Clinical trial NCT04753164
Conditions: Binge-Eating Disorder
Sponsor: Idorsia Pharmaceuticals Ltd.
Start date: 2021-02-16; Completion date: 2022-03-25
Enrollment: 136 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Placebo-controlled study to evaluate the efficacy and safety of oral ACT-539313 in the treatment of adults with moderate to severe binge eating disorder

Detailed description:

Arms: arm 1: None arm 2: None
Interventions: intervention 1: ACT-539313 intervention 2: Placebo
Intervention descriptions: intervention 1: ACT-539313 as capsules at a strength of 100 mg, taken orally, b.i.d. in the morning at breakfast and in the evening at dinner, with a glass of water during the treatment period. intervention 2: Matching placebo as identical capsules indistinguishable from ACT-539313, taken orally, b.i.d. in the morning at breakfast and in the evening at dinner, with a glass of water during the treatment period.

Protocol documents:
Prot_000.pdf: 
 
 
TPL-100601_v03 
 
 
ACT-539313 
Binge Eating Disorder 
 
Protocol ID-082A201 
 
Multicenter, double-blind, randomized, placebo-controlled, parallel-group, 
proof‑of-concept study to evaluate the efficacy and safety of oral ACT-539313 in the 
treatment of adults with moderate to severe binge eating disorder 
 
 
 
Study Phase: 
2 
EudraCT Number: 
Not applicable 
Status and version: 
Final Version 3 
Date: 
4 May 2021 
Document type: 
Amended Global protocol 
Idorsia document number  
(Doc No.): 
D-21.148 
 
 
 
The information contained in this document, especially unpublished data, is the property of the sponsor 
of this study, Idorsia Pharmaceuticals Ltd. It is therefore provided to you in confidence as an investigator, 
potential investigator, or consultant, for review by you, your personnel, and an independent ethics 
committee or institutional review board. It is understood that this information will not be disclosed to 
others without written authorization from Idorsia Pharmaceuticals Ltd, except to the extent necessary to 
obtain informed consent from those persons to whom the study treatment may be administered. 
 
 
 
 


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SPONSOR CONTACT DETAILS 
Sponsor 
Idorsia Pharmaceuticals Ltd 
Hegenheimermattweg 91 
CH-4123 Allschwil 
Switzerland 
 +41 58 844 00 00 
Clinical Trial Physician  
Contact details of the Clinical Trial Physician can 
be found in the Investigator Site File 
Medical Emergency Hotline 
Toll Telephone Number  
Site-specific toll telephone numbers and toll-free 
numbers for the Medical Emergency Hotline can 
be found in the Investigator Site File 
 
 
COORDINATING INVESTIGATOR 
Name / Title 
Address 
 
 
 
 
 
 
  
  
 
 
CONTRACT RESEARCH ORGANIZATION INFORMATION 
Some study activities will be delegated to Contract Research Organizations (CROs). A 
list of site-specific contact details can be found in the Investigator Site File. 
 
 
 




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INVESTIGATOR SIGNATURE PAGE 
Treatment name / number 
ACT-539313 
Indication 
Binge eating disorder 
Protocol number, study title 
ID-082A201 
Multicenter, 
double-blind, 
randomized, 
placebo-controlled, 
parallel-group, 
proof‑of‑concept study to evaluate the efficacy and safety of oral ACT-539313 in the 
treatment of adults with moderate to severe binge eating disorder. 
I agree to the terms and conditions relating to this study as defined in this protocol 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 participants 
(other than those procedures necessary for the well-being of the study participants). 
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. 
 
 
Principal 
Investigator 
Country 
Site 
number 
Town 
Date 
 
Signature 
 
 
 
 
 
 
 
 
 
 
 


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TABLE OF CONTENTS 
 
SPONSOR CONTACT DETAILS ..................................................................................... 2 
LIST OF ABBREVIATIONS AND ACRONYMS ......................................................... 11 
NON-SUBSTANTIAL AMENDMENT 2 ....................................................................... 15 
1 
PROTOCOL SUMMARY ......................................................................................... 18 
1.1 
Synopsis ........................................................................................................18 
1.2 
Scheme ..........................................................................................................28 
1.3 
Schedule of activities ....................................................................................28 
2 
INTRODUCTION ...................................................................................................... 32 
2.1 
Binge eating disorder ....................................................................................32 
2.1.1 
Definition ..........................................................................................32 
2.1.2 
Current treatment options .................................................................32 
2.1.3 
Unmet medical need in BED ............................................................33 
2.2 
ACT-539313 .................................................................................................33 
2.3 
Study rationale ..............................................................................................34 
2.4 
Benefit/risk assessment .................................................................................34 
3 
STUDY OBJECTIVES AND ENDPOINTS ............................................................. 36 
3.1 
Efficacy endpoints ........................................................................................38 
3.1.1 
Primary efficacy endpoint .................................................................38 
3.1.2 
Exploratory efficacy endpoints .........................................................39 
3.2 
Safety endpoints ...........................................................................................39 
3.3 
Pharmacokinetic endpoints ...........................................................................39 
3.4 
Appropriateness of endpoints .......................................................................40 
4 
STUDY DESIGN AND PLAN .................................................................................. 41 
4.1 
Study design .................................................................................................41 
4.1.1 
Study periods for an individual study participant .............................41 
4.2 
Study duration and global End-of-Study definition .....................................41 
4.3 
Study design rationale ..................................................................................42 
4.4 
Justification for dose .....................................................................................42 
4.5 
Study committee(s) .......................................................................................43 
5 
STUDY POPULATION ............................................................................................ 43 


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5.1 
Study participant population description ......................................................43 
5.2 
Rationale for the selection of the study population ......................................43 
5.3 
Inclusion criteria ...........................................................................................44 
5.4 
Exclusion criteria ..........................................................................................45 
5.5 
Contraception requirements for women of childbearing potential ...............47 
5.5.1 
Definition of childbearing potential ..................................................47 
5.5.2 
Methods of contraception .................................................................48 
5.6 
Contraception for male study participants with WOCBP partner ................49 
5.7 
Dietary aspects and physical activity restrictions .........................................49 
5.8 
Screen failures and re-screening ...................................................................50 
5.9 
Criteria for withdrawal of study participants ................................................50 
5.9.1 
Study treatment premature discontinuation ......................................50 
5.9.1.1 
Pregnancy ............................................................................... 51 
5.9.1.2 
Lack of compliance with methods of contraception .............. 51 
5.9.1.3 
Liver aminotransferase abnormalities .................................... 51 
5.9.1.4 
COVID-19 .............................................................................. 52 
5.9.2 
Withdrawal from the study ...............................................................53 
5.9.3 
Loss to follow-up ..............................................................................54 
6 
TREATMENTS ......................................................................................................... 55 
6.1 
Study treatment .............................................................................................55 
6.1.1 
Investigational treatment and matching placebo description ............55 
6.1.2 
Study treatment dosing and administration ......................................55 
6.1.2.1 
Study treatment dose adjustments .......................................... 55 
6.1.3 
Treatment assignment .......................................................................55 
6.1.4 
Blinding ............................................................................................55 
6.1.5 
Unblinding ........................................................................................56 
6.1.5.1 
Unblinding for final analyses ................................................. 56 
6.1.5.2 
Unblinding for Independent Data Monitoring Committee 
or interim analyses .................................................................. 56 
6.1.5.3 
Unblinding for suspected unexpected serious adverse 
reactions .................................................................................. 56 
6.1.5.4 
Emergency procedure for unblinding ..................................... 56 
6.1.6 
Study treatment handling/preparation/storage/accountability ..........57 
6.1.6.1 
Study treatment packaging and labeling ................................ 57 
6.1.6.2 
Study treatment distribution and storage at the site ............... 57 
6.1.6.3 
Study treatment dispensing .................................................... 57 
6.1.6.4 
Study treatment accountability ............................................... 58 
6.1.6.5 
Study treatment return and destruction .................................. 59 
6.1.7 
Study treatment compliance ..............................................................59 


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6.2 
Previous and concomitant medications ........................................................59 
6.2.1 
Allowed concomitant therapy ...........................................................59 
6.2.2 
Forbidden concomitant therapy ........................................................59 
6.3 
Medical care of study participants after study completion / withdrawal 
from study .....................................................................................................60 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS AND PROCEDURES .......... 60 
7.1 
General information ......................................................................................60 
7.1.1 
Screening ..........................................................................................61 
7.1.2 
Unscheduled visits ............................................................................61 
7.1.3 
Study completion ..............................................................................61 
7.2 
Study assessments and procedures ...............................................................62 
7.2.1 
Demographics / baseline characteristics ...........................................63 
7.2.2 
Reporting of previous/concomitant medications / non-
pharmacological therapy / medical or surgical interventions or 
procedures and methods of birth control in the eCRF ......................64 
7.2.3 
Eligibility assessments ......................................................................64 
7.2.3.1 
Structured Clinical Interview for DSM-5 - Clinical Trial 
Version (SCID-5) ................................................................... 64 
7.2.3.2 
Eating Disorder Examination Questionnaire (EDE-Q) .......... 65 
7.2.3.3 
Mini International Neuropsychiatric Interview© .................... 65 
7.2.3.4 
Binge Eating Diary ................................................................. 65 
7.2.4 
Efficacy assessments .........................................................................65 
7.2.4.1 
Binge Eating Diary ................................................................. 65 
7.2.4.2 
Yale-Brown Obsessive-Compulsive Scale Modified for 
Binge Eating ........................................................................... 66 
7.2.4.3 
Clinical Global Impression of Severity Scale ........................ 66 
7.2.4.4 
Clinical Global Impression of Change Scale ......................... 66 
7.2.4.5 
Patient Global Impression of Severity scale ........................... 66 
7.2.4.6 
Patient Global Impression of Change scale ............................ 67 
7.2.4.7 
Eating Disorder Examination Questionnaire (EDE-Q7) ........ 67 
7.2.4.8 
Hamilton Depression Rating Scale (HAMD-17) ................... 67 
 
 
7.2.4.10 
Body weight and height .......................................................... 68 
7.2.5 
Safety assessments ............................................................................68 
7.2.5.1 
Physical examination .............................................................. 68 
7.2.5.2 
Vital signs ............................................................................... 68 
7.2.5.3 
Electrocardiograms ................................................................. 69 
7.2.5.4 
Clinical laboratory assessments .............................................. 70 
7.2.5.5 
Stanford Sleepiness Scale ....................................................... 72 


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7.2.5.6 
Benzodiazepine Withdrawal Symptom Questionnaire ........... 72 
7.2.5.7 
Columbia Suicide Severity Rating Scale©.............................. 72 
7.2.5.8 
Assessments in the context of COVID-19: 
Recommendations and instructions ........................................ 73 
7.2.5.9 
COVID-19 testing .................................................................. 76 
7.2.6 
Pharmacokinetic assessments ...........................................................76 
8 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS .......................... 76 
8.1 
Safety definitions ..........................................................................................76 
8.1.1 
Definition of adverse events .............................................................76 
8.1.2 
Definition of serious adverse events .................................................77 
8.1.3 
Intensity of adverse events ................................................................78 
8.1.4 
Relationship to study treatment ........................................................78 
8.1.5 
Relationship to study design or protocol-mandated procedure ........78 
8.1.6 
Definition of adverse events of special interest ................................78 
8.1.7 
Definition of study treatment overdose, misuse and abuse ..............79 
8.2 
Reporting procedures ....................................................................................79 
8.2.1 
Reporting and follow-up of AEs .......................................................79 
8.2.2 
Reporting and follow-up of SAEs ....................................................80 
8.2.3 
Reporting procedure for SUSARs ....................................................80 
8.3 
Pregnancy .....................................................................................................80 
8.3.1 
Reporting of pregnancy ....................................................................81 
8.3.2 
Follow-up of pregnancy ....................................................................81 
9 
STATISTICAL METHODS ...................................................................................... 81 
9.1 
Analysis sets .................................................................................................81 
9.1.1 
Screened set ......................................................................................81 
9.1.2 
All randomized set ............................................................................81 
9.1.3 
Full analysis set .................................................................................82 
9.1.4 
Per-protocol analysis set ...................................................................82 
9.1.5 
Safety set ...........................................................................................82 
9.1.6 
PK set ................................................................................................82 
9.1.7 
Usage of the analysis sets .................................................................82 
9.2 
Description of statistical analyses .................................................................83 
9.2.1 
Overall testing strategy .....................................................................83 
9.2.2 
Analysis of the primary efficacy outcome(s) ....................................85 
9.2.2.1 
Variable definition .................................................................. 85 
9.2.2.2 
Primary analysis ..................................................................... 85 
9.2.2.3 
Handling of missing data and intercurrent events .................. 86 
9.2.2.4 
Sensitivity analyses ................................................................ 86 


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9.2.2.5 
Supplementary analyses ......................................................... 86 
9.2.2.6 
Subgroup analyses .................................................................. 87 
9.2.3 
Analysis of the secondary efficacy outcome(s) ................................87 
9.2.4 
Analysis of exploratory efficacy outcomes ......................................87 
9.2.4.1 
Variable definitions ................................................................ 87 
9.2.4.2 
Analyses ................................................................................. 88 
9.2.5 
Analysis of safety outcomes .............................................................89 
9.2.6 
Adverse events ..................................................................................89 
9.2.7 
Laboratory data .................................................................................90 
9.2.8 
Vital signs .........................................................................................90 
9.2.9 
Electrocardiography ..........................................................................90 
9.2.10 
Specific safety endpoints ..................................................................90 
9.2.11 
Analyses of other outcomes ..............................................................91 
9.3 
Interim analyses ............................................................................................91 
9.4 
Sample size ...................................................................................................91 
10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS ................................................................................................. 92 
10.1 
Regulatory and ethical considerations ..........................................................92 
10.2 
Informed consent process .............................................................................93 
10.3 
Data protection and privacy ..........................................................................94 
10.4 
Indemnification, compensation and refund of expenses to study 
participants and investigators .......................................................................94 
10.5 
Essential documents and retention of documents .........................................95 
10.5.1 
Investigator Site File .........................................................................95 
10.5.2 
Source documents .............................................................................95 
10.6 
Data handling ................................................................................................96 
10.6.1 
Data collection, data transfer procedure, and data access .................96 
10.6.2 
Database management and quality control .......................................97 
10.7 
Protocol deviations .......................................................................................98 
10.8 
Clinical monitoring .......................................................................................98 
10.9 
Study safety oversight ..................................................................................99 
10.10 
Premature termination or suspension of the study ........................................99 
10.11 
Audit ...........................................................................................................100 
10.12 
Inspections ..................................................................................................100 
10.13 
Reporting of study results and publication .................................................100 
11 REFERENCES ......................................................................................................... 102 
12 APPENDICES .......................................................................................................... 107 




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LIST OF ABBREVIATIONS AND ACRONYMS 
 
AAT  
Approach Avoidance Task 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
APA  
American Psychiatric Association 
AST  
Aspartate aminotransferase 
AUC  
Area under the plasma concentration vs time curve 
AUCτ  
Area under the plasma concentration vs time curve during a dose 
interval 
b.i.d.  
Twice daily 
BE  
Binge eating 
BED  
Binge eating disorder 
BMI  
Body mass index 
BWSQ  
Benzodiazepine Withdrawal Symptoms Questionnaire 
CDC  
US Centers for Disease Control and Prevention  
CFR  
Code of Federal Regulations (US) 
CGI-C  
Clinical Global Impression of Change scale 
CGI-S  
Clinical Global Impression of Severity scale 
CI  
Confidence interval 
CNS  
Central nervous system 
COVID-19  
Coronavirus disease 2019 
CRA  
Clinical Research Associate 
CRO  
Contract Research Organization 
CSR  
Clinical study report 
C-SSRS©  
Columbia Suicide Severity Rating Scale© 
CYP  
Cytochrome P450 
DB  
Double-blind 
DDI  
Drug-drug interaction(s) 


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DSM-(IV/5)  
Diagnostic and Statistical Manual of Mental Disorders (4th / 5th 
edition) 
ECG  
Electrocardiogram 
eCRF  
Electronic case report form 
EDE-Q(7)  
Eating Disorder Examination Questionnaire (7-item) 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
FAS  
Full analysis set 
FDA  
Food and Drug Administration (US) 
FERT  
Facial Expression Recognition Task  
GCP  
Good Clinical Practice 
GLP-1  
Glucagon-like peptide-1 
GSET  
Grip Strength Effort Task 
HAMD-17  
Hamilton Rating Scale for Depression (17-item) 
HbA1c  
Glycated hemoglobin 
HIV  
Human immunodeficiency virus 
HR  
Heart rate 
IB  
Investigator’s Brochure 
ICF   
Informed consent form 
ICH  
International Council for Harmonisation 
IEC  
Independent Ethics Committee 
IRB  
Institutional Review Board 
IRT  
Interactive Response Technology 
ISF  
Investigator Site File 
LSMean  
Least squares mean 
MAD  
Multiple-ascending dose 
MAR  
Missing at random 
MedDRA  
Medical Dictionary for Regulatory Activities 
MINI©  
Mini International Neuropsychiatric Interview© 
MPS  
Maier-Philipp subscale 
  
 


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OX1R  
Orexin receptor type 1 
OX2R  
Orexin receptor type 2 
PD  
Pharmacodynamic 
PGI-C  
Patient Global Impression of Change scale 
PGI-S  
Patient Global Impression of Severity scale 
PI  
Principal investigator 
PK  
Pharmacokinetic(s) 
POC  
Proof-of-concept 
PPS   
Per-protocol analysis set 
QTc  
Corrected QT interval 
QTcB  
QT interval corrected according to Bazett’s formula 
QTcF  
QT interval corrected according to Fridericia’s formula 
RND  
All-randomized analysis set 
RT  
Reaction time 
SAD  
Single-ascending dose 
SAE  
Serious adverse event 
SAF  
Safety analysis set 
SAP  
Statistical analysis plan 
SARS-CoV-2  
Severe acute respiratory syndrome coronavirus 2 
SCID-5  
Structured Clinical Interview for DSM-5 
SCR  
Screened analysis set 
SD  
Standard deviation 
SI  
International system of units 
SOC  
System Organ Class 
SSS  
Stanford Sleepiness Scale 
SUSAR  
Suspected unexpected serious adverse reaction 
TEAE  
Treatment-emergent adverse event 
TSH  
Thyroid-stimulating hormone 
ULN  
Upper limit of normal 
USPI  
United States Prescribing Information 
WHO  
World Health Organization 


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WOCBP  
Women of childbearing potential 
YBOCS  
Yale-Brown Obsessive-Compulsive Scale 
YBOCS-BE  
Yale-Brown Obsessive-Compulsive Scale modified for Binge 
Eating 
 


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NON-SUBSTANTIAL AMENDMENT 2 
Amendment rationale 
This amendment applies to protocol ID-082A201 Version 2 dated 17 December 2020. The 
resulting amended global protocol is Version 3 dated 4 May 2021. 
The purpose of this amendment is to simplify the language of, and therefore clarify, 
inclusion criterion #4 related to the definition of severity of BED assessed at screening 
(Visit 1). 
As the definition of BED (inclusion criterion #3) is based on DSM-5, and since DSM-5 
also includes a severity grading scale (while previous versions did not), it was considered 
appropriate to use that scale to define severity in inclusion criterion #4.  
However, in this study the criterion for inclusion at randomization is based on binge eating 
days per week (criterion #9) rather than on binge eating episodes. An attempt was made to 
harmonize the definition of severity based on binge eating episodes, as per DSM-5, with 
the requirement of days with binge eating episodes (inclusion criterion #9) at 
randomization.  
Inclusion criterion #4 reads: “Self-reported BED severity of at least moderate level, defined 
in this study as 4−7 BE episodes per week, and spread out over ≥ 3 days, for a duration of 
≥ 6 months” 
Feedback received from the study sites, however, showed that such a hybrid definition, 
consisting of both binge eating episodes and days, was too complex to interpret and may 
lead to confusion, and therefore requires revision.  
With this protocol amendment, study inclusion criterion #4 now reads “Self-reported BED 
severity of at least moderate level, defined as at least 4 BE episodes per week, on average, 
for a duration of at least 6 months” 
The rewording does not modify the target population, which remains identical to that 
described in previous protocol versions by inclusion criterion #9 (Section 5.3), assessed at 
Visit 2 (prior to randomization), which remains unchanged, and reads: “Reporting ≥ 3 BE 
days for each of the 2 weeks prior to randomization as documented in the participant’s BE 
diary and with BE diary entries completed for at least 6 days per week during this 2‑week 
period (between Visit 1 and 2).”  
In addition, the following modifications have been made: 
• In the Protocol Summary, correction of numbering for inclusion criterion 7, for 
consistency with core text in Section 5.3.  


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• Clarification on the administration of study drug on study visit days is provided in 
Section 6.1.6.3. 
• Exclusion criterion #19 did not explicitly exclude morphine and other opioids, although 
these are listed in the relevant section on forbidden medications. Sections have been 
aligned for consistency. 
• More detailed guidance on the recommended order of assessment/questionnaires is 
provided in Section 7.2. 
• The SCID-5 version used in this protocol is a customized version of the standard one, 
and it should be referenced as Structured Clinical Interview for DSM-5 – Clinical Trial 
version. The title of Section 7.2.3.1 has been revised accordingly. 
• Precision is added in Section 7.2.5.4 that all laboratory reports must be printed, 
reviewed, signed and dated by the investigator or delegate within 5 calendar days. 
• Reiteration of the reference time frame for the eligibility assessment based on items 2, 
3, 4 and 5 of the C-SSRS at Screening (exclusion criterion #26) is provided in 
Section 7.2.5.7 where the scale is discussed under “Safety assessments”. 
• Guidance has been added regarding COVID-19 vaccination during trial participation 
(Section 5.9.1.4). 
• Instructions for completion of the Stanford Sleepiness Scale (Appendix 3) have been 
clarified. 
• The C-SSRS version in Appendix 12 is slightly different from the version used in the 
electronic system. In section ‘Intensity of ideation’, Deterrents, the last item was not 
correct. Alignment with the ePRO version has been made.  
Minor editorial corrections have also been made. 
Changes to the protocol 
Two versions of the amended protocol have been prepared: 1) a clean version and 2) a 
comparison document showing deletions and insertions in comparison to the previous 
protocol version. 
Amended protocol sections 
The main sections of the protocol affected by this global amendment are listed below. 
Where applicable, the same changes have also been made to the corresponding sections of 
the protocol synopsis: 
Section 5.1 
Study participant population description 
Section 5.3 
Inclusion criteria  


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Section 5.4 
Exclusion criteria  
Section 5.9.1.4 
COVID-19 
Section 6.1.6.3 
Study treatment dosing and administration 
Section 7.2 
Study assessments and procedures 
Section 7.2.3.1 
Structured Clinical Interview for DSM-5 – Clinical Trial Version 
(SCID-5) 
Section 7.2.5.4 
Clinical laboratory assessments 
Section 7.2.5.7 
Columbia Suicide Severity Rating Scale 
Appendix 3 
Stanford Sleepiness Scale 
Appendix 12 
Columbia Suicide Severity Rating Scale© 
 
Summary of previous amendments 
Amendment Date 
Main reason(s) 
1 
17 December 
2020 
• Implement the modifications requested by the FDA at 
the time of the IND review to ensure that the safety 
and well-being of the research participants are 
protected. 
• BED severity aligned with DSM-5 definition. 
• Remote assessments in the context of COVID-19 
further described. 
 
 
 


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1 
PROTOCOL SUMMARY 
1.1 Synopsis 
TITLE 
Multicenter, double-blind, randomized, placebo-controlled, 
parallel‑group, proof-of-concept study to evaluate the efficacy 
and safety of oral ACT-539313 in the treatment of adults with 
moderate to severe binge eating disorder 
OBJECTIVES 
Evaluate the efficacy of ACT-539313 in the treatment of binge 
eating disorder (BED). 
Evaluate the safety and tolerability of ACT-539313 in 
participants with BED.  
Other objectives are described in Section 3.  
ENDPOINTS 
Primary efficacy endpoint 
The primary endpoint is the change from baseline to Week 12 
in the number of binge eating (BE) days per week. A BE day is 
defined as a day with at least one confirmed BE episode.  
Exploratory efficacy endpoints  
• Change from baseline to Week 12 in the number of BE 
episodes per week. 
• Percentage of study participants without BE episodes during 
the last 4 weeks of the treatment period. 
• Change from baseline to Week 12 in the total score of the 
Yale‑Brown Obsessive-Compulsive Scale modified for 
Binge Eating (YBOCS-BE). 
• Change from baseline to Week 12 in the subscale scores 
(compulsive/obsessive, 
restraint, 
control) 
of 
the 
YBOCS‑BE. 
• Change from baseline to Week 6 and to Week 12 in the 
Hamilton 
Rating 
Scale 
for 
Depression 
(17‑item) 
(HAMD‑17) total score. 
• Change from baseline to Week 6 and to Week 12 in the 
HAMD‑17 subitems 10 and 11.  
• Change from baseline to Week 6 and to Week 12 in the 
HAMD‑17 Maier-Philipp subscale (MPS) score. 
• Change from baseline to Week 12 in the Eating Disorder 
Examination Questionnaire (7‑item; EDE‑Q7) global score 


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and 3 subscales scores (dietary restraint, shape/weight 
overvaluation, and body dissatisfaction). 
Safety endpoints 
• Treatment-emergent adverse events (TEAEs) defined as an 
adverse event (AE) occurring from the start of study 
treatment administration up to the End‑of-Study (EOS).  
• Treatment-emergent serious AEs (SAEs) defined as an SAE 
occurring from the start of study treatment administration 
up to the EOS. 
• TEAEs leading to premature discontinuation of the study 
treatment. 
• Treatment-emergent AEs of special interest (AESIs), i.e., 
somnolence, from the start of study treatment administration 
up to the EOS.  
• Occurrence of daytime sleepiness assessed by Stanford 
Sleepiness Scale (SSS) from the start of study treatment 
administration up to Visit 4 (Week 2). 
• Treatment-emergent marked laboratory abnormalities from 
the start of study treatment administration to all assessed 
time points during the study. 
• Change in vital signs from baseline to all assessed time 
points during the study. 
• Medically relevant ECG abnormalities while on study 
treatment from baseline to all assessed time points during 
the study. 
• Occurrence of withdrawal symptoms upon treatment 
discontinuation, 
as 
measured 
by 
change 
between 
Week 12 / End‑of‑Treatment 
(EOT) 
and 
EOS 
visit, 
assessed by the Benzodiazepine Withdrawal Symptoms 
Questionnaire (BWSQ), and HAMD-17 total score. 
• Occurrence of suicidal ideation and/or behavior while on 
study treatment based on the Columbia Suicide Severity 
Rating Scale© (C-SSRS©) from baseline to all assessed time 
points during the study up to EOS. 
Details of endpoints are further described in Section 3. 


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DESIGN 
ID-082A201 is a Phase 2, proof-of-concept, randomized, 
double‑blind, parallel-group, multicenter study evaluating the 
efficacy and safety of 100 mg twice daily (b.i.d.) ACT‑539313 
in adults with moderate to severe BED versus placebo over a 
12‑week treatment period. 
PERIODS 
The study comprises the following consecutive periods: 
screening period (14–28 days), followed by a treatment period 
(12 weeks) and a safety follow-up period (7–13 days). 
PLANNED 
DURATION 
Approximately 14 months from first study participant, first visit 
to last study participant, last visit.  
SITE(S)/ 
COUNTRY(IES) 
Approximately 30 sites in the United States of America.  
STUDY 
PARTICIPANTS / 
GROUPS 
Approximately 120 study participants will be randomized to 
receive either ACT-539313 at a dose of 100 mg b.i.d. or placebo 
in a 1:1 ratio. 
INCLUSION 
CRITERIA 
Study participants must meet all the following inclusion criteria: 
Criteria assessed at Visit 1: 
1. Signed and dated informed consent form prior to any 
study‑mandated procedure. 
2. Male or female study participants aged 18 to 55 years at the 
time of signing the informed consent form. 
3. BED in accordance with Diagnostic and Statistical Manual 
of Mental Disorders Fifth Edition (DSM-5) criteria 
diagnosed using the Structured Clinical Interview for 
DSM‑5 (SCID‑5). 
4. Self-reported BED severity of at least moderate level, 
defined as at least 4 BE episodes per week, on average, for 
a duration of at least 6 months. 
5. BED in accordance with Eating Disorder Examination 
Questionnaire (EDE-Q). 
6. Clinical Global Impression of Severity scale (CGI-S) score 
of ≥ 4. 


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7. For women of childbearing potential (WOCBP) [see 
definition in Section 5.5]:  
• Negative serum pregnancy test at Visit 1; and  
• Agreement to undertake monthly urine or serum 
pregnancy tests during the study and up to the EOS visit; 
and  
• Agreement to use an acceptable contraceptive method 
as described in Section 5.5.2. 
8. Able to speak, read and understand English, to communicate 
well with the investigator, to understand the study 
requirements, and judged by investigator to be alert and 
oriented to person, place, time, and situation. 
Criteria assessed at Visit 2: 
9. Reporting ≥ 3 BE days for each of the 2 weeks prior to 
randomization as documented in the participant’s BE diary 
and with BE diary entries completed for at least 6 days per 
week during this 2‑week period (between Visit 1 and 2). 
10. CGI-S score of ≥ 4. 
11. For WOCBP: negative urine pregnancy test. 
EXCLUSION 
CRITERIA 
Study participants must not meet any the following exclusion 
criteria: 
Criteria assessed at Visit 1: 
1. Body mass index (BMI) < 18.0 kg/m2 or > 45 kg/m2. 
2. Any acute or chronic-persistent psychiatric disorder (see 
also under 3 and 4 below) other than BED diagnosed in the 
past, including anorexia nervosa, bulimia, psychotic 
disorders, bipolar disorder, hypomania, or dementia, as 
defined by the DSM-5 criteria or by the Mini International 
Neuropsychiatric Interview© (MINI©). 
3. Episode(s) of major depressive disorder or any anxiety 
disorder occurring within the 6 months prior to Screening as 
defined by the DSM-5 criteria or by the MINI©; or currently 


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taking, or has taken, any medication for depression or 
anxiety during the 3 months prior to Screening. 
4. History of substance use disorder (including alcohol use 
disorder), excluding nicotine and caffeine, within the 
12 months prior to Screening, as defined by the DSM-5 
criteria or by the MINI©. 
5. Any clinically unstable medical condition, significant 
medical disorder or acute illness that, in the investigator’s 
opinion, could interfere with the participants ability to 
comply with study assessments or abide by study 
restrictions. 
6. History of malignancy within 5 years prior to the Screening 
visit, except for adequately treated basal cell or squamous 
cell skin cancer. History of pituitary tumor, whether benign 
or malignant, is exclusionary. 
7. Presence of significant psychosocial or environmental 
stressors (e.g., loss of employment, loss of housing) or any 
factor that could impede participant’s ability to adhere to 
protocol requirements, as judged by the investigator. 
8. Participants whose work requires them to operate 
heavy‑duty vehicles or other heavy or dangerous machinery. 
Note: Participants must be cautioned on the potential risk of 
somnolence and it is recommended to refrain from engaging in 
hazardous activities that require complete mental alertness, 
including driving, following study treatment intake until fully 
alert and comfortable to do so [see also Section 5.7]. 
9. Use of any medications for the treatment of BED (including 
lisdexamfetamine [Vyvanse®]), any other eating disorder, 
obesity, or weight gain, or any other medication that could 
result in weight gain or weight loss, including 
over‑the‑counter and herbal products, within 3 months prior 
to Screening. 
10. Any ECG findings of corrected QT interval (QTc) 
prolongation or history of additional risk factors for torsade 
de pointes, which, in the opinion of the investigator, could 


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affect the participant’s safety or interfere with the study 
assessments. 
11. Any abnormal hematology or biochemistry test results, 
which, in the opinion of the investigator, could affect the 
participant’s safety or interfere with the study assessments. 
12. Aspartate 
aminotransferase 
(AST) 
and/or 
alanine 
aminotransferase (ALT) > 1.5 × upper limit of normal 
(ULN) and/or total/direct bilirubin > 1.5 × ULN and/or 
moderate to severe hepatic impairment defined as Child-
Pugh Score B or C. 
13. Positive test for either hepatitis B surface antigen or 
hepatitis C antibody and AST and/or ALT and/or total 
bilirubin test results at Screening above the ULN for the 
reference laboratory. 
14. Positive HIV test. 
15. Thyroid-stimulating hormone (TSH) level outside of the 
established reference range to an extent that is considered 
clinically relevant per investigator judgment. Participants 
diagnosed with hyper- or hypothyroidism who have been on 
therapy with a stable dose for at least 3 months prior to 
Visit 1 and are clinically and chemically euthyroid are 
allowed. 
16. Current or previous participation in any clinical trial within 
the last 90 days, or participation in more than 2 clinical trials 
within the past year. This includes studies using marketed 
drugs or devices. 
17. Psychological or behavioral weight-loss interventions for 
BED initiated during the 3 months prior to Screening or 
planned to be initiated during the study. A participant 
treated with those therapies is eligible if the therapy has 
been started at least 3 months prior to randomization and the 
participant agrees to keep it stable during the study. 
18. Any history of bariatric surgery including gastric jejunal 
bypass, Roux-en-Y gastric bypass, sleeve gastrectomy, lap 


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bands, duodenal stents, or other procedures for weight loss 
or planned to be performed during the study.  
19. Treatment with central nervous system (CNS)-active drugs, 
such 
as 
centrally 
active 
anticholinergics, 
sedating 
antihistamines, 
morphine 
and 
other 
opioids, 
anticonvulsants, 
antidepressants, 
anxiolytics, 
mood 
stabilizers, 
antipsychotics, 
stimulants, 
sleep 
drugs, 
anti‑Parkinson’s drugs, etc., within 30 days prior to 
Screening or planned to be initiated during the study. 
20. Treatment with sensitive substrates of CYP3A4, moderate 
or strong inhibitors and/or inducers of CYP3A4, and 
sensitive substrates of CYP2C19, CYP2C8 and CYP2C9 
within 2 weeks of randomization (Visit 2) or planned to be 
initiated during the study. 
21. Consumption of the following fruits and their juices is not 
permitted within 2 weeks of randomization (Visit 2) to EOT 
visit: grapefruit, grapefruit hybrids, Seville orange, 
pomelos, pomegranates, and star fruits.  
22. Use of medications that affect body weight or appetite, 
including weight loss medications, insulin, glucagon‑like 
peptide-1 
(GLP‑1) 
receptor 
agonists, 
systemic 
corticosteroids, 
over‑the‑counter 
(including 
herbal) 
medications, within 3 months prior to Screening or planned 
to be initiated during the study. 
23. Known hypersensitivity to drugs of the same chemical or 
pharmacological class as ACT-539313, or any of its 
excipients. 
24. Previous exposure to ACT-539313. 
Criteria assessed at Visit 1 and Visit 2 
25. HAMD-17 score ≥ 17 points at Visit 1 and/or Visit 2. 
26. Any of the following conditions related to suicidality: 
a) Participant is considered to have a suicide risk in the 
investigator’s opinion or has a previous history of suicide 
attempt within the past 12 months. 


