Conditions: Insomnia Disorder
Keywords: insomnia elderly Polysomnography
Allocation: RANDOMIZED | Intervention model: CROSSOVER
Enrollment: 58
Healthy volunteers: no

Brief summary:
This study evaluates the dose response of ACT-541468 on the change of wake after sleep onset (WASO) assessed by polysomnography (PSG) on the first 2 days of each treatment period.

Detailed description:
The study consists of 3 phases: a screening phase, a double-blind treatment phase consisting of 5 periods, and a safety follow-up phase. Safety is monitored throughout the study.

Arms:
arm 1: Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D4, D2, D3, D1 and P, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout. arm 2: Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D2, P, D4, D3 and D1, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout. arm 3: Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D3, D1, D2, P and D4, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout. arm 4: Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: P, D4, D1, D2, D3, with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout. arm 5: Each subject participates in 5 treatment periods. On the evening of the first 2 days of each period they receive one dose (D) of ACT-541468 or placebo orally in the following order: D1, D3, P, D4 and D2 with D4 = the highest dose (50 mg) and D1 the lowest dose (5 mg). Each treatment period is separated from the next one by a 5- to 12-day washout.

Interventions: intervention 1: ACT-541468 intervention 2: Placebo
Intervention descriptions: intervention 1: Capsules for oral administration containing ACT-541468 at a strength of 5 mg, 10 mg or 25 mg intervention 2: Capsules for oral administration matching the ACT-541468 capsules

Protocol document:
Prot_000.pdf: 
Study Protocol AC-078A202 
Multi-center, Double-blind, Randomized, Placebo-controlled, 5-period, 5-treatment Crossover, 
Polysomnography Dose-response Study to Assess the Efficacy and Safety of 
ACT-541468 in Elderly Subjects With Insomnia Disorder. 
ClinicalTrials.gov Identifier NCT02841709 
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-078A202 
Multi-center, double-blind, randomized, placebo-controlled, 5-period, 5-treatment 
crossover, polysomnography dose-response study to assess the efficacy and safety of 
ACT-541468 in elderly subjects with insomnia disorder 
Study Phase: 
2 
EudraCT Number: 
2016-000827-16 
Status and version: 
Final Version 2 
Date: 
10 August 2016 
Document type 
Amended global protocol 
Actelion 
document 
number 
(Doc No.): 
D-16.394
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 staff, 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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SPONSOR CONTACT DETAILS 
Sponsor 
ACTELION Pharmaceuticals Ltd 
Gewerbestrasse 16 
CH-4123 Allschwil 
Switzerland 
Clinical Trial Physician 
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File 
ACTELION CONTRIBUTORS TO THE PROTOCOL 
Clinical Trial Scientist 
Clinical Trial Statistician 
Clinical Trial Physician 
Clinical Trial Pharmacologist 
Drug Safety Physician 






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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
ACT-541468 
Indication 
Insomnia Disorder 
Protocol number, study title 
AC-078A202 
Multi-center, double-blind, randomized, placebo-controlled, 5-period, 5-treatment crossover, 
polysomnography dose-response study to assess the efficacy and safety of ACT-541468 in elderly 
subjects with insomnia disorder.  
I agree to the terms and conditions relating to this study as defined in this protocol, the electronic 
Case Report Form (eCRF), 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 
CONTRACT RESEARCH ORGANIZATIONS INFORMATION ...................................3 
TABLE OF CONTENTS .....................................................................................................6 
LIST OF ABBREVIATIONS AND ACRONYMS ..........................................................13 
SUBSTANTIAL GLOBAL AMENDMENT 1 .................................................................16 
PROTOCOL SYNOPSIS AC-078A202 ............................................................................20 
PROTOCOL ......................................................................................................................34 
1 
BACKGROUND .........................................................................................................34 
1.1 
Insomnia disorder .........................................................................................34 
 
Definition ..........................................................................................34 
1.1.1
 
Epidemiology ....................................................................................34 
1.1.2
 
Treatments ........................................................................................35 
1.1.3
 
Unmet medical need .........................................................................37 
1.1.4
1.2 
Study treatment: ACT-541468 .....................................................................38 
 
The orexin system .............................................................................38 
1.2.1
 
ACT-541468 properties ....................................................................38 
1.2.2
1.2.2.1 
Nonclinical data .......................................................................38 
1.2.2.2 
Clinical studies ........................................................................40 
1.3 
Purpose and rationale of the study ................................................................43 
 
Purpose of the study ..........................................................................43 
1.3.1
 
Rationale for study ............................................................................43 
1.3.2
1.4 
Summary of known and potential risks and benefits ....................................44 
 
ACT-541468 .....................................................................................44 
1.4.1
 
Safety and risk-minimization measures taken in the present 
1.4.2
study ..................................................................................................45 
2 
STUDY OBJECTIVES ...............................................................................................46 
2.1 
Primary objective ..........................................................................................46 
2.2 
Secondary objective ......................................................................................46 
2.3 
Other objectives ............................................................................................46 


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3 
OVERALL STUDY DESIGN AND PLAN ...............................................................47 
3.1 
Study design .................................................................................................47 
 
Study phases .....................................................................................48 
3.1.1
3.1.1.1 
Screening phase .......................................................................48 
3.1.1.2 
Double-blind treatment phase .................................................48 
 
Study duration ...................................................................................49 
3.1.2
3.2 
Study design rationale ..................................................................................49 
3.3 
Site staff and their roles: polysomnography technologists ...........................50 
3.4 
Study committees .........................................................................................51 
4 
SUBJECT POPULATION ..........................................................................................51 
4.1 
Subject population description .....................................................................51 
4.2 
Rationale for the selection of the study population. .....................................51 
4.3 
Inclusion criteria ...........................................................................................52 
4.4 
Exclusion criteria ..........................................................................................53 
5 
TREATMENTS ..........................................................................................................54 
5.1 
Study treatment .............................................................................................54 
 
Investigational treatment and matching placebo: description 
5.1.1
and rationale ......................................................................................55 
 
Study treatment administration during the different study 
5.1.2
phases ................................................................................................55 
5.1.2.1 
Screening phase .......................................................................55 
5.1.2.2 
Double-blind treatment phase .................................................55 
 
Treatment assignment .......................................................................56 
5.1.3
 
Blinding ............................................................................................56 
5.1.4
5.1.4.1 
Screening phase .......................................................................56 
5.1.4.2 
Double-blind treatment phase .................................................57 
 
Unblinding ........................................................................................57 
5.1.5
5.1.5.1 
Unblinding for final analyses ..................................................57 
5.1.5.2 
Unblinding for IDMC review ..................................................57 
5.1.5.3 
Unblinding for suspected unexpected serious adverse 
reaction ....................................................................................57 
5.1.5.4 
Emergency procedure for unblinding ......................................57 
 
Study treatment supply .....................................................................58 
5.1.6
5.1.6.1 
Study treatment packaging and labeling .................................58 
5.1.6.2 
Study treatment distribution and storage .................................58 
5.1.6.3 
Study treatment dispensing .....................................................58 
5.1.6.4 
Study treatment return and destruction ...................................59 


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Study treatment accountability and compliance with study 
5.1.7
treatment ...........................................................................................59 
5.1.7.1 
Study treatment accountability ................................................59 
5.1.7.2 
Study treatment periods compliance .......................................59 
 
Study treatment dose adjustments and interruptions ........................60 
5.1.8
 
Premature discontinuation of double-blind study treatment .............60 
5.1.9
5.2 
Previous and concomitant therapy ................................................................61 
 
Definitions ........................................................................................61 
5.2.1
 
Reporting of previous/concomitant therapy in the eCRF .................61 
5.2.2
 
Allowed concomitant therapy ...........................................................61 
5.2.3
 
Forbidden concomitant therapy ........................................................61 
5.2.4
 
Forbidden concomitant diet and activities ........................................62 
5.2.5
6 
STUDY ENDPOINTS ................................................................................................62 
6.1 
Efficacy endpoints ........................................................................................62 
 
Primary efficacy endpoint .................................................................62 
6.1.1
 
Secondary efficacy endpoint .............................................................63 
6.1.2
 
Other efficacy endpoints ...................................................................63 
6.1.3
6.2 
Safety endpoints ...........................................................................................64 
6.3 
Pharmacokinetic endpoints ...........................................................................65 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS ................................................65 
7.1 
Study visits ...................................................................................................65 
 
Screening/re-screening ......................................................................65 
7.1.1
 
Unscheduled visits ............................................................................65 
7.1.2
7.2 
Study assessments .........................................................................................69 
 
Demographics ...................................................................................71 
7.2.1
 
Insomnia severity index ..................................................................71 
7.2.2
 
Efficacy assessments .........................................................................71 
7.2.3
7.2.3.1 
Polysomnography ....................................................................71 
7.2.3.2 
Sleep diary ...............................................................................73 
 
Safety assessments ............................................................................73 
7.2.4
7.2.4.1 
Weight and height ...................................................................73 
7.2.4.2 
Vital signs ................................................................................74 
7.2.4.3 
Physical examination ...............................................................74 
7.2.4.4 
Digit Symbol Substitution Test .............................................75 
7.2.4.5 
Sheehan Disability Scale .......................................................75 
7.2.4.6 
Karolinska Sleepiness Scale ....................................................75 
7.2.4.7 
Columbia Suicide Severity Rating Scale ..............................75 
7.2.4.8 
Neurological examinations ......................................................76 


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7.2.4.9 
ECG assessment ......................................................................76 
 
Laboratory assessments ....................................................................77 
7.2.5
7.2.5.1 
Type of laboratory ...................................................................77 
7.2.5.2 
Laboratory tests .......................................................................78 
 
Pharmacokinetic assessments ...........................................................79 
7.2.6
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / MEDICAL 
CARE ..........................................................................................................................79 
8.1 
Study completion as per protocol .................................................................79 
8.2 
Premature withdrawal from study ................................................................79 
8.3 
Premature termination or suspension of the study ........................................80 
8.4 
Medical care of subjects after study completion / withdrawal from 
study ..............................................................................................................81 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS ...........................81 
9.1 
Adverse events ..............................................................................................81 
 
Definition of adverse events .............................................................81 
9.1.1
 
Intensity of adverse events ................................................................81 
9.1.2
 
Relationship to study treatment ........................................................82 
9.1.3
 
Reporting of adverse events ..............................................................82 
9.1.4
 
Follow-up of adverse events .............................................................83 
9.1.5
9.2 
Serious adverse events ..................................................................................83 
 
Definitions of serious adverse events ...............................................83 
9.2.1
 
Reporting of serious adverse events .................................................83 
9.2.2
 
Follow-up of serious adverse events .................................................84 
9.2.3
 
After the 30-day follow-up period ....................................................84 
9.2.4
 
Reporting procedures ........................................................................84 
9.2.5
9.3 
Study safety monitoring ................................................................................85 
10 STATISTICAL METHODS .......................................................................................85 
10.1 
Analysis sets .................................................................................................85 
 
Screened Analysis Set .......................................................................85 
10.1.1
 
Randomized Analysis Set .................................................................85 
10.1.2
 
Full Analysis Set ...............................................................................85 
10.1.3
 
Modified FAS ...................................................................................86 
10.1.4
 
Per-protocol Analysis Set .................................................................86 
10.1.5
 
Safety Set ..........................................................................................86 
10.1.6
 
PK Analysis Set ................................................................................86 
10.1.7
 
Usage of the analysis sets .................................................................86 
10.1.8
10.2 
Variables .......................................................................................................87 


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Primary efficacy variable ..................................................................87 
10.2.1
10.2.1.1 
Missing values .........................................................................88 
 
Secondary efficacy variable ..............................................................88 
10.2.2
10.2.2.1 
Missing values .........................................................................88 
 
Other exploratory efficacy variables .................................................88 
10.2.3
10.2.3.1 
Sleep-maintenance endpoint ....................................................88 
10.2.3.2 
Sleep-initiation endpoint .........................................................89 
10.2.3.3 
Total sleep time endpoint ........................................................89 
10.2.3.4 
SQ ............................................................................................89 
10.2.3.5 
Sleep architecture ....................................................................89 
10.2.3.6 
Sleep continuity .......................................................................89 
10.2.3.7 
SE ............................................................................................89 
10.2.3.8 
Next-day performance .............................................................90 
 
Safety variables .................................................................................90 
10.2.4
10.2.4.1 
Adverse events ........................................................................90 
10.2.4.2 
Laboratory data ........................................................................90 
10.2.4.3 
ECG .........................................................................................90 
10.2.4.4 
Other safety parameters of interest ..........................................90 
10.2.4.5 
Vital signs ................................................................................91 
10.2.4.6 
Body weight ............................................................................91 
 
Other variables ..................................................................................91 
10.2.5
10.3 
Description of statistical analyses .................................................................91 
 
Overall testing strategy .....................................................................91 
10.3.1
 
Analysis of the primary efficacy variable .........................................91 
10.3.2
10.3.2.1 
Hypotheses and statistical model ............................................91 
10.3.2.2 
Handling of missing data .........................................................92 
10.3.2.3 
Main analysis ...........................................................................92 
10.3.2.4 
Supportive/sensitivity analyses ...............................................93 
 
Analysis of secondary efficacy variable ...........................................94 
10.3.3
 
Analysis of other exploratory efficacy variables ..............................94 
10.3.4
10.3.4.1 
Subgroup analyses ...................................................................94 
 
Analysis of the safety variables ........................................................94 
10.3.5
10.3.5.1 
Analysis of safety and tolerability endpoints ..........................94 
10.3.5.2 
Adverse events ........................................................................94 
10.3.5.3 
Laboratory variables ................................................................95 
10.3.5.4 
ECG .........................................................................................95 
10.3.5.5 
Vital signs ................................................................................95 
10.3.5.6 
Other safety parameters of interest ..........................................95 
10.3.5.7 
Exposure-safety analysis .........................................................96 
10.3.5.8 
Pharmacokinetic ......................................................................96 


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10.4 
Interim analyses ............................................................................................96 
10.5 
Sample size ...................................................................................................96 
11 DATA HANDLING ....................................................................................................97 
11.1 
Data collection ..............................................................................................97 
11.2 
Maintenance of data confidentiality .............................................................98 
11.3 
Database management and quality control ...................................................98 
12 PROCEDURES AND GOOD CLINICAL PRACTICE .............................................99 
12.1 
Ethics and Good Clinical Practice ................................................................99 
12.2 
Independent Ethics Committee / Institutional Review Board ......................99 
12.3 
Informed consent ..........................................................................................99 
12.4 
Compensation to subjects and investigators ...............................................100 
12.5 
Protocol adherence/compliance ..................................................................100 
12.6 
Protocol amendments .................................................................................101 
12.7 
Essential documents and retention of documents .......................................101 
12.8 
Monitoring ..................................................................................................102 
12.9 
Investigator Site File ...................................................................................103 
12.10 
Audit ...........................................................................................................103 
12.11 
Inspections ..................................................................................................103 
12.12 
Reporting of study results and publication .................................................104 
13 REFERENCES ..........................................................................................................106 
14 APPENDICES ...........................................................................................................112 
 
LIST OF TABLES 
 
Table 1 
Latin square design sequences ..........................................................47 
Table 2 
Number of capsules taken according to treatment dose ...................56 
Table 3 
Visits and assessments schedule .......................................................67 
Table 4 
Usage of analysis datasets .................................................................87 
 
LIST OF FIGURES 
 
Figure 1 
Study design ......................................................................................49 
Figure 2 
Candidate dose-response curves .......................................................93 
 


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LIST OF APPENDICES 
 
Appendix 1  
Marked laboratory abnormalities ....................................................112 
Appendix 2  
Alcohol Restrictions during the study ............................................116 
Appendix 3  
Caffeine content of common beverages ..........................................117 
Appendix 4  
Forbidden and restricted concomitant medications ........................118 
Appendix 5 
Digit Symbol Substitution Test ....................................................121 
Appendix 6  
Insomnia Severity Index ...............................................................122 
Appendix 7  
Sheehan Disability Scale ..............................................................123 
Appendix 8  
Karolinska Sleepiness Scale ...........................................................124 
Appendix 9  
Sleep diary ......................................................................................125 
Appendix 10  
Summary table of efficacy variables ..............................................127 


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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 
AST  
Aspartate aminotransferase 
AUC  
Area under the plasma concentration-time curve 
AUC0-∞  
Area under the plasma concentration-time curve from zero to 
infinity 
BCRP  
Breast Cancer Resistance Protein 
BMI  
Body mass index 
BP  
Blood pressure 
bpm  
Beats per minute 
CBT  
Cognitive behavioral therapy 
Cmax  
Maximum 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 
eCRF  
Case Report Form (eCRF, electronic CRF) 
EMA  
European Medicines Agency 
Emax  
Effect maximum 
EOS  
End of Study 


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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 
MCP-Mod  
Multiple Comparison Procedure – Modeling 
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 
PD  
Pharmacodynamics 
P-gP  
P-glycoprotein 1 
PI  
Principal investigator 
PK  
Pharmacokinetics 
PLMAI  
Periodic limb movement with arousal index 
PPS  
Per-protocol Set 
PRO  
Patient-Reported Outcome 


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PSG 
Polysomnography 
QS 
Quality System 
QTC 
Corrected QT interval 
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 
sNA 
Self-reported number of awakenings 
SOC 
System organ class 
SOP 
Standard operating procedure 
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 
t½ 
Half-life 
TEAE 
Treatment-emergent adverse event 
tmax 
Time to reach maximum plasma concentration 
TST 
Total sleep time 
ULN 
Upper limit of the normal range 
USPI 
US package insert 
V 
Visit 
VAS 
Visual analog scales 
VHP 
Voluntary Harmonization Procedure  
WASO 
Wake after sleep onset 


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PROTOCOL SYNOPSIS AC-078A202 
TITLE 
Multi-center, double-blind, randomized, placebo-controlled, 
5-period, 
5-treatment 
crossover, 
polysomnography 
dose-response study to assess the efficacy and safety of 
ACT-541468 in elderly 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) assessed by polysomnography (PSG) on 
the first two days of each treatment period. 
Secondary objective 
The secondary objective of the study is to evaluate the 
dose response of ACT-541468 on latency to persistent sleep 
(LPS) on the first two days of each treatment period. 
Other objectives 
Other objectives are described in Section 2.3.  
DESIGN 
Multi-center, double-blind, randomized, placebo-controlled, 
5-period, 
5-treatment 
crossover, 
polysomnography 
dose-response Phase 2 study in elderly subjects with insomnia 
disorder. 
PHASES 
The screening phase lasts a minimum of 14 days and a 
maximum of 28 days. It starts with the signature of the 
Informed Consent Form 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 (V) 1, 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 and until V2.  
The run-in period occurs between Day −14 and Day −1 and 
starts with V2. V2 consists of two 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.  


