit Symbol Substitution Test© 




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Insomnia disorder 
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16 December 2016, page 125/131 
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Doc No D-16.648 
 
Appendix 7 
Sheehan Disability Scale© 


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Insomnia disorder 
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Version 3 
16 December 2016, page 126/131 
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Doc No D-16.648 
 
Appendix 8 
Karolinska Sleepiness Scale 
 


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Insomnia disorder 
Protocol AC-078A201 
Version 3 
16 December 2016, page 127/131 
Confidential 
EudraCT 2016-000826-21 
Doc No D-16.648 
 
Appendix 9 
Benzodiazepine Withdrawal Symptoms Questionnaire 


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Insomnia disorder 
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Version 3 
16 December 2016, page 128/131 
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Doc No D-16.648 
 
Appendix 10 Sleep diary 


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Insomnia disorder 
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Version 3 
16 December 2016, page 129/131 
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Insomnia disorder 
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Version 3 
16 December 2016, page 130/131 
Confidential 
EudraCT 2016-000826-21 
Doc No D-16.648 
 
Appendix 11 Summary table of objectives, endpoints and variables 
Objectives 
Variables 
Endpoints 
 
Sleep maintenance 
WASO 
Change from Baselinea to Days 1&2b 
Primary 
sWASO 
Change from Baselinec to Week 4d 
Secondary 
WASO 
Change from Baselinea to Days 15&16e, and to Days 28&29f 
Exploratory 
WASO over time 
Change from Baselinea to Days 1&2b, Days 15&16e, and to Days 28&29f by hour of the 
night and by quarter of the night 
sWASO 
Change from Baselinec to Weeks 1&2&3g 
Sleep initiation 
LPS 
Change from Baselinea to Days 1&2b 
Secondary 
sLSO 
Change from Baselinec to Week 4d 
LPS 
Change from Baselinea to Days 15&16e, and to Days 28&29f 
Exploratory 
sLSO 
Change from Baselinec to Weeks 1&2&3g 
Total sleep time 
TST 
Change from Baselinea to Days 1&2b, Days 15&16e, and to Days 28&29f 
Exploratory 
sTST 
Change from Baselinec to Weeks 1&2&3&4h 
Sleep quality 
VAS 
Change from Baselinec to Weeks 1&2&3&4h 
Exploratory 
Sleep architecture 
Sleep stages duration 
Meani duration and mean percent of TST of each sleep stage (S1, S2, SWS and REM) 
for the whole night, and for each quarter of the night. 
Exploratory 
Sleep stages latency 
Meani latency to each sleep stage (S1, S2, SWS, and REM). 
Sleep continuity 
Shifts between sleep 
stages 
Meani number and frequency of shifts from S2, SWS or REM to S1 or wake for the 
whole night. 
Exploratory 
Wake time during 
sleep 
Meani wake time during sleep: time spent in epochs scored as wake between LPS and 
last epoch not scored wake for the whole night. 
Awakenings 
Meani frequency of awakenings: number of awakenings between first epoch and last 
epoch not scored wake for the whole night, by hour of the night and by quarter of the 
night. 
sNA 
Change from Baselinec to Weeks 1&2&3&4h 
Sleep efficiency 
SE 
Change from Baselinea to Days 1&2b, Days 15&16e, and to Days 28&29f 
Exploratory 


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Insomnia disorder 
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Insomnia severity 
ISI scores 
Change from Baseline (V1) to V5 (Day 30, morning) 
Exploratory 
Next-day 
performance 
VAS 
Change from Baselinec to Weeks 1&2&3&4h 
Exploratory 
 
Where: 
a ‘Baseline’ is the mean of the 2 PSG nights during the run-in period (V2).  
b ‘Days 1&2’ are the mean of the corresponding 2 PSG treatment nights (V3).  
c ‘Baseline’ is the mean value in the screening sleep diary entries at home prior to start of study treatment between V2 and V3 during 7 consecutive 
days. 
d ‘Week 4’ is the mean value based on the sleep diary entries at home under last week double-blind study treatment. 
e ‘Days 15&16’ is the mean of the corresponding 2 PSG treatment nights (V4). 
f ‘Days 28&29’ is the mean of the corresponding 2 PSG treatment nights (V5).  
g ‘Weeks 1&2&3’ is the mean value based on the sleep diary entries at home under double-blind study treatment (between V3 and V5). 
h ‘Weeks 1&2&3&4’ is the mean value based on the sleep diary entries at home under double-blind study treatment (between V3 and V5). 
i mean values calculated based on the 2 PSG treatment nights of each visits. 
  

SAP_001.pdf: 
 
 
Statistical Analysis Plan AC-078A201 
 
 
Multi-center, double-blind, randomized, placebo-controlled, active-reference, 
parallel-group, polysomnography dose-response study to assess the efficacy and 
safety of ACT-541468 in adult subjects with insomnia disorder. 
 
 
ClinicalTrials.gov Identifier NCT02839200 
 
 
 
 
The study was sponsored was sponsored by Actelion Pharmaceuticals Ltd. 
Study sponsorship was transferred to Idorsia Pharmaceuticals Ltd in July 2018. 


 
 
 
TPL-000241 v02 
 
 
 
STATISTICAL ANALYSIS PLAN 
FOR CLINICAL STUDY REPORT 
Protocol AC-078A201 
Multi-center, double-blind, randomized, placebo-controlled, active-reference, 
parallel-group, polysomnography dose-response study to assess the efficacy and 
safety of ACT-541468 in adult subjects with insomnia disorder 
 
Investigational Drug 
ACT-541468 
Actelion Document Number 
D-17.384 
Document Status/Version Number 
Final Version 2.0 
Date 
3 July 2017 
 
Author 
 
Reviewers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
Property of Actelion Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Actelion Pharmaceuticals Ltd. 
 
 


ACT-541468 
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3 July 2017, page 2/43 
Confidential  
Statistical Analysis Plan 
Doc No D-17.384 
 
TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................5 
1 
INTRODUCTION .........................................................................................................7 
2 
STUDY DESIGN ..........................................................................................................7 
3 
OBJECTIVES ...............................................................................................................8 
3.1 
Primary objective ............................................................................................8 
3.2 
Secondary objectives ......................................................................................8 
3.3 
Other objectives ..............................................................................................8 
4 
GENERAL ANALYSIS CONSIDERATIONS ............................................................9 
5 
ANALYSIS SETS .........................................................................................................9 
5.1 
Screened analysis set ......................................................................................9 
5.2 
Randomized analysis set .................................................................................9 
5.3 
Full analysis set ..............................................................................................9 
5.4 
Modified full analysis set .............................................................................10 
5.5 
Per-protocol analysis set ...............................................................................10 
5.6 
Safety set .......................................................................................................10 
5.7 
Withdrawal set ..............................................................................................10 
5.8 
Pharmacokinetic analysis set ........................................................................10 
6 
STUDY SUBJECTS VARIABLES AND ANALYSES ............................................10 
6.1 
Screening failures .........................................................................................10 
6.2 
Subject disposition ........................................................................................11 
6.3 
Protocol deviations .......................................................................................12 
6.4 
Subject characteristics ..................................................................................12 
6.4.1 
Demographics ...................................................................................12 
6.4.2 
Medical history and current medical conditions ...............................12 
6.4.3 
Previous and concomitant therapies .................................................12 
6.5 
Study treatment exposure and compliance ...................................................14 
6.5.1 
Exposure ...........................................................................................14 
6.5.2 
Compliance .......................................................................................15 
7 
ANALYSIS OF THE PRIMARY VARIABLE ..........................................................15 
7.1 
Endpoint: Objective sleep maintenance .......................................................15 
7.2 
Handling of missing data ..............................................................................15 
7.3 
Statistical hypothesis, model and method of analysis ..................................16 
7.3.1 
Design ...............................................................................................16 


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Statistical Analysis Plan 
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7.3.1.1 
Candidate dose response models .............................................16 
7.3.2 
Analysis ............................................................................................18 
7.3.2.1 
Implementation of the MCP step .............................................18 
7.3.2.2 
Implementation of the Mod step .............................................19 
7.3.2.3 
Dose selection based on WASO ..............................................20 
7.3.3 
Other .................................................................................................21 
7.4 
Supportive/sensitivity analyses .....................................................................21 
8 
ANALYSIS OF THE SECONDARY EFFICACY VARIABLES .............................22 
8.1 
Subjective sleep maintenance .......................................................................22 
8.2 
Objective sleep onset ....................................................................................22 
8.3 
Subjective sleep onset ...................................................................................23 
9 
ANALYSIS OF OTHER EFFICACY VARIABLES .................................................23 
9.1 
Objective and subjective sleep maintenance ................................................23 
9.2 
Objective and subjective sleep onset ............................................................23 
9.3 
Objective and subjective sleep onset and sleep maintenance .......................24 
9.4 
Objective and subjective Total Sleep Time ..................................................24 
9.5 
Sleep Quality ................................................................................................24 
9.6 
Sleep architecture .........................................................................................24 
9.7 
Objective and subjective sleep continuity ....................................................24 
9.8 
Sleep efficiency ............................................................................................25 
9.9 
Insomnia severity ..........................................................................................25 
9.10 
Next-day performance ..................................................................................26 
10 SAFETY ANALYSIS .................................................................................................26 
10.1 
Adverse events ..............................................................................................26 
10.2 
Laboratory data .............................................................................................28 
10.3 
Vital signs, weight and physical examination ..............................................31 
10.4 
Electrocardiograms .......................................................................................32 
10.5 
Withdrawal symptoms ..................................................................................33 
10.6 
Insomnia rebound effect ...............................................................................34 
10.7 
Other safety parameters of interest ...............................................................35 
10.7.1 
Digit Symbol Substitution Test©.......................................................35 
10.7.2 
Karolinska Sleepiness Scale .............................................................35 
10.7.3 
Sheehan Disability Scale© ................................................................35 
10.7.4 
Neurological Examination ................................................................35 
10.7.5 
Columbia Suicide Severity Rating Scale© ........................................36 
10.8 
Pharmacokinetic ...........................................................................................36 
10.9 
Exposure-safety analysis ..............................................................................37 