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b) Participant answers “yes” to “suicidal ideation” item 2 
(non-specific active suicidal thoughts), item 3 (active 
suicidal ideation with any methods [not plan] without intent 
to act), item 4 (active suicidal ideation with some intent to 
act, without specific plan), or item 5 (active suicidal ideation 
with specific plan and intent) on the C-SSRS© assessment at 
Screening (in the past month). Participants who answer 
“yes” to this question must be referred to the investigator for 
follow-up evaluation. 
27. Female participants: pregnant, lactating or planning to 
become pregnant during the projected course of the study. 
28. Positive 
urine 
drug 
screen 
(for 
benzodiazepines, 
barbiturates, 
cannabinoids, 
opiates, 
amphetamines, 
phencyclidine, antidepressants, or cocaine).  
STUDY 
TREATMENTS 
ACT-539313 as capsules at a strength of 100 mg, taken orally, 
b.i.d. in the morning at breakfast and in the evening at dinner, 
with a glass of water (approx. 240 mL / 8 fl. oz.), during the 
treatment period. 
Matching placebo as identical capsules indistinguishable from 
ACT‑539313, taken orally, b.i.d. in the morning at breakfast and 
in the evening at dinner, with a glass of water (approx. 
240 mL / 8 fl. oz.), during the treatment period. 
STATISTICAL 
METHODOLOGY 
Analysis sets 
The Full analysis set (FAS) includes all participants who were 
randomized, received at least one dose of study treatment, and 
have a baseline assessment of the primary endpoint.  
The Per-protocol analysis set (PPS) includes all participants 
from the FAS without protocol deviations that potentially affect 
the primary endpoint (to be defined in the statistical analysis 
plan).  
The Safety analysis set (SAF) includes all randomized 
participants who received at least one dose of study treatment. 
Participants will be evaluated according to the study treatment 
they received. 


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Statistical hypotheses 
The null hypothesis (H0) is that there is no difference between 
ACT‑539313 and placebo mean change from baseline to 
Week 12 in the number of BE days per week. 
This hypothesis will be tested at a two-sided 0.05 level vs the 
alternative hypothesis that there is a difference between 
treatment groups. 
Analysis of the primary efficacy variable 
The primary analysis will be performed on the FAS. The 
primary estimand is a hypothetical strategy estimand. Changes 
from baseline to post-baseline time points in the number of BE 
days per week will be analyzed using a mixed model for 
repeated measurements with factors for treatment group, sex, 
BMI 
category 
and 
time 
point 
(Weeks 
1–2, 
3–4,  
5–6, 7–8, 9–10, and 11–12), treatment by time interaction, and 
covariates for baseline number of BE days per week and the 
interaction between baseline and time point. An unstructured 
covariance matrix will be used to account for the correlation 
between repeated measurements from the same participant. H0 
will be tested using the difference in least squares mean 
(LSMean) changes from baseline to Weeks 11–12. The null 
hypothesis will be rejected if the 95% confidence interval 
around this difference excludes zero. The analysis will also be 
evaluated in the PPS. Supplementary estimands are defined in 
the core text of this protocol.  
Safety analyses 
All safety analyses will be performed on the SAF. Adverse 
events, laboratory data, vital signs and ECG data will be 
summarized by treatment group using descriptive statistics. 
Daytime sleepiness is defined daily as any score > 3 on the SSS 
after the morning dose. It will be collected on Days 1–14 and 
expressed as a number of days per week. The mean number of 
days with daytime sleepiness per week will be summarized by 
treatment group. 
Interim analysis 
No interim analysis is planned. 


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Sample size 
The sample size is based on the primary efficacy endpoint. It is 
anticipated that a treatment group difference of 1 BE day per 
week (corresponding to an effect size of 0.5 to 0.7, depending 
on the standard deviation [SD]) is clinically meaningful as 
demonstrated in recent studies. 
The sample size needed for 90% power to detect an effect size 
of 0.6 is 120 participants (60 participants per arm). Such a 
sample size would also provide 78% power to detect a smaller 
effect size of 0.5. 
 
The associated estimands [ICH 2020] are given in Section 9.2. 
 




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Table 1 
Schedule of activities 
PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
UNSCHEDULED 
 
Duration 
2–4 weeks 
12 weeks  
 
7–13 days 
NA 
VISITS 
Number 
1 
2 
3 
4 
5 
6 
7 
8 
EOT 
EOS 
U1 
 
Name 
Screening 
Randomization Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 
Week 12 / 
End-of-Treatment8 
End-of-Study 
visit  
Unscheduled visit9 
 
Time window 
Day –28 to  
Day –1 
Day 1 
Day 8 
(±1) 
Day 15 
(±2) 
Day 29 
(±2) 
Day 43 
(±2) 
Day 57 
(±2) 
Day 71 
(±2) 
Day 85 (±2) or 1 to 
5 days after last 
dose if premature 
EOT 
10 ± 3 days 
after EOT 
 
Any day between ICF 
signature and EOS 
Signature of Informed consent 
form 
X 
  
 
 
 
 
 
 
 
 
 
Eligibility 
X 
X 
 
 
 
 
 
 
 
 
 
Demographics 
X 
 
 
 
 
 
 
 
 
 
 
Medical history 
X 
 
 
 
 
 
 
 
 
 
 
Previous/concomitant therapy 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Physical examination 
X 
 
 
 
 
 
 
 
X 
 
 
Body weight and height1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Vital signs (BP, PR, RR, T°) 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X)9 
12-lead ECG (central) 
X 
 
 
 
 
 
 
 
X 
 
(X)9 
Hematology / blood chemistry2 
X 
 
 
 
X 
 
X 
 
X 
 
(X)9 
Serum/urine pregnancy test3 
X 
X 
 
 
X 
 
X 
 
X 
X 
(X)9 
Thyroid function 
X 
 
 
 
 
 
 
 
 
 
 
Urine drug screen  
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Viral serology 
X 
 
 
 
 
 
 
 
 
 
 
PK sampling4 
 
 
 
 
X 
 
X 
 
X 
 
 
Binge eating diary completion 
 
 
 
 
 
 
 
 
 
 
 
Stanford Sleepiness Scale10 
 
 
 
 
 
 
 
 
 
 
 
Binge eating diary check 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
YBOCS-BE 
 
X 
 
 
X 
 
X 
 
X 
 
 
PGI-S 
 
X 
 
 
X 
 
X 
 
X 
 
 


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PERIODS 
Name 
SCREENING 
TREATMENT 
FOLLOW-UP 
UNSCHEDULED 
 
Duration 
2–4 weeks 
12 weeks  
 
7–13 days 
NA 
VISITS 
Number 
1 
2 
3 
4 
5 
6 
7 
8 
EOT 
EOS 
U1 
 
Name 
Screening 
Randomization Week 1 Week 2 Week 4 Week 6 Week 8 Week 10 
Week 12 / 
End-of-Treatment8 
End-of-Study 
visit  
Unscheduled visit9 
 
Time window 
Day –28 to  
Day –1 
Day 1 
Day 8 
(±1) 
Day 15 
(±2) 
Day 29 
(±2) 
Day 43 
(±2) 
Day 57 
(±2) 
Day 71 
(±2) 
Day 85 (±2) or 1 to 
5 days after last 
dose if premature 
EOT 
10 ± 3 days 
after EOT 
 
Any day between ICF 
signature and EOS 
CGI-S 
X 
X 
 
 
X 
 
X 
 
X 
 
 
CGI-C / PGI-C 
 
 
X 
 
X 
 
X 
 
X 
 
 
C-SSRS© 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
MINI© 
X 
 
 
 
 
 
 
 
 
 
 
SCID-5  
X 
 
 
 
 
 
 
 
 
 
 
EDE-Q 5 
X 
X 
 
 
X 
 
X 
 
X 
 
 
HAMD-17 
X 
X 
 
 
 
X 
 
 
X 
X 
 
BWSQ 
 
 
 
 
 
 
 
 
X 
X 
 
 
   
Contact IRT 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Study treatment 
dispensing/return 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
IMP capsule count 
 
 
X 
X 
X 
X 
X 
X 
X 
 
 
Study treatment intake 
 
 
 
 
 
 
 
 
 
 
 
AEs/SAEs/Procedures7 
 
 
 
 
 
 
 
 
 
 
 
1. 
Height only measured at Visit 1. 
2. 
A central laboratory will be used for all protocol-mandated laboratory tests, including re-tests due to laboratory abnormalities and laboratory tests performed at unscheduled visits. Blood 
samples will be drawn under fasted condition. 
3. 
For WOCBP, serum test (central laboratory) at Visit 1 and EOT, urine test (performed locally) at Visit 2, Visit 5, Visit 7 and EOS. If urine pregnancy test is positive, it must be confirmed 
by a serum pregnancy test. 
4. 
PK pre-dose assessment in the morning. Study participant to be instructed to withhold the morning dose until blood samples are drawn. Time of sample collection will be recorded in the 
eCRF. 
5. 
EDE-Q full (28-item) version will be applied at Visit 1 and the brief (7-item) version EDE-Q7 at all other visits. 
 
 


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7. 
All AEs, SAEs and procedures that occur after signing the ICF and up to EOS must be reported.  
8. 
All participants will be asked to return for an EOT visit. For participants who prematurely discontinue study treatment, the EOT visit will occur within 5 days of the last intake of study 
treatment. For participants who complete the treatment period as planned, the Week 12 visit corresponds to the EOT visit. 
9. 
During unscheduled visits, additional assessments may be performed at the discretion of the investigator. The assessments in brackets are recommended to be performed on an 
unscheduled visit, based on medical judgment. 
10. Stanford Sleepiness Scale to be filled in for the first 2 weeks of study treatment, twice daily, at breakfast (before morning dose) and around midday, prior to lunch time. 
 
AE = adverse event; BP = blood pressure; BWSQ = Benzodiazepine Withdrawal Symptom Questionnaire; CGI-C = Clinical Global Impression of Change scale; CGI-S = Clinical Global 
Impression of Severity scale; C-SSRS© = Columbia Suicide Severity Rating Scale©; eCRF = electronic Case Report Form; ECG = electrocardiogram; EDE-Q: Eating Disorder Examination 
Questionnaire; EOS = End‑of‑Study; EOT = End-of-Treatment; HAMD-17 = Hamilton Rating Scale for Depression (17‑item); ICF = informed consent form; IMP = Investigational Medicinal 
Product; IRT = Interactive Response Technology; MINI© = Mini International Neuropsychiatric Interview©; NA = not applicable; 
 PGI-C = Patient 
Global Impression of Change scale ; PGI-S = Patient Global Impression of Severity scale; PK = pharmacokinetic(s); PR = pulse rate; RR = respiratory rate; SAE = serious adverse event; 
SCID-5 = Structured Clinical Interview for DSM-5; T° = temperature; U1 = unscheduled visit; V = visit; WOCBP = women of childbearing potential; YBOCS-BE = Yale-Brown 
Obsessive‑Compulsive Scale Modified for Binge Eating. 
 
 


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2 
INTRODUCTION 
ACT-539313 is being developed for the treatment of BED.  
2.1 Binge eating disorder 
2.1.1 Definition 
BED is characterized by recurrent episodes of BE, i.e., eating episodes that occur in a 
discrete period of time (≤ 2 hours) and involve the consumption of an amount of food that 
is definitely larger than most people would consume under similar circumstances 
[APA 2013]. Other core features of BED include a sense of lack of control over eating 
during binge episodes, significant psychological distress (e.g., shame, guilt, 
embarrassment) about BE, and the absence of recurrent inappropriate compensatory 
behaviors such as purging, fasting, and excessive exercise. 
In 2013, the APA recognized BED as a distinct eating disorder in the DSM-5 [APA 2013], 
whereas it was previously considered only a provisional diagnosis in DSM-IV. The key 
difference in the diagnostic criteria is the reduction of the required minimum average 
frequency and duration of BE from at least 2 days a week for 6 months (DSM-IV) to at 
least 1 day a week for 3 months (DSM‑5). 
The population prevalence of BED ranges between < 1% and 3.5% [Hudson 2007, 
Kessler 2013, Mustelin 2015, Preti 2009, Smink 2014]. The 12-month prevalence of BED 
(using DSM-5 diagnostic criteria) in the US population has been estimated at 1.6%, with a 
lifetime prevalence of 2.0% [Cossrow 2016].  
BED is usually first diagnosed in young adulthood (early to mid-20s) [Kessler 2013, 
Stice 2013] and symptoms may persist in midlife and old age [Guerdjikova 2012]. 
2.1.2 Current treatment options 
Treatment for BED includes a variety of approaches targeting the core behavioral features 
and psychological features of the disease. Psychological and behavioral approaches remain 
the mainstay of therapy and include cognitive behavioral therapy, interpersonal 
psychotherapy, and behavioral weight loss [Wilson 2011, Iacovino 2012, Steinberg 2014]. 
In January 2015, lisdexamfetamine became the first medication to receive US FDA 
approval for treating moderate to severe BED [Vyvanse® USPI]. Many other medications 
are used off-label, including antidepressants (selective serotonin reuptake inhibitors, 
serotonin–norepinephrine 
reuptake 
inhibitors, 
and 
bupropion), 
anticonvulsants 
(topiramate), and anti-obesity agents [McElroy 2017a, Citrome 2019].  


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2.1.3 Unmet medical need in BED 
Patients with BED have significant functional impairment, decreased quality of life and 
psychiatric (primarily anxiety and mood disorders) as well as medical comorbidities, 
including obesity, type 2 diabetes and sleep problems [Kornstein 2017, Bellows 2015, 
Ling 2017].  
While psychological and cognitive behavioral interventions have been recommended as 
first-line treatment [Hilbert 2017] and are supported by meta-analytic reviews, these 
treatments require specialized expertise and are often not widely available and/or costly. 
Furthermore, about 50% of patients with BED do not fully respond to psychological or 
behavioral treatments [Linardon 2018]. Currently available pharmacologic treatments, 
including those used off-label, are limited by unfavorable side effects. The CNS stimulant 
lisdexamfetamine (available in the US and Australia) is an amphetamine derivative with a 
significant abuse potential and is associated with cardiovascular adverse effects 
[Vyvanse® USPI].  
2.2 ACT-539313 
ACT-539313 is a selective, orally available, and brain-penetrating OX1R antagonist. 
Orexin neuropeptides regulate feeding behavior, compulsive reactions, stress processing, 
and the motivation for obtaining rewards through activation of OX1R, as well as sleep and 
wakefulness through OX2R. 
ACT-539313 demonstrated reduction of compulsive eating of highly palatable food in rats 
where binge-like eating behavior was induced by prior dieting and stress. ACT-539313 
will be evaluated as a novel medication for the treatment of BED. 
The human clinical experience with ACT-539313 consists of a single-center, double-blind, 
randomized, placebo-controlled, single- and multiple-ascending doses, and exploratory 
pharmacodynamic Phase 1 study (AC-082-101) and a single-center, randomized, 
open‑label, DDI study on CYP3A4 inhibition (ID‑082-102). ACT-539313 was well 
tolerated at single oral doses of up to and including 400 mg and at multiple oral doses of 
up to and including 200 mg b.i.d. for 10 days.  
Data from pharmacodynamic assessments showed signs of CNS activity but did not 
suggest any marked signs of reduced alertness, fatigue, or somnolence. Saccadic peak 
velocity decreased in a statistically significant manner following single-dose 
administration of 200 mg and 400 mg ACT-539313 when compared to placebo. Neither 
SAEs nor AEs leading to study treatment or study discontinuation were reported in the 
Phase 1 studies. The most frequently reported AEs were somnolence (SAD: 5/40 subjects 
[12.5%] and MAD: 4/28 subjects [14.3%]), dizziness (MAD: 2/28 subjects [7.1%]) and 
headache (SAD: 3/40 subjects [7.5%] and MAD: 2/28 subjects [7.1%]). In the MAD part 
of the study, reporting of somnolence increased with dose and was not observed in subjects 


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treated with placebo, whereas one subject on placebo reported headache (1/28 subjects 
[3.6%]). 
More detailed information can be found in the IB [ACT‑539313 IB]. 
2.3 Study rationale 
The proposed effect of ACT-539313 on BED is based on its antagonism of OX1R. Recent 
studies have corroborated the primary role of orexins in compulsive, binge-like feeding 
behaviors in rodents [Merlo Pich 2014, Alcaraz-Iborra 2015]. OX1R antagonists reduced 
binge-like eating behavior in rat models [Piccoli 2012,Vickers 2015]. Another study 
showed that an OX1R antagonist could also inhibit the binge-like intake of sucrose and 
saccharin in mice [Alcaraz-Iborra 2014].  
In nonclinical studies, ACT-539313 reduced compulsive binge eating-like behavior in a rat 
model of BE.  
In the Phase 1 studies, ACT-539313 was well tolerated at single oral doses of up to and 
including 400 mg and at multiple oral doses of up to and including 200 mg b.i.d. for 10 days 
in studies in healthy subjects. This POC study will investigate the potential of ACT-539313 
to show similar effects on BED in humans and will assess its impact on core behavioral 
features of the disease.  
2.4 Benefit/risk assessment 
The benefits of ACT-539313 on BED are not yet known. This is the first clinical study to 
assess the efficacy of OX1R antagonism as a new mechanism of action in the treatment of 
BED. Results of studies in an animal model of binge eating support the expectation of a 
benefit in this disorder. BED currently has limited therapeutic solutions, which are not 
devoid of safety concerns. 
ACT‑539313 is a selective OX1R antagonist and human experience so far has been limited 
to healthy subjects. Based on the safety and tolerability findings in healthy subjects in the 
clinically completed SAD, MAD, and DDI studies [see further details in the 
ACT‑539313 IB], ACT-539313 was well tolerated: 
• At single oral doses of up to and including 400 mg and multiple oral doses of up to and 
including 200 mg b.i.d. for 6.5 days in healthy male and female subjects; and  
• At single and multiple oral doses of 200 mg b.i.d. for up to 10 days in healthy male 
subjects, and when given concomitantly with a single dose of 2 mg midazolam. 
Accumulation of ACT-539313 was observed after multiple-dose administration (AUCτ 
measured on Day 4 or Day 7 divided by AUCτ on Day 1) was in the range of 1.6- to 


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2.1‑fold. Similar to single dose administration, AUCτ was dose-proportional, while 
maximum plasma concentration was less than dose-proportional.  
ACT-539313 is classified as a moderate inhibitor of CYP3A4 at 200 mg b.i.d. and may 
affect the PK of CYP3A4 substrates; concomitant use of sensitive CYP3A4 substrates is 
not allowed in the study. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 Dose-related somnolence was reported 
in the MAD study (4/28, 14.3%) and was not observed in subjects treated with placebo. 
The dose of ACT-539313 selected for this Phase 2 trial for treating BED in humans aims 
at an exposure resulting in selective antagonism of OX1R, avoiding sleep induction. 
Nonetheless, potential safety risks from daytime somnolence will be mitigated by 
excluding from study participation those individuals whose work requires them to operate 
heavy machinery [see Section 5.4]. In addition, excessive daytime sleepiness following 
study drug intake will be regularly assessed until the ability to remain alert while taking 
the drug is established. Cautionary advice will be given by the investigator with respect to 
activities requiring complete mental alertness, including driving. Standard monitoring and 
reporting of AEs, including assessment of prespecified AEs related to somnolence will be 
put in place [see Section 8]. 
 
 
 
 Hematologic and hepatic variables were unaffected in the Phase 1 studies. Liver 
and hematology variables will be monitored in this study. 
ACT-539313 is not teratogenic nor embryotoxic in rats and rabbits. However, not all 
reproductive toxicity studies of ACT‑539313 have been performed at this stage; therefore, 
ACT‑539313 may be given to WOCBP only when absence of pregnancy has been verified. 
WOCBP must use a highly effective method of contraception during treatment and for 
1 month after end of study treatment [see Section 5.5]. 


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More information about the known and expected benefits, risks, and anticipated AEs can 
be found in the IB [ACT‑539313 IB]. 
It is the investigator’s/delegate’s responsibility to monitor the benefit/risk ratio of study 
treatment administration, as well as the degree of distress caused by study procedures on 
an individual study participant level, and to discontinue study treatment or the study if, on 
balance, he/she believes that continuation would be detrimental to the study participant’s 
wellbeing. Provided the protocol is adhered to, exclusion criteria, careful observation, and 
medical management will minimize any associated risk in this study. Overall, the 
benefit/risk assessment supports the conduct of the proposed ID-082A201 study. 
3 
STUDY OBJECTIVES AND ENDPOINTS 
The overall objective of this POC study is to evaluate the clinical efficacy, safety, and 
tolerability of ACT-539313 100 mg administered b.i.d. compared to placebo in adult 
patients with moderate to severe BED over a period of 12 weeks. 
All the objectives and their related endpoints are listed in Table 2. 
Table 2 
Objectives and endpoints  
Objectives 
Corresponding endpoints 
Primary efficacy objective 
To assess the efficacy of 
ACT-539313 in the 
treatment of BED  
The primary endpoint is the change from baseline to Week 12 in the 
number of BE days per week. A “BE day” is defined as a day with at least 
one confirmed BE episode. 
Exploratory efficacy objectives 
To assess the efficacy of 
ACT-539313 in the 
treatment of BED  
• 
Change from baseline to Week 12 in the number of BE episodes per 
week. 
• 
Percentage of study participants without BE episodes during the last 
4 weeks of the treatment period. 
To assess the efficacy of 
ACT-539313 in decreasing 
disease-specific obsessive 
and compulsive symptoms 
• 
Change from baseline to Week 12 in the total score of the 
YBOCS‑BE. 
• 
Change from baseline to Week 12 in the subscale scores 
(compulsive/obsessive, restraint, control) of the YBOCS-BE. 


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Objectives 
Corresponding endpoints 
To assess treatment effect on 
anxiety and depressive 
symptoms 
• 
Change from baseline to Week 6 and to Week 12 in the HAMD-17 
total score. 
• 
Change from baseline to Week 6 and to Week 12 in the HAMD‑17 
subitems 10 and 11. 
• 
Change from baseline to Week 6 and to Week 12 in the HAMD‑17 
MPS score. 
To assess treatment effect on 
attitudinal and behavioral 
dimensions of eating and 
overall symptomatology in 
BED  
• 
Change from baseline to Week 12 in the EDE-Q7 global score and 
3 subscales scores (dietary restraint, shape/weight overvaluation and 
body dissatisfaction). 
• 
CGI-C score at Week 12. 
• 
PGI-C score at Week 12. 
• 
Change from baseline to Week 12 in the CGI-S. 
• 
Change from baseline to Week 12 in the PGI-S. 
To assess treatment effect on 
body weight and glucose 
levels 
• 
Change from baseline to Week 12 in body weight. 
• 
Change from baseline to Week 12 in HbA1c. 
 
 
 
 
 
 
  
 
 
 
 
  
Safety objectives 
To assess the safety of 
ACT‑539313 in patients 
with BED 
• 
TEAEsa defined as an AE occurring from the start of study treatment 
administration up to the EOS.  
• 
Treatment-emergent SAEs defined as an SAE occurring from the start 
of study treatment administration up to the EOS. 
• 
TEAEsa leading to premature discontinuation of the study treatment. 
• 
Treatment-emergent AESIs up to EOS. AESIs include AEs related to 
somnolence (defined by pre‑specified terms) from the start of study 
treatment administration up to the EOS. 
• 
Occurrence of daytime sleepiness assessed by SSS from the start of 
study treatment administration up to Visit 4 (Week 2). 


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Objectives 
Corresponding endpoints 
• 
Treatment-emergent marked laboratory abnormalitiesb from the start 
of study treatment administration to all assessed time points during 
the study. 
• 
Change in vital signs (systolic and diastolic blood pressure, 
temperature, respiratory rate, and pulse rate) from baseline to all 
assessed time points during the study. 
• 
Medically relevant ECG abnormalitiesb while on study treatment 
from baseline to all assessed time points during the study. 
• 
Occurrence of withdrawal symptoms upon treatment discontinuation, 
as measured by change between Week 12 / EOT and EOS visit in 
BWSQ total score and HAMD‑17 total score. 
• 
Occurrence of suicidal ideation and/or behavior while on study 
treatment based on the C-SSRS© from baseline to all assessed time 
points during the study up to EOS. 
Other exploratory objectives 
To assess the PK of 
ACT‑539313  
• 
ACT-539313 plasma concentrations prior to morning dosing at 
Week 4, Week 8, and Week 12. 
a A treatment-emergent AE is any AE temporally associated with the use of study treatment (from study treatment start 
up to EOS, whether or not considered by the investigator as related to study treatment). 
b A treatment-emergent marked laboratory abnormality or medically relevant ECG abnormality is any marked 
laboratory abnormality or medically relevant ECG abnormality temporally associated with the use of study 
treatment (from study treatment start to all assessed time points during the study). The selection of 
marked/medically relevant abnormalities considered for the analyses will be based on standard definitions and 
described in the SAP. 
AE = adverse event; AESI = adverse event of special interest; BE = binge eating; BED = binge eating disorder; 
CGI‑C = Clinical Global Impression of Change scale ; CGI-S = Clinical Global Impression of Severity scale ; 
C-SSRS© = Columbia Suicide Severity Rating Scale; ECG = electrocardiogram; EDE-Q7 = Eating Disorder 
Examination Questionnaire (7-item); EOS = End‑of‑Study; EOT = End-of-Treatment; HAMD‑17 = Hamilton 
Rating Scale for Depression (17-item); FERT = Facial Expression Recognition Task; HbA1c = glycated 
hemoglobin; MPS = Maier-Philipp subscale; 
PGI‑C = Patient Global 
Impression of Change scale; PGI‑S = Patient Global Impression of Severity; PT = preferred term; SAE = serious 
adverse event; SAP = statistical analysis plan; SSS = Stanford Sleepiness Scale: TEAE = treatment-emergent 
adverse event; YBOCS‑BE = Yale‑Brown Obsessive-Compulsive Scale modified for Binge Eating 
 
3.1 Efficacy endpoints 
3.1.1 Primary efficacy endpoint 
The primary efficacy endpoint of the study is the change from baseline to Week 12 in the 
number of BE days per week. 
A “BE day” is a day in which at least one confirmed BE episode occurred [see 
Section 7.2.4.1]. 


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A BE episode is defined as “eating, in a discrete period of time (e.g., within any 2-hour 
period), an amount of food that is definitely larger than most people would eat in a similar 
period of time under similar circumstances” (as defined in the DSM-5 criteria) 
[APA 2013]. In addition, a BE episode is characterized by “a sense of lack of control over 
eating during the episode (e.g., a feeling that one cannot stop eating or control what or how 
much one is eating)”. 
Throughout the study, from Screening to Week 12, study participants record each BE 
episode they experience on a diary card that is filled in daily. At randomization and at each 
subsequent study visit, the investigator reviews the diary entries with the study participant 
to determine whether a recorded episode fulfilled criteria for a BE episode and to ascertain 
if there were other unrecorded BE episodes during the preceding interval. The investigator 
records in the eCRF the BE episodes that have been confirmed. In the eCRF, every day 
must be described as either having an entry (0 or x number of BE episodes) or not having 
an entry (missing data).  
The “number of BE days per week at baseline” is calculated as the number of BE days 
from Day −14 to Day −1 divided by the number of days with diary entries in this period 
and multiplied by 7. A minimum of 6 entries for each of the 2 weeks preceding 
randomization is required per inclusion criteria to ensure study participant compliance with 
filling in the BE diary. 
The “number of BE days per week” during the study, from randomization up to Week 12, 
is calculated as the number of BE days over a 2-week period divided by the number of days 
with diary entries in this period and multiplied by 7. A minimum of 7 diary entries per 
14‑day time interval is required [see Section 9.2.2.1]. The last calculation, covering 
Weeks 11 and 12, will be used for the primary endpoint. 
All calculations will be done by the sponsor; the calculations at baseline should also be 
done by the investigator as part of the eligibility assessment, as per Section 7.2.3. The 
sponsor may collect the original diaries for data reconciliation. 
3.1.2 Exploratory efficacy endpoints 
Exploratory efficacy endpoints are listed in Table 2. 
3.2 Safety endpoints 
Safety endpoints are listed in Table 2. 
3.3 Pharmacokinetic endpoints 
ACT-539313 plasma concentrations will be measured prior to the morning dosing at 
Week 4, Week 8, and Week 12 to determine individual trough concentrations and the 
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may also be evaluated on an exploratory basis. Plasma samples may also be used by Idorsia 
Preclinical Pharmacokinetics and Metabolism department for exploratory assessments of 
circulating metabolites of ACT-539313. 
3.4 Appropriateness of endpoints 
The assessment of the change in the number of BE days per week as an endpoint has been 
accepted by the FDA, supporting approval of other therapies in this indication. The FDA 
review of the lisdexamfetamine dimesylate dossier [FDA 2015], discussing the adequacy 
of weight loss as primary endpoint in BED, did not consider weight loss as a suitable 
primary endpoint for this disease: “... primary efficacy endpoint is most important 
information for clinicians, and for patients with BED (reducing binge eating days), and so 
the emphasis in labeling should be on the psychiatric aspects of the disorder...”. 
A change in BED may be assessed either by a reduction in the frequency of BE episodes 
or by a reduction in the frequency of BE days. The frequency of BE episodes is a good 
descriptor of disease severity and it allows the reduction in severity for study participants 
not reaching remission to be assessed. In patients with severe BED, if the reduction in 
episode frequency is large enough it could lead to a meaningful benefit. With 
lisdexamfetamine dimesylate, treatment effects were observed consistently across several 
BE-related endpoints including BE episodes and BE days, reinforcing the clinical 
relevance of both endpoints [McElroy 2017b]. Similar conclusions were drawn in clinical 
trials with topiramate [McElroy 2007] and sibutramine [Wilfley 2008].  
Attitudinal and behavioral dimensions of the eating psychopathology in BED will be 
assessed by the change from baseline to Week 12 in the EDE-Q 7-item scale global score 
and subscale scores on dietary restraint, shape/weight overvaluation, and body 
dissatisfaction. 
BED shares many characteristics with addictive behaviors, e.g., diminished control, 
continued food intake despite negative consequences [Gearhardt 2012], and with 
obsessive-compulsive symptoms (or features) in that symptoms are intrusive, time 
consuming, distressing, potentially inhibit or hinder functioning, and may or may not be 
successfully resisted [Deal 2015]. The study will also assess the efficacy of the drug on 
disease-specific obsessive and compulsive symptoms by using the YBOCS-BE 
[Goodman 1989, Deal 2015]. 
The study will use the CGI-S/C as well as the PGI-S/C scales to assess the global 
impression of disease related to severity and change from a clinician and patient 
perspective. 
Anxiety and depression are common comorbidities in BED [Guerdjikova 2017]; the study 
will use HAMD-17 to assess symptoms of anxiety and depression. 
 


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In summary, all efficacy assessments have been well documented and regarded as reliable, 
accurate and relevant in this patient population. 
4 
STUDY DESIGN AND PLAN 
4.1 Study design 
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled, 
parallel‑group, proof-of-concept study assessing ACT-539313 at a dosing regimen of 
100 mg b.i.d. vs placebo over a 12-week treatment period in adult participants with 
moderate to severe BED.  
The study treatment will be taken in the morning at breakfast and in the evening at dinner.  
This study will randomize approximately 120 participants to either ACT-539313 at a dose 
of 100 mg b.i.d., or placebo in a 1:1 ratio.  
4.1.1 Study periods for an individual study participant 
The study comprises the following consecutive periods: 
Screening period: Lasts a minimum of 14 days and up to 28 days; starts with the full 
signature (study participant, investigator/delegate) of the ICF and ends with the study 
participant’s randomization or screening failure. 
Treatment period: Starts with the administration of the first dose of study treatment and 
ends on the day of the last dose of study treatment. The study participants will be treated 
for 12 weeks. 
Safety follow-up period: Starts on the day after the last dose of study treatment and ends 
at the EOS visit (10 ± 3 days after EOT). 
Participation in the study ends with the completion of the EOS visit [Table 1]. The duration 
of participation in the study of a study participant is expected to be up to 128 days. 
The visit schedule and protocol-mandated procedures are performed according to the 
schedule of activities [Table 1] and are described in Section 7.2. 
The overall study design is depicted in Figure 1. 
4.2 Study duration and global End-of-Study definition 
The study starts with the recruitment of the first study participant. A study participant is 
considered recruited when the study participant’s ICF has been fully signed.  


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The study primary completion date is the date of the last study participant’s EOT visit. 
The global EOS is defined as completion of the EOS visit of the last study participant. The 
study is expected to last approximately 14 months. 
4.3 Study design rationale 
The proposed clinical study ID-082A201 has been designed based on previously conducted 
clinical studies in BED [McElroy 2017b, Wilfley 2008, FDA 2015] as well as data from 
the two ACT-539313 Phase 1 studies, AC-082-101 [D-18.013, D‑20.035] and ID-082-102 
[D‑18.159]. This is the first clinical study to assess selective OX1R antagonism as a new 
mechanism of action in patients with eating disorders and to establish an initial signal for 
efficacy and to ensure safety. Based on the results of this study, ACT-539313 may be 
further investigated in a Phase 2 dose-finding study and in a confirmatory Phase 3 program 
in BED. 
The DB, randomized, and placebo-controlled design minimizes the chance of bias in the 
implementation, execution, assessment, and interpretation of the effects of treatment. 
While there is a drug approved for BED (lisdexamfetamine), its status as a Schedule II 
controlled substance limits its use in this POC study as an active control.  
A treatment duration of 12 weeks has been selected as this duration has been adequate to 
evaluate the benefit/risk of compounds tested in this indication [McElroy 2017b, 
FDA 2015]. In addition, it is unclear how long it would take for an OX1R antagonist to 
modulate the neuronal dysregulation of BED, leading to a reduction in the compulsive 
behavior that will then translate into a reduction in BE episodes. The 12-week duration is 
expected to provide an adequate time period to allow for both efficacy and safety data 
assessment. 
4.4 Justification for dose  
For this POC study, the dose of 100 mg b.i.d. was chosen to assess the effect of 
ACT‑539313 on BED.  
The selected dose of 100 mg b.i.d. is expected to cover the exposure to ACT-539313 that 
was necessary in a rat model to reduce BE by selective OX1R antagonism. Safety 
pharmacology and toxicity studies have demonstrated appropriate safety margins,
 
 
. 
Single doses up to 400 mg and multiple doses up to 200 mg b.i.d. for 6.5 days have been 
tested in healthy male and female study participants, while a dose of 200 mg b.i.d. for up 
to 10 days has been tested in healthy male study participants. No safety issue of concern 
was detected as all AEs were transient and of mild or moderate intensity, and no 


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treatment‑related effects on vital signs, clinical laboratory, or ECG variables were 
observed. 
4.5 Study committee(s) 
No study committee will be appointed for this study. 
5 
STUDY POPULATION 
5.1 Study participant population description 
This study will enroll male and female participants aged 18–55 years (inclusive), with a 
diagnosis of BED in accordance with DSM-5 criteria. In addition, the disease severity 
should be at least moderate, defined in this study as having at least 4 BE episodes per week, 
on average, for a duration of at least 6 months. 
To ensure proper application of the diagnostic criteria, the BED diagnosis section of the 
SCID‑5 will be used at Screening. This is a semi-structured interview guide for making the 
major DSM-5 diagnoses. It is administered by a clinician or trained mental health 
professional who is familiar with the DSM-5 classification and diagnostic criteria. In 
addition, the EDE-Q will be completed at Screening to further confirm the diagnosis of 
BED, assess all dimensions of the eating psychopathology, as well as confirm the 
self‑reported BED severity. 
More details on inclusion and exclusion criteria follow below [see Sections 5.3 and 5.4]. 
5.2 Rationale for the selection of the study population 
The rationale for selecting patients with at least moderate severity and longer duration of 
BE symptoms (≥ 6 months) is that these patients are more likely to be impacted by the 
disease, more likely to seek treatment, and thus more likely to respond to the effects of a 
pharmacological intervention such as ACT-539313. In studies looking at both clinical and 
community samples, patients with moderate to severe BED, and especially those with 
overvaluation 
of weight/shape, 
were found to 
have 
greater 
eating-disorder 
psychopathology than patients with mild BED [Grilo 2015a, Grilo 2015b]. Patients with 
moderate to severe BED are often considered for pharmacotherapy as either monotherapy 
or in combination with behavioral treatment options.  
Placebo response during clinical trials of medications for BED has been reported to range 
from 26% to 38%, with less severe eating pathology at baseline being associated with a 
higher placebo response [Blom 2014].  
In comparison to other eating disorders, BED is distributed more broadly across age, sex, 
and racial/ethnic groups and no restrictions are made in this study with respect to these 
factors. However, in this initial POC study, an upper age limit of 55 years is included to 
increase the probability of detecting an efficacy signal as persistence of BED in older 


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individuals may be a sign of intractable BE and poorer response to treatment. Subsequent 
studies will allow a broader age range, beyond the 55 years limit. 
5.3 Inclusion criteria 
Study participants must meet all the following inclusion criteria: 
Criteria assessed at Visit 1: 
1. Signed and dated informed consent form prior to any study-mandated procedure.  
2. Male or female study participants aged 18 to 55 years at the time of signing the 
informed consent form. 
3. BED in accordance with DSM-5 criteria diagnosed using the SCID-5. 
4. Self-reported BED severity of at least moderate level, defined as at least 4 BE episodes 
per week, on average, for a duration of at least 6 months. 
5. BED in accordance with EDE-Q. 
6. CGI-S score of ≥ 4. 
7. For WOCBP [see definition in Section 5.5]:  
• Negative serum pregnancy test at Visit 1; and  
• Agreement to undertake monthly urine or serum pregnancy tests during the study 
and up to the EOS visit; and 
• Agreement to use an acceptable contraceptive method as described in Section 5.5.2. 
8. Able to speak, read and understand English, to communicate well with the investigator, 
to understand the study requirements, and judged by investigator to be alert and 
oriented to person, place, time, and situation. 
Criteria assessed at Visit 2: 
9. Reporting ≥ 3 BE days for each of the 2 weeks prior to randomization as documented 
in the participant’s BE diary and with BE diary entries completed for at least 6 days 
per week during this 2‑week period (between Visit 1 and 2). 
10. CGI-S score of ≥ 4. 
11. For WOCBP: negative urine pregnancy test. 