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The double-blind treatment phase starts with the first dose of 
double-blind study treatment in the first evening of the 
Randomization visit (V3) and ends in the second morning of 
V7. It consists of five treatment periods, each consisting of 
two consecutive PSG nights on the assigned study treatment 
followed by a 5- to 12-day washout. 
The End of Treatment (EOT) is reached in the second 
morning of V7, after the last dose of double-blind treatment 
and after all morning assessments have been performed. 
The safety follow-up phase starts after EOT and lasts at least 
30 days (i.e., until the second follow-up telephone call). A first 
telephone call is done 5 days (+7 days) after EOT to collect 
treatment-emergent adverse events (TEAEs) from last study 
treatment dose.  
The End of Study (EOS) for a single subject is defined as the 
date of the 30-day follow-up telephone call. 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 16 weeks (see diagram below). 
 
V = visit; ▬ polysomnographic (PSG) nights; D = dose; P = placebo. 


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PLANNED DURATION 
Approximately 9 months from first subject first visit to last 
subject last visit. 
SITE(S) 
/ COUNTRY(IES) 
Approximately 10 sites in two countries (US, Germany). 
SUBJECTS/SEQUENCE
S 
Approximately 50 subjects will be centrally randomized to five 
different sequences of five study treatments according to a 
Latin square design. 
INCLUSION CRITERIA 
1. Signed informed consent prior to any study-mandated 
procedure (V1). 
2. Male or female aged ≥ 65 years (V1). 
3. Body mass index (BMI): 18.5 ≤ BMI (kg/m2) < 32.0 (V1). 
4. Insomnia disorder according to Diagnostic and Statistical 
Manual of Mental Disorders-5 criteria (V1). 
5. 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 
• Total sleep time (TST) of ≤ 6.5 h  
6. Insomnia Severity Index (ISI) score greater than or equal 
to 15 (V1).  
7. Willing to comply with all aspects of the study protocol 
(V1). 
8. Ability to communicate well with the investigator, to 
understand the study requirements and judged by the 
investigator to be alert and oriented to person, place, time 
and situation (V1). 
9. 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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10. Usual bedtime between 21:30 and 00:30 as reported on the 
sleep diary completed at home between V1 and V2 (to be 
checked at V2). 
11. Regular time in bed between 6 and 9 hours as reported on 
the sleep diary completed at home between V1 and V2 (to 
be checked at V2). 
12. Meeting the following sleep parameters on the two PSG 
nights (V2): 
• Mean LPS ≥ 20 minutes (with neither of the two nights 
< 15 minutes), and 
• Mean WASO ≥ 30 minutes (with neither of the two 
nights < 20 minutes), 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 
on ≥ 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 ≥ three time zones within 1 week prior to the 
screening visit, or planned travel ≥ three time zones during 
study (V1). 
6. Hematology or biochemistry test results deviating from 
the normal range to a clinically relevant extent as per 
judgment of the investigator (V1, V2)  
7. Aspartate 
aminotransferase 
and/or 
alanine 
aminotransferase > 2 × the upper limit of normal (ULN) 
and/or direct bilirubin > 1.5 × ULN (V1, V2). 


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8. 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). 
9. Unstable medical condition, significant medical disorder 
or acute illness within 1 month prior to the screening visit 
that in the opinion of the investigator could affect the 
subject’s safety or interfere with the study assessments 
(V1). 
10. Systolic blood pressure (BP) > 150 mmHg and diastolic 
BP > 90 mmHg (V1,V2). 
11. Resting pulse rate < 50 or ≥ 100 beats per minute (V1, 
V2). 
12. Any of the following conditions related to corrected QT 
(QTc) intervals (V1,V2): 
• A prolonged QTc interval (QTc greater than 450 ms). 
In case of QTc greater than 450 msec on the first 
electrocardiogram (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). 
13. 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). 
14. 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, neurological disorders which 
may impact sleep, motor performance, or cognition, 
including Parkinson disease, predementia, dementia, other 
neurodegenerative disorders, and stroke, (V1).  
15. Treatment with another investigational drug within 
1 month prior to V1. 
16. Known hypersensitivity or contraindication to drugs of the 
same class of the study treatment or to any excipients of 
the study drug formulation (V1). 
17. 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, including 
over-the-counter (OTC) medication and herbal medicines. 
18. Cognitive behavioral therapy (CBT) within one month 
prior to V1.  
19. Treatment with moderate to strong cytochrome P450 
(CYP) 3A4 inhibitors, CYP3A4 inducers, sensitive 
CYP3A4 substrates, P-glycoprotein 1 (P-gP) substrates, 
Breast Cancer Resistance Protein (BCRP) substrates and 
CYP2B6 substrates [as defined in Appendix 4] within 
1 week prior to V1 until 24 h after EOT.  
20. Consumption of grapefruit and grapefruit juice within 
1 week prior to V1.  
21. 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).  
22. 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). 
23. Heavy tobacco use (≥ 10 cigarettes per day) and/or 
inability to refrain from smoking for at least 14 hours 
during the night (V1).  


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24. Apnea/hypopnea index ≥ 15/h on the first PSG screening 
night according to the American Academy of Sleep 
Medicine (AASM) criteria (V2).  
25. Apnea or hypopnea event (according to AASM criteria) 
associated with oxygen saturation by pulse oximetry 
< 80%, on the first PSG screening night (V2). 
26. Periodic limb movement with arousal index ≥ 15/h on the 
first PSG screening night (V2). 
STUDY TREATMENTS 
Investigational treatment 
ACT-541468 capsules will be administered orally, once daily 
in the first two evenings of the assigned 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. 
Placebo 
Placebo capsules matching ACT-541468 will also be 
administered orally, once daily in the first two evenings of the 
assigned treatment period and in addition at V2. 
Number of capsules taken according to treatment dose 
 
Placebo 
(0) 
5 
10 
25 
Placebo (0) 
2 
0 
0 
0 
5 
1 
1 
0 
0 
10 
1 
0 
1 
0 
25 
1 
0 
0 
1 
50 
0 
0 
0 
2 
CONCOMITANT 
THERAPY 
(MEDICATION, DIET, 
ACTIVITIES) 
The following therapies are forbidden during the study: 
• Treatment with another investigational drug until the end of 
the safety follow-up phase.  
• Prohibited CNS-active medications, including OTC and 
herbal medicines, until 24 hours after EOT [see 
Appendix 4]. 
• Treatment with moderate to strong CYP3A4 inhibitors, 
CYP3A4 inducers, sensitive CYP3A4 substrates (i.e., have 
Treatment  
dose (mg) 
Dose strength  
(mg) 


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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/day 
– after 14:00 on the days of PSG nights 
• Alcohol consumption [more details in Appendix 2]: 
– > 2 drinks a day 
– 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(s) 
The primary efficacy endpoint of this study is defined as the 
change of WASO from Baseline1 to Days 1 and 22 as 
determined by PSG. 
WASO is the time (minutes) 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 minutes (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 
                                                 
1 ‘Baseline’ is the mean of the two PSG nights during run-in period (V2). 
2 ‘Days 1 and 2’ are the mean of the corresponding two PSG treatment nights for a given treatment period. 


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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 assessors. 
Secondary efficacy endpoints 
The secondary efficacy endpoint of this study is defined as the 
change from Baseline1 to Days 1 and 22 in mean LPS. 
LPS is the time (minutes) from start of recording to the 
beginning of the first continuous 20 epochs (i.e., 10 minutes) 
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. 
Other efficacy endpoints 
Other efficacy endpoints are described in Section 6.1.3. 
Safety endpoints 
• TEAEs3 up to 5 days after study treatment discontinuation. 
• 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. 
• AEs of special interest starting or worsening after the first 
dose of the first treatment period until EOS (and after 
adjudication by the ISB): 
– Narcolepsy-like 
events 
(e.g., 
excessive 
daytime 
sleepiness, cataplexy) 
– Complex sleep behavior events. 
– Suicidal thoughts and/or behaviors. 
• Change from Baseline (mean of the first and second 
morning values after the two PSG nights at V2, run-in 
period) to Days 1 and 24 of each period in vital signs 
(systolic and diastolic BP, pulse rate and body 
                                                 
3 A TEAE is any AE temporally associated with the use of study treatment from Day 1 until 5 days after last study drug 
intake in each treatment period and until 5 days after study treatment discontinuation whether or not considered 
by the investigator as related to study treatment. 
4 Days 1 and 2 refers to the mean of the first and second morning values after the two PSG nights of a treatment period. 


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temperature). 
• Change from Baseline (V1) to the second morning after the 
PSG nights at V7 in body weight. 
• Treatment-emergent ECG abnormalities from V3 until 
EOT. 
• Change from Baseline (V2, second morning) to the second 
morning after the PSG nights at V3, V4, V5, V6 and V7 in 
ECG parameters.  
• Marked laboratory abnormalities on double-blind study 
treatment. 
• Change from Baseline (V2, second morning) to the second 
morning after the PSG nights at V3, V4, V5, V6 and V7 in 
laboratory variables. 
• Change from Baseline (mean of the two PSG nights at V2, 
run-in period) to Days 1 and 24 of each treatment period in: 
– 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. 
• Incidence of most severe suicidal ideation and suicidal 
behavior according to the C-SSRS for each treatment 
group. 
Pharmacokinetic endpoints 
Concentration of ACT-541468 (and possibly several of its 
metabolites) approximately 9–10 hours post-dose at V3, V4, 
V5, V6 and V7. 
ASSESSMENTS 
Refer to the schedule of assessments in Table 3. 
STATISTICAL 
METHODOLOGY 
Analysis Sets 
Screened Analysis Set 
The Screened Analysis Set includes all subjects who are 
screened and have a subject identification number. 
Randomized Analysis Set 
The Randomized Analysis Set includes all subjects who have 
been assigned to a study treatment. 


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Full Analysis Set 
The Full Analysis Set (FAS) includes all subjects from the 
Randomized Analysis Set who received any dose of study 
treatment. 
Modified FAS 
The modified FAS (mFAS) includes all patients from the FAS 
and who have at least one WASO assessment at Baseline and 
at least one at Days 1 and 2 of any given treatment period. 
Per-protocol Analysis Set 
The Per-protocol Analysis Set comprises all subjects from the 
mFAS, who have two consecutive WASO values at both 
Baseline and Days 1 and 2 of each treatment period, and who 
complied with the protocol sufficiently to allow relevant 
assessment of treatment effects. 
Safety Set 
The Safety Set (SS) includes all randomized subjects who 
received at least one dose of study treatment. Subjects will be 
evaluated according to the actual dose they received, which 
may differ from the randomly assigned dose. 
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. 
Primary efficacy analysis 
The primary statistical analysis will be performed on the 
mFAS.  
The study is using the generalized Multiple Comparison 
Procedure – Modeling (MCP-Mod) approach [Bretz 2005, 
Pinheiro 
2006, 
Pinheiro 
2014], 
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 (based on the primary efficacy endpoint). The 
generalized approach is appropriate for this study design where 


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each patient receives different doses in a sequence. A 
univariate dose-response relationship is modeled based on the 
mean change from baseline in WASO at each dose. 
The 
following 
pre-defined 
dose-response 
models 
are 
considered: one linear, and three Emax models. The analysis 
will be performed using the R-package DoseFinding. A 
dose-response relationship is demonstrated if at least one of the 
four multiple contrast tests 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 minutes with a 95% confidence interval excluding 0. 
The primary endpoint will be summarized by dose using the 
mean, median, standard deviation, standard error, quartiles, 
minimum, maximum and 95% confidence limits of mean. 
Secondary efficacy analysis 
Similarly, an MCP-Mod-based analysis will be conducted on 
the secondary endpoint. 
Treatment effects on the secondary efficacy endpoint will also 
be assessed using a mixed model similar as for the primary 
analysis  
Safety analysis 
Safety analyses will be performed on the SS. Observations 
(e.g. AEs, laboratory data) occurring within a treatment period 
(from the time of dosing to the time immediately prior to the 
next dose) will be assigned to the dose taken in that period. 
Adverse events: AEs and SAEs in subjects who were screened 
but not part of the SS will be listed. 
The number and percentage of subjects experiencing TEAEs 
and SAEs will be tabulated by dose 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 


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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 screening and first day of 
double-blind 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 dose 
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 dose providing their incidence and 
frequency.  
The 
number 
and 
percentage 
of 
subjects 
with 
treatment-emergent laboratory abnormalities will be tabulated 
by dose. 
Other endpoints analysis 
Treatment effects on other endpoints will be evaluated and 
described in detail in the statistical analysis plan. 
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 enrollment of the first subject into the 
study. The composition and operation of the IDMC is 


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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 
1.1 Insomnia disorder 
 Definition 
1.1.1
The definition of insomnia disorder used in the protocol is the one described in the 
Diagnostic and Statistical Manual of Mental Disorders (DSM) [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.” 
 Epidemiology 
1.1.2
Insomnia is a common problem in the elderly population. Population-based 
epidemiological studies suggest that insomnia symptoms (difficulties initiating sleep, 
early morning awakenings, and dissatisfaction with sleep) increase with age 
[Ohayon 2001]. However, the decrease in ability to sleep is associated with factors 
associated with aging, such as depressed mood, respiratory symptoms, poor perceived 
health and physical disability, not with age per se. A stagnation or decline in insomnia 
disorder diagnosis in age groups ≥ 65 years is seen, as the negative consequences of 
insomnia symptoms on functioning and well-being are likely less endorsed in the elderly 
than in adults [Ancoli-Israel 2009, Ohayon 2009]. Prevalence of insomnia disorder in 
elderly populations ≥ 65 years based on DSM-IV criteria in Europe was estimated at 
approximately 8% [Ohayon 2010, Ohayon 2002, Schlack 2013]. Insomnia in the elderly 
is twice as common Lopez-Torres Hidalgo 2012]. 
Changes in sleep architecture, such as slow-wave sleep decreases, as well changes in 
sleep parameters such as increase in sleep onset latency and decreases in sleep 
maintenance and efficiency have been described in elderly people. Those changes are 
associated with age, occur in middle age and stabilize from 60 years onwards. Only sleep 
efficiency continues to decline with age [Ohayon 2004]. 
The co-morbidities associated with insomnia in the elderly have been examined in a 
number of studies [Ohayon 2005, Dam 2008, Blackwell 2006]. Elderly individuals with 
insomnia symptoms have poor physical and mental health, as well as an increased risk of 


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mortality, at least in older women. Disrupted sleep in the elderly results in reduced 
physical performance and impairment in cognitive functioning. Insomnia in elderly 
subjects may also precipitate falls and be an important factor for nursing-home placement 
due to associated injuries [McCall 2004]. After adjustment for many confounders, 
including the use of antidepressant or benzodiazepine, there is a 30–40% increased risk of 
subsequent falls with short sleep duration and poor sleep efficiency.  
 Treatments 
1.1.3
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 it may be limited by the lack of therapists with 
adequate training and experience [Pigeon 2007, Schutte-Rodin 2008]. Pharmacological 
options may be warranted. 
Prescription of sleep medications (hypnotics) 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 gamma-aminobutyric acid 
(GABA) type A receptor subtypes [Lieberman 2007]. Drugs in this class, which include 
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 incoordination, 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 sub-type, while eszopiclone 
shows affinity for the alpha 2 and 3 receptor sub-types [Nutt 2006]. All of these drugs 
reduce latency to sleep onset, but zolpidem CR and eszopiclone have also been shown to 
reduce wake after sleep onset (WASO), reflecting an improvement in sleep maintenance 


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[Ambien® USPI, Lunesta® USPI]. Although they have less impact on sleep architecture, 
possibly by virtue of their receptor selectivity, the drugs in this group have similar 
adverse effects as benzodiazepines. For example, 15% of subjects experienced 
anterograde amnesia after zolpidem administration, and in approximately 50% of those 
patients, it occurred within 30 minutes [Praplan-Pahud 1990]. Zolpidem and other drugs 
in this group also are known to impair postural stability as much as benzodiazepines and 
may increase the risk of falling [Mets 2010]. This represents a safety concern for older 
people who use hypnotics [Agostini 2004]; about 1% of falls result in hip fractures that 
lead to restricted mobility for 60%, increased functional dependence for 25%, and death 
within 6 months for 25 % of the patients [Avidan 2005]. In addition to these concerns, in 
2007 the US Food and Drug Administration (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 [FDA 2007]. 
Newer hypnotics that do not act at the GABA receptor have been developed. The 
melatonin 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 subjects 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 act through selective 
histamine-1 receptor blockade [Scharf 2008].  
Suvorexant is an oral dual orexin receptor antagonist (DORA) that was approved by the 
FDA (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]. 
Generally, use of sleep medications among all subjects increases with age and is highest 
in the elderly [Ohayon 2002, Ohayon 2010]. In Germany, 7.4% of women and 5% of 
men in the age group of 60–79 years reported consumption of sleep medications at least 
once per week [Schlack 2013]. In Italy, the prevalence of sleep medication use in the 