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Statistical Analysis Plan 
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11 INTERIM ANALYSES ..............................................................................................37 
12 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................37 
12.1 
Changes to the analyses planned in the study protocol ................................37 
12.2 
Changes in the conduct of the study / data collection ..................................38 
12.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................38 
13 GENERAL DEFINITIONS AND DERIVATIONS ...................................................38 
13.1 
Treatment start and end dates .......................................................................38 
13.2 
Study periods ................................................................................................38 
13.3 
Study day ......................................................................................................38 
13.4 
Baseline ........................................................................................................39 
13.5 
Absolute change from baseline .....................................................................39 
13.6 
Handling of data when total sleep time is zero .............................................39 
13.7 
Handling of missing/incomplete date and time fields ..................................39 
13.8 
Time window definitions for calculating subjective endpoints ....................40 
14 REFERENCES ............................................................................................................42 
DOCUMENT HISTORY...................................................................................................43 
 
LIST OF TABLES 
 
Table 1 
Imputation rules for an incomplete or missing concomitant therapy date ......14 
Table 2 
Imputation rules for an incomplete or missing AE date .................................28 
Table 3 
Marked abnormalities in laboratory parameters for reporting ........................29 
Table 4 
Marked abnormalities in ECG parameters ......................................................33 
Table 5 
Meaning of the first and last PSG end date at visit V2, V3, V4 or V5 ...........40 
 
LIST OF FIGURES 
 
Figure 1 
Study design ......................................................................................................8 
Figure 2 
Candidate dose response models.....................................................................17 
 
 


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Statistical Analysis Plan 
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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
AEs of special interest 
ANCOVA  
Analysis of covariance 
AST  
Aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
CI  
Confidence interval 
CRO  
Contract research organization 
CSR  
Clinical study report 
C-SSRS©  
Columbia Suicide Severity Rating Scale 
DSST©  
Digit Symbol Substitution Test 
ECG  
Electrocardiogram 
ED50  
Dose that is expected to give half the maximum change 
Emax  
Maximum change in effect associated with dose 
EODB  
End of Double-Blind treatment 
EOS  
End of Study 
FAS  
Full analysis set 
IDMC  
Independent Data Monitoring Committee 
ISB  
Independent Safety Board 
ISI©  
Insomnia Severity Index 
KSS  
Karolinska Sleepiness Scale 
LLOQ  
Lower Limit of Quantification 
LPS  
Latency to Persistent Sleep 
LS  
Least squares 
MCP-Mod  
Multiple Comparison Procedure – Modeling 
MedDRA  
Medical Dictionary for Regulatory Activities 
mFAS  
Modified full analysis set 
NAW  
Number of awakenings 
PK  
Pharmacokinetic 


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Statistical Analysis Plan 
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PPS  
Per-protocol analysis set 
PSG  
Polysomnography 
PT  
Preferred term 
QTcB  
QT corrected according to Bazett’s formula 
QTcF  
QT corrected according to Fridericia’s formula 
REM  
Rapid eye movement 
RND  
Randomized analysis set 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SAS  
Statistical analysis system 
SCR  
Screened analysis set 
SDS©  
Sheehan Disability Scale 
sLSO  
Subjective Latency to Sleep Onset 
sNAW  
Subjective NAW 
SOC  
System organ class 
SQ  
Sleep quality 
SS  
Safety set 
sTST  
Subjective TST 
sWASO  
Subjective Wake After Sleep Onset 
SWS  
Slow wave sleep 
TD  
Target dose 
TIB  
Time in bed 
TST  
Total Sleep Time 
VAS  
Visual Analog Scale 
WASO  
Wake After Sleep Onset 
WHO  
World Health Organization 
WHO DRL  
WHO Drug Reference Listing 
 


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Statistical Analysis Plan 
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1 
INTRODUCTION 
This statistical analysis plan (SAP) describes in detail the analyses and data presentation 
for the final clinical study report (CSR). 
Obvious corrections to address minor formatting errors or spelling mistakes may be 
performed at the time of analysis without amending this document. 
Data will be analyzed by Actelion and/or designated contract research organizations 
(CROs) using Statistical Analysis System (SAS) version 9.3, and for the Multiple 
Comparison Procedure – Modeling (MCP-Mod) analysis, R version 3.1.2 will be used. 
The analyses for the closed session in the Independent Data Monitoring Committee 
(IDMC) meetings will be performed by an independent statistical analysis center. 
Protocol AC-078A201, Final Version 2, dated 3 August 2016 was used when writing this 
SAP. 
2 
STUDY DESIGN 
This is a multi-center, double-blind, randomized, placebo-controlled, active-reference, 
parallel-group, polysomnography (PSG) dose-response Phase 2 study to assess the 
efficacy and safety of ACT-541468 in adult subjects with insomnia disorder. 
Approximately 300 subjects will be randomized (stratified by gender) in a 1:1:1:1:1:1 
ratio to either ACT-541468 5 mg, 10 mg, 25 mg, 50 mg, placebo or zolpidem 10 mg. 
The study design is shown in Figure 1. Double-blind study treatment will be administered 
from V3 to the End of Double-Blind treatment (EODB - V5); an expected duration of 
29 days. The double-blind treatment period starts with the first dose of double-blind study 
treatment in the first evening of the Randomization Visit (V3, Day 1). The EODB is 
reached in the second morning of V5 (Day 30) after the last dose of double-blind study 
treatment and after all second morning assessments have been performed. 


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Figure 1 
Study design 
 
Note: V = Visit; ▬ = PSG nights; EODB = End of Double-Blind treatment; EOT = End of Treatment. 
3 
OBJECTIVES  
3.1 Primary objective 
The primary objective of the study is to evaluate the dose response of ACT-541468 on 
the change of Wake After Sleep Onset (WASO) assessed by PSG after treatment on 
Days 1&2. 
3.2 Secondary objectives 
The secondary objectives of the study are to evaluate the dose response relationship of 
ACT-541468 on Latency to Persistent Sleep (LPS) on Days 1&2, and subjective Latency 
to Sleep Onset (sLSO) and subjective WASO (sWASO) at Week 4. 
3.3 Other objectives 
To explore the effect of ACT-541468 on sleep parameters during the study, sleep 
parameters will include various objective and subjective measures. 
To assess the safety and tolerability of oral administration of ACT-541468 in subjects 
with insomnia disorder. 


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To explore the relationship between ACT-541468 exposure (concentration of 
ACT-541468 approximately 9–10 h post-dose at second morning of V3, V4, and V5) and 
safety. 
4 
GENERAL ANALYSIS CONSIDERATIONS 
Categorical data will be summarized by frequency counts and percentages. Unless 
specified otherwise, the percentage will be based on the corresponding treatment group 
size. 
Continuous data will be summarized using descriptive statistics (N, mean, standard 
deviation, median, minimum and maximum). 
Unless noted otherwise, all statistical summaries will be presented by treatment group 
and in the following order (Placebo, ACT-541468 5 mg, ACT-541468 10 mg, 
ACT-541468 25 mg, ACT-541468 50 mg, zolpidem 10 mg). 
5 
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 each analysis set will be summarized 
and listed. 
5.1 Screened analysis set  
The screened analysis set (SCR set) includes 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). 
5.2 Randomized analysis set 
The randomized analysis set (RND set) includes all subjects who have been assigned to a 
double-blind study treatment. 
5.3 Full analysis set  
The Full analysis set (FAS) includes all subjects from the RND set who received at least 
one dose of double-blind study treatment. 
In order to adhere to the intention-to-treat principle: 
• Subjects will be evaluated according to the study treatment they have been assigned 
to (which may be different from the study treatment they actually receive), 
• All available data are included. 