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5.4 Exclusion criteria 
Study participants must not meet any of the following exclusion criteria:  
Criteria assessed at Visit 1: 
1. BMI < 18.0 kg/m2 or > 45 kg/m2. 
2. Any acute or chronic-persistent psychiatric disorder (see also under 3 and 4 below) 
other than BED diagnosed in the past, including anorexia nervosa, bulimia, psychotic 
disorders, bipolar disorder, hypomania, dementia, as defined by the DSM-5 criteria or 
by the MINI©. 
3. Episode(s) of major depressive disorder or any anxiety disorder occurring within the 
6 months prior to Screening as defined by the DSM-5 criteria or by the MINI©; or 
currently taking, or has taken, any medication for depression or anxiety during the 
3 months prior to Screening. 
4. History of substance use disorder (including alcohol use disorder), excluding nicotine 
and caffeine, within the 12 months prior to Screening, as defined by the DSM-5 criteria 
or by the MINI©. 
5. Any clinically unstable medical condition, significant medical disorder or acute illness 
that, in the investigator’s opinion, could interfere with the participant’s ability to 
comply with study assessments or abide by study restrictions. 
6. History of malignancy within 5 years prior to the Screening visit, except for adequately 
treated basal cell or squamous cell skin cancer. History of pituitary tumor, whether 
benign or malignant, is exclusionary. 
7. Presence of significant psychosocial or environmental stressors (e.g., loss of 
employment, loss of housing) or any factor that could impede participant’s ability to 
adhere to protocol requirements, as judged by the investigator. 
8. Participants whose work requires them to operate heavy-duty vehicles or other heavy 
or dangerous machinery. 
Note: Participants must be cautioned on the potential risk of somnolence and it is 
recommended to refrain from engaging in hazardous activities that require complete 
mental alertness, including driving, following study treatment intake until fully alert and 
comfortable to do so [See also Section 5.7]. 
9. Use of any medications for the treatment of BED (including lisdexamfetamine 
[Vyvanse®]), any other eating disorder, obesity, or weight gain, or any other medication 
that could result in weight gain or weight loss, including over-the-counter and herbal 
products, within 3 months prior to Screening. 


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10. Any ECG findings of QTc prolongation or history of additional risk factors for torsade 
de pointes, which, in the opinion of the investigator, could affect the participant’s safety 
or interfere with the study assessments. 
11. Any abnormal hematology or biochemistry test results, which, in the opinion of the 
investigator, could affect the participant’s safety or interfere with the study 
assessments. 
12. AST and/or ALT > 1.5 × ULN and/or total/direct bilirubin > 1.5 × ULN and/or 
moderate to severe hepatic impairment defined as Child Pugh Score B or C. 
13. Positive test for either hepatitis B surface antigen or hepatitis C antibody and AST 
and/or ALT and/or total bilirubin test results at Screening above the ULN for the 
reference laboratory. 
14. Positive HIV test. 
15. TSH level outside of the established reference range to an extent that is considered 
clinically relevant per investigator judgment. Participants diagnosed with hyper- or 
hypothyroidism who have been on therapy with a stable dose for at least 3 months prior 
to Visit 1 and are clinically and chemically euthyroid are allowed. 
16. Current or previous participation in any clinical trial within the last 90 days, or 
participation in more than 2 clinical trials within the past year. This includes studies 
using marketed drugs or devices. 
17. Psychological or behavioral weight-loss interventions for BED initiated during the 
3 months prior to Screening or planned to be initiated during the study. A participant 
treated with those therapies is eligible if the therapy has been started at least 3 months 
prior to randomization and the participant agrees to keep it stable during the study. 
18. Any history of bariatric surgery including gastric jejunal bypass, Roux-en-Y gastric 
bypass, sleeve gastrectomy, lap bands, duodenal stents, or other procedures for weight 
loss or planned to be performed during the study. 
19. Treatment with CNS-active drugs, such as centrally active anticholinergics, sedating 
antihistamines, morphine and other opioids, anticonvulsants, antidepressants, 
anxiolytics, mood stabilizers, antipsychotics, stimulants, sleep drugs, anti-Parkinson’s 
drugs, etc., within 30 days prior to Screening or planned to be initiated during the study. 
20. Treatment with sensitive substrates of CYP3A4, moderate or strong inhibitors and/or 
inducers of CYP3A4, and sensitive substrates of CYP2C19, CYP2C8 and CYP2C9 
within 2 weeks of randomization (Visit 2) or planned to be initiated during the study. 


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21. Consumption of the following fruits and their juices is not permitted within 2 weeks of 
randomization (Visit 2) to EOT visit: grapefruit, grapefruit hybrids, Seville orange, 
pomelos, pomegranates, and star fruits.  
22. Use of medications that affect body weight or appetite, including weight loss 
medications, 
insulin, 
GLP-1 
receptor 
agonists, 
systemic 
corticosteroids, 
over‑the‑counter (including herbal) medications, within 3 months prior to Screening or 
planned to be initiated during the study.  
23. Known hypersensitivity to drugs of the same chemical/pharmacological class as 
ACT‑539313, or any of its excipients. 
24. Previous exposure to ACT-539313. 
Criteria assessed at Visit 1 and Visit 2 
25. HAMD-17 score ≥ 17 points at Visit 1 and/or Visit 2. 
26. Any of the following conditions related to suicidality: 
a) Participant is considered to have a suicide risk in the investigator’s opinion or has 
a previous history of suicide attempt within the past 12 months. 
b) Participant answers “yes” to “suicidal ideation” item 2 (non-specific active 
suicidal thoughts), item 3 (active suicidal ideation with any methods [not plan] 
without intent to act), item 4 (active suicidal ideation with some intent to act, without 
specific plan), or item 5 (active suicidal ideation with specific plan and intent) on the 
C-SSRS© assessment at Screening (in the past month). Participants who answer “yes” 
to this question must be referred to the investigator for follow-up evaluation. 
27. Female participants: pregnant, lactating or planning to become pregnant during the 
projected course of the study. 
28. Positive urine drug screen (for benzodiazepines, barbiturates, cannabinoids, opiates, 
amphetamines, phencyclidine, antidepressants or cocaine).  
5.5 Contraception requirements for women of childbearing potential 
5.5.1 Definition of childbearing potential 
A woman is considered to be of childbearing potential, i.e., fertile, following menarche and 
until becoming post-menopausal unless permanently sterile. 
Permanent sterilization methods include hysterectomy, bilateral salpingectomy, and 
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Post-menopausal state is defined as 12 consecutive months with no menses without an 
alternative medical cause (ICH M3 definition).  
5.5.2  Methods of contraception 
WOCBP [see definition in Section 5.5.1 must use a highly effective contraceptive method 
from Screening visit up to 30 days after study treatment discontinuation. 
Contraceptive methods with low user dependency should preferably be used, particularly 
when contraception is introduced as a result of participation in the study.  
Highly effective contraceptive methods are defined as those, alone or in combination, that 
result in a failure rate of less than 1% per year when used consistently and correctly. Such 
methods include: 
1. Hormonal contraceptives: Combined (containing estrogen and progestogen) or 
progestogen-only hormonal contraception associated with inhibition of ovulation using 
one of the following routes of administration: 
a. Oral 
b. Intravaginal 
c. Transdermal 
d. Injectable 
e. Implantable (low user dependency) 
If a hormonal contraceptive is chosen from this group, it must be taken for at least 
30 days prior to administration of the first study treatment dose. If during the study 
treatment period a study participant switches, or starts, a hormonal contraceptive 
method, additional contraceptive protection may be required to ensure a highly 
effective contraceptive method is used without discontinuation. 
Hormonal contraception from the above list must be used in conjunction with a 
supplemental barrier. The acceptable supplemental barrier methods to be used in 
conjunction with hormonal contraception are: male condom (preferred method), female 
condom, cervical cap, or diaphragm. Cervical cap and diaphragm must be used in 
combination with a spermicide. In countries in which spermicides are not 
available/authorized, cervical cap and diaphragm must not be used. 
2. Intrauterine device (low user dependency). 
3. Intrauterine hormone-releasing system (low user dependency). 
4. Bilateral tubal occlusion/ligation at least 6 weeks prior to Screening visit (low user 
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5. Vasectomized partner; this is a highly effective birth control method provided that the 
partner is the sole sexual partner of the WOCBP study participant and that the 
vasectomized partner has received medical assessment of the surgical success. 
6. Sexual abstinence, defined as refraining from heterosexual intercourse during the entire 
period of risk associated with the study treatment(s). The reliability of sexual 
abstinence needs to be evaluated in relation to: the duration of the clinical study; 
whether it is the preferred and usual lifestyle of the study participant; and whether it is 
locally accepted as a highly effective method of contraception. 
The following contraception schemes used alone are NOT considered as highly effective 
methods of contraception: 
• Male or female condom with or without spermicide.  
• Cap, diaphragm, or sponge with or without spermicide. 
The following methods are NOT ALLOWED as methods of contraception for this study: 
• Progestogen-only oral hormonal contraception (except if inhibition of ovulation is the 
primary mode of action).  
• Periodic abstinence (calendar, symptothermal, post-ovulation methods). 
• Withdrawal (coitus interruptus). 
• Spermicides only. 
• Lactational amenorrhea method. 
• Combination of female condom and male condom. 
If the investigator/delegate finds that the protocol-mandated highly effective method of 
contraception is not consistently and correctly followed by the study participant, the study 
treatment must be permanently discontinued [see Section 5.9.1.2].  
Note: The documentation of method of contraception can be based on the site personnel’s 
review of the study participant’s medical records, medical examination, or medical history 
interview of the study participant. 
5.6 Contraception for male study participants with WOCBP partner 
No contraceptive methods are needed for male study participants participating in this 
clinical study. 
5.7 Dietary aspects and physical activity restrictions 
During the study, study participants will be instructed to: 


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• Refrain from consumption of grapefruit, grapefruit hybrids, Seville orange, pomelos, 
pomegranates, and star fruits, and their juices from 2 weeks before the start of study 
treatment until the last dose of study treatment. 
• Abstain from strenuous exercise before each blood collection for clinical laboratory 
tests. 
• Refrain from consuming alcohol > 2 drinks a day. 
• A drink is defined as: 
a. A bottle/can of 33 cl / 12 ounces of beer (≈14 grams alcohol) 
b. A glass of 10–12 cl / 4 ounces of wine (≈12 grams alcohol) 
c. A small glass of 3–4 cl / 1 ounce of liquor (≈9 grams alcohol) 
• Refrain from engaging in hazardous activities that require complete mental alertness, 
such as driving or operating heavy machinery, following study treatment intake until 
fully alert and comfortable to do so. 
5.8 Screen failures and re-screening 
Screen failures are defined as participants recruited in the clinical study (i.e., ICF fully 
signed) but not subsequently enrolled in the study. Minimum information includes 
demography, medical history, screen failure details (i.e., reason for screen failure), BE 
diary data, concomitant medication, adverse events and eligibility criteria not met. 
It is not permitted to re-screen study participants in this study. 
5.9 Criteria for withdrawal of study participants 
A study participant has the right to prematurely discontinue study treatment at any time, 
by withdrawing from study treatment only or by withdrawing from study treatment and 
any further participation in the study (i.e., premature withdrawal from the study). It is 
recommended that the investigator/delegate makes a reasonable effort to maintain study 
participants on treatment, as medically appropriate, and follow the schedule of visits, since 
data robustness depends on such compliance. Should a study participant stop treatment or 
withdraw from the study, the investigator/delegate should ascertain the reason(s), while 
fully respecting the study participant’s rights. 
Study participants who prematurely discontinue study treatment, or the study, for any 
reason will not be replaced. 
5.9.1 Study treatment premature discontinuation 
The decision to prematurely discontinue study treatment may be made by the study 
participant, the investigator/delegate, or the sponsor personnel.  


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The investigator/delegate has the option of prematurely discontinuing study treatment for 
a given study participant in response to an AE, a diagnostic or therapeutic procedure, a 
laboratory abnormality, or for administrative reasons. If study treatment is interrupted by 
the study participant for any reason, she/he must inform the investigator/delegate as soon 
as possible. Study treatment dose interruptions must be recorded in the eCRF. 
The investigator/delegate must permanently discontinue study treatment for a given study 
participant if, on balance, he/she believes that continued administration would be contrary 
to the best interests of the study participant. 
Study-specific criteria for permanent discontinuation of study treatment are described in 
Sections 5.9.1.1 to 5.9.1.4.  
The main reason for permanent discontinuation of study treatment (e.g., due to 
pre-specified study treatment discontinuation criteria, an AE, lack of efficacy, study 
termination) must be documented in the eCRF.  
A study participant who prematurely discontinues study treatment is not considered as 
withdrawn from the study.  
The study participant who prematurely discontinues study treatment or who is permanently 
discontinued from study treatment will be asked to return for an EOT visit within 1 to 
5 days of last intake of study treatment and thereafter to attend follow-up visits as defined 
in the schedule of activities [Table 1, Section 7.2].  
5.9.1.1 Pregnancy 
If a study participant becomes pregnant while on study treatment, study treatment must be 
permanently discontinued. The investigator/delegate must counsel the study participant 
and discuss the risks of continuing with the pregnancy and the possible effects on the fetus. 
For reporting of pregnancies, refer to Section 8.3.1. 
5.9.1.2  Lack of compliance with methods of contraception 
If the investigator/delegate considers that the study participant is not compliant with the 
protocol instructions on methods of contraception; study treatment must be permanently 
discontinued. 
5.9.1.3  Liver aminotransferase abnormalities 
If ALT or AST ≥ 3 × ULN and < 8 × ULN, a re-test of aminotransferases, total and direct 
bilirubin, and alkaline phosphatase must be performed within 7 calendar days. If the 
aminotransferase values return to pre-treatment levels or within normal ranges, study 
treatment can be continued. If AST or ALT elevation is confirmed, study treatment must 
be stopped and not re-introduced. Aminotransferases, total and direct bilirubin, and 


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alkaline phosphatase levels must be monitored at least once every 7 calendar days until 
values return to pre-treatment levels or within normal ranges.  
Study treatment must be stopped, and its reintroduction is not to be considered in the 
following cases: 
• Aminotransferases ≥ 8 × ULN 
• Aminotransferases ≥ 3 × ULN and associated clinical symptoms of liver injury, e.g., 
nausea, vomiting, fever, abdominal pain, jaundice, unusual lethargy or fatigue, flu-like 
syndrome (arthralgia, myalgia, fever) 
• Aminotransferases ≥ 3 × ULN and associated increase in total bilirubin ≥ 2 × ULN 
Aminotransferases, total and direct bilirubin, and alkaline phosphatase levels must be 
monitored at least once every 7 calendar days after study treatment discontinuation until 
values return to pre-treatment levels or within normal ranges. 
Furthermore, other diagnoses (e.g., viral hepatitis, mononucleosis, toxoplasmosis, 
cytomegalovirus, alcoholic hepatitis, non-alcoholic steatohepatitis, autoimmune disease) 
and/or etiologies (e.g., hepatic toxicity of concomitant medication[s] or other substances) 
should be considered and ruled out by performing the appropriate tests. 
All liver aminotransferases abnormalities leading to study treatment discontinuation must 
be recorded as AEs [see Section 8.1.1]. 
5.9.1.4 COVID-19 
Provisions for study participants infected with SARS-CoV-2 or quarantined due to 
pandemic  
Testing for SARS-CoV-2 should follow local guidance. Mandatory testing is not required 
for this study; however, standards for testing and management should be followed 
according to local and site-specific guidelines. 
Should a study participant become infected with SARS-CoV-2 / contract COVID‑19, or 
should a study participant be quarantined:  
• Information about COVID-19 infection, whether positively confirmed with a 
SARS‑CoV-2 test or not, and its corresponding diagnosis (including pneumonia related 
to COVID-19), symptoms, as well as administered medications, will be collected on 
the AE and Concomitant Medication pages of the eCRF.  
• If a study participant is without symptoms and remains asymptomatic, study treatment 
can be continued as per protocol.  


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• If a study participant presents with mild symptoms, study treatment can be continued 
as per protocol and the study participant should be closely monitored. Should the 
symptoms worsen, study treatment may be discontinued as per investigator judgment. 
• If a study participant develops severe symptoms or requires hospitalization for COVID-
19, the study participant must be discontinued from study treatment. 
• When shipping blood samples from study participants who tested positive or have a 
high potential to test positive for SARS-CoV-2 virus infection to the study central 
laboratory, the central laboratory manual and the most up-to-date COVID-19 regional 
guidance should be followed.  
• DDI with medications used to treat COVID-19: Certain treatments used for COVID‑19, 
such as lopinavir/ritonavir (strong CYP3A4 inhibitor) are contraindicated in 
association with ACT-539313. Please refer to the IB for more details on potential DDIs 
with ACT-539313. If possible, such treatments should be avoided for at least 24 hours 
after the last dose of study treatment. Details of any medication given for COVID-19 
management should be recorded in the eCRF under Concomitant medications. 
COVID-19 vaccination 
COVID-19 vaccination with authorized vaccines, as per CDC and local guidelines, is 
allowed, provided the vaccination conditions set forth by the respective manufacturer 
(consistent with the respective prescribing information / package insert) are observed. Prior 
to any planned vaccination the study participant should, after consultation with his/her 
primary care physician, inform the investigator of such plan. Study visits and assessments 
should continue as planned if possible and appropriate as per investigator judgment. 
Receipt of the vaccine, and details thereof, should be recorded in the medical notes and in 
the eCRF under Concomitant medications.  
General reporting of AEs should continue to be implemented as described in Section 8.2, 
including vaccination-related AEs, and reports of AEs for approved vaccines should be 
submitted as appropriate to the Vaccine Adverse Events Reporting System (VAERS) as 
per FDA guidance [FDA 2021]. 
5.9.2 Withdrawal from the study  
Study participants may voluntarily withdraw from the study without justification for any 
reason at any time. Study participants 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 [see Section 5.9.3. If a study participant withdraws 
consent for further study participation, no further data will be collected in the eCRF from 
the date of withdrawal onward. The investigator/delegate may withdraw a study participant 
from the study (without regard to the study participant’s consent) if, on balance, he/she 
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the study participant. Withdrawal from the study may also result from a decision by the 
sponsor for any reason, including premature termination or suspension of the study [see 
Section 10.10].  
Enrolled study participants who prematurely discontinue from the study for any reason will 
not be replaced 
If, for whatever reason (except death or loss-to-follow-up), a study participant is withdrawn 
from the study, the investigator/delegate should make best efforts to schedule a last 
appointment / telephone call to assess the safety and well-being of the study participant, 
collect unused study treatment and discuss follow-up medical care. Data obtained during 
this last appointment / telephone call will be recorded in the study participant’s medical 
records, but they will not be collected in the eCRF.  
The main reason for premature withdrawal from the study must be documented in the 
eCRF.  
The investigator must provide follow-up medical care for all study participants who are 
prematurely withdrawn from the study, or must refer them for appropriate ongoing care, as 
described in Section 6.3. 
5.9.3 Loss to follow-up 
A study participant will be considered as lost to follow-up if he/she repeatedly fails to 
return for scheduled visits and cannot be contacted by the site. 
The site must take preventive measures to avoid a study participant 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 study participant cannot be reached).  
The following actions must be taken if a participant fails to return to the site for a scheduled 
study visit: 
• The site staff must attempt to contact the study participant and reschedule the missed 
visit as soon as possible and counsel the study participant on the importance of 
maintaining the assigned visit schedule and ascertain if the study participant wishes to 
and/or should continue in the study. 
• If the study participant cannot be reached, the site must make a reasonable effort to 
contact the study participant and document all attempts in the study participant medical 
chart. Reasonable efforts include, where possible, three telephone calls to the last 
available telephone number and one registered/certified letter to the study participant’s 
last known mailing address or local equivalent methods. 
• If the study participant is still unreachable after all contact attempts listed above, he/she 
will be considered to be lost to follow-up. 


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The date of last contact with the study participant will be collected in the eCRF. 
6 
TREATMENTS 
6.1 Study treatment 
6.1.1 Investigational treatment and matching placebo description  
ACT-539313 is supplied by the sponsor as capsules at a strength of 100 mg. Matching 
placebo will be supplied by the sponsor as identical capsules indistinguishable from 
ACT‑539313. 
6.1.2 Study treatment dosing and administration 
ACT-539313 or matching placebo will be available as capsules at a strength of 100 mg, 
taken orally, b.i.d. in the morning at breakfast and in the evening at dinner with a glass of 
water (approx. 240 mL / 8 fl. oz.), during the treatment period. 
On study visit days when blood samples will be collected, participants will be asked not to 
take their morning dose until blood samples are drawn.  
6.1.2.1 Study treatment dose adjustments  
Study treatment dose adjustments are not permitted. 
6.1.3 Treatment assignment 
A total of approximately 120 study participants will be randomized in a 1:1 ratio to 
ACT‑539313 or placebo. Randomization will not be stratified. 
After verifying that the study participant meets all inclusion criteria and none of the 
exclusion criteria, the investigator/delegate contacts the IRT system at Visit 2 to randomize 
the study participant. The IRT assigns a randomization number to the study participant and 
assigns the treatment kit number, which matches the treatment arm assigned by the 
randomization list to the randomization number.  
The IRT system is handled by an external independent vendor who will generate the 
randomization list. 
6.1.4 Blinding 
This study will be performed in a DB fashion. The investigator, site study personnel, the 
study participants, CRAs, sponsor personnel, and vendor/CRO personnel responsible of 
the conduct of the study, will remain blinded to the study treatment allocation until study 
database lock.  
To ensure adequate supply of study treatment, the IRT vendor personnel responsible for 
clinical study distribution and the sponsor individuals contributing to clinical supply 
distribution will need to be unblinded at study participant level and depot level, 


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respectively. These persons will be clearly identified, their unblinding status will be 
documented in the trial master file and controlled as per sponsor/CRO procedures. 
Until the time of unblinding for final data analysis, the randomization list is kept strictly 
confidential, and accessible only to IRT vendor and authorized persons (i.e. dedicated 
members of the Pharmaceutical Development group), who are not involved in the conduct 
of the study. 
The investigational treatment and its matching placebo are indistinguishable, and all 
treatment kits will be packaged in the same way. 
To minimize the possibility of systematic unblinding, the results of the PK data will not be 
communicated to the investigator, study personnel, study participants, CRAs, any sponsor 
or vendor/CRO personnel involved in the conduct of the study. Results will be transferred 
by the sponsor Bioanalytical Laboratory group (for PK data) to the sponsor and CRO 
personnel involved in the conduct of the study only after database lock. 
6.1.5 Unblinding 
6.1.5.1 Unblinding for final analyses 
Full randomization information will be made available for data analysis only after database 
lock, in accordance with the sponsor and/or the CRO’s Quality System documents. 
6.1.5.2 Unblinding for Independent Data Monitoring Committee or interim analyses 
Not applicable. 
6.1.5.3 Unblinding for suspected unexpected serious adverse reactions 
If a SUSAR see definition in Section 8.2.3 occurs for a study participant, sponsor’s 
Global Drug Safety will perform unblinding of the treatment assignment for that study 
participant in order to meet regulatory reporting requirements.  
Unblinded information will be accessible only to sponsor personnel who need to be 
involved in the safety reporting to the regulatory authorities and/or IECs/IRBs.  
6.1.5.4 Emergency procedure for unblinding 
The identity of the study treatment may be revealed only if the study participant 
experiences a medical event, the management of which would require knowledge of the 
blinded treatment assignment. In this case, the investigator/delegate can receive the 
unblinded treatment assignment through the IRT.  
In these situations, the decision to unblind resides solely with the investigator and must be 
clearly justified and explained. Whenever it is possible, and if it does not interfere with (or 
does not delay) any decision in the best interest of the study participant, the investigator is 


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invited to discuss the intended unblinding with the sponsor personnel. The occurrence of 
any emergency unblinding during the study must be clearly justified and explained by the 
investigator. In all cases, the sponsor personnel must be informed as soon as possible before 
or after the unblinding. 
Once unblinding has occurred, the knowledge of the blinded treatment assignment must 
stay restricted at the site level.  
A study participant may stay on study treatment after unblinding provided the investigator 
considers it is in the participant’s best interest. 
The circumstances leading to unblinding must be documented in the hospital charts, the 
ISF, and in the IRT system. 
6.1.6 Study treatment handling/preparation/storage/accountability 
Manufacture, labeling, packaging, and supply of study treatment will be conducted 
according to Good Manufacturing Practice, GCP, and any local or national regulatory 
requirements. 
All study treatment supplies are to be used only in accordance with this protocol, and not 
for any other purpose. 
6.1.6.1 Study treatment packaging and labeling 
Study treatment is provided as capsules and supplied in childproof bottles. 
Study treatment is labeled to comply with the applicable laws and regulations of the 
countries in which the study sites are located. 
6.1.6.2 Study treatment distribution and storage at the site 
Study treatment supplies must be kept in an appropriate, secure area and stored according 
to the conditions specified on the label and in the IB and/or Investigational Medicinal 
Product handling manual [ACT‑539313 IB]. 
6.1.6.3 Study treatment dispensing 
The study participants will receive sufficient study treatment to cover the period up to the 
next scheduled visit. Study participants are asked to return all used, partially used, and 
unused study treatment bottles at each visit. Should the treatment bottle dispensed at a 
scheduled visit be lost or damaged, a replacement bottle can be requested via the IRT 
system. In exceptional circumstances (e.g., pharmacist not available on the date of the 
scheduled visit), the investigator/delegate may contact the IRT system shortly prior to the 
scheduled visit (with the exception of the randomization visit [see Section 6.1.3] to obtain 
the treatment kit number(s) to be dispensed at the visit. 


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The protocol-mandated study treatment dispensing procedures may not be altered without 
prior written approval from the sponsor. In exceptional circumstances (e.g., if the study 
participant lost the study treatment between two visits, or if the study participant is unable 
to return to the site due to a medical emergency / hospitalization at another hospital / long 
travel distance), unscheduled dispensing and delivery of study treatment may occur outside 
of a scheduled visit. If the study treatment needs to be shipped to the study participant, the 
site staff must first contact the sponsor representative to check whether the dispensing and 
delivery process is in accordance with the sponsor/CRO’s Quality System documents as 
well as any local or national regulatory requirements.  
An accurate record of the date and amount of study treatment dispensed to each study 
participant must be available for inspection at any time. 
Study participant will be dispensed new bottle(s) at each visit. Study drug from the newly 
received bottle is always to be taken in the evening at home.  
The morning dose will be taken at home from the current bottle, except for Visit 5 
(Week 4), Visit 7 (Week 8) and EOT visit where the morning dose will be withheld until 
the participant is on site and will be taken after PK laboratory samples are drawn. 
6.1.6.4 Study treatment accountability 
The inventory of study treatment dispensed to and returned by the study participant (i.e., 
study treatment accountability) must be performed by site personnel on the day of the visit 
and before dispensing further study treatment. The inventory is to be recorded by site 
personnel in the site documentation and in the eCRF. The study treatment accountability 
log in the eCRF will include at least the following information for each study treatment 
unit dispensed to the study participant: 
• Number of bottles dispensed 
• Dispensed bottle ID number 
• Date dispensed / number of capsules dispensed 
• Date returned / number of capsules returned 
All study treatment supplies, including partially used or empty bottles must be retained at 
the site until verified by the CRA. 
If the study participant forgets to bring the remaining study treatment to a study visit, he/she 
must be instructed to not take any capsules from the remaining study treatment bottle and 
to return it at the next visit. 