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elderly is approximately twice higher than in Germany, and half of the subjects using 
sleep medications report daily use [Ohayon 2002]. Benzodiazepines indicated for anxiety 
or sleep disorders as well as zolpidem and zopiclone were the most common sleep 
medications accounting for about three-quarters of all self-reported sleep medications in 
those countries [Ohayon 2002, Ohayon 2010]. In the US, the use of sleep medications 
increases with age. Up to 7% in people aged 80 years and more report to use prescription 
sleep medications in the 30 days prior to a survey [Chong 2013]. 
Use of benzodiazepines and zolpidem has been correlated with an increased risk of 
falling and a higher serum concentration of benzodiazepines or zolpidem has been noted 
in those who fall compared with those who do not fall [McCall 2004]. Despite the 
increased risk for falls, benzodiazepines and generic antidepressants (such as trazodone) 
are among the most popular classes of medications prescribed for elderly patients in the 
US. An analysis of inappropriate (risk > benefit) psychotropic prescribing determined 
that antidepressant agents, anti-anxiety drugs, and sedative-hypnotics were the drug 
classes most frequently prescribed to ambulatory elderly patients [Mort 2000]  
 Unmet medical need 
1.1.4
There are effective treatments for insomnia in the elderly [Schutte-Rodin 2008]. 
However, currently available treatments are limited to short-term use with the exception 
of eszopiclone (in the US), and caution and dose reduction are often advised in the 
elderly. Pharmacological treatments that address sleep onset problems alone do not 
provide relief to people with sleep maintenance difficulties, and treatments indicated for 
those with sleep maintenance problems may be associated with risks of cognitive 
impairment, postural instability, next-day residual sedation and increased risk of falls 
[Neubauer 2014]. This represents an important unmet medical need. Moreover, the use of 
benzodiazepines and benzodiazepine receptor agonists has been also correlated with an 
increased risk of falling [McCall 2004] leading to hip and femur fractures, to increased 
disability and use of healthcare resources. There is also 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. ACT-541468 
is a DORA that has been investigated so far in nonclinical and early-phase clinical 
studies. Results of nonclinical and early-phase clinical studies [Section 1.2.2] warrant the 
evaluation of ACT-541468 as a sleep medication in order to investigate its efficacy and 
safety in insomnia as well as its potential lack of next-day impairment or significant 
abuse liability. 


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1.2 Study treatment: ACT-541468 
 The orexin system 
1.2.1
The orexin system is involved in the regulation of sleep and arousal by the central 
nervous system (CNS) and is currently being targeted in the development of new 
therapies for sleep disorders. 
The neuropeptides orexin-A and orexin-B are synthesized in the lateral hypothalamic 
areas [de Lecea 1998] and activate the orexin-1 and orexin-2 receptors [Kilduff 2000]. 
Nerve fibers from orexin neurons make projections to the basal forebrain, corticolimbic 
structures, and brainstem, particularly to those regions related to waking and regulation of 
sleep [Hagan 1999, Sakurai 2007]. Infusing exogenous orexins into cerebral ventricles in 
rats leads to enhanced behavioral activity, arousal, delayed onset of sleep, and 
maintenance of cortical activation [Hagan 1999, Samson 2010]. Orexin-producing 
neurons are active during wakefulness and fall quiet during sleep [Sakurai 2007]. 
Orexin-A levels in the cerebrospinal fluid of several species fluctuate according to 
circadian rhythms, being highest during active wake periods [Zeitzer 2003, 
Desarnaud 2004]. 
Orexins may be implicated in the genesis of narcolepsy, due to findings of low cerebral 
spinal fluid orexin levels in most patients with unequivocal narcolepsy [Mignot 2002] 
and near-complete atrophy of orexin neurons in post-mortem brains of patients with 
narcolepsy [Thannickal 2000], coupled with the observation of behavioral phenotypes 
consistent with narcolepsy in multiple animal models of orexin deficiency or dysfunction 
[Lin 1999].  
One DORA, suvorexant, has shown efficacy in subjects with insomnia, and is approved 
notably in the US. For a description of the effects of suvorexant, refer to Section 1.1.3. 


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1.3 Purpose and rationale of the study 
 Purpose of the study 
1.3.1
The main purpose of this dose-response study is to define the ACT-541468 dose(s) that 
will show a favorable efficacy and safety profile and to assess the safety and tolerability 
of the compound in elderly subjects with insomnia disorder. 
The dose to be studied in future clinical trials will be established based on the change in 
objectively assessed WASO and safety data, such as next-day residual effect from 
baseline versus placebo.  
 Rationale for study 
1.3.2
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 in adults 
and elderly [Citrome 2014]. Another DORA, almorexant, demonstrated objective and 
subjective improvements in sleep maintenance and TST compared with placebo in two 
studies in subjects with primary insomnia. 
Elderly people exhibit a different sleep pattern than younger adults and the sensitivity of 
elderly and younger adults to the PD properties of a compound may differ. European 
guidelines therefore advise that the efficacy and the safe dose (range) of a drug must be 
defined in elderly, and they recommend a specific dose-finding study in elderly subjects 
[EMA 2011]. This dose-finding study in the elderly will be performed in addition to a 
dose-finding study in adult subjects.  
The dose levels of 5, 10, 25, and 50 mg of ACT-541468 planned for this study were all 
investigated in Phase 1 studies, with clear sleep-promoting effects starting at 25 mg in 
healthy adult subjects. In healthy elderly subjects who received a single morning dose of 
15 mg, effects lasting > 12 h were observed on saccadic peak velocity, the most sensitive 
PD parameter. All other PD variables showed no effect at 15 mg. No effects on the VAS 
Bond & Lader subjective alertness were observed at 5, 15 and 25 mg in healthy elderly 
subjects. 


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The highest dose tested after evening administration in healthy elderly subjects was 
25 mg for 7 days and was well tolerated with no more AEs reported by the elderly 
subjects than by the healthy young adults at similar doses. After morning administration 
in healthy young adults, single doses up to 200 mg and doses up to 75 mg for 5 days were 
well tolerated. The t½ is longer in healthy elderly than in healthy young adults. However, 
the study drug will be administered for periods of 2 days in a sleep center and subjects 
will be discharged from the center after a neurological examination. With these 
risk-minimization measures, the good tolerability of ACT-541468 at higher doses than 
50 mg in healthy young adults, the lower percentage of AEs reported by elderly subjects 
than by young adults after multiple 25 mg doses, and consistent CNS-depressant effects 
observed starting only from 25 mg in young and elderly subjects, a dose of 50 mg 
administered in a sleep center can be tested in elderly subjects with insomnia disorder to 
assess the high end of the dose-response relationship. 
The ACT-541468 mechanism of action, the results of nonclinical studies and 
Phase 1 studies in healthy young and elderly adults and the limitations of the existing 
sleep medications justify the need for evaluating ACT-541468 in insomnia disorder and 
identifying the compound’s efficacious and safe doses in elderly with insomnia. 
1.4 Summary of known and potential risks and benefits  
 ACT-541468 
1.4.1
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.  
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.  
This study will be the first study with the compound in elderly subjects with insomnia 
disorder. In humans, clear and consistent CNS-depressant effects were observed at the 
morning dose of 25 mg in healthy young adults and elderly subjects. An effect was also 
seen on the most sensitive PD parameter, saccadic peak velocity, after morning single 
dose administration of 15 mg ACT-541468 in healthy elderly subjects. There were no 
relevant differences between PD effects measured on Day 1 and Day 5. In the 


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Phase 1 studies, no next-day residual effects were observed after multiple evening dose 
administration both in healthy young and elderly subjects at 25 mg.  
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. Elderly subjects reported fewer AEs than young 
adults in Phase 1 studies at the equivalent dose. 
The results of the ACT-078-103 study have shown that ACT-541468 metabolism is 
mainly dependent on CYP3A4; co-administration of ACT-541468 and strong or 
moderate CYP3A4 inhibitors must be avoided.  
Considering both the mode of action of DORA and common adverse reactions associated 
with the use of sleep medications, potential risks include: 
• Induction of next-day somnolence, which is associated with increased risk of 
impaired alertness and motor coordination.  
• Narcolepsy-like events. 
• Complex sleep-related behaviors, including night-time sleep driving and other 
complex behaviors while out of bed and not fully awake.  
• Suicidal thoughts and/or behavior.  
 Safety and risk-minimization measures taken in the present study 
1.4.2
Next-day sleepiness may potentially occur with ACT-541468. On each of the mornings 
following drug administration in sleep centers, the subjects will undergo neurological 
examinations 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 subjects and decide whether it is safe for the subject to leave the study centers.  
As required by current guidelines, the Columbia Suicide Severity Rating Scale 
(C-SSRS©) will be completed by the subjects on each morning after the 
polysomnography (PSG) nights at visit (V) 2 to V7 to assess suicidality prior to 
randomization and during the double-blind treatment phase.  
Liver variables and other laboratory variables will be monitored in the study at each study 
visit. 


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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. 
Elderly subjects enrolled in this study will receive the study treatment only at the sleep 
centers and will not be discharged from the sleep centers with the study treatment. 
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 safety and 
efficacy 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 subjects’ well-being. 
In conclusion, based on available data on the study drug ACT-541468 and the 
risk-minimization measures mandated by the protocol, the expected benefit-risk 
assessment supports the conduct of this study in elderly subjects with insomnia. The short 
duration of the study (five periods of 2 consecutive days’ exposure to study treatment 
separated by a wash-out of 5–12 days), and the careful follow-up of subjects mandated by 
the protocol minimize inconvenience and risk. 
2 
STUDY OBJECTIVES 
2.1 Primary objective 
The primary objective of the study is to evaluate the dose response of ACT-541468 on 
the change of WASO assessed by PSG on the first two days of each treatment period. 
2.2 Secondary objective 
The secondary objective of the study is to evaluate the dose response of ACT-541468 on 
latency to persistent sleep (LPS) on the first two days of each treatment period. 
2.3 Other objectives 
To explore the effect of ACT-541468 on other sleep parameters at each treatment period. 
Sleep 
parameters 
will 
include 
various 
objective 
and 
subjective 
measures 
[see Appendix 10]. 


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To assess the safety and tolerability of oral administration ACT-541468 in elderly 
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, V5, V6, and V7) and 
safety. 
3 
OVERALL STUDY DESIGN AND PLAN 
3.1 Study design 
This is a multi-center, double-blind, randomized, placebo-controlled, five-period, 
five-treatment crossover, PSG dose-response Phase 2 study in elderly subjects with 
insomnia disorder.  
In order to have approximately 50 subjects randomized, approximately 120 subjects will 
be screened (estimated screen failure rate is up to 60%). Subjects will be randomized 
1:1:1:1:1 to five different sequences of five study treatments according to a Latin square 
design [see Table 1]. The five study treatments are oral fixed doses of AC-541468 5 mg 
(D1), 10 mg (D2), 25 mg (D3) and 50 mg (D4), and placebo (P).  
Table 1 
Latin square design sequences 
 
Periods 
1 
2 
3 
4 
5 
Sequence 
1 
Dose 4 
Dose 2 
Dose 3 
Dose 1 
Placebo 
2 
Dose 2 
Placebo 
Dose 4 
Dose 3 
Dose 1 
3 
Dose 3 
Dose 1 
Dose 2 
Placebo 
Dose 4 
4 
Placebo 
Dose 4 
Dose 1 
Dose 2 
Dose 3 
5 
Dose 1 
Dose 3 
Placebo 
Dose 4 
Dose 2 
 
The study will be conducted in approximately 10 sites in two countries (US and 
Germany). 
Subjects who prematurely discontinue the study will not be replaced. Estimated dropout 
rate for the study is around 10%.  
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 investigator’s opinion.  


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 Study phases 
3.1.1
3.1.1.1 Screening phase 
The screening phase lasts a minimum of 14 days and a maximum of 28 days. It starts 
with the signature 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 V1, which occurs between Day −28 and Day −14 and is 
followed by the completion of the screening sleep diary for at least 7 consecutive days at 
home and until V2.  
The run-in period occurs between Day −14 and Day −1 and starts with V2. V2 consists 
of two 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.  
3.1.1.2 Double-blind treatment phase 
The double-blind treatment phase starts with the first dose of study treatment in the first 
evening of the Randomization visit (V3) and ends in the second morning of V7. It 
consists of five treatment periods, each consisting of two consecutive PSG nights on the 
assigned study treatment followed by a 5- to 12-day washout.  
The End of Treatment (EOT) is reached in the second morning of V7, after the last 
dose of double-blind treatment and after all morning assessments have been performed.  
The safety Follow-up phase starts after the EOT and lasts at least 30 days (i.e., until the 
second follow-up telephone call). A first telephone call is done 5 days (+ 7 days) after 
EOT to collect TEAEs from the last study treatment dose.  
The End of Study (EOS) for a single subject is defined as the date of the 30-day 
follow-up telephone call. 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 [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 3] and are described in Section 7. 
The overall study design is depicted in [Figure 1]. 


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Figure 1 
Study design 
 
V = visit; ▬ polysomnographic (PSG) nights; D = dose; P = placebo. 
 
 Study duration 
3.1.2
The study starts with the first act of recruitment (i.e., ICF signed) and ends with the last 
visit of the last subject. 
The double-blind treatment phase for each subject lasts 30 to 58 days. The assigned 
treatment will be administered during the first two days of the five treatment periods. For 
an individual subject, the study is completed with EOS (30-day safety follow-up 
telephone call). The duration of participation in the study of a subject is expected to be 
approximately 74 to 116 days.  
3.2 
Study design rationale 
This is a multi-center, double-blind, randomized, placebo-controlled, five-period, 
five-treatment crossover, PSG dose-response study.  
The study is double-blind and randomized to prevent any possible bias in the parameters, 
assessment or analysis. 
The effects of each dose of ACT-541468 will be compared to those of placebo for every 
subject. This allows for conclusions as to the level of relevance and significance of any 
effect detected. 


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A crossover design was chosen due to the nature of the disease under investigation 
(i.e., chronic and stable), the short treatment duration (2 days for each dose), and the 
possibility to have a long wash-out period (5–12 days) compared to the t½ (9.9 h) of 
ACT-541468 in elderly subjects. Furthermore, recruitment is anticipated to be 
challenging in the elderly population, and for this design, the sample size required in 
comparison with a parallel-group design is much smaller [ICH 1998]. As a balanced 
complete block design, the five-sequence Latin square crossover design minimizes the 
influence of confounding covariates because each patient serves as his or her own control 
(i.e., each subject will receive each of the four different doses of ACT-541468 and 
placebo). Any potential order (or learning) effect occurring over time will be averaged 
across all doses since each dose of ACT-541468 and placebo is given in each treatment 
period. 
Subjects screened at V1 will complete a run-in period to confirm final eligibility and to 
perform baseline assessments of parameters, as well as to exclude subjects with major 
short-term fluctuation of their conditions.  
ACT-541468 is expected to be effective from the first day of dose intake. PSG 
assessments during 2 consecutive nights are considered sufficient to evaluate acute 
ACT-541468 effects on sleep parameters in elderly subjects. Since no accumulation of 
ACT-541468 was observed [see Section 1.2.2.2], there is no need to expose subjects 
longer to reach study drug steady state. It is expected that the effect on sleep parameters 
observed after 2 days’ treatment in elderly will evolve over time in a similar way to what 
is seen in adults treated over longer time [Herring 2016]. Effects over longer time in the 
elderly will therefore be extrapolated based on results of the dose-finding study in adults. 
3.3 Site staff and their roles: 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. 
Adequate training for the PSG procedures will be conducted by the contract research 
organization (CRO; i.e., Clinilabs).  
Documentation of technologists’ prior experience and training, and study-specific 
training, will be maintained at each clinical trials site. 


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3.4 Study committees 
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 
4.1 Subject population description  
This study will enroll elderly male and female subjects aged ≥ 65 years with insomnia 
disorder. For more details on inclusion and exclusion criteria, please see Section 4.3 and 
Section 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 that would be different from that in general population. 
Insufficient sleep quantity is operationalized in this study by a self-reported history of 
≥ 30 minutes to fall asleep and ≥ 30 minutes wake time during sleep, as well as by a TST 
≤ 6.5 hours during the night. Those three 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 data collected for at least 7 consecutive days at home and until 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 an 
Insomnia Severity Index (ISI©) score ≥ 15 at screening.  
4.2 Rationale for the selection of the study population. 
The study will recruit elderly subjects (≥ 65 years). The selective inclusion of elderly 
subjects is justified by the differences in SQ patterns and architecture between elderly 
and adults. A separate dose-finding study will be performed in 300 adult subjects. 
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 results in different drug exposure level in females and male subjects [FDA 2013]. 
Therefore, both male and female will be included in this study. 