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5.4 Modified full analysis set 
The modified FAS (mFAS) includes all subjects from the FAS and who have at least one 
WASO assessment at baseline and one at Days 1&2. 
5.5 Per-protocol analysis set  
The Per-protocol analysis set (PPS) comprises all subjects from the mFAS who have two 
consecutive WASO values at Baseline and at Days 1&2, and who complied with the 
protocol sufficiently to allow relevant assessment of treatment effects. 
Criteria for sufficient compliance: 
• Subject has taken required treatment on both PSG nights during run-in period and 
Days 1&2, 
• Absence of major protocol deviations (i.e., those leading to exclusion from the PPS), 
as defined in a separate protocol deviation document. 
Subjects not meeting the criteria above will be excluded from the PPS. 
5.6 Safety set  
The Safety set (SS) includes all subjects who received at least one dose of double-blind 
study treatment. Subjects will be evaluated according to the actual treatment they 
received (based on dispensed kit number), which may differ from the randomly assigned 
treatment. 
5.7 Withdrawal set 
The Withdrawal set comprises all subjects included in the SS who received single-blind 
placebo treatment (at least one capsule) in the run-out period. 
5.8 Pharmacokinetic analysis set 
The pharmacokinetic analysis set (PK set) includes all subjects in the SS who have at 
least one PK sample collected after initiation of study drug. Subjects receiving placebo or 
zolpidem will be excluded from the PK set. 
6 
STUDY SUBJECTS VARIABLES AND ANALYSES 
6.1 Screening failures 
The following summaries will be based on the SCR set: 
• Number (%) of subjects who discontinued during screening period (based on ‘Was 
the subject randomized?’ recorded as ‘No’ in the ‘Randomization’ page), 
• Number (%) of subjects who discontinued during screening period, but did not enter 
the run-in period (based on ‘Was the subject randomized?’ recorded as ‘No’ in the 
‘Randomization’ page, missing ‘Date of capsules dispensed’ in the ‘Study Single 


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Blind Treatment Dispensing & Accountability’ page at V2 and no assessments at 
V2), 
• Number (%) of subjects who failed screening during the run-in period (based on ‘Was 
the subject randomized?’ recorded as ‘No’ in the ‘Randomization’ page, and either a 
non-missing ‘Date of capsules dispensed’ in the ‘Study Single Blind Treatment 
Dispensing & Accountability’ page at V2, or a non-missing assessment recorded at 
V2), 
• Primary reasons for screening period discontinuation (i.e., inclusion/exclusion criteria 
not met, subject withdrew consent, or other). 
Subjects may be re-screened once. For these subjects, only the timing and reason of the 
last screen failure will be reported in the summary table. Re-screened subjects that are 
randomized will be excluded from this summary. However, all reasons for screening 
failure will be included in the listing. 
Demographic data for subjects who fail screening and corresponding reason(s) for screen 
failure will be listed. 
6.2 Subject disposition 
The following will be based on the SCR set: 
• Number of subjects screened, 
• Number of subjects treated in single-blind placebo treatment run-in period (based on 
non-missing date of capsules dispensed at Visit 2), 
• Number of subjects randomized (based on non-missing randomization number), 
• Number of subjects treated in double-blind treatment period (based on non-missing 
treatment start date), 
• Number of subjects treated at last PSG treatment nights, 
• Number of subjects treated in single-blind placebo treatment run-out period (based on 
non-missing date of capsules dispensed at Visit 6), 
• Number of subjects completing the end of study (EOS) safety follow-up (based on 
non-missing date of phone call on the ‘Safety Follow-up Phone Call Summary - EOS’ 
page). 
The following summaries will be based on the FAS: 
• Number (%) of subjects who prematurely discontinued double-blind study treatment 
(based on discontinuation reason entered as ‘Premature Discontinuation’ in the ‘Study 
Double-blind Treatment Log’ page), 
• Primary reasons for premature double-blind study treatment discontinuation (based 
on discontinuation reason entered on the ‘Premature Discontinuation of Study 
Treatment’ page). 


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The following summaries will be based on the RND set: 
• Number (%) of subjects who prematurely discontinued from study (based on 
non-missing discontinuation reason entered in the ‘Study Discontinuation’ page), 
• Primary reasons for premature discontinuation from the study (based on 
discontinuation reason entered in the ‘Study Discontinuation’ page). 
Premature treatment and study discontinuations will be listed based on the RND set. 
6.3 Protocol deviations 
The RND set will be used for the protocol deviation summary tables and the SCR set for 
listings. All important and other protocol deviations will be summarized per pre-specified 
category (i.e., During screening period; During run-in period (V2); During double-blind 
treatment phase; During follow-up phase; Non study phase specific) by treatment group 
and overall. A subject with multiple occurrences of a protocol deviation is counted only 
once per protocol deviation category. A listing of all protocol deviations will be provided. 
6.4 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 overall. Data will be listed 
individually by subject. 
6.4.1 Demographics 
Demographic data including age, gender, race, ethnicity, height, and baseline weight and 
body mass index will be listed and summarized. In addition, age categories (< 18,  
18–< 50, ≥ 50 years), and BMI categories (< 25, 25–30, > 30 kg/m2) will be summarized. 
6.4.2 Medical history and current medical conditions 
Relevant medical history and current medical conditions will be coded using MedDRA 
terminology. Medical history and current (ongoing) medical conditions, excluding 
insomnia-related conditions and symptoms, will be summarized and listed. Summaries 
will be presented by primary system organ class (SOC) and preferred term (PT). 
The MedDRA version used for reporting will be specified in the footnote of the 
applicable output. 
6.4.3 Previous and concomitant therapies 
Therapies collected will be coded using the WHO Drug Reference Listing (WHO DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (ATC) 
classification system. The WHO DRL version used for reporting will be specified in the 
footnote of the applicable output. 
Number (%) of subjects having taken at least one previous or concomitant treatment will 
be summarized by ATC class and individual PT within each ATC class based on the SS. 


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Summaries will be provided for previous, study-concomitant and double-blind study 
treatment-concomitant therapies defined below. 
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. 
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 
30 days after study treatment discontinuation. 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 double-blind study 
treatment or initiated during the double-blind treatment period until 1 day after the last 
dose of double-blind study treatment. 
All concomitant therapies will be listed using the SS. 
An incomplete (day or month missing) or missing concomitant therapy date will be 
imputed as described in the table below. The ‘lower limit’ and ‘upper limit’ refer to the 
earliest and latest possible dates, respectively. 
As an example: If concomitant therapy start date is MAR2017 (day missing), the lower 
limit is 01MAR2017 and the upper limit is 31MAR2017; If concomitant therapy start 
date is 2017 (day and month missing), the lower limit is 01JAN2017 and the upper limit 
is 31DEC2017. 


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Table 1 
Imputation rules for an incomplete or missing concomitant therapy 
date 
Field 
Incomplete date 
Missing date 
Concomitant 
therapy end date 
The upper limit. 
No imputation; the therapy is 
considered as ongoing. 
Concomitant 
therapy start 
date 
If the (imputed) concomitant therapy end date is 
on or after the start of double-blind study 
treatment, and if the study treatment start falls 
within the upper and lower limits (inclusive), the 
study treatment start date is used. 
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. 
If the concomitant therapy resolution date is 
missing, then: 
1. if the double-blind study treatment start falls 
within the upper and lower limits (inclusive), the 
double-blind study treatment start date is used 
else: 
2. 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. 
In all the other cases, the lower limit is used. 
Whichever is the earlier of the 
concomitant therapy end date or 
double-blind study treatment start 
date. 
 
6.5 Study treatment exposure and compliance 
Unless noted otherwise, summaries and listings described in this section will be based on 
the SS. 
Duration of treatment, reasons for treatment end and compliance data will be listed. 
6.5.1 Exposure 
Duration of double-blind study treatment (in days) is defined as the difference between 
the treatment end date and the treatment start date plus one day. This calculation ignores 
periods of treatment interruption. The duration of double-blind study treatment will be 
summarized. 


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6.5.2 Compliance 
Compliance will be assessed through study treatment accountability. Compliance will be 
based on a non-missing date recorded for ‘Last Study Treatment Intake date’ in the 
‘Polysomnography (PSG)’ page, and an unmarked record for ‘I did not take my study 
medication’ in the sleep diary. 
Compliance to double-blind treatment, defined as the percentage of capsules taken 
compared to the planned capsules during the double-blind treatment period 
(V3 to V5 [EODB]), will be summarized. The number (%) of subjects with compliance to 
double-blind treatment < 70% will be tabulated. 
Compliance to double-blind treatment for each week (cumulatively) will be summarized. 
The number (%) of subjects with compliance to double-blind treatment < 70% for every 
cumulative week will be tabulated. 
Week 1 (7 consecutive days) includes and extends until 6 days after the start date of 
double-blind treatment (V3 - 1st PSG evening). Weeks 1&2 includes Week 1, and extends 
until one day before the date of double-blind treatment at V4 - 1st PSG evening. 
Weeks 1&2&3 includes Weeks 1&2, and includes and extends until 6 days after the date 
of double-blind treatment at V4 - 1st PSG evening. Weeks 1&2&3&4 includes 
Weeks 1&2&3 and extends until one day before the date of double-blind treatment at 
V5 - 1st PSG evening. 
7 
ANALYSIS OF THE PRIMARY VARIABLE 
7.1 Endpoint: Objective sleep maintenance 
The primary efficacy endpoint relates to objective sleep maintenance and is assessed 
through the absolute change in WASO from Baseline to Days 1&2. 
Baseline is the mean of the two PSG nights during the run-in period (V2). Days 1&2 is 
the mean of the corresponding two PSG treatment nights at V3. 
WASO is the time (in minutes) spent awake after onset of persistent sleep (see definition 
of LPS in Section 8.2) until lights on as determined by PSG. The PSG recording is 
centrally scored by independent scorers. 
7.2 Handling of missing data 
No imputation will be performed for missing WASO values. However, if one of the two 
values is missing either for Baseline or for Days 1&2, the single value available will be 
used as the mean for this time point. This implies implicit imputation: the missing data 
point is given the same value as the non-missing data point. 