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6.1.6.5 Study treatment return and destruction 
The protocol-mandated study treatment returning procedures may not be altered without 
prior written approval from the sponsor. On an ongoing basis and/or on termination of the 
study, the CRA will collect used and unused treatment kits, which will be sent to the 
warehouse, where the sponsor/depot personnel or a deputy will check treatment 
reconciliation.  
In certain circumstances (e.g., local hospital procedures), used and unused study treatment 
containers may be destroyed at the site. In general, this can only be done once study 
treatment accountability is finalized and has been checked by the sponsor personnel 
representative and written permission for destruction has been obtained from the sponsor. 
Exception might happen in case a local process requests immediate destruction of the study 
treatment. Such local study treatment destruction processes must be provided and approved 
by the sponsor in advance. 
6.1.7 Study treatment compliance 
The investigator/delegate must discuss the non-compliance with the study participant 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. 
6.2 Previous and concomitant medications 
A previous medication / non-pharmacological therapy is any treatment for which the end 
date is prior to the start of study treatment. 
A concomitant medication / non-pharmacological therapy is any treatment that is either 
ongoing at the start of study treatment or is initiated during the treatment period.  
6.2.1 Allowed concomitant therapy 
Therapies considered necessary for the study participant’s well-being and not categorized 
as prohibited concomitant medications can be used in this study and must be documented 
in the medical charts. However, initiation of a new medication is to be discouraged and any 
concomitant (i.e., ongoing maintenance) medication will preferably not be changed during 
the study. 
6.2.2 Forbidden concomitant therapy 
Study participants must not be withdrawn from medically necessary therapies in order to 
participate in the study. These participants must rather be considered as non-eligible for 
the study due to their medical condition and their requirement for these therapies. 
The following concomitant therapies are forbidden during the study: 
• CNS-active drugs, such as centrally active anticholinergics, sedating antihistamines, 
morphine and other opioids, anticonvulsants, antidepressants, anxiolytics, mood 


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stabilizers, antipsychotics, stimulants, sleep drugs, and anti-Parkinson’s drugs within 
30 days prior to Screening or planned to be initiated during the study and until EOS.  
• Medications that affect body weight or appetite, including weight-loss medications, 
insulin, GLP-1 receptor agonists, systemic corticosteroids etc., within 3 months prior 
to Screening and until EOT. 
• Moderate and strong inducers and inhibitors of CPY3A4, sensitive substrates of 
CYP3A4, CYP2C19, CYP2C8, and CYP2C9 within 2 weeks prior to randomization 
(Visit 2) or planned to be initiated during the study and until 24 h after EOT.  
• Any medications for the treatment of BE, including lisdexamfetamine (Vyvanse®), any 
other eating disorder, obesity, or weight gain, or any other medication that could result 
in weight gain or weight loss including over the counter and herbal products within 
3 months prior to Screening. 
• Psychotherapy or behavioral weight‑loss interventions for BED during the study and 
until 24 h after EOT. 
6.3 Medical care of study participants after study completion / withdrawal 
from study  
After the study participant’s study completion or premature withdrawal from the study, 
whichever applies, the investigator/delegate will explain to study participants what 
treatment(s) / medical care is necessary and available according to local medical practice 
and applicable guidelines.  
Female study participants of childbearing potential will be reminded of the contraception 
requirements as described in Section 5.5.2. 
7 
VISIT SCHEDULE AND STUDY ASSESSMENTS AND PROCEDURES  
7.1 General information 
The treatment period starts with the administration of the first dose of study treatment and 
ends on the day of the last dose of study treatment (EOT). The study participants will be 
treated for 12 weeks. 
The safety follow-up period starts on the day after the last dose of study treatment (EOT) 
and ends at the EOS visit.  
For participants who prematurely discontinue study treatment, the EOT visit will occur 
within 5 days of the last intake of study treatment. For participants who complete the 
treatment period as planned, the Week 12 visit corresponds to the EOT visit. 
The study visits and their respective time windows are listed in the schedule of activities 
[Table 1]. All assessments pertaining to a visit must be performed on the same day. If it is 


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not possible to complete all assessments on the same day, a visit may extend over more 
than 1 day within the allowed time window. 
7.1.1 Screening 
The study participants who agree to be part of the study and the investigator/delegate must 
sign the ICF prior to participation in the study. The ICF must be fully signed [see 
Section 10.2 for informed consent procedure] on the day of the Screening visit.  
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. Screening 
assessments may be performed at any time during the screening period. 
It is the responsibility of the investigator/delegate to obtain written informed consent from 
each participant in this study after adequate face-to-face explanation of the study 
objectives, design, and potential hazards of the study. 
If the first study-specific procedures or assessments are performed on the day that the ICF 
is signed, it must be clear from the source documents that informed consent was obtained 
prior to any study-specific procedures being performed (i.e., time of signature must be 
available). 
Procedures or assessments conducted as part of the study participant’s routine clinical 
management (e.g., laboratory samples) which were obtained before signing of the ICF may 
be used for screening or baseline purposes provided the procedures met the 
protocol‑specified criteria and were performed within the time frame defined in the 
schedule of activities [Table 1]. In such cases, it must be clear from the source documents 
when and for which reason the assessment was done prior to the signing of the ICF. 
After the ICF has been fully signed, the investigator/delegate contacts the IRT system to 
get a study participant number allocated to the study participant.  
It is not permitted to re-screen study participants in this study.  
7.1.2 Unscheduled visits 
Unscheduled visits may be performed at any time during the study and will be recorded in 
the eCRF. Depending on the reason for the unscheduled visit (e.g., AE), appropriate 
assessments will be performed based on the judgment of the investigator and the results 
will be recorded in the eCRF. After an unscheduled visit, the regular scheduled study visits 
must continue according to the schedule of activities [Table 1]. 
7.1.3 Study completion  
A study participant who completes 12 weeks of treatment and the safety follow-up period 
is considered to have completed the study per protocol. A study participant who 


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prematurely discontinues the study due to pre-defined criteria [see Section 5.9.1], withdrew 
from the study, was lost to follow-up, or was withdrawn from the study because of study 
closure or premature termination or suspension of the study [see Section 10.10 is 
considered as an early discontinuation. 
7.2 Study assessments and procedures 
The study assessments and procedures and their timing are summarized in the schedule of 
activities [Table 1].  
All study assessments performed during study visits (scheduled or unscheduled) are done 
by the investigator/delegate and are recorded in the eCRF, unless otherwise specified.  
In general, it is recommended to start visits by performing blood sample collection, so that 
study participants do not stay under fasted conditions too long. Questionnaires and scales 
are recommended to be performed in the following order: 
At Screening: 
• SCID-5 (paper-based) to confirm diagnosis of BED   
• EDE-Q (ePRO) which helps confirm diagnosis of BED and rule out bulimia nervosa 
• MINI (paper-based) should ideally be done after the EDE-Q 
• CGI-S (ePRO), taking into account results of all other eating disorder evaluations 
• Instructions to the study participant on how to complete the BE diary (paper-based)  
At Randomization and subsequent visits: 
• Review of paper-based questionnaires BE diary (and SSS) 
• YBOCS-BE (ePRO) 
• CGI-S (ePRO) 
• Other scales can be done in order of investigator’s clinical judgment 
 
 
 
The following assessments will be analyzed by an external provider (results will be 
transferred to sponsor and to the investigators): 
• Laboratory variables 


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• ECG variables 
• Questionnaires completed using a touchscreen device (handheld tablet device or 
laptop), listed below. 
If the PI delegates any study procedure/assessment for a study participant to an external 
facility, he/she must inform the sponsor to whom these tasks are delegated. The setup and 
oversight must be agreed upon with the sponsor. 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 recruitment of 
the first study participant. Calibration certificates / evidence of equipment maintenance for 
other equipment must be available as per local requirements. 
Equipment for which calibration certificates are needed: 
• Temperature measurement devices for study treatment storage area and laboratory 
sample storage (e.g., freezer) 
• Body-weight scale  
• Use of touchscreen device  
• Study participants will be required to complete the following questionnaires on a 
touchscreen device at the study site/clinic during the appropriate visit days [see Table 1 
and Sections 7.2.3 and 7.2.4 for further description of the respective questionnaires]: 
• EDE-Q, BWSQ, PGI-S, PGI-C, 
 tasks  
• Investigators, delegated physicians, specialist nurses or nurse practitioners trained 
according to local requirements and local clinical practice will be required to complete 
the following questionnaires on a touchscreen device at the site:  
– YBOCS-BE, HAMD-17, C-SSRS©, CGI-S, CGI-C  
• Sites will be properly trained on the accurate use of the touchscreen device by the 
sponsor or an external CRO and are then expected to train their study participants on 
how to appropriately complete the questionnaires. Data collected from the touchscreen 
device will be electronically transferred to the sponsor by the CRO. 
• For further details refer to the touchscreen device manual. 
7.2.1 Demographics / baseline characteristics 
Demographic and baseline characteristics data to be collected in the eCRF for all study 
participants include: age, sex, race and ethnicity (if allowed in the country). Relevant 
medical history and/or current medical conditions, based on the investigator/delegate’s 
judgment (e.g., chronic and ongoing acute conditions, serious past conditions including 


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previous surgeries), present before and/or at the time of signing of the ICF will be recorded 
in the eCRF. Where possible, diagnoses rather than symptoms will be recorded. 
The reason for not being of childbearing potential will be recorded in the eCRF.  
7.2.2 Reporting of previous/concomitant medications / non-pharmacological 
therapy / medical or surgical interventions or procedures and methods of 
birth control in the eCRF  
A concomitant medication / non-pharmacological therapy is any treatment that is either 
ongoing at the start of study treatment or is initiated during the treatment period.  
A previous medication / non-pharmacological therapy is any treatment for which the end 
date is prior to the start of study treatment. 
The use of all concomitant medications / non-pharmacological therapy (including 
contraceptives and traditional and alternative medicines, e.g., plant-, animal-, or 
mineral-based 
medicines) 
will 
be 
recorded 
in 
the 
eCRF. 
Previous 
medications / non‑pharmacological therapy must be recorded in the eCRF if discontinued 
less than 30 days prior to signing of the informed consent. 
Any medical or surgical intervention performed on the study participant at any time during 
the study, will be documented in the eCRF.  
The methods of birth control used (including non-pharmacological methods) by the 
WOCBP (and partner if applicable) must be recorded in the eCRF.  
In addition, the investigator/delegate will record any change in the method of contraception 
in the eCRF at monthly intervals and will remind the study participant to follow the 
protocol‑mandated method of contraception up to 30 days after study treatment 
discontinuation. 
Note: The documentation of method of contraception can be based on the site personnel’s 
review of the study participant’s medical records, medical examination, or medical history 
interview of the study participant. 
7.2.3 Eligibility assessments 
7.2.3.1 Structured Clinical Interview for DSM-5 - Clinical Trial Version (SCID-5) 
The SCID-5 is a semi-structured interview guide for making the major DSM-5 diagnoses. 
It is conducted by a clinician or trained mental health professional who is familiar with the 
DSM-5 classification and diagnostic criteria. 
The SCID-5 Eating Disorder module will be conducted at Screening to diagnose BED and 
to exclude other eating disorders e.g., anorexia nervosa and bulimia nervosa. 


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7.2.3.2 Eating Disorder Examination Questionnaire (EDE-Q) 
The EDE-Q is a 28-item scale that assesses attitudinal and behavioral dimensions of the 
eating psychopathology in BED. It will be used to confirm the SCID-5 diagnosis of BED. 
EDE-Q focuses on the previous 28 days, except for the diagnostic items that are rated for 
the durations stipulated in the DSM-5 (SCID-5).The EDE-Q also assesses in more detail 
the frequency of different forms of overeating, including objective bulimic episodes (binge 
eating defined as unusually large quantities of food with a subjective sense of loss of 
control) and subjective bulimic episodes (defined as a subjective sense of loss of control 
but a normal or small amount of food).  
The EDE-Q will be answered by the study participant and reviewed by a clinician or trained 
mental health professional to confirm the diagnosis of BED as well as to confirm the 
self‑reported severity of binge eating in BE days, based on the last 28 days. The full EDE‑Q 
(28-item) version will be assessed at Visit 1. 
7.2.3.3 Mini International Neuropsychiatric Interview© 
The MINI© is a psychiatric examination [Sheehan 1999] used to identify study participants 
with exclusionary psychiatric conditions. The MINI© will be conducted at Screening by a 
trained clinician. The MINI© will be conducted to ascertain the psychiatric diagnoses, and 
any clinically relevant psychiatric conditions will be reported in the eCRF. 
7.2.3.4 Binge Eating Diary  
The number of BE episodes will be recorded by the study participant daily, preferably in 
the evening, for at least 2 weeks prior to randomization in a paper-based diary. The diary 
captures the number of binges per day, total time spent BE each day, type of binge 
(mealtime vs non-mealtime), and a description of the binge (amount and types of food). A 
BE day is defined as a day with at least one BE episode. These data will be reviewed by 
the investigator with the study participant at Visit 2 and will determine whether the 
participant meets inclusion criterion 9. The investigator will confirm whether each 
recorded eating episode is a binge or not. The number of confirmed binges each day will 
also be recorded in the eCRF. 
7.2.4 Efficacy assessments 
The schedule of activities is presented in Table 1. 
7.2.4.1 Binge Eating Diary 
As above, the number of BE episodes will continue to be recorded by the study participant 
daily, preferably in the evening, until end of study treatment. Data from the diary will be 
reviewed by the investigator with the study participant at each visit until end of study 
treatment and will help the investigator confirm whether each recorded eating episode is a 


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binge or not. The number of confirmed binges each day must be recorded in the eCRF. A 
BE day is defined as a day with at least one BE episode. 
7.2.4.2 Yale-Brown Obsessive-Compulsive Scale Modified for Binge Eating 
The YBOCS [Goodman 1989] is an interviewer‑administered assessment developed to 
measure the severity of obsessive‑compulsive symptoms in patients with a diagnosis of 
OCD. The YBOCS-BE is a version of the YBOCS modified to measure the obsessiveness 
of BE thoughts and the compulsiveness of BE behaviors. The BE behavior of BED is 
similar to an OCD compulsion in that it is time-consuming, distressing, may inhibit or 
hinder functioning, and may or may not be successfully resisted [Deal 2015]. The scale has 
been modified by replacing the term “obsessive thoughts” with “thoughts, impulses, or 
ideas to binge eat” for the first 5 items, and “compulsive behaviors” with “binge eating” 
for items 6–10. The 10 items are clinician/investigator-rated on a 5-point Likert scale. The 
YBOCS‑BE [Machado 2020,Yee 2019] will be administered on a touchscreen device on 
site, at Visit 2 (Randomization), Visit 5 (Week 4), Visit 7 (Week 8), and EOT (Week 12). 
7.2.4.3 Clinical Global Impression of Severity Scale 
The CGI-S is a 1-item, 7-point scale that requires the investigator to rate the severity of the 
study participant’s illness at the time of assessment, relative to the clinician’s experience 
with patients who have the same diagnosis.  
After a clinical evaluation, the CGI-S form can be completed in less than a minute by an 
experienced rater. In practice, the CGI-S captures clinical impressions that transcend mere 
symptom checklists. It ranges between “Normal, not at all ill” and “Among the most 
extremely ill patients”. The CGI-S will be administered on a touchscreen device on site, at 
Visit 1 (Screening), Visit 2 (Randomization), Visit 5 (Week 4), Visit 7 (Week 8), and EOT 
(Week 12).  
7.2.4.4 Clinical Global Impression of Change Scale 
The CGI-C is a 1-item, 7-point scale that requires the clinician to assess how much the 
study participant’s illness has improved or worsened relative to a baseline state at the 
beginning of the intervention. The range is between “Very much improved” and “Very 
much worse”. The CGI-C will be administered on a touchscreen device on site at Visit 3 
(Week 1), Visit 5 (Week 4), Visit 7 (Week 8), and EOT (Week 12).  
7.2.4.5 Patient Global Impression of Severity scale 
The PGI-S is a question concerning the overall severity of symptoms and impact that the 
study participant may have experienced due to his/her BE episodes over the 7 days 
preceding the PGI-S completion.  


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It ranges between “No binge eating” and “Very severe”. It is a self-administered 
questionnaire completed on a touchscreen device on site at Visit 2 (Randomization), Visit 5 
(Week 4), Visit 7 (Week 8), and EOT (Week 12). 
7.2.4.6 Patient Global Impression of Change scale 
The PGI-C is a 1-item, 7-point scale that asks the study participant to evaluate all aspects 
of his/her health and to assess if there has been an improvement or decline in clinical status 
from the baseline of the observation.  
The scale starts at “Very much worse” escalating to “Very much improved”. The PGI-C 
will be administered on a touchscreen device on site at Visit 3 (Week 1), Visit 5 (Week 4), 
Visit 7 (Week 8), and EOT (Week 12). 
7.2.4.7 Eating Disorder Examination Questionnaire (EDE-Q7) 
The EDE-Q7 is a self-reported questionnaire containing 7 out of the 28 questions from the 
EDE-Q about eating behaviors (Items #1, 3, 4, 22, 23, 25 and 26). It will be completed on 
a touchscreen device on site at Visit 2 (Randomization), Visit 5 (Week 4), Visit 7 (Week 8), 
and EOT (Week 12).  
7.2.4.8 Hamilton Depression Rating Scale (HAMD-17) 
The HAMD-17 [Hamilton 1960] will be used to provide an indication of depression. The 
total score will be used to exclude study participants with symptoms of depression of at 
least moderate severity at baseline (score of 17 or more). In addition, it will also be used to 
assess the change from baseline to Weeks 6 and 12 on the total score in study participants 
who may have signs of depressive symptoms as well as on its anxiety-related subitems 10 
& 11 and the MPS. The MPS combines the items 1, 2, 7, 8, 9, and 10 and is an observational 
rating measure to assess the severity of depressive symptoms and its improvement under 
therapy. It will be completed on a touchscreen device on site at Visit 1 (Screening), Visit 2 
(Randomization), Visit 6 (Week 6), EOT (Week 12), and EOS. 
 
 
 
 
  
 
 
 
 
 
 


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7.2.4.10 Body weight and height  
Body weight will be measured at all visits up to EOT and recorded in the eCRF. Height 
will only be measured at Screening. Body weight measurements will be done in lightweight 
clothes, without shoes, with an empty bladder, and approximately at the same time of the 
day. The same calibrated scale should be used throughout the trial.  
The BMI will be calculated at Visit 1 (for eligibility) and displayed automatically upon 
entry of weight and height in the eCRF. 
Unless otherwise specified, the date of each assessment will be collected in the eCRF. 
7.2.5 Safety assessments 
Unless otherwise specified, the date of each assessment will be collected in the eCRF. 
The definitions, reporting, and follow-up of AEs, SAEs and pregnancies are described in 
Section 8. 
7.2.5.1 Physical examination 
Physical examination includes the examination of the general appearance (heart, lungs, 
abdomen, skin, extremities, eyes, ears, nose, throat, lymph nodes, nervous system, etc.). 
Physical examination is to be performed at Visit 1 and at EOT visit.  
Other examinations 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 physical examination will be reported in the eCRF as either normal or abnormal; in 
the latter case, the investigator should specify whether it is clinically relevant. Clinically 
relevant findings (other than those related to BED) that are present prior to signing the ICF 
must be recorded as medical history in the eCRF. Physical examination findings, which 
meet the definition of an AE [Section 8.1.1] and are made after signing of the ICF, must 
be recorded on the AE form of the eCRF. 
7.2.5.2 Vital signs 
Oral or axillary temperature, pulse rate, respiratory rate, and blood pressure (systolic and 
diastolic) will be assessed and recorded in the eCRF. The date and actual time of vital sign 
measurements will be entered in the eCRF. Any clinically significant abnormal vital sign 


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value should be repeated after a reasonable interval (e.g., 10–15 min) to ensure accuracy. 
If the abnormality persists upon repeat measurement, the participant should be assessed by 
the investigator.  
Blood pressure and pulse measurements will be assessed with the study participant in a 
seated position. It is recommended to allow the study participant to rest for at least 
5 minutes in a quiet setting without distractions (e.g., television, cell phones), and to use 
the same position (i.e., sitting), same device and same arm throughout the study for an 
individual study participant.  
Vital signs are to be assessed at each visit until EOT visit. 
7.2.5.3 Electrocardiograms 
A standard 12-lead ECG will be performed at Visit 1 (Screening) and EOT visit using the 
ECG machine provided by the central ECG vendor. ECGs will be performed with the study 
participant in a fully rested supine position after the study participant has been allowed to 
rest for a minimum of 5 minutes. The date and actual time of ECGs will be recorded in the 
eCRF. 
A central ECG vendor (see ECG manual for contact details) will be used for the evaluation 
of all protocol-mandated ECGs, including re-tests due to ECG abnormalities and ECGs 
performed at unscheduled visits. The site personnel will electronically transmit the ECGs 
to the central ECG vendor for central reading. 
The 12-lead ECG measurements (e.g., HR and the intervals PR, QRS, QT, QTcF, and 
QTcB), qualitative ECG findings (e.g., rhythm, ectopy, conduction and morphology) and 
the overall interpretation of the ECG (normal/abnormal) will be provided by the ECG 
central vendor. 
ECG reports will be provided by the central ECG vendor to the investigator/delegate. 
If specific (pre-defined in the ECG manual) ECG abnormalities are observed, the central 
ECG vendor will alert the sponsor and the investigator/delegate. 
All ECG reports must be reviewed, signed and dated by the investigator or delegate within 
10 calendar days of receipt and filed with the source documentation. The 
investigator/delegate must indicate on the ECG report whether abnormal values or findings 
are considered clinically relevant or not. Clinically relevant ECG findings that are known 
at the time of signing of the ICF must be recorded as medical history in the eCRF.  
Details on ECG procedures (recording, transfer of data and reporting) will be provided in 
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7.2.5.4 Clinical laboratory assessments 
See schedule of activities [Table 1 for the timing and frequency. 
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 may require recording of local laboratory results (with 
corresponding normal ranges) include hospitalization of the study participant due to a 
medical emergency and missing central laboratory results from a scheduled or unscheduled 
visit. 
If two or more consecutive central laboratory samples are lost or cannot be analyzed for 
whatever reason, the investigator/delegate 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. 
Under specific circumstances (e.g., if the study participant lives far from the site and cannot 
return every month), laboratory samples may be collected at a laboratory close to where 
the study participant lives (satellite laboratory) and sent to the central laboratory for 
analysis. In such a case, the satellite laboratory must be provided with the central laboratory 
sampling kits. Shipment of the samples will be organized by the satellite laboratory. The 
supervision of the satellite laboratory remains the responsibility of the PI. 
Central laboratory reports will be sent to the investigator. In the event of specific 
(pre-defined) laboratory abnormalities, the central laboratory will alert the sponsor 
personnel and the concerned site personnel. Alert flags that will trigger such notifications 
will be displayed in the laboratory manual. 
All laboratory reports must be printed, reviewed, signed and dated by the investigator or 
delegate within 5 calendar days, and filed with the hospital chart. The investigator/delegate 
must indicate on the laboratory report whether abnormal values are considered clinically 
relevant or not. Clinically relevant laboratory findings that are known at the time of signing 
of the ICF must be recorded as medical history in the eCRF.  
Blood samples will be drawn in the morning under fasted conditions (i.e., before breakfast) 
and when applicable before the morning administration of the study treatment at all 
scheduled and unscheduled visits. However, it is not permitted to request that study 
participants are in a fasted state (for the study) at the Screening visit unless the ICF has 
already been signed. 
A serum pregnancy test for WOCBP will be performed at the Screening visit and EOT 
visit.  


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Urine pregnancy tests will be performed at randomization before first study treatment 
administration (Visit 2) and monthly thereafter (i.e., Visit 5 and Visit 7) up to EOS visit. 
Urine pregnancy tests will be performed with locally approved kits. 
The results of the urine pregnancy tests will be collected in the eCRF. Serum pregnancy 
tests will be sent to the central laboratory for analysis and the result will be sent to the 
investigator/delegate. If pregnancy is suspected during the study, i.e., in each case of 
delayed menstrual period (e.g., over one month between menstruations), a serum 
pregnancy test must be performed as soon as possible. Reporting procedures of pregnancy 
are described in Section 8.3.1.  
Hematology: 
• Hemoglobin 
• Hematocrit 
• Erythrocytes 
• Reticulocyte 
• Leukocytes with differential counts 
• Platelets. 
Clinical chemistry: 
• ALT 
• AST 
• Alkaline phosphatase 
• Creatine kinase 
• Total and direct bilirubin 
• Gamma-glutamyl transferase 
• Creatinine and estimated glomerular filtration rate 
• Blood urea nitrogen 
• Uric acid 
• Glucose 
• HbA1c 
• Total cholesterol  
• Triglycerides 
• Sodium, potassium, chloride, calcium 
• Albumin 
• Thyroid hormones, i.e., triiodothyronine (total and free) and thyroxine (total and free), 
and TSH (Visit 1 only). 
Viral serology: 
• At Screening, blood sample will be collected to test for HIV, Hepatis B and C.  


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Other tests: 
The urine drug screening kits (testing for presence of benzodiazepines, barbiturates, 
cannabinoids, opiates, amphetamines, phencyclidine or cocaine) will be provided by the 
central laboratory.  
Details about the collection, sampling, storage, shipment procedures, and reporting of 
results and abnormal findings can be found in the laboratory manual. 
7.2.5.5 Stanford Sleepiness Scale 
The SSS [Hoddes 1972, Hoddes 1973] is a self‑administered questionnaire that uses a 7-
point Likert scale, developed to quantify the subjective sleepiness at any given time. 
Participants will be asked to pick the response (number) that best represents how they are 
feeling two times during the day: once before breakfast (i.e., before the morning dose of 
the study treatment) and then at midday or any time before lunch to capture daytime 
sleepiness temporally related to intake of study treatment. Participants will be asked to 
answer the paper based SSS questionnaire during the first 2 weeks after randomization. 
This will then be transcribed by the site into the eCRF. 
7.2.5.6 Benzodiazepine Withdrawal Symptom Questionnaire 
The BWSQ assesses the occurrence of symptoms which might be experienced by study 
participants after discontinuation of treatment with ACT-539313 [Tyrer 1990]. The 
questionnaire consists of 20 items. The symptoms will be rated from 0 (No), 1 
(Yes‑moderate) to 2 (Yes-severe). The questionnaire will be self-administered using the 
touchscreen device at EOT visit and EOS visit. 
7.2.5.7 Columbia Suicide Severity Rating Scale© 
The C-SSRS© is an instrument that reports the presence and severity of both suicidal 
ideation and behaviors.  
Suicidal ideation is classified on a 5-item scale:  
1. Wish to be dead 
2. Non-specific active suicidal thoughts 
3. Active suicidal ideation with any methods (no 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 questions and answers on 
suicidal behaviors, specifically: actual, interrupted, and aborted attempts; preparatory acts 


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or behaviors; and the presence of suicidal behaviors 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.  
At Screening the C-SSRS© will be completed for the study participant’s lifetime history of 
suicidal ideation and behaviors and participants who answer “yes” in the past month to 
items 2, 3, 4, or 5 on the C-SSRS© assessment will be excluded from the study [see 
Section 5.4, criterion #26). At all other visits, the C-SSRS© will be completed for ideation 
and behaviors since the previous visit. All time points will be collected on a touchscreen 
device on site. 
Participants who answer “yes” to items 2, 3, 4, or 5 on the C-SSRS© assessment at any 
post-randomization visit must undergo further evaluation by the investigator to assess the 
risk. No study treatment will be dispensed to such participants until after the investigator 
confirms suitability of the participant to remain in the study. This evaluation and decision 
should also be clearly recorded in the source documents. 
As part of routine clinical care, participants will be provided with 24-hour emergency 
contact details in the event of an emergency should the participant feel that he/she is acutely 
at risk. In addition, participants who are recruited into the study will be advised of the 
location of their nearest hospital. 
7.2.5.8 Assessments in the context of COVID-19: Recommendations and instructions 
Flexibility regarding site visits for study participants who can still go to sites 
If the study participant can travel to the investigator’s site: 
• The investigator should ensure the study participant’s safety on his/her way to the site 
by following local/country regulations (e.g., not using public transportation). 
Alternatively, study participants can use taxis or private cars, the cost of which will be 
reimbursed by the sponsor. 
• The on-site visit assessments should be performed according to the protocol. 
• An on-site visit is always preferable. Therefore, this may mean that the visit windows 
need to be extended, as long as the study participant has enough study treatment. Study 
treatment can be delivered to the study participant’s home following the instructions 
below. The reason for this delayed scheduled visit must be documented in the study 
participant’s medical charts and in the eCRF.  
Conduct of remote visits for study participants who cannot, are not allowed to, or are not 
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If the study participant cannot, is not allowed to, or is not willing to travel to the 
investigator’s site, the clinic visit(s) can be replaced by a telephone call or video call to 
keep close contact with study participants (remote visits), these visits should be at least as 
frequent as the protocol‑mandated clinic visits. The investigator should notify the IEC / 
IRB in advance of remote visits if this is a local requirement.  
Before the telephone call or video call visit:  
If the study treatment needs to be delivered to the study participant’s home, the investigator 
should ensure the following:  
• Obtain study participant’s verbal consent by telephone to provide his/her name and 
home address to the courier service responsible for delivering study treatment and 
pregnancy tests, if applicable. 
• The date and time that verbal consent was obtained is documented in the study 
participant’s medical records.  
• Make sure that WOCBP have enough home urine pregnancy kits (send them along with 
study medications to the study participant’s home if necessary) and remind them to 
perform the test as mandated by the protocol. 
• If the approval must be in writing, according to the site’s local regulation, the 
investigator/delegate must act accordingly and document it in the study participant’s 
medical charts. 
• Arrange for the delivery of study treatment (in accordance with local regulation) to the 
study participant’s home in advance. 
• Arrange for the delivery of additional BE diaries and SSS questionnaires. 
• Arrange for the delivery of appropriately calibrated devices for measuring vital signs 
to the study participant’s home in advance. Clear instructions on how to use these 
devices will also be provided on paper; in addition, the investigator or site staff will 
review these instructions with the participant. 


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During the telephone call or video call visit:  
All efforts should be made to collect the same information as collected during an on-site 
visit. The investigator will check and record the vital signs measured by the participant 
using the devices provided. Efficacy data will be collected, questionnaires and other 
assessments should be performed, even remotely, if possible. To ensure study participants’ 
safety, investigator/delegate will conduct an interview to detect any potential AE as 
described below. 
Special attention is to be paid to the primary efficacy endpoint. Each study participant will 
go over the BE diary entries with the investigator who will confirm whether each recorded 
eating episode is a binge or not. 
The investigator will interview the study participant for:  
• Occurrence of any new AEs or worsening of existing ones. 
• When asking about the occurrence of AEs, please follow the same process as for a site 
visit, i.e., use an open-ended question, such as: “Have you had any significant medical 
problems since the last study visit?”. 
• Collection of additional information about AESI as applicable.  
• Reviewing the SSS entries with the study participant to check for daytime sleepiness 
symptoms (Visit 2, Visit 3 and Visit 4 only).  
• Assessing withdrawal symptoms (only applicable between EOT and EOS visits). 
• Completion of the C-SSRS© questionnaire, on-site by the investigator. 
• Completion of the YBOCS-BE, on-site by the investigator. 
• Completion of the HAMD-17, on-site by the investigator. 
• Completion of the CGI-S and CGI-C, on-site by the investigator. 
• Reviewing SSS scores (in addition to BE diary data). These paper‑based 
questionnaires, completed at home by study participant, will have to be brought back 
to the site at the next visit. 
• Changes in any ongoing medication or start of new medication(s).  
• Check compliance with study medication and potential overdose or other medication 
error(s). 
Note: If closer monitoring of any of the above detected findings is required but not possible, 
depending on the severity of the symptoms observed and the investigator’s assessment of 
the benefit-risk for the study participants inclusion in the trial, the investigator may 
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The telephone or video contact must be entered under the visit it replaces (e.g., if the 
assessments were intended for Visit 3, please use the Visit 3 form) and documented in 
detail (day, time and conversation) in the study participant’s medical charts. All 
assessments not performed must be entered as “Not done”. 
Should any additional telephone calls be performed to ensure the study participant’s safety 
that are not part of the regular visit plan, the call must be entered as an unscheduled visit 
in the eCRF and documented in detail (day and reason for the ‘UNS’) in the study 
participant’s medical charts.  
7.2.5.9 COVID-19 testing 
There is no mandatory COVID-19 testing required as part of this protocol. Testing for 
SARS‑Cov-2 virus will be done as per each site’s local requirements. The need to perform 
COVID-19 testing for a study participant already enrolled in the study will likewise be 
guided by the site’s local standard measures and requirements. See Section 5.9.1.4 for 
details on what happens to a study participant who becomes infected during the study.  
7.2.6 Pharmacokinetic assessments 
PK samples will be collected prior to the morning dose at Visit 5 (Week 4), Visit 7 
(Week 8), and EOT visit (Week 12). 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 also be entered in the eCRF.  
Details about the collection, sampling, storage, and shipment procedures can be found in 
the laboratory manual. 
8 
SAFETY DEFINITIONS AND REPORTING REQUIREMENTS 
8.1 Safety definitions 
8.1.1 Definition of adverse events 
An AE is any untoward medical occurrence, i.e., any unfavorable and unintended sign, 
including an abnormal laboratory finding, symptom, or disease that occurs in a study 
participant during the course of the study, whether or not considered by the 
investigator/delegate as related to study treatment. 
AEs include: 
• Exacerbation of a pre-existing disease if considered medically relevant.  
• Exacerbation of a pre-existing disease with the exception of efficacy endpoints and 
associated symptoms. 


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• 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 after the 
signing of the ICF. 
• Abnormal 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 as per investigator medical assessment. 
• 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 as per investigator judgment, led to dose reduction, interruption or 
permanent discontinuation of study treatment. 
8.1.2 Definition of serious adverse events 
An SAE is defined by the ICH guidelines as any AE fulfilling at least one of the following 
criteria: 
• Fatal. 
• Life-threatening: refers to an event in which the study participant 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 (i.e., the AE required admission to hospital) 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 based upon appropriate medical judgment, as they may jeopardize the study 
participant, and/or may require medical or surgical intervention to prevent one of the 
outcomes listed in the definitions above. 
The following reasons for hospitalization are not considered as SAEs: 
• Hospitalization for cosmetic elective surgery, or social and/or convenience reasons. 
• Hospitalization for pre-planned (i.e., planned prior to signing the ICF) surgery or 
standard monitoring of a pre-existing disease or medical condition that did not worsen, 
e.g., hospitalization for coronary angiography in a study participant with stable angina 
pectoris. 


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8.1.3 Intensity of adverse events 
The intensity of AEs is graded on a three-point scale — mild, moderate, severe — as 
follows: 
❑ Mild 
The event may be noticeable to the study participant. It does not usually influence daily 
activities, and normally does not require intervention. 
❑ Moderate 
The event may make the study participant 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 
study participant 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. These terms are used to 
describe the intensity of a specific event. Medical judgment should be used on a 
case‑by‑case basis. 
8.1.4 Relationship to study treatment  
Each AE/SAE must be assessed by the investigator/delegate as to whether or not there is a 
reasonable possibility of causal relationship to the study treatment and reported as either 
related or unrelated.  
8.1.5 Relationship to study design or protocol-mandated procedure  
An AE/SAE is defined as related to the study design or protocol-mandated procedure if it 
appears to have a reasonable possibility of a causal relationship to either the study design 
or to a protocol-mandated procedure. 
The determination of the likelihood that a protocol-mandated procedure caused the 
AE/SAE will be provided by the investigator/delegate. 
8.1.6 Definition of adverse events of special interest 
AESIs for this study include AEs related to somnolence, defined by pre-specified terms. 
At each visit, as per good clinical care, the investigator must ask the study participant for 
any AEs and specifically ask for the occurrence of somnolence and document this as 
appropriate. 


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8.1.7 Definition of study treatment overdose, misuse and abuse 
An overdose is defined as the administration of a study treatment dose (per intake or 
cumulatively) which is above the instructions provided in the protocol. When applying this 
definition, clinical judgement should always be applied. 
The sponsor does not recommend specific treatment for an overdose. 
Study treatment misuse is defined as any intentional and inappropriate use of the study 
treatment which is different from the instruction provided in the protocol.  
Study treatment abuse is defined as any intentional and excessive use of the study 
treatment with harmful physical or psychological effects. 
In the event of a study treatment overdose, abuse or misuse, the investigator/delegate must 
contact the sponsor and closely monitor the study participant for any AEs/SAEs. 
If a mismatch is detected during study medication compliance check, the investigator 
should review and record in the eCRF as an AE if it is consistent with a medication error 
or overdose. The number of extra capsules taken, the time period, and whether it was 
intentional or accidental must also be recorded in the eCRF. 
8.2 Reporting procedures 
8.2.1 Reporting and follow-up of AEs 
The occurrence of an AE may come to the attention of study personnel during study visits, 
telephone calls, or interviews of study participants presenting for medical care.  
At each study visit (scheduled or unscheduled), the investigator/delegate will inquire about 
the occurrence of AEs since the last visit. 
All AEs with an onset date after signing of the ICF up to EOS must be recorded in the 
eCRF.  
The AE should be reported as a final diagnosis (if possible) rather than a list of symptoms. 
Information to be collected on an AE form in the eCRF includes date of onset, time of 
onset, action taken with the study treatment, outcome of the AE, date and time of resolution 
(if applicable), and PI/delegate’s assessment of intensity as well as its relationship to study 
treatment or protocol-mandated procedures.  
Information on worsening of intensity will be collected. If the AE lessens in intensity, no 
change in the severity is required to be reported. 
AEs still ongoing after study treatment discontinuation must be followed up until 
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8.2.2 Reporting and follow-up of SAEs 
All SAEs must be reported by the investigator/delegate to the sponsor’s Global Drug Safety 
department within 24 hours of site staff’s first awareness/knowledge of the event. 
All SAEs occurring after signing of the ICF up to EOS must be recorded on an SAE form, 
regardless of the investigator/delegate-attributed causal relationship with study treatment 
or study-mandated procedures. 
The SAE forms must be sent to the sponsor’s Global Drug Safety department (see contact 
details on the SAE form). The investigator/delegate 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 be promptly reported. The 
sponsor’s Global Drug Safety personnel may contact the investigator/delegate to obtain 
further information. 
If the study participant is hospitalized in a hospital other than that of the study site, it is the 
investigator/delegate’s responsibility to contact this hospital to obtain all SAE-relevant 
information and documentation. 
New SAEs occurring after EOS must be reported to the sponsor’s Global Drug Safety 
department within 24 hours of site staff’s first awareness/knowledge of the event, only if 
considered relevant and study treatment-related by the investigator/delegate. 
SAEs still ongoing after EOS must be followed up until resolution, stabilization, or until 
the event outcome is provided. 
8.2.3 Reporting procedure for SUSARs 
The expectedness of an SAE is determined by the sponsor according to the reference safety 
information section provided in the IB.  
Any SAE that is assessed as related and unexpected against the reference safety 
information is considered as a SUSAR. 
Any SUSAR must be reported by the sponsor or designee (CRO) as determined to 
concerned health authorities, and investigators. Submission to central/local IECs/IRBs will 
be done as per their requirements. 
8.3 Pregnancy 
If a woman becomes pregnant while on study treatment, study treatment must be 
discontinued see Section 5.9.1.1. The investigator/delegate must counsel the study 


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participant and discuss the risks of continuing with the pregnancy and the possible effects 
on the fetus. 
8.3.1 Reporting of pregnancy 
Any pregnancy occurring in a female study participant after signing of the ICF and up to 
EOS must be reported to the sponsor’s Global Drug Safety department within 24 hours of 
site staff first awareness/knowledge of the event. 
All pregnancies must be reported on the sponsor Pregnancy form, which is sent to the 
sponsor’s Global Drug Safety department (see contact details provided on the Pregnancy 
form). 
The investigator must complete the Pregnancy form in English. 
8.3.2 Follow-up of pregnancy 
Any pregnancies must be followed up to their conclusion and the outcome must be reported 
to the sponsor’s Global Drug Safety department.  
Any AE associated with the pregnancy of a female study participant occurring during the 
AE reporting time must be reported on separate AE forms in the eCRF as described in 
Section 8.2.1.  
Any SAE occurring during the pregnancy must be reported on an SAE form as described 
in Section 8.2.2. 
9 
STATISTICAL METHODS 
All statistical analyses will be conducted by the sponsor or by a designated CRO supervised 
by the sponsor. 
A SAP will provide full details of the analyses, data displays, and algorithms to be used 
for data derivations. 
9.1 Analysis sets 
9.1.1 Screened set 
The SCR includes all study participants who entered screening and have a study participant 
identification number.  
Summaries based on the SCR set will be presented as one group (i.e., all study participants). 
9.1.2 All randomized set 
The All-randomized analysis set includes all study participants from the SCR who were 
randomized. 