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Since this study is the first trial of ACT-541468 conducted in elderly subjects with 
insomnia disorders, concomitant treatments for insomnia (pharmacological or not) or 
concomitant medications active in the CNS are not allowed in the study to avoid 
confounding effects on safety and efficacy of the study treatments. 
4.3 Inclusion criteria 
For inclusion in the study, all of the following inclusion criteria must be fulfilled. It is not 
permitted to waive any of the criteria for any subject (V1 and V2 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 ≥ 65 years (V1). 
3. Body mass index (BMI): 18.5 ≤ BMI (kg/m2) < 32.0 (V1). 
4. Insomnia disorder according to DSM-5 criteria (V1). 
5. Self-reported history of all of the following on at least 3 nights per week and for at 
least 3 months prior to V1: 
5.1 
≥ 30 minutes to fall asleep  
5.2 
Wake time during sleep ≥ 30 minutes  
5.3 
TST of ≤ 6.5 h  
6. ISI© score ≥ 15 (V1).  
7. Willing to comply with all aspects of the study protocol (V1). 
8. 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). 
9. 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):  
9.1 
≥ 30 minutes to fall asleep  
9.2 
Wake time during sleep ≥ 30 minutes  
9.3 
TST of ≤ 6.5 hours  
10. Usual bedtime between 21:30 and 00:30 as reported on the sleep diary completed at 
home between V1 and V2 (to be checked at V2). 
11. Regular time in bed between 6 and 9 hours as reported on the sleep diary completed 
at home between V1 and V2 (to be checked at V2). 
12. Meeting the following sleep parameters on the two PSG nights (V2):  
12.1 Mean LPS ≥ 20 minutes (with neither of the two nights < 15 minutes), and 
12.2 Mean WASO ≥ 30 minutes (with neither of the two nights < 20 minutes), 
and 
12.3 Mean TST < 420 minutes  


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4.4 Exclusion criteria 
Subjects must not fulfill any of the following exclusion criteria. It is not permitted to 
waive any of the criteria for any subject (V1 and V2 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 on ≥ 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 ≥ three time zones within 1 week prior to the screening visit, or planned travel 
≥ three time zones during study (V1). 
6. Hematology or biochemistry test results deviating from the normal range to a 
clinically relevant extent as per judgment of the investigator (V1, V2)  
7. AST and/or ALT > 2 × the ULN and/or direct bilirubin > 1.5 × ULN (V1, V2). 
8. 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) 
9. Unstable medical condition, significant medical disorder or acute illness within 
1 month prior to the screening visit that in the opinion of the investigator could affect 
the subject’s safety or interfere with the study assessments (V1). 
10. Systolic blood pressure (BP) > 150 mmHg and diastolic BP > 90 mmHg (V1,V2). 
11. Resting pulse rate < 50 or ≥ 100 beats per minute (V1, V2). 
12. Any of the following conditions related to corrected QT (QTc) intervals (V1,V2): 
11.1 A prolonged QTc interval (QTc greater than 450 ms). In case of QTc greater 
than 450 msec 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.  
11.2 A history of additional risk factors for torsade de pointes (e.g., heart failure, 
hypokalemia, family history of long QT syndrome).  
13. Any of the following conditions related to suicidality: 
12.1 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). 
12.2 Lifetime history of suicide attempt (V1). 
14. Any known factor or disease that might interfere with treatment compliance, study 
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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).  
15. Treatment with another investigational drug within 1 month prior to V1. 
16. Known hypersensitivity or contraindication to drugs of the same class of the study 
treatment or to any excipients of the study drug formulation (V1). 
17. 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 hours after EOT, including over-the-counter (OTC) medication and herbal 
medicines. 
18. CBT within one month prior to V1.  
19. Treatment with moderate to strong CYP3A4 inhibitors, CYP3A4 inducers, sensitive 
CYP3A4 substrates, P-glycoprotein 1 (P-gP) substrates, Breast Cancer Resistance 
Protein (BCRP) substrates, and CYP2B6 substrates [as defined in Appendix 4] 
within 1 week prior to V1 until 24 h after EOT.  
20. Consumption of grapefruit and grapefruit juice within 1 week prior to V1. 
21. 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).  
22. Positive drug test (for benzodiazepines, barbiturates, cannabinoids, opiates, 
amphetamines, or cocaine) or presence of alcohol in exhaled breath as detected by a 
breathalyzer test (V1,V2). 
23. Heavy tobacco use (≥ 10 cigarettes per day), and/ or inability to refrain from 
smoking for at least 14 hours during the night (V1).  
24. Apnea/hypopnea index (AHI) ≥ 15/h on the first PSG screening night according to 
the American Academy of Sleep Medicine (AASM) criteria [Meoli 2001, 
CMS 2008] (V2).  
25. 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). 
26. Periodic limb movement with arousal index (PLMAI) ≥ 15/h on the first PSG 
screening night (V2). 
5 
TREATMENTS 
5.1 Study treatment 
The study drugs are ACT-541468 and ACT-541468-matching placebo. Single-blind 
placebo will be administered at V2. Double-blind study treatment will be administered at 
V3, V4, V5, V6 and V7. 


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 Investigational treatment and matching placebo: description and rationale 
5.1.1
ACT-541468 capsules will be administered orally, once daily in the first two evenings of 
the assigned treatment period. ACT-541468 doses will include: 5 mg, 10 mg, 25 mg and 
50 mg. Rationale for the selection of these ACT-541468 doses is described in 
Section 1.3.2.Placebo capsules matching ACT-541468 will also be administered orally, 
once daily in the first two evenings of the assigned treatment period and in addition at 
V2. 
ACT-541468 is supplied by Actelion as the hydrochloride salt, in hard gelatin capsules at 
the strengths of 5, 10 and 25 mg. The ACT-541468-matching placebo is supplied by 
Actelion as identical capsules, formulated with the inactive ingredients (excipients) but 
without the active ingredient. 
 Study treatment administration during the different study phases 
5.1.2
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 an evening meal (including 
V2). Each capsule will be swallowed whole. The date and time of treatment intake will 
be recorded by the site staff in the electronic Case Report Form (eCRF). 
5.1.2.1 Screening phase 
At V1, after signing the ICF and preferably prior to 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 her/his 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, in the evening of each of the two PSG nights, 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). 
5.1.2.2 Double-blind treatment phase 
During the double-blind treatment phase (i.e., at V3, V4, V5, V6 and V7), ACT-541468 
and/or ACT-541468-matching placebo will be taken approximately 30 minutes before 
lights off (= habitual bedtime ± 5 minutes) in the evening of each of the PSG nights, as 
shown in Table 2.  


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Table 2 
Number of capsules taken according to treatment dose 
 
Placebo (0) 
5 
10 
25 
Placebo (0) 
2 
0 
0 
0 
5 
1 
1 
0 
0 
10 
1 
0 
1 
0 
25 
1 
0 
0 
1 
50 
0 
0 
0 
2 
For dose levels 5, 10 and 25 mg only one capsule of ACT-541468 is required, while for 
the 50 mg dose, two capsules of 25 mg will be administered. Therefore, to keep the blind, 
a placebo capsule matching ACT-541468 will be administered concomitantly with one 
capsule of ACT-541468 for the 5, 10 and 25 mg doses. 
 Treatment assignment 
5.1.3
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 system (IRT) to get a subject number allocated to the 
subject. 
At V2, subjects will receive single-blind placebo matching ACT-541468 treatment.  
At V3, 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 site kit number, which matches the treatment sequence 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. 
 Blinding 
5.1.4
5.1.4.1 Screening phase 
At V2, placebo matching ACT-541468 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 staff, the monitors, Actelion staff, and CROs involved in the 
conduct of the study will be unblinded to treatment. 
Treatment  
dose (mg) 
Dose strength  
(mg) 


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5.1.4.2 Double-blind treatment phase 
From V3 until V7, the study will be performed in a double-blind fashion. The subjects, 
investigator and study staff, monitors, Actelion staff, and CROs involved in the conduct 
of the study will remain blinded to the study treatment until study closure. The Clinical 
Trial Supplies Manager will monitor the depot stock levels in collaboration with the 
study team data on recruitment 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. 
 Unblinding 
5.1.5
5.1.5.1 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. 
5.1.5.2 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 standard operating procedures (SOPs). 
5.1.5.3 Unblinding for suspected unexpected serious adverse reaction 
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 randomization code will not be communicated to the site staff 
or to the Actelion study team. Unblinded SUSAR information will be provided to 
respective health authorities and institutional review boards (IRBs) / independent ethics 
committee (IECs) only. SUSARs will be reported to investigators in a blinded fashion. 
5.1.5.4 Emergency procedure for unblinding 
The investigator, study staff and sponsor staff must remain blinded to the subject’s study 
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 randomization code for study treatment allocation 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 


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interest of the subject, the investigator is invited to discuss the intended unblinding with 
Actelion staff. 
The occurrence of any unblinding during the study must be clearly justified and 
explained by the investigator. In all cases, Actelion 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. 
 Study treatment supply 
5.1.6
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, Good Clinical Practice (GCP), and any local 
or national regulatory requirements. 
All study treatment supplies are to be used only in accordance with this protocol and not 
for any other purpose. 
5.1.6.1 Study treatment packaging and labeling 
Swallow test and V2: 
Study treatment is supplied as a site kit and provided in childproof bottles containing 
36 capsules.  
V3 to V7: 
Study treatment is supplied as a site kit and provided in a wallet containing the 
20 capsules required for treatment of one subject over the five treatment periods.  
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
5.1.6.2 Study treatment distribution and storage 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label. Temperature measurement devices for study 
treatment storage area are required. 
5.1.6.3 Study treatment dispensing 
The study treatment will be kept at study site for administration by the site staff and will 
not be dispensed to the subjects when they leave the site. 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. 


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5.1.6.4 Study treatment return and destruction 
The protocol-mandated study treatment return procedures may not be altered without 
prior written approval from Actelion. On an ongoing basis and/or on termination of the 
study, the Clinical Research Associate (CRA) will collect used and unused site kits, 
which will be sent to the warehouse, where Actelion staff or a deputy will check 
treatment reconciliation. In certain circumstances, used and unused study treatment 
containers may be destroyed at the site once study treatment accountability is finalized 
and has been checked by Actelion staff or the deputy and written permission for 
destruction has been obtained from Actelion. 
 Study treatment accountability and compliance with study treatment 
5.1.7
5.1.7.1 Study treatment accountability 
The inventory of study treatment dispensed to the subject (i.e., study treatment 
accountability) must be performed by site staff at each visit and before dispensing further 
study treatment. It is to be recorded by site staff 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): 
• Bottle number  
• Number of capsules dispensed 
Double-blind treatment phase 
• Dispensed site kit number 
• Date and Number of capsules administered. 
All study treatment supplies, including partially used or empty site kits and bottles must 
be retained at the site for review by the CRA. 
5.1.7.2 Study treatment periods compliance 
Study treatment compliance is based on study treatment accountability. Study treatment 
compliance for each of the five treatment periods will be calculated by the site staff using 
the below formula and entered in the eCRF. 
Compliance = [number of capsules administered / total number of capsules that 
must have been taken during the period*] × 100 
*The number of capsules for a treatment period equals 4. 
Compliance during each treatment period is expected to be 100%. Compliance values 
outside of this number will be considered as a protocol deviation, which will be reported 
in the eCRF by the CRA. The investigator must discuss the non-compliance with the 


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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. 
 Study treatment dose adjustments and interruptions 
5.1.8
Study treatment dose adjustments are not permitted. 
Study treatment dose interruptions must be recorded in the eCRF. 
 Premature discontinuation of double-blind study treatment  
5.1.9
The decision to prematurely discontinue study treatment may be made by the subject, the 
investigator or Actelion. The main reason and whether discontinuation of study treatment 
is the decision of the subject (e.g., tolerability- or efficacy-related), the investigator 
(e.g., due to pre-specified study treatment discontinuation criteria, an AE or lack of 
efficacy), or Actelion (e.g., study terminated) must be documented in the eCRF and in the 
subject medical charts. 
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 he/she believes 
that continued administration would be contrary to the best interests of the subject. 
A subject must be discontinued from the study in case of: 
• ALT ≥ 3 × the ULN and total Bilirubin > 2 × the ULN on the morning laboratory test 
following the second drug intake of each treatment period,  
or 
• ALT and / or AST > 5 × the ULN on the morning laboratory test following the 
second drug intake of each treatment period. 
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 consents to 
this limited participation in the study. 
Subjects who prematurely discontinue treatment during a treatment period at the center 
will undergo the morning assessments after the last study drug intake. All subjects who 
prematurely discontinue study treatment will be asked to agree to be called for the safety 


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follow-up (one telephone call 5 days [+ 7 days] after the last intake of study treatment, 
and a second telephone call 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. 
5.2 Previous and concomitant therapy 
 Definitions 
5.2.1
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 
discontinuation.  
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 
phase until 1 day after the last dose of double-blind study treatment (V7).  
 Reporting of previous/concomitant therapy in the eCRF  
5.2.2
The use of all study-concomitant therapy (including 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. 
 Allowed concomitant therapy 
5.2.3
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 
medications is to be discouraged and concomitant medications are preferably not to be 
changed during the course of the study. 
 Forbidden concomitant therapy 
5.2.4
Patients 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 


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therapies are associated with excluded medical disorders (e.g., cardiovascular disease, 
stroke). 
The following therapies are forbidden during the study: 
• Treatment with another investigational drug until the end of the safety follow-up 
phase.  
• Prohibited CNS-active medications, including OTC medications and herbal 
medicines, until 24 hours after EOT [see Appendix 4]. 
• 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 
[see Appendix 4]. 
• CBT and other psychological therapies, excluding common advice related to sleep 
hygiene, until 24 hours after EOT. 
 Forbidden concomitant diet and activities 
5.2.5
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/day 
– after 14:00 on the days of PSG nights 
• Alcohol consumption [more details in Appendix 2]: 
– > 2 drinks a day 
– 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 
6.1 Efficacy endpoints 
 Primary efficacy endpoint 
6.1.1
The primary efficacy endpoint of this study is defined as the change of WASO (min) 
from Baseline5 to Days 1 and 26 as determined by PSG. 
                                                 
5 ‘Baseline’ is the mean of the two PSG nights during run-in period (V2).  
6 ‘Days 1 and 2’ is the mean of the corresponding two PSG treatment nights for a given treatment period. 


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WASO is the time (minutes) 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 as an adequate endpoint for 
dose finding studies [EMA 2011].  
Total time in bed is fixed at 480 minutes (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. 
 Secondary efficacy endpoint 
6.1.2
The secondary efficacy endpoint of this study is defined as the change from Baseline5 to 
Days 1 and 26 in mean LPS.  
LPS is the time (minutes) from start of recording to the beginning of the first continuous 
20 epochs (i.e., 10 minutes) 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. 
 Other efficacy endpoints 
6.1.3
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:  
• Subjective WASO (sWASO), WASO overnight 
• Subjective LSO (sLSO) 
• TST and subjective TST (sTST) 
• SQ 
• Sleep stage S1, S2, SWS and REM, 
• Shifts from S2, SWS or REM to S1 or wake 
• Wake time during sleep 
• Frequency of awakenings as measured by PSG and self-reported 
• Sleep efficiency (SE; defined as 100 × [TST / time in bed]) 
• Next-day performance 


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6.2 Safety endpoints 
• TEAEs7 up to 5 days after study treatment discontinuation 
• SAEs up to 30 days after study treatment discontinuation 
• AEs leading to premature discontinuation of the double-blind study treatment 
• AEs of special interest starting or worsening after the first dose of the first treatment 
period until EOS (and after adjudication by the ISB): 
– Narcolepsy-like events (e.g., excessive daytime sleepiness, cataplexy) 
– Complex sleep behavior events. 
– Suicidal thoughts and/or behaviors. 
• Change from Baseline (mean of the two PSG nights at V2, run-in period) to the 
Days 1 and 28 of each period in vital signs (systolic and diastolic BP, pulse rate and 
body temperature) 
• Change from Baseline (V1) to the second morning after the PSG nights at V7 in body 
weight 
• Treatment-emergent ECG abnormalities from V3 until EOT 
• Change from Baseline (V2, second morning) to the second morning after the PSG 
nights at V3, V4, V5, V6 and V7 in ECG parameters 
• Marked laboratory abnormalities on double-blind study treatment 
• Change from Baseline (V2, second morning) to the second morning after the PSG 
nights at V3, V4, V5, V6 and V7 in laboratory variables 
• Change from Baseline (mean of the two PSG nights at V2, run-in period) to Days 1 
and 28 of each treatment period 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 
• Incidence of most severe suicidal ideation and suicidal behaviors according to the 
C-SSRS© for each treatment period. 
                                                 
7 A TEAE is any AE temporally associated with the use of study treatment from Day 1 until 5 days after last study drug 
intake in each treatment period and until 5 days after study treatment discontinuation whether or not considered 
by the investigator as related to study treatment. 
8 Days 1 and 2 is the mean of the first and second morning values after the two PSG nights of a treatment period. 


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6.3 Pharmacokinetic endpoints 
Concentration of ACT-541468 (and possibly several of its metabolites) approximately  
9–10 hours post-dose on the second morning at V3, V4, V5, V6 and V7 and in the event 
of excessive sleepiness also on the first morning at these visits. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS 
7.1 Study visits  
The study visits are listed in Table 3. For all double-blind treatment phase visits (V3 to 
V7), the subjects must be seen between 5 and 12 days after the previous visit. Two 
follow-up safety telephone calls must be performed: one telephone call 5 days (+ 7 days) 
after the last intake of study treatment, and a second telephone call at least 30 days 
(+ 7 days) after the last intake of study treatment.  
 Screening/re-screening 
7.1.1
Screening starts with the signature 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 
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, he/she will 
be considered a screen failure and will be discontinued from the study. 
 Unscheduled visits 
7.1.2
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 


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visit, the regular scheduled study visits must continue according to the planned visit and 
assessment schedule [Table 3]. 
 