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7.3 Statistical hypothesis, model and method of analysis 
The primary statistical analysis will be performed on the mFAS. 
To evaluate the dose response relationship of ACT-541468 on the change from baseline 
in WASO, this study uses the generalized MCP-Mod methodology [Bretz 2005, 
Pinheiro 2006, Pinheiro 2014]. This approach combines a Multiple Comparison 
Procedure (MCP) to assess the efficacy of ACT-541468 versus placebo followed by a 
modeling (Mod) step to characterize the dose response relationship and to identify a dose 
(or dose range) that has shown signs of a clinically relevant effect. 
The MCP-Mod analysis will be performed using the R DoseFinding package 
[Bornkamp 2016]. 
Details on how the primary endpoint will be analyzed within the MCP-Mod framework 
are provided below. 
7.3.1 Design 
7.3.1.1 Candidate dose response models 
To begin, the set of pre-specified candidate parametric dose response models that could 
possibly represent the underlying dose response shape are determined. For this study, 
four pre-specified dose response models are considered: three Emax models and one linear 
model. A graphical display of these models are shown in Figure 2. Here, the maximum 
mean reduction in WASO from baseline to Days 1&2 with ACT-541468 50 mg dose is 
assumed to be 25 minutes longer than with placebo. 




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E0 = 0 and Emax = 1). Rearranging the formula above gives 
(
)
p
p
d
ED
−
=
1
50
. The 
specification of ED50 will fully parameterize the standardized form of the model. 
The ED50 for each Emax model (i.e., 1.11, 3.75, 15) was calculated assuming a p of 90%, 
80% and 40% at an ACT-541468 dose (d) of 10 mg, 15 mg, and 10 mg, respectively. 
The calculation of each optimal contrast [see Section 7.3.2.1] depends on the pre-defined 
estimates of ED50 and dose levels (including placebo as 0 mg). Since three Emax models 
are pre-specified, three different sets of testing contrasts will be determined for the Emax 
model (family). 
The functional form of the linear model is defined as (
)
d
E
d
f
δ
θ
+
=
0
,
, where d = dose; 
E0 = placebo (basal) effect. Hence, the standardized form of the linear model is a function 
of dose only 
( )
d
d
f
=
0
. Since no parameter estimates θ0 are required, the determination 
of the appropriate single testing contrast is derived based on dose alone. 
To ensure no inflation of type I error, the pre-specified parameter values θ0 (i.e., ED50) 
are not to be changed after the blind is broken. 
7.3.2 Analysis 
Key components of MCP-Mod at the analysis stage include: 
• MCP step: Testing for the presence of a dose response signal, 
• Mod step: Selecting the best dose response model for the observed data out of a 
pre-specified set of candidate models, and 
• Mod step: Estimating target dose(s; TDs) of interest via modeling. 
7.3.2.1 Implementation of the MCP step 
The MCP step consists of testing a set of optimal contrasts: each testing contrast 
representing one of the pre-specified dose response models. At the same time, this step 
addresses the issue of possible model misspecifications (the reason why multiple 
candidate dose response shapes are pre-defined) and also includes the associated 
adjustments for multiplicity within a rigorous hypothesis testing framework. 
For a single given candidate dose response model, the optimal contrast for testing the 
hypothesis of a flat dose-response profile with maximal power is given by: 






−
∝
−
−
−
1
S
1
1
S
μ
μ
S
c
1
1
0
m
0
m
1
opt
m
ˆ
ˆ
ˆ
'
'
  


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Where 
0
m
μ  is the standardized mean response at each dose for a given candidate dose 
response 
model 
(m) 
and 
Ŝ 
denotes 
the 
estimated 
variance-covariance 
of 
d
μˆ  [Pinheiro 2014] (i.e., the estimated mean response per individual dose level from 
the observed data; further details below). 
In the calculation of the optimal contrasts (one for each candidate dose response model 
copt
1,…, copt
4), 
0
m
μ  relies on the standardized form of the dose response model (not the 
complete functional form). 
For convenience, the contrast coefficients are normalized such that ||copt|| = 1. 
Once data are available, the optimal contrasts are applied to 
d
μˆ . 
For 
each 
candidate 
dose 
response 
model 
(m), 
the 
null 
hypothesis 
H0: (copt
m)’μ = 0 (absence of a dose-response relationship) will be tested against the 
two-sided alternative H1: (copt
m)’μ ≠ 0 (existence of a dose response). μ is the true, but 
unknown vector of means. 
The t-test statistic associated with each of the candidate dose response models is given by 
[
]
1/2
m
m,
opt
m
ˆ
ˆ
)
(
C
S
C
μ
c
'
'
Tm =
 with [A]m,m denoting the mth diagonal element of the matrix A, and 
C = [copt
1,…, copt
4] representing the matrix containing the optimal contrasts. 
The test statistic used for establishing an overall dose-response signal will be the 
maximum of the individual model contrast test statistics Tmax = maxm(Tm), or 
alternatively, the associated multiplicity adjusted p-value associated with Tmax. 
Analysis will only proceed to the modeling (Mod) step if a statistically significant 
dose-response signal is established, i.e., the null hypothesis is rejected under any 
candidate dose response model (adjusted two-sided p-value < 0.05). 
7.3.2.2 Implementation of the Mod step 
The Mod step involves model selection, fitting the univariate dose response profile, and 
estimating TD(s) based on the fitted model. 
A two-stage approach will be used to fit the dose-response model to the observed data. 
This approach utilizes generalized least squares (LS; [Pinheiro 2014]) and relies on 
asymptotic results, but has the appeal of being a general purpose application as it depends 
only on 
d
μˆ  and Ŝ. For example, the obtained (adjusted) estimates for 
d
μˆ and Ŝ inherit the 
missing data assumptions of the underlying first stage model. 


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First stage 
An analysis of covariance (ANCOVA) model (first stage model) will be used to calculate 
estimates for 
d
μˆ  (i.e., LS mean estimates for each ACT-541468 dose level and placebo) 
and Ŝ (i.e., variance-covariance matrix of 
d
μˆ ). 
The change from baseline in WASO (assumed to be normally distributed) will be 
modeled using a fixed effect for treatment group (placebo and each ACT-541468 dose 
level), an additional fixed effect for gender, and a linear slope to adjust for WASO at 
baseline. 
The variance of the change from baseline in WASO is assumed to be constant across 
each treatment group. 
The LS mean for each treatment group 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. 
Second stage 
Among the candidate dose response models with a significant contrast test (i.e., adjusted 
two-sided p-value < 0.05) identified in the MCP step, the dose response model 
parameters (e.g., ED50) are estimated by fitting the dose response model (family) to the 
estimates obtained from the mixed effects model (
d
μˆ  and Ŝ) in the first stage. The best 
fitting dose response model (Emax or linear) will be selected based on the gAIC (smaller is 
better). This chosen dose response model will then be used to estimate the TD. 
Based on the selected dose response model, the predicted mean (95% CI) dose response 
profile for the change from baseline in WASO will be graphically displayed. 
7.3.2.3 Dose selection based on WASO 
Estimation of a TD will be performed on the basis of the fitted dose response model 
(Emax or linear) chosen in the second stage. The estimated TD will be the lowest dose 
strength anywhere within the studied dose range (0 mg to 50 mg) which shows a 
clinically meaningful effect (i.e., 15 minutes better than predicted mean value of placebo) 
and a statistically significant effect (i.e., lower 95% CI of the predicted mean value at 
TD > observed mean value of placebo). Note: the choice of 95% CI is not driven by the 
purpose of controlling type I error rates. 
To aid understanding of the accuracy/variation associated with the selected dose response 
model, the following parameters of interest will be derived using a nonparametric 
bootstrap technique. 


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• The 0.025, 0.5 (median) and 0.975 bootstrap percentiles of the predicted mean (on the 
change in reduction in WASO of ACT-541468 relative to placebo) for the chosen 
dose response model, 
• The 0.025, 0.5 (median) and 0.975 bootstrap percentiles of the TD defined as 
15 minutes better than predicted mean value of placebo, 
• The 0.025, 0.5 (median) and 0.975 bootstrap percentiles of the TD defined as 
20 minutes better than predicted mean value of placebo, 
• If the Emax model is selected, the 0.025, 0.5 and 0.975 bootstrap percentiles of the E0, 
ED50 and Emax will be presented. 
The nonparametric bootstrap technique will proceed as follows: 
1. Sample, with replacement, the data available at each period per subject until the 
resampled dataset contains the same number of subjects as in the original dataset, 
2. From the resampled dataset, calculate and store the parameter estimates that define 
the dose response model, 
3. Repeat steps 1 and 2 numerous times (say 1000) to derive the bootstrap distribution 
for each parameter, 
4. Use the bootstrap distribution to calculate the parameters of interest described above. 
7.3.3 Other 
The primary endpoint will also be summarized by gender and overall using descriptive 
statistics. 
7.4 Supportive/sensitivity analyses 
Sensitivity analyses will be conducted on the PPS if this analysis set differs from the 
mFAS significantly (e.g., > 10% reduction in number of subjects). 
Change from baseline to Days 1&2 in mean WASO will also be analyzed using an 
ANCOVA model with the same factors as in the main analysis with the addition of 
region, race and age. 
Each of the four doses of ACT-541468 (5, 10, 25 and 50 mg) will be compared to 
placebo using the single-step Dunnett procedure. For each comparison, the 
placebo-adjusted LS mean will be displayed along with associated standard error, 95% CI 
and multiplicity adjusted two-sided p-value. 
The active comparator (zolpidem) will be compared separately versus placebo using an 
ANCOVA model with a factor for treatment group (placebo or active comparator) and a 
covariate for Baseline mean WASO and gender. This analysis is considered exploratory 
and no formal multiplicity adjustment will be made. 