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9.1.3 Full analysis set 
The FAS includes all study participants who were randomized, received at least one dose 
of study treatment and have a baseline assessment of the primary endpoint.  
In order to adhere to the intention-to-treat principle, study participants will be evaluated 
according to their assigned study treatment. 
This set will be used for the analysis of the study participant demographics and disease 
baseline characteristics, and efficacy. 
9.1.4 Per-protocol analysis set 
The PPS includes all study participants from the FAS without protocol deviations that 
potentially affect the primary endpoint. These deviations will be defined in the SAP. Study 
participants will be evaluated according to the study treatment they received.  
This set will be used for supportive analyses of the efficacy. 
9.1.5 Safety set 
The SAF includes all randomized study participants who received at least one dose of study 
treatment. Study participants will be evaluated according to the study treatment they 
received. 
This set will be used for the analyses of exposure, previous and concomitant medication 
and safety data. 
9.1.6 PK set 
The PK analysis set includes all study participants in the SAF who have at least one PK 
sample collected after initiation of study drug. 
9.1.7 Usage of the analysis sets 
The main efficacy analyses will be performed on the FAS, and a supportive analysis will 
be conducted using the PPS. 
Safety analyses will be performed on the SAF based on actual study treatment received. 
Subject listings will be based on the SAF, unless otherwise specified. Subject disposition 
will be described for the SCR. 
Table 3 describes the analysis sets used for the analysis of each data set. 


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Table 3 
Usage of analysis datasets 
Analysis 
SCR 
RND 
FAS 
PPS 
SAF 
PK set 
Subject disposition 
X 
 
 
 
 
 
Baseline demographics and disease 
characteristics 
X 
(x) 
X 
(x) 
 
 
Previous and concomitant medication 
 
 
 
 
X 
 
Study drug exposure 
 
 
 
(x) 
X 
 
Efficacy analysis 
 
 
X 
x 
 
 
Safety and tolerability analyses 
 
 
 
 
X 
 
PK data analysis 
 
 
 
 
 
X 
Note: X: main analysis, (x): only if > 10% difference in size with FAS.  
FAS = Full analysis set; PK = pharmacokinetic; PPS = Per-protocol analysis set; RND = Randomized analysis set; 
SAF = Safety analysis set; SCR = Screened analysis set. 
9.2 Description of statistical analyses 
9.2.1 Overall testing strategy 
The H0 to be tested is that there is no difference between ACT-539313 and placebo with 
respect to the primary efficacy endpoint: 
H0: µA = µP 
vs 
Ha µA ≠ µP 
Here, µA and µP is the mean change from baseline to Week 12 in the number of BE days 
per week in the ACT-539313 and placebo group, respectively. The null hypothesis will be 
tested at a two-sided 0.05 significance level. 
A preview of the main analyses is given in Table 4 using the estimand terminology 
[ICH 2020]. Estimands are defined by five attributes: treatment condition of interest, target 
population, endpoint, strategy for addressing intercurrent events (i.e., premature 
discontinuation of treatment or use of other, forbidden, medication for BE) and 
population‑level summary. The primary estimand is based on the primary endpoint. A 
supplementary estimand is obtained by changing one or more attributes. For both estimands 
the treatment condition is ACT-539313 b.i.d. for up to 12 weeks, whereas the alternative 
condition is placebo b.i.d. for the same period. The other four attributes are given in the 
table below. Differences vs the primary estimand are indicated in bold italics. 


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Table 4 
Estimands for the primary objective 
Estimand 
Target 
Population 
Endpoint 
Strategy for 
addressing 
intercurrent 
events 
Population-level 
summary 
Primary 
Estimand 
Adult study 
participants with 
BED according to 
DSM-5, having at 
least 3 BE days 
per week. 
Change from 
baseline to 
Week 12 in the 
number of BE 
days per week. 
Hypothetical, i.e., 
endpoint data after 
intercurrent event 
are not used. 
Mean change from 
baseline for each 
treatment group. 
Treatment effect 
expressed as difference 
of LSMean changes 
from baseline 
(ACT‑539313 minus 
placebo; from mixed 
model). 
Supplementary 
Estimand #1 
Adult study 
participants with 
BED according to 
DSM-5, having at 
least 3 BE days 
per week. 
Change from 
baseline to 
Week 12 in the 
number of BE 
episodes per 
week. 
Hypothetical, i.e., 
endpoint data after 
intercurrent event 
are not used. 
Mean change from 
baseline for each 
treatment group. 
Treatment effect 
expressed as difference 
of LSMean changes 
from baseline 
(ACT‑539313 minus 
placebo; from mixed 
model). 
Supplementary 
Estimand #2 
Adult study 
participants with 
BED according to 
DSM-5, having at 
least 3 BE days 
per week, 
completing 
12 weeks of 
treatment 
without use of 
other medication. 
Change from 
baseline to 
Week 12 in the 
number of BE 
days per week. 
Hypothetical, i.e., 
endpoint data after 
intercurrent event 
are not used. 
Mean change from 
baseline for each 
treatment group. 
Treatment effect 
expressed as difference 
of LSMean changes 
from baseline 
(ACT‑539313 minus 
placebo; from mixed 
model). 
Intercurrent events are premature discontinuation of treatment and use of other, forbidden, medication for BE. 
BE = binge eating; BED = binge eating disorder; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders (5th 
edition); LSMean = least squares mean. 


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9.2.2 Analysis of the primary efficacy outcome(s) 
The main efficacy analyses will be performed on the FAS. Supportive analyses will be 
performed on the PPS. 
9.2.2.1 Variable definition  
The primary efficacy variable is the change from baseline to Week 11–12 in the number of 
BE days per week based on diary data. In the analysis, changes from baseline to 
intermediate time points will also be considered. 
The number of BE days per week will be calculated based on 2-week (rather than 1‑week) 
intervals in order to improve the precision of the variable. A minimum of 7 diary entries 
per 14-day time interval is required, otherwise the number of BE days will be considered 
missing. 
The baseline number of BE days per week is defined as the number of diary days with at 
least one BE episode divided by the total number of diary days during the 14 days prior to 
randomization (study Days –14 to –1), times 7. A diary day is a day for which the number 
of BE episodes is entered in the study participant’s diary (this includes a zero value, i.e., 
no BE episode). 
The number of BE days per week at Weeks 1–2, 3–4, 5–6, 7–8, 9–10, and 11–12 are 
calculated similarly based on diary entries during study days 1–14, 15–28, 29–42, 43–56, 
57–70, and 71–84, respectively. 
9.2.2.2 Primary analysis 
The primary analysis will be performed on the FAS. Measurements obtained after 
premature treatment discontinuation will be excluded from the analysis, leading to a 
hypothetical strategy estimand [the primary estimand, Table 4]. This estimand addresses 
the full potential of ACT-539313 which is most relevant for this type of study. 
Changes from baseline to post-baseline time points in the number of BE days per week 
will be analyzed using a mixed model for repeated measurements with factors for treatment 
group, sex, BMI category (< 30 vs ≥ 30 kg/m2) and time point (Weeks 1–2, 3–4, 5–6,  
7–8, 9–10, and 11–12), treatment by time interaction and covariates for baseline number 
of BE days per week and the interaction between baseline and time point.  
An unstructured covariance matrix will be used to account for the correlation between 
repeated measurements from the same study participant. If this analysis fails to converge, 
the following structures will be tested in a subsequent order until model-convergence is 
achieved: heterogeneous Toeplitz; Toeplitz; autoregressive; compound symmetry. The 
Kenward-Roger approximation will be used to estimate denominator degrees of freedom. 


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A restricted maximum likelihood approach in combination with the Newton Raphson 
Algorithm will be used. 
LSMeans for each treatment group and time point will be obtained from the mixed model. 
The null hypothesis associated with the primary endpoint is that there is no difference 
between ACT-539313 and placebo in the mean change from baseline to Week 11–12 in 
the number of BE days per week. This hypothesis will be tested at a two‑sided significance 
level of 5% based on the (ACT-539313 minus placebo) difference in LSMeans at 
Weeks 11–12. The null hypothesis will be rejected if the 95% CI around this difference 
excludes zero.  
Mean changes from baseline in the number of BE days per week by treatment group will 
be displayed graphically to illustrate the time course of the primary endpoint. 
9.2.2.3 Handling of missing data and intercurrent events 
All efforts will be implemented to minimize the amount of missing data. Visits are 
performed at regular and short intervals for the investigator to closely follow-up with the 
diary completion. 
The primary efficacy analysis assumes a missing at random mechanism (i.e., missingness 
is conditionally independent from the unobserved values of the primary endpoint, given 
the covariates in the mixed model).  
Potential impact of COVID-19 pandemic on statistical analyses. The COVID-19 pandemic 
may lead to missed or postponed visits, but the study participant’s binge eating diaries can 
still be evaluated at the next visit to collect the information for the primary endpoint [see 
Section 7.2.5.8]. Any missing diary data due to the COVID-19 pandemic is considered 
missing completely at random and satisfies the assumption underlying the main analysis 
(linear mixed-effects model, assuming missing at random). 
9.2.2.4 Sensitivity analyses  
Sensitivity analyses will be performed assuming a missing not at random mechanism, 
where missingness is related to the unobserved value of the endpoint. The model will utilize 
a multiple imputations approach based on a control-based imputation, which assumes that 
missing values of study participants in the ACT-539313 group are similar to observed 
values of study participants in the placebo group.  
These sensitivity analyses will be described in the SAP. 
9.2.2.5 Supplementary analyses 
The same analysis will be performed on the PPS [supplementary estimand #2, Table 4]. 


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9.2.2.6 Subgroup analyses 
The aim of the subgroup analyses is to explore the consistency of the treatment effect across 
the following subgroups: 
• Age (18–29 vs 30–55 years) 
• Sex (male vs female) 
• Race (Black, Caucasian, other) 
• BMI (< 30 vs ≥ 30 kg/m2) 
Results of the subgroup analyses will be displayed in a forest plot displaying treatment 
effects per subgroup and their 95% CIs (obtained by conducting the primary analysis by 
subgroup) with vertical reference lines at no effect as well as at the overall treatment effect. 
P-values for treatment by subgroup interaction will be provided for exploratory purposes, 
based on the primary analysis model extended with treatment by time and by subgroup 
interaction.  
9.2.3 Analysis of the secondary efficacy outcome(s) 
Not applicable. 
9.2.4 Analysis of exploratory efficacy outcomes 
Only the analyses of select exploratory endpoints [Table 2] are described here. The 
analyses of endpoints associated other objectives will be described in the SAP. 
9.2.4.1 Variable definitions 
• Changes from baseline up to Weeks 11–12 in the number of BE episodes per week 
based on diary data, defined based on the 2-week intervals defined for the primary 
endpoint. The number of BE episodes per week is defined as the number of BE episodes 
in the applicable 14-day time interval divided by the total number of diary days, 
times 7. 
• Absence of BE episodes during the last 4 weeks of the treatment period, defined as no 
BE episodes during study days 57–84. A minimum of 4 out of 7 diary entries are 
required for days 57–63, 64–70,71-77 and 78–84, otherwise the outcome will be set to 
‘No absence’.  
• Change from baseline to Week 12 in EDE-Q7 global score, defined as the difference 
of EDE-Q7 global score at Week 12 and at Baseline. Variables for the EDE-Q7 
subscales are change from Baseline to Week 12 in EDE-Q7 dietary restraint subscale 
score, change from Baseline to Week 12 in EDE-Q7 shape/weight overvaluation 
subscale score and change from Baseline to Week 12 in EDE-Q7 body dissatisfaction 
subscale scores. 


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• CGI-C score at Week 12. Missing assessments at Week 12 will be imputed using last 
on-treatment observation carried forward. Study participants with no on-treatment 
assessment will have a missing value. Additionally, improvement according to CGI-C 
is defined as CGI-C at Week 12 equal to “Much Improved” or “Very Much Improved”. 
If CGI-C at Week 12 is missing, the study participant will be assumed to not have 
improved. 
• PGI-C score at Week 12. Missing assessments at Week 12 will be imputed using last 
on‑treatment observation carried forward. Study participants with no on-treatment 
assessment will have a missing value. Additionally, improvement according to PGI-C 
is defined as PGI-C at Week 12 equal to “Much Improved” or “Very Much Improved”. 
If PGI-C at Week 12 is missing, study participant will be assumed to not have 
improved. 
• Change from baseline to Week 12 in the CGI-S score, defined as the difference of 
CGI‑S score at Week 12 and at Baseline. Missing assessments at Week 12 will be 
imputed using last on-treatment observation carried forward. 
• Change from baseline to Week 12 in the PGI-S score, defined as the difference of PGI‑S 
score at Week 12 and at Baseline. Missing assessments at Week 12 will be imputed 
using last on-treatment observation carried forward. 
9.2.4.2 Analyses 
Other efficacy endpoints will be tested at the two-sided 5% significance level. No further 
Type I error control is applied, so these analyses are to be considered descriptive.  
Change from baseline to Weeks 11-12 of the number of BE episodes per week 
Changes from baseline to post-baseline time points will be analyzed using the same mixed 
model for repeated measurements as for the primary efficacy endpoint, only with a 
covariate for the baseline number of BE episodes (rather than the number of BE days) per 
week. Measurements obtained after premature treatment discontinuation will be excluded 
from the analysis [supplementary estimand #1, Table 4]. 
Absence of BE episodes during the last 4 weeks of the treatment period 
Absence of BE episodes will be analyzed using a logistic regression model with a factor 
for treatment group, sex and BMI category and a covariate for the baseline number of BE 
episodes per week. For study participants who discontinued treatment prematurely, the 
outcome will be set to ‘No absence’. 
Change from baseline to Week 12 in EDE-Q7 global score and 3 subscales 
Changes from baseline in EDE-Q7 scores will be analyzed using a mixed model for 
repeated measurements as described for the primary endpoint, but with less time points.  


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CGI-C score at Week 12 
CGI-C scores will be compared between treatment groups using the Kruskal Wallis test.  
Improvement according to CGI-C at Week 12  
This variable will be analyzed using a logistic regression model with a factor for treatment 
group. The relationship between improvement according to CGI-C at Week 12 and the 
primary efficacy outcome will be investigated. 
PGI-C score at Week 12 
This variable will be analyzed using same methods as for CGI-C score at Week 12.  
Change from baseline to Week 12 in the CGI-S score  
Changes from baseline to Week 12 in CGI-S score will be analyzed in an analysis of 
covariance (ANCOVA) model with a factor for treatment group and a covariate for 
baseline score.  
Change from baseline to Week 12 in the PGI-S score  
This variable will be analyzed using same methods as for change from baseline to Week 12 
in the CGI-S score.  
9.2.5 Analysis of safety outcomes 
The SAF will be used to perform all safety analyses. 
Unless otherwise stated, only treatment-emergent safety data will be considered in tables 
and figures. All safety data will be included in listings.  
9.2.6 Adverse events 
9.2.6.1.1. TEAEs and SAEs 
TEAEs and SAEs, including AESIs, will be tabulated by study treatment, SOC, and 
preferred terms within each SOC: the number and percentage of study participants who 
experienced at least one (S)AE, at least one (S)AE within each SOC, and at least one (S)AE 
within each preferred term will be displayed. (S)AEs will also be summarized by 
decreasing frequency of preferred term. (S)AEs will also be tabulated by maximum 
intensity and by relationship to study treatment. 
9.2.6.1.2. AEs leading to premature discontinuation of study treatment 
AEs leading to premature discontinuation of study treatment will be summarized in a 
similar manner as that described in Section 9.2.6.1.1. 


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9.2.7 Laboratory data 
9.2.7.1.1. Changes from baseline in laboratory variables 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values as well as for changes from baseline for laboratory tests 
(hematology, blood chemistry, urinalysis). 
Data will be displayed in SI units whenever possible and graphical approaches may be 
applied for certain variables.  
9.2.7.1.2. Treatment-emergent marked laboratory abnormalities 
Laboratory abnormalities will be summarized descriptively by study treatment as 
categorical variables.  
9.2.8 Vital signs 
Descriptive summary statistics by visit and study treatment will be provided for observed 
values and changes from baseline in pulse rate, respiratory rate, temperature, systolic and 
diastolic blood pressure, and body weight.  
Notable blood pressure abnormalities will also be summarized descriptively. 
9.2.9 Electrocardiography 
Descriptive summary statistics by visit and study treatment will be provided for observed 
treatment-emergent values and changes from baseline in numeric 12-lead ECG values (HR, 
and the intervals PR, QRS, QT, QTcB, and QTcF).  
Treatment-emergent marked abnormalities for 12-lead ECG variables will be summarized 
at all visits.  
In addition, morphological ECG abnormalities that were not present before first study 
treatment intake (using data from the ECG provider) will be summarized.  
9.2.10 Specific safety endpoints 
Daytime sleepiness is defined daily as any score > 3 on the SSS after taking the morning 
dose. It will be collected on Days 1–14 and expressed as a number of days per week (as for 
the primary efficacy outcome). A minimum of 7 diary entries are required, otherwise the 
data will be considered missing. The mean number of days with daytime sleepiness per 
week will be summarized by treatment group. 
The number (%) of study participants with suicidal ideation and/or behavior based on the 
C-SSRS© will be tabulated by visit and treatment group.  
Withdrawal effects will be described summarizing changes from changes from 
Week 12/EOT to EOS in BWSQ and HAMD-17 by treatment group. 


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9.2.11 Analyses of other outcomes 
A full description of all other analyses will be provided in the SAP.  
9.3 Interim analyses 
No interim analysis is planned for this study.  
9.4 Sample size 
The sample size is based on the primary efficacy endpoint, change from baseline to 
Week 12 in the number of BE days per week.  
In 2 studies using lisdexamfetamine in study participants with BED [McElroy 2016] the 
difference between lisdexamfetamine and placebo for this endpoint was –1.35 (SD = 1.6) 
and –1.66 (SD = 1.6) days per week. The corresponding effect size was 0.83 (95% CI: 
0.60–1.05) and 0.97 (95% CI: 0.72–1.21), respectively. In the USA, lisdexamfetamine is 
categorized as a Schedule II medication. For this reason, a smaller effect size by 
ACT-539313 may still be considered clinically important if it has a better safety profile 
than lisdexamfetamine. 
In an earlier study comparing topiramate to placebo in study participants with BED 
[McElroy 2007] the difference in the means of the changes from Baseline to Week 16 
between topiramate and placebo was –1.0 with a common SD of 2.0, providing an effect 
size of 0.5 (95% CI: 0.3–0.7).  
In a recent study with dasotraline, the LSmean reduction from Baseline in number of BE 
days per week was significantly greater for dasotraline vs placebo at Week 12 (−3.74 vs 
−2.75), for an effect size = 0.74 [McElroy 2020]. 
Based on the above, it is assumed that a treatment group difference of 1 BE day per week 
(corresponding to an effect size of 0.5 to 0.7, depending on the SD) is clinically meaningful. 
The sample size is based on the power to detect a reduction of at least 1 BE day per week 
at Week 12 (with an SD of 1.6, this corresponds to an effect size of 0.65), between 
ACT-539313 and placebo, at a significance level of 5% two sided. Table 5 shows the 
sample size needed to detect a difference between placebo and ACT-539313 for different 
effect sizes. 


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Table 5 
Total sample size for 90% power 
Effect size 
0.5 
0.6 
0.7 
Power 
 
 
 
90% 
170 
118 
86 
80% 
126 
88 
66 
For a two-sided α = 0.05 and 1:1 randomization 
 
The sample sizes reported in Table 5 are based on a t-test, but are also valid for a mixed 
model for repeated measures, retaining close to 90% (or 80%) power in the case of missing 
Week 11–12 data (up to 20%). 
Table 6 shows the power to detect a difference between placebo and ACT-539313 for a 
sample size of 100–120 study participants. 
Table 6 
Power for sample sizes of 100 and 120 
Effect size 
0.5 
0.6 
0.7 
Sample size 
 
 
 
100 
71% 
85% 
94% 
120 
78% 
91% 
97% 
For a two-sided α = 0.05 and 1:1 randomization 
 
Assuming a sample size of 120 study participants (60 participants per arm), the power 
achieved in any of the scenarios described above, will be at least equal to 78% (α = 0.05, 
two-sided). 
10 REGULATORY, ETHICAL, AND STUDY OVERSIGHT 
CONSIDERATIONS 
10.1 Regulatory and ethical considerations 
The sponsor personnel and the investigators will ensure that the study is conducted in full 
compliance with ICH GCP guidelines, the principles of the “Declaration of Helsinki”, and 
with the laws and regulations of the country in which the study is conducted. 
The investigator and/or sponsor/CRO will submit this protocol and any related 
document(s) provided to the study participant (such as the ICF) to an IEC/IRB and to the 
health authority (as applicable). Approval from both the IEC/IRB and the health authority 
must be obtained before starting the study and must be documented in a dated letter to the 


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investigator and/or sponsor/CRO, 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/delegate and/or sponsor/CRO to the IEC/IRB 
and to the health authority in accordance with local procedures and regulations. 
10.2 Informed consent process 
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 and/or his/her legally designated representative. The 
investigator/delegate must explain to study participants 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 must be paid to the 
information needs of specific study participant populations and of individual study 
participants, as well as to the methods used to deliver the information. Adequate time must 
be given for the study participant and/or his/her legally designated representative to 
consider his or her decision to participate in the study and it must be verified that the study 
participant has understood the information (e.g., by asking the study participant to explain 
what is going to happen).  
If a revised version of the ICF is approved by health authorities (if applicable) and 
IRBs/IECs:  
• Newly recruited study participants and/or their legally designated representative must 
provide consent using the most current version of the ICF(s). 
• Study participants who are already participating in the study (e.g., already recruited) 
and/or their legally designated representative must be re-consented using the most 
current version of the ICF(s) if necessary (e.g., additional study procedure, new safety 
information) and/or requested (e.g., as per IRB/IEC requirements). 
A copy of the signed and dated ICF is given to the study participant and/or his/her legally 
designated representative; the original is filed in the site documentation. The informed 
consent process must be fully documented in the study participant’s medical records. This 
must include at a minimum the study reference, the study participant number, the date and, 
if applicable, time when the study participant was first introduced to the study, the date 
and, if applicable, time of consent, who participated in the consent discussion, who 
consented the study participant, and any additional person present during the consent 
process (e.g., study participant’s family member[s]), and the information that a copy of the 
signed ICF was given to the study participant / his/her legally designated representative. 


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Site personnel authorized (according to local regulation) to participate in the consent 
process and/or to obtain consent from the study participant and/or his/her legally 
designated representative will be listed on the Delegation of Authority form. A study 
physician must always be involved in the consent process. 
If the site intends to recruit study participants who are considered to be vulnerable (e.g., 
study participant cannot read or write, does not speak or understand the ICF language), 
additional measures must be implemented to ensure the study participant’s rights are 
respected and the consent obtained is legally valid. The sponsor, the regulatory authorities 
(if applicable), and the IEC/IRB must be informed prior to the recruitment. The consent 
process (e.g., involvement of an impartial witness) must be fully described, submitted to, 
and approved by the IEC/IRB, according to procedures and before study participants are 
recruited. 
10.3 Data protection and privacy 
Study participant data confidentiality and privacy are strictly held in trust by the 
investigators, their staff and the sponsor or delegate.  
The investigator/delegate must ensure that data confidentiality is maintained. On eCRFs or 
other documents (e.g., documents attached to SAE forms / Pregnancy forms) submitted to 
the sponsor and any vendors or CROs, study participants must be identified only by number 
and never by their name or initials, date of birth, hospital numbers, or any other personal 
identifier. The investigator/delegate must keep a study participant identification code list 
at the site. Documents identifying the study participants (e.g., signed ICFs) must not be 
sent to the sponsor or any vendors or CROs, and must be kept in strict confidence by the 
investigator/delegate.  
In the BE Diary, there will be no possibility to enter any personal identifier and the study 
participant will only be identified by the study site and study participant number.  
The study participants must be informed that their personal study-related data will be used 
by the sponsor in accordance with local data protection law.  
The study participants must be informed that their medical records may be inspected by 
the sponsor or sponsor’s delegate, by appropriate IRB/IEC members, and by inspectors 
from regulatory authorities. 
10.4 Indemnification, compensation and refund of expenses to study 
participants and investigators 
The sponsor 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. 


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The indemnification of the study participant in the event of study-related injuries will 
comply with applicable regulations. 
Study participants will be reimbursed for study-related expenses (e.g., travel costs, meals, 
hotel), and may be offered financial compensation for their participation in the study only 
to the extent permitted by applicable local regulations. 
10.5 Essential documents and retention of documents 
The investigator/delegate must maintain adequate records necessary for the reconstruction 
and evaluation of the study. Several 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 a certified copy), attributable, 
complete, consistent, enduring, and available when needed. 
These records are to be classified into two different categories of documents: ISF and study 
participants’ source documents. 
These records must be kept by the investigator / trial site for as long as is necessary to 
comply with the sponsor’s requirements (i.e., as specified in the clinical study agreement), 
ICH GCP and national and/or international regulations, whichever would be the longest 
period. If the investigator/ trial site 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/site and the sponsor to store these documents 
outside the site, so that they can be retrieved in the event of a regulatory inspection. No 
study document should be destroyed without prior written approval from the sponsor. If 
the site needs to transfer the study records to another location and/or if the site facility can 
no longer store the study records, the investigator/site must immediately inform the 
sponsor.  
10.5.1 Investigator Site File 
Each site will maintain an ISF. It will contain all the essential documents that are required 
to be up-to-date and filed at the site as per ICH GCP section 8. 
The ISF must be stored in a secure and access-restricted area during and after the study.  
10.5.2 Source documents 
All source documents should be completed in a neat and legible manner to ensure accurate 
interpretation and traceability of the data. Data reported in the eCRF derived from source 
documents must be consistent with the source documents. 
If the site is using electronic/computerized system(s) to store study participant medical 
records, it can be used for the purpose of the clinical study if it is validated (as per 21 CFR 
Part 11 ) and if the CRA has been provided personal access to study participant’s medical 


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records in order to verify consistency between electronic source data and the eCRF during 
monitoring visits. 
If the site is using electronic/computerized system to store study participant medical 
records but it could not be confirmed that the system(s) is/are validated (as per 21 CFR 
Part 11) or if the CRA could not be provided access to the system(s), the site is requested 
to print the complete set of source data needed for verification by the CRA. The printouts 
must be numbered, stapled together with a coversheet, signed, and dated by the 
investigator/delegate to confirm that these certified copies are exact copies containing the 
same information as the original source data. The printouts will be considered as the official 
clinical study records and must be filed adequately. Once printed and certified, the 
document must not be edited/changed (e.g., manual notes added, clinical value changed) 
in order not to impact the validity of the certification. In case the data needed to be changed 
(e.g., correction of a mistake) the change(s) must be done in the electronic/computerized 
system and a new copy must be printed and certified. 
Entries recorded by the study participant in the BE Diary and SSS are considered source 
data.  
10.6 Data handling 
10.6.1 Data collection, data transfer procedure, and data access 
The investigator/delegate is responsible for ensuring the accuracy, completeness, and 
timely reporting of study participant’s data.  
Electronic data capture will be used to collect eCRF data. The investigator and site 
personnel will be trained to enter and edit the data via a secure network, with secure access 
features (username, password, and identification — an electronic password system). A 
complete electronic audit trail will be maintained. The investigator/delegate will approve 
the data (i.e., confirm the accuracy of the data recorded) using an electronic signature (as 
per US 21 CFR Part 11). 
Study participant recruitment and enrollment data will be completed for all study 
participants (i.e., eligible and non-eligible) through the IRT system and eCRF. 
For each study participant recruited, regardless of study treatment initiation, an eCRF must 
be completed and signed by the investigator/delegate. This also applies to those study 
participants who fail to complete the study.  
Entries recorded by the study participant on the touchscreen device and on paper as well 
as the physician-reported global assessment on a touchscreen device at site and on paper 
are considered source data. Site personnel will review and ensure completeness and 
readability of the study participants’ entries. If inconsistent data is detected by the site 


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personnel or indicated by the study participant, a data correction form will be completed 
by the site personnel to request any data changes and sent to the CRO provider that will 
process the changes as per CRO data management procedures. 
10.6.2 Database management and quality control 
The investigator/delegate will have “write” access to the site eCRF data until the end of 
the study. The investigators will be informed in a timely manner of “write” access 
removals. The eCRF must be completed in a timely manner as per eCRF completion 
guidelines. 
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 the sponsor 
personnel or delegate on an ongoing basis to look for unexpected patterns in data and for 
study monitoring. Should discrepant data be detected, a query specifying the matter 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 the sponsor 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 study participant data 
confidentiality is protected. 
This process will continue until database lock. 
Laboratory samples, ECGs, and touchscreen device data will be processed through a 
central vendor and the results of the enrolled study participants will be electronically sent 
to the sponsor at pre-specified intervals with a final transfer prior to database lock. During 
the course of the study, the site staff and sponsor representatives can access the data in 
view‑only mode on the central server of the respective vendor see also Section 10.6.1. 
Respective vendors will generate their own queries/programmed checks based on their 
respective data management plans. 
AEs and medical history are coded with MedDRA. Medications are coded with the WHO 
Global Drug Dictionary. 
After the database has been declared complete and accurate, the database will be locked. 
Any changes to the database after that time may only be made as described in the 
appropriate sponsor/CRO Quality System documents. The investigator/delegate will have 
read-only access to the site eCRF study participant data, until receipt of an electronic copy 
of the site eCRFs (including the audit trail). 


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10.7 Protocol deviations 
A protocol deviation is any change, divergence, or departure from the study design or 
procedures defined in the protocol. 
Prospective approval of protocol deviations, also known as protocol waivers or 
exemptions, is not permitted.  
The investigator must conduct the study in compliance with the IEC/IRB-approved 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 study participant. 
Protocol deviations must be reported to the IEC/IRB and regulatory authorities according 
to local requirements. 
Reporting of protocol deviations related to the COVID-19 pandemic  
Despite the provisions made to allow flexibility and adaptations to the per protocol 
schedule of assessments, protocol deviations due to COVID-19 are expected to occur 
during the pandemic and fall under the ICH GCP 4.5.4 “The investigator may implement 
a deviation from, or change of, the protocol to eliminate an immediate hazard(s) to trial 
subjects”. 
Any protocol deviation occurring due to COVID-19 must be documented according to ICH 
GCP 4.5.3 and be clearly recorded as related to COVID-19. All protocol deviations will be 
reported to the sponsor, IEC/IRB and regulatory authorities according to local 
requirements. 
10.8 Clinical monitoring 
Prior to study start at a site, all required approvals must be obtained. A site initiation visit 
will be performed after the required essential study documents are approved by the sponsor. 
The study treatment will be shipped to the site upon approval of the required essential 
documents. 
The PI must ensure that all key site personnel involved in the study are present/available 
during the site initiation visit and will dedicate enough time to it. 
The site initiation visit must be completed before the site can start recruiting study 
participants. Following the site initiation visit, 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 
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entered in the eCRFs and other protocol-related documents. Monitoring activities will be 
performed according to the study-specific monitoring guidelines. The methodology and the 
frequency of the monitoring visits will be mainly based on study participant recruitment 
rate and critical data-collection times. 
The PI/delegate must ensure that the eCRF is completed as per the eCRF completion 
guidelines and that all requested study participant files (e.g., ICFs, medical notes/charts, 
other documentation verifying the activities conducted for the study) are available for 
review by the CRA. The required site personnel must be available during monitoring visits 
and allow adequate time to meet with the CRA to discuss study-related issues. 
The PI agrees to cooperate with the CRA to ensure that any issues detected in the course 
of these monitoring visits are resolved. 
A close-out visit will be performed for any initiated site when there are no more active 
study participants and all follow-up issues have been resolved. If a site does not screen any 
study participants, the close-out visit may be performed prior to study closure at the 
discretion of the sponsor. 
Monitoring during Covid-19 pandemic: 
If on-site monitoring cannot be performed by the CRA as described above, and if deemed 
acceptable under local law with the IEC/IRB, the CRA will conduct remote monitoring 
and remote source data verification, provided that the study participant’s confidentiality is 
maintained throughout the process and all local approvals to do so are in place. If remote 
monitoring or remote SDV are not allowed, alternatives as applicable, according to local 
regulations, may be agreed with the PI to ensure data integrity. 
10.9 Study safety oversight 
Study safety information (AEs, SAEs, laboratory values, ECGs, vital signs, and 
study-specific examinations, as required) are monitored and reviewed on a continuous 
basis by the sponsor.  
The sponsor may request additional data pertaining to the diagnostic work-up of an AE or 
SAE (e.g., medical imaging, local laboratory values) for the purpose of monitoring safety. 
Such additional data may be shared with external experts. 
10.10 Premature termination or suspension of the study 
The sponsor reserves the right to terminate the study at any time globally or locally. 
Investigators can terminate the participation of their site in the study at any time. 
If the study is suspended or prematurely terminated, the sponsor will promptly inform the 
investigators, the IECs/IRBs, and health authorities, as appropriate, and provide the reasons 
for the suspension or termination. 


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If the study is suspended or prematurely terminated for any reason, the investigator — in 
agreement with the sponsor — must promptly inform all recruited study participants and 
ensure their appropriate treatment and follow-up, as described in Section 6.3. The sponsor 
may inform the investigator of additional procedures to be followed in order to ensure that 
adequate consideration is given to the protection of the study participants’ interests. 
In addition, if the investigator suspends or terminates the study without prior agreement 
from the sponsor, the investigator must promptly inform the sponsor personnel and the 
IEC/IRB and provide both with a detailed written explanation of the termination or 
suspension.  
10.11 Audit 
The sponsor 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 the sponsor requirements 
(e.g., standard operating procedures) will also be verified. Prior to initiating this audit, the 
investigator will be contacted by the sponsor to arrange a time for the audit. 
The investigator and site personnel must cooperate with the auditor(s) and allow access to 
all study documentation (e.g., study participant records) and facilities. 
10.12 Inspections 
Health authorities and/or IEC/IRB may also conduct an inspection of this study at the site 
(during the study or after its completion). 
Should an inspection be announced by a health authority and/or IEC/IRB, the investigator 
must immediately inform the sponsor (usually via the CRA and copying the following 
mailbox: gcp@idorsia.com) that such a request has been made. 
The investigator and site personnel must cooperate with the sponsor to handle the 
inspection related to sponsor studies. The investigator and site personnel must also 
cooperate with inspector(s) to ensure proper performance of the inspection and allow 
access to all study documentation (e.g., study participant records) and study facilities. 
10.13 Reporting of study results and publication 
The sponsor will post the key elements of this protocol and the summary of results within 
the required timelines on publicly accessible databases (e.g., clinicaltrials.gov), as required 
by law and regulation. 
Study results will be documented in a CSR that will be signed by the sponsor’s 
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In accordance with the Good Publication Practices and ethical practice as outlined in 
internationally recognized guidance documents (e.g., European Medical Writers 
Association, American Medical Writers Association, International Society for Medical 
Publication Professionals), the results of the study will be submitted for publication in a 
peer-reviewed journal. Study results can be submitted for presentation at a congress before 
submission to a peer-reviewed journal. 
The coordinating investigator will have the opportunity to review the analysis of the data 
and to discuss the interpretation of the study results with the sponsor personnel prior to 
submission to a peer-reviewed journal or presentation at a congress. 
Authorship will be determined in accordance with the International Committee of Medical 
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 the 
sponsor and will be determined by mutual agreement. 
Any study-related publication written independently by investigators must be submitted to 
the sponsor for review at least 30 days prior to submission for publication or presentation 
at a congress. Upon review, the sponsor may provide comments, and may also request 
alterations and/or deletions for the sole purpose of protecting its confidential information 
and/or patent rights. Neither the institution nor the investigator should permit publication 
during such a review period. 
 