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7.2 Study assessments 
The mandatory study assessments are listed in Table 3.  
All study assessments are performed by qualified study staff (medical, nursing, or 
specialist technical staff) 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 PSG night: 
– Physical examination (first evening) 
– Vital signs and body temperature (first evening) 
– Drug and alcohol test 
– Hematology and blood chemistry (first evening at V3, V4, V5, V6 and V7) 
– Evening questionnaire in sleep diary, including VAS (second evening) 
– Recording of concomitant medications 
– AEs and SAEs 
– Study drug intake 30 minutes (± 5 minutes) before lights off 
• In the morning after PSG night, after completion of normal morning routine (e.g., 
using the bathroom, eating breakfast): 
– Physical examination (second morning at V7) 
– Vital signs and body temperature 
– DSST  
– SDS  
– KSS  
– C-SSRS 
– Morning questionnaire in sleep diary (including VAS) 
– Recording of concomitant medications 
– AEs and SAEs 
– Neurological examination* 


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– Hematology and blood chemistry (second morning) 
– PK sampling* (second morning at V3, V4, V5, V6 and V7) 
– 12-lead ECG (second morning) 
*The neurological examination must be performed approximately 1 hour after lights on 
and repeated approximately every 30 minutes until it is safe for the subject 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 at this time. 
The following assessments will be analyzed by an external provider (results will be 
transferred to the Actelion database and to the investigators): 
• Lab parameters 
• ECG parameters 
• PSG recordings 
• Questionnaires completed using a hand-held device (listed below) 
If the principal investigator (PI) delegates any study procedure/assessment for a subject to 
an external facility, he/she must inform Actelion to whom these tasks are delegated. The 
set-up and oversight will 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 
• PSG 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, 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.  


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 Demographics 
7.2.1
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.  
 Insomnia severity index 
7.2.2
The ISI assesses the severity of a subject’s insomnia by scoring the severity of 
sleep-onset and sleep maintenance difficulties and any insomnia-related interference with 
daytime functioning [see Appendix 6]. The assessment is on a 5-point scale (0–4), where 
the composite score is obtained by summing the seven 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 license agreement for the use of ISI. 
 Efficacy assessments 
7.2.3
7.2.3.1 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.  
All PSG recordings are supervised by qualified technical staff. 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 the sleep diary between V1 and V2); this time is then considered 
as the habitual bedtime and held constant (± 5 minutes) throughout the study. Study 
medication is administered 30 minutes (± 5 minutes) 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 will take place at V2, V3, V4, V5, V6 and V7. 
The first PSG screening night (at V2) also includes AHI, PLMAI, and SpO2. 


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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 remain 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 activity (such as 
reading, listening to radio, etc.) and is recommended not to have access to any watch or 
mobile phone device. 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 the 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 subjects and decide whether it is safe for the subject to leave the study 
centers. 
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 the file’s receipt by the CRO. Based on this information, the investigator 
assesses the subject’s potential eligibility. 
After the last PSG night at Visit 7, results of all the PSG nights for the subject (V2, V3, 
V4, V5, V6 and V7) are sent by the CRO to Actelion. The following sleep variables will 
be assessed by PSG: WASO, LPS, TST, sleep stages S1 (called N1 in the scoring 
procedures of the Clinilabs manual), S2 (N2), SWS (N3) and REM (R), wake time during 
sleep (W). The definitions of the sleep variables are given in the scoring procedures of 
the Clinilabs manual. 
Incidental findings identified by central reading will be communicated to the PI. If the 
incidental findings are considered clinically relevant by the PI, they will be reported in 
the medical history or as an AE, as applicable. 


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For more detailed information, refer to the ‘Investigator site operations manual for the 
acquisition, processing, scoring, archiving, and transfer of digital PSG data (provided by 
Clinilabs, NY)’. 
7.2.3.2 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 at home every day for at 
least 7 consecutive days between V1 and V2. The self-administered sleep diary includes 
a morning and an evening questionnaire and VAS.  
On each morning after the two PSG nights at V2, V3, V4, V5, V6 and V7, the subject 
will complete the sleep diary morning questionnaire and VAS.  
On the second evening before the second PSG night at V2, V3, V4, V5, V6 and V7, the 
subject will complete the sleep diary evening questionnaire and VAS. 
7.2.3.2.1 Morning and evening questionnaires 
These questions collect information on self-reported sleep characteristics (sleep induction 
and maintenance) and bedtime and timing of study treatment intake.  
For further details, see Appendix 9. 
7.2.3.2.2 Visual analog scale 
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 VAS. 
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 9.  
 Safety assessments 
7.2.4
The definitions, reporting and follow-up of AEs and SAEs are described in Section 9. 
7.2.4.1 Weight and height 
Height will be measured at V1 only and recorded in the eCRF. 
Body weight will be measured at V1 and in the second morning of V7 (recommended 
within 24 hours after last dose of double-blind study drug intake) and recorded in the 
eCRF. BMI will be calculated according to the BMI formula (weight in kg/m2) and 
displayed automatically upon entry of weight and height in the eCRF.  


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7.2.4.2 Vital signs 
Systolic and diastolic BP, pulse rate and body temperature will be measured 
non-invasively at each study visit (i.e., V1 as well as first evening and each morning at 
V2, V3, V4, V5, V6 and V7). 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 measurement and conditions will be collected in the eCRF. 
7.2.4.3 Physical examination 
Physical examination is to be performed at V1 and on the second morning of V7 
(recommended within 24 hours after last dose of double-blind study drug intake) as well 
as on the first evening at V2, V3, V4, V5, V6 and V7. 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 that 
meet the definition of an AE [Section 9.1.1] must be recorded on the AE form of the 
eCRF. 


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7.2.4.4 Digit Symbol Substitution Test 
The DSST is to be performed each morning after a PSG night at V2, V3, V4, V5, V6 
and V7. 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 centers are provided with eight different test versions that use the same symbols in a 
different sequence. At each administration, a different test version is assigned among the 
eight versions, in order to minimize the impact of symbol/coding learning from one test 
to the subsequent one. 
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 
7.2.4.5 Sheehan Disability Scale 
The SDS is to be performed each morning after a PSG night at V2, V3, V4, V5, V6 and 
V7. The SDS consists of three questions on impairment of work, social life, and family 
life/home responsibilities [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. 
7.2.4.6 Karolinska Sleepiness Scale 
The KSS is to be performed each morning after a PSG night at V2, V3, V4, V5, V6 and 
V7. The 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. 
7.2.4.7 Columbia Suicide Severity Rating Scale 
The C-SSRS is to be performed at V1 and on each morning after a PSG night at V2, V3, 
V4, V5, V6 and V7. The C-SSRS is an instrument that reports the severity of both 
suicidal ideation and behavior [Posner 2007]. Suicidal ideation is classified on a 5-item 
scale:  
1. wish to be dead 
2. nonspecific active suicidal thoughts 


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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 behavior, specifically actual, interrupted, and aborted attempts; 
preparatory acts or behavior; and if suicidal behavior was 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 behavior. At all other visits, the C-SSRS will be completed for 
ideation and behavior 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 the 
presence of an adequately trained staff member.  
Actelion has been granted the license agreement for the use of the electronic C-SSRS.  
7.2.4.8 Neurological examinations 
In the morning following each PSG night (V2, V3, V4, V5, V6 and V7), 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 it is safe 
for the subject to leave the center [see Section 7.2]. The time when it is considered safe 
for the subject to leave the center will be recorded in the eCRF. 
7.2.4.9 ECG assessment 
A standard 12-lead ECG is to be performed, at V1 and in the second morning of V2, V3, 
V4, V5, V6 and V7. 


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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 
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 on the same day). 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 that meet the definition of an AE 
must be recorded in the eCRF.  
ECG data collected by the CRO will be electronically transferred to Actelion.  
 Laboratory assessments 
7.2.5
7.2.5.1 Type of laboratory 
A central laboratory (see central laboratory manual for contact details) will be used for all 
protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and 
laboratory tests performed at unscheduled visits.  
Exceptional circumstances that will require recording of local laboratory results of the 
parameters described in Section 7.2.5.2 (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 case of specific (pre-defined) 
laboratory abnormalities, the central laboratory will alert Actelion and the concerned site. 
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 


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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 signature of informed consent must be recorded on the medical 
history page of the eCRF. Any clinically relevant laboratory abnormalities detected after 
signature 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. 
7.2.5.2 Laboratory tests 
Hematology 
• Hemoglobin (g/L) 
• Hematocrit (L/L) 
• Erythrocytes (109/L) 
• Reticulocytes (%) 
• 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 (mcg/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 (triiodothyronine, thyroxine), and thyroid-stimulating hormone 


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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 lab.  
Study drug is administered as described in Section 5 only if the results of these other tests 
are negative.  
 Pharmacokinetic assessments 
7.2.6
PK samples will be collected in the morning after the second PSG night after lights on, 
approximately 9–10 hours post-dose at V3, V4, V5, V6 and V7. 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 at this time. 
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 staff will ship the plasma samples to the central laboratory, who will ship 
the samples to Actelion preclinical drug metabolism and pharmacokinetics department 
for the PK analysis. 
8 
STUDY COMPLETION AND POST-STUDY TREATMENT / 
MEDICAL CARE 
8.1 Study completion as per protocol 
A subject who completes the double-blind treatment phase and the follow-up period is 
considered to have completed the study as per protocol. 
8.2 Premature withdrawal from study 
Subjects may voluntarily withdraw from the study without justification for any reason at 
any time. Subjects are considered withdrawn if they state an intention to withdraw further 
participation in all components of the study (i.e., withdrawal of consent), die, or are lost 
to follow-up. If a subject withdraws consent, no further data will be collected in the eCRF 
from the date of withdrawal onward. The investigator may withdraw a subject from the 
study (without regard to the subject’s consent) if 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 


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cannot be reached). If the subject cannot be reached, the site must make a reasonable 
effort to contact the subject, document all attempts, and enter the loss of follow-up 
information into the eCRF. The following methods must be used: at least three telephone 
calls must be placed to the last available telephone number and one registered letter must 
be sent by post to the last available home address. Additional methods may be acceptable 
if they are compliant with local rules/regulations (e.g., a visit by site staff 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 staff) 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 must make efforts to schedule a last appointment / telephone call 
to assess the safety and well-being of the subject, and discuss follow-up medical care. 
Data obtained during this last appointment / telephone call will be recorded in the 
subjects’ medical records but it will not be collected in the eCRF. The investigator must 
provide follow-up medical care for all subjects who are prematurely withdrawn from the 
study, or must refer them for appropriate ongoing care, as described in Section 8.4. 
8.3 Premature termination or suspension of the study  
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 the participation of his/her site to 
the study without prior agreement from Actelion, the investigator must promptly inform 
Actelion staff 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 staff and provide a detailed written 
explanation of the termination or suspension. 


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8.4 Medical care of subjects after study completion / withdrawal from study 
After the subject’s study completion or premature withdrawal from the study, whichever 
applies, the investigator/delegate will explain to subjects what treatment(s) / medical care 
is necessary and available according to local regulations. 
9 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
9.1 Adverse events 
 Definition of adverse events 
9.1.1
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a subject 
during the course of the study, whether or not considered by the investigator as related to 
study treatment. 
A TEAE is any AE temporally associated with the use of study treatment (from Day 1 
until 5 days after last study drug intake in each treatment period and until 5 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.  
 Intensity of adverse events 
9.1.2
The intensity of clinical AEs is graded on a three-point scale – mild, moderate, severe – 
and is reported on a specific AE form of the eCRF. 


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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]. 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. 
 Relationship to study treatment  
9.1.3
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. 
 Reporting of adverse events  
9.1.4
All AEs with an onset date after signature of informed consent and up to 5 days after 
study treatment discontinuation must be recorded on the specific AE form of the eCRF.  


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 Follow-up of adverse events  
9.1.5
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. 
9.2 Serious adverse events  
 Definitions of serious adverse events 
9.2.1
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the 
following criteria: 
• Fatal. 
• Life-threatening: Refers to an event in which the subject was at risk of death at the 
time of the event. It does not refer to an event that hypothetically might have caused 
death had it been more severe. 
• Requiring in-patient hospitalization or prolongation of existing hospitalization. 
• Resulting in persistent or significant disability or incapacity. 
• Congenital anomaly or birth defect. 
• Medically significant: Refers to important medical events that may not immediately 
result in death, be life-threatening, or require hospitalization but may be considered to 
be SAEs when, based upon appropriate medical judgment, they may jeopardize the 
subject and may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
The following reasons for hospitalization are not considered as SAEs: 
1. Hospitalization for cosmetic elective surgery, or social and/or convenience 
reasons. 
2. 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). 
 Reporting of serious adverse events 
9.2.2
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. 


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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). 
 Follow-up of serious adverse events 
9.2.3
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. 
 After the 30-day follow-up period 
9.2.4
New SAEs occurring after the 30-day follow-up period must be reported to 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. 
 Reporting procedures 
9.2.5
All SAEs must be reported by the investigator to the Actelion Global Drug Safety 
department 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 the Actelion Global Drug Safety department (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. The Actelion Global Drug Safety department may contact the 
investigator to obtain further information. 
If the subject is hospitalized in a hospital other than the study site, it is the investigator’s 
responsibility to contact this hospital to obtain all SAE-relevant information and 
documentation. 
The expectedness of an adverse reaction is determined by Actelion in the reference safety 
information (RSI) section provided in the most recent version of the IB. Any SAE that is 
assessed as related and unexpected against the RSI is known as a SUSAR and must be 


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reported by Actelion to concerned health authorities (including the EudraVigilance 
database if the study is conducted in Europe), IECs/IRBs and investigators. 
9.3 Study safety monitoring  
Clinical study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
project-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]. 
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. 
This study is using a Latin square crossover design, hence each subject is to receive each 
treatment (including placebo). All analyses described in this section are based on the 
assumption that there is no carry-over effect [see Section 3.2]. 
In the below section the term Days 1 and 2 refers to the two days or nights of each period, 
i.e., corresponding to a given dose level.  
10.1 Analysis sets 
 Screened Analysis Set 
10.1.1
The Screened Analysis Set includes all subjects who are screened and have a subject 
identification number. 
 Randomized Analysis Set 
10.1.2
The Randomized Analysis Set includes all subjects who have been assigned to a study 
treatment. 
 Full Analysis Set 
10.1.3
The Full Analysis Set (FAS) includes all subjects from the randomized analysis set who 
received any 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 taken into account. 


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 Modified FAS 
10.1.4
Modified FAS (mFAS) includes all patients from the FAS and who have at least one 
WASO assessment at Baseline and at least one at Days 1 and 2 of any given treatment 
period. 
 Per-protocol Analysis Set 
10.1.5
The Per-Protocol Analysis Set (PPS) comprises all subjects from the mFAS, who have 
two consecutive WASO values at both Baseline and Days 1 and 2 of each treatment 
period, and who complied with the protocol sufficiently to allow relevant assessment of 
treatment effects. 
Criteria for sufficient protocol compliance include adequate exposure to treatment 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. 
 Safety Set 
10.1.6
The Safety Set (SS) includes all randomized subjects who received at least one dose of 
study treatment. Subjects will be evaluated according to the actual dose they received, 
which may differ from the randomly assigned dose. 
 PK Analysis Set 
10.1.7
The PK Analysis Set includes all subjects in the SS who have at least one PK sample 
collected after initiation of study drug. 
 Usage of the analysis sets 
10.1.8
The primary efficacy analysis will be performed on the mFAS based on dose as 
randomized. Secondary and exploratory efficacy endpoint analyses will also be 
performed on the mFAS, while FAS and PPS will be considered for sensitivity analyses. 
Safety analyses will be performed on the SS based on actual dose received. 
Subject listings will be based on the SS, unless otherwise specified. Subject disposition 
will be described for the Screened and Randomized Analysis Set. 
Table 4 describes the analysis sets used for the analysis of each data set. 


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Table 4 
Usage of analysis datasets  
 
Screened 
Randomized 
FAS 
mFAS 
PPS 
SS 
PK set 
Patient disposition 
X 
X 
 
 
 
 
 
Baseline and disease 
characteristics 
 
(x) 
X 
(x) 
(x) 
 
(x) 
Previous and concomitant 
medication 
 
 
 
 
 
X 
 
Study drug exposure 
 
 
 
 
(x) 
X 
 
Primary efficacy endpoint 
 
 
(x) 
X 
(x) 
 
 
Secondary and exploratory 
efficacy endpoints 
 
 
(x) 
X 
(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. 
 