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8 
ANALYSIS OF THE SECONDARY EFFICACY VARIABLES 
The analysis of the secondary efficacy variables will be performed on the FAS. 
(Also applicable to Section 9.) Questionnaire data based on the nights in the sleep 
laboratory (i.e., the mornings following any PSG night) will be excluded from the 
calculation of the weekly averages since: 
• Data may be influenced by the subject being at the sleep laboratory compared to the 
outpatient environment, 
• Time in bed (TIB) is limited to 8 hours in the sleep laboratory. 
(Also applicable to Section 9.) For objective endpoints, subjects must have at least one 
value at a given time point (e.g., Days 1&2) to calculate a mean. For subjective 
endpoints, subjects must have at least 3 days of data during each week (time windows 
defined in Section 13.8) to calculate a weekly mean. Otherwise, the mean value will be 
considered missing for that time point or week. 
The same MCP-Mod analysis as performed for the primary endpoint will be conducted to 
evaluate the dose response of ACT-541468 on each of the secondary endpoints 
(separately) defined below. Three Emax models with an ED50 of 1.11, 3.75, 15, 
respectively, and one linear model will be considered. Summary statistics will also be 
provided. 
The active comparator (zolpidem) will be compared separately versus placebo using an 
ANCOVA model with a factor for treatment group (placebo or active comparator) and a 
covariate for Baseline mean WASO and gender. 
8.1 Subjective sleep maintenance 
Subjective sleep maintenance is assessed through the absolute change in sWASO from 
Baseline to Week 4. 
sWASO is the self-reported time (min) spent awake after sleep onset as reported in the 
sleep diary. 
8.2 Objective sleep onset 
Objective sleep onset is assessed through the absolute change in LPS from Baseline to 
Days 1&2. 
Baseline is the mean of the two PSG nights during the run-in period (V2), and 
Days 1&2 is the mean of the corresponding two PSG treatment nights (V3). 
LPS is the time (min) from start of recording to the beginning of the first continuous 
20 epochs (i.e., 10 min) scored as non-wake, 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. 


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8.3 Subjective sleep onset 
Subjective sleep onset is assessed through the absolute change in sLSO from Baseline to 
Week 4. 
sLSO is the self-reported time (min) to fall asleep as reported in the sleep diary. 
9 
ANALYSIS OF OTHER EFFICACY VARIABLES 
The analysis of other efficacy variables will be performed on the FAS. 
For endpoints based on objective assessments (e.g., WASO, LPS and Total Sleep Time 
[TST] as determined by PSG): 
• Baseline is the mean of the two PSG nights during the run-in period (V2), 
• Days 1&2 is the mean of the corresponding two PSG treatment nights at V3, 
• Days 15&16 is the mean of the corresponding two PSG treatment nights at V4, 
• Days 28&29 is the mean of the corresponding two PSG treatment nights at V5. 
For endpoints based on subjective assessments (e.g., sWASO, sLSO, subjective TST 
[sTST], Sleep Quality [SQ]): 
• Weeks 1&2&3&4 are the mean values of each week separately based on the sleep 
diary entries at home while on double-blind study treatment during Week 1, Week 2, 
Week 3 and Week 4 as defined in Section 13.8. 
9.1 Objective and subjective sleep maintenance 
Summary statistics will be provided for: 
• Absolute values of WASO at Baseline, Days 1&2, Days 15&16 and Days 28&29 by 
gender and overall, 
• Absolute change in WASO from Baseline to Days 15&16, and to Days 28&29 by 
gender and overall, 
• WASO over time (by hour of the night and by quarter of the night), 
• Absolute values of sWASO at Baseline and Weeks 1&2&3&4 by gender and overall, 
• Absolute change in sWASO from Baseline to Weeks 1&2&3 by gender and overall. 
9.2 Objective and subjective sleep onset 
Summary statistics will be provided for: 
• Absolute values of LPS at Baseline, Days 1&2, Days 15&16 and Days 28&29 by 
gender and overall, 
• Absolute change in LPS from Baseline to Days 15&16, and to Days 28&29 by gender 
and overall, 
• Absolute values of sLSO at Baseline and Weeks 1&2&3&4 by gender and overall, 
• Absolute change in sLSO from Baseline to Weeks 1&2&3 by gender and overall. 


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9.3 Objective and subjective sleep onset and sleep maintenance  
The effect of ACT-541468 treatment versus placebo on the changes from baseline over 
time (i.e., repeated measures) in WASO, sWASO, LPS, and sLSO (separately) will be 
estimated by fitting a linear mixed model adjusted for baseline, with treatment group, 
time point, treatment group by time point interaction and gender as fixed effects, and 
subject as a random effect. A compound symmetry structure will be considered since the 
correlation of the changes from baseline over time is assumed to be constant and similar 
for each treatment group. 
9.4 Objective and subjective Total Sleep Time 
TST is the amount of actual sleep time (min), i.e., time spent in epochs scored as 
non-wake as determined by PSG. 
sTST is the self-reported time (min) spent asleep as reported in the sleep diary. 
Summary statistics will be provided for: 
• Absolute values of TST at Baseline, Days 1&2, Days 15&16 and Days 28&29 by 
gender and overall, 
• Absolute change in TST from Baseline to Days 1&2, Days 15&16, and 
Days 28&29 by gender and overall, 
• Absolute values of sTST at Baseline and Weeks 1&2&3&4 by gender and overall, 
• Absolute change in sTST from Baseline to Weeks 1&2&3&4 by gender and overall. 
9.5 Sleep Quality 
SQ is the sleep quality as determined by scores on the Visual Analog Scale (VAS; mm). 
Summary statistics will be provided for: 
• Absolute values of SQ at Baseline and Weeks 1&2&3&4, 
• Absolute change in SQ from Baseline to Weeks 1&2&3&4. 
9.6 Sleep architecture 
Absolute change from Baseline to Days 1&2, Days 15&16, and Days 28&29 in the 
duration (min) and percentage of TST in each sleep stage (S1, S2, SWS and REM) will 
be summarized over the whole night, and for each quarter of the night. Absolute values 
will also be summarized. 
Absolute change from Baseline to Days 1&2, Days 15&16, and Days 28&29 in the 
latency (min) to each sleep stage (S1, S2, SWS, and REM) will be summarized. Absolute 
values will also be summarized. 
9.7 Objective and subjective sleep continuity 
Mean values are the mean of the two PSG treatment nights at each visit. 


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Absolute change from Baseline to Days 1&2, Days 15&16, and Days 28&29 in mean 
number of shifts from S2, SWS or REM to S1 or wake for the whole night will be 
summarized. Absolute values will also be summarized. 
Absolute change from Baseline to Days 1&2, Days 15&16, and Days 28&29 in mean 
wake time during sleep (defined as the time [min] spent in epochs scored as wake 
between LPS and last epoch not scored wake) for the whole night will be summarized. 
Absolute values will also be summarized. 
Absolute change from Baseline to Days 1&2, Days 15&16, and Days 28&29 in mean 
number of awakenings (NAW; defined as the NAW between first epoch and last epoch 
not scored wake) will be summarized for the whole night, for each quarter of the night, 
and for each hour of the night. Absolute values will also be summarized. 
Absolute change from Baseline to Weeks 1&2&3&4 in the mean self-reported NAW will 
be summarized. Absolute values will also be summarized. Baseline and Weeks 
1&2&3&4 are defined in Section 9. 
9.8 Sleep efficiency 
Sleep efficiency (%) is defined as 100 × (TST [min] / total TIB [min]) where total TIB is 
fixed to 480 min during the PSG nights. 
Absolute change from Baseline to Days 1&2, Days 15&16 and Days 28&29 in sleep 
efficiency will be summarized. Absolute values will also be summarized. 
9.9 Insomnia severity 
The Insomnia Severity Index (ISI©) is a validated instrument to quantify perceived 
insomnia severity [Bastien 2001]. The ISI is composed of seven items that evaluate 
(1) severity of sleep-onset (initial), (2) sleep maintenance (middle), (3) early morning 
awaking (terminal) problems, (4) satisfaction with current sleep pattern, (5) interference 
with daily functioning, (6) noticeability of impairment attributed to the sleep problem, 
and (7) level of distress caused by the sleep problem. Each item is scored as 0 (not at all), 
1, 2, 3 or 4 (extremely) and the time interval considered is the last 2 weeks. Total scores 
range from 0–28 with high scores indicating greater insomnia. 
Absolute change from Baseline (V1) to the second morning of V5 (Day 30) in ISI scores. 
Absolute values will also be summarized. 
The number (%) of subjects meeting the criteria defined below will be tabulated: 
• ≥ 6 point reduction in ISI. 