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11 REFERENCES 
[D-18.013] Single-center, double-blind, randomized, placebo-controlled, single- and 
multiple 
ascending 
dose 
study 
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safety, 
tolerability, 
pharmacokinetics (including food effect), and pharmacodynamics of orally 
administered ACT-539313 in healthy subjects. Idorsia Pharmaceuticals Ltd; Clinical 
Study Report AC-082-101, 14 May 2018 
[D‑18.159] A single-center, open-label study to investigate the effect of a single oral dose 
and repeated oral doses of ACT-539313 on the pharmacokinetics of midazolam and 
its 
metabolite 
1-hydroxymidazolam 
in 
healthy 
male 
subjects. 
Idorsia 
Pharmaceuticals Ltd; Clinical Study Report ID-082-102, 28 September 2018. 
[D‑20.035] Single-center, double-blind, randomized, placebo-controlled, single- and 
multiple-ascending 
dose 
study 
to 
investigate 
the 
safety, 
tolerability, 
pharmacokinetics (including food effect), and pharmacodynamics of orally 
administered ACT-539313 in healthy subjects. Idorsia Pharmaceuticals Ltd; 
Addendum to Clinical Study Report AC-082-101, 26 February 2020.  
[ACT‑539313 IB] Investigator’s Brochure for ACT-539313, version 6. Idorsia 
Pharmaceuticals Ltd; October 2020. 
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disorder. Int J Eat Disord. 2017 Aug;50(8):884-92.  
[McElroy 2020] McElroy SL, Hudson JI, Grilo CM, Guerdjikova AI, Deng L, Koblan KS, 
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02lbl.pdf  
[Wilfley 2008] Wilfley DE, Crow SJ, Hudson JI, Mitchell JE, Berkowitz RI, Blakesley V, 
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[Yee 2019] Yee K, Serrano D, Kando J, McElroy SL. A psychometric analysis and 
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Eating in adults with binge eating disorder. Qual Life Res. 2019 Dec;28(12):3385‑94. 
 
 


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12 APPENDICES 


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SAP_001.pdf: 
 
 
 
TPL-100721_v02 
 
 
 
ACT-539313 
 
 
STATISTICAL ANALYSIS PLAN 
 
 
FOR CLINICAL STUDY REPORT  
 
ID-082A201 
 
Version 3 
 
Multicenter, double-blind, randomized, placebo-controlled, 
parallel-group, proof-of-concept study to evaluate the efficacy and 
safety of oral ACT-539313 in the treatment of adults with moderate to 
severe binge eating disorder 
 
 
 
Document Number: D-22.100 
 
 
1 April 2022 
 
 
 
 
Property of Idorsia Pharmaceuticals Ltd 
 
Confidential 
 
May not be used, divulged, published or otherwise disclosed  
without the consent of Idorsia Pharmaceuticals Ltd 
 
 


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Statistical Analysis Plan  
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Revision history 
Version date 
Version 
Implemented change(s) 
23 September 2021 
1 
Initial version 
9 February 2022 
2 
• Section 4.1: Added reason for exclusion from 
FAS. 
• Section 4.1.4: Updated compliance threshold for 
exclusion from PPS. 
• Section 5.3.1: Updated demographic summary for 
screen failures. 
• Section 5.3.4: Removed summary for study 
participants currently receiving psychological or 
behavioral weight-loss interventions for BED. 
• Section 5.4.2: Updated the calculation of 
treatment 
compliance 
and 
the 
treatment 
interruption definition. 
• Section 6.1.3: Added use of sandwich estimator, 
model diagnostic for normality assumption, and 
non-parametric 
method 
in 
case 
normality 
assumption is not met. 
• Section 6.1.6: Added one sensitivity analysis so 
called delta-adjusted tipping point. 
• Section 6.1.8: Updated model to perform 
subgroup analyses. 
• Section 7.3: Removed summary table for change 
from baseline to last value in the treatment period 
for hematology and blood chemistry parameters. 
Updated list of laboratory parameters considered 
for the shift table. Added boxplots for main 
laboratory parameters. 
• Section 7.6: Updated summary and graphic 
presentation of SSS score. 
• Section 11.2; Updated imputation for missing 
study treatment end date. 
• Section 11.7: Updated Table 6 and added a 
sentence for the time window to be considered for 
the SSS calculation. 
• Section 14.1: Updated the SAS code to account for 
model diagnostic and sandwich estimator. 


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• Section 14.5: Added SAS code for multiple 
imputation under MNAR assumption for delta-
adjusted tipping point analysis. 
• Section 14.6: Updated the SAS code for logistic 
regression of absence of BE episodes during the 
last 4 weeks of treatment. 
• Section 14.7: Updated the SAS code for logistic 
regression of improvement according to CGI-C 
score at Week 12. 
• Section 14.10: Added SAS code for subgroup 
analysis. 
• Section 14.11: Added SAS code for non-
parametric analysis. 
• Section 14.13: Updated the MedDRA version. 
1 April 2022 
3 
• Section 5.3.1: Added listing for screen failures. 
• Section 5.3.2: Removed summary of baseline 
disease characteristics for screen failures. 
• Section 5.4.2: Added clarification for treatment 
interruption. 
• Section 6.1.3.1: Updated model diagnostic plots. 
• Section 6.1.5: Updated plot of the mean change of 
the primary endpoint over time adding SE. 
• Section 6.1.6: Added possible error message in the 
SAS log for delta-adjusted tipping point analysis. 
• Section 14.5: Updated the SAS code for multiple 
imputation under MNAR assumption for delta-
adjusted tipping point analysis. 
• Section 14.10: Updated the SAS code for 
subgroup analysis of race. 
• Section 14.14: Added triglycerides, chloride and 
cholesterol as marked laboratory abnormality 
parameters. 
 
 
 


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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS AND ACRONYMS ............................................................8 
1 
INTRODUCTION .......................................................................................................11 
2 
STUDY DESIGN AND FLOW ..................................................................................11 
3 
OBJECTIVES .............................................................................................................12 
3.1 
Primary objectives ........................................................................................12 
3.2 
Secondary objectives ....................................................................................12 
3.3 
Safety objectives ...........................................................................................13 
4 
ANALYSIS SETS .......................................................................................................13 
4.1 
Definitions of analysis sets ...........................................................................13 
4.1.1 
Screened set ......................................................................................13 
4.1.2 
All randomized set ............................................................................13 
4.1.3 
Full analysis set .................................................................................13 
4.1.4 
Per-protocol set .................................................................................13 
4.1.5 
Safety set ...........................................................................................14 
4.1.6 
Pharmacokinetic analysis set ............................................................14 
4.2 
Usage of the analysis sets .............................................................................14 
5 
SUBJECT VARIABLES AND ANALYSES .............................................................15 
5.1 
Subject disposition ........................................................................................15 
5.1.1 
Screening failures .............................................................................15 
5.1.2 
Study disposition ...............................................................................15 
5.1.3 
Study and study treatment completion/discontinuation ....................16 
5.1.4 
Study enrollment ...............................................................................16 
5.2 
Protocol deviations .......................................................................................16 
5.3 
Subject characteristics ..................................................................................17 
5.3.1 
Demographics ...................................................................................17 
5.3.2 
Baseline disease characteristics ........................................................17 
5.3.3 
Medical history and concomitant diseases at screening ...................17 
5.3.4 
Previous and concomitant therapy ....................................................18 
5.4 
Study treatment exposure and compliance ...................................................18 
5.4.1 
Exposure ...........................................................................................18 
5.4.2 
Compliance with study treatment .....................................................19 
6 
EFFICACY VARIABLES AND ANALYSES ...........................................................20 
6.1 
Primary endpoint analysis ............................................................................20 


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6.1.1 
Primary efficacy endpoint .................................................................20 
6.1.2 
Overall testing strategy .....................................................................20 
6.1.3 
Statistical model ................................................................................22 
6.1.3.1 
Model diagnostic and checks for normality ........................... 23 
6.1.4 
Handling of partially missing data ....................................................24 
6.1.5 
Descriptive statistics .........................................................................24 
6.1.6 
Sensitivity analyses ...........................................................................25 
6.1.7 
Supportive analyses ..........................................................................28 
6.1.8 
Subgroup analyses ............................................................................28 
6.2 
Secondary endpoint analysis ........................................................................28 
6.3 
Analysis of exploratory efficacy variables ...................................................29 
 
 
7 
SAFETY VARIABLES AND ANALYSES ...............................................................31 
7.1 
Overview of safety analyses including subgroup analyses ..........................31 
7.2 
Adverse events ..............................................................................................31 
7.3 
Laboratory tests ............................................................................................33 
7.4 
Electrocardiography ......................................................................................34 
7.5 
Vital signs and body weight .........................................................................35 
7.6 
Daytime sleepiness .......................................................................................35 
7.7 
Withdrawal symptoms ..................................................................................36 
7.7.1 
Benzodiazepine Withdrawal Symptoms Questionnaire ...................36 
7.7.2 
Hamilton Depression Rating Scale ...................................................36 
7.8 
Columbia-Suicide Severity Rating Scale© ...................................................36 
8 
PHARMACOKINETIC VARIABLES AND ANALYSES .......................................37 
9 
GENERAL STATISTICAL METHODOLOGY ........................................................38 
9.1 
General rules for data presentations .............................................................38 
9.2 
Handling of missing dates ............................................................................38 
10 INTERIM ANALYSES ..............................................................................................39 
11 GENERAL DEFINITIONS AND DERIVATIONS ...................................................39 
11.1 
Treatment start and end dates .......................................................................39 
11.2 
Study periods ................................................................................................39 
11.3 
Treatment day and Study day .......................................................................40 
11.4 
Baseline ........................................................................................................40 
11.5 
Change from baseline ...................................................................................41 
11.6 
Missing data patterns ....................................................................................41 


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11.7 
Time window definitions for calculating efficacy and safety endpoints 
collected through diary .................................................................................42 
11.8 
Time window definitions for calculating exploratory efficacy and 
safety endpoints collected during site visits .................................................42 
12 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN THE 
STUDY PROTOCOL .................................................................................................43 
12.1 
Changes to the analyses planned in the study protocol ................................43 
12.2 
Changes in the conduct of the study / data collection ..................................43 
12.3 
Clarifications concerning endpoint definitions and related variables or 
statistical methods .........................................................................................43 
12.4 
Additional analyses to those planned in the study protocol .........................44 
13 REFERENCES ............................................................................................................44 
14 APPENDICES .............................................................................................................46 
14.1 
SAS® code for Mixed Model for Repeated Measures ..................................46 
14.2 
SAS® code for multiple imputation with MCMC for monotone 
missingness mechanism ................................................................................46 
14.3 
SAS® code for multiple imputation under MAR assumption .......................47 
14.4 
SAS® code for multiple imputation under MNAR assumption for the 
jump to reference method .............................................................................48 
14.5 
SAS® code for multiple imputation under MNAR assumption for the 
delta-adjusted tipping point method .............................................................50 
14.6 
SAS® code for logistic regression of absence of BE episodes during 
the last 4 weeks of treatment ........................................................................51 
14.7 
SAS® code for logistic regression of improvement according to CGI-C 
score at Week 12 ...........................................................................................52 
14.8 
SAS® code for Kruskal-Wallis test of CGI-C and PGI-C scores at 
Week 12 ........................................................................................................52 
14.9 
SAS® code for ANCOVA of change from baseline to Week 12 in 
CGI-S score, PGI-S score, body weight and HbA1c ....................................52 
14.10 
SAS® code for subgroup analyses ................................................................53 
14.10.1 
Age ....................................................................................................53 
14.10.2 
Sex ....................................................................................................53 
14.10.3 
BMI ...................................................................................................54 
14.10.4 
Race ..................................................................................................54 
14.11 
SAS® code for non-parametric analysis of the primary endpoint ................55 
14.12 
List of BE forbidden medication ..................................................................56 
14.13 
List of adverse events of special interest ......................................................56 
14.14 
Marked abnormalities in laboratory parameters for reporting ......................57 


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LIST OF TABLES 
 
Table 1 
Study documents ............................................................................................ 11 
Table 2 
Usage of analysis datasets .............................................................................. 15 
Table 3 
Estimands for the primary objective .............................................................. 21 
Table 4 
Marked abnormalities in ECG parameters ..................................................... 35 
Table 5 
Imputation rules for an incomplete or missing concomitant therapy or 
AE date ........................................................................................................... 39 
Table 6 
Time windows (in days) to calculate weekly averages for the efficacy 
endpoints BE episodes/days collected daily through the diary ...................... 42 
Table 7 
Time windows (in days) for visit-based exploratory efficacy endpoints: 
YBOCS-BE, PGI-S, CGI-S, PGI-C, CGI-C, EDE-Q, HAMD-17................. 43 
Table 8 
Time windows (in days) for C-SSRS© ........................................................... 43 
Table 9 
BE forbidden medication ............................................................................... 56 
Table 10 
Adverse events of special interest .................................................................. 56 
Table 11 
Abnormal laboratory values: Hematology (SI units) ..................................... 57 
Table 12 
Abnormal laboratory values: Hematology (Conventional units) ................... 57 
Table 13 
Abnormal laboratory values: Blood chemistry (SI units) .............................. 58 
Table 14 
Abnormal laboratory values: Blood chemistry (Conventional units) ............ 59 
 
 
LIST OF FIGURES 
 
Figure 1 
Study design for ID-082A201 ........................................................................ 12 
 
 
 
 


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LIST OF ABBREVIATIONS AND ACRONYMS 
AE  
Adverse event 
AESI  
Adverse event of special interest 
ALP  
Alkaline phosphatase 
ALT  
Alanine aminotransferase 
ANCOVA  
Analysis of covariance 
AST  
Aspartate aminotransferase 
ATC  
Anatomical Therapeutic Chemical 
BE  
Binge eating  
BED  
Binge eating disorder 
b.i.d.  
Twice daily 
BILI  
Total bilirubin 
BMI  
Body mass index 
BWSQ  
Benzodiazepine Withdrawal Symptom Questionnaire 
CGI-C  
Clinical Global Impression of Change scale 
CGI-S  
Clinical Global Impression of Severity scale 
CI  
Confidence interval 
COVID-19  
Coronavirus disease 2019 
CRO  
Contract research organization  
CSR  
Clinical study report 
C-SSRS©  
Columbia-Suicide Severity Rating Scale© 
CV%  
Coefficient of variation 
DB  
Double-blind 
DSM-5  
Diagnostic and Statistical Manual of Mental Disorders (5th edition) 
ECG  
Electrocardiogram 
eCRF  
Electronic case report form 
EDE-Q  
Eating Disorder Examination Questionnaire 
EDE-Q7  
Eating Disorder Examination Questionnaire (7-item) 
EOS  
End-of-Study 
EOT  
End-of-Treatment 
FAS  
Full analysis set 
GGT  
Gamma-glutamyltransferase  


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HAMD-17  
Hamilton Rating Scale for Depression (17-item) 
HbA1c  
Glycated hemoglobin 
HR  
Heart rate 
ICF  
Informed consent form 
J2R  
Jump to reference 
LSMean  
Least-squares mean 
MAR  
Missing at random 
MCMC  
Markov Chain Monte Carlo 
MedDRA  
Medical Dictionary for Regulatory Activities 
MI  
Multiple imputation 
MMRM  
Mixed model for repeated measures 
MNAR  
Missing not at random 
MPS  
Maier-Philipp subscale 
  
 
PD  
Protocol deviation 
PGI-C  
Patient Global Impression of Change scale 
PGI-S  
Patient Global Impression of Severity scale 
PK  
Pharmacokinetic 
POC  
Proof-of-concept 
PPS  
Per-protocol set 
PT  
Preferred term 
QTc  
Corrected QT interval 
QTcB  
QT interval corrected according to Bazett’s formula 
QTcF  
QT interval corrected according to Fridericia’s formula 
RND  
All-randomized analysis set 
SAE  
Serious adverse event 
SAF  
Safety analysis set 
SAP  
Statistical analysis plan 
SCR  
Screened analysis set 
SD  
Standard deviation 
SE  
Standard error 
SI  
International system of units 


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SOC  
System organ class 
SSS  
Stanford Sleepiness Scale 
T3  
Tri-iodothyronine 
T4  
Thyroxine 
TEAE  
Treatment-emergent adverse event 
TSH  
Thyroid stimulating hormone 
ULN  
Upper limit of normal 
USA  
United States of America 
WHO  
World Health Organization 
YBOCS-BE  
Yale-Brown Obsessive-Compulsive Scale modified for Binge 
Eating 
 


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1 
INTRODUCTION 
This SAP describes in detail the analyses and data presentation for the CSR prepared for 
ID-082A201.  
Obvious corrections to address minor formatting errors or spelling mistakes may be 
performed at the time of analysis without amending this and related documentation (e.g., 
mock shells).  
Data will be analyzed by Idorsia and/or designated CROs supervised by Idorsia using SAS® 
version 9.4 or higher and R version 3.4.3 or higher. 
 
 
 
This SAP is based on Version 3 of Protocol ID-082A201, dated 4 May 2021 [Table 1]. 
Table 1 
Study documents 
Document 
Date, Version 
Clinical Study Protocol (CSP) 
04MAY2021, Version 3 
eCRF specifications 
01FEB2021, Version 2 
Protocol deviation list 
21JAN2022, Version 4 
During the drafting of the current SAP, three sites withdrew from the study due to financial 
reasons related to COVID-19: sites 1012, 1015, and 1061. Consequently, all study 
participants randomized in these sites discontinued treatment and finished the study. 
Section 6 describes how these study participants will be considered for the efficacy 
analyses. 
2 
STUDY DESIGN AND FLOW 
This is a Phase 2, multicenter, double-blind, randomized, placebo-controlled, 
parallel-group, proof-of-concept study assessing ACT-539313 at a dosing regimen of 
100 mg b.i.d. vs placebo over a 12-week treatment period in adult participants (18 to 
55 years of age) with moderate to severe binge eating disorder (BED). 
Approximately 120 participants will be randomized to either ACT-539313 at a dose of 
100 mg b.i.d., or placebo in a 1:1 ratio.  
The study will be conducted at approximately 30 sites in the USA. 
The study design is shown in Figure 1. 


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Figure 1 
Study design for ID-082A201 
 
b.i.d. = twice daily; EOS = End-of-Study; EOT = End-of-Treatment; V = Visit. 
 
The study comprises the following 3 periods: the screening period, the treatment period 
and the safety follow-up period.  
The screening period starts with the signing of the ICF at Visit 1 and ends with 
Randomization at Visit 2 or with a screening failure. It lasts a minimum of 14 days and up 
to 28 days.  
The treatment period starts with the administration of the first dose of study treatment 
and ends on the day of the last dose of study treatment. The study participants will be 
treated for 12 weeks. 
The safety follow-up period starts on the day after the last dose of study treatment and 
ends at the EOS visit (10 ± 3 days after EOT).  
See Section 11.2 for detailed definitions of the study periods.  
3 
OBJECTIVES 
The overall objective of this POC study is to evaluate the clinical efficacy, safety and 
tolerability of ACT-539313 100 mg administered b.i.d. compared to placebo in adult 
participants with moderate to severe BED over a period of 12 weeks. 
3.1 
Primary objectives 
To assess the efficacy of 100 mg ACT-539313 in the treatment of BED. 
3.2 
Secondary objectives 
Not applicable. 


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3.3 
Safety objectives 
To assess the safety of ACT-539313 in participants with BED. 
4 
ANALYSIS SETS 
4.1 
Definitions of analysis sets 
A study participant must have given informed consent before being included in any 
analysis set.  
The number of study participants in each analysis set defined below will be tabulated. Any 
study participant excluded along with reason(s) for exclusion from the FAS, PPS, or PK 
analysis sets will be summarized and listed. 
4.1.1 
Screened set 
The Screened set (SCR) includes all study participants who entered screening and have a 
subject number.  
Summaries based on the SCR set will be presented as one group (i.e., all study participants) 
unless otherwise specified. 
4.1.2 
All randomized set 
The All-randomized analysis set (RND) includes all study participants from the SCR who 
were randomized. 
4.1.3 
Full analysis set 
The Full analysis set (FAS) includes all study participants who were randomized, received 
at least one dose of study treatment, and have a baseline assessment of the primary endpoint. 
In order to adhere to the intention-to-treat principle as much as possible, study participants 
will be evaluated according to the treatment they have been assigned to, which may differ 
from the treatment they received.  
4.1.4 
Per-protocol set 
The Per-protocol set (PPS) includes all study participants from the FAS who complied with 
the protocol sufficiently to be likely to exhibit the treatment effects.  
Criteria for sufficient compliance: 
• Absence of important PDs, which may affect the primary endpoint, leading to exclusion 
from the PPS, as defined in a separate PD document that will be finalized before 
unblinding.  
• Study treatment compliance is ≥ 80% [as calculated in Section 5.4.2]. 
• Absence of premature treatment discontinuation. 


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Study participants not meeting the criteria for sufficient compliance will be excluded from 
the PPS. Study participants will be evaluated according to the treatment they have been 
assigned to. 
4.1.5 
Safety set 
The Safety set (SAF) includes all randomized study participants who received at least one 
dose of study treatment.  
Study participants will be evaluated according to the actual treatment they received, which 
may differ from the randomly assigned treatment. 
Actual treatment received is defined as the assigned study treatment when received at least 
once, or the other study treatment if the assigned study treatment was never received. 
4.1.6 
Pharmacokinetic analysis set 
The Pharmacokinetic (PK) analysis set includes all study participants in the SAF who have 
at least one PK sample collected after initiation of study treatment.  
Study participants will be evaluated according to the actual treatment they received. Study 
participants receiving placebo will be excluded from the PK set. 
4.2 
Usage of the analysis sets 
The analyses of efficacy endpoints will be performed using the FAS, and the PPS for 
supportive analysis. 
The RND will be used for the analysis of demographic and baseline disease characteristics, 
and the SCR set to provide the same summaries for the screen failures. 
The SAF will be used for the analysis of safety endpoints (including previous and 
concomitant medication, and study treatment exposure). 
The PK set will be used for the analysis of ACT-539313 plasma concentrations. 
Study participants’ listings will be based on the SAF, unless otherwise specified. Subject 
disposition will be described for the SCR. 


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Table 2 
Usage of analysis datasets 
Analysis 
SCR 
RND 
FAS 
PPS 
SAF 
PK set 
Subject disposition 
X 
 
 
 
 
 
Demographics and baseline disease 
characteristics 
x 
X 
 
 
 
 
Previous and concomitant medication 
 
 
 
 
X 
 
Study drug exposure 
 
 
 
 
X 
 
Efficacy analysis 
 
 
X 
(x) 
 
 
Safety and tolerability analyses 
 
 
 
 
X 
 
PK data analysis 
 
 
 
 
 
X 
Note: X: main analysis, (x): only if > 10% difference in size with FAS.  
FAS = Full analysis set; PK = pharmacokinetic; PPS = Per-protocol analysis set; RND = Randomized analysis set; 
SAF = Safety analysis set; SCR = Screened analysis set. 
 
5 
SUBJECT VARIABLES AND ANALYSES 
5.1 
Subject disposition 
5.1.1 
Screening failures 
Screening failures will be summarized based on the SCR set and will include:  
• Number (%) of study participants who did not successfully complete the screening 
period (based on ‘Was the subject randomized?’ recorded as ‘No’ in the 
‘Randomization’ page). 
• Primary reason for screen failure (based on reason for not randomized entered on the 
‘Randomization’ page).  
The eligibility criteria not met will be summarized. All reasons for screening failure will 
be listed.  
Of note: No re-screening is allowed in the study. 
5.1.2 
Study disposition  
Study participant disposition will be summarized based on the SCR, presented by 
randomized treatment group and all screened study participants combined, and will include:  
• Number of study participants screened.  
• Number (%) of study participants randomized (based on non-missing randomization 
number).  
• Number (%) of study participants who received study treatment during the treatment 
period (based on non-missing ‘Treatment start date’ in the ‘Study Treatment Log’ page). 
Percentage will be based on randomized subjects. 


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• Number (%) of study participants who completed the treatment period (based on 
‘Reason for treatment stop’ entered as ‘Completion as per protocol’ in the ‘Study 
Treatment Log’ page). Percentage will be based on study participants who received 
study treatment. 
• Number (%) of study participants completing the study (based on ‘Did the subject 
complete the study?’ recorded as ‘Yes’ in the ‘End of Study Status’ page). Percentage 
will be based on randomized subjects. 
5.1.3 
Study and study treatment completion/discontinuation 
The following summary will be based on the SAF and presented by treatment group and 
all treatment groups combined:  
• Number (%) of study participants who prematurely discontinued study treatment 
(based on ‘Reason for treatment stop’ entered as ‘Discontinuation’ in the ‘Study 
Treatment Log’ page).  
• Primary reason for premature study treatment discontinuation (based on 
‘Discontinuation, Reason’ entered on the ‘Study Treatment Log’ page). 
The following summary will be based on the RND and presented by treatment group and 
all treatment groups combined:  
• Number (%) of study participants who prematurely discontinued from the study (based 
on non-missing reason for stopping study entered in the ‘End of Study Status’ page).  
• Primary reason for premature discontinuation from the study (based on ‘Study stopped 
due to’ entered in the ‘End of Study Status’ page).  
All reasons for premature study treatment discontinuation and study discontinuation will 
be listed based on the RND. 
5.1.4 
Study enrollment 
The number (%) of screened study participants as well as randomized will be displayed by 
site based on the SCR by treatment group and all treatment groups combined.   
The randomization scheme and codes will be listed for randomized study participants only. 
5.2 
Protocol deviations 
The RND will be used for the summary of PDs. All PDs and important PDs will be 
summarized in separate tables as per pre-specified category (i.e., selection criteria, 
Investigational Medicinal Product, study conduct/procedure, forbidden medication, 
withdrawal criteria and other) by treatment group and all treatment groups combined. In 
addition, the same summary of all PDs and important PDs will be provided separately for 
PDs related to COVID-19. 


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A study participant with multiple occurrences of a protocol deviation is counted only once 
per protocol deviation category.  
A listing of protocol deviations will be provided using the SCR. PDs related to COVID-19 
will be flagged in the listings. 
5.3 
Subject characteristics 
Unless noted otherwise, summaries and listings described in this section will be based on 
the RND.  
Summaries will be provided for all treatment groups combined as well as by treatment 
group separately. Data will be listed individually by study participant. 
5.3.1 
Demographics  
Demographic data at screening, including age, sex, race, ethnicity, height, weight and BMI 
will be summarized and listed.  
The number (%) of study participants randomized in each age category (< 30, ≥ 30 years 
at screening), and in each BMI category (< 30, ≥ 30 kg/m2 at screening), will be further 
summarized. 
The same summary and listing will be provided also for screen failures. Height, weight and 
BMI will not be shown since these variables are not collected for screen failures. 
5.3.2 
Baseline disease characteristics 
Baseline disease characteristics include BE severity based on number of BE days per week 
and on number of BE episodes per week (both assessed during the two weeks prior to 
randomization [see Section 11.4 for baseline definition]). In addition, CGI-S, PGI-S, 
YBOCS-BE total score, HAMD-17 total score and EDE-Q total score assessed at 
randomization will be described. 
These baseline disease characteristics will be listed and summarized.  
5.3.3 
Medical history and concomitant diseases at screening 
Relevant medical history and current medical conditions will be coded using MedDRA.  
Any disease or diagnosis is defined as previous if ‘Ongoing at informed consent’ is 
answered as ‘No’; all other diseases/diagnoses are considered as study concomitant (where 
answer is ‘Yes’).  
Medical history and current (ongoing) medical conditions, excluding BED and BED-
related symptoms, will be summarized separately, and listed. Summaries will be presented 
for each treatment group by primary SOC and PT. Medical history will be sorted by SOC 
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The MedDRA version used for reporting will be specified in the footnote of the applicable 
output. 
5.3.4 
Previous and concomitant therapy 
Previous and concomitant therapies will be coded using the WHO Drug Global reference 
dictionary that employs the WHO ATC classification system. The WHO Drug Global 
version used for reporting will be specified in the footnote of the applicable output.  
Previous therapies are any treatments for which the end date is prior to signing of the ICF. 
Any 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 
EOS. The use of all study-concomitant therapies (including contraceptives and traditional 
and alternative medicines, e.g., plant-, animal-, or mineral-based medicines) is to be 
recorded in the ‘Previous/Concomitant Medication’ page.  
Study treatment-concomitant therapies (a subset of study-concomitant therapies) are any 
treatments that are either ongoing at the start of study treatment or initiated during the study 
period until 1 day after the last dose of study treatment.  
The number (%) of study participants having taken at least one previous or concomitant 
therapy will be summarized by ATC classification level 4 (or next highest available level) 
and individual preferred name within each ATC classification based on the SAF. Previous 
and concomitant therapy will be sorted by ATC class and preferred name within each ATC 
class by descending frequency based on all treatment groups combined.  
Summary tables will be provided for previous, study-concomitant and study 
treatment-concomitant therapies separately. All concomitant therapies will be listed using 
the SAF and those related to an AE will be flagged. 
5.4 
Study treatment exposure and compliance 
Summaries and listings described in this section will be based on the SAF.  
5.4.1 
Exposure 
The duration of study treatment (including categories: ≤ 1, > 1 – 2, > 2 – 4, > 4 – 6, > 6 – 8, 
> 8 – 10, > 10 – 12, > 12 – 13, > 13 weeks) will be summarized.   
The duration of treatment (in days) is defined as the difference between the treatment end 
date and the treatment start date plus one day. This calculation ignores periods of treatment 
interruption. 


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In addition, time from first dose of study treatment to treatment discontinuation will be 
summarized by treatment group using Kaplan-Meier plots. 
The duration of treatment along with reason for treatment stop will be listed. 
5.4.2 
Compliance with study treatment 
Study treatment compliance will be assessed through study treatment dispensing and 
accountability.  
The following formula will be used to calculate compliance for the treatment period: 
Study treatment compliance (%) = [(number of capsules dispensed – number of capsules 
returned*) / (treatment duration – total duration of treatment interruptions)] × 0.5** × 100 
* If a study participant did not return his/her bottle (e.g., it is lost), compliance will not be 
calculated, and the compliance will be set to missing. 
** To account for 2 capsules taken per day (i.e., b.i.d.). 
Treatment duration and total duration of treatment interruptions are calculated using the 
dedicated eCRF page ‘Study Treatment Log’ as follows:  
• Treatment duration (days) = date of last drug intake of study treatment – date of first 
drug intake of study treatment + 1 day. 
• Total duration of treatment interruptions (days) is the sum of all the treatment 
interruptions’ durations. A treatment interruption duration = date restarted study 
treatment – end date of study treatment due to an interruption. For example, if a study 
participant stopped his/her treatment on 19MAR2021 and started again on 
23MAR2021, as the treatment is taken on the start and end dates, the calculation will 
be 23MAR2021 – 19MAR2021 = 4 days of interruption. Should the study participant 
interrupt the treatment again for 7 days, the total duration of interruptions will be 
11 days. Moreover, if a study participant misses one dose, either the evening or the 
morning dose, a treatment interruption of 1 day will be counted. 
Study treatment compliance (including categories 0%, > 0% – < 50%, 50% – < 70%, 
70% – < 80%, 80% – < 90%, 90% – < 100%, 100%, > 100%), treatment interruptions 
(Yes/No), and duration of treatment interruptions will be summarized.  
The number (%) of study participants who have treatment interruptions, and the 
corresponding reasons will be tabulated. 
Study treatment compliance, dispensing and accountability data will be listed. 


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6 
EFFICACY VARIABLES AND ANALYSES 
The analyses of efficacy endpoints will be performed using the FAS. Efficacy data 
described below will be listed using the FAS. 
6.1 
Primary endpoint analysis 
The time windows used for the primary endpoint analysis will follow the definition 
provided in Section 11.7.  
6.1.1 
Primary efficacy endpoint 
The primary efficacy endpoint of this study is defined as the change from baseline to 
Week 12 in the number of BE days per week based on diary data. 
A ‘BE day’ is a day in which at least one confirmed BE episode occurred.  
The number of BE days per week will be calculated based on 2-week (rather than 1-week) 
intervals in order to improve the precision of the variable, as shown by simulations. A 
minimum of 7 diary entries per 14-day time interval is required, otherwise the number of 
BE days will be considered missing.  
The number of BE days per week is defined as the number of diary days with at least one 
BE episode during the applicable 14-day time interval divided by the total number of diary 
days, times 7. A diary day is a day for which the number of BE episodes is entered in the 
study participant’s diary (this includes a zero value, i.e., no BE episode). 
6.1.2 
Overall testing strategy  
The H0 to be tested is that there is no difference between ACT-539313 and placebo with 
respect to the primary efficacy endpoint: 
H0: μA = μP vs Ha: μA ≠ μP 
Here, μA and μP is the mean change from baseline to Week 12 in the number of BE days 
per week in the ACT-539313 and placebo group, respectively. The null hypothesis will be 
tested at a two-sided 0.05 significance level. 
A preview of the main analyses is given in Table 3 using the estimand terminology 
[ICH 2020]. Estimands are defined by five attributes: treatment condition of interest, target 
population, endpoint, strategy for addressing intercurrent events (i.e., premature 
discontinuation of treatment or use of other, forbidden, medication for BE), and 
population‑level summary. The primary estimand is based on the primary endpoint. A 
supplementary estimand is obtained by changing one or more attributes. For both estimands 
the treatment condition is ACT-539313 b.i.d. for up to 12 weeks, whereas the alternative 
condition is placebo b.i.d. for the same period. The other four attributes are given in 
Table 3. Differences vs the primary estimand are indicated in bold italics. 


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Table 3 
Estimands for the primary objective 
Estimand 
Target 
Population 
Endpoint 
Strategy for 
addressing 
intercurrent 
events 
Population-
level summary 
Primary 
Estimand 
Adult study 
participants with 
BED according 
to DSM-5, 
having at least 
3 BE days per 
week at baseline. 
Change from 
baseline to 
Week 12 in the 
number of BE 
days per week 
Hypothetical, 
i.e., endpoint 
data after 
intercurrent 
event are not 
used. 
Mean change 
from baseline to 
Week 12 for 
each treatment 
group.  
 
Treatment effect 
expressed as 
difference of 
LSMean 
changes from 
baseline to 
Week 12 
(ACT‑539313 
minus placebo; 
from mixed 
model) 
Supplementary 
Estimand #1 
Adult study 
participants with 
BED according 
to DSM-5, 
having at least 
3 BE days per 
week at baseline. 
Change from 
baseline to 
Week 12 in the 
number of BE 
episodes per 
week 
Hypothetical, 
i.e., endpoint 
data after 
intercurrent 
event are not 
used. 
Mean change 
from baseline to 
Week 12 for 
each treatment 
group. 
 