10.2 Variables 
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.  
 Primary efficacy variable 
10.2.1
Efficacy variables are described in Appendix 10. 
The primary efficacy endpoint relates to sleep maintenance and is assessed through the 
absolute change in minutes of WASO from Baseline9 to Days 1 and 210. 
WASO is defined in Section 6.1.1. 
                                                 
9 ‘Baseline’ is the mean of the two PSG nights during run-in period (V2). 
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10.2.1.1 Missing values 
No imputation will be performed for missing WASO values. However, if the proportion 
of missing values is significant (e.g., > 10%), sensitivity analyses will be considered to 
assess the influence on the primary analysis. 
If one of the two values is missing either at Baseline or at Days 1 and 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. 
 Secondary efficacy variable 
10.2.2
The secondary efficacy endpoint relates to sleep initiation and is assessed through the 
absolute change from Baseline11 to Days 1 and 212 in mean LPS. 
LPS is defined in Section 6.1.2. 
10.2.2.1 Missing values 
Similarly to the primary endpoint, no imputation is to be performed; however, sensitivity 
analyses will be considered as necessary. 
 Other exploratory efficacy variables 
10.2.3
Other exploratory efficacy endpoints include:  
• sWASO, WASO overnight 
• sLSO 
• TST and sTST 
• SQ 
• Sleep stage S1, S2, SWS and REM 
• Shifts from S2, SWS or REM to S1 or wake 
• Wake time during sleep 
• Frequency of awakenings as measured by PSG and self-reported 
• SE (defined as 100 × (TST / time in bed) 
• Next-day performance 
For each variable, multiple aspects will be considered in the analysis:  
10.2.3.1 Sleep-maintenance endpoint 
• WASO overnight (by hour of the night and by quarter of the night). 
• sWASO absolute change from Baseline13 to Days 1 and 214. 
                                                 
11 ‘Baseline’ is the mean of the two PSG nights during run-in period (V2). 
12 ‘Days 1 and 2’ is the mean of the corresponding two PSG treatment nights for a given treatment period. 


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10.2.3.2 Sleep-initiation endpoint 
• sLSO absolute change from Baseline13 to Days 1 and 214. 
10.2.3.3 Total sleep time endpoint 
• TST absolute change from Baseline11 to Days 1 and 212. 
• sTST absolute change from Baseline13 to Days 1 and 214. 
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. 
10.2.3.4 SQ 
• Change from Baseline13 to Days 1 and 214 in SQ. 
SQ is the sleep quality as determined by scores on the VAS.  
10.2.3.5 Sleep architecture 
• Mean15 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. 
• Mean15 latency to each sleep stage (S1, S2, SWS, and REM).  
10.2.3.6 Sleep continuity 
• Mean15 number and frequency of shifts from S2, SWS or REM to S1 or wake for the 
whole night. 
• Mean15 wake time during sleep: time spent in epochs scored as wake between LPS 
and last epoch not scored wake for the whole night. 
• Mean15 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 Baseline13 to Days 1 and 214 in self-reported number of awakenings 
(sNA). 
10.2.3.7 SE 
• Change from Baseline11 to Days 1 and 212. 
SE is defined as 100 × (TST [minutes] / time in bed [minutes]). 
                                                                                                                                                 
13 ‘Baseline’ is the mean value of the sleep diary entries during run-in period (V2). 
14 ‘Days 1 and 2’ is the mean value of the corresponding sleep diary entries for a given treatment period. 
15 ‘Mean’ calculated based on two PSG nights for a given treatment period. 


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10.2.3.8 Next-day performance 
• Change from Baseline13 to Days 1 and 214 in next-day performance assessed by 
scores on the VAS assessing morning sleepiness, daytime alertness and daytime 
ability to function. 
 Safety variables 
10.2.4
Safety analysis will be conducted on the SS, and will include all safety data collected up 
to 30 days after study drug discontinuation. 
10.2.4.1 Adverse events 
An AE is defined as any event that is recorded on the AE eCRF module regardless of the 
onset date. 
TEAEs for a given treatment group are those with onset date/time ≥ start date/time of 
double-blind study treatment of each treatment period and ≤ 5 days after end of study 
treatment of each treatment period, and ≤ 5 days after study treatment discontinuation. 
AE, including AEs of special interest [see Section 6.2], with onset prior to study 
treatment dose that worsened during the treatment phase will also be reported as TEAEs. 
The handling of missing or incomplete dates/time of AEs and assessments will be 
described in the SAP. 
10.2.4.2 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.  
10.2.4.3 ECG 
• Treatment-emergent ECG abnormalities from V3 until EOT. 
• Change from Baseline (V2, second morning) to the second morning after the PSG 
nights at V3, V4, V5, V6 and V7 in ECG parameters. 
10.2.4.4 Other safety parameters of interest 
Change from Baseline (mean of the two PSG nights at V2, run-in period) to Days 1 and 2 
(mean of the two PSG treatment nights) of each treatment period 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. 


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Incidence of most severe suicidal ideation and suicidal behaviors according to the 
C-SSRS for each treatment period. 
10.2.4.5 Vital signs 
Change from Baseline (mean of the first and second morning values after the two PSG 
nights at V2, run-in period) to the Days 1 and 2 (mean of the first and second morning 
values after the two PSG treatment nights) for a given treatment period in vital signs 
(systolic and diastolic BP, pulse rate and body temperature). 
10.2.4.6 Body weight 
Change from Baseline (V1) to the second morning after the PSG nights at V7 in body 
weight. 
  Other variables 
10.2.5
Pharmacokinetic 
Plasma concentration of ACT-541468 (~9–10 hours post-dose) at V3, V4, V5, V6 and 
V7. 
10.3 Description of statistical analyses 
 Overall testing strategy 
10.3.1
The study is intended to select the dose that allows a clinically meaningful reduction of 
WASO compared to placebo.  
The analyses described in the following sections assume no carry-over effect 
[see Section 3.2]. The duration of the washout is considered sufficient for all doses of 
ACT-541468. 
The incidence and pattern of missing values will be explored in order to evaluate the 
possible impact on the planned analyses. 
 Analysis of the primary efficacy variable 
10.3.2
10.3.2.1 Hypotheses and statistical model  
Subjects will be randomized 1:1:1:1:1 to five different sequences of five study treatments 
according to a Latin square design [see Table 1]. The five study treatments are oral fixed 
doses of AC-541468 (5, 10, 25, 50 mg) and placebo. 
The study is using the generalized Multiple Comparison Procedure – Modeling 
(MCP-Mod) approach [Bretz 2005, Pinheiro 2006, Pinheiro 2014], 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 (based on the primary efficacy endpoint).  


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The generalized approach is appropriate for this study design where each patient receives 
different doses in a sequence. A univariate dose-response relationship is modeled based 
on the mean change from baseline in WASO at each dose [see Section 10.3.2.3]. 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) larger 
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 given treatment 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 that is based on a pre-specified set of dose-response models 
describing the potential dose-response relationship. 
The following pre-defined dose-response models are 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 mean 
response estimates per individual dose and using optimal contrast coefficients 
corresponding to the candidate model. The mean response estimates are the least-squares 
mean (for change from baseline in WASO) of each dose group estimated by fitting a 
mixed model adjusted for baseline WASO, with dose group and period as fixed effects, 
and subject as a random effect. 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 




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 Analysis of secondary efficacy variable 
10.3.3
Similarly, an MCP-Mod-based analysis will be conducted on the secondary endpoint. 
Treatment effects on the secondary efficacy endpoint will also be assessed using a mixed 
model similar as for the primary analysis. 
 Analysis of other exploratory efficacy variables 
10.3.4
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. 
Further exploratory analysis will be conducted to assess the relationship of the changes 
between the perceived efficacy (subjective measures) and the objective measures from 
PSG. 
Additional exploratory analysis will be described in full detail in the SAP. 
10.3.4.1 Subgroup analyses 
Subgroup analyses may be considered and will be described in the SAP. 
 Analysis of the safety variables 
10.3.5
All safety analyses will be performed on the SS, by dose, using descriptive statistics. All 
safety data will be listed, with flags for quantitative abnormalities.  
Observations and assessments (e.g., AEs, laboratory data) occurring within a treatment 
period (from the time of dosing to the time immediately prior to the next dose) will be 
assigned to the dose taken in that period. 
10.3.5.1 Analysis of safety and tolerability endpoints 
Safety and tolerability quantitative endpoints will be summarized using descriptive 
statistics (mean, standard deviation, median, first and third quartiles, minimum, and 
maximum) while frequency counts and proportions will be used for categorical data. 
Unless stated otherwise, percentages will be computed on the number of subjects who 
received the given dose. 
10.3.5.2 Adverse events 
AEs and SAEs in subjects who were screened but not part of the SS will be listed. 
The number and percentage of subjects experiencing TEAEs and SAEs will be tabulated 
by dose 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. 


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• 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 screening and first day of double-blind 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. 
10.3.5.3 Laboratory variables 
Descriptive summary statistics by dose 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. Marked laboratory abnormalities [Appendix 1] 
will be summarized for each laboratory variable by dose providing their incidence and 
frequency.  
The number and percentage of subjects with treatment-emergent laboratory abnormalities 
will be tabulated by dose. 
10.3.5.4 ECG 
Incidence of clinically abnormal ECG on double-blind study treatment as well as 
treatment-emergent ECG abnormalities will be tabulated (frequency and percentage) by 
dose.  
On-treatment change in ECG parameters will be described using descriptive statistics. 
10.3.5.5 Vital signs 
Change will be summarized by dose. 
10.3.5.6 Other safety parameters of interest 
Change from Baseline (mean of the two PSG nights at V2, run-in period) to Days 1 and 2 
(mean of the two PSG treatment nights) in KSS, DSST, and SDS will be summarized 
by dose. 
The incidence of most severe suicidal ideation and suicidal behaviors according to the 
C-SSRS will be summarized by dose. 


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All scales analyses will be performed according to their respective manual and 
interpretation guide. 
10.3.5.7 Exposure-safety analysis 
The exposure-safety relationship will be explored using C9-10h (plasma concentration of 
ACT-541468 the morning of the second PSG night at V3, V4, V5, V6 and V7) 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. 
10.3.5.8 Pharmacokinetic 
Plasma concentrations of ACT-541468 will be analyzed by descriptive statistics, 
including arithmetic and geometric means, standard deviation, minimum, maximum, and 
median. 
10.4 Interim analyses  
No formal interim analysis will be performed for determining whether to stop (or modify) 
the study early (i.e. no hypothesis testing will be conducted at 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 charters, 
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. 
10.5 Sample size 
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 Days 1 and 2 with an 
ACT-541468 dose is 25 minutes (standard deviation = 40 minutes) larger than with 
placebo, and values from 8% of subjects are not available for analysis, a total sample size 
of approximately 50 (i.e., 10 subjects per sequence allocated in a 1:1:1:1:1 ratio) provides 
between 89–92% power (power is 90% when averaged over all candidate models 
[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. 


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The between-subject standard deviation in WASO across all arms is expected to be no 
more than 40 minutes. The sample size is conservative, since a correlation of zero (and 
non-negative) is assumed between assessments across dose within the same subject. 
Assuming the maximum mean reduction in WASO is considered to be 20 minutes larger 
than with placebo, a sample size of 71 subjects (with no dropout) are required. This 
number decreases to 32 subjects if we consider a maximum reduction of 30 minutes 
compared to placebo. 
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 
provide a certain precision in estimation of a given target dose. 
11 DATA HANDLING  
11.1 Data collection 
The investigator/delegate is responsible for ensuring the accuracy, completeness and 
timelines 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 staff 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) and on paper (i.e., DSST) are considered source data. Site staff 
will review and ensure completeness and readability of the subjects’ 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. 


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11.2 Maintenance of data confidentiality 
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs 
or other documents (e.g., documents attached to SAE forms) submitted to Actelion and 
any CROs, subjects must be identified only by number and never by their name or 
initials, 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 investigator/delegate. 
11.3 Database management and quality control 
eCRFs will be used for all subjects. The investigators will have access to the site eCRF 
data until the database is 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 
staff 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 and ECG recordings will be processed through a central laboratory. 
PSG data will be read by a central reviewer. Patient-reported outcomes (PRO) will be 
collected on hand-held devices. All the results of the laboratory analyses, ECGs, PSG 
data and PRO will be electronically sent 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. 
AEs are coded according to the latest Medical Dictionary for Regulatory Activities 
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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  
12.1 Ethics and Good Clinical Practice 
Actelion staff and the investigators will ensure that the study is conducted in full 
compliance with ICH-GCP Guidelines, the principles of the ‘Declaration of Helsinki’, 
and with the laws and regulations of the country in which the study is conducted. 
12.2 Independent Ethics Committee / Institutional Review Board 
The investigator will submit this protocol and any related document(s) provided to the 
subject (such as the ICF) to an IEC/IRB. Approval from the committee/board must be 
obtained before starting the study, and must be documented in a dated letter to the 
investigator, clearly identifying the study, the documents reviewed, and the date of 
approval. 
Modifications made to the protocol or the ICF after receipt of the approval must also be 
submitted as amendments by the investigator to the IEC/IRB in accordance with local 
procedures and regulations [see Section 12.6]. 
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 staff was present during an IEC/IRB meeting, it must be clear 
that this person did not vote. 
12.3 Informed consent 
It is the responsibility of the investigator/delegate to obtain informed consent according 
to ICH-GCP and Declaration of Helsinki guidelines and local regulations from each 
individual participating in this study. 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 study and it shall 


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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 staff 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 staff 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 study-related 
procedures (i.e., any procedures required by the protocol) begin.  
A copy of the signed and dated ICF is given to the subject; the original is filed in the site 
documentation. The informed consent process must be fully documented in the subject’s 
medical records. This must include at a minimum the study reference, the subject 
number, the date and, if applicable, time when the subject was first introduced to the 
study, the date and, if applicable, time of consent, who participated in the consent 
discussion, who consented the subject, and any additional person present during the 
consent process (e.g., subject’s family member[s]), and the information that a copy of the 
signed ICF was given to the subject. 
12.4 Compensation to subjects and investigators 
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. 
12.5 Protocol adherence/compliance 
The investigator must conduct the study in compliance with the IEC/IRB and/or the 
regulatory authority-approved version of the protocol and must not implement any 
deviation/change from the protocol, except when deviation is necessary to eliminate an 
immediate hazard to the subject. 
If a protocol deviation occurs, the investigator/delegate will inform 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 
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All protocol deviations will be reported in the CSR. IECs/IRBs will be provided with 
listings of protocol deviations as per local requirements. 
12.6 Protocol amendments 
Any change to the protocol can only be made through a written protocol amendment. An 
amended protocol must be submitted to the IEC/IRB and regulatory authorities, 
according to their requirements. 
12.7 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the 
reconstruction and evaluation of the study. A number of attributes are considered of 
universal importance to source data and the records that hold those data. These include 
that the data and records are accurate, legible, contemporaneous, original (or certified 
copy), attributable, complete, consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and 
subjects’ source documents. 
These records must be kept by the investigator for 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 case 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 source data. The 


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printouts will be considered as the official clinical study records and must be filed either 
with the subject’s medical records or with the subject’s eCRF. 
In order to verify that the process the site uses to prepare certified copies is reliable, the 
CRA must be able to observe this process and confirm that the comparison of the source 
documents and the certified copy did not reveal inconsistencies. The CRA does not need 
to verify this process for all data of all subjects but at least for some of them (e.g., first 
subject; regular check during the study of critical data like inclusion/exclusion criteria, 
endpoints for some subjects) as per 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. 
12.8 Monitoring 
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 staff 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 staff must be available during monitoring visits and allow 
adequate time to meet with the CRA to discuss study-related issues. 


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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. In case a site does not enroll any 
subjects, the close-out visit may be performed prior to study database closure at the 
discretion of Actelion. 
12.9 Investigator Site File 
Each site will be provided with an ISF prior to the SIV. It will contain all the essential 
documents that are required to be up-to-date and filed at site as per ICH-GCP section 8. 
The ISF will include a table of content 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. 
12.10 Audit 
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., SOPs) 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 staff must cooperate with the auditor(s) and allow access to all 
study documentation (e.g., subject records) and facilities. 
12.11 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study (during 
the study or after its completion) at the site. 


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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 staff must cooperate with the inspector(s) and allow access to all 
study documentation (e.g., subject records) and study facilities. 
12.12 Reporting of study results and publication 
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 Trial 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 staff 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 


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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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[Scharf 2007] Scharf MB, Black J, Hull S, Landin R, Farber R. Long-term nightly 
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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 
INR = International Normalized Ratio; M/F = male/female; N/A = not applicable. 
 
 




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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 
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 
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 
M/F = male/female; NA = not applicable; TSH = thyroid-stimulating hormone. 
 


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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. 
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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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 drinks contains approximately 150–200 mg caffeine. 
 
 
 


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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 (V7). 
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 
 
 
Mood stabilizers, e.g.: 
Lamotrigine 
Gabapentin 
Lithium 
Oxcarbazepine 
Carbamazepine 
F 
 


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Valproic acid 
 
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 
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 
14.00, 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. 
 
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. 