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9.10 Next-day performance 
Absolute change from Baseline to Weeks 1&2&3&4 in next-day performance assessed at 
home by scores on the VAS (mm) assessing morning sleepiness, daytime alertness and 
daytime ability to function. Absolute values will also be summarized. 
10 SAFETY ANALYSIS 
Unless noted otherwise, the SS will be used for summaries and listings of safety data. 
Unless noted otherwise, the safety summary tables and figures will include 
assessments/events occurring during the on-treatment period (i.e., from day of first dose 
of double-blind study treatment to EOS), also defined as being treatment-emergent. 
All safety data will be listed, and those collected during the post-treatment period will be 
flagged. 
10.1 Adverse events 
Adverse events (AEs) will be coded using MedDRA. The MedDRA version used for 
reporting will be specified in the footnote of the applicable output. 
AEs will be summarized (frequency counts and percentages) by SOC and/or PT, and 
maximum intensity. 
The following AE summaries will be provided: 
• Treatment-emergent AEs, 
• AEs emerging during the run-in period [see Section 13.2], 
• AEs emerging during the withdrawal period [see Section 13.2], 
• Treatment-emergent AEs related to study treatment, 
• Treatment-emergent AEs leading to premature discontinuation of double-blind study 
treatment, 
• Treatment-emergent AEs leading to temporary interruption of double-blind study 
treatment, 
• Occurrence of treatment-emergent non-serious AEs, 
• Treatment-emergent serious AEs (SAEs), 
• Occurrence of treatment-emergent SAEs, 
• Treatment-emergent SAEs related to study treatment, 
• Treatment-emergent AEs with fatal outcome, 
• Treatment-emergent AEs related to study treatment with fatal outcome, 
• On-treatment deaths with cause of death. 
All AEs will be listed as well as all deaths with cause of death. In addition, separate 
listings will be provided for AEs leading to discontinuation of double-blind study 
treatment, and SAEs. 


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Treatment-emergent AEs of special interest (AESI) both according to investigator (based 
on the question ‘Do you consider this AE an Adverse Event of Special Interest (AESI)?’ 
recorded as ‘Yes’ on the ‘Adverse Event’ page), and after adjudication by an Independent 
Safety Board (ISB), will be summarized. The following summaries will be provided: 
• Treatment-emergent AESI as per investigator, 
• Treatment-emergent AESI after ISB adjudication. 
AESI will be listed separately. 
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., system organ class, preferred term). 
An incomplete (day or month missing) or missing AE date will be imputed as described 
in the table below. The ‘lower limit’ and ‘upper limit’ refer to the earliest and latest 
possible dates, respectively. 
As an example: If AE onset date is MAR2017 (day missing), the lower limit is 
01MAR2017 and the upper limit is 31MAR2017; If AE onset date is 2017 (day and 
month missing), the lower limit is 01JAN2017 and the upper limit is 31DEC2017. 


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Table 2 
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 
If the (imputed) AE resolution date is on or after 
the start of double-blind study treatment, and if 
the double-blind study treatment start falls within 
the upper and lower limits (inclusive), the 
double-blind study treatment start date is used. 
If the (imputed) AE resolution 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. 
If the AE resolution date is missing then: 
1. if the double-blind study treatment start falls 
within the upper and lower limits (inclusive), the 
double-blind study treatment start date is used 
else: 
2. 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. 
In all the other cases, the lower limit is used. 
Whichever is the earlier of the AE 
resolution date or double-blind 
study treatment start date. 
AE = Adverse event 
10.2 Laboratory data 
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 unscheduled assessments. 
Descriptive summary statistics by scheduled visit will be provided for observed values 
and absolute changes from baseline in both hematology and blood chemistry laboratory 
parameters. Only scheduled assessments will be considered for this summary. 
The absolute change from baseline to last value in the double-blind treatment period for 
hematology and blood chemistry parameters will be summarized. 


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Marked laboratory abnormalities are defined in table below. The number (%) of subjects 
with treatment-emergent [defined in Section 10] marked laboratory abnormalities 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: those not meeting the criterion at baseline (or having a 
missing baseline value) and having at least one post-baseline value for a given parameter. 
All laboratory data for subjects with at least one treatment-emergent marked laboratory 
abnormality will be listed. 
Table 3 
Marked abnormalities in laboratory parameters for reporting 
Laboratory parameter 
Criteria for marked laboratory abnormalities 
Hematology 
Hemoglobin (g/L) 
< 100 (LL) 
< 80 (LLL) 
> 20 above ULN or > 20 above baseline if baseline > ULN (HH) 
> 40 above ULN or > 40 above baseline if baseline > ULN (HHH) 
Hematocrit (%) 
< 32% (Male); < 28% (Female) (LL) 
< 20% (LLL) 
> 60% (Male); > 55% (Female) (HH) 
> 65% (HHH) 
Platelets (109/L) 
< 75 (LL) 
< 50 (LLL) 
> 600 (HH) 
> 999 (HHH) 
Leucocytes (109/L) 
< 3.0 (LL) 
< 2.0 (LLL) 
> 20.0 (HH) 
> 100.0 (HHH) 
Neutrophils (109/L) 
< 1.5 (LL) 
< 1.0 (LLL) 
Eosinophils (109/L) 
> 5.0 (HH) 
Eosinophils (%) 
> 5% (HH) 
Lymphocytes (109/L) 
< 0.8 (LL) 
< 0.5 (LLL) 
> 4.0 (HH) 
> 20.0 (HHH) 
WBC count (109/L) 
< 3.0 (LL) 
< 2.0 (LLL) 
> 20.0 (HH) 
> 100.0 (HHH) 


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Laboratory parameter 
Criteria for marked laboratory abnormalities 
Prothrombin INR 
> 1.5 × ULN (HH) 
> 2.5 × ULN (HHH) 
Reticulocyte (%) 
> 2.5% (HH) 
Blood chemistry 
ALT (U/L) 
> 3 × ULN (HH) 
> 5 × ULN (HHH) 
> 10 × ULN (HHHH) 
AST (U/L) 
> 3 × ULN (HH) 
> 5 × ULN (HHH) 
> 10 × ULN (HHHH) 
ALP (U/L) 
> 2.5 × ULN (HH) 
> 5 × ULN (HHH) 
TBIL (µmol/L) 
> 2 × ULN (HH) 
> 5 × ULN (HHH) 
Creatinine (µmol/L) 
> 1.5 × ULN or > 1.5 × baseline if baseline > ULN (HH) 
> 3 × ULN or > 3 × baseline if baseline > ULN (HHH) 
Albumin (g/L) 
< 30 (LL) 
< 20 (LLL) 
Calcium (mmol/L) 
< 2.0 (LL) 
< 1.75 (LLL) 
> 2.9 (HH) 
> 3.1 (HHH) 
Potassium (mmol/L) 
< 3.2 (LL) 
< 3.0 (LLL) 
> 5.5 (HH) 
> 6.0 (HHH) 
Sodium (mmol/L) 
< 130 (LL) 
> 150 (HH) 
> 155 (HHH) 
Chloride (mmol/L) 
< 74 (LL) 
> 131 (HH) 
Creatine kinase (μg/L) 
> 5 × ULN (HH) 
> 10 × ULN (HHH) 
Gamma-glutamyl 
transferase (U/L) 
> 2.5 × ULN (HH) 
> 5 × ULN (HHH) 
Blood urea nitrogen 
(mmol/L) 
> 2.5 × ULN (HH) 
> 5 × ULN (HHH) 
Uric acid (μmol/L) 
> 590 (HH) 
> 720 (HHH) 


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Laboratory parameter 
Criteria for marked laboratory abnormalities 
Glucose (mmol/L) 
< 3 (LL) 
< 2.2 (LLL) 
> 8.9 (HH) 
> 13.9 (HHH) 
TSH (mIU/L) 
< 0.28 (LL) 
> 6.6 (HH) 
Free T3 (pmol/L) 
< 2.8 (LL) 
> 7.8 (HH) 
Total T3 (nmol/L) 
< 0.9 (LL) 
> 3.0 (HH) 
Free T4 (pmol/L) 
< 7.2 (LL) 
> 30 (HH) 
Total T4 (nmol/L) 
< 45 (LL) 
> 160 (HH) 
ALP = Alkaline phosphatase; ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = International 
Normalized Ratio; TBIL = Total bilirubin; TSH = thyroid-stimulating hormone; T3 = thyroxine; T4 = 
triiodothyronine; ULN = upper limit of normal; WBC = white blood cell. LL, LLL, HH, HHH, HHHH = flags for 
low and high marked abnormalities. 
 
Elevated liver parameters during and up to 30 days after the EODB will be summarized: 
the number (%) of subjects meeting the criteria defined below within a given central 
laboratory sample will be tabulated by treatment group, including all ACT-541468 dose 
levels combined. Percentages will be based on the number of subjects at risk: those not 
meeting the criterion at baseline (or having a missing baseline value) and having at least 
one post-baseline value for a given parameter. 
• AST or ALT > 3 × ULN 
• AST or ALT > 5 × ULN 
• AST or ALT > 10 × ULN 
• TBIL > 1.5 × ULN and 2 × ULN 
• ALP > 1.5 × ULN 
• (ALT or AST > 3 × ULN) and INR > 1.5 × ULN 
• (ALT or AST > 3 × ULN) and (TBIL > 1.5 × ULN) 
• (ALT or AST > 3 × ULN) and (TBIL > 2 × ULN) 
10.3 Vital signs, weight and physical examination 
Each summary and listing will include unscheduled assessments. Assessments from 
supine and sitting position will be presented together. 
Absolute changes from baseline (mean of the two PSG nights at V2, run-in period) to last 
value on double-blind study treatment in vital signs (systolic and diastolic BP, pulse rate 


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and body temperature) will be summarized. The absolute values at baseline and last value 
on double-blind study treatment will also be summarized. 
The changes from baseline (V1 or last value before double-blind treatment) to V5 (or last 
value on or following double-blind study treatment) in body weight will be summarized. 
Physical examination abnormalities will be listed. 
10.4 Electrocardiograms 
Each electrocardiogram (ECG) summary and listing will include unscheduled 
assessments. 
The absolute change from baseline to last value in the double-blind treatment period for 
ECG parameters (QT corrected according to Fridericia’s formula, QT corrected 
according to Bazett’s formula, heart rate, PR, QRS) will be summarized. The absolute 
values at baseline and last value on double-blind study treatment will also be 
summarized. 
Marked ECG abnormalities are defined in the table below. 
The following summaries will be provided for each ECG parameter: 
• Number (%) of subjects having a marked ECG abnormality during the double-blind 
treatment period, 
• Number (%) of subjects having a marked ECG abnormality during the withdrawal 
period [see Section 13.2]. 
Percentages will be based on the number of subjects at risk: those not meeting the 
criterion at baseline (or having a missing baseline value) and having at least one 
post-baseline value for a given parameter. 
All ECG values for subjects with at least one marked ECG abnormality will be listed.  