Treatment effect 
expressed as 
difference of 
LSMean 
changes from 
baseline to 
Week 12 
(ACT‑539313 
minus placebo; 
from mixed 
model) 


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Estimand 
Target 
Population 
Endpoint 
Strategy for 
addressing 
intercurrent 
events 
Population-
level summary 
Supplementary 
Estimand #2 
Adult study 
participants with 
BED according 
to DSM-5, 
having at least 
3 BE days per 
week at baseline, 
completing 
12 weeks of 
treatment 
without use of 
other 
medication 
Change from 
baseline to 
Week 12 in the 
number of BE 
days per week 
Hypothetical, 
i.e., endpoint 
data after 
intercurrent 
event are not 
used. 
Mean change 
from baseline to 
Week 12 for 
each treatment 
group. 
 
Treatment effect 
expressed as 
difference of 
LSMean 
changes from 
baseline to 
Week 12 
(ACT‑539313 
minus placebo; 
from mixed 
model) 
Intercurrent events are premature discontinuation of treatment and use of other, forbidden, medication for BE. 
BE = binge eating; BED = binge eating disorder; DSM-5 = Diagnostic and Statistical Manual of Mental Disorders (5th 
edition); LSMeans = Least Squares Means.  
 
In the choice of intercurrent events it was considered that, in symptomatic settings, it is not 
the usual practice to continue to assess effectiveness in subjects after they have stopped 
taking the assigned treatment [O’Neill 2012]. Also, if an alternative (or additional) drug is 
started, this could influence the outcome for a subject [O’Neill 2012]. Therefore, two types 
of intercurrent events were considered: premature discontinuation of double-blind 
treatment (ACT-539313 or placebo) and use of other forbidden medication for BE.  
Excluding measurements obtained after an intercurrent event will lead to a hypothetical 
strategy estimand (ICH E9[R1]). A hypothetical strategy is related to the scenario in which 
the intercurrent events would not occur (i.e., all subjects completing the 12 weeks of 
assigned treatment without using forbidden BE medication), which is a reasonable 
approach for this proof-of-concept study.  
6.1.3 
Statistical model 
A linear mixed effects model will be used for the analysis of change from baseline in the 
number of BE days per week.  
The analysis model will include the baseline number of BE days per week, treatment group 
(ACT-539313; placebo), sex, BMI category (< 30; ≥ 30 kg/m2), time point (Weeks 1–2;  


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3–4; 5–6; 7–8; 9–10; 11–12), and the interaction of treatment by time point and baseline 
by time point. 
An unstructured covariance matrix will be used to model the correlation among repeated 
measurements. A restricted maximum likelihood approach in combination with the 
Newton Raphson Algorithm will be used to derive (unbiased) estimates of variance 
components. The Kenward-Roger approximation will be used to compute the denominator 
degrees of freedom and adjust standard errors [Kenward 1997]. If the analysis fails to 
converge, the following structures will be tested in a subsequent order until 
model-convergence is achieved: heterogeneous Toeplitz; Toeplitz; autoregressive; 
compound symmetry. A sandwich estimator will be used to address the potential mis-
specification of the aforementioned structured covariance matrixes. 
To test the null hypothesis (H0), appropriate contrasts will be used to test the treatment 
difference of interest (i.e., the difference in least squares [LS] mean change from baseline 
between ACT-539313 vs placebo at Week 12) [see Section 14.1]. 
The LSMean for each treatment group per time point will be displayed along with 
associated standard errors and 95% CIs. For the ACT-539313 comparison with placebo, 
the placebo-adjusted LSMean will be displayed along with associated standard error, 
95% CI and unadjusted two-sided p-value. The null hypothesis will be rejected if the 95% 
CI around this difference excludes zero. 
6.1.3.1 Model diagnostic and checks for normality 
In order to assess the normality assumption of the MMRM, QQ-Plots and histograms 
(including an overlay of a normal density curve) of the studentized residuals, and figures 
comparing the studentized residuals versus the predicted residuals will be produced.  
If the normality assumption does not hold, the primary endpoint will be analyzed using a 
non-parametric rank analysis of covariance [Quade 1967, Koch 1982, Koch 2016, Stokes 
2012] adjusted for the baseline value as follows: 
1. Produce standardized ranks for the baseline value (covariate) and the change from 
baseline to Week 12 variable (response). 
2. Fit a linear regression model with the standardized ranks of the baseline variable and 
the change from baseline to Week 12 variable as independent and dependent variable, 
respectively. Retain the regression residuals. 
3. Apply the Cochran-Mantel-Haenszel mean score test using the residuals as scores to 
compare treatment groups. The p-value from this test will be used to test the null 
hypothesis. 
The rank analysis of covariance does not provide an interpretable treatment effect estimate. 
Therefore, the magnitude of the treatment effect will be estimated using the unadjusted 


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non-parametric win ratio [Wang 2016] between ACT-539313 and placebo with 
corresponding 95% CI, derived via bootstrap (10,000 samples) using the bias-corrected 
method [Carpenter 2000] on the log-transformed win ratio. The rejection of the null 
hypothesis will be solely based on the p-value from the rank analysis of covariance and not 
the 95% CI of the unadjusted win ratio estimator. 
All study participants with a valid value for the change from baseline to Week 12 will be 
ranked based on these values (such that larger decreases are associated with better ranks). 
Study participants with a missing value for the change from baseline to Week 12 will be 
assigned worse ranks than study participants with available change from baseline to 
Week 12 values based on their last available change from baseline value prior to Week 12. 
Study participants with a non-missing baseline value but no post-baseline data will be 
excluded from the analysis. Mid-ranks are used in the event of ties. 
6.1.4 
Handling of partially missing data 
Partially missing data refers to some missing entries in the BE diary that should be filled 
in daily.  
Partially missing data for the BE diary will be handled as follows: a minimum of 7 days of 
entries per 14-day time interval is required; otherwise, the mean value will be considered 
missing for that time point.  
This approach uses implicit imputation: missing data points are given the same value as 
the mean of the non-missing data points of that same time point or week. 
The (partially) missing data patterns of the primary efficacy endpoint will be shown with 
a shift table for each treatment group. The table will show the shifts in the number of 
available BE values (categorized as < 7, 7–10, 11–14 days) from baseline to Week 3–4, 
Week 7–8, and Week 11–12 (Week 1–2, Week 5–6 and Week 9–10 will be available in the 
listing).  
6.1.5 
Descriptive statistics 
The primary efficacy endpoint along with its observed values (i.e., bi-weekly averages of 
BE episodes; see Table 6) will be summarized using descriptive statistics.  
A plot of the mean (± SE) change from baseline over time (per weeks, as defined in 
Table 6) for the number of BE days by treatment group will be provided together with a 
summary table.  
The incidence and pattern of missing values will be explored to assess the appropriateness 
of the statistical analysis and possible impact on results. The incidence of missing data and 
the observed missing data patterns for the primary endpoint at Baseline and time point 
(Weeks 1–2; 3–4; 5–6; 7–8; 9–10; 11–12) will be presented for each treatment group. The 


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missing data patterns will be sorted from completely missing to completely observed by 
the order of the first occurrence of missing data.  
The mean change from baseline of the primary efficacy endpoint, for both study completers 
and for premature study withdrawals, will be plotted over time (Weeks 1–2; 3–4; 5–6;  
7–8; 9–10; 11–12) and displayed in a summary table by treatment group. In case the 
percentage of study withdrawals will be above 15%, the reasons for study withdrawals will 
also be plotted.  
The same plot and table will also be provided for study treatment completers and study 
treatment discontinuers.  
Based on the exploration of the observed missing data patterns, further sensitivity analyses 
to those described below may be performed. 
6.1.6 
Sensitivity analyses 
The linear mixed effects model (or MMRM) relies on the MAR assumption. That is, 
conditional on the statistical model and observed values of the outcome, the probability of 
missing data does not depend on the unobserved values of that outcome. Consequently, the 
study participant’s missing values are estimated based on similar study participants who 
remain in the study. MAR is a common assumption for analyses associated with a 
hypothetical strategy estimand.  
Sensitivity analyses will be performed to assess the robustness of the conclusions of the 
main analysis to departures from the MAR assumption. For this, a model that assumes 
MNAR will be used [Mallinckrodt 2013]. This model will be based on MI methodology 
[Rubin 1987] and will be specifically used to assess the bias that can result when the 
outcomes for participants who discontinue differ from those who complete. Sensitivity 
analyses will be performed for the analysis of the primary endpoint.  
As a general approach, imputations will be performed on observed values (i.e., bi-weekly 
averages at Baseline, Weeks 1–2, 3–4, 5–6, 7–8, 9–10, 11–12) specifying a minimum and 
a maximum threshold. The change from baseline will not be imputed to avoid imputation 
of nonsensical values (e.g., an imputed change from baseline to Week 12 equal to −5 with 
a baseline of 4 would lead to an implicit imputed value of −1 for Week 12, which is not 
possible). The boundaries will range from 0 to 7.  
When an intended imputed value is outside the defined boundaries, this value will be 
discarded, and the procedure will draw another value for imputation. The maximum 
number of discarded values will be set to 100 for each imputed dataset, i.e., an imputed 
dataset will not be generated if more than 100 values have been discarded (SAS will print 
an error message in the log: “An imputed variable value is not in the specified range after 
100 tries”). If more than 20% of the planned imputed datasets are not produced, the results 
for that analysis will not be shown as this would likely lead to unreliable conclusions. Once 


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all the multiply-imputed datasets are generated, the change from baseline to Week 12 will 
be calculated from the bi-weekly averages for each data set.  
In all the MI analyses described below, a single preliminary step will be performed to 
obtain a monotone missing data pattern [see Section 11.6]. That is, any non-monotone (or 
intermediate) missing data of the bi-weekly averages will be imputed using the MCMC 
methodology [Schafer 1997] under MAR assumptions within each treatment group. This 
assumption is considered reasonable given that study participants could miss intermediate 
visits due to reasons unrelated to their BE disorder (e.g., scheduling conflicts or 
COVID-19). The MCMC imputation will be performed by treatment group, and the 
variables included in the model are: sex, BMI (continuous), baseline, and time point 
(Weeks 1–2, 3–4, 5–6, 7–8, 9–10, 11–12). The MCMC methodology assumes a 
multivariate normal distribution of these variables [see SAS® code in Section 14.2]. 
As a reference for the sensitivity analyses under MNAR (described below), the main 
analyses will be repeated using MI methodology under MAR. Imputation for monotone 
missing data will be performed sequentially, one time point at a time using the linear 
regression method [Ratitch 2013]. A linear regression model will be fitted sequentially for 
each time point (i.e., Weeks 1–2 and then Weeks 3–4, Weeks 5–6, Weeks 7–8,  
Weeks 9–10, Weeks 11–12) with treatment (ACT-539313; placebo), sex, BMI category, 
baseline, and any prior time point (e.g., Weeks 1–2 when fitting the linear regression model 
to Weeks 3–4 values and so on) as predictors. Missing values are then replaced for each 
visit sequentially (i.e., Weeks 1–2 and then Weeks 3–4, Weeks 5–6, Weeks 7–8, Weeks 9–
10, Weeks 11–12) by predictions from the respective linear regression model 
[Rubin 1987]. Note that values imputed at Weeks 1–2 are included when fitting the linear 
regression model to Weeks 3–4 values (the same approach will be implemented for the 
imputation of the other time points). The resulting multiple data sets are analyzed using the 
same statistical model as for the primary analysis (i.e., linear mixed effects model with the 
same factors). Results from these analyses are combined using Rubin’s methodology 
[Rubin 1987]. The results obtained from this MI analysis are expected to be similar to the 
main MMRM analysis since both methods rely on the same MAR assumption. 
Two sensitivity analyses assuming MNAR will be performed: a control-based imputation 
method called J2R [Carpenter 2013] and a delta-adjusted imputation method [Yan 2009]. 
In each method, study participants from the placebo group that prematurely discontinue or 
withdraw from the study are assumed to evolve in the same way as placebo study 
participants who remain in the study (i.e., MAR is assumed for the placebo group). Study 
participants who withdraw from the study due to site closure will not be penalized. 
Therefore, they are assumed to evolve in the same way as the study participants who remain 
in the study from the same treatment group (i.e., MAR is assumed for these study 
participants). 


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The J2R imputation method can be considered conservative as it assumes that study 
participants from the ACT-539313 group who prematurely discontinue, or withdraw, from 
the study exhibit the same future evolution as placebo study participants. The same 
sequential procedure using linear regression models for imputing monotone missing data 
as described above will be used. However, predictions to replace the missing values in the 
ACT-539313 group will be based on data from the placebo study participants only. 
Consequently, the factor for treatment is omitted from the sequential regression models. 
After imputation, the multiply-imputed datasets are then analyzed and combined as 
described above. Note that the same linear mixed effects model as in the main analysis will 
be used. 
A delta-adjusted imputation method will be used to progressively stress test the MAR 
assumption of the main analysis. That is, a tipping-point analysis will be performed to see 
how severe departures from the MAR assumption must be to overturn the conclusions of 
the main analysis (i.e., the point where significant results become non-significant). The 
assumption here is that study participants from the ACT-539313 group who discontinue 
from the study would have, on average, their observed efficacy score worsened by some 
amount (delta) compared with the efficacy observed from study participants of the same 
ACT-539313 group that remain in the study. A series of analyses with progressively 
increasing deltas (δBE days per week = 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2; from less 
conservative to more conservative) will be performed. The delta adjustment will only be 
made to the multiply-imputed values (based on the MAR assumption) for the subjects in 
the ACT-539313 group. Note that a delta of zero corresponds to the standard MAR-based 
MI analysis that is described above to obtain a reference for the sensitivity analyses. Again, 
the same linear mixed effects model as in the main analysis will be used. 
For all the analyses described above which use MI methodology, 100 multiply-imputed 
datasets are created. The decision to impute 100 datasets was based on O’Kelly 
[O’Kelly 2014], where it is stated that the number of imputations should typically be 
between 20 and 100 [Graham 2007]. Similar recommendations have also been provided by 
other authors [Bodner 2008, Von Hippel 2009, White 2011].  
For each planned sensitivity analysis, the LSMean estimate of the difference in change 
from baseline between ACT-539313 vs placebo at Week 12 will be provided, together with 
its estimated standard error and associated p-value. The LSMean estimate of the change 
from baseline for each treatment group at Week 12 will also be provided, together with its 
estimated standard error and associated p-value. 
A plot over time for the primary efficacy endpoint showing the LSMean of each treatment 
group per imputation method (i.e., MAR; J2R; delta-adjusted including δ = 0) will be 
provided.  


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Any missing diary data due to the COVID-19 pandemic is considered missing completely 
at random and satisfies the assumption underlying the main analysis (linear mixed-effects 
model, assuming missing at random). Nevertheless, efforts will be made to retain study 
participants in the trial and adhere to the schedule of assessments. Visits are performed at 
regular and short intervals for the investigator to closely follow-up with the diary 
completion. The COVID-19 pandemic may lead to missed or postponed visits, but the 
study participant’s BE diary can still be evaluated at the next visit to collect the information 
for the primary endpoint. In addition, the study protocol accounts for remote visits in case 
study participants cannot, are not allowed to, or are not willing to travel to the investigator’s 
site because of the COVID-19 pandemic. The paper-based BE diary, used to assess the 
primary endpoint, will be filled in by the study participants at home and subsequently 
reviewed by the investigator during the clinic visits. If in-person visits will be not possible 
because of the COVID-19 pandemic, the data will be reviewed remotely via a telephone 
call or a video call; delivery of BE diary booklets and/or study treatment to the trial 
participants’ home is also foreseen under such circumstances. 
6.1.7 
Supportive analyses 
The main analysis performed for the primary efficacy endpoint [Section 6.1.3] will be 
repeated using the PPS to assess the effect protocol deviations may have on the results. 
In addition, the main analysis performed for the primary efficacy endpoint [Section 6.1.3] 
will be repeated considering all data collected to evaluate the effect intercurrent events may 
have on the results (see Section 14.12 for the list of BE forbidden medications).  
6.1.8 
Subgroup analyses 
Subgroup analyses for the primary efficacy endpoint will be performed to investigate the 
consistency of the treatment effect (i.e., ACT-539313 vs placebo) across subgroups defined 
by: 
Age:   
18–29, 30–55 years 
Sex:   
Male, female 
Race:  
Black, White, other 
BMI:  
< 30, ≥ 30 kg/m2 
Treatment effect estimates (LS Means) and their 95% CIs (obtained by conducting the 
primary analysis by subgroup) will be presented as forest plots with vertical reference lines 
at ‘no effect’ as well as at the ‘overall treatment effect’. P-values for treatment by subgroup 
interaction will be provided for exploratory purposes, based on the primary analysis model 
extended with treatment by time and by subgroup interaction. 
6.2 
Secondary endpoint analysis 
Not applicable. 


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6.3 
Analysis of exploratory efficacy variables 
The following efficacy endpoints will be summarized using descriptive statistics: 
• Change from baseline up to Week 12 (EOT) in the number of BE episodes per weeka.  
• Absence of BE episodes (‘Yes’b/’No’) during the last 4 weeks of the treatment periodc. 
• Change from baseline to Week 12 (EOT) in the total score of the YBOCS-BE. 
• Change from baseline to Week 12 (EOT) in the subscales scores (i.e., 
compulsive/obsessive, restraint, control) of the YBOCS-BE. 
• Change from baseline to Week 6 (Visit 6) and to Week 12 (EOT) in the HAMD-17 
total score. 
• Change from baseline to Week 6 (Visit 6) and to Week 12 (EOT) in the HAMD-17 
subitems 10 and 11. 
• Change from baseline to Week 6 (Visit 6) and to Week 12 (EOT) in the HAMD-17 
Maier-Philipp Subscale (MPS) score. 
• Change from baseline to Week 12 (EOT) in EDE-Q7 global score and 3 subscales 
scores (i.e., dietary restraint, shape/weight overvaluation, body dissatisfaction). 
• CGI-C score at Week 12 (EOT). 
• PGI-C score at Week 12 (EOT). 
• Change from baseline to Week 12 (EOT) in the CGI-S score. 
• Change from baseline to Week 12 (EOT) in the PGI-S score. 
• Change from baseline to Week 12 (EOT) in body weight. 
• Change from baseline to Week 12 (EOT) in HbA1cd. 
• Improvemente according to CGI-C score at Week 12 (EOT). 
a ‘Number of BE episodes per week’ is defined as the number of BE episodes in the applicable 
14-day time interval divided by the total number of diary days, times 7. 
b ‘Yes’ is defined as BE episodes equal to 0.  
c ‘Last 4 weeks of the treatment period’ are defined as study days 57–84 [see Section 11.7].   
d Glycated hemoglobin. 
e Improvement according to CGI-C score is defined as CGI-C at Week 12 equal to “Much 
Improved” or “Very much improved”. If CGI-C at Week 12 is missing, the study participant will 
be assumed to not have improved. 
The above variables related to change from baseline will be summarized along with their 
observed values. 
The YBOCS-BE is an interviewer-administered assessment developed to measure the 
severity of obsessive-compulsive symptoms in subjects with a diagnosis of obsessive-
compulsive disorder modified to measure the BE thoughts and behaviors. The YBOCS-BE 


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presents three subscales: compulsive/obsessive (Items #1, 2, 3, 6, 7 and 8), restraint (Items 
#4 and 9), and control (Items #5 and 10). 
The HAMD-17 is an indicator of depression and anxiety. The HAMD-17 consists of 
17 items, with most items providing a score that ranges between ‘Absent’ and ‘Almost all 
the time’. The MPS sub-score combines items 1 (depressed mood), 2 (guilt), 7 (work and 
activities), 8 (psychomotor retardation), 9 (psychomotor agitation), and 10 (anxiety, 
psychic). 
EDE-Q7 is a self-reported questionnaire containing 7 of the 28 questions from the EDE-Q 
about eating behaviors (Items #1, 3, 4, 22, 23, 25 and 26). The EDE-Q7 presents three 
subscales: dietary restraint (Items #1, 3 and 4), shape/weight overvaluation (Items #22 and 
23), and body dissatisfaction (Items #25 and 26). 
The CGI-C is a 1-item, 7-point scale that ranges from “Very much improved” to “Very 
much worse”. 
The PGI-C is a 1-item, 7-point scale that ranges from “Very much improved” to “Very 
much worse”. 
The CGI-S is a 1-item, 7-point scale that ranges from “Normal, not at all ill” to “Among 
the most extremely ill patients”. 
The PGI-S is a question concerning the overall severity of symptoms and impact that the 
study participant may have experienced due to his/her BE episodes over the 7 days 
preceding the PGI-S completion. It ranges from “No binge eating” to “Severe”. 
The exploratory efficacy endpoints will be tested at two-sided 5% significance level. No 
further Type I error control is applied; hence, these analyses are to be considered 
descriptive. 
The MMRM [Section 6.1.3], will be fitted for: 
• The change from baseline to Week 12 (EOT) in the number of BE episodes per week, 
with a covariate for the baseline number of BE episodes (rather than the number of BE 
days) per week.  
• The change from baseline to Week 12 (EOT) in EDE-Q7 global score and 3 subscales, 
with a covariate for the time points limited to Week 4 (Visit 5), Week 8 (Visit 7), and 
Week 12 (EOT). 
• The change from baseline to Week 12 (EOT) in the total score of the YBOCS-BE and 
in the subscales scores (i.e., compulsive/obsessive, restraint, control), with a covariate 
for the time points limited to Week 4 (Visit 5), Week 8 (Visit 7) and Week 12 (EOT). 


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• The change from baseline to Week 6 (Visit 6) and to Week 12 (EOT) in the HAMD-17 
total score, subitems 10 and 11, and MPS score, with a covariate for the time points 
limited to Week 6 (Visit 6) and Week 12 (EOT). 
Absence of BE episodes will be analyzed using a logistic regression model with a factor 
for treatment group, sex and BMI category, and a covariate for the baseline number of BE 
episodes per week. For study participants who discontinued treatment prematurely, the 
outcome will be set to ‘No absence’. 
The CGI-C and PGI-C scores at Week 12 (EOT) will be compared between treatment 
groups using the Kruskal-Wallis test. Missing assessments at Week 12 will be imputed 
using last on-treatment observation carried forward. 
The change from baseline to Week 12 (EOT) in the CGI-S score, PGI-S score, body weight 
and HbA1c will be analyzed using an ANCOVA model with a factor for treatment group 
and a covariate for baseline score. Missing assessments for CGI-S and PGI-S score at 
Week 12 will be imputed using last on-treatment observation carried forward. 
The improvement according to CGI-C score at Week 12 (EOT) will be analyzed using a 
logistic regression model with a factor for treatment group. 
 
 
 
  
7 
SAFETY VARIABLES AND ANALYSES 
7.1 
Overview of safety analyses including subgroup analyses 
The SAF will be used for tables and listings of safety data, unless otherwise stated.  
Unless noted otherwise, only the treatment-emergent safety data will be considered in 
tables and figures.  
All safety data described below will be listed. 
7.2 
Adverse events 
TEAEs are defined as AEs that started or worsened on or after study treatment start date 
up to the EOS.  
AEs will be coded using MedDRA. The MedDRA version used for reporting will be 
specified in the footnote of the applicable output.  
The number (%) of study participants experiencing a TEAE (including SAEs, AESIs, AEs 
leading to premature discontinuation and/or temporary interruption of study treatment) will 
be summarized by SOC and/or PT, and/or maximum intensity.  


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AESIs, defined as AE PTs denoting somnolence and fatigue will be summarized separately 
[Section 14.13]. Additionally, this summary will be provided by 2-week interval  
(Week 1–2 until Week 11–12). 
A subject with multiple intensities reported for an AE will be summarized under the 
maximum intensity recorded for the event.  
Apart from the summaries of occurrences, where each event is counted, a subject with 
multiple occurrences of an AE is counted only once in the AE category (e.g., SOC, PT). If 
a single AE worsens on the same treatment group, then this event will be considered as one 
occurrence.  
AEs will be sorted by descending frequency, first in the ACT-539313 group, then in the 
placebo group. After this sorting, SOCs are presented in alphabetical order and PTs are 
sorted alphabetically within each SOC. 
The following AE summary tables will be provided:  
• Treatment-emergent AEs. 
• Treatment-emergent AEs during the treatment perioda. 
• TEAEs during the treatment perioda related to study treatment. 
• AEs leading to premature discontinuation of study treatment. 
• AEs leading to temporary interruption of study treatment. 
• Treatment-emergent SAEs (including occurrences). 
• Treatment-emergent SAEs related to study treatment (including occurrences). 
• Treatment-emergent AESIs. 
• Treatment-emergent AEs during the safety follow-up period. 
• TEAEs with fatal outcome. 
• TEAEs related to study treatment with fatal outcome. 
• Total number of deaths. 
a Includes only those TEAEs occurring (i.e., that started or worsened) during the treatment period 
[see Section 11.2].  
All AEs will be listed, and AESI and SAE will be flagged in the AE listing.  
Separate listings will be provided for AEs leading to premature discontinuation of study 
treatment, AEs leading to temporary interruption of study treatment, SAEs and AESI. 
All deaths will be listed, with cause of death, using the SCR set.  


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An AE listing, using the SCR set, will also be provided for study participants who were 
not randomized (i.e., screen failures) and study participants who were randomized but did 
not take study treatment. This listing will therefore include any study participants who 
discontinued the study due to AE but did not receive any study treatment.  
Any other summary required for disclosure to public database will be generated as 
appropriate. 
7.3 
Laboratory tests 
Laboratory analyses are based on data received from the central laboratory. Laboratory 
data will be converted into SI units. Unless noted otherwise, summaries and listings will 
include scheduled, re-test, and unscheduled assessments.  
Descriptive summary statistics for each scheduled visit (re-test excluded) will be provided 
for observed values and change from baseline in both hematology and blood chemistry 
laboratory parameters.  
The main laboratory parameters will be displayed graphically using boxplots considering 
only scheduled visit (re-test and unscheduled assessments excluded) and will be grouped 
(i.e., shown in the same panel) as follows: 
• Hemoglobin, hematocrit, platelets, leukocytes (white blood cell count) 
• Glucose, uric acid, cholesterol, triglycerides 
• Total bilirubin, ALT, AST 
• ALP, GGT 
Marked laboratory abnormalities are defined in the appendix [Section 14.14]. The number 
(%) of participants with treatment-emergent 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 participants having at least one post-baseline value for a given parameter.  
Shift from baseline to worst value post-baseline based on laboratory normal ranges will be 
provided for the following laboratory parameters: 
• Liver enzymes: ALT, AST, GGT and BILI.  
• Lipids: total cholesterol and triglycerides. 
• Hematology: hemoglobin, hematocrit, platelets, leukocytes (absolute count), 
neutrophils (absolute count), lymphocytes (absolute count). 
All laboratory data for participants with at least one marked laboratory abnormality during 
the treatment period will be listed. Any local laboratory data collected will be listed 
separately. 


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Elevated liver parameters during the treatment period will be summarized: the number (%) 
of study participants meeting the criteria defined below within a given central laboratory 
sample will be tabulated by treatment group. Percentages will be based on the number of 
study participants having at least one post-baseline value for all parameters listed below. 
• AST or ALT > 3 × ULN 
• AST or ALT > 5 × ULN 
• AST or ALT > 10 × ULN 
• BILI > 2 × ULN 
• ALP > 1.5 × ULN 
• (ALT or AST > 3 × ULN) and (BILI > 2 × ULN) 
A summary table for study participants falling into the Hy’s Law criteria will be provided 
[Andrade 2019]. This will include study participants meeting all the following criteria: 
• AST or ALT > 3 × ULN 
• BILI > 2 × ULN 
• ALP < 2 × ULN 
7.4 
Electrocardiography 
ECG analyses are based on data received from the central reader. Unless noted otherwise, 
ECG summaries and listings will include scheduled, re-test, and unscheduled assessments.  
Descriptive summary statistics for each scheduled visit (re-test excluded) will be provided 
for observed values and change from baseline in ECG parameters (QT, QRS, QT corrected 
according to Fridericia’s formula, QT corrected according to Bazett’s formula, heart rate, 
and PR interval). 
Marked ECG abnormalities are defined in Table 4. The number (%) of study participants 
with a marked ECG abnormality will be provided for each ECG parameter. 
Percentages will be based on the number of participants having at least one post-baseline 
value for criteria based on post-baseline values only, or those having a baseline value and 
at least one post-baseline value per ECG parameter for criteria based on change from 
baseline. For non-mutually exclusive criteria (i.e., HR, PR and QRS), a subject will be 
counted only once in case of multiple occurrences but may be reported in more than one 
marked ECG abnormality criterion of a given parameter. For mutually exclusive criteria 
(i.e., QTc), only the subject’s worst post-baseline value (or worst change from baseline 
value) will be counted. 
ECG findings during the treatment period will be summarized separately and listed. ECG 
abnormality categories and findings will be sorted by descending frequency, first in the 
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abnormality categories will be presented in alphabetical order with ECG finding sorted 
within ECG abnormality category in alphabetical order. All ECG values for study 
participants with at least one marked ECG abnormality during the treatment period will be 
listed.  
Table 4 
Marked abnormalities in ECG parameters 
ECG parameter 
Criteria for marked ECG abnormalities 
QTcF, QTcB (ms) 
> 450 and ≤ 480 
> 480 and ≤ 500 
> 500 
> 30 and ≤ 60 increase from baseline 
> 60 increase from baseline 
HR (bpm) 
< 45 
< 50 
> 10 and ≤ 20 decrease from baseline 
> 20 decrease from baseline 
PR (ms) 
> 200 
QRS (ms) 
> 110 
bpm = beats per minute; ECG = electrocardiogram; HR = heart rate; QTcB = QT interval corrected according to 
Bazett’s formula; QTcF = QT interval corrected according to Fridericia’s formula. 
7.5 
Vital signs and body weight  
Each summary will include only scheduled assessments (re-test excluded) and listings will 
include both scheduled and unscheduled assessments.  
The change from baseline to each visit (Week 1, 2, 4, 6, 8, 10, 12) in vital signs (systolic 
and diastolic blood pressure, respiratory rate, temperature, body weight, and pulse rate) 
will be summarized. The observed values at baseline and each scheduled post-baseline visit 
will also be summarized.  
7.6 
Daytime sleepiness 
Daytime sleepiness will be assessed using the SSS during the first two weeks of study 
treatment. The SSS is filled in twice daily, at breakfast before morning dose (pre-dose) and 
around midday, prior to lunch time (post-dose). 
The SSS is a 1-item, 7-point scale that ranges between “Feeling active, vital, alert, or wide 
awake” and “No longer fighting sleep, sleep onset soon; having dream-like thoughts”.  
Daytime sleepiness is defined daily as any score > 3 on the SSS after the morning dose 
(post-dose). 
The number of days per week with daytime sleepiness is defined as the number of diary 
days with at least an SSS score > 3, during the first 2 weeks of treatment only, divided by 


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the total number of diary days, times 7. A minimum of 7 diary entries during this 14-day 
time interval is required, otherwise the number of daytime sleepiness days will be 
considered missing. A diary day is a day for which the rate of daytime sleepiness is entered 
in the study participant’s diary. This approach uses implicit imputation: if a subject does 
not have 14 entries but has at least 7, missing data points are given the same value as the 
mean of the non-missing data points of that same time point or week. 
The mean number of days with daytime sleepiness pre- and post-dose during the 2-week 
period will be summarized by treatment group. In addition, the observed value and change 
from baseline at each study day will be summarized by treatment group. The number (%) 
of study participants with a post-dose SSS score ≤ 3, 4, 5, 6 and 7, having a pre-dose SSS 
score ≤ 3 and equal to 4 will be provided by treatment group. 
The SSS score pre- and post-dose over the 2-week period will be produced by treatment 
group using series plot (mean ± SE) and boxplots. In addition, the series plot will be 
provided only for study participants with AESIs.  
7.7 
Withdrawal symptoms 
7.7.1 
Benzodiazepine Withdrawal Symptoms Questionnaire 
The BWSQ consists of 20 items with each item rated by the subject as either 0 (No), 
1 (Yes-moderate), or 2 (Yes-severe). The change in BWSQ Total score (possible range: 
0 to 40) from the last available assessment during the treatment period to EOS will be 
summarized. Observed values will also be summarized.  
The number (%) of study participants with a BWSQ Total score above 20 will be tabulated 
by visit (EOT and EOS). 
The number (%) of study participants with one or more BWSQ symptom scored as ‘severe’ 
will be tabulated by visit (EOT and EOS). 
In addition, withdrawal symptoms after study treatment discontinuation will be assessed 
through the incidence of AEs occurring during the safety follow-up period. As described 
in the respective section [Section 7.2], the incidence of AEs occurring during the safety 
follow-up period will be summarized.  
7.7.2 
Hamilton Depression Rating Scale  
The change in HAMD-17 Total score from the last available assessment during the 
treatment period to EOS will be summarized. Observed values will also be summarized. 
7.8 
Columbia-Suicide Severity Rating Scale©  
The C-SSRS© is an instrument that evaluates suicidal ideation and behaviors.  
The C-SSRS© outcome categories are provided below. Each category has a binary response 
(yes/no).  


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1 
Wish to be dead  
2 
Non-specific active suicidal thoughts  
3 
Active suicidal ideation with any methods (not plan) without intent to act  
4 
Active suicidal ideation with some intent to act, without specific plan  
5 
Active suicidal ideation with specific plan and intent  
6 
Preparatory acts or behavior  
7 
Aborted attempt  
8 
Interrupted attempt  
9 
Actual attempt (non-fatal)  
10 Completed suicide  
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.  
Self-injurious behavior without suicidal intent is also a C-SSRS© outcome (although not 
suicide-related) and has a binary response (yes/no).  
Based on the C-SSRS©, the number (%) of study participants with suicidal ideation by 
category, suicidal behavior by category, suicidal ideation or suicidal behavior, and/or 
self-injurious behavior without suicidal intent, during the treatment period and the safety 
follow-up period will be tabulated. Percentages will be based on the number of study 
participants with at least one post-baseline C-SSRS© assessment. The assessments done at 
Week 1, 2, 4, 6, 8, 10, 12 will be assigned to the treatment period while the assessment 
done at EOS will be assigned to the safety follow-up period. 
Shift from baseline showing any change in suicidal ideation and suicidal behavior during 
the treatment period and the safety follow-up period will be provided. Study participants 
will be summarized under the worst of the following three categories, shown here in the 
order from best to worst: 1) No suicidal ideation or behavior, 2) Suicidal ideation, and 
3) Suicidal behavior (study participants with both suicidal ideation and suicidal behavior 
are also included in the suicidal behavior category). 
8 
PHARMACOKINETIC VARIABLES AND ANALYSES 
PK analyses will be performed using the PK set.  
Descriptive statistics for the ACT-539313 plasma concentrations collected prior to the 
morning dosing at Week 4, Week 8 and Week 12 will be provided by age group and overall: 
n, mean, SD, CV%, m (number of non-zero concentrations), geometric mean, geometric 
SD, geometric CV%, median, minimum and maximum. These concentration values will 
also be displayed graphically by visit: scatter plots vs BMI by sex; and boxplots for age 
categories (18–29, 30–55 years) and all ages combined. 
Concentration values below the lower limit of quantification will be displayed in listings 
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and maximum, but handled as missing for the calculation of the geometric mean, 
geometric SD, and geometric CV%. 
All individual ACT-539313 plasma concentration data will be listed. 
Plasma samples might also be used by Idorsia Preclinical Pharmacokinetics and 
Metabolism department for exploratory assessments of circulating metabolites of 
ACT-539313. 
9 
GENERAL STATISTICAL METHODOLOGY 
9.1 
General rules for data presentations 
Data are listed and summarized as described below.  
The tables will use the following header structure (label and order): 
ACT-539313 100 mg 
N = xxx 
Placebo 
N = xxx 
 
Where N indicates the total number randomized or treated appropriate to the analysis set 
in the corresponding treatment group, unless otherwise specified.  
All listings will be sorted by randomized treatment or actual treatment received 
(appropriate to the analysis set), subject number (ascending) and, when appropriate, by 
visit / date of assessment (ascending). Listings related to the SCR set will present a 
treatment group label ‘screening failure’ to indicate study participants who were not 
randomized and will be listed after the study participants who were randomized or received 
study treatment, as relevant.  
Unless noted otherwise, the following descriptive statistics will be used to summarize data: 
number (%) of study participants for categorical variables, or descriptive statistics (number 
of non-missing values, mean, SD, median, Q1, Q3, minimum, maximum) for continuous 
variables. 
9.2 
Handling of missing dates 
An incomplete date (day or month missing), or missing concomitant therapy / AE date, 
will be imputed as described in Table 5. The ‘lower limit’ and ‘upper limit’ refer to the 
earliest and latest possible dates, respectively.  
As an example: if concomitant therapy start date / AE onset date is MAR2021 (day 
missing), the lower limit is 01MAR2021 and the upper limit is 31MAR2021; if 
concomitant therapy start date / AE onset date is 2021 (day and month missing), the lower 
limit is 01JAN2021 and the upper limit is 31DEC2021. 