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Those medications must be discontinued no later than 1 week prior to V1 and are 
forbidden until 24 hours after EOT (V6).  
CYP3A4 moderate and strong inhibitors and CYP3A4 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, nevirapine 
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, phenytion, St John’s Wort 
Cardiovascular: amiodarone, diltiazem, 
dronedarone, mibefradil, verapamil  
Cardiovascular: bosentan 
 
Hypoglycemics: pioglitazone, troglitazone 
Aprepitant, conivaptant, cimetidine, imatinib 
 
Grapefruit and grapefruit juice 
 
CYP3A4 substrates: alfentanil, apixaban, budesonide, buspirone, cisapride, crizotinib, 
cyclosporine, darifenacin, dihydroergotamine, domperidone, dronedarone, erlotinib, 
ergotamine, ethinylestradiol, 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. 
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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Appendix 5 
Digit Symbol Substitution Test 


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Appendix 6  
Insomnia Severity Index 


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Appendix 7  
Sheehan Disability Scale 


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Appendix 8  
Karolinska Sleepiness Scale 


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Appendix 9  Sleep diary 


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Appendix 10  Summary table of efficacy variables 
Objectives 
Variables 
Endpoints 
Sleep 
maintenance 
WASO 
Absolute change from Baselinea to Days 1 and 2b 
Primary 
WASO overnight 
Absolute change from Baselinea to Days 1 and 2b by hour of the night and by quarter of 
the night 
Exploratory 
Sleep initiation 
LPS 
Absolute change from Baselinea to Days 1 and 2b 
Secondary 
sLSO 
Absolute change from Baselinec to Days 1 and 2d 
Exploratory 
Total sleep time 
TST 
Absolute change from Baselinea to Days 1 and 2b 
Exploratory 
sTST 
Absolute change from Baselinec to Days 1 and 2d 
Sleep quality 
VAS 
Absolute change from Baselinec to Days 1 and 2d 
Exploratory 
Sleep architecture 
Sleep stages duration Meane 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 Meane latency to each sleep stage (S1, S2, SWS, and REM). 
Sleep continuity 
Shifts between sleep 
stages 
Meane number and frequency of shifts from S2, SWS or REM to S1 or wake for the 
whole night. 
Exploratory 
Wake time during 
sleep 
Meane wake time during sleep: time spent in epochs scored as wake between LPS and 
last epoch not scored wake for the whole night. 
Awakenings 
Meane 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 
Absolute Change from Baselinec to Days 1 and 2d in self-reported number of awakenings  
Sleep efficiency 
SE 
Absolute change from Baselinea to Days 1 and 2b 
Exploratory 


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Next-day 
performance 
VAS 
Absolute change from Baselinec to Days 1 and 2d 
Exploratory 
Note: a ‘Baseline’ is the mean of the two PSG nights during run-in period (V2), b ‘Days 1 and 2’ is the mean of the corresponding two PSG treatment nights for a given 
treatment period, c ‘Baseline’ is the mean value of the sleep diary entries during run-in period (V2), d ‘Days 1 and 2’ is the mean value of the corresponding sleep 
diary entries for a given treatment period, e ‘Mean’ calculated based on two PSG nights value for a given treatment period. 
LPS = latency to persistent sleep; PSG = polysomnography; REM = rapid eye movement; SE = sleep efficiency; sLSO = subjective latency to sleep onset; sNA = self-
reported number of awakenings; sTST = subjective total sleep time; SWS = slow-wave sleep; TST = total sleep time; VAS = visual analog scale; WASO = wake 
after sleep onset.  

SAP_001.pdf: 
 
 
Statistical Analysis Plan AC-078A202 
 
Multi-center, Double-blind, Randomized, Placebo-controlled, 5-period, 5-treatment Crossover,  
Polysomnography Dose-response Study to Assess the Efficacy and Safety of  
ACT-541468 in Elderly Subjects With Insomnia Disorder. 
 
ClinicalTrials.gov Identifier NCT02841709 
 
 
 
 
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-078A202 
Multi-center, double-blind, randomized, placebo-controlled, 5-period, 5-treatment 
crossover, polysomnography dose-response study to assess the efficacy and safety of 
ACT-541468 in elderly subjects with insomnia disorder 
 
Investigational Drug 
ACT-541468 
Idorsia Document Number 
D-17.014 
Document Status/Version Number 
Final Version 2.0 
Date 
12 July 2017 
 
Author 
 
Reviewers 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Confidential 
Property of Idorsia Pharmaceuticals Ltd. May not be used, divulged, published or 
otherwise disclosed without the consent of Idorsia Pharmaceuticals Ltd. 
 
 


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Statistical Analysis Plan 
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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 
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 ...............................13 
6.4.3 
Previous and concomitant therapies .................................................13 
6.5 
Study treatment exposure and compliance ...................................................14 
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 ..................................15 
7.3.1 
Design ...............................................................................................15 
7.3.1.1 
Candidate dose response models .............................................15 
7.3.2 
Analysis ............................................................................................17 
7.3.2.1 
Implementation of the MCP step .............................................17 


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7.3.2.2 
Implementation of the Mod step .............................................18 
7.3.2.3 
Dose selection based on WASO ..............................................19 
7.3.3 
Other .................................................................................................20 
7.4 
Supportive/sensitivity analyses .....................................................................20 
8 
ANALYSIS OF THE SECONDARY EFFICACY VARIABLES .............................21 
8.1 
Objective sleep onset ....................................................................................21 
9 
ANALYSIS OF OTHER EFFICACY VARIABLES .................................................21 
9.1 
Objective and subjective sleep maintenance ................................................22 
9.2 
Objective and subjective sleep onset ............................................................22 
9.3 
Objective and subjective Total Sleep Time ..................................................22 
9.4 
Sleep Quality ................................................................................................22 
9.5 
Sleep architecture .........................................................................................23 
9.6 
Objective and subjective sleep continuity ....................................................23 
9.7 
Sleep efficiency ............................................................................................23 
9.8 
Insomnia severity ..........................................................................................23 
9.9 
Next-day performance ..................................................................................24 
10 SAFETY ANALYSIS .................................................................................................24 
10.1 
Adverse events ..............................................................................................24 
10.2 
Laboratory data .............................................................................................26 
10.3 
Vital signs, weight and physical examination ..............................................29 
10.4 
Electrocardiograms .......................................................................................29 
10.5 
Other safety parameters of interest ...............................................................30 
10.5.1 
Digit Symbol Substitution Test .........................................................30 
10.5.2 
Karolinska Sleepiness Scale .............................................................31 
10.5.3 
Sheehan Disability Scale ..................................................................31 
10.5.4 
Neurological Examination ................................................................31 
10.5.5 
Columbia Suicide Severity Rating Scale ..........................................31 
10.6 
Pharmacokinetic ...........................................................................................32 
10.7 
Exposure-safety analysis ..............................................................................32 
11 INTERIM ANALYSES ..............................................................................................33 
12 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................33 
12.1 
Changes to the analyses planned in the study protocol ................................33 
12.2 
Changes in the conduct of the study / data collection ..................................33 
12.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................33 


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13 GENERAL DEFINITIONS AND DERIVATIONS ...................................................33 
13.1 
Treatment start and end dates .......................................................................33 
13.2 
Treatment period ...........................................................................................34 
13.3 
Study day ......................................................................................................34 
13.4 
Baseline ........................................................................................................35 
13.5 
Absolute change from baseline .....................................................................35 
13.6 
Handling of data when total sleep time is zero .............................................35 
13.7 
Handling of missing/incomplete date and time fields ..................................35 
14 REFERENCES ............................................................................................................37 
DOCUMENT HISTORY...................................................................................................38 
 
LIST OF TABLES 
 
Table 1 
Latin square design sequences ..........................................................................7 
Table 2 
Imputation rules for an incomplete or missing AE date .................................26 
Table 3 
Marked abnormalities in laboratory parameters for reporting ........................27 
Table 4 
Marked abnormalities in ECG parameters ......................................................30 
 
LIST OF FIGURES 
 
Figure 1 
Study design ......................................................................................................8 
Figure 2 
Candidate dose response models.....................................................................16 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ALT  
Alanine aminotransferase 
AST  
Aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
CI  
Confidence interval 
C-SSRS©  
Columbia Suicide Severity Rating Scale 
CV%  
Coefficient of Variation 
DSST©  
Digit Symbol Substitution Test 
ECG  
Electrocardiogram 
FAS  
Full analysis set 
IDMC  
Independent Data Monitoring Committee 
ISB  
Independent Safety Board 
ISI©  
Insomnia Severity Index 
KSS  
Karolinska Sleepiness Scale 
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 
PPS  
Per-protocol analysis set 
PSG  
Polysomnography 
PT  
Preferred term 
QTcB  
QT interval corrected according to Bazett’s formula 
QTcF  
QT interval corrected according to Fridericia’s formula 
REM  
Rapid eye movement 


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RND set  
Randomized analysis set 
SAE  
Serious adverse event 
SAP  
Statistical analysis plan 
SCR set  
Screened analysis set 
SDS©  
Sheehan Disability Scale 
sLSO  
Subjective Latency to Sleep Onset 
sNAW  
Subjective Number of Awakenings 
SOC  
System organ class 
SQ  
Sleep Quality 
SS  
Safety set 
sTST  
Subjective Total Sleep Time 
sWASO  
Subjective Wake After Sleep Onset 
SWS  
Slow wave sleep 
TBIL  
Total bilirubin 
TD  
Target dose 
TIB  
Time in bed 
TST  
Total sleep time 
ULN  
Upper limit of normal 
VAS  
Visual analog scale 
WASO  
Wake After Sleep Onset 
WHO  
World Health Organization 
WHO DRL  
WHO Drug Reference Listing 
 


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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. 
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 Idorsia and/or designated contract research organizations using 
Statistical Analysis System 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-078A202, Final Version 2, dated 10 August 2016 was used when writing 
this SAP. 
2 
STUDY DESIGN 
This is a multi-center, double-blind, randomized, placebo-controlled, 5-period, 
5-treatment crossover, polysomnography (PSG) dose-response Phase 2 study to assess 
the efficacy and safety of ACT-541468 in elderly subjects with insomnia disorder. 
Approximately 50 subjects will be randomized in a 1:1:1:1:1 ratio to five different 
sequences of five study treatments according to a Latin square design as shown in 
Table 1. The five study treatments are ACT-541468 5 mg (Dose 1), 10 mg (Dose 2), 
25 mg (Dose 3), 50 mg (Dose 4), and placebo. In each treatment period, subjects are to 
receive one of five study treatments in the order of the sequence they are randomized to. 
Table 1 
Latin square design sequences 
 
Treatment period (double-blind) 
1 
2 
3 
4 
5 
Sequence 
1 
Dose 4 
Dose 2 
Dose 3 
Dose 1 
Placebo 
2 
Dose 2 
Placebo 
Dose 4 
Dose 3 
Dose 1 
3 
Dose 3 
Dose 1 
Dose 2 
Placebo 
Dose 4 
4 
Placebo 
Dose 4 
Dose 1 
Dose 2 
Dose 3 
5 
Dose 1 
Dose 3 
Placebo 
Dose 4 
Dose 2 
 
The study design is shown in Figure 1. Single-blind placebo (two capsules of 
ACT-541468-matching placebo) is administered at V2 (run-in) and double-blind study 
treatment is administered at V3, V4, V5, V6 and V7. To keep the blind, a placebo capsule 
matching ACT-541468 will be administered concomitantly with one capsule of 
ACT-541468 for the 5, 10, and 25 mg doses, while for the 50 mg dose, two capsules of 
ACT-541468 25 mg will be administered. The double-blind treatment phase consists of 
five treatment periods starting with the first dose of study treatment in the first evening of 


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the randomization visit (V3) and ending in the second morning of V7. Each treatment 
period consists of two consecutive PSG nights on the assigned study treatment which is 
directly followed by a 5- to 12-day washout period. The End-of-Treatment is reached in 
the second morning of V7 after the last dose of double-blind treatment and after all 
morning assessments have been performed. 
Figure 1 
Study design
Note: V = Visit; ▬ = PSG nights; D = dose; P = placebo. 
 
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 on the first 2 days of 
each treatment period. 
3.2
Secondary objectives 
The secondary objective of the study is to evaluate the dose response of ACT-541468 on 
Latency to Persistent Sleep (LPS) on the first 2 days of each treatment period. 
3.3
Other objectives 
To explore the effect of ACT-541468 on other sleep parameters at each treatment period. 
Sleep parameters will include various objective and subjective measures. 
To assess the safety and tolerability of oral administration ACT-541468 in elderly 
subjects with insomnia disorder. 


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To explore the relationship between exposure (concentration of ACT-541468 
approximately 9–10 h post-dose) and safety. 
4 
GENERAL ANALYSIS CONSIDERATIONS 
Unless noted otherwise, all statistical summaries will be presented by dose group and in 
the following order: Placebo, ACT-541468 5 mg, ACT-541468 10 mg, ACT-541468 
25 mg, ACT-541468 50 mg. 
Categorical data will be summarized by frequency counts and percentages. Unless 
specified otherwise, percentages will be based on the total number of subjects in the 
corresponding dose group. 
Continuous data will be summarized using descriptive statistics (N, mean, standard 
deviation, median, minimum and maximum). 
5 
ANALYSIS SETS 
A subject must have given informed consent to be included in any analysis set. 
The number of subjects in each analysis set defined below will be tabulated by dose 
group (including single-blind placebo). 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. Unless noted otherwise, 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 (i.e., a treatment sequence). 
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 (i.e., treatment sequence) 
they have been assigned to (which may be different from the study treatment [or 
treatment sequence] 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 who have at least one 
WASO assessment at Baseline and at least one WASO assessment at Days 1 and 2 of any 
given treatment period. 
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 both Baseline and Days 1 and 2 of each treatment period, 
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 and 2 of each treatment period, 
• 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 randomized subjects who received at least one dose of 
study treatment (including single-blind placebo). Subjects will be evaluated according to 
the actual dose (i.e., treatment sequence) they received (based on the kit number, visit and 
period recorded on the ‘Study Double Blind Treatment Dispensing & Accountability’ 
page), which may differ from the randomly assigned dose (or treatment sequence). One 
SS will be defined per dose group (including single-blind placebo). 
5.7 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. 
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 phase (based on ‘Was the 
subject randomized?’ recorded as ‘No’ in the ‘Randomization’ page), 
• Number (%) of subjects who discontinued during screening period and not treated in 
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 
Blind Treatment Dispensing & Accountability’ page at V2 and no assessments at 
V2), 


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• 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 phase 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 and presented by randomized treatment 
sequence and as one group (i.e., All subjects): 
• 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 first double-blind treatment period (based on 
non-missing double-blind treatment start date at Visit 3), 
• Number of subjects treated in second double-blind treatment period (based on 
non-missing double-blind treatment start date at Visit 4), 
• Number of subjects treated in third double-blind treatment period (based on 
non-missing double-blind treatment start date at Visit 5), 
• Number of subjects treated in fourth double-blind treatment period (based on 
non-missing double-blind treatment start date at Visit 6), 
• Number of subjects treated in fifth double-blind treatment period (based on 
non-missing double-blind treatment start date at Visit 7), 
• Number of subjects completing the first safety follow-up phone call (based on 
non-missing date of phone call on the ‘Safety Follow-up Phone Call Summary’ page), 
• Number of subjects completing the end of study safety follow-up (based on 
non-missing date of phone call on the ‘Safety Follow-up Phone Call Summary - EOS’ 
page). 


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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 in the ‘Premature Discontinuation of Study 
Treatment’ page). 
Reasons for premature double-blind study treatment discontinuation will be assigned to 
the dose group of the last drug intake before date of premature treatment discontinuation. 
The following summaries will be based on the RND set: 
• Number (%) of subjects who prematurely discontinued from study (based on 
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). 
Reasons for premature study discontinuations will be assigned to the dose group of the 
last drug intake before date of premature study discontinuation. 
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. Important and other protocol deviations will be summarized per pre-specified 
category (i.e., During screening period; During run-in period; During follow-up phase; 
Non-study phase specific) as one group (i.e., All subjects). Important and other protocol 
deviations during double-blind treatment phase will be summarized by dose group. A 
subject with multiple occurrences of a protocol deviation is counted only once per 
protocol deviation category and dose group. 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 presented as one group (i.e., All subjects). 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 (< 65, 65–74, 
≥ 75 years), and BMI categories (< 25, 25 to 30, > 30 kg/m2) will be summarized. 


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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. 
Summaries 
will 
be 
provided 
for 
previous, 
study-concomitant 
and 
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. 
Study treatment concomitant therapies (a subset of study-concomitant therapies) are any 
treatments taken at least once during at least one treatment period. Study treatment 
concomitant therapies will be assigned to a dose group (including single-blind placebo) 
according to the time windows defined in Section 13.2 and the concomitant therapy start 
and end dates. One therapy might be concomitant to one or several treatment periods. 
Previous and study concomitant therapies will be presented as one group (i.e., All 
subjects). Study treatment concomitant therapies will be presented by dose group 
(including single-blind placebo) and as one group (i.e., All subjects). 
All concomitant therapies will be listed using the SS. 


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An incomplete (day or month missing) or missing concomitant therapy date will be 
imputed as described in the algorithm below. The ‘lower limit’ and ‘upper limit’ refers to 
the earliest and latest possible dates, respectively. 
As an example: If concomitant therapy end date is MAR2017 (day missing), the lower 
limit is 01MAR2017 and the upper limit is 31MAR2017. If concomitant therapy end date 
is 2017 (day and month missing), the lower limit is 01JAN2017 and the upper limit is 
31DEC2017. 
The following algorithm will be applied for therapies having an incomplete start date 
and/or end date: 
Previous therapy: 
If therapy end date (upper limit) is before the signing of the informed consent form. 
Study concomitant therapies: 
1. If therapy end date (lower limit) is after the signing of the informed consent form and 
≤ 30 days after study treatment discontinuation, or 
2. If therapy is ongoing (no end date). 
Study treatment concomitant therapies: 
If therapy start and end dates are incomplete: 
If therapy start date (upper limit) is ≤ run-in single-blind placebo treatment start date and 
either: 
1. the therapy is ongoing (no end date), or 
2. the therapy end date (lower limit) is ≥ last study treatment intake. 
Here, therapy is assigned to all dose groups. 
If only therapy end date is incomplete: 
When therapy is taken during at least one treatment period (including single-blind 
placebo) and end date (lower limit) is ≥ last study treatment intake. 
If only therapy start date is incomplete: 
When therapy is taken during at least one treatment period (including single-blind 
placebo) and start date (upper limit) is ≤ run-in single-blind placebo 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. 