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Table 4 
Marked abnormalities in ECG parameters 
ECG parameter 
Criteria for marked ECG abnormalities 
QTcF, QTcB (ms) 
> 450 and ≤ 480 (H) 
> 480 and ≤ 500 (HH) 
> 500 (HHH) 
> 30 and ≤ 60 increase from baseline (HH) 
> 60 increase from baseline (HHH) 
HR (bpm) 
< 45 (LLL) 
< 50 (LL) 
> 10 and ≤ 20 decrease from baseline (LL) 
> 20 decrease from baseline (LLL) 
PR (ms) 
> 200 (HH) 
QRS (ms) 
> 110 (HH) 
HR = Heart rate; QTcB = QT corrected according to Bazett’s formula; QTcF = QT corrected according to Fridericia’s 
formula; LL, LLL, H, HH, HHH = flags for low and high marked abnormalities. 
10.5 Withdrawal symptoms 
The following analyses will be based on the Withdrawal set. 
The Benzodiazepine Withdrawal Symptom Questionnaire (BWSQ) consists of 20 items. 
Response 
to 
each 
item 
is 
scored 
as 
‘No’ = 0, 
‘Yes - moderate’ = 1, 
‘Yes - severe’ = 2 meaning the BWSQ total score can range from 0 to 40. 
The BWSQ total score will be summarized using descriptive statistics for the absolute 
values and changes from V5 (2nd morning) to V6 (morning), and changes from baseline 
to each scheduled visit. 
The generalized MCP-Mod methodology will be used to explore the dose response 
relationship for the change from V5 to V6 in BWSQ total score. One linear model and 
various sigmoid Emax dose response models covering a wide range of monotonic shapes 
will be used to determine the different sets of testing contrasts. An ANCOVA model 
(using a fixed effect for treatment group [placebo and each ACT-541468 dose level], and 
a linear slope to adjust for BWSQ total score at V5) will be used to calculate estimates 
for 
d
μˆ  (i.e., LS mean estimates for each ACT-541468 dose level and placebo) and 
Ŝ (i.e., variance-covariance matrix of 
d
μˆ ). The LS means for each treatment group will 
be displayed along with associated standard errors and 95% CIs. For each 
ACT-541468 dose level comparison to placebo, the placebo-adjusted LS means will be 
displayed along with associated standard error, 95% CI and unadjusted two-sided 
p-value. The best fitting dose response model (linear or sigmoid Emax) will be selected 
based on the gAIC (smaller the better). For the selected dose response model, the 
predicted mean (95% CI) dose response profile for the change from V5 to V6 in BWSQ 
total score will be graphically displayed. 


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The number (%) of subjects with a BWSQ total score above 20 will be tabulated by visit.  
The number (%) of subjects with one or more BWSQ symptom scored as ‘severe’ will be 
tabulated by visit. 
In addition, withdrawal symptoms after double-blind study treatment discontinuation will 
be assessed through the incidence of AEs, and marked ECG abnormalities, occurring 
during the withdrawal period [see Section 13.2]. As described in their respective section, 
the incidence of AEs [Section 10.1] and marked ECG abnormalities [Section 10.4] 
occurring during the withdrawal period (between V5 and V6) will be summarized. 
The following analyses will be based on the SS. 
The generalized MCP-Mod methodology will be used to explore the dose response 
relationship on the incidence of AEs, and marked ECG abnormalities, separately, 
occurring during the withdrawal period. One linear model and various sigmoid Emax dose 
response models covering a wide range of monotonic shapes will be used to determine 
the different sets of testing contrasts. A logistic regression model using a fixed effect for 
treatment group (placebo and each ACT-541468 dose level) will be used to calculate 
estimates for 
d
μˆ  (i.e., LS mean estimates for each ACT-541468 dose level and placebo 
on the logit scale) and Ŝ (i.e., variance-covariance matrix of 
d
μˆ ). The best fitting dose 
response model (linear or sigmoid Emax) will be selected based on the gAIC (smaller the 
better). For the selected dose response model, the predicted mean (95% CI) dose response 
profile (on the logit scale) for incidence of AEs, and marked ECG abnormalities, 
occurring during the withdrawal period will be graphically displayed. 
10.6 Insomnia rebound effect 
The following will be based on the Withdrawal set. 
In order to assess the potential rebound insomnia, descriptive statistics are provided for 
the change from the worst PSG screening night (V2) to the first value after double-blind 
treatment (V6) in WASO, TST, and LPS. 
The generalized MCP-Mod methodology will be used to explore the dose response 
relationship for the occurrence of worsening from the worst PSG screening night (V2) to 
V6 in WASO, TST, and LPS, separately. One linear model and various sigmoid Emax 
dose response models covering a wide range of monotonic shapes will used to determine 
the different sets of testing contrasts. A logistic regression model using a fixed effect for 
treatment group (placebo and each ACT-541468 dose level) will be used to calculate 
estimates for 
d
μˆ  (i.e., LS mean estimates for each ACT-541468 dose level and placebo 
on the logit scale) and Ŝ (i.e., variance-covariance matrix of 
d
μˆ ). The best fitting dose 
response model (linear or sigmoid Emax) will be selected based on the gAIC (smaller the 
better). For the selected dose response model, the predicted mean (95% CI) dose response 


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profile (on the logit scale) for the occurrence of worsening from the worst PSG screening 
night (V2) to V6 in WASO, TST, and LPS will be graphically displayed. 
An occurrence of worsening in WASO/LPS is when the value at V6 is greater than the 
worst (i.e., highest) PSG screening night (V2) value. An occurrence of worsening in TST 
is when the value at V6 is less than the worst (i.e., lowest) PSG screening night (V2) 
value. 
10.7 Other safety parameters of interest 
10.7.1 Digit Symbol Substitution Test© 
The Digit Symbol Substitution Test (DSST)© is a measure of attention, perceptual speed, 
motor speed, visual scanning and memory. The total DSST score is the number of correct 
symbols entered. 
Absolute change from baseline (mean of the two PSG morning assessments at V2, run-in 
period) to Days 1&2, 15&16 and 28&29 (mean of the two PSG morning assessments at 
V3, V4 and V5, respectively) in total DSST score will be summarized by gender and 
overall. Absolute values will also be summarized. 
10.7.2 Karolinska Sleepiness Scale 
The Karolinska Sleepiness Scale (KSS) is a 9-point scale. The scale has a range from 
1 being ‘very alert’ to 9 being ‘very sleepy, great effort to keep awake, fighting sleep’. 
Absolute change from baseline (mean of the two PSG morning assessments at V2, run-in 
period) to Days 1&2, 15&16 and 28&29 (mean of the two PSG morning assessments at 
V3, V4 and V5, respectively) in KSS will be summarized by gender and overall. 
Absolute values will also be summarized. 
10.7.3 Sheehan Disability Scale© 
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). 
Absolute change from baseline (mean of the two PSG morning assessments at V2, run-in 
period) to Days 1&2, 15&16 and 28&29 (mean of the two PSG morning assessments at 
V3, V4 and V5, respectively) in SDS will be summarized by gender and overall. 
Absolute values will also be summarized. 
10.7.4 Neurological Examination 
The number (%) of subjects answering ‘Yes’ to the question ‘Is excessive sleepiness 
observed one hour after lights on?’ on the ‘Neurological Examinations’ page will be 
tabulated for each scheduled visit by gender and overall. 