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Table 5 
Imputation rules for an incomplete or missing concomitant therapy 
or AE date 
Field 
Incomplete date 
Missing date 
Concomitant 
therapy end 
date / AE 
resolution date 
The upper limit. 
No imputation. The therapy / AE 
is considered as ongoing. 
Concomitant 
therapy start 
date / AE onset 
date 
The rules below apply in the order presented: 
1. If the (imputed) concomitant therapy / AE end 
date is on or after the start of study treatment, and 
if the study treatment start falls within the upper 
and lower limits (inclusive), the study treatment 
start date is used. 
2. If the concomitant therapy end date / AE 
resolution date is missing, and if the study 
treatment start falls within the upper and lower 
limits (inclusive), the study treatment start date is 
used. 
3. In all the other cases, the lower limit is used. 
Whichever is the earlier of the 
concomitant therapy end date / AE 
resolution date or study treatment 
start date. 
AE = adverse event. 
 
The purpose of imputing concomitant therapy / AE dates is only to assign a concomitant 
therapy / AE to a specific study period for the summary tables. No imputed date is 
considered in the medical evaluation or causal relationship to an individual AE.  
10 INTERIM ANALYSES  
No 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).   
11 GENERAL DEFINITIONS AND DERIVATIONS 
11.1 Treatment start and end dates  
Study treatment start or end date is the earliest or latest, respectively, date of dose intake 
recorded on the ‘Study Treatment Log’ page.   
11.2 Study periods  
The Screening period is defined as the time from the informed consent date until one day 
before the study treatment start date, or date of screening failure.  
The treatment period is defined as the time from the day of study treatment start until the 
day of EOT (Week 12), or, for those who prematurely discontinued study treatment (i.e., 
those without an EOT date), until the day of study treatment end date. In case of missing 


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study treatment end date, EOT will be imputed using the last available visit/assessment 
date. 
The safety follow-up period is defined as the time from one day after EOT until EOS date. 
11.3 Treatment day and Study day  
The Treatment day for an assessment or event will be calculated using the study treatment 
start date as reference. 
For assessments/events occurring on or after the start date of study treatment, Treatment 
day will be positive and will be calculated as:  
Treatment day (days) = Date of assessment/event – Start date of study treatment + 1 day 
The first day of study treatment is Treatment day 1. 
For all assessment/events occurring prior to the start date of study treatment, Treatment 
day will be negative and will be calculated as:  
Treatment day (days) = Date of assessment/event – Start date of study treatment  
The Study day for an assessment or event will be calculated using the randomization date 
as reference. For assessments/events occurring on or after the randomization date, Study 
day will be positive and will be calculated as:  
Study day (days) = Date of assessment/event – randomization date + 1 day 
The day of randomization date is Study day 1. 
For all assessment/events occurring prior to the randomization date, Study day will be 
negative and will be calculated as:  
Study day (days) = Date of assessment/event – randomization date 
Treatment day and/or Study day will be displayed in the data listings as appropriate.  
11.4 Baseline  
Baseline is the last non-missing assessment performed or value measured before or on the 
day of first dose of study treatment, unless otherwise defined in the specific analysis section.  
The baseline number of BE days per week is defined as the number of diary days with at 
least one BE episode divided by the total number of diary days during the 14 days prior to 
randomization (Study day –14 to –1), times 7 [see Section 6.1.1 for definition of diary day]. 
A minimum of 6 entries for each of the 2 weeks preceding randomization is required per 
inclusion criteria to ensure study participant compliance with filling in the BE diary. 


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Study participants with no data for a given parameter before the first treatment 
administration will have a missing baseline (and missing change from baseline) for this 
parameter.  
11.5 Change from baseline  
The change from baseline is defined as the post-baseline value (any assessment performed 
after baseline and up to EOS) minus the baseline value. A positive number indicates an 
increase as compared to baseline.  
11.6 Missing data patterns 
A monotone missing data pattern is defined as follows: given a dataset with variables Y1, 
Y2, …, Yt (in that order) and Vj is missing for a particular subject, then all subsequent 
variables Vk, k > j, are missing for that subject. In addition, given the same dataset and Vj 
is observed for a particular subject, then all previous variables Vk, k < j, are also observed 
for that subject. Monotone missing data patterns are typically encountered when a subject 
prematurely withdraws from a study and is expected to be more likely seen than 
non-monotone missing data patterns.  
In the examples below, an ‘X’ indicates that the variable is observed in the corresponding 
group and a ‘.’ means that the variable is missing.  
Example of monotone missing data patterns: 
Subject 
Y1 
Y2 
Y3 
1 
X 
X 
X 
2 
X 
X 
. 
3 
X 
. 
. 
When missing data are non-monotone, data can also be missing at intermediate visits (i.e., 
missing at a given visit, but observed again at the next visit). Non-monotone missing data 
patterns are commonly turned into monotone missing data patterns using MI (based on 
MCMC), which are then subsequently analyzed using MI methods based on monotone 
missing data.  
Example of non-monotone missing data patterns: 
Subject 
Y1 
Y2 
Y3 
1 
X 
X 
X 
2 
. 
X 
X 
3 
. 
. 
X 
4 
. 
X 
. 
5 
X 
. 
X 
 


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11.7 Time window definitions for calculating efficacy and safety endpoints 
collected through diary  
BE episodes (efficacy) and daytime sleepiness (safety; measured using the SSS) are the 
endpoints collected daily through a diary. The BE diary will be filled in from the start of 
the screening period until EOT while the SSS will only be filled in during the first 2 weeks 
of treatment (from randomization [Visit 2] to Visit 4). 
Table 6 defines the time windows used to calculate number of BE episodes/days per week. 
Table 6 
Time windows (in days) to calculate weekly averages for the efficacy 
endpoints BE episodes/days collected daily through the diary  
Weeks 
Study day (14-day window) 
1–2 
1–14 
3–4 
15–28 
5–6 
29–42 
7–8 
43–56 
9–10 
57–70 
11–12 
71–84 
 
For the calculation of absence of BE episodes (‘Yes’/’No’) during the last 4 weeks of the 
treatment period, a minimum of 4 out of 7 diary entries are required for days 57–63,  
64–70, 71–77 and 78–84, otherwise the outcome will be set to ‘No absence’. Absence of 
BE episodes (‘Yes’) is defined as BE episodes equal to 0. 
For the calculation of SSS, study days falling in the time window 2–15 will be considered 
for the analyses since study day 1 corresponds to assessments done on the day of the 
randomization where information on the SSS should not be collected. 
11.8 Time window definitions for calculating exploratory efficacy and safety 
endpoints collected during site visits 
The exploratory efficacy endpoints YBOCS-BE, PGI-S, CGI-S, PGI-C, CGI-C, EDE-Q, 
and HAMD-17 are collected during specific site visits [Table 7].  
The safety endpoint C-SSRS© is collected during all site visits [Table 8].  
For both efficacy and safety endpoints, if more than one assessment falls within the same 
time window, the assessment which is performed closest to the target study day will be 
considered for the analysis. 


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Table 7 
Time windows (in days) for visit-based exploratory efficacy 
endpoints: YBOCS-BE, PGI-S, CGI-S, PGI-C, CGI-C, EDE-Q, 
HAMD-17 
Week 
Target study day 
Window 
Endpoint 
Baseline 
1 
1–1 
YBOCS-BE, PGI-S, CGI-S, EDE-Q, HAMD-17 
1 
8 
2–14 
CGI-C, PGI-C 
4 
29 
22–36 
YBOCS-BE, PGI-S, CGI-S, PGI-C, CGI-C, EDE-Q 
6 
43 
37–49 
HAMD-17 
8 
57 
50–64 
YBOCS-BE, PGI-S, CGI-S, PGI-C, CGI-C, EDE-Q 
12 
85 
78–92 
YBOCS-BE, PGI-S, CGI-S, PGI-C, CGI-C, EDE-Q, HAMD-
CGI-C = Clinical Global Impression of Change scale; CGI-S = Clinical Global Impression of Severity scale; 
EDE-Q = Eating Disorder Examination Questionnaire; HAMD-17 = Hamilton Rating Scale for Depression 
(17-item); PGI-C = Patient Global Impression of Change scale; PGI-S = Patient Global Impression of Severity scale; 
YBOCS-BE = Yale-Brown Obsessive-Compulsive Scale modified for Binge Eating. 
Table 8 
Time windows (in days) for C-SSRS© 
Week 
Target study day 
Window 
Baseline 
1 
1–1 
1 
8 
5–11 
2 
15 
12–18 
4 
29 
22–36 
6 
43 
37–49 
8 
57 
50–64 
10 
71 
65–77 
12 
85 
78–92 
C-SSRS© = Columbia-Suicide Severity Rating Scale© 
12 CHANGES OR CLARIFICATIONS TO ANALYSES PLANNED IN 
THE STUDY PROTOCOL  
12.1 Changes to the analyses planned in the study protocol 
Demographics and disease characteristics will be analyzed using the RND and the same 
summaries will be produced also for screen failures using the SCR. The FAS and PPS will 
not be used for these analyses. 
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. 


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12.4 Additional analyses to those planned in the study protocol 
Not applicable. 
 
13 REFERENCES 
[Andrade 2019] Andrade RJ, Chalasani N, Björnsson ES, Suzuki A, Kullick-Ublick GA, 
Watkins PB, et al. Drug-induced liver injury. Nat Rev Dis Primers. 2019;5(58). doi: 
10.1038/s41572-019-0105-0.  
[Bodner 2008] Bodner TE. What Improves with Increased Missing Data Imputations? 
Structural Equation Modeling 2008;15(4):651–75. 
[Carpenter 2000] Carpenter J, Bithell J. Bootstrap confidence intervals: when, which, 
what? A practical guide for medical statisticians. Stat Med. 2000;19:1141–64. 
[Carpenter 2013] Carpenter JR, Roger JH, Kenward MG. Analysis of longitudinal trials 
with protocol deviation: a framework for relevant accessible assumptions and 
inference via multiple imputation. J Biopharm Stat 2013;23(6):1352–71. 
[Graham 2007] Graham JW, Olchowski AE, Gilreath TD. How many imputations are 
really needed? Some practical clarifications of multiple imputation theory. Prev Sci 
2007;8(3):206–13. 
[ICH 2020] ICH E9 (R1) Addendum on estimands and sensitivity analysis in clinical trials 
to the guideline on statistical principles for clinical trials. 17 February 2020 [accessed 
on 8 June 2021]. Available from: https://www.ema.europa.eu/en/documents/ 
scientific-guideline/ich-e9-r1-addendum-estimands-sensitivity-analysis-clinical-
trials-guideline-statistical-principles_en.pdf 
[Kenward 1997] Kenward MG, Roger JH. Small sample inference for fixed effects from 
restricted maximum likelihood. Biometrics 1997;53(3):983–97. 
[Koch 1982] Koch G, Amara I, Davis G, Gillings D. A review of some statistical methods 
for covariance analysis of categorical data. Biometrics 1982;38(3):563–95. 
[Koch 2016] Koch G, Carr G, Amara I, Stokes M, Uryniak T. Categorical data analysis. 
In: D. A. Berry, editor. Statistical methodology in the pharmaceutical sciences. Boca 
Raton: CRC Press; 2016. p. 403–488. 
[Mallinckrodt 2013] Mallinckrodt C, Roger J, Chuang-stein C, Molenberghs G. Missing 
data: turning guidance into action. Stat Biopharm Res 2013;4:369–82. 
[O’Kelly 2014] O’Kelly M, Ratitch B. Clinical Trials with Missing Data: A Guide for 
Practitioners. 1st ed. Wiley; 2014. 


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[O’Neill 2012] O’Neill RT, Temple R. The prevention and treatment of missing data in 
clinical trials: an FDA perspective on the importance of dealing with it. Clin 
Pharmacol Ther. 2012;91(3):550-554. 
[Quade 1967] Quade D. Rank Analysis of Covariance. J Am Stat Assoc. 1967;62(320): 
1187–1200. 
[Ratitch 2013] Ratitch B, O’Kelly M, Tosiello R. Missing data in clinical trials: from 
clinical assumptions to statistical analysis using pattern mixture models. Pharm Stat 
2013;12:337–47. 
[Rubin 1987] Rubin DB. Multiple imputation for nonresponse in surveys. New York: John 
Wiley & Sons; 1987. 
[Schafer 1997] Schafer JL. Analysis of incomplete multivariate data. New York: Chapman 
& Hall; 1997. 
[Stokes 2012] Stokes M, Davis C, Koch G. Chapter 7: Nonparametric methods. In: Stokes 
M, Davic C, Koch, G. Categorical data analysis using SAS. 3rd ed. Cary (NC): SAS 
Institute Inc; 2012. p. 175–188. 
[Von Hippel 2009] Von Hippel PT. How to impute interactions, squares, and other 
transformed variables. Sociological Methodology 2009;39(1):265–91. 
[Wang 2016] Wang D, Pocock S. A win ratio approach to comparing continuous 
nonnormal outcomes in clinical trials. Pharm Stat. 2016;15(3):238–245. 
[White 2011] White IR, Royston P, Wood AM. Multiple imputation using chained 
equations: issues and guidance for practice. Stat Med 2011;30(4):377–99. 
[Yan 2009] Yan X, Lee S, Li N. Missing data handling methods in medical device clinical 
trials. J Biopharm Stat 2009;19:1085–98. 


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14 APPENDICES 
14.1 SAS® code for Mixed Model for Repeated Measures  
This model is used, for example, for the main analyses of the primary and some exploratory 
efficacy endpoints. Assuming the data are in ‘long’ format (i.e., one row for each 
subject/visit) example SAS® statements for the primary endpoint analysis are: 
proc mixed data=data; 
class SUBJID SEX BMIGR TRT VIS; 
 
model CHG = BASE SEX BMIGR TRT VIS TRT*VIS BASE*VIS / ddfm=kr 
residual outp=mixtable; 
 
lsmeans TRT*VIS / diff cl; 
 
repeated VIS / subject=SUBJID type=un; 
 
estimate ‘ACT-539313 vs placebo at Week 12’ TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 
0 0 0 -1 / cl; 
 
ods output lsmeans=lsmeans estimates=estimates StudentPanel=StudentPanel 
FitStatistics=aic NObs=nobs; 
run; 
The dataset data includes baseline number of BE days (BASE) as well as changes (CHG) 
from baseline to Weeks 1–2, 3–4, 5–6, 7–8, 9–10, 11–12 (VIS) and BMI as categorical 
variable (BMIGR). Furthermore, TRT equals 1 and 2 for ACT-539313 and placebo, 
respectively. The model option residual, outp=mixtable and the statement ods outout are 
used to run the model diagnostic for the main analysis only. 
If a sandwich estimator has to be used, the option ‘empirical’ will be added to the proc 
mixed statement: proc mixed data=data empirical. 
14.2 SAS® code for multiple imputation with MCMC for monotone 
missingness mechanism  
This SAS® statement is used to set the missing data with a monotone pattern for the 
preliminary step of the multiple imputation. Assuming the data are in ‘wide’ format (i.e., 
one row for each subject with one variable for each visit) example SAS® statements are: 
proc mi data=data wide nimpute=100 seed=401293 minimum=. . 0 0 0 0 0 0 0 
maximum=. . 7 7 7 7 7 7 7 out=data mono; 
by TRT ; 
 
var SEX BMI BASE OBST1 OBST2 OBST3 OBST4 OBST5 OBST6; 
 
/* BMI is continuous */ 
 
mcmc impute=monotone; 
run; 


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The dataset data_wide includes baseline number of BE days (BASE) as well as number of 
BE days at Week 1–2 (OBST1), Week 3–4 (OBST2), Week 5–6 (OBST3), Week 7–8 
(OBST4), Week 9–10 (OBST5) and Week 11–12 (OBST6). The dataset data_mono 
includes the same variables but with eventual non-monotone missing data for BASE or 
OBST1 or OBST2 or OBST3 or OBST4 or OBST5 or OBST6 being imputed. The 
imputation is performed 100 times, so data_mono includes 100 different data sets, one for 
each non-monotone missing data imputation.    
14.3 SAS® code for multiple imputation under MAR assumption 
This SAS® statement is used to perform multiple imputation under MAR assumption after 
the dataset has being set to a monotone missingness pattern. Assuming the data are in ‘wide’ 
format (i.e., one row for each subject with one variable for each visit) and with a monotone 
pattern, example SAS® statements are: 
/* multiple imputation */ 
proc mi data=data mono nimpute=1 seed=375910 minimum=. . . 0 0 0 0 0 0 0 
maximum=. . . 7 7 7 7 7 7 7 out=data mi noprint; 
by IMPUTATION ;  
/* flag variable for imputation from proc mi */ 
 
class TRT SEX BMIGR; 
 
var TRT SEX BMIGR BASE OBST1 OBST2 OBST3 OBST4 OBST5 OBST6; 
 
monotone regression; 
run; 
The dataset data_mono includes baseline number of BE days (BASE) as well as number 
of BE days at Week 1–2 (OBST1), Week 3–4 (OBST2), Week 5–6 (OBST3), Week 7–8 
(OBST4), Week 9–10 (OBST5) and Week 11–12 (OBST6), and BMI as categorical 
variable (BMIGR). The dataset data_mi includes the same variables but without missing 
data because eventual monotone missing data for BASE or OBST1 or OBST2 or OBST3 
or OBST4 or OBST5 or OBST6 have been imputed. 
The following SAS® statements are used to perform the analysis with the MMRM and to 
combine all the 100 datasets produced with the MI under MAR assumption. Assuming the 
data are in ‘long’ format (i.e., one row for each subject/visit) after data_mi has been 
transposed to data_mi_long, with a monotone pattern and without missing data, example 
SAS® statements are: 
/* analyze the results */ 
ods output lsmeans=mixparms diffs=diffparms (where=( TRT=‘PLACEBO’ and 
VIS= VIS)); 
proc mixed data=data_mi_long; 
by IMPUTATION ;  
/* flag variable for imputation from proc mi */ 
 
class SUBJID SEX BMIGR TRT VIS; 
 
model CHG = BASE SEX BMIGR TRT VIS TRT*VIS BASE*VIS / ddfm=kr; 


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lsmeans TRT*VIS / diff cl; 
 
repeated VIS / subject=SUBJID type=un; 
run; 
The model is the same as for the main analysis [Section 14.1] but is run for each of the 
100 datasets produced with the MI under MAR assumption (_IMPUTATION_).  
The results are then combined with the following SAS® statements: 
/* combine the results */ 
proc mianalyze parms=mixparms; 
class TRT VIS; 
 
modeleffects TRT*VIS; 
run; 
proc mianalyze parms=diffparms; 
class TRT VIS; 
 
modeleffects TRT*VIS; 
run; 
The dataset mixparms includes the LSMeans from the 100 imputed datasets and the dataset 
diffparms includes the treatment differences (ACT-539313 – Placebo) from the 
100 imputed datasets.  
14.4 SAS® code for multiple imputation under MNAR assumption for the 
jump to reference method 
This SAS® statement is used to perform multiple imputation under MNAR assumption 
after the dataset has being set to a monotone missingness pattern. Imputations are 
performed sequentially for each time point: Week 1–2 (OBST1) then Week 3–4 (OBST2) 
then Week 5–6 (OBST3) then Week 7–8 (OBST4) then Week 9–10 (OBST5) and finally 
Week 11–12 (OBST6). Assuming the data are in ‘wide’ format (i.e., one row for each 
subject with one variable for each visit) and with a monotone pattern, example SAS® 
statements are: 
/*** multiple imputation ***/ 
 
/*** OBST1 ***/ 
proc mi data=data mono nimpute=1 seed=163882 minimum=. . . 0 0 maximum=. . . 7 7  
out=data mi2 noprint; 
by IMPUTATION ;  
/* flag variable for imputation from proc mi */ 
 
class TRT SEX BMIGR; 
 
var SEX BMIGR BASE OBST1; 
 
monotone regression; 
 
mnar model (OBST1 / modelobs=(TRT=‘PLACEBO’)); 


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run; 
The dataset data_mono includes baseline number of BE days (BASE) as well as BMI as 
categorical variable (BMIGR) and the number of BE days at all time points (i.e.,  
Week 1–2, Week 3–4, Week 5–6, Week 7–8, Week 9–10 and Week 11–12), but 
imputations are performed sequentially for each time point. In this case is Week 1–2 
(OBST1). The model imputes missing data taking information from subjects receiving 
placebo (modelobs = (TRT = ‘PLACEBO’)).  
The dataset generated (data_mi2) is then used to impute the missing data at the next time 
point (Week 3–4) as shown in the SAS® statement below (OBST2). The process proceeds 
in the same way for the other time points until the last one (Week 11–12, OBST6). 
/*** OBST2 ***/ 
proc mi data=data mi2 nimpute=1 seed=163882 minimum=. . . 0 0 maximum=. . . 7 7  
out=data mi3 noprint; 
by IMPUTATION ;  
/* flag variable for imputation from proc mi */ 
 
class TRT SEX BMIGR; 
 
var SEX BMIGR BASE OBST2; 
 
monotone regression; 
 
mnar model (OBST2 / modelobs=(TRT=‘PLACEBO’)); 
run; 
 
/*** OBST3 ***/ 
proc mi data=data mi3 nimpute=1 seed=163882 minimum=. . . 0 0 maximum=. . . 7 7  
out=data mi4 noprint; 
by IMPUTATION ;  
/* flag variable for imputation from proc mi */ 
 
class TRT SEX BMIGR; 
 
var SEX BMIGR BASE OBST3; 
 
monotone regression; 
 
mnar model (OBST3 / modelobs=(TRT=‘PLACEBO’)); 
run; 
 
/*** OBST4 ***/ 
proc mi data=data mi4 nimpute=1 seed=163882 minimum=. . . 0 0 maximum=. . . 7 7  
out=data mi5 noprint; 
by IMPUTATION ;  
/* flag variable for imputation from proc mi */ 
 
class TRT SEX BMIGR; 
 
var SEX BMIGR BASE OBST4; 
 
monotone regression; 
 
mnar model (OBST4 / modelobs=(TRT=‘PLACEBO’)); 
run; 


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/*** OBST5 ***/ 
proc mi data=data mi5 nimpute=1 seed=163882 minimum=. . . 0 0 maximum=. . . 7 7  
out=data mi6 noprint; 
by IMPUTATION ;  
/* flag variable for imputation from proc mi */ 
 
class TRT SEX BMIGR; 
 
var SEX BMIGR BASE OBST5; 
 
monotone regression; 
 
mnar model (OBST5 / modelobs=(TRT=‘PLACEBO’)); 
run; 
 
/*** OBST6 ***/ 
proc mi data=data mi6 nimpute=1 seed=163882 minimum=. . . 0 0 maximum=. . . 7 7  
out=data mi7 noprint; 
by _IMPUTATION_;  
/* flag variable for imputation from proc mi */ 
 
class TRT SEX BMIGR; 
 
var SEX BMIGR BASE OBST6; 
 
monotone regression; 
 
mnar model (OBST6 / modelobs=(TRT=‘PLACEBO’)); 
run; 
The 9 study participants forced to discontinue due to site closure will be imputed using 
MAR assumption setting the seed to 163882. 
14.5 SAS® code for multiple imputation under MNAR assumption for the 
delta-adjusted tipping point method 
This SAS® statement is used to perform multiple imputation under MNAR assumption 
after the dataset has being set to a monotone missingness pattern. Imputations are 
performed sequentially for each time point: Week 1–2 (OBST1) then Week 3–4 (OBST2) 
then Week 5–6 (OBST3) then Week 7–8 (OBST4) then Week 9–10 (OBST5) and finally 
Week 11–12 (OBST6). Assuming the data are in ‘wide’ format (i.e., one row for each 
subject with one variable for each visit) and with a monotone pattern, example SAS® 
statements for the implementation of the macro for delta-adjusted tipping point are: 
/*** multiple imputation ***/ 
%macro midata(data=, smin=, smax=, sinc=, out=); 
data &out; 
 
set null ; 
run; 
/*------------# of shift values ------------*/ 
%let ncase= %sysevalf( (&smax-&smin)/&sinc, ceil ); 


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/*-------Imputed data for each shift -------*/ 
%do jc=0 %to &ncase; 
%let sj= %sysevalf( &smin + &jc * &sinc); 
proc mi data=&data seed=295104 nimpute=1 minimum=. . . 0 0 0 0 0 0 0 maximum=. . . 
7 7 7 7 7 7 7 out=outmi; 
 
by IMPUTATION ; /* flag variable for imputation from proc mi */ 
 
class TRT ASEX BMIGR; 
 
monotone regression; 
 
mnar adjust(obst1 / shift=&sj adjustobs=(TRT = 'ACT-539313 100 mg')); 
 
mnar adjust(obst2 / shift=&sj adjustobs=(TRT = 'ACT-539313 100 mg')); 
 
mnar adjust(obst3 / shift=&sj adjustobs=(TRT = 'ACT-539313 100 mg')); 
 
mnar adjust(obst4 / shift=&sj adjustobs=(TRT = 'ACT-539313 100 mg')); 
 
mnar adjust(obst5 / shift=&sj adjustobs=(TRT = 'ACT-539313 100 mg')); 
 
mnar adjust(obst6 / shift=&sj adjustobs=(TRT = 'ACT-539313 100 mg')); 
 
var TRT ASEX BMIGR BASE obst1 obst2 obst3 obst4 obst5 obst6; 
run; 
data outmi; 
 
set outmi; 
 
Shift= &sj; 
run; 
data &out; 
 
set &out outmi; 
run; 
%end; 
%mend midata; 
 
%midata(data=fin_mi_mono, smin=0, smax=2, sinc=0.25, out=be5); 
The 9 study participants forced to discontinue due to site closure will be imputed using 
MAR assumption setting the seed to 295104. 
14.6 SAS® code for logistic regression of absence of BE episodes during the 
last 4 weeks of treatment 
This model adjusts for baseline number of BE days (BASE), sex (SEX), BMI as categorical 
variable (BMIGR), and treatment (TRT). Reference categories are placebo for treatment 
and obese (BMI ≥ 30) for BMI. Example SAS® statements for the analysis are: 
proc logistic data=data; 
class TRT (ref=‘PLACEBO’) SEX BMIGR (ref=‘OBESE’); 
 
model Y (event=‘1’) = TRT SEX BMIGR BASE / clodds=wald orpvalue; 
 
run; 


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This code provides confidence limit for the proportion of study participants with and 
without absence of BE episodes during the last 4 weeks of treatment. 
proc freq data=data; 
table Y / binomial(level=‘1’); 
 
by TRT; 
 
run; 
14.7 SAS® code for logistic regression of improvement according to CGI-C 
score at Week 12 
This model adjusts only for treatment (TRT) and the reference category is placebo. 
Example SAS® statements for the analysis are: 
proc logistic data=data; 
class TRT (ref=‘PLACEBO’); 
 
model Y2 (event=‘1’) = TRT / clodds=wald orpvalue; 
 
run; 
This code provides confidence limit for the proportion of study participants with and 
without improvement according to CGI-C score at Week 12. 
proc freq data=data; 
table Y / binomial(level=‘1’); 
 
by TRT; 
 
run; 
14.8 SAS® code for Kruskal-Wallis test of CGI-C and PGI-C scores at 
Week 12 
Example SAS® statements for the analysis are: 
proc npar1way data=data wilcoxon; 
class TRT; 
 
var CGI-C;  
/* this will be updated with PGI-C for PGI-C analysis */ 
run; 
14.9 SAS® code for ANCOVA of change from baseline to Week 12 in CGI-S 
score, PGI-S score, body weight and HbA1c 
This model is used for some exploratory efficacy endpoints. Example SAS® statements for 
the analysis are: 
proc mixed data=data; 
class TRT; 
 
model CHG = BASE TRT / noint solution; 
 


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/* change and baseline will be updated with the corresponding endpoint */ 
 
lsmeans TRT / diff cl;  
run; 
The dataset data includes baseline number of BE days (BASE) as well as change (CHG) 
from baseline to Week 11–12 and treatment (TRT).  
14.10 SAS® code for subgroup analyses 
14.10.1 Age 
The dataset data is the same dataset used for the main analysis. The order of the variable 
is important: TRT equals 1 and 2 for ACT-539313 and placebo, respectively. The first 
AGEGR is age 18–29 and then 30–55. 
proc mixed data=data; 
class SUBJID SEX BMIGR TRT VIS AGEGR; 
 
model CHG = BASE SEX BMIGR TRT VIS TRT*VIS BASE*VIS AGEGR 
AGEGR*TRT AGEGR*VIS AGEGR*TRT*VIS / ddfm=kr; 
 
repeated VIS / subject=SUBJID type=un; 
 
estimate ’Age 18-29: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*AGEGR 1 0 -1 0  
 
 
AGEGR*TRT*VIS 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 0 / cl; 
 
estimate ’Age 30-55: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*AGEGR 0 1 0 -1  
 
 
AGEGR*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 -1 / cl; 
 
estimate ’Treatment by age interaction p-value at Week 12’  
 
 
TRT*AGEGR 1 -1 -1 1  
 
 
AGEGR*TRT*VIS 0 0 0 0 0 0 0 0 0 0 1 -1 0 0 0 0 0 0 0 0 0 0 -1 1; 
run; 
14.10.2 Sex 
The dataset data is the same dataset used for the main analysis. The order of the variable 
is important: TRT equals 1 and 2 for ACT-539313 and placebo, respectively. The first SEX 
is female and then male. 
proc mixed data=data; 
class SUBJID SEX BMIGR TRT VIS; 
 
model CHG = BASE SEX BMIGR TRT VIS TRT*VIS BASE*VIS SEX*TRT 
SEX*VIS SEX*TRT*VIS / ddfm=kr; 
 
repeated VIS / subject=SUBJID type=un; 
 
estimate ’Female: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*SEX 1 -1 0 0  
 
 
SEX*TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 0 0 0 0 0 0 0 / cl; 
 
estimate ’Male: ACT-539313 vs placebo at Week 12’  


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TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*SEX 0 0 1 -1  
 
 
SEX*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 / cl; 
 
estimate ’Treatment by sex interaction p-value at Week 12’  
 
 
TRT*SEX 1 -1 -1 1  
 
 
SEX*TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 -1 0 0 0 0 0 1; 
run; 
14.10.3 BMI 
The dataset data is the same dataset used for the main analysis. The order of the variable 
is important: TRT equals 1 and 2 for ACT-539313 and placebo, respectively. The first BMI 
is < 30 and then ≥ 30. 
proc mixed data=data; 
class SUBJID SEX BMIGR TRT VIS; 
 
model CHG = BASE SEX BMIGR TRT VIS TRT*VIS BASE*VIS BMI*TRT 
BMI*VIS BMI*TRT*VIS / ddfm=kr; 
 
repeated VIS / subject=SUBJID type=un; 
 
estimate ’BMI < 30: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*BMI 1 -1 0 0  
 
 
BMI*TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 0 0 0 0 0 0 0 / cl; 
 
estimate ’BMI ≥ 30: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*BMI 0 0 1 -1  
 
 
BMI*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 -1 / cl; 
 
estimate ’Treatment by BMI interaction p-value at Week 12’  
 
 
TRT*BMI 1 -1 -1 1  
 
 
BMI*TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 0 0 0 0 0 -1 0 0 0 0 0 1; 
run; 
14.10.4 Race 
The dataset data is the same dataset used for the main analysis. The order of the variable 
is important: TRT equals 1 and 2 for ACT-539313 and placebo, respectively. The variable 
RACE is a new variable where all categories different from ‘white’ and ‘black’ are grouped 
under ‘other’ (i.e., the new derived variable race has 3 levels: first black, then other and 
finally white). 
proc mixed data=data; 
class SUBJID SEX BMIGR TRT VIS RACE; 
 
model CHG = BASE SEX BMIGR TRT VIS TRT*VIS BASE*VIS RACE 
RACE*TRT RACE*VIS RACE*TRT*VIS / ddfm=kr; 
 
repeated VIS / subject=SUBJID type=un; 
 
estimate ’Black: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*RACE 1 0 0 -1 0 0  


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RACE*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
-1 0 0 / cl; 
 
estimate ’Other: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*RACE 0 1 0 0 -1 0  
 
RACE*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
0 -1 0 / cl; 
 
estimate ’White: ACT-539313 vs placebo at Week 12’  
 
 
TRT 1 -1 TRT*VIS 0 0 0 0 0 1 0 0 0 0 0 -1 TRT*RACE 0 0 1 0 0 -1  
 
RACE*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
0 0 -1 / cl; 
 
contrast ’Treatment by race interaction p-value at Week 12’  
 
 
TRT*RACE 1 -1 0 -1 1 0  
 
RACE*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 -1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
0 -1 1 0, 
 
 
TRT*RACE 1 0 -1 -1 0 1  
 
RACE*TRT*VIS 0 0 0 0 0 0 0 0 0 0 0 0 0 0 0 1 0 -1 0 0 0 0 0 0 0 0 0 0 0 0 0 0 
0 -1 0 1; 
run; 
14.11 SAS® code for non-parametric analysis of the primary endpoint 
This code produces standardized ranks for covariate baseline (BASE) and response 
variable change (CHG): 
proc rank data=data nplus1 ties=mean out=ranks; 
var BASE CHG; 
run; 
Linear regression on standardized ranks: 
proc reg data=ranks noprint; 
model CHG = BASE; 
 
output out=residual r=resid; 
run; 
Mean score test, using values of residuals as scores, to compare treatment groups: 
proc freq data=residual; 
table TRT*resid / noprint cmh2; 
run; 
Bootstrapping for win/ratio estimate will be implemented using the following SAS code: 










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NA = not applicable; ULN = upper limit of normal.