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For each dose group, the number (%) of subjects receiving zero, one or two days of 
double-blind treatment will be tabulated by dose group (including single-blind placebo). 
Double-blind treatment exposure and compliance data will be listed along with reasons 
for treatment end. 
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 and 2. 
Baseline is the mean of the two PSG nights during the run-in period (V2). Days 1 and 2 is 
the mean of the corresponding two PSG treatment nights for a given treatment period. 
WASO is the time (min) spent awake after onset of persistent sleep [see definition of LPS 
in Section 8.1] until lights on as determined by PSG. The PSG recording is centrally 
scored by independent scorers. 
7.2 Handling of missing data 
For the main analysis, 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 and 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. 
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 version 
0.9.14 [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, 


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four pre-specified dose response models are considered: three Emax models and one linear 
model. A graphical display of these models is shown in Figure 2. Here, the maximum 
mean reduction in WASO from baseline to Days 1 and 2 with ACT-541468 50 mg dose 
is assumed to be 25 minutes longer than with placebo. 
Figure 2 
Candidate dose response models 
 
The following describes how the parameters (i.e., ED50) of these models are calculated. 
For the purpose of determining optimal contrasts, only the standardized form 


0
0
,
d
f
 
of the dose response model 




0
0
1
0
,
,




d
f
d
f


 needs to be considered 
[Bretz 2005], i.e., the scale parameters (
0
 and 
1
) are removed from the functional 
form. 
The functional form of the Emax model is defined as 

d
ED
d
E
E
d
f



50
max
0
,
, where 
d = dose; E0 = placebo (basal) effect; Emax = maximum change in effect associated with 
dose; ED50 = dose that is expected to give half of the maximum change. 
Dose (mg)
Mean reduction from baseline in WASO (min)
10
15
20
25
30
35
Emax (ED50=1.11)
0
10
20
30
40
50
Emax (ED50=3.75)
0
10
20
30
40
50
Emax (ED50=15)
10
15
20
25
30
35
Linear


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The standardized form of the Emax model is therefore 
(
)
d
ED
d
d
f
+
=
50
0
0
,θ
, which 
represents the percentage (p) of the maximum change from the basal effect associated 
with dose (d) (since the standardized Emax model is the same as the functional form when 
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) 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. 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. 


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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
'
'
  
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 target dose(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 [Pinheiro 2014] and relies on asymptotic 


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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. 
First stage 
A linear mixed effects model (first stage model) will be used to calculate estimates for 
d
μˆ  (i.e., least squares [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 dose group (placebo and each ACT-541468 dose level), 
an additional fixed effect for period (five periods), a linear slope to adjust for WASO at 
baseline, and a random effect for subject. 
The variance of the change from baseline in WASO is assumed to be constant across 
each dose group, therefore a compound symmetry structure for Ŝ will be considered. 
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 
to 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 target dose. 
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 target dose (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. 


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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. 
• 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 target dose defined as 
15 minutes better than predicted mean value of placebo, 
• The 0.025, 0.5 (median) and 0.975 bootstrap percentiles of the target dose 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 and 2 in mean WASO will also be analyzed using a 
linear mixed effects model with the same factors as in the main analysis with the addition 
of region, race, gender, and age. 
If the proportion of missing WASO values is significant (e.g., > 10% of expected data 
points missing based on the FAS), a sensitivity analysis will be conducted using the FAS 
to assess the influence of missing data on the main analysis. A data point is considered 
missing if both WASO assessments are missing at a given visit (i.e., Baseline or Days 1 
and 2 of each treatment period). After the missing data is imputed, the change from 
baseline to Days 1 and 2 in mean WASO will be analyzed using the same linear mixed 
effects model as in the main analysis. A worst case scenario for imputing missing data 
will be considered: If the missing post-baseline value is for a dose group other than 


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placebo, then the worst post-baseline value recorded for that subject on any other dose 
group (including placebo) will be imputed. If the missing post-baseline value is for 
placebo, then the best post-baseline value recorded for that subject on any other dose 
group will be imputed. The dose group to which the missing value is imputed is based on 
the assigned treatment sequence. If the baseline value is missing, then the mean of all 
available baseline values will be imputed. A subject missing baseline as well as all 
post-baseline WASO values will be excluded from this analysis. 
Using the FAS, the number (%) of subjects missing both WASO assessments at Baseline 
(run-in period) and Visits 3, 4, 5, 6, and 7 will be presented by randomized treatment 
sequence and as one group (i.e., All subjects). 
8 
ANALYSIS OF THE SECONDARY EFFICACY VARIABLES 
The analysis of the secondary efficacy variable will be performed on the FAS. 
8.1 Objective sleep onset 
The secondary efficacy endpoint relates to objective sleep onset and is assessed through 
the absolute change in LPS from Baseline to Days 1 and 2. 
Baseline is the mean of the two PSG nights during the run-in period (V2), and Days 1 and 
2 is the mean of the corresponding two PSG treatment nights for a given treatment 
period. 
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. 
The same MCP-Mod analysis as performed for the primary endpoint will be conducted to 
evaluate the dose response of ACT-541468 on the secondary efficacy endpoint. 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. 
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 and 2 is the mean of the corresponding two PSG treatment nights for a given 
treatment period. 


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For endpoints based on subjective assessments (e.g., subjective WASO [sWASO], 
subjective Latency to Sleep Onset [sLSO], subjective TST [sTST], Sleep Quality [SQ]): 
• Baseline is the mean value of the sleep diary entries during the run-in period (V2), 
• Days 1 and 2 is the mean value of the corresponding sleep diary entries for a given 
treatment period. 
9.1 Objective and subjective sleep maintenance 
Summary statistics will be provided for: 
• Absolute values of WASO at Baseline and Days 1 and 2 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 Days 1 and 2 by gender and overall, 
• Absolute change in sWASO from Baseline to Days 1 and 2 by gender and overall. 
9.2 Objective and subjective sleep onset 
Summary statistics will be provided for: 
• Absolute values of LPS at Baseline and Days 1 and 2 by gender and overall, 
• Absolute values of sLSO at Baseline and Days 1 and 2 by gender and overall, 
• Absolute change in sLSO from Baseline to Days 1 and 2 by gender and overall. 
9.3 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 and Days 1 and 2 by gender and overall, 
• Absolute change in TST from Baseline to Days 1 and 2 by gender and overall, 
• Absolute values of sTST at Baseline and Days 1 and 2 by gender and overall, 
• Absolute change in sTST from Baseline to Days 1 and 2 by gender and overall. 
9.4 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 Days 1 and 2, 
• Absolute change in SQ from Baseline to Days 1 and 2. 


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9.5 Sleep architecture 
Absolute change from Baseline to Days 1 and 2 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 and 2 in the latency (min) to each sleep stage 
(S1, S2, SWS, and REM) will be summarized. Absolute values will also be summarized. 
9.6 Objective and subjective sleep continuity 
Mean values are the mean of the two PSG treatment nights at each visit. 
Absolute change from Baseline to Days 1 and 2 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 and 2 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 and 2 in mean number of awakenings (defined 
as the number of awakenings 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 Days 1 and 2 in the mean self-reported number of 
awakenings will be summarized. Absolute values will also be summarized. 
9.7 Sleep efficiency 
Sleep efficiency (%) is defined as 100 × (TST [min] / total time in bed [min]) where total 
time in bed is fixed to 480 min during the PSG nights. 
Absolute change from Baseline to Days 1 and 2 in Sleep efficiency will be summarized. 
Absolute values will also be summarized. 
9.8 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 values at screening (V1) will be summarized. 


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9.9 Next-day performance 
Daytime alertness and daytime ability to function are to be assessed once per treatment 
period (i.e., on the second PSG evening). Morning sleepiness is to be assessed twice per 
treatment period (i.e., on the first and second PSG evening). 
Absolute change from Baseline to Days 1 and 2 in next-day performance assessed 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. 
All safety data will be listed. 
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 assigned to the dose group based on the AE start date. AEs with an 
incomplete or missing start date will not be assigned to a treatment period. 
Treatment-emergent AEs are those that occurred from the start of the treatment period 
[see Section 13.1] until 5 days after last study treatment intake in each treatment period 
(or until the start of the next treatment period, if earlier). 
Non-treatment emergent AEs are those that occurred before the first treatment period or 
more than 5 days after the last study treatment intake of a given treatment period until the 
start of the next treatment period, or until the end of the last treatment period [see 
Section 13.2]. 
Post-treatment emergent AEs are those that occurred after the end of the last treatment 
period [see Section 13.2]. 
AEs will be summarized (frequency counts and percentages) by SOC and/or PT, and 
maximum intensity. AEs occurring during the run-in single-blind placebo treatment 
period will also be included in AE summaries defined below (except for AEs leading to 
premature discontinuation or temporary interruption, or on-treatment deaths). 
Deaths (whether on-treatment or not), and AEs (whether treatment-emergent or not) 
leading to premature study treatment discontinuation or temporary interruption will be 
assigned to the dose group (including single-blind placebo) of the last dose taken before 
death or onset of AE, respectively. 
The following AE summaries will be provided: 
• Treatment-emergent AEs, 


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• Treatment- and non-treatment emergent AEs, 
• Post-treatment emergent AEs, 
• Treatment-emergent AEs related to study treatment, 
• Treatment- and non-treatment emergent AEs related to study treatment, 
• AEs leading to premature discontinuation of double-blind study treatment, 
• AEs leading to temporary interruption of double-blind study treatment, 
• Occurrence of treatment and non-treatment emergent non-serious AEs, 
• Treatment-emergent serious AEs (SAEs), 
• Treatment- and non-treatment emergent SAEs, 
• Occurrence of treatment- and non-treatment emergent SAEs, 
• Treatment-emergent SAEs related to study treatment, 
• Treatment- and non-treatment emergent SAEs related to study treatment, 
• Treatment- and non-treatment emergent AEs with fatal outcome, 
• Treatment- and non-treatment emergent AEs related to study treatment with fatal 
outcome, 
• 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. 
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- and non-treatment emergent AESI as per investigator, 
• Treatment- and non-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., SOC, PT). 
An incomplete (day or month missing) or missing AE date will be imputed as described 
in the Table 2 below. The ‘upper limit’ refers to the latest possible date. 
As an example: If AE resolution date is MAR2017 (day missing), the upper limit is 
31MAR2017. If AE resolution date is 2017 (day and month missing), 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 
No imputation. 
No imputation. 
 
10.2 Laboratory data 
Laboratory analyses are based on data received from the central laboratory. Unless noted 
otherwise, laboratory data will be converted into SI units, and summaries and listings will 
include unscheduled assessments. 
Descriptive summary statistics of the observed values and absolute changes from baseline 
to the morning after the second PSG night (scheduled visit) in both hematology and blood 
chemistry laboratory parameters will be provided. Only scheduled assessments will be 
considered for this summary. 
Baseline is the scheduled assessment performed on the evening of the first PSG night. 
This assessment is planned immediately prior to treatment intake and is the baseline 
value for the dose group that immediately follows the assessment. Subjects missing 
baseline data on a particular parameter will have a missing baseline (and change from 
baseline) for that parameter. 
Descriptive summary statistics of the observed values and absolute changes from baseline 
[as per definition in Section 13.4] to the last value in the study in hematology and blood 
chemistry laboratory parameters will be provided, and presented as one group (i.e., All 
subjects). 
Marked laboratory abnormalities are defined in Table 3 below. A marked laboratory 
abnormality will be assigned to the dose group where it is present regardless of its 
presence in previous treatment periods. 
The number (%) of subjects with 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 
and treatment period. 
All laboratory data for subjects with at least one marked laboratory abnormality will be 
listed. 


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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) 
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) 
Alkaline phosphatase (U/L) 
> 2.5 × ULN (HH) 
> 5 × ULN (HHH) 


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Laboratory parameter 
Criteria for marked laboratory abnormalities 
Total bilirubin (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 (LLL) 
> 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) 
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) 


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Laboratory parameter 
Criteria for marked laboratory abnormalities 
Total T4 (nmol/L) 
< 45 (LL) 
> 160 (HH) 
ALT = alanine aminotransferase; AST = aspartate aminotransferase; INR = International Normalized Ratio; 
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 double-blind treatment will be summarized: the number 
(%) of subjects meeting the criteria defined below within a given central laboratory 
sample will be tabulated by dose group. 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 and treatment 
period. 
• Aspartate aminotransferase (AST) or alanine aminotransferase (ALT) > 3 × upper 
limit of normal (ULN) 
• AST or ALT > 5 × ULN 
• AST or ALT > 10 × ULN 
• TBIL > 1.5 × ULN and 2 × ULN 
• Alkaline phosphatase > 1.5 × ULN 
• (ALT or AST > 3 × ULN) and (TBIL > 2 × ULN) 
All AST and ALT values for subjects with an AST or ALT > 3 × ULN will be listed. 
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 first and second morning values after the 
PSG nights at V2, run-in period) to Days 1 and 2 (mean of the first and second morning 
values after the PSG treatment nights of each treatment period) in vital signs (systolic and 
diastolic blood pressure, pulse rate and body temperature) will be summarized. The 
absolute values at baseline and Days 1 and 2 will also be summarized. 
The changes from baseline (V1 or last value before double-blind treatment) to V7 (or last 
value on or following double-blind study treatment) in body weight will be summarized 
as one group (i.e., All subjects). 
Physical examination abnormalities will be listed. 
10.4 Electrocardiograms 
Unless noted otherwise, ECG summaries and listings will include unscheduled 
assessments. 


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The absolute change from baseline (V2, second morning) to the second morning of the 
PSG nights of each treatment period for ECG parameters (QTcF, QTcB, heart rate, PR, 
QRS) will be summarized. The absolute values will also be summarized. Only scheduled 
assessments will be considered for these summaries. 
Marked ECG abnormalities are defined in Table 4 below. A marked ECG abnormality 
will be assigned to the dose group where it is present regardless of its presence in 
previous treatment periods. 
The number (%) of subjects meeting the criteria of a marked ECG abnormality will be 
tabulated. 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 and treatment period. 
All ECG values for subjects with at least one marked ECG abnormality will be listed. 
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 interval corrected according to Bazett’s formula; QTcF = QT interval corrected according 
to Fridericia’s formula. LL, LLL, H, HH, HHH = flags for low and high marked abnormalities. 
 
10.5 Other safety parameters of interest 
10.5.1 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 and 2 (mean of the two PSG morning assessments for a given treatment 
period) in total DSST score will be summarized by gender and overall. Absolute values 
will also be summarized. 


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10.5.2 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 and 2 (mean of the two PSG morning assessments for a given treatment 
period) in KSS will be summarized by gender and overall. Absolute values will also be 
summarized. 
10.5.3 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 and 2 (mean of the two PSG morning assessments for a given treatment 
period) in SDS will be summarized by gender and overall. Absolute values will also be 
summarized. 
10.5.4 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 PSG morning by dose group (including single-blind 
placebo) by gender and overall. 
The time from treatment until the subject is considered safe to leave the center the next 
day will be summarized for each scheduled PSG morning by dose group (including 
single-blind placebo) by gender and overall. 
10.5.5 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 


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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 in 
each treatment period will also be provided. Subjects will be summarized under the worst 
of the following three categories, shown here in the order from best to worst: 1) No 
suicidal ideation or behavior, 2) Suicidal ideation only, and 3) Suicidal ideation and 
behavior. 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). 
10.6 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, 
minimum and maximum) of ACT-541468 plasma concentration collected approximately 
9–10 h post-dose in each treatment period (excluding double-blind placebo) 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 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. 
10.7 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 in each treatment period [excluding 


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double-blind placebo]) 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. 
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 independent statistical 
analysis center 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 
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 and 2 
of any given treatment period. 
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 
Not applicable. 
13 GENERAL DEFINITIONS AND DERIVATIONS 
13.1 Treatment start and end dates 
Double-blind study treatment start and end dates are the earliest and latest dates, 
respectively, of dose intake recorded on the ‘Study Double-blind Treatment Log’ page. 
Run-in single-blind placebo treatment start date (i.e., the start date of the single-blind 
placebo treatment period), is the earliest date of dose intake (i.e., date of capsules 
administered) recorded on the ‘Study Single Blind Treatment Dispensing & 
Accountability’ page at V2. 


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Treatment period 1 start date is the earliest date of dose intake (i.e., date of capsules 
administered) recorded for Visit 3 on the ‘Study Double Blind Treatment Dispensing & 
Accountability’ page. 
Treatment period 2 start date is the earliest date of dose intake (i.e., date of capsules 
administered) recorded for Visit 4 on the ‘Study Double Blind Treatment Dispensing & 
Accountability’ page. 
Treatment period 3 start date is the earliest date of dose intake (i.e., date of capsules 
administered) recorded for Visit 5 on the ‘Study Double Blind Treatment Dispensing & 
Accountability’ page. 
Treatment period 4 start date is the earliest date of dose intake (i.e., date of capsules 
administered) recorded for Visit 6 on the ‘Study Double Blind Treatment Dispensing & 
Accountability’ page. 
Treatment period 5 start date is the earliest date of dose intake (i.e,. date of capsules 
administered) recorded for Visit 7 on the ‘Study Double Blind Treatment Dispensing & 
Accountability’ page. 
13.2 Treatment period 
A treatment period is defined as the time from the start of the treatment period [see 
Section 13.1] until the start of the next treatment period. The end of the last treatment 
period (e.g., the fifth treatment period or an earlier treatment period if subject 
prematurely discontinued) is the date of first safety follow-up telephone call, or 12 days 
after the last study treatment intake, whichever is earlier. 
After the single-blind placebo treatment period, subjects are to receive one of 5 study 
treatments in each of the 5 double-blind treatment periods in order of the sequence they 
are randomized to. 
These treatment periods are used to assign assessments/events to dose groups (including 
single-blind placebo). 
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 number of awakenings (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 time in bed (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. 


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• 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’. 
• 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. 


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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 
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general 
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2014;33(10):1646-61.