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The time from treatment until the subject is considered safe to leave the center the next 
day will be summarized for each scheduled visit by gender and overall. 
10.7.5 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 
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. 
Number (%) of subjects with suicidal ideation, suicidal behavior, and/or self-injurious 
behavior without suicidal intent based on the C-SSRS during double-blind treatment will 
be tabulated. Percentages will be based on the number of subjects with at least one 
post-baseline C-SSRS assessment. 
Shifts from baseline showing any changes in suicidal ideation and suicidal behavior 
during double-blind 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. 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). 
10.8 Pharmacokinetic 
PK analyses will be performed based on the PK set. 
Descriptive statistics (n, mean, standard deviation, CV%, m [number of non-zero 
concentrations], geometric mean, geometric standard deviation, geometric CV%, median, 


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minimum 
and 
maximum) 
of 
ACT-541468 
plasma 
concentration 
collected 
approximately 9–10 h post-dose at V3, V4, and V5 will be provided for each time point 
(morning after the first and second PSG nights), by gender and overall. Note that the 
protocol recommends to draw a PK sample in the morning after the first PSG night 
(at V3, V4, and V5) only in subjects where excessive sleepiness is observed (according to 
investigator opinion) one hour after lights on. 
Concentration values below the lower limit of quantification (< 1.0 ng/mL) will be 
displayed in listings as zero with a flag and handled as zero in the calculations for mean, 
CV%, standard deviation, median, minimum, and maximum, but handled as missing for 
the calculation of the geometric mean, geometric standard deviation and geometric CV%. 
All individual ACT-541468 plasma concentration data will be listed. 
10.9 Exposure-safety analysis 
The exposure-safety relationship will be explored using C9-10h (plasma concentrations of 
ACT-541468 in the morning of the second PSG night at V3, V4, and V5) and will be 
based on the PK set. Safety parameters considered for this analysis will include selected 
AEs (e.g., somnolence and/or excessive sleepiness), changes from baseline in DSST, 
KSS, SDS, and morning sleepiness (VAS for ‘the way you feel this morning’). C9-10h will 
be assessed against each safety parameter using graphical presentations and/or statistical 
models with dose, time, gender, age and BMI as possible factors. 
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 IDMC and ISB charter, 
respectively. Safety and efficacy data supporting the review by IDMC will be provided 
by Actelion for the part of analyses that are blinded and by an ISAC for the unblinded 
part. 
12 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
12.1 Changes to the analyses planned in the study protocol 
The AEs and SAEs with onset between randomization and first day of study treatment 
will not be summarized. However, AEs emerging during the run-in period will be 
summarized instead. 
The change from baseline (second PSG morning at V2) to the last value on double-blind 
study treatment in C-SSRS© will not be summarized. However, the changes (shifts) from 
baseline to worst reported outcome in suicidal ideation and suicidal behavior will be 
summarized instead. 


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Analyses of secondary and exploratory efficacy endpoints will be based on the FAS 
(a broader analysis set) instead of the modified FAS which is linked only to the primary 
endpoint by requiring at least one WASO assessment at baseline and one at Days 1&2. 
12.2 Changes in the conduct of the study / data collection 
Not applicable. 
12.3 Clarifications concerning endpoint definitions and related variables or 
statistical methods 
In case not all subjects in the SS participate in the withdrawal period, a withdrawal set 
was added as an analysis set to analyze assessments (e.g., withdrawal symptoms and 
rebound effect) taken during the withdrawal period. 
13 GENERAL DEFINITIONS AND DERIVATIONS 
13.1 Treatment start and end dates 
Run-in single-blind placebo treatment start date is the earliest date of dose intake 
(i.e., date of capsules dispensed) recorded on the ‘Study Single Blind Treatment 
Dispensing & Accountability’ page at V2. 
Double-blind study treatment start (end) date is the earliest (latest) 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 date of dose intake 
(i.e., date of capsules dispensed) recorded on the ‘Study Single Blind Treatment 
Dispensing & Accountability’ page at V6. 
13.2 Study periods 
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 double-blind study treatment. 
The withdrawal period is defined as the time from two days after double-blind study 
treatment end date to one day after run-out single-blind placebo treatment end date. 
13.3 Study day 
The study day for an assessment or event will be calculated using the start date of 
double-blind study treatment as reference. 
For assessments/events occurring on or after the start date of double-blind study 
treatment, study day will be positive and will be calculated as: 
Study day (days) = Date of assessment/event – Start date of study treatment + 1 
The first day of double-blind study treatment is study day 1. 


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For all assessment/events occurring prior to the start date of double-blind study treatment, 
study day will be negative and will be calculated as: 
Study day (days) = Date of assessment/event – Start date of study treatment 
Study day will be displayed in the data listings. 
13.4 Baseline 
Baseline is the last non-missing assessment performed or value measured before or on the 
day of first dose of double-blind study treatment, unless otherwise defined in the specific 
analysis section. 
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. 
13.5 Absolute change from baseline 
The absolute change from baseline is defined as post-baseline value minus baseline 
value. A positive number indicates an increase as compared to baseline. 
13.6 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 and NAW is set as missing since subject is never at risk of either, and 
• LPS is set as 480 minutes which is equal to the duration of TIB. 
If the sTST is recorded as zero, then similarly: 
• sWASO and subjective NAW (sNAW) is set as missing, 
• sLSO is set as 480 minutes. 
13.7 Handling of missing/incomplete date and time fields 
This section describes some general principles to be followed in the case of missing or 
incomplete date/time. 
Missing or incomplete dates are handled as follows: 
• Dates are split into 3 parts: year, month and day. Year is the top-level, month is 
medium level and day is low level. If a part that is expected to contain a number is 
numeric but the value is outside a valid range, the complete date is handled as 
missing. For example, if date = 44Nov2000 the whole date is considered to be 
missing. 
• If a part that is expected to contain a number is not numeric, i.e., contains values such 
as ND, NA, --, ??, 2?, that part is considered to be missing. 
• If a part is missing, all lower level parts are considered to be missing. This means that 
a ddmmyy date ‘21ND99’ is considered as ‘----99’. 


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• If year is missing, then whole date is considered to be missing, unless reasonable 
assumptions support an imputation (imputation rule and rationale for assumption will 
be provided). 
Imputation of missing or incomplete dates/times are further specified in the associated 
analysis section. Unless noted otherwise, the non-imputed date/time will be reported in 
listings. 
13.8 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 (V2, V3, 
V4 or V5) are shown in the table below [Table 5]. 
Table 5 
Meaning of the first and last PSG end date at visit V2, V3, V4 or V5 
V2, V3, V4 or V5 
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: 
Screening: the 7 consecutive days immediately preceding the first PSG at V2 (i.e., 7–day 
window = [End date of first PSG at V2 – 7 days; End date of first PSG at V2 – 1 day]). 
Baseline (run-in period): the 7 consecutive days immediately preceding the first PSG at 
V3, but after V2 (i.e., [Max(End date of first PSG at V3 – 7 days; End date of last PSG at 
V2); End date of first PSG at V3 − 1 day]). The time window for Baseline may be less 
than 7 days. Baseline will be missing for any subjects without a PSG at V3. 
Week 1: the remaining days between Baseline and Week 2 time windows (i.e., [End date 
of last PSG at V3 + 1 day; End date of first PSG at V4 – 8 days]). The time window for 
Week 1 may be greater or less than 7 days. 
Week 2: the 7 consecutive days immediately preceding the first PSG at V4 (i.e., 7–day 
window = [End date of first PSG at V4 – 7 days; End date of first PSG at V4 – 1 day]). In 
the unlikely event that this time window overlaps with a PSG at V3 (i.e., time window is 
less than 7 days), then this time window will begin from the end date of the last PSG at 
V3 + 1 day, and Week 1 will be missing. Week 2 will be missing for any subjects who 
discontinue the study before V4. 
Week 3: the remaining days between Week 2 and Week 4 time windows (i.e., [End date 
of last PSG at V4 + 1 day; End date of first PSG at V5 – 8 days]). The time window for 
Week 3 may be greater or less than 7 days. 


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Week 4: the 7 consecutive days immediately preceding the PSG at V5 (i.e., 7–day 
window = [End date of first PSG at V5 − 7 days; End date of first PSG at V5 − 1 day]). 
In the unlikely event that this time window overlaps with a PSG at V4 (i.e., time window 
is less than 7 days), then this time window will begin from the end date of the last PSG at 
V4 + 1 day, and Week 3 will be missing. Week 4 will be missing for any subjects who 
discontinue the study before V5. 
For any subjects who discontinue the study between V3 and V4 (i.e., without a PSG 
at V4) 
Week 1: all days from the last PSG at V3 until last entry date in sleep diary 
(i.e., [End date of last PSG at V3 + 1 day; Last entry date in sleep diary]). 
For any subjects who discontinue the study between V4 and V5 (i.e., without a PSG 
at V5) 
Week 3: all days from the last PSG at V4 until last entry date in sleep diary 
(i.e., [End date of last PSG at V4 + 1 day; Last entry date in sleep diary]). 


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14 REFERENCES 
[Bastien 2001] Bastien C, Vallieres A, Morin C. Validation of the Insomnia Severity 
Index as an outcome measure for insomnia research. Sleep Med. 2001;2:297–307. 
[Bretz 2005] Bretz F, Pinheiro JC, Branson M. Combining multiple comparisons and 
modeling techniques in dose-response studies. Biometrics. 2005;61(3):738–48. 
[Bornkamp 2016] Bornkamp B, Pinheiro J, Bretz F. Documentation of the R Package 
‘DoseFinding’. 2016, Version 0.9–14. 
[Pinheiro 2006] Pinheiro J, Bornkamp B, Bretz F. Design and analysis of dose-finding 
studies combining multiple comparisons and modeling procedures. J Biopharm 
Stat. 2006;16(5):639–56. 
[Pinheiro 2014] Pinheiro J, Bornkamp B, Glimm E, Bretz F. Model-based dose finding 
under model uncertainty using general parametric models. Statistics in Medicine 
2014;33(10):1646–61. 


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DOCUMENT HISTORY 
 
Version 
Effective Date 
Reason 
Final 1.0 
19 December 2016 
Initial release 
Final 2.0 
3 July 2017 
Comments from dry-